Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
FIBRINOGEN RECEPTOR ANTAGONISTS
BACKGROUND OF THE INVENTION
S The invention relates generally to modulating cell adhesion
and to inhibiting the binding of fibrinogen and other proteins to blood
platelets, and inhibiting the aggregation of blood platelets specifically to
the gp IIb/IIIa fibrinogen receptor site. Fibrinogen is a glycoprotein
present in blood plasma that participates in platelet aggregation and in
10 fibrin formation. Platelets are cell-like anucleated fragments, found in
the blood of all m~mm~ , that also participate in blood coagulation.
Interaction of fibrinogen with the IIb/IIIa receptor site is known to be
essential for normal platelet function.
When a blood vessel is damaged by an injury or other
15 causative factor, platelets adhere to the disrupted subendothethial
surface. The adherent platelets subsequently release biologically active
constituents and aggregate. Aggregation is initiated by the binding of
agonists, such as thrombin, epinephrine, or ADP to specific platelet
membrane receptors. Stirnulation by agonists results in exposure of
20 latent fibrinogen receptors on the platelet surface, and binding of
fibrinogen to the glycoprotein IIb/IIIa receptor complex.
Attempts have been made to use natural products and
synthetic peptides to determine the mech~ni~m of adhesion and platelet
aggregation. For example, Rouslahti and Pierschbacher in Science, 238,
25 491-497 (1987), describe adhesive proteins such as fibronectin,
vitronectin, osteopontin, collagens, thrombospondin, fibrinogen, and
von Willebrand factor that are present in extracellular matrices and in
blood. The proteins contain the tripeptide arginine-glycine-aspartic acid
(RGD) as their glycoprotein IIb/IIIa recognition site. These arginine-
30 glycine-aspartic acid containing tripeptides are recognized by at least
one member of a family of structurally related receptors, integrins,
which are heterodimeric proteins with two membrane-spanning
subunits. The authors state that the conformation of the tripeptide
CA 022~8093 1998-12-10
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sequence in the individual proteins may be critical to recognition
specificity.
Cheresh-in Proc. Nat'l Acad. Sci. U.S.A., 84, 6471 -6475,
(1987), describes an Arg-Gly-Asp directed adhesion receptor expressed
S by human endothethial cells that is structurally simi}ar to the IIb/~Ia
complex on platelets but is antigenically and functionally distinct. This
receptor is directly involved in endothelial cell attachment to fibrinogen,
von Willebrand factor, and vitronectin.
Pierschbacher and Rouslahti, in J. of Biol. Chem., 262,
(36), 17294-17298 (1987) hypothesized that the Arg-Gly-Asp sequence
alone would be a sufficient signal for receptor recognition and binding
and that, therefore, the conformation of the tri-peptide sequence would
be determinative. Various synthetic peptides were produced and the
authors concluded that the stereochemical conformation of Arg-Gly-Asp
as influenced by enantiomeric substitutions or additions to this sequence
significantly influenced receptor-ligand interaction. The authors further
showed that cyclization of a decapeptide by forming a disulfide bridge
between non-terminal residues Pen and Cys, rendered the peptide much
less effective at inhibiting attachment to fibronectin.
In Proc. Nat'l Acad. Sci. U.S.A., 81, 5985-5988 (1984), the
same authors describe tetrapeptide variants of the cell recognition site of
fibronectin that retain attachment-promoting activity. Peptides having a
tetrapeptide recognition site are described in U.S. Pat. Nos. 4,589,881
and 4,614,517. A number of large polypeptide fragments in the cell-
binding domain of fibronectin have cell-attachment activity. For
example, see U.S. Pat. Nos. 4,517,686, 4,661,111 and U.S. Pat. No.
4,578,079.
Ruggeri et al., Proc. Nat'l Acad. Sci. U.S.A., 83, 5708-
5712 (1986) explore a series of synthetic peptides designed in lengths to
16 residues, that contain RGD and a valine attached to the aspartic acid
residue of RGD that inhibit fibrinogen binding to platelets. See also
Koczewiak et al., Biochem. 23, 1767-1774 (1984); Ginsberg et al.,
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WO 98/00134 PCT/US97/11133
J. Biol. Chem. 260(7), 3931-3936 (1985); and Haverstick et al., Blood
66(4), 946-952 (1985). Other inhibitors are disclosed in Eur. Pat. App.
Nos. 275,748 and 298,820.
A number of low molecular weight polypeptide factors
have been isolated from snake venom. These factors apparently have
high affinity for the gp IIb/IIIa complex. For example, Huang et al., J.
Biol Chem., 262, 16157-16163 (1987); Huang et al., Biochemistry, 28,
661-666 (1989) describe the primary structure of the venom trigramin
which is a 72 amino acid polypeptide that contains the RGD subunit.
Echistatin is another compound which has high affinity for the gp
IIb/~Ia complex. This polypeptide contains 49 amino acids and has the
RGD subunit and various disulfide bridges. Gan et al., J. Biol. Chem.,
263, 19827-19832 (1988). See also, Dennis et al., Proc. Nat'l Acad. Sci.
USA, 87, 2471-2475 (1989). However, these snake venom factors also
have high affinity for other members of the adhesive protein receptor
family including the vitronectin and fibronectin receptors so are not
selective for the gp IIb/~IIa complex.
While it is known that the tripeptide sequence Arg-Gly-Asp
is present in certain polypeptides that can duplicate or inhibit the cell
attachment-promoting effects of fibronectin and vitronectin, the
tripeptide Arg-Gly-Asp has low activity. At present, there is little
understanding of how other amino acids coupled to this sequence
influence binding specificity. U.S. Pat. No 5,023,233 discloses small
cyclic hexapeptides which contain the sequence Arg-Gly-Asp and are
useful platelet aggregation inhibitors. U.S. Pat. No. 5,037,808 discloses
the use of indolyl platelet-aggregation inhibitors which are believed to
act by antagonizing interactions between fibrinogen and/or extracellular
matrix proteins and the platelet gp IIb/IIIa receptor. U.S. Pat. No.
5,037,808 discloses guanidino peptide mimetic compounds that retain an
~ 30 Asp residue which inhibit platelet aggregation. WO9014103 describes
the use of antibody-polypeptide conjugates wherein said polypeptides
contain the Arg-Gly-Asp (RGD) sequence.
WO9111458 discloses the use of large cyclic peptides
containing RGD flanked by proline residues which are platelet
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WO 98/00134 PCT/US97/11133
aggregation inhibitors. WO9101331 discloses small cyclic platelet
aggregation inhibitors which are synthetic cyclic pentapeptides
cont~ining the tripep~ide sequence Arg-Gly-Asp and a thioether linkage
in the cycle. U.S. Patent No. 5,051,405 also discloses the use of peptides
and pseudopeptides such as N-amidino-piperidine-3-carboxylglycyl-L-
aspartyl-L-valine that inhibit platelet aggregation and thrombus
formation in m~mm~lian blood. EP 445 796 discloses linear compounds
which can include internal piperazinyl or piperidinyl derivatives.
EP437 367 discloses linear polypeptide fibrinogen receptor antagonists.
U.S. Patent No. 5,256,812 discloses compounds of the formula R 1 -A-
(W)a-X-(CH2)b-(Y)C-B-z-cooR wherein R 1 is a guandidino or
amidino moiety and A and B are chosen from specific monosubstituted
aryl or heterocyclic moieties.
While a multitude of compounds or peptide analogs
believed to inhibit platelet aggregation by inhibiting binding to a blood
platelet by fibrinogen are known, the present invention provides novel
fibrinogen receptor antagonists that have significant binding activity and
are, therefore, useful for the reasons stated herein. A number of very
serious diseases and disorders involve hyperthrombotic complications
which lead to intravascular thrombi and emboli. Myocardial infarction,
stroke, phlebitis and a number of other serious conditions create the
need for novel and effective fibrinogen receptor antagonists.
SUMMARY OF THE INVENTION
The invention includes compounds of the formula
X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein
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xis
a 5, 6 or 7 membered aromatic or nonaromatic ring, having 1, 2
or 3 heteroatorns selected from N, O, and S, and either
unsubstituted or monosubstituted on the carbon and nitrogen
S atoms with R1, or disubstituted on the carbon and nitrogen atoms
with Rl and R2, where Rl and R2 are independently selected
from the group consisting of
hydrogen,
halogen,
Cl loalkyl,
C3-8 cycloalkyl,
aryl,
aryl Cl 8 alkyl,
ammo,
amino C1 8 alkyl,
Cl 3 acylarnino,
Cl 3 acylamino C1 8 alkyl,
C1 6 alkylamino C1 8 alkyl,
C1 6 alkylamino,
C1 6 dialkylarnino C1 8 alkyl,
C 1 6 alkoxy,
C1 6 alkoxy C1 6 alkyl,
aryl Cl 6 alkyloxy,
aryl C1 6 alkyloxy C1 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
Cl 3 alkoxycarbonyl,
C1 3 alkoxycarbonyl C1 6 alkyl,
carboxy C1 6 alkyloxy,
~ 30 hydroxy, and
hydroxy C1 6 alkyl, or
a 9 or 10 membered fused aromatic or nonaromatic ring, having
1, 2 or 3 heteroatoms selected from N, O, and S, and either
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unsubstituted or monosubstituted on the carbon and nitrogen
atoms with R1, or disubstituted on the carbon and nitrogen atoms
with Rl and R~, where Rl and R2 are independently selected
from the group consisting of
S hydrogen,
halogen,
Cl -10 alkyl,
C3-8 cycloalkyl,
aryl,
aryl C1 8 alkyl,
amino,
amino C1 8 alkyl,
Cl 3 acylamino,
C1 3 acylamino C1 8 aIkyl,
C1 6 alkylamino C1 8 alkyl,
C1 6 alkylarnino,
Cl 6 dialkylamino C1 8 alkyl,
C1 6 alkoxy,
C 1 6 alkoxy C 1 6 alkyl,
aryl C1 6 alkyloxy,
aryl C1 6 alkyloxy C1 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
C1 3 alkoxycarbonyl,
C1 3 alkoxycarbonyl C1 6 alkyl,
carboxy C1 6 alkyloxy,
hydroxy, and
hydroxy C1 6 alkyl;
30 Y is
a S or 6 membered aromatic or nonaromatic ring, having 0, 1, 2
or 3 heteroatoms selected from N, O, and S, and either
unsubstituted or substituted on carbon and nitrogen atoms with R3
selected from the group consisting of
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hydrogen,
halogen,
C l l o alkyl,
C3-8 cycloalkyl,
S aryl,
aryl C1 8 alkyl,
amino,
amino C1 8 alkyl,
Cl 3 acylamino,
C1 3 acylamino C1 8 alkyl,
C1 6 alkylamino,
C 1 6 alkylamino C1 8 alkyl,
C1 6 dialkylamino,
C1 6 dialkylamino C1 8 alkyl,
Cl-6 alkoxy,
C1 6 alkoxy C1 6 alkyl,
aryl C1 6 alkyloxy,
aryl C1 6 alkyloxy Cl 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
C1 3 alkoxycarbonyl,
C1 3 alkoxycarbonyl C1 6 alkyl,
carboxy C1 6 alkyloxy,
hydroxy, and
hydroxy C1 6 alkyl;
or
X and Y combined together form the structures
R1 N~ ~ 1 RN~ ~
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o
R1N~ RN~
zis
o R4
Il
--C-N--
1R4 1~l
--N--C--
--CH2CH2--
--CH=CH--
--CH2-~--
--O--CH2
--C--CH2--
--CH2-C--
--CH2NR~
--NR4CH2--
OH
--CH--CH2--
OH
--CH2--CH , or
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WO 98/00134 PCTAUS97tlll33
Z representes a bond;
R4 is
hydrogen,
S C1 4 alkyl, or
C3-6 cycloalkyl;
Ais
a S or 6 membered aromatic ring, having 0, 1, 2 or 3 heteroatoms
selected from N, O, and S, and either unsubstituted or
monosubstituted on carbon and nitrogen atoms with RS,
disubstituted on carbon and nitrogen atoms with RS and R6, or
trisubstituted on carbon and nitrogen atoms with RS, R6 and R7,
where R5, R6 and R7 are each independently selected from the
group consisting of
1 5 hydrogen,
halogen,
C1 -10 alkyl,
C3-8 cycloalkyl,
aryl,
aryl C 1-8 alkyl,
arylsulfonylamino,
amino,
amino C1 8 alkyl,
nitro,
C1 3 acylarnino,
Cl 3 acylamino C1 8 alkyl,
C 1 6 alkylamino,
C1-3 alkylsulfonylamino,
C1 6 alkylamino C1 8 alkyl,
C1 6 dialkylamino,
C 1 6 dialkylamino C 1 8 alkyl,
C 1 6 alkoxy,
C1 6 alkoxy C1 6 alkyl,
trihaloalkyl,
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- 10-
aryl Cl 6 alkyloxy,
aryl C1 6 alkyloxy C1 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
C 1-3 alkoxycarbonyl,
Cl 3 alkoxycarbonyl C1 6 alkyl,
carboxy C1 6 alkyloxy,
hydroxy, and
hydroxy C1 6 alkyl, or
A is
a 9 or 10 membered fused aromatic ring, having 0, 1, 2 or 3
heteroatoms selected from N, O, and S, and either unsubstituted
or monosubstituted on carbon and nitrogen atoms with R5,
lS disubstituted on carbon and nitrogen atoms with RS and R6, or
trisubstituted on carbon and nitrogen atoms with R5, R6 and R7,
where R5, R6 and R7 are each independently selected from the
group consisting of
hydrogen,
halogen,
Cl lo alkyl,
C3-8 cycloalkyl,
aryl,
aryl C1 8 alkyl,
amino,
amino C1 8 alkyl,
C1 3 acylamino,
Cl 3 acylamino C1 8 alkyl,
C 1 6 alkylamino,
C1 6 alkylamino C1 8 alkyl,
C 1 6 dialkylamino,
Cl 6 dialkylamino C1 8 alkyl,
C 1 6 alkoxy,
C 1 6 alkoxy C1 6 alkyl,
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PCT/US97111133
WO 98100134
aryl C1 6 alkyloxy,
aryl Cl 6 alkyloxy C1 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
C1 3 alkoxycarbonyl,
Cl 3 alkoxycarbonyl C1 6 alkyl,
carboxy C1 6 alkyloxy,
hydroxy, and
hydroxy C1 6 alkyl;
B is
--O(CH2)mC02R
--(CH2)nco2R
--CH(CH2)pCO2R9, or
R8
--OCH(R8)(CH2)pCO2R'
wherein
m is 1, 2, or 3,
n is 0, 1, 2, or 3, and
p is 0, 1, 2, or 3;
R8 is selected from the group consisting of
hydrogen,
C 1-10 alkyl,
C3-8 cycloalkyl,
aryl,
aryl C1 8 alkyl,
. amino,
arnino C1 8 alkyl,
Cl 3 acylamino,
Cl 3 acylamino Cl 8 alkyl,
C1 6 alkylamino,
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C1 6 alkylamino C1 8 alkyl,
C1 6 dialkylamino,
C1 6 dialkylamino C1 8 alkyl,
C1 6 alkoxy,
S C1 6 alkoxy C1 6 alkyl,
aryl C1 6 alkyloxy,
aryl C1 6 alkyloxy C1 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
C 1-3 alkoxycarbonyl,
C1 3 alkoxycarbonyl C1 6 alkyl,
carboxy C1 6 alkyloxy,
hydroxy,
hydroxy C1 6 alkyl; and
R9 is
hydrogen,
C 1 8 alkyl,
aryl,
aryl C1 6 alkyl,
C1 8 alkylcarbonyloxy C1 6 alkyl
aryl carbonyloxy C1 6 alkyl,
aryl C1 6 alkylcarbonyloxy C1 6 alkyl,
C1 8 alkylaminocarbonyl C1 6 alkyl, or
C1 8 dialkylamino carbonyl C1 6 alkyl.
The invention also includes the use of a compound of the
invention, or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for inhibiting the aggregation of blood
30 platelets, preventing platelet thrombosis, preventing thromboembolism
or preventing reocclusion, in a m~mm~l.
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- 13 -
DETAILED DESCRIPI~ION OF THE INVENTION
The invention includes compounds of the formula
X-Y-Z-A-B
5 and pharmaceutically acceptable salts,
wherein
xis
a 5, 6 or 7 membered aromatic or nonaromatic ring, having 1, 2
or 3 heteroatoms selected from N, O, and S, and either
unsubstituted or monosubstituted on the carbon and nitrogen
atoms with Rl, or disubstituted on the carbon and nitrogen atoms
with Rl and R2, where Rl and R2 are independently selected
from the group consisting of
1 5 hydrogen,
halogen,
Cl 1o alkyl,
C3-8 cycloalkyl,
aryl,
aryl C1 8 alkyl,
amino,
amino C1 8 alkyl,
C l 3 acylamino,
Cl 3 acylamino C1 8 alkyl,
C1 6 alkylamino C1 8 alkyl,
C1 6 alkylamino,
C1 6 dialkylamino C1 8 alkyl,
C 1 6 alkoxy,
C 1 6 alkoxy C 1 6 alkyl,
aryl C1 6 alkyloxy,
aryl C1 6 alkyloxy C1 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
Cl 3 alkoxycarbonyl,
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- 14 -
C 1 3 alkoxycarbonyl C l 6 alkyl,
carboxy C1 6 alkyloxy,
hydroxy, and
hydroxy C l 6 alkyl, or
s
a 9 or 10 membered fused aromatic or nonaromatic ring, having
l, 2 or 3 heteroatoms selected from N, O, and S, and either
unsubstituted or monosubstituted on the carbon and nitrogen
atoms with R I, or disubstituted on the carbon and nitrogen atoms
with R1 and R2, where R1 and R2 are independently selected
from the group consisting of
hydrogen,
halogen,
C l 1 o alkyl,
C3-8 cycloalkyl,
aryl,
aryl C1 8 alkyl,
arnino,
amino C1 8 alkyl,
C 1-3 acylamino,
Cl 3 acylamino C1 8 alkyl,
C1 6 alkylamino C1 8 alkyl,
C 1 6 alkylamino,
Cl 6 dialkylamino C1 8 alkyl,
C l -6 alkoxy,
C1 6 alkoxy C1 6 alkyl,
aryl C1 6 alkyloxy,
aryl C1 6 alkyloxy C1 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
Cl 3 alkoxycarbonyl,
C 1-3 alkoxycarbonyl C 1-6 alkyl,
carboxy C1 6 alkyloxy,
hydroxy, and
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- 15 -
hydroxy C1-6 alkyl;
Yis
a S or 6 membered aromatic ring or non-aromatic ring, having 0,
1, 2 or 3 heteroatoms selected from N, O, and S, and either
unsubstituted or substituted on the carbons and nitrogens with R3
selected from the group consisting of
hydrogen,
halogen,
C1 1o alkyl,
C3-8 cycloalkyl,
aryl,
aryl C1 8 alkyl,
amino,
amino C1 8 alkyl,
C1 3 acylamino,
Cl 3 acylamino C1 8 alkyl,
C1 6 alkylamino,
C1 6 alkylamino C1 8 alkyl,
Cl -6 dialkylamino,
C1 6 dialkylamino C1 8 alkyl,
C1 6 alkoxy,
C1 6 alkoxy C1 6 alkyl,
aryl C1 6 alkyloxy,
aryl Cl 6 alkyloxy C1 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
C1 3 alkoxycarbonyl,
C1 3 alkoxycarbonyl C1 6 alkyl,
- 30 carboxy C 1-6 alkyloxy,
hydroxy, and
hydroxy C1 6 alkyl;
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- 16 -
X and Y combined together form the structures
R 1--N ~5~ R 1 N~
l RN~ R 1
5 Zis
1~l ~4
--C--N--
~4 1~l
--N-C--
--CH2CH2--
--CH=CH--
--CH2-~--
--O--CH2
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-
--C--CH2--
--CH2-C--
--CH2NR4--
--NR4CH2--
OH
--CH--CH2--
OH
--CH2--CH , or
Z represents a bond;
5 R4is
hydrogen,
Cl 4 alkyl, or
C3-6 cycloalkyl;
A is
a 5 or 6 membered aromatic ring, having 0, l, 2 or 3 heteroatoms
selected from N, O, and S, and either unsubstituted or
monosubstituted on the carbons or nitrogen with R5, disubstituted
with RS and R6, or trisubstituted with RS, R6 and R7, where R5,
R6 and R7 are independently selected from the group consisting
of
hydrogen,
halogen,
C1-10 alkyl,
- C3-8 cycloalkyl,
aryl,
, .. , . ., ~ ... ,.................... .. , . ~. ... . . .. ..
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aryl C1 8 alkyl,
arylsulfonylamino,
amino,
amino C 1 8 alkyl,
nitro,
C l 3 acylamino,
Cl 3 acylamino C1 8 alkyl,
C1 6 alkylamino,
C l 3 alkylsulfonylamino,
C1 6 alkylamino C1 8 alkyl,
C 1 6 dialkylamino,
C1 6 dialkylamino C1 8 alkyl,
C 1 6 alkoxy,
C1 6 alkoxy C1 6 alkyl,
1 5 trihaloalkyl,
aryl C1 6 alkyloxy,
aryl C1 6 alkyloxy C1 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
C 1-3 alkoxycarbonyl,
C l 3 alkoxycarbonyl C 1 6 alkyl,
carboxy C1 6 alkyloxy,
hydroxy, and
hydroxy C 1 6 alkyl, or
a 9 or 10 membered fused aromatic ring, having 0, 1, 2 or 3
heteroatoms selected from N, O, and S, and either unsubstituted
or monosubstituted on the carbons or nitrogen with R5,
disubstituted with R5 and R6, or trisubstituted with RS, R6 and
R7, where R5, R6 and R7 are independently selected from the
group consisting of
hydrogen,
- halogen,
C1-10 alkyl,
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- 19-
C3-8 cycloalkyl,
aryl,
aryl C1 8 alkyl,
amino,
arnino C1 -8 alkyl,
Cl 3 acylamino,
C 1-3 acylarnino C 1-8 alkyl,
C 1 6 alkylamino,
C1 6 alkylamino C1 8 alkyl,
C1 -6 dialkylamino,
C1 6 dialkylamino C1 8 alkyl,
C 1 6 alkoxy,
C1 6 alkoxy C1 6 alkyl,
aryl C1 6 alkyloxy,
aryl C1 6 alkyloxy C1 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
Cl 3 alkoxycarbonyl,
C1 3 alkoxycarbonyl C1 6 alkyl,
carboxy C1 6 alkyloxy,
hydroxy, and
hydroxy C1 6 alkyl;
B is
--O(cH2)mco2R
--(CH2)nCO2R9, or
--CH(CH2)pC02R9,
R8
--OCH(R8)(CH2)pCO2R'
wherein
m is 1, 2, or 3,
n is O, 1, 2, or 3, and
~ ._ . .. ~ ,. . . .
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- 20 -
p is 0, 1, 2, or 3;
R8 is selected from the group consisting of
hydrogen,
C1 1oalkyl,
C3-8 cycloalkyl,
aryl,
aryl C1 8 alkyl,
amino,
amino C1 8 alkyl,
C1 3 acylamino,
C1 3 acy}amino C1 8 alkyl,
C1 6 alkylamino,
C1 6 alkylamino C1 8 alkyl,
C1 -6 dialkylamino,
C1 6 dialkylamino C1 8 alkyl,
C1 6 alkoxy,
C1 6 alkoxy C1 6 alkyl,
aryl Cl 6 alkyloxy,
aryl C1 6 alkyloxy C1 6 alkyl,
carboxy,
carboxy C1 6 alkyl,
C1 3 alkoxycarbonyl,
C1 3 alkoxycarbonyl C1 6 alkyl,
carboxy C1 6 alkyloxy,
hydroxy,
hydroxy C1 6 alkyl; and
R9 is
hydrogen,
C1 8 alkyl,
aryl,
aryl C1 6 alkyl,
Cl-8 alkylcarbonyloxy C1 6 alkyl
.
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- 21 -
aryl carbonyloxy C1 6 alkyl,
aryl C1 6 alkylcarbonyloxy C1 6 alkyl,
C1 8 alkylaminocarbonyl C1 6 alkyl, or
Cl g dialkylamino carbonyl C1 6 alkyl.
s
In one class, the compounds have the structure
X-Y-Z-A-B
10 and pharmaceutically acceptable salts,
wherein
X is a 5, 6 or 7 membered aromatic or nonaromatic ring
having 1, 2 or 3 nitrogen atoms and unsubstituted or
substituted with NH2;
Y is a 5 or 6 membered aromatic or nonaromatic ring having 0,
1, 2 or 3 nitrogen atoms and unsubstituted or substituted
with Cl 3alkyl;
or X and Y together form the fused ring systems:
H sSS , HN~--
1''~5~ ~55s
HN or HN O
~ . ._.. . . . . . . .
CA 02258093 1998-12-10
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- 22 -
zis
O O
Il 11
--CNH-- , --NH-- , --C-- ,--CH2CH2--
O O
--CH=CH-- , --C--N-- , --NHC-- , or
CH3
Z represents a bond;
S A is a 5 or 6 membered aromatic ring, having 0, 1, 2, or 3nitrogen atoms and unsubstituted or monosubstituted on
the carbons or nitrogen with RS, disubstituted with RS and
R6, same or different, or trisubstituted with RS, R6 and
R7, same or different, wherein R5, R6 and R7 are selected
from the group consisting of
arylsulfonylamino,
Cl 3 alkylsulfonylamino,
Cl 3 alkyl,
-CF3,
l S C 1 3alkyloxy,
halogen,
nitro,
or
A is a 9 membered fused aromatic ring system having 0, 1, 2 or
3 nitrogen atoms,
or
A is isoindolinone or indolinone;
B is -OCH(R8)(CH2)pCO2R9,
(CH2)nC02R9,
. , .. . , . ~
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- 23 -
- n=0, 1,2,3,
p=0, 1,2,3,
wherein
R8 is hydrogen or Cl 3alkyl and
R9 is hydrogen or-(CH2)1 3C(O)NH(CH2)0 2CH3
or-(CH2)1 3 C(O)N((CH2)0-2CH3)2
In a subclass of the class, the compounds have the structure
1 0 X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein
X is a 5 or 6 membered aromatic or nonaromatic ring having 1
or 2 nitrogen atoms and unsubstituted or substituted with
NH2;
Y is a 6 membered aromatic or nonaromatic ring having 0 or I
nitrogen atoms and unsubstituted or substituted with CH3;
or X and Y form the fused ring systems:
HN~ HN~--
HN or HN O
CA 02258093 1998-12-lO
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Z is
O O
Il 11
--CNH-- , --NH-- , --C-- ,--CH2CH2--
1~l 11
--CH=CH-- , --C--N-- , --Nl IC-- , or
CH3
Z represents a bond;
A is phenyl unsubstituted, monosubstituted with RS,
disubstituted with R5 and R6, or trisubstituted with RS, R6,
or R7, where R5, R6, or R7 are selected from
-NHS02C6H5,
-NHS02CH3
(~ 11
--NHSO2 ~ N
-C~3,
-CF3,
-OCH3,
-Cl,
lS -NO2, and
-Br,
or
A is a 9 membered fused aromatic ring system having 1
nitrogen atom,
or
A is isoindolinone or indolinone;
B is -OCH(R8)CO2R9,
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-(CH2)nC02R9
wherein n = 1 or 2
R8 ishydrogen or Cl 3alkyl and
R9 is hydrogen, -(CH2)1 3C(O)NH(CH2)0-2cH3~ or
-(CH2)1 3 C(O)N((CH2)0 2CH3)2.
In a group of the subclass, the compounds have the
structure
X-Y-Z-A-B
and pharmaceutically acceptable salts,
wherein
xiS
HN N--~ HN~ N~
H2N~ ~ N~
H2N
Yis
~N~ N~
CH3
N
, .. .. ... . .
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WO g8/00134
- 26 -
or X and Y form the fused ring systems:
1~,~ , or
HN
HN~
S zis
--CNH-- , --NH-- , --C-- ,--CH2CH2
--CH=CH-- , --g--N-- , --NHC-- , or
CH3
Z represents a bond;
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A ls
NHSO2C6H5 CH3 OCH3
CF3 Cl
CH3 CH3
~N~
CH3
~N~
NHSO2CH3 NHSO
Br
NO2 OCH3 CH3 Br
and
B is
-OCH2C02H,
-OCH2C02CH2C(O)NHCH3,
-OCH2CO2CH2C(O)N(CH2CH3)2,
1 0 -OCH2C02CH2CH3,
-CH2CH2C02H,
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-CH2COOH,
-OCH(CH3)CO2H, or
-OCH(C~I3)C02CH2CH3.
Exemplary compounds of the group include
3-(4-(4-piperazin- 1 -ylphenylcarbonylamino)phenyl)
propanoic acid,
10 2-(4-(4-Piperazinyl- 1 -yl)phenylcarbonylamino)phenoxy)
acetic acid,
Ethyl 2-(4-(4-(1-piperazinyl)phenylcarbonylamino)phenoxy)acetate,
hydrochloride,
2-(S-(4-( 1 -Piperazinyl)phenylcarbonylamino)indol- 1 -yl)
acetic acid,
3-(3-(4-Piperazin- 1 -ylphenyl)carbonylamino)phenyl)
20 propanoic acid,
E~thyl 2-(4-(4-(piperazin-1-yl)phenylcarbonylamino)
phenoxy)propanoate
25 2-(4-(4-(Piperazin- 1 -yl)phenylcarbonylamino)phenoxy)
propionic acid,
2-(4-(((2-Piperazin- 1 -yl)pyridin-S-yl)carbonylamino)phenoxy)acetic
acld,
3-Methyl-4-(( 1 ,2,3 ,4-tetrahydro-9H-pyrido[3 ,4-b]indol-7-
yl)carbonylamino)phenoxyacetic acid,
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2-(4-(5-(4-(1,1 -Dimethylethoxycarbonyl)-piperazin- 1 -yl)-2-
thienylcarbonylamino)-3-methylphenoxy)-acetic acid,
4-(2-(1,1 -dimethylethoxycarbonyl)- 1,2,3 ,4-tetrahydro-9H-pyrido[3 ,4-
b]benzofuran-7-yl)carbonylamino)-3-methylphenoxy acetic acid,
4-((2,3,4,5-tetrahydropyrazino-[ 1 ,2-a]indole-8-yl)carbonylamino)-3-
methylphenoxyacetic acid, and
(+ /-) 4-((3-(1,1-Dimethylethoxycarbonyl)-l,la,2,3,4,5-hexahydro-
pyrazino-[ 1 ,2-a]indole-8-yl)carbonylamino)-3-methylphenoxyacetic
acid.
One test which is used to evaluate fibrinogen receptor
antagonist activity is based on evaluation of inhibition of ADP-
stimulated platelets. Aggregation requires that fibrinogen bind to and
occupy the platelet fibrinogen receptor site. Inhibitors of fibrinogen
binding inhibit aggregation. In the ADP-stimulated platelet aggregation
assay used to determine inhibition associated with the compounds
claimed in the instant invention, human platelets are isolated from fresh
blood, collected into acid citrate/dextrose by differential centrifugation
followed by gel filtration on Sepharose 2B in divalent ion-free Tyrode's
buffer (pH 7.4) cont~ining 2% bovine serurn albumin.
Platelet aggregation is measured at 37~C in a Chronolog
aggregometer. The reaction mixture contains gel-filtered human
platelets (2 x 108 per ml), fibrinogen (100 micrograrns per ml (ug/ml)),
Ca2+ (1 mM), and the compound to be tested. The aggregation is
initiated by adding 10 mM ADP 1 minute after the other components
are added. The reaction is then allowed to proceed for at least 2
- 30 minutes. The extent of inhibition of aggregation is expressed as the
percentage of the rate of aggregation observed in the absence of
inhibitor. The IC50 is the dose of a particular compound inhibiting
aggregation by 50% relative to a control lacking the compound.
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The following compounds were tested and found to have
IC50 values in the range between 10 nM and 50 mM:
3-(4-(4-piperazin- 1 -ylphenylcarbonylamino)phenyl)
5 propanoic acid,
2-(4-(4-Piperazinyl- I -yl)phenylcarbonylamino)phenoxy)
acetic acid,
10 Ethyl 2-(4-(4-(1-piperazinyl)phenylcarbonylamino)phenoxy)acetate,
hydrochloride,
2-(5-(4-(1 -Piperazinyl)phenylcarbonylamino)indol- 1 -yl)
acetic acid,
3-(3-(4-Piperazin- 1 -ylphenyl)carbonylamino)phenyl)
propanoic acid,
Ethyl 2-(4-(4-(piperazin-1-yl)phenylcarbonylamino)
20 phenoxy)propanoate
2-(4-(4-(Piperazin- 1 -yl)phenylcarbonylarnino)phenoxy)
propionic acid,
25 2-(4-(((2-Piperazin- 1 -yl)pyridin-5-yl)carbonylamino)phenoxy)acetic
acld,
3-Methyl-4-(( 1,2,3 ,4-tetrahydro-9H-pyrido[3 ,4-b]indol-7-
yl)carbonylamino)phenoxyacetic acid,
2-(4-(5-(4-(1,1 -Dimethylethoxycarbonyl)-piperazin- 1 -yl)-2-
thienylcarbonylamino)-3-methylphenoxy)-acetic acid
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4-(2-(1,1 -dimethylethoxycarbonyl)- 1 ,2,3,4-tetrahydro-9H-pyrido[3,4-
b]benzofuran-7-yl)carbonylamino)-3-methylphenoxy acetic acid,
4-((2,3,4,5-tetrahydropyrazino-[ 1 ,2-a]indole-8-yl)carbonylamino)-3-
methylphenoxyacetic acid, and
(+ /-) 4-((3-(1,1 -Dimethylethoxycarbonyl)- 1,1 a,2,3 ,4,5-hexahydro-
pyrazino-[ 1 ,2-a]indole-8-yl)carbonylamino)-3-methylphenoxyacetic
acid.
Additionally, these compounds are useful for treating
m~mm~ suffering from a bone condition caused or mediated by
increased bone resorption, who are in need of such therapy.
Ph~ cologically effective amounts of the compounds, including
pharamaceutically acceptable salts thereof, are administered to the
m~mm~l, to inhibit the activity of m~mm~ n osteoclasts.
Additionally, these compounds are useful for treating
angiogenesis (formation of new blood vessels). It has been postulated
that the growth of tumors depends on an adequate blood supply, which
in turn is dependent on the growth of new vessels into the tumor.
Inhibition of angiogenesis can cause tumor regression in ~nim~l models.
(See, Harrison's Principles of Internal Medicine, 12th ed., 1991). These
compounds are therefore useful in the treatment of cancer by inhibiting
tumor growth. (See e.g., Brooks et al., Cell, 79:1157-1164 (1994)).
The term "pharmaceutically acceptable salts" shall mean
non-toxic salts of the compounds of this invention which are generally
prepared by reacting the free base with a suitable organic or inorganic
acid. Representative salts include the following salts:
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,
borate, bromide, calcium edetate, camsylate, carbonate, chloride,
clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate,
fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynapthoate, iodide, isothionate, lactate~ lactobionate, laurate,
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malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,
pa!mitate, panthothe~ate, phosphate/diphosphate, polygalacturonate,
salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate,
5 tosylate, triethiodide, valerate.
Compounds of the present invention may be chiral;
included within the scope of the present invention are racemic mixtures
and separated enantiomers of the general formula. Furthermore, all
diastereomers, including E, Z isomers, of the general formula are
10 included in the present scope. Furthermore, hydrates as well as
anhydrous compositions and polymorphs of the general formula are
within the present invention.
Prodrugs, such as ester derivatives of described
compounds, are compound derivatives which, when absorbed into the
15 bloodstream of a warm-blooded ~nim~l, cleave in such a manner as to
release the drug form and permit the drug to afford improved
therapeutic efficacy.
The term "pharmaceutically effective amount" shall mean
that amount of a drug or pharmaceutical agent that will elicit the
20 biological or medical response of a tissue, system or ~nim~l that is being
sought by a researcher or clinician. The term "anti-coagulant" shall
include heparin, and warfarin. The term "thrombolytic agent" shall
include agents such as streptokinase and tissue plasminogen activator.
The term "platelet anti-aggregation agent" shall include agents such as
25 aspirin and dipyridamole.
The term "alkyl" means straight or branched alkane
cont~ining 1 to about 10 carbon atoms, e.g., methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,
hexy, octyl radicals and the like; the term alkenyl means straight or
30 branched alkene cont~ining 2 to about 10 carbon atoms, e.g.,
propylenyl, buten- l -yl, isobutenyl, pentenylen- 1 -yl, 2,2-methylbuten- ~ -
yl, 3-methylbuten-l-yl, hexen-l-yl, hepten-1-yl, and octen-1-yl radicals
- and the like; alkynyl means straight OF branched alkyne containing 2 to
about lO carbon atoms, e.g., ethynyl, propynyl, butyn-l-yl, butyn-2-yl,
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pentyn-l-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-l-yl, hexyn-2-yl,
hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term "aryl" means a S- or 6-membered aromatic ring
cont~inin~ 0, 1, or 2 heteroatoms selected from O, N, and S, e.g.
S phenyl, pyridine, pyrimidine, imidazole, thiophene, oxazole, isoxazole,
thiazole, and amino- and halogen- substituted derivatives thereof.
The terms "alkyloxy" or "alkoxy" include an alkyl portion
where alkyl is as defined above, e.g., methyloxy, propyloxy, and
butyloxy.
The terms "arylalkyl" and "alkylaryl" include an alkyl
portion where alkyl is as defined above and to include an aryl portion
where aryl is as defined above. The Co-n or Cl n designation where n
may be an integer from 1-10 or 2-10 respectively refers to the alkyl
component of the arylalkyl or alkylaryl unit. Examples of arylalkyl
lS include benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl,
fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and
thienylpropyl. Examples of alkylaryl include toluene, ethylbenzene,
propylbenzene, methylpyridine, ethylpyridine, propylpyridine,
butylpyridine, butenylpyridine, and pentenylpyridine.
The term "halogen" includes fluorine, chlorine, iodine and
bromine.
The term "oxy" means an oxygen (O) atom. The term
"thio" means a sulfur (S) atom. Under standard nonmenclature used
throughout this disclosure, the terminal portion of the designated side
chain is described first followed by the adjacent functionality toward the
point of attachment. For example, a Cl 6 alkyl substituted with Cl 5
alkyl-carbonylamino is equivalent to
HO
1 11
C1 6-alkyl-N-C-C1 s-alkyl
In the schemes and examples below, various reagent
symbols have the following meanings:
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- 34 -
BOC
(or Boc): t-butyloxycarbonyl
Pd-C: palladium on activated carbon catalyst
DMF: dime~ylformamide
5 DMSO: dimethylsulfoxide
CBZ: carbobenzyloxy
CH2C12: methylene chloride
CHC13: chloroform
EtOH: ethanol
MeOH: methanol
EtOAc: ethyl acetate
HOAc: acetic acid
BOP: benzotriazol- 1 -yloxytris(dimethylamino)phosphonium,
hexafluorophosphate
EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride
Oxone: potassium peroxymonosulfate
LDA: lithium diisopropylamide
PYCLU: Chloro-N,N,N',N'-bis(pentamethylene)formamidinium
hexafluorophosphate
NMM: N-methylmorpholine
The compounds of the present invention can be
~(1mini.~tered in such oral forms as tablets, capsules (each of which
includes sustained release or timed release formulations), pills, powders,
25 granules, elixirs, tinctures, suspensions, syrups, and emulsions.
Likewise, they may be a-lmini~tered in intravenous (bolus or infusion),
intraperitoneal, subcutaneous, or intramusculsar form, all using forms
well known to those of ordinary skill in the pharmaceutical arts. An
effective but non-toxic amount of the compound desired can be
30 employed as an anti-aggregation agent.
Compounds of the invention may be a-lmini~tered to
patients where prevention of thrombosis by inhibiting binding of
fibrinogen to the platelet membrane glycoprotein complex IIb/IIIa
receptor is desired. They are useful in surgery on peripheral arteries
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- 35 -
(arterial grafts, carotid endarterectomy) and in cardiovascular surgery
where manipulation of arteries and organs, and/or the interaction of
platelets with artificial surfaces, leads to platelet aggregation and
consumption. The aggregated platelets may form thrombi and
5 thromboemboli. Compounds of this invention may be ~tlmini~tered to
these surgical patients to prevent the formation of thrombi and
thromboemboli.
Extracorporeal circulation is routinely used for
cardiovascular surgery in order to oxygenate blood. Platelets adhere to
10 surfaces of the extracorporeal circuit. Adhesion is dependent on the
interaction between gp IIb/IIIa on the platelet membranes and
fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer.
J. Physiol.. 252(H), 615-621 (1987)). Platelets released from artificial
surfaces show impaired hemostatic function. Compounds of the
15 invention may be a~lministered to prevent adhesion.
Other applications of these compounds include prevention
of platelet thrombosis, thromboembolism and reocclusion during and
after thrombolytic therapy and prevention of platelet thrombosis,
thromboembolism and reocclusion after angioplasty or coronary artery
20 bypass procedures. They may also be used to prevent myocardial
infarction.
The dosage regimen utilizing the compounds of the present
invention is selected in accordance with a variety of factors including
type, species, age, weight, sex and medical condition of the patient; the
25 severity of the condition to be treated; the route of ~lmini~tration; the
renal and hepatic function of the patient; and the particular compound
or salt thereof employed. An ordinarily skilled physician or
veterinarian can readily determine and prescribe the effective amount of
the drug required to prevent, counter, or arrest the progress of the
30 condition.
Oral dosages of the present invention, when used for the
indicated effects, will range between about 0.01 mg per kg of body
weight per day (mg/kg/day) to about 100 mg/kg/day and preferably
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- 36 -
0.01-100 mg/kg/day and most preferably 0.01-20 mg/kg/day. For
example, a typical 90 kg patient would receive oral dosages ranging
between about 0.9 mg/day and about 9 g/day, most preferably between
about 0.9 mg/day and 1.8 g/day. Suitable pharmaceutical oral
compositions such as tablets or capsules may contain between 10-500 mg
of active drug, for example, lO mg, lO0 mg, 200 mg and 500 mg.
Intravenously, the most preferred doses will range from about l to
about 10 mg/kg/minute during a constant rate infusion.
Advantageously, compounds of the present invention may
be ~(lmini~tered in divided doses of two, three, or four times daily.
Furthermore, preferred compounds for the present invention can be
~ministered in intranasal form via topical use of suitable intranasal
vehicles, or via transdermal routes, using those forms of transdermal
skin patches well known to those of ordinary skill in that art. To be
a~lministered in the form of a transderrnal delivery system, the dosage
a~mini.~tration will, or course, be continuous rather that intermittent
throughout the dosage regime.
In the methods of the present invention, the compounds
herein described in detail can form the active ingredient, and are
typically arlmini.stered in admixture with suitable pharmaceutical
diluents, excipients or carriers (collectively referred to herein as
"carrier" materials) suitably selected with respect to the intended form
of ~f~mini~tration, that is, oral tablets, capsules, elixirs, syrups and the
like, and consistent with convention pharmaceutical practices.
For instance, for oral ~lrnini.~tration in the form of a tablet
or capsule, the active drug component can be combined with an oral,
non-toxic, pharmaceutically acceptable, inert carrier such as lactose,
starch, sucrose, glucose, methyl cellulose, magnesium stearate,
dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for
oral a-lmini~tration in liquid form, the oral drug components can be
combined with any oral, non-toxic, pharmaceutically acceptable inert
carrier such as ethanol, glycerol, water and the like. Moreover, when
desired or necessary, suitable binders, lubricants, distintegrating agents
and coloring agents can also be incorporated into the mixture. Suitable
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binders include starch, gelatin, natural sugars such as glucose or beta-
lactose, corn-sweeteners, natural and synthetic gums such as acacia,
tragacanth or sodium alginate, carboxymethylcellulose, polyethylene
glycol, waxes and the like. Lubricants used in these dosage forms
5 include sodium oleate, sodium stearate, magnesium stearate, sodium
benzoate, sodium acetate, sodium chloride and the like. Disintegrators
include, without limitation, starch methyl cellulose, agar, bentonite,
xanthan gum and the like.
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SCHEME 1
H2N~CO2CH3
1 -1
n-butanol / \ ~
+ ~ HN N~Co2cH3
Cl ~-3
BOC2O, NEt3
HCI HN
L, DMF
1-2 Cl BOC-N N~CO2CH3
1 N NaOH/ 1-4
BOC-N N~ ,~EtOH
1 -5
H2N~Br
1 -6
BOP, NMM, DMF
60~ O
BOC-N~ N~3C-NH~3Br
~\CO2Me,
1-7 N Et3
o(tolyl)3P,
CH3CN
Pd(oAc)2
sealed tube
1 00~C
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- 39 -
SCHEME 1. CONTINUED
O
~ 11 ~ /~ CO2Me
Boc--N~N~ C-N H~--
1 -8
10% Pd/C, H2
EtOH
~ 11 ~ CO2Me
Boc--N~N~ C-NH~--
1 -9
1 N NaOH
EtOH
o
Boc--N N~ C-NH~3--CO2H
1-10
TFA, CH2CI2
A ~ 1 1 ~ CO2H
HN N~C-NH~--
1 -1 1
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- 40 -
HN N~CO2CH3
1 -3
Methyl 4-(1-piperazinyl)benzoate (1-3)
A solution of amine 1 1 (20.0 g, 132 mmol), arnine 1 2
5 (23.6 g, 132 mmol) and n-butanol (500 ml) was refluxed for 168 h.
The solution was allowed to cool to ambient temperature. The crystals
were collected, washed with Et20 and dried in vacuo to give ester 1 3
as a white solid.
lH NMR (CD30D): o 7.86 (d, J=9Hz, 2H), 7.98 (d, J=9Hz, 2H), 3.78
10 (s, 3H), 3.53 (m, 4H), 3.31 (m, 4H).
BocN N~Co2cH3
1 -4
Methyl 4-(4-(1 .1 -dimethylethoxycarbonyl)piperazin- 1 -yl)benzoate ( 1-4)
To a stirred solution of amine 1 3 (15.0 g, 61.1 mmol),
NEt3 (7.42 g, 73.4 mmol) and DMF (150 ml) was added Boc20 (14.7
g, 67.2 mmol). After 1.0 h, the solution was diluted with EtOAc and
then washed with H20, 10% KHS04, brine, dried (MgS04) and
concentrated to furnish ester 1 4 as a yellow solid.
20 TLC Rf = 0.63 (silica, 40% EtOAc/hexanes)
lH NMR (CD30D): ~ 7.91 (d, J=9Hz, 2H), 7.01 (d, J=9Hz, 2H), 3.8
(s, 3H), 3.59 (m, 4H), 3.38 (m, 4H).
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- 41 -
BocN ~N~ CO2H
1 -5
4-(4-(1. l -Dimethylethoxycarbonyl)piperazin- 1 -vl)benzoic acid (1 -5)
A solution of ester 1 4 (21.1 g, 61.1 mrnol) 1 N NaOH (100
ml, 100 m~nol) and EtOH (200 ml) was heated to 60~C for 2.0 h. The
5 solution was acidifed with 10% KHSO4 and then extracted with EtOAc.
The EtOAc phase was washed with brine, dried (MgSO4) and
concentrated to furnish acid 1 5 as a white solid.
1H NMR (CD30D): ~ 7.81 (d, J=9Hz, 2H), 6.88 (d, J=9Hz, 2H), 3.49
(m, 4H), 3.24 (m, 4H), 1.40 (s, 9H).
~/ ~N H ~ Br
N-(4-bromophenyl)-4-(4-(1, I -dimethylethoxycarbonyl)piperazin- 1 -
yl)benzamide (1 -7)
A solution of acid 1 5 (400 mg, 1.31 ~T~nol), amine 1 6
(248 mg, 1.44 mrnol), BOP reagent (867 mg, 1.97 mmol), NMM (575
~1, 5.24 mmol) and DMF was heated at 60~C for 72 h. The solution was
diluted with EtOAc and then washed with H2O, sat. NaHCO3, 10%
KHSO4 brine, dried (MgSO4) and concentrated. Flash chromatography
20 (silica, 20% EtOAc/hexanes) furnished amide 1 7 as a yellow solid.
TLC Rf = 0.36 (silica, 20% EtOAc~exanes)
lH NMR (CDC13): ~ 7.78 (d, J=9Hz, 2H), 7.70 (s, lH), 7.54 (d, J=9Hz,
2H), 7.46 (d, J=9Hz, 2H), 6.92 (d, J=9Hz, 2H), 3.58 (m, 4H), 3.30 (m,
4H), 1.49 (s, 9H).
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-
- 42 -
BocN N~NH~_, CO2Me
(O-Methyl 3-(4-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -
yl)phenylcarbonylaminophenyl)prop-3-enoate (l-~S)
5A solution of amide 1 7 (300 mg, 0.6519 mmol), methyl
acrylate (587 ,ul, 6.52 mmol), O(tolyl)3P (120 mg, 0.311 mmol), NEt3
(184 ~l, 1.30 mmol), Pd (OAc)2 (15 mg, 0.0512 mrnol) and CH3CN (5
ml) was heated to 100~C in a sealed tube for 18 h. The solution was
diluted with EtOAc and then washed with H2O, sat. NaHCO3, 10%
10 KHSO4, brine, dried (MgSO4) and concentrated. Flash
chromatography (silica, 25% ~ 40% EtOAc/hexanes) furnished olefin
1 8 as a yellow solid.
TLC Rf = 0.36 (silica, 50% EtOAc/hexanes)
1H NMR (CDCl3): ~ 7.87 (s, lH), 7.81 (d, J=9Hz, 2H), 7.68 (m, 3H),
15 7.53 (d, J=9Hz, 2H), 6.94 (d, J=9Hz, 2H), 6.39 (d, J=16Hz, IH), 3.81 (s,
3H), 3.61 (m, 4H), 3.30 (m, 4H), 1.50 (s, 9H).
BocN N~NH~_ CO2Me
20 Methyl 3-(4-(4-(4-(1, l -dimethylethoxycarbonyl)piperazin- 1 -
yl)phenylcarbonylaminophenyl)propanoate (1-9)
A mixture of ester 1 8 (260 mg, 0.56 mmol), 10% Pd/C
(100 mg) and EtOH (10 ml) was stirred under l atm H2 for 18 h. The
reaction mixture was filtered through a celite pad and concentrated to
25 furnish ester 1 9 as a brown solid.
lH NMR (CDCl3): ~ 7.79 (d, J=9Hz, 2H), 7.67 (s, lH), 7.54 (d, J=8Hz,
2H), 7.19 (d, J=8Hz, 2H), 6.92 (d, J=9Hz, 2H), 3.67 (s, 3H), 3.60 (m,
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- 43 -
4H), 3.29 (m, 4H), 2.94 (t, J=8Hz, 2H), 2.63 (t, J=~Hz, 2H), 1.49 (s,
9H).
o
BocN N~ C-N H~ ,CO2H
1 -10
3 -(4-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -
yl)phenylcarbonylaminophenyl)propanoic acid (1 - 10)
A solution of ester 1 9 (250 mg, 0.53 mmol), 1 N NaOH (1
ml, 1.00 mmol) and EtOH (3 ml) was stirred at ambient temperature for
1.5 h. The solution was acidified with 10% KHSO4 and then extracted
10 with EtOAc. The EtOAc phase was washed with brine, dried (MgSO4)
and concentrated to furnish acid 1 - 10 as a tan solid.
TLC Rf = 0.11 (silica, 10:0.2:0.2 CH2C12/MeOH/AcOH)
lH NMR (CD30D): ~ 7.86 (d, J=9Hz, 2H), 7.55 (d, J=8Hz, 2H), 7.20
(d, J=9Hz, 2H), 7.08 (d, J-8Hz, 2H), 3.60 (bs, 4H) 3.45 (m, 4H), 2.89
15 (t, J=8Hz, 2H), 2.59 (t, J=8Hz, 2H), 1.48 (s, 9H).
HN N~C-NH~"CO2H
1-11
3-(4-(4-piperazin- 1 -ylphenylcarbonylamino)phenyl)
20 propanoic acid (1-11)
To a solution of acid 1-10 (215 mg, 0.4743 mmol), TFA
(3.0 ml) and CH2C12 (3.0 ml) was stirred at ambient temperature for
- 1.5 h. The solution was concentrated and then azeotroped with toluene.
The re.sidue was trituated with 10:0.2:0.2 EtOH/NH40H/H20? filtered,
25 washed with Et2O and dried in vacuo to furnish acid 1 - 11 as a tan solid.
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TLC Rf = 0.55 (silica, 10:1 :1 EtOH/NH40H/H20)
lH NMR (D20): ~ 7.83 (d, J=9Hz, 2H), 7.42 (d, J=8Hz, 2H), 7.31 (d,
J=8Hz, 2H), 7.16 (d,-J=9Hz, 2H), 3.25 (m, 4H), 2.96 (m, 4H, 2.89 (t,
J=8Hz, 2H), 2.49 (t, J=8Hz, 2H).
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-
-45-
SCHEME2
BOC-N N ~ CO2H + HCI-H2N ~ OH
2-2
BOP,NMM
DMF
60~
BOC-N N ~ C NH ~ OH
2-3
Br~CO2tBu
~ Cs2CO3,DMF
BOC-N N ~ C - NH ~ O CO2tBu
TFA,CH2Cl2
o
HN N ~ C NH ~ O CO2H
2-6
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- 46 -
BocN N~e--NH--~OH
2~
N-(4-Hydroxyphenyl)-4-(4-( 1,1 -dimethylethoxycarbonyl)piperazinyl-
l-yl)benzamide (2-3)
A solution of carboxylic acid 2-1 (400 mg, 1.31 rnmole), 4-
aminophenyl 2-2 (210 mg, 1.44 mmol), BOP reagent (867 mg, 1.97
mmole), NMM (575 ~l, 5.24 mmol) and DMF (10 ml) was heated to
60~C for 72 h. The reaction mixture was diluted with EtOAc and then
washed with H20, sat NaHCO3, 10% KHSO4, dried (MgSO4) and then
10 concentrated. Flash chromatography (silica, 50% EtOAc/hexanes)
furnishea the amide 2-3 as a white solid.
TLC Rf = 0.25 (silica, 50% EtOAc/hexanes)
1H NMR (CD30D): ~ 7.82 (d, J=9Hz, 2H), 7.40 (d, J=9Hz, 2H), 7.0 (d,
J=9Hz, 2H), 6.75 (d, J=9Hz, 2H), 3.57 (bs, 4H), 3.30 (bs, 4S), 1.47 (s,
1 5 9H).
BocN N~e-- NH~OCH2CO2tBu
2-5
tert-Butyl 2-(4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazinyl-l-
20 yl)phenylcarbonylamino)phenoxy)acetate (2-5)
To a stirred solution of amide 2-3 (400 mg, 1.01 mmol)
and DMF (5 ml) was added cesium carbonate (820 mg, 2.53 mmole)
followed by t-butyl bromoacetate (195 ~l, 1.21 mmol). After 20 h, the
reaction mixture was diluted with EtOAc and then washed with H2O,
25 10% KHSO4, brine, dried (MgSO4) and concentrated. Flash
chromatography (silica, 25% EtOAc/hexanes) furnished ester 2-5 as a
white solid.
.... ...
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TLC Rf = 0.40 (silica, 50% EtOAc/hexanes)
1H NMR (CDC13): o 7.79 (d, J=9Hz, 2H), 7.63 (s, lH), 7.54 (d, J=9Hz,
2H), 6.92 (m, 4H), 4~51 (s, 2H), 3.60 (m, 4H), 3.30 (m, 4H), 1.50 (s,
l 8H).
s
o
HN N~C NH ~ocH2co2H
2-6
2-(4-(4-Piperazinyl- 1 -yl)phenylcarbonylamino)phenoxy)
acetic acid (2-6)
A solution of ester 2-5 (275 mg, 0.5378 mmol), TFA (S
ml) and CH2C12 (5 ml) was stirred at ambient temperature for 2.0 h.
The solution was concentrated and then azeotroped with toluene. The
residue was trituated with 10:0.5:0.5 EtOH/NH40H/H20, filtered,
washed with EtOH and then washed with EtOH to furnish acid 2-6 as a
15 white solid.
TLC Rf = 0.34 (silica, 10:0.5:0.5 EtOH/NH40H/H20)
1H NMR (CD30D): ~ 7.83 (d, J=9Hz, 2H), 7.50 (d, J=9Hz, 2H), 7.00
(d, J=9Hz, 2H), 6.92 (d, J=9Hz, 2H), 4.36 (s, 2H), 3.30 (m, 4H), 2.96
(m, 4H).
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- 48 -
SCHEME 3
BoC-N~ N~3C-NH~o CO2tBu
2-5
CH31, CS2CO3
DMF, 60~C
BOC-N N~3C-N ~O CO2tBu
3 1 CH3
TFA, CH2CI2
HN Ng~C-N ~3O CO2H
3-2 3
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- 4 9 -
BocN N~C--I ~OCH2CO2tBu
3-1 3
tert-Butyl 2-(4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-
yl)phenylcarbonyl(N-methyl)amino)phenoxy)acetate (3-1)
S To a stirred solution of ester 2-5 (200 mg, 0.3911 mmol)
was added cesium carbonate (318 mg, 0.9778 mmole) followed by CH3I
(29 ~1, 0.47 mmol). After heating at 60~ for 2.0 h, the reaction mixture
was diluted with EtOAc and then washed with H20, 10% KHSO4, brine,
dried (MgSO4) and concentrated. Flash chromatography (silica, 40%
EtOAc/hexanes) furnished ester 3-1 as a yellow solid.
TLC Rf = 0.45 (silica, 50% EtOAc/hexanes)
lH NMR (CDC13): ~ 7.21 (d, J=9Hz, 2H), 6.97 (d, J=9Hz, 2H), 6.75 (d,
J=9Hz, 2H), 6.63 (d, J=9Hz, 2H), 4.45 (s, 2H), 3.52 (bt, 4H), 3.43 (s,
3H), 3.13 (bt, 4H), 1.47 (s, 18H).
HN N~C-N ~OCH2C02H
3-2 3
2-(4-(4-( 1 -Piperazinyl)phenylcarbonyl(N-methyl)amino)phenoxy)-acetic
acid (3-2)
A solution of ester 3-1 (190 mg, 0.3617 mmole), TFA (3
ml) and CH2C12 (3 ml) was stirred at ambient temperature for 30
minutes. The solution was concentrated and then azeotroped with
toluene. Flash chromatography (silica, 10:0.2:0.2 EtOH/NH40H/H20)
- furnished acid 3-2 as a white solid.
TLC Rf= 0.42 (silica, 10:0.2:0.2 EtOH/NH40H/H20)
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lH NMR (CD30D): â 7.25 (d, J=9Hz, 2H), 7.06 (d, J=9Hz, 2H), 6.91
(d, J=9Hz, 2H), 6.82 (d, J=9Hz, 2H), 4.66 (s, 2H), 3.50 (m, 4H), 3.41 (s,
3H), 3.35 (m, 4H).
SCHEME 4
HN N~3C-NH ~30 CO2H
\
HCI (g)
EtOH, 0~C ~ RT
HCI-HN N~C-NH -~O CO2CH2CH~
Ethyl 2-(4-(4~ piperazinyl)phenylcarbonylamino)phenoxy)acetate
10 hydrochloride (4-1)
To a stirred solution of acid 2-6 (40 mg, 0.1125 mmol) and
EtOH (2 ml) at 0~C was bubbled HCl gas for 3 minlltes. After 24 h at
ambient temperature, the solution was concentrated to give ethyl ester 4-
1 as a white solid.
1H NMR (D2O): ~ 7.87 (d, J=9Hz, 2H), 7.44 (d, J=9Hz, 2H), 7.19 (d,
J=9Hz, 2H), 7.05 (d, J=9Hz, 2H), 4.80 (s, 2H), 4.31 (q, J=7Hz, 2H) 3.62
(m, 4H), 3.43 (m, 4H), 1.30 (t, J=7Hz, 3H).
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SCHEME S
Boc--N~N~ CO2H + H2N ~ / H
t-5 5-1
BOP, NMM
DMF
Boc--N N~3C - NH ~N,/H
5-2
Br~CO2tBu
5-3
NaH, THF
Boc--N N~3C - N H ~N--CO2tBU
\ ~
5-4
TFA, CH2CI2
HN N~C-NH~,~N--CO2H
5-5
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~ ~C-NH~N/H
N-(5-Indolyl)-4-(4-( 1,1 -dimethylethoxycarbonyl)piperazin- 1-
yl)benzamide (5-2)
To a stirred solution of acid 2-1 (500 mg, 1.63 mmol),
NMM (715 ~11, 6.52 mmol) and DMF (5 ml) was added BOP reagent
(1.08 g, 2.45 mmol). After 30 minutes, amine 5-1 (Aldrich 260 mg,
1.96 mmole) was added. After 18 h at 60~C, the solution was diluted
with EtOAc and then washed with H2O, brine, dried (MgSO4) and
concentrated. Flash chromatography (silica, 20% EtOAc/CHCl3)
afforded amide 5-2 as a yellow solid.
TLC Rf = 0.13 (silica, 20% EtOAc/CHCl3)
lH NMR (10% CD30D/CDCl3): ~ 7.90 (s, lH), 7.83 (d, J=9Hz, 2H),
7.63 (m, 2H), 7.22 (9s, lH), 6.94 (d, J=9Hz, 2H), 6.52 (d, J=3Hz, lH),
3.59 (m, 4H), 3.28 (m, 4H), 1.49 (s, 9H).
BOC - N N ~ C - NH ~ ~N~--CO2tBu
5-4
tert-Butyl 2-(5-(4-(4-( l, l -dimethylethoxycarbonyl)piperazin- 1-
yl)phenylcarbonylamino)indol-1-yl)acetate (5-4)
To a stirred solution of amide 5-2 (300 mg, 0.71 mmol)
and THF (5 ml) was added NaH (60% dispersion in mineral oil; 29 mg,
0.7137 mmol). After 10 minutes, bromide 5-3 (115 ~l, 0.71 mmol) was
added. After 30 minutes, the solution was diluted with EtOAc and then
washed with H2O, brine, dried (MgSO4) and concentrated. Flash
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chromatography (silica, 40% EtOAc/hexanes) afforded ester 5-4 as a
yellow solid.
TLC Rf = 0.18 (silica, 40% EtOAc/hexanes)
lH NMR: â 7.92 (s, lH), 7.83 (d, J=9Hz, 2H), 7.77 (s, lH), 7.39 (dd,
5 J=9Hz, 2Hz, lH), 6.93 (d, J=9Hz, 2H), 6.52 (d, J=3Hz, lH), 4.72 (s,
2H), 3.60 (m, 4H), 3.28 (m, 4H), 1.49 (s, 9H), 1.43 (s, 9H).
HN N~C-NH~N~--CO2H
5-5
10 2-(5-(4-(1-Piperazinyl)phenylcarbonylamino)indol-l-yl)
acetic acid (5-5)
To a stirred solution of ester 5-2 (250 mg, 0.4678 mmol),
anisole (203 ~1, 1.87 mmol) and CH2C12 (3 ml) at 0~C was added TFA.
After 30 min., the solution was concentrated and then azeotroped with
15 toluene. Flash chromatography (silica, 10:0.1 :0.1 EtOH/NH4O/H2O)
afforded crude acid. The crude material was purified by prep HPLC to
furnish acid 5-5.
TLC Rf = 0.31 (silica, 10:0.5 :0.5 EtOH/NH40H/H20)
1H NMR (50:50 d6- DMSO/D2O~ 2 drops lN NaOD): ~ 7.87 (d,
20 J=9Hz, 2H), 7.71 (s, lH), 7.24 (m, 3H), 7.07 (d, J=9Hz, 2H), 6.47 (d,
J=3Hz, lH), 4.63 (s, 2H), 3.25 (m, 4H), 2.89 (m, 4H).
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- 54 -
S C~DE~IE 6
Boc--N~l~ CO2H ~
6-1 NH2
BOP, NMM,
DMF, 60~C~
Boc--N~N~ C - N H ~
6-2 Br
~CO2Me, NEt3,
o(tolyl)3P, CH3CN,
Pd(OAc)2
sealedtube 100~C
o ~CO2Me
Boc--N N~C - NH
6-3
1 0% Pd/C
EtOH, H2
O ~CO2Me
Boc--N N~C - NH
6-4
1 N NaOH
EtOH
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- 55 -
SCHEME 6 CONTlNUED
O ~C02H
Boc--N N~C - NH
6-5
TFA, CH2CI2
O Co2H
HN N~C--NH ~~
/
6-6
BocN N~C-NH ~
6-2 Br
N-(3-bromophenyl)-4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -
yl))benzamide (6-2)
A solution of acid 1 5 (400 mg, 1.31 mmol), amine 6-1
10 (248 mg, 1.44 mmol), BOP reagent (867 mg, 1.97 mmol), NMM (575
~1, 5.24 mmol) and DMF (10 ml) was heated to 60~C for 72 h. The
solution was diluted with EtOAc and then washed with H2O, sat.
NaHCO3, 10% KHSO4, brine, dried (MgSO4) and concentrated. Flash
chromatography (silica, 25% EtOAc/hexanes) furnished amide 6-2 as a
15 yellow solid.
TLC Rf = 0.31 (silica, 25% EtOAc/hexanes)
lH NMR (CD30D): ~ 7.99 (s, lH), 7.~4 (d, J=9Hz, 2H), 7.60 (m, lH),
7.25 (m, 2H), 7.02 (d, J-9Hz, 2H), 3.57 (m, 4H), 3.31 (m, 4H), 1.47 (s,
9H).
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~CO2Me
BocN N ~C - N H ~)
(O-Methyl (3-(3 -(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin-1 -
S yl))phenyl)carbonylaminophenyl)prop-3-enoate (6-3)
A solution of amide 6-2 (400 mg, 0.86 mmol), methyl
acrylate (783 !11, 8.69 mmole), O(tolyl)3P (159 mg, 0.415 mmol), NEt3
(245 ,ul, 1.74 mmole), Pd(OAc)2 (20 mg, 0.069 mmole) and CH3CN (S
ml) was heated to 100~C in a sealed tube for 18 h. The solution was
10 diluted with EtOAc and then washed with H2O, sat. NaHCO3, 10%
KHSO4, brine, dried (MgSO4) and concentrated. Flash
chromatography (silica, 20% ~ 30% EtOAc/hexanes) furnished olefin
6-3 as a yellow solid.
TLC Rf = 0.47 (silica, 50% EtOAc/hexanes)
1H NMR (CD30D): ~ 7.94 (s, lH), 7.87 (dd, J=2Hz, 9Hz, 2H), 7.71
(m, 2H), 7.36 (m, 2H), 7.03 (dd, J=2Hz, 9Hz, 2H), 6.52 (d, J=16Hz,
lH), 3.78 (s, 3H), 3.57 (m, 4H), 3.29 (m, 4H), 1.47 (s, 9H).
O ~ CO2Me
BocN N--~C-NH
6-4
Methyl (3-(3-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -
yl))phenyl)carbonylaminophenyl)propanoate (6-4)
A mixture of ester 6-3 (300 mg, 0.64 mmol), 10% Pd/C
(100 mg) and EtOH (10 ml) was stirred under 1 atm H2 for 18 h. The
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reaction mixture was filtered through a celite pad and concentrated to
furnish ester 6-4 as a yellow oil.
1H NMR (CDCl3): ~ 7.80 (m, 3H), 7.54 (s, lH), 7.47 (d, J=8Hz, lH),
7.27 (m, lH), 6.96 (d, 8Hz, lH), 6.92 (d, J=9Hz, 2H), 3.68 (s, 3H), 3.60
5 (m, 4H), 3.29 (m, 4H), 2.96 (t, J=8Hz, 2H), 2.66 (t, J=8Hz, 2H), 1.50 (s,
9H).
BOC-N N~C-NH ~,CO2H
~-5
10 3 -(3-(4-(4-(1,1 -Dimethylethoxycarbonyl)piperazin- 1 -yl))phenyl~-
carbonylaminophenyl)propanoic acid (6-5)
A solution of ester 6-4 (260 mg, 0.5563 mmol), 1 N NaOH
(1 ml, 1 mmol) and EtOH (3 ml) was stirred at ambient temperature for
1.0 h. The solution was acidified with 10% KHSO4 and then extracted
15 with EtOAc. The EtOAc phase was washed with brine, dried (MgSO4)
and concentrated to furnish acid 6-5 as a white solid.
TLC Rf = 0.08 (silica, 10:0.2:0.2 CH2C12/MeOH/AcOH)
1H NMR (CD30D): ~ 7.84 (d, J=9Hz, 2H), 7.51 (m, 2H), 7.25 (t,
J=8Hz, lH), 7.03 (m, 3H), 3.57 (m, 4H), 3.29 (m, 4H), 2.91 (t, J=8Hz,
20 2H), 2.60 (t, J=8Hz, 2H), 1.47 (s, 9H).
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O ~,CO2H
HN N~C-NH
6-6
3-(3-(4-Piperazin- 1 -ylphenyl)carbonylamino)phenyl)
propanoic acid (6-6)
S A solution of acid 6-5 (210 mg, 0.4633 mmol), TFA (3 ml)
and CH2cl2 (3 ml) was stirred at ambient temperature for 1.0 h. The
solution was concentrated and then azeotroped with toluene. Flash
chromatography (silica, 10:0.1:0.1 ~ 10:0.5:0.5 EtOH/NH40H/H20)
fumished acid 6-6 as a tan solid.
TLcRf=o.s9(silica~ 10:1:1 EtOH/NH40H/H20)
lH NMR (D20): â 7.82 (d, J=9Hz, 2H), 7.38 (m, 2H), 7.34 (s, lH),
7.15 (d, J=9Hz, 3H), 3.25 (m, 4H), 2.96 (m, 4H), 2.90 (t, J=8Hz, 2H),
2.50 (t, J=8Hz, 2H).
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-
_ 59 _
SCHEME 7
~/ ~3~ CH3
H~OH + BrlCO Et
2~ 7-1
Cs2CO3, DMF
BocN N~H~ ~CO2Et
7-2
TFA, CH2C12
HN N~ H3C~
7-3
NaOH, EtOH
HN N~H~ o~CO2H
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- 60 -
BocN N ~ ~ lH3
Ethyl 2-[4-(4-(4-(1,1-Dimethylethoxycarbonyl)piperazin-1-
yl)phenylcarbonylamino)phenoxypropanoate (7-2)
S Phenol 2-3 (381 mg, 0.993 mrnol), ethyl 2-bromopro-
pionate (7-1, 129 ,uL, 0.99 mmol), and Cs2C03 (807 mg, 2.5 mrnol)
were combined in S mL DMF. After stirring overnight the reaction
was diluted with EtOAc, washed with water (3x), 10% KHS04 (3x) and
brine, dried (MgS04), filtered and concentrated. Flash chromato-
graphy (silica, 40% EtOAc/hexane) provided 7-2 as a white solid.
TLC Rf= 0.41 (silica, 50% EtOAc/hexane)
1H NMR (400 MHz, CDC13): ~ 7.78 (d, J=9Hz, 2H), 7.60 (s, lH), 7.52
(d, J=9Hz, 2H), 6.92 (d, J=9Hz, 2H), 6.89 (d, J=9Hz, 2H), 4.72 (q,
J=7Hz, lH), 4.22 (q, J=7Hz, 2H), 3.59 (m, 4H), 3.28 (m, 4H), 1.61 (d,
J=7Hz, 3H), 1.49 (s, 9H), 1.26 (t, J=7Hz, 3H).
HN~N~NIl~ lH3
Ethyl 2-(4-(4-(piperazin-1-yl)phenylcarbonylamino)
phenoxy)propanoate(7-3)
A solution of 7-2 (266 mg, 0.53 mmol) and anisole (200
~LL, 1.8 mmol) in 5 mL 1:1 CH2C12~rFA was stirred for 20 min. After
concentration and azeotroping with toluene, flash chromatography
(silica, 33:1:1 EtOH/H20/NH40H) provided ~ as a white solid.
- 25 TLC Rf= 0.37 (silica, 20:1:1 EtOH/H20/NH40H
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lH NMR (400 MHz, CD30D): ~ 7.84 (d, J=9Hz, 2H), 7.54 (d, J=9Hz,
2H), 7.01 (d, 3=9Hz, 2H), 6.88 (d, J=9Hz, 2H), 4.21 (q, J=7Hz, 2H),
3.31 (m, 4H), 2.98 (m, 4H), 1.57 (d, J=7Hz, 3H), 1.26 (t, J=Hz, 3H).
HN N~NH~ lH3
7-4
2-(4-(4-(Piperazin- 1 -yl)phenylcarbonylamino)phenoxy)
propionic acid (7-4)
Ester 7-3 (44 mg, 0.11 rnmol) was dissolved in 1 mL
EtOH, then 1 M NaOH (122 ~L, 0.12 rnmol) was added. After 3 h the
reaction was neutralized with l N HCl, concentrated, then purified by
flash chromatography (silica, 50:1:1 EtOH/H20/NH40H) providing 7-4
as a white solid.
TLC Rf = 0.15 (silica, 50:1:1 EtOH/H2O/NH4OH)
lH NMR (400 MHz, D2O): ~ 7.69 (d, J=9Hz, 2H), 7.22 (d, J=9H, 2H),
7.01 (d, J=9Hz, 2H), 6.80 (d, J=9Hz, 2H), 4.48 (q, J=7Hz, lH), 3.10 (m,
4H), 2.82 (m, 4H), 1.40 (d, J=7Hz, 3H).
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SCHEME 8
Cl~ CO2Et
1) Piperazine, NMP, 50~C
2) Boc20 ~ ,~
BocN N~/ ~CO2Et
~-2
NaOH, EtOH
BocN N~3co2H
8-3
o 1) BOP Reagent, DMF
BocN N~N~ 2) 4-aminophenol, 60~C
8-4 H
t-Butyl bromoacetate
\~s2CO3, DMF
BocN N ~N ~3 r CO2-t-Bu
/TFA, CH2 C12
HN N~O Or CO2H
8-6 H
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- 63 -
BocN N~ CO2Et
8-2
Ethyl 6-r4-(1~1-dimethylethoxycarbonyl)piperazin-l-yllnicotinate (~-2)
Ethyl 6-chloronicotinate (~, Maybridge Chemical Co.,
5 2.0 g, 10.8 rnmol) and piperazine (1.4 g, 15 mmol) were combined in
54 mL NMP and heated at 50~C overnight. After cooling, Boc2O (2.6
g, 11.9 mmol) was added. The reaction mixture was stirred overnight
then diluted with EtOAc, washed with water, sat NaHCO3 and brine,
dried (MgSO4), filtered and concentrated. Flash chromatography
10 (silica, 25% EtOAclhexane) provided 8-2 as a white solid.
TLC Rf = 0.63 (silica, 40% EtOAc/hexane)
lH NMR (400 MHz, CDCl3): ~ 8.80 (d, J=2Hz, lH), 8.04 (dd, J=9,
2Hz, lH), 6.58 (d, J=9Hz, lH), 4.34 (q, J=7Hz, 2H), 3.68 (m, 4H), 3.54
(m, 4H), 1.49 (s, 9H), 1.37 (t, J=7Hz, 3H).
BocN N~CO2H
8-3
6-f4-(1~1-Dimethylethoxycarbonyl)piperazin-l-yllnicotinic acid (8-3)
Ester 8-2 (3.0 g, 9.3 mmol) was dissolved in 93 mL EtOH,
20 1 M NaOH (23 rnL, 23 mmol) was added, and the reaction mixture was
stirred overnight. After concentrating, the residue was dissolved in
water, washed with EtOAc, and the aqueous layer was acidified with
10% KHSO4. After extracting with EtOAc, the organic layer was
washed with brine, dried (MgSO4), filtered and concentrated providing
25 ~-3 as a white solid.
lH NMR (400 MHz, CD30D): ~ 8.71 (d, J=2Hz, lH), 8.08 (dd, J=9,
2Hz, lH), 6.77 (d, J=9Hz, lH), 3.61 (m, 4H), 3.53 (m, 4H), 1.49 (s,
9H).
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A ~H ~ OH
N-(4-Hydroxyphenyl)-6-(4-(1, l -dimethylethoxycarbonyl)piperazin- 1-
yl)nicotinamide (8-4)
Acid 8-3 (500 mg, 1.6 mmol), NMM (720 ,uL, 6.5 mmol)
and BOP reagent (793 mg, 1.8 mmol) were combined in 8 mL DMF.
After 1.5 h, 4-aminophenol (260 mg, 1.8 mmol) was added and the
reaction was heated to 60~C overnight. The reaction mixture was
diluted with EtOAc, washed with water (5x), sat. NaHCO3 and brine,
dried (MgSO4), f1ltered and concentrated. Flash chromatography
(silica, 50-60% EtOAc/hexane) provided 8-4 as a brown solid.
TLC Rf = 0.40 (silica, 70% EtOAc/hexane)
1H NMR (400 MHz, CDC13): ~ 8.66 (d, J=2Hz, lH), 7.98-7.95 (m,
2H), 7.33 (d, J=9Hz, 2H), 6.75 (d, J=9Hz, 2H), 6.58 (d, J=9Hz, lH),
3.61 (m, 4H), 3.52 (m, 4H), 1.48 (m, 9H).
A ~OCH2CO2tBu
tert-Butyl 2-((4-(2-(4-(1,1-dimethylethoxycarbonyl)piperazin-l-
yl)pyridin-S-yl)carbonylamino)phenoxy)acetate (8-5)
Phenol 8-4 (374 mg, 0.94 mmol), t-butyl bromoacetate
(lS1 ~L, 0.94 mmol) and Cs2CO3 (761 mg, 2.3 rnmol) were combined
in 5 mL DMF. After 90 min. the reaction mixture was diluted with
EtOAc, washed with water (4x) and brine, dried (MgSO4), filtered and
concentrated. Flash chromatography (silica, 50% EtOAc/hexane)
provided 8-5 as a brown solid.
TLC Rf = 0.53 (silica, 70% EtOAc/hexane)
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lH NMR (400 MHz, CDC13): ~ 8.66 (d, J=2Hz, lH), 7.99 (dd, J=9,
2Hz, lH), 7.56 (s, lH), 7.52 (d, J=8Hz, 2H), 6.90 (d, J=8Hz, 2H), 6.65
(d, J=9Hz, lH), 4.51~(s, 2H), 3.68 (m, 4H), 3.56 (m, 4H), 1.49 (s, 18H).
HN N~H~OCH2CO2H
2-(4-(((2-Piperazin- 1-yl)pyridin-S-yl)carbonylamino)phenoxy)acetic
acid (8-6)
Ester 8-5 (290 mg, 0.57 mrnol) was dissolved in S mL 1: 1
10 TFA/CH2C12. After 1 h the reaction was concentrated and azeotroped
with toluene. Flash chromatography (silica, 10: 1: 1 EtOH/H2O/NH4OH)
and trituration with Et2O provided 8 6 as a light brown solid.
lH NMR (400 MHz, D2O): ~ 8.42 (d, J=2Hz, lH), 7.89 (dd, J=9, 2Hz,
lH), 7.04 (d, J=8 Hz, 2H), 6.78 (d, J=9Hz, 2H), 6.76 (d, J=10 Hz, lH),
15 4.32 (s, 2H), 3.37 (m, 4H), 2.74 (m, 4H).
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SCHEME 9
Br~NHNH2
o
H3C J~, Et
r O
Br~3H =~3 9-1
o o
PPA
Br~ CO2Et
H 9-2
NaH / DMF
CICH2CN
Br~ CO2Et
~CN
LAH / Et20
9-4
Br~N H
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SCHEME 9 (CONT'D)
~ Br 9 4
HN
BOC20 / TEA
BOCN ~ Br
Pd(OAc)2 / dppp/ DMF
CO(g) CH30H
~CO2CH3
BOCN
LiOH
THF/H20/MeOH
f~,~C02H 9 7
BOCN
H2N~O~,CO2Et PYCLU/i-Pr2NEt
HCI ~ CH~ 10-4
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SCHEME 9 (CONT'D)
BOCN ~H ~O~CO2Et 9-8
CH~
LiOH
THF/H20/MeOH
HCI/EtOAC
HN ~N~O~C02H 9 9
CH~
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SCHEME 9 (CONT'D)
~N ~ CO2CH3 9-6
BOCN ~'
NaBH3CN / EtOAc
(+/~)BOCN ~CO2CH~ 9-10
LiOH / MeOH / H20/THF
(+/-)BoCN~3co2H 9-11
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SCHEME 9 (CONT'D)
H2N~O~,CO2Et PYCLU/i-Pr2NEt
HCI . CH3 10-4
BOCN~ ~H~O~CO2Et 9-12
CH3
LiOH
THF/H20/MeOH
HCI/EtOAC
HN ~ O~CO2H .9-13
CH3
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- 7 1 -
Br ~ H ~ 3 9-1
o
o
Ethyl 2-(4-bromo-l-hydr~7.inimine)propanoate 9-1
A mixture of 4-bromophenylhydrazine (Aldrich, 0.5 g, 2.2
5 mmol) and ethyl acetoacetate (Aldrich, 0.24 mL, 2.2 mrnol) in pyridine
(0.6 mL) was heated to reflux overnight. The reaction was cooled,
diluted with water and the precipitate that resulted was collected and
washed with water, dried under vacuum to give 9-E
Rf(10% MeOH/CHC13 saturated with NH3)=0.86
lH NMR (400 MHz, CDC13) ~,7.64 (s, lH), 7.41 (d, 2H), 7.39 (d, 2H),
4.30-4.34 (q, 2H), 2.10 (s, 3H), 1.36 (t, 3H).
Br~ CO2Et
H 9-2
15 5-Bromo-2-ethoxycarbonyl indole 9-2
A mixture of 9-1 (0.54 g, 1.9 mmol) and polyphosphoric
acid (1.6 mL) was heated to 115~C for 10 minutes, then diluted with
cold water and extracted with EtOAc. The layers were separated and
the aqueous layer extracted with EtOAc. The organic layers were
20 combined, washed with brine, dried with MgSO4, filtered and
concentrated to give 9-2 as a brown solid.
Rf(30% EtOAc/hexanes)=0.45
lH NMR (400 MHz, CDC13) ~ 8.95(bs, lH), 7.82 (s, lH), 7.41 (d, lH),
7.30 (d, lH), 7.15 (s, lH), 4.44 (q, 2H), 1.40 (t, 3H).
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Br~CO2Et
~CN
l-(Cyanomethyl)-2-ethoxycarbonyl-5-bromo-indole 9-3
A solution of 9-2 (11.2 g, 44.4 mmol) in DMF (400 mL)
5 was treated with NaH (3.2 g of 60% dispersion in oil, 66.6 mmol) for
0.5 hour and then chloroacetonitrile (Aldrich, 5.6 mL, 88.8 mmol) was
added and the reaction was stirred overnight. The solvent was removed
in vacuo and the residue was partitioned between water and EtOAc.
The water layer was extracted with EtOAc, the organic layers were
10 combined, washed with water, brine, dried with MgSO4, filtered and
evaporated to give 9-3 as a brown solid.
Rf(30% EtOAc/hexanes)=0.46
lH NMR (400 MHz, CDC13) o 7.82-7.83 (bs, lH), 7.51-7.54 (dd, lH),
7.30-7.32 (bd, 2H), 5.60 (s, 2H), 4.41-4.43 (q, 2H), 1.41-1.43 (t, 3H).
Br~ 9 4
~-Bromo-2~3~4~5-tetrahydropyrazino-~1~2-alindole 9-4
A slurry of 9-3 (12.2 g, 39.7 mrnol) in diethyl ether (400
20 mL) was added via dropping funnel to a solution of LAH in ether (79.4
mL, 1 M in ether, 79.4 mmol) and stirred at room temperature
overnight. The slurry was diluted with saturated sodium potassium
tartrate (Rochelle's salt) and stirred for 15 minutes, then transferred to
a separatory funnel containing EtOAc and the layers separated. The
25 a~ueous layer was extracted with EtOAc, the organic layers were
- combined, washed with water, brine, dried with MgSO4, filtered and
evaporated to give 9-4 as a brown solid.
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Rf(10% MeOH/CHC13 saturated with NH3)=0.42
lH NMR (400 MHz, CDC13) ~ 8.38-8.41 (bs, lH), 7.66 (s, lH), 7.21-
7.22 (dd, 2H), 7.14 (~, 2H), 6.14 (s, lH), 4.22 (s, 2H), 3.99 (t, 2H),
3.36-3.37 (t, 2H).
s
I~N~ ~Br g
BOCN ~
8-Bromo-3-( 1,1 -dimethylethoxycarbonyl)-2,3 ,4,5-tetrahydro-
pyrazino-~ 1 .2-alindole 9-5
A solution of 9-4 (10 g, 40 mmol) in CH2C12 (200 mL)
was cooled to 0~C and treated with di-tertbutyldicarbonate (8.7 g, 40
mrnol) and triethylamine (5.6 mL, 40 mmol). The solution was allowed
to warm slowly and after 48 hours was concentrated and the residue
dissolved in EtOAc, washed with water and brine, dried over Na2SO4,
filtered and evaporated. The residue was chromatographed (30%
EtOAc~exanes) to give 9-5 as a solid.
Rf(30% EtOAc/hexanes)=0.22
lH NMR (400 MHz, CDC13) o 7.67 (d, lH), 7.23 (d, lH), 7.13 (d, lH),
6.21 (s, lH), 4.80 (s, 2H), 4.04 (t, 2H), 3.93 (t, 2H), 1.50 (s, 9H).
~\N ~ co2CH3 9-6
BOCN ~
8-Methoxycarbonyl-3-( 1,1 -dimethylethoxycarbonyl)-2,3 ,4,5-
tetrahydropyrazino-l 1.2-alindole 9-6
A solution of 9-5 (3.0 g, 8.5 mmol) in MeOH (60 mL) and
DMSO (20 mL) was treated with triethylamine (3.55 mL, 25.5 mrnol),
1,3-Bis(diphenylphosphino)propane (1.75 g, 4.25 mmol) and palladium
(~I) acetate (0.952 g, 4.25 mmol). Carbon monoxide was bubbled
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through the solution while it was heated to reflux for 2 hours. The
reaction was heated at reflux overnight under a balloon atmosphere of
carbon monoxide. ~dditional 1,3-Bis(diphenylphosphino)propane (0.8
g, 2.12 mmol) and palladiurn acetate (0.476 g, 2.12 mmol) were added
S and the reaction was heated at reflux for 48 hours under a balloon
atmosphere of carbon monoxide. The reaction was cooled to room
temperature, the residue was partitioned between water and EtOAc.
The water layer was extracted with EtOAc, the organic layers were
combined, washed with water, brine, dried with MgSO4, filtered and
evaporated. The residue was chromatographed (25% EtOAc/hexanes)
to give 9-6 as a yellow solid.
Rf(30% EtOAc/hexanes)=0.21
1H NMR (400 MHz, CDC13) ~ 8.32 (s, lH), 7.90 (d, lH), 7.26 (d, lH),
6.38 (s, lH), 4.83 (s, 2H), 4.12 (t, 2H), 3.96-3.93 (m, SH), 1.50 (s, 9H).
~N 4~ CO2H 9 7
BOCN~
3-(1 ,1 -dimethylethoxycarbonyl)-2,3 ,4,5-tetrahydropyrazino-[ 1,2-
alindole-8-carboxylic acid 9-7
A slurry of 9-6 (150 mg, 0.454 mmol) in THF/H20/MeOH
was treated with LiOH (38.2 mg, 0.91 mmol) and stirred for 1 hour.
TLC indicated no reaction. LiOH (38.2 mg.) was added and the
reaction mixture (still a slurry) was stirred for an additional hour with
no reaction. The reaction mixture was concentrated to dryness and
dissolved in MeOH and H2O. LiOH (114 mg) was added and the
reaction mixture was stirred and heated to 75~ for 3 hours and stirred at
RT for 16 hours resulting in a complete reaction. The reaction mixture
is diluted with EtOAc and 10% citric acid. The layers are separated and
the organic layer is washed with water and brine, dried, filtered and
concentrated to give 9-7 as a white solid.
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lH NMR (400 MHz; CDC13) ~ 8.40 (s, lH), 7.95(d, lH), 7.32 (d, lH),
6.41 (s, lH), 4.84 (s, 2H), 4.14-4.11 (m, 2H), 3.96 (m, 2H), 1.50 (s,
9H).
BOCN~, ~~ O~CO2Et 9-8
.~ CH3
Ethyl 4-((3-(1,1-dimethylethoxycarbonyl)-2,3,4,5-tetrahydropyrazino-
rl.2-alindole-8-yl)carbonylamino)-3-methylphenoxyacetate 9-~
- A solution of 9-7 (110 mg, 0.35 rnmol) and 10-4 (85.7 mg,
10 0.35 mrnol) in CH2C12 were treated with diisopropylethylamine and
PYCLU as described for 23-5 to give 9-8 as a white solid after
chromatography in 50% EtOAC/Hexane.
Rf (50% EtOAc/Hexane) 0.34
lH NMR (400 MHz, CDC13) ~ 8.12 (s, lH), 7.8-7.65 (m, 2H), 7.59 (s,
lH)~ 7.36 (d, lH), 6.84 (m, 2H), 6.39 (s, lH), 4.85 (s, 2H), 4.62 (s, 2H),
4.29-4.27 (q, 2H), 4.15-4.13 (t, 2H), 3.96 (t, 2H), 2.33 (s, 3H), 1.50 (s,
9H), 1.33-1.31 (t, 3H).
/--~H~O~CO2H 9-9
CH3
4-((2,3,4,5-tetrahydropyrazino-[1,2-a]indole-8-yl)carbonylamino)-3-
methylphenoxyacetic acid 9-9
A slurry of 9-~s (0.15 mmol, 75 mg) and THF/H20/MeOH
- was treated with LiOH (13 mg, 0.30 mmol) and stirred for 1 hour. The
25 reaction mixture was diluted with EtOAC and 10% citric acid. The
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layers were separated and the organic layer was washed with H2O and
brine. The organic layer was dried, filtered and concentrated to give
desired acid as a white solid. This solid is slurried in EtOAc, cooled to
-78~ and saturated with HCI. The reaction mixture is warmed to 0~ and
S stirred for 15 min. The reaction mixture was concentrated to yield a
white solid which was taken up in a EtOAc~exane/ether mixture and
filtered. The solids were washed with ether to give 9-9 as a white solid.
Rf 10/1/1 EtoHlNH4oHlH2o) 0.16
lH NMR (400 MHz; D20) ~ 8.09 (s, lH), 7.62-7.60 (d, lH), 7.45 (d,
lH), 7.14-7.12 (d, lH), 6.84 (d, lH), 6.79-6.76 (dd, lH), 6.35 (s, lH),
4.40 (s, 2H), 4.07-4.02 (m, 4H), 3.23-3.22 (t, 2H), 2.15 (s, 3H).
~N~CO2CH3
BOCN ,~='
15 (+ /-) 8-Methoxycarbonyl-3-(1, l -dimethylethoxycarbonyl)- 1,1 a,2,
3.4.5-hexahydropyrazino-r 1.2-alindole 9- 10
9-6 (0.091 mmol, 30 mg) was dissolved in EtOAc and
cooled to 0~C. NaBH3CN (0.45 mmol, 28 mg) was added portion-wise
and the reaction was warmed to room temperature for 15 min. The
20 reaction mixture was basified with saturated NaHCO3 and extracted into
EtOAc. The organic layer was washed with brine, dried (MgSO4),
filtered and concentrated to yield 9-10 as a colorless oil.
Rf (2: 1 hexane/ EtOAc)=0.4
1H NMR (400 MHz; CDC13) ~ 7.83-7.82 (d, lH), 7.73 (s, lH), 6.40-
25 6.38 (d, lH), 4.15-4.0 (bs, 2H), 3.85 (s, 3H), 3.60-3.56 (m, 2H), .305-
2.65 (m, 4H), 2.60-2.58 (dd, lH), 1.50 (s, 9H).
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~\N~co2H 9-1 1
BOCN ~= '
(+ /-) 3-(1,1 -Dimethylethoxycarbonyl)- l,1 a,2,3,4,5-hexahydro-
pyrazino-rl~2-alindole-P~-carboxylic acid 9-11
S 9-10 (0.90 mmol, 300 mg) was slurried in THF/H20/MeOH
(2mL/2/2). LiOH (1.8 mmol, 76 mg) was added and the reaction
mixture was heated to 50~C. After 0.5 hours, the reaction mixture
became homogeneous, and was then stirred at room temperature for an
additional 2 hours. The reaction mixture was diluted with 10% citric
acid and EtOAc. The layers were separated, and the organic layer was
washed with H2O and brine. Drying (MgSO4), filtering and
concentrating gave 9-11 as a yellow solid.
Rf (97/3/1 CHCl3/~IeOH/HOAC)=0.70
lH NMR (400 MHz; CDCl3) ~ 7.90 (d, lH), 7.87 (s, lH), 6.41-6.39 (d,
lH), 4.25-4.0 (bs, 2H), 3.65-3.57 (m, 2H), 3.10-3.0 (dd, lH), 3.02-2.98
d, lH), 2.98-2.91 (bs, lH), 2.69-2.66 (bs, lH), 2.62-2.60 (dd, lH), 1.50
(s, 9H).
BOCN ~ ~~ O~CO2Et 9-12
CH3
(+ /-) Ethyl 4-((3-( l, l -Dimethylethoxycarbonyl)- l, l a,2,3,4,5-
hexahydro-pyrazino-[1,2-a]indole-8-yl)carbonylamino)-3 -
methylphenoxyacetate 9- 12
- A solution of 9-l l (250 mg, 0.79 rnmol) and 10-4 (193 mg,
25 0.79 mmol) in CH2C12 were treated with diisopropylethylamine and
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PYCLU as described for 23-5 to give 9-12 as a white solid after
chromatography in 50% EtOAC/Hexane.
Rf (50% EtOAc/Hexane) 0.35
lH NMR (400 MHz, CDC13) ~ 7.70-7.63 (m, 3H), 7.36 (s, lH), 6.82-
6.76 (m, 2H), 6.45-6.43 (d, lH), 4.60 (s, 2H), 4.30-4.25 (q, 2H), 4.21-
4.09 (bs, 2H), 3.59-3.57 (m, 2H), 3.10-3.09 (m, lH), 3.05-2.51 (m, 3H),
2.78-2.60 (m, lH), 2.29 (s, 3H), 1.50 (s, 9H), 1.32-1.29 (t,3H).
HN ~,~~ O~CO2H 9-13
CH3
(+ /-) 4-((3-(1,1 -Dimethylethoxycarbonyl)- 1,1 a,2,3,4,5-hexahydro-
pyrazino-~1,2-a]indole-8-yl)carbonylamino)-3-methylphenoxyacetic acid
9-13
A slurry of 9-12 (0.25 mmol, 125 mg) and
THF!H20/MeOH was treated with LiOH (21 mg, 0.50 mrnol) and heated
to 80~ for 1 hour. The reaction mixture was diluted with EtOAC and
10% citric acid. The layers were separated and the orgallic layer was
washed with H2O and brine. The organic layer was dried, filtered and
concentrated to give desired acid as a white solid. This solid is slurried
in EtOAc, cooled to -78~ and saturated with HCI. The reaction mixture
is warmed to 0~ and stirred for 15 min. The reaction mixture was
concentrated and the white solid triturated with ether to give 9-13 as a
white solid.
Rf 10/1/1 EtOH/NH40H/H20) 0.3
lH NMR (400 MHz, D2O) ~ 7.70-7.67 (d, lH), 7.63 (s, lH), 7.11-7.09
(d, lH), 6.86 (d, lH), 6.78-6.76 (dd, lH), 6.69-6.68 (d, lH), 4.57 (s,
2H), 3.93-3.90 (bd, 2H), 3.39-3.31 (m, 3H), 3.19-3.07 (m, 3H), 2.74-
2.68 (dd, lH).
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SCHEME 10
OH OH
~ Boc20, CHCI3 ~b Br~'COOEt
H3C~/ reflux H3C~ Cs2CO3, DMF
NH2 NHBoc
10-1 10-2
o'~f OEt o~OEt
~ ~ HCI (gas) ~ ~
H3C~ EtOAc,0~CH CJ~ ~HCI
NHBoc NH2
t0-3 10-4
COOH Cl PF6-
N~l N~)
N~ + 10-4
N, J i-pr2NEt~ CH2CI2
Boc
1-5
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SCHEME lO CONrrINUED
,0 oNaOH, H20
Boc--N~N~H~O OEt MeOH, RT
~ H~C
Boc--N N~N~O OH
H3C
10-6
HCI (gas) , HN N~
EtOAc, 0~C ~ / N ~O OH
H3C
10-7
5 4-(1, l -Dimethylethoxycarbonyl)amino-3-methylphenol (10-2)
To a 1 L round bottomed flask with a stirring bar, reflux
condenser and an argon inlet was added 4-amino-3-methylphenol (15.00
g, 121.79 mmol), di-tert-butylpyrocarbonate (27.25 g, 124.84 mmol)
and CHC13 (300 mL). This heterogeneous mixture was heated at reflux
10 for 24 h during which time all of the solids dissolved. The mixture was
cooled to room temperature and the solid product was collected by
filtration. The material was triturated with a mixture of Et2O-hexanes
(1:1), collected on a frit and dried in vacuo to give 21.25 g (92%) of 4-
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(1,1 -dimethylethoxycarbonyl)arnino-3-methylphenol (10-2), mp: 143-
144~C.
1H NMR (CDC13): ~ 1.51 (s, 9H), 2.14 (s, 3H), 6.08 (br s, lH), 6.4
(m, 2H), 6.60 (br s, lH), 7.20 (d, j=~.5Hz, lH).
s
Ethyl 4-(1,1 -Dimethylethoxycarbonyl)amino-3-methylphenoxyacetate
(10-3)
To a 200 mL round bottomed flask with a stirring bar, and
an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-
10 methylphenol (5.00 g, 22.39 mmol), Cs2CO3 (14.59 g, 44.78 mmol),DMF (50 mL), and ethyl bromoacetate (2.61 mL, 23.51 mmol). This
mixture was stirred vigorously at ambient temperature for 24 h. The
mixture was filtered through a frit and the DMF was removed under
high vacuum. The residue was dissolved in EtOAc (300 rnL) and
15 washed with H2O (2x) and brine (lx). Drying (MgSO4), filtration, and
removal of the solvent in vacuo gave a solid. This material was
triturated with 5% Et2O-hexane, the solid was collected by filtration
and dried in vacuo to give 5.40 g (78%) of ethyl 4-(1,1-dimethyl-
ethoxycarbonyl)amino-3-methylphenoxyacetate as a white, crystalline
20 solid.
lH NMR (CDC13): ~ 1.29 (t, j=7.2Hz, 3H), 1.51 (s, 9H), 2.22 (s, 3H),
4.26 (q, j=7.2Hz, 2H), 4.57 (s, 2H), 6.08 (br s, lH), 6.72 (m, 2H), 7.56
(s, lH).
25 Ethvl 4-amino-3-methylphenoxyacetate. hydrochloride (10-4)
To a 500 mL round bottomed flask with a gas dispersion
tube was added a solution of ethyl 4-(1,1-dimethylethoxycarbonyl)-
amino-3-methylphenoxyacetate (5.31 g, 17.13 mmol) in EtOAc (200
mL). This solution was cooled in an ice bath and dry HCI gas was
30 sparged through the solution, vigorously, for 10 min. The resulting
mixture was aged for 15 min. at 0~C. The excess HCl gas was removed
with a stream of argon and the solvent was removed in vacuo. The
- product was triturated with 50 mL of EtOAc and collected on a frit.
The crystals were washed with additional EtOAc and dried in vacuo to
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- ~2-
give 4.21 g (100%) of ethyl 4-amino-3-methylphenoxyacetate,
hydrochloride as white crystals, mp: 198-200~C.
1H NMR (DMSO-d6): ~ 1.21 (t, j=7.1Hz, 3H), 2.33 (s, 3H), 4.17 (q,
j=7.1Hz, 2H), 4.78 (s, 2H), 6.82 (dd, j=3,9Hz, lH), 6.92 (d, j=3Hz, lH),
5 7.39(d,j=9Hz, lH), 10.21 (brs,3H).
Ethyl 2-(4-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -yl)phenyl-
carbonylamino)-3-methy~phenoxy)acetate (10-5)
To a 100 mL round bottomed flask with a stirring bar and
10 an argon inlet was added 4-(4-(1,1-dimethylethoxycarbonyl)
piperazinyl)benzoic acid (0.75 g, 2.45 mmol), ethyl 4-amino-3-
methylphenoxyacetate hydrochloride (0.60 g, 2.45 rnmol), chloro-
N,N,N',N',-bis(pentamethylene)foImamidinium hexafluorophosphate
(0.97 g, 2.69 mmol), and CH2C12 (30 mL). This mixture was cooled in
15 an ice bath and diisopropylethylamine (1.74 mL, 10.0 mmol) was added.
The ice bath was allowed to expire and the solution was stirred at
ambient temperature for 48 h. The solution was diluted with CHC13 and
washed with 10% aqueous citric acid, saturated aqueous NaHCO3, and
brine. Drying (MgSO4), filtration and removal of the solvent in vacuo
20 gave an oil. This material was chromatographed on 75 g of silica gel
using 50% EtOAc-hexane as e}uant. There was obtained 1.22 g (100%)
of ethyl 2-(4-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -
yl)phenylcarbonylamino)-3-methylphenoxy)acetate as a crystalline solid.
1H NMR (CDC13): ~ 1.30 (t, j=7.1Hz, 3H), 1.49 (s, 9H), 2.27 (s, 3H),
25 3.27 (m, 4H), 3.59 (m, 4H), 4.26 (q, j=7.1Hz, 2H), 4.59 (s, 2H), 6.75
(m, 2H), 6.90 (d, j=8.8Hz, 2H), 7.54 (br s, lH), 7.65 (m, lH), 7.79 (d,
j=8.8Hz, 2H).
2-(4-(4-(4-(1, I -Dimethylethoxycarbonyl)piperazin- 1 -yl)phenyl-
30 carbonylamino)-3-methylphenoxy)acetic acid (10-6)
To a 100 mL round bottomed flask with a stirring bar and
an argon inlet was added ethyl 2-(4-(4-(4-(1,1-dimethylethoxy-
carbonyl)piperazin- 1 -yl)phenylcarbonylamino)-3-methylphenoxy)-
acetate (1.22 g, 2.45 mmol) and 20 mL of CH30H. To this solution was
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- 83 -
added aqueous NaOH (10 mL of a lN solution). The mixture was
stirred at ambient temperature for 18 h. The mixture was neutralized
with 10 mL of lN HCl and diluted with H2O. The product was
collected on a frit and washed with a little H2O. This materia~ was
dried in vacuo to give 0.953 g (83%) of 2-(4-(4-(4-(1,1-dimethyl-
ethoxycarbonyl)piperazin- 1 -yl)phenylcarbonylamino)-3-methyl-
phenoxy)acetic acid as a white solid.
1H NMR (CDC13): ~ 1.49 (s, 9H), 2.26 (s, 3H), 3.27 (m, 4H), 3.58 (m,
4H), 4.57 (s, 2H), 6.74 (m, 2H), 6.90 (d, j=8.5 Hz, 2H), 7.60 (m, lH),
7.65 (m, lH), 7.79 (d, j=8.5 Hz, 2H).
2-(4-(4-(1 -Piperazinyl)phenylcarbonylamino)-3-methylphenoxy)acetic
acid~ dihydrochloride (10-7)
To a 200 mL round bottomed flask equipped with a stirring
bar and a gas dispersion tube was added 2-(4-(4-(4-(1,1-dimethyl-
ethoxycarbonyl)piperazin- 1 -yl)phenylcarbonylamino)-3-methyl-
phenoxy)acetic acid (0.95 g, 2.03 mmol) and 100 mL of dry EtOAc.
This well stirred suspension was cooled in an ice bath and HCI gas was
sparged through the solution for 15 min. This mixture was aged 30
min. at 0~C then the excess HCl was removed with a stream of argon
and the EtOAc was removed in vacuo. The product was triturated with
EtOAc, collected on a frit and dried in vacuo to give 895 mg of 2-(4-(4-
(l-piperazinyl)phenylcarbonylamino)-3-methylphenoxy)acetic acid,
dihydrochloride, mp: >250~C.
lH NMR (DMSO-d6): ~ 2.16 (s, 3H), 3.20 (m, 4H), 3.54 (m, 4H), 4.66
(s, 2H), 6.72 (d, j=3Hz, lH), 6.75 (s, lH), 7.06 (d, j=9.OHz, 2H), 7.15
(d, j=3.0Hz, lH), 7.90 (d, j=9.OHz, 2H), 9.43 (br s, lH), 9.56 (s, lH).
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SCHEME 1 1
~OH 11-1
Il I R.A. Glennon.; et. al.
Br~OH J. Med. Chem. 1992 35 734.
SOCI2 / MeOH
o
Br ~¢~ol'~OC H3 1 1-2
Kl
C l~,CO2Et A2C~3
o
~ O C ~3 11-3
Br O~,CO2Et
NaH / Toluene
Br J~Na+ 11-4
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SCHEME 1 1 (CONT'D)
NaOH / EtOH reflux
Br~ 1 1-5
(EtO)2P(O)CHCN- Na+
rCN
,,¢~ 1 1-6
Br O
THHF6
NH2- HCI
~ 11-7
Br O
NaOH HCOEt
Br J~HN 4 11 -8
. .
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SCHEME 11 (CONT'D)
~ ~,0
~ NH 11-8
Br O
~¢~N 1 1-9
Br O
1. NaBH4
2. BOC2O / TEA
Br~N~OtBu 1 1-10
Pd(OAc)2
1,3 bis diphenyl phosphino propane
TEA / DMSO / MeOH
~3~ 11-1 1
o~N O OCH3
OtBu
LiOH
~_~~ 11-1 2
o ~,N OH
OtBu
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SCHEME 1 1 (CONT'D)
1. oxalyl chloride / DMF cat.
2.
H2N~O~CO2Et
~ HCI ~
~,H3C 10-4
O:~Nf~H~O~CO2Et 1 1-13
OtBu H3C
1. LiOH
2. HCI
.
HN~HI~O~CO2H 1 1-14
H3C
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,¢~OCH3 1 1-2
Br OH
Methyl 4-bromo-2-hydroxy benzoate 11-2
200 mL of MeOH was cooled to 0~C and treated dropwise
5 with thionyl chloride (30 mL, 0.4 mole) so that the reaction temperature
was kept below 15~C throughout the addition. A solution of 11 1
(12.7g, prepared by the method of R. Glannon et al., J. Med. Chem.
1992 35, 734, 0.0585 mol) in 50 mL MeOH was added to the reaction
and the mixture was warmed to room temperature and stirred for 48
10 hours, then heated to 60~C for 7 hours. The volatile components were
removed under high vacuum and the residue chromatographed (silica,
gradient straight hexanes to 10% EtOAc/Hexanes) to give 11-2 as a
bright yellow oil ~at solidified on standing.
Rf (5% EtOAc/Hexanes) 0.6
lH NMR (400 MHz, CDC13) ~ 10.8 (s, lH), 7.68 (d, lH), 7.19 (s, lH),
7.03 (d, lH), 3.95 (s, 3H).
1~
~ OC H3 11 -3
Br~O~CO2Et
20 Methyl 4-Bromo-2-(ethyl acet-2-yloxy)-benzoate 1 1-3
A solution of 11-2 (26.6 g, 0.115 mole) in acetone (80 mL)
was treated with chloroethylacetate (14 g, 0.115 mole), potassium iodide
(3 g, 0.018 mole), and potassium carbonate (31.7 g, 0.23 mole) and
heated to 50~C with vigorous stirring for 2 hours. The suspension was
25 filtered, evaporated to dryness, resuspended in ether, re-filtered and
concentrated to give 11-3 as a golden-brown oil.
t .....
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- - 89 -
Rf (10% EtOAc/Hexanes) 0.11
1H NMR (400 MHz, CDC13) ~ 7.7 (d, lH), 7.2 (d, lH), 7.04 (s, lH), 4.7
(s, 2H), 4.3 (q, 2H), 3.9 (s, 3H), 1.3 (t, 3H).
~ 11-5
Br ~
6-Bromo-benzofuran-3-one 1 1-5
Sodium hydride (5.52 g, 60% dispersion in oil, 0.138 mole)
was placed in a 3L vessel equipped with an overhead stirrer, argon line,
10 reflux condenser and addition funnel. Toluene (215 mL) was added and
the solution heated to reflux. A solution of 11-3 (36.3 g, 0.115 mole) in
100 mL toluene was added dropwise over 1.5 hours to give an orange
suspension. The reaction was heated for an additional 3 hours, then
cooled to room temperature and filtered through a glass-fiber filter.
15 The cake was washed with 500 mL Et20 and dried under vacuum to
give 11-4 as a sandy orange solid (streaks from baseline in 30~o EtOAc/
Hexanes). A suspension of 11-4 (5 g, 0.016 mol) in EtOH (20 rnL) was
added to a solution of NaOH (4 g, 0.1 mole) in H2O (35 mL). The
reaction was heated to reflux for 1.25 hours, then cooled and the
20 volatile components removed under vacuum. The residue was
suspended in 200 mL 6N HCI and 200 mL, CHC13 and stirred vigorously
for 0.5 hours. The layers were separated and the aqueous layer was
washed with CHC13. The organic layers were combined, dried with
MgSO4, filtered and evaporated to give 1 I-5 as a deep red solid.
25 Rf (20% EtOAc/Hexanes) 0.61
lH NMR (400 MHz, CDC13) ~ 7.53 (d, lH), 7.35 (s, lH), 7.24 (d,
lH), 4.64 (s, 2H).
~ ....
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rCN
Br ~ 11 -6
(6-Bromo-benzofuran-3-yl)-acetonitrile 11-6
Sodium hydride (0.7 g, 0.0173 mol) was washed with
5 hexanes then suspended in THF (8 mL). Diethyl
cyanomethylphosphonate (3.07 g, 0.0173 mol) was added dropwise and
stirred 10 minutes to give clear yellow solution. A solution of 11-5
(3.38 g, 0.0158 mol) in THF (20 mL) was added dropwise, the solution
stirred for 0.5 hour, then heated to reflux for 0.5 hour. A solution of
10 6N HCL (3.4 mL) was added and the THF was removed under vacuum.
The concentrated solution was diluted with Et2O and washed with 4 X
30 rnL 6N HCl, the ether layer was dried (MgSO4), filtered and
evaporated. The residue was chromatographed (20% EtOAc/Hexanes)
to give 11-6 as an orange solid.
15 Rf (20% EtOAc/Hexanes) 0.45
1H NMR (400 MHz, CDC13) ~ 7.7 (s, lH), 7.65 (s, lH), 7.45 (s, 2H),
3.75 (s, 2H).
NH2- HCI
2-(6-Bromo~benzofuran-3-yl)-ethylamine 11-7
A solution of 11-6 (10.9 g, 0.0462 mol) in THF (100 mL)
was cooled to 0~C and treated dropwise with BH3/THF solution
(lMolar, 110.8 mL, 0.11 mol). The cold bath was removed and the
25 reaction stirred overnight. MeOH was carefully added (20 mL) and the
solvent removed under vacuum.. The residue was dissolved in 50 mL
. .
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MeOH and 400 mL MeOH saturated with HCI and heated to reflux for 3
hours. The volatile components were removed under vacuum and the
residue was suspend~d in Et20. A bright yellow solid percipitated and
was collected and washed five times with Et20, then dried under
S vacuum to give 11-7 as a tan solid.
Rf (5% MeOH/ CHCl3 saturated with NH3) 0.23
lH NMR (400 MHz, CD30D) ~ 7.72 (s, 2H), 7.6 (d, lH), 7.45 (d,
IH), 3.25 (m, 2H), 3.06 (m, 2H).
Br'¢~ OtBu
7-bromo-2-(1,1 -dimethylethoxycarbonyl)- l ,2,3,4-tetrahydro-9H-
pyrido~3.4-blbenzofuran 11-10
A solution of 11-7 (11.8 g, 0.043 mol) in MeOH (150 mL)
was diluted with CHCl3 (400 mL) and washed with 75 mL lN NaOH.
The aqueous layer was backwashed with CHCl3, the organic layers were
combined, evaporated, and the residue azeotroped with toluene to
remove residual water. The resulting brown oil was treated with 200
mL ethyl formate and brought to reflux for 1.5 hours until the solution
was homogenous. The solvent was removed, the residue was dissolved
in 200 mL CHCl3, washed with 30 mL lN HCl, brine, dried over
MgS04, filtered and evaporated to give 11 8 as a solid that was used
without further purification. Rf (5% MeOH/ CHCl3 saturated with
NH3) 0.47
1H NMR (400 MHz, CD30D) ~ 8.04 (s, lH), 7.67 (s, lH), 7.63 (s,
lH), 7.55 (d, lH), 7.4 (d, lH), 3.53 (m, 2H), 2.4 (m, 2H). Solid l 1-8
was crushed and placed in a flask equipped with an overhead stirrer.
Polyphosphoric acid (20 mL) and CHCl3 (5 mL) was added and the
reaction heated to 80~C for 1.5 hours. The reaction was removed from
the oil bath and 250 mL H20, 30 mL NH40H, and 200 mL CHC13 was
added and stirred vigorously. The resulting opaque mixture was
.. . . ..
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transferred to a separatory funnel, the layers separated, and the aqueous
layer was extracted repeatedly with CHC13. The organic layers were
combined, filtered thlough a pad of SolkaFloc, dried over Na2S04,
filtered and evaporated to give the intermediate cyclic imine (11-9) as a
pale yellow foam. A 5g sarnple of this material (0.02 mol) was
dissolved in 200 mL MeOH and 20 mL lN HCI. Sodium borohydride
(1.5g, 0.04 mol) was added in portions. After 0.5 hours the solvent was
removed and the residue was partitioned between saturated NaHCO3 and
CHC13. The aqueous layer was extracted with CHC13, the organic
layers were combined, dried (Na2SO3) and filtered to give a clear
yellow solution. (Rf amine (5% MeOH/ CHC13 saturated with NH3)
0.45). Di-tert-butyl dicarbonate (4.5 g, 0.02 mol) and TEA (2.8 mL,
0.02 mol) were added and the solution stirred overnight, then washed
with 10% KHSO4. The organic layer was evaporated and the residue
was chromatographed in 10% EtOAc/Hexanes to give 11-10 as a white
solid.
Rf (20% EtOAc/Hexanes) 0.60
1H NMR (400 MHz, CDC13) ~ 7.6 (s, lH), 7.35 (d, lH), 7.3 (d, lH),
4.56 (bs, 2H), 3.75 (bs, 2H), 2.7 (bs, 2H), 1.5 (s, 9H).
o~N~OC H3 1 1-1 1
OtBu
Methyl 2-(1,1-dimethylethoxycarbonyl)-1,2,3,4-tetrahydro-9H-
pyridor3~4-blbenzofuran-7-yl carboxylate 11-11
A solution of 11-10 (lg, 2.84 mmol), 1,3 di-phenyl
phosphino propane (0.35 g, 0.852 rnrnol) in DMSO/MeO~ 1, 15 mL)
was treated with TEA (1.5 mL, 10.7 mrnol) and thouroughly purged
with carbon monoxide, then treated with Pd(OAc)2 (0.19lg, 0.852
- rnmol) and warmed to 80~C. After heating overnight, the reaction was
cooled, treated with an additional amount of 1,3 di-phenyl phosphino
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_
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propane (0.35g, 0.852 mmol), re-purged with carbon monoxide and
treated with an additional amount of Pd(oAc)2 (0.191 g, 0.852 mmol).
After heating for thr~e days the reaction was evaporated, partitioned
between water and CHC13, and the water layer washed with CHC13.
S The organic layers were combined, dried over MgSO4, filtered through
a sintered glass filter and concentrated. The residue was
chromatographed (silica, gradient 5% EtOAc/Hexanes to 10%
EtOAc/Hexanes) to give 1 1-1 1 as a yellow oil.
Rf (20% EtOAc/Hexanes) 0.5
lH NMR (400 MHz, CDC13) ~ 8.13 (s, lH), 7.96 (d, lH), 7.48 (d, lH),
4.6 (bs, 2H), 3.95 (s, 3H), 3.75 (bs, 2H), 2.75 (bs, 2H), 1.5 (s, 9H).
Oq'N~O H 1 1 -1 2
OtBu
15 2-(1,1-dimethylethoxycarbonyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-
blbenzofuran-7-yl carboxylic acid 1 1-12
A solution of 11-11 (0.79 g, 2.38 rnmol) in 1:1 THF/MeOH
(30 mL) was treated with LiOH (0.95 g, 23.8 mmol) in 10 mL of H2O
and heated to 30~C overnight. The solvents were removed under
20 vacuum and the residue was dissolved in H20 and acidified with 10%
KHSO4 and extracted with EtOAc. The organic layer was dried over
MgSO4, filtered and evaporated to give l 1-12 as an off-white solid.
Rf (97:3 :1 CHC13/MeOH/HOAc) 0.27
1H NMR (400 MHz, CDC13) ~ 8.2 (s, lH), 8.0 (d, lH), 7.50 (d, lH),
25 4.65 (bs, 2H), 3.8 (bs, 2H), 2.75 (bs, 2H), 1.52 (s, 9H).
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o~,N~4HN~o~co2Et 11-1 3
OtBu H3C
Ethyl 4-(2-(1,1 -dimethylethoxycarbonyl)- 1,2,3,4-tetrahydro-9H-
pyrido [3,4-b]benzofuran-7-yl)carbonylamino)-3 -methylphenoxy-
5 acetate 11-13
A solution of 11-12 (0.1 g, 0.321 mmol) in CH2C12 (10
mL) was treated with oxalyl chloride (0.06 mL, 0.7 mmol) and two
drops of DMF. After stirring at room temperature for 0.5 hours, the
reaction was diluted with benzene and evaporated. The resulting acid
10 chloride was dissolved in CHC13 (5 mL) and treated with 10-4 (0.075 g,
0.26 mmol), then cooled to 0~C and treated with diisopropylethylamine
(0.167 mL, 0.3 mmol). The reaction was warrned to room temperature
and stirred overnight, then evaporated, partitioned between EtOAc and
10% KHSO4, and the EtOAc layer was washed again with 10% KHSO4.
15 The EtOAc layer was washed with brine, dried over MgSO4, filtered
and evaporated to give 11 -13.
Rf (60% EtOAc/Hexanes) 0.64
1H NMR (400 MHz, CDC13) ~ 8.0 (s, lH), 7.73 (m, 2H), 7.62 (s, lH),
7.53 (d, lH), 6.85 (s, lH), 6.8 (m, lH), 4.62 (d, 2H), 4.61 (s, 2H), 4.29
20 (q, 2H), 3.68 (bs, 2H), 2.75 (bs, 2H), 2.30 (s, 3H), 1.5 (s, 9H), 1.3 (t,
3H).
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H N~N ~O~C O2 H 1 1 -1 4
H3C
4-(2-(1,1 -dimethylethoxycarbonyl)- 1,2,3 ,4-tetrahydro-9H-pyrido[3 ,4-~ blbenzofuran-7-yl)carbonylamino)-3-methylphenoxy acetic acid 11-14
A solution of 11-13 (0.145 g, 0.285 mmol) in 1:1
THF/MeOH (6 mL) was treated with LiOH (0.114 g, 28.5 mmol)
dissolved in 6 mL of H2O. After stirring for 1 hour at room
temperature the solvents were removed, the residue dissolved in
10 H2O/EtOAc/10% KHSO4 and the layers separted. The water layer was
washed with EtOAc, the organic layers were combined, dried, and
filtered to give the intermediate acid as a yellow oil. This material was
dissolved in EtOAc (10 mL), cooled to -78~C, the solution saturated
with HCl gas and warmed to 0~C for 0.5 hours, then concentrated and
15 dried under vacuum to give 11-14 as fluffy solid.
Rf (9:1:1 EtoHlH2olNH4oH) 0.78
lH NMR (400 MHz, D2O) ~ 7.84 (s, lH), 7.65 (d, lH), 7.5 (d, lH),
7.1 (d, lH), 6.81 (s, lH), 6.72 (d, lH), 4.28 (s, 2H), 3.8 (bs, 2H),
2.96 (m, 2H), 2.6 (bs, 2H), 2.13 (s, 3H).
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SCHEME 12
H3C ~ 1 . HO3S ~ N2 Cl H3C
2.Na2S204 NH2
12-1 12-2
OH
Boc20, CHC13 H3C~ Br~'COOEt
reflux ~ Cs2CO3, DMF
NHBoc
12-3
O~COOEt
H3C ~ HCI (gas) r
EtOAc, 0~C
NHBoc
12-4
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SCHEME 12 CONTINUED
O~COOEt ~
H3C~ Boc--N N~COOH 1-5
.HCI
Cl PF6-
NH2
12-5 ~N N~ i-pr2NEtl CH2CI2
r ~2-6 ~r LiOH
Boc--N~N~ ~ r COOH
12-7
.HCI
EtOAc 0~C ~ CH3
12-8
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2-Methyl-3-aminophenol (12-2)
To a 500 mL erlenmeyer flask was added sulfanilic acid
(14.38 g, 83 mmol), sodium carbonate (4.29 g, 40.5 mrnol) and distilled
H20 (83 mL), when all of the sulfanilic acid dissolved, the solution was
5 cooled in an ice bath to 0~C and a solution of sodium nitrite (6.16 g,
89.3 mmol) in H20 (15 mL) was added in one portion. The ice bath
was allowed to warm to +15~C and the mixture was stirred at this
temperature 1 h. The reaction mixture was poured onto a mixture of
ice (100 g) and 12N HCl (17.4 mL). The ice was allowed to melt and
10 the solid diazonium salt was collected by suction filtration on a scintered
glass frit. O-cresol (9.10 g, 84.1 mmol) was dissolved in a solution of
NaOH (1.21 g, 30.25 mmol) in H20 (100 mL). This solution was
cooled to 0~C and the solid diazonium salt was added in one portion.
This well stirred mixture was maintained at +15~C for 4 h. The
15 temperature of the mixture was raised to +60~C and sodium dithionite
(35 g, 1.03 mol) was added portionwise. The reaction was allowed to
proceed at +60~C for 15 min. The mixture was cooled to room
temperature, diluted with saturated a~ueous NaHC03 and extracted with
EtOAc. The EtOAc extract was dried (MgS04), filtered, concentrated
20 in vacuo and chromatographed on 100 g of silica gel using 1:3 EtOAc-
hexane as eluant. There was obtained 2-methyl-3-amino-phenol as a tan
solid.
lH NMR (CDCl3) â 2.18 (s, 3H), 3.35 (br s, 2H), 4.24 (br s, lH), 6.42
(m, lH), 6.50 (m, lH), 6.61 (d, j=9Hz, lH).
4-(1~1-Dimethylethoxycarbonyl)amino-2-methylphenol (12-4)
Using a method similar to that described for compound
10-2, 4-(1,1-dimethylethoxycarbonyl)amino-2-methylphenol was
prepared.
30 lH NMR (CDC13): â 1.51 (s, 9H), 2.21 (s, 3H), 4.62 (br s, lH), 6.22
(br s, lH), 6.62 (m, lH), 6.98 (m, lH), 7.08 (br s, lH).
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_
_ 99 _
Ethyl 4-(1,1 -dimethylethoxycarbonyl)amino-2-methylphenoxyacetate
(12-4)
Using a method similar to that described for compound
10-3, ethyl 4-(1,1 -dimethylethoxycarbonyl)amino-2-methylphenoxy-
5 acetate was prepared.
lH NMR (CDC13): ~ 1.29 (t, j=7.2Hz, 3H), 1.52 (s, 9H), 2.28 (s, 3H),
4.25 (q, j=7.2Hz, 2H), 4.58 (s, 2H), 6.25 (br s, lH), 6.65 (d, j=8.5Hz,
lH), 7.08 (br d, j=8.5Hz, lH), 7.17 (br s, lH).
10 Ethyl 4-amino-2-methylphenoxyacetate~ hydrochloride (12-5)
Using a method similar to that described for compound
10-4, ethyl 4-amino-2-methylphenoxyacetate, hydrochloride was
prepared.
lH NMR (CD30D): ~ 1.21 (t, j=7.1Hz, 3H), 2.35 (s, 3H), 4.25 (q,
15 j=7.1Hz, 2H), 4.81 (s, 2H), 6.95 (d, j=,9Hz, lH), 7.21 (m, 2H).
Ethyl 2-(4-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -yl)phenyl-
carbonylamino)-2-methylphenoxy)acetate (12-6)
Using a method similar to that described for compound
20 l O-~, ethyl 2-(4-(4-(4-( l, l -dimethylethoxycarbonyl)piperazin- 1 -
yl)phenylcarbonylamino)-2-methylphenoxy)acetate was prepared.
1H NMR (DMSO-d6): ~ 1.41 (t, j=7Hz, 3H), 1.42 (s, 9H), 2.20 (s, 3H),
2.50 (m, 4H), 3.29 (m, 4H), 4.29 (q, j=7Hz, 2H), 4.78 (s, 2H), 6.80 (d,
j=8.5 Hz, lH), 7.01 (d, j=8.8Hz, 2H), 7.50 (m, 2H), 7.86 (d, j=8.8Hz,
25 2H), 9.68 (s, lH).
2-(4-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -yl)phenyl-
carbonylamino)-2-methylphenoxy)acetic acid (12-7)
Using a method similar to that described for compound
30 l O-6, 2-(4-(4-(4-( l, l -dimethylethoxycarbonyl)piperazin- 1 -yl)phenyl-
carbonylamino)-2-methylphenoxy)acetic acid was prepared and used in
the next step without purification.
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2-(4-(4-( 1 -Piperazinyl)phenylcarbonylamino)-2-methylphenoxy)acetic
acid. dihydrochloride ( 12-8)
Using a ~nethod similar to that described for compound
10-7, 2-(4-(4-(1-piperazinyl)phenylcarbonylamino)-2-methyl-
5 phenoxy)acetic acid, dihydrochloride was prepared, mp: >250~C.
lH NMR (D2O): ~ 2.15 (s, 3H), 3.29 (m, 4H), 3.48 (m, 4H), 4.65 (s,
2H), 6.76 (d, j-8.5Hz, lH), 7.04 (d, j=8.6, 2H), 7.17 (m, 2H), 7.69 (d,
j=8.6Hz, 2H).
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SCHEME 13
COOH- COOCH3
H3CJ~ MeOH, HCI (g), RT ,~
NH2 NH2
13-1 13-2
H3C
(CICH2CH2)2NH HCI A ~
HN N~' '~COO(CH3, n-Bu)
n-BuOH, reflux \~ \=
13-3
H3C
Boc20, CHCI3 A ~
RT ~ BocNN~COO(CH3, n-Bu)
13-4
H3C
1N NaOH A ~
BocN N ~' ~ COOH
EtOH, reflux
13-5
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SCHEME 13 CONTII'lUED
OH OH
h B~C2~ . CHC13 ~ BrCH2COOEt
refiux ~ Cs2CO3, DMF
NH2 NHBoc
13-6 1 3-7
O COOEt O COOEt
¢~ HCI (g)
NHBoc NH2
13-8 13-9
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Cl ~PF6
~NJ~ N+--l
13-5 + 13-9
i-Pr2NEt~ CH2CI2
H3C
BocN N~3~ ~ r COOEt
13-10
LiOH
HCI
H3C
~\ ~~ rCO2H
N~O
~Q
Methvl 3-methyl-4-aminobenzoate (13-2)
To a 500 mL round bottomed flask equipped with a stirring
S bar, reflux condenser and a drying tube was added 3-methyl-4-
aminobenzoic acid (8.00 g, 52.92 mmol) and anhydrous methanol (300
mL). This solution was saturated with anhydrous HCl gas and the
mixture was stirred at ambient temperature for 26 h. The methanol and
HCl were removed in vacuo and the solid product was suspended in 400
10 mL of EtOAc. This mixture was made basic by careful addition of
aqueous NaHCO3 solution. The layers were separated and the organic
phase was washed with brine, dried (MgSO4), filtered and concentrated
in vacuo to give methyl 3-methyl-4-aminobenzoate as a yellow solid.
1H NMR (CDC13): ~ 2.18 (s, 3H), 3.85 (s, 3H), 3.99 (br s, 2H), 6.63
- 15 (d, j=8.3 Hz, lH), 7.75 (m, 3H).
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Methyl and n-Butyl 3-methyl-4-(1-piperazinyl)benzoate (13-3)
To a lL round bottomed flask with a stirring bar, reflux
condenser, and an ar~on inlet was added methyl 3-methyl-4-
aminobenzoate (8.74 g, 52.74 mmol), bis 2-chloroethylamine
S hydrochloride (9.81 g, 55.0 mmol) and n-BuOH (175 mL). This
mixture was heated at reflux for 8 days. The n-BuOH was removed in
vacuo and the residue was partitioned between EtOAc (200 mL) and
0.2N HCl (300 mL). The layers were separated and the organic phase
was extracted with another 100 mL portion of 0.2 N HCl. The aqueous
10 phases were combined and made basic with solid NaHCO3. This
mixture was extracted with EtOAc (2 x 200 mL) and the combined
EtOAc extracts were washed with brine, dried (Na2SO4), filtered and
concentrated in vacuo to give 10.39 g of a mixture of ethyl and n-butyl
3-methyl-4-(1-piperazinyl)benzoates. This material was used in the next
15 step without further purification.
Methyl and n-Butyl 3-methyl-4-(1 -(4-(1,1 -dimethylethoxy)carbonyl)-
piperazinyl)benzoates (13-4)
To a lL round bottomed flask equipped with a stirring bar
20 and an argon inlet was added a mixture of ethyl and n-butyl 3-methyl-4-
(1-piperazinyl)benzoates (10.39 g, 44.35 mmol based on the mw of the
methyl ester only; vide sllpra), di-tert-butyldicarbonate (14.67 g, 67.22
mmol) and dry CHC13 (100 mL). This solution was heated at reflux for
19 h. The cooled reaction mixture was concentrated in vacuo and the
25 residue was chromatographed on silica gel (300 g) using 40% EtOAc-
hexane as eluant to give 5.0 g of a mixture of methyl and n-butyl 3-
methyl-4-(1 -(4-(1,1 -dimethylethoxy)carbonyl)piperazinyl)benzoates.
This material was used in the next step without further purification.
30 3 -Methyl-4-(1 -(4-(1,1 -dimethylethoxy)carbonyl)piperazinyl)benzoic
acid (13-5)
The product from the preceding step, a mixture of methyl
and n-butyl 3-methyl-4-(1 -(4-(1,1 -dimethylethoxy)carbonyl)piper-
azinyl)benzoates (5.00 g) was dissolved in 95% EtOH (100 mL) and
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NaOH (10 g, 250 mmol) was added. This solution was heated at reflux
for 2 h. The mixture was cooled to room temperature and the EtOH
was removed in vacw. The residue was dissolved in 300 mL of H20.
This solution was washed with Et20 (200 mL) then acidified with 10%
5 aqueous citric acid. This mixture was extracted with EtOAc (2 x 250
mL). The combined EtOAc extracts were washed with H20 and brine.
Drying (MgSO4), filtration and removal of the solvent in vacuo gave an
oil. This material was chromatographed on 75 g of silica gel using 40%
EtOAc-hexane as eluant. The chromatographed product was
10 recrystallized from 15 mL of 20% EtOAc-hexane to give 228 mg of 3-
methyl-4-(1 -(4-(1,1 -dimethylethoxy)carbonyl)piperazinyl)benzoic acid
as white c~ystals.
lH NMR (CDC13): ~ 1.49 (s, 9H), 2.35 (s, 3H), 2.94 (m, 4H), 3.59 (m,
4H), 6.99 (d, j=8Hz, lH), 7.92 (m, 2H), 11.65 (br s, lH).
4-(1 ~ 1 -Dimethylethoxycarbonylamino)phenol (13-7)
To a 500 mL round bottomed flask with a stirring bar,
reflux condenser and an argon inlet was added 4-aminophenol (10.00 g,
91.63 mmol), di-tert-butyldicarbonate (20.00 g, 91.63 mmol) and dry
20 CHC13 (250 mL). This solution was heated at reflux for 6 h. The
mixture was cooled in an ice bath and the product was collected by
filtration. The product was washed with a little cold CHC13 and dried in
vacuo to give 16.43 (86%) of 4-(l,l~dimethylethoxycarbonyl-
amino)phenol as white crystals, mp: 142-143~C.
25 lH NMR (CDC13): ~ 1.51 (s, 9H), 5.27 (br s, IH), 6.34 (br s, lH), 6.72
(d, j=8Hz, 2H), 7.16 (d, j=8Hz, 2H).
Ethyl (4-(1.1 -dimethylethoxycarbonylamino)phenoxy)acetate (13-~)
To a 500 mL round bottomed flask with a stirring bar and
30 an argon inlet was added 4-(1,1-dimethylethoxycarbonylamino)phenol
(8.20 g, 39.19 mmol), Cs2CO3 (25.54 g, 78.38 mmol), DMF (75 mL),
and ethyl bromoacetate (4.78 mL, 43.11 mmol). This heterogeneous
mixture was stirred at ambient temperature for 3.5 h. The mixture was
diluted with a little CHCl3 and filtered through a frit to remove the
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- 106-
salts. The DMF was removed under high vacuum and the residue was
suspended in 500 mL of EtOAc. This mixture was washed with H20
(3x), and brine. Drying (MgSO4), filtration and removal of the solvent
in vacuo, gave an oil. This material was chromatographed on 400g of
S silica gel using 20% EtOAc-hexane as eluant. There was obtained 11.9
g (100%) of ethyl (4-(1,1 -dimethylethoxycarbonyl-
amino)phenoxy)acetate as an oil.
lH NMR (CDCl3): ~ 1.29 (t, j=6.4Hz, 3H), 1.50 (s, 9H), 4.25 (q,
j=6.4Hz, 2H), 4.57 (s, 2H), 6.36 (br s, lH), 6.84 (d, j=8Hz, 2H), 7.26
10 (d, j-8Hz, 2H).
Ethyl 4-aminophenoxyacetate. hydrochloride (13-9)
To a 500 mL round bottomed flask with a stirring bar and
a gas dispersion tube was added ethyl (4-(1,1-dimethylethoxycarbonyl-
15 amino)phenoxy)acetate (11.9 g, 40.29 mmol) and dry EtOAc. Thissolution was cooled in an ice bath and saturated with anhydrous HCI gas
over 15 min. The resulting suspension was aged 30 min. at 0~C. The
excess HCI was removed with a stream of argon and the EtOAc was
removed in vacuo. The solid product was triturated with EtOAc,
20 collected on a frit, and dried in vacuo at room temperature to give 7.33
g (78%) of ethyl 4-arninophenoxyacetate, hydrochloride as a white
crystalline soild.
lH NMR (DMSO-d6): ~ 1.211 (t, j=6.4Hz, 3H), 4.16 (q, j=6.4Hz, 2H),
4.82 (s, 2H), 7.05 (d, j=8Hz, 2H), 7.34 (d, j=8Hz, 2H), 10.27 (br s, 3H).
25 Ethyl 2-(4-(4-(3 -methyl-4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -
yl)phenylcarbonvlamino)phenoxy)acetate (13- 10)
In a manner similar to that described for compound 10-5,
using acid 13-5 and aniline 13-8, ethyl 2-(4-(4-(3-methyl-4-(1,1 -
dimethylethoxycarbonyl)piperazin- 1 -yl)phenyl-carbonylamino)-
30 phenoxy)acetate was prepared.lH NMR (CDC13): ~ 1.29 (t, j=7.0Hz, 3H), 1.48 (s, 9H), 2.37 (s, 3H),
2.95 (m, 4H), 3.59 (m, 4H), 4.25 (q, j= 7.Hz, 2H), 4.61 (s, 2H), 6.95 (d,
j=8.5Hz, 2H), 7.03 (d, j=8.5Hz, lH), 7.55 (d, j-8.5Hz, 2H), 7.62 (m,
2H).
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2-(4-(4-(3-Methyl-4-( l -piperazinyl)phenylcarbonylamino)phen-
oxy)acetic acid (13- l l )
To a 10Q mL round bottomed flask with a stirring bar was
added ethyl 2-(4-(4-(3-methyl-4-(1, l -dimethylethoxycarbonyl)piper-
5 azin-1-yl)phenylcarbonylamino)phenoxy)acetate (311 mg, 0.63 mmol),
MeOH (5 mL), THF (20 mL), and lN LiOH (20 mL). This solution
was stirred at ambient temperature for 24 h. The solvents were
removed in vacuo and the residue was acidified with 10% aqueous citric
acid. This mixture was extracted with EtOAc. The EtOAc extract was
10 dried (MgSO4), filitered and cooled to 0~C in an ice bath. This solution
was saturated with dry HCl gas and aged 30 min. at 0~C. The excess
HCl was removed with a stream of argon and the solvent was removed
in vacuo. The product was purified by preparative reverse phase HPLC
using a H2O-CH3CN gradient on a Waters C-18 column. Obtained 105
15 mg of 2-(4-(4-(3-methyl-4-(1-piperazinyl)phenylcarbonyl-
arnino)phenoxy)acetic acid as a white solid.
lH NMR (D2O): ~ 2.28 (s, 3H), 3.17 (m, 4H), 3.35 (m, 4H), 4.55 (s,
2H), 6.94 (d, j=7.5Hz, 2H), 7.12 (d, j=8.2Hz, lH), 7.33 (d, j=7.5Hz,
2H), 7.63 (m, 2H).
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SCHEME 14
A ~NO2 2 ~ , Boc-N N~No2
14-1 14-2
HO ~- COOH
5% Pd-C A /=\
Boc-N N~\ ,~ NH2
H2 (45 psig) / ~Y Cl ~PF6
EtOAc-MeOH 14-3 C~N ,l N~
i-Pr2NEt, CH2CI2
Boc-N N~NH BrCH2COOBut
/ ~OH
O/ ~ Cs2CO3, DMF, RT
14-4
Boc-N N~3N~_ r COOBut
HCI (g) ~ HN N~N rCOOH
EtOAc, 0~C / ~o
14-6
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1 -Nitrophenyl-4-(1.1 -dimethylethoxycarbonyl)piperazine (14-2)
To a 200 mL round bottomed flask was added l-nitro-
phenylpiperazine (5.01 g, 24.2 mmol), di-tert-butyldicarbonate (5.85 g,
26.8 mrnol), triethylarnine (3.87 mL, 27.8 mmol), and dry THF (100
5 mL). This solution was heated at reflux for 1 P~ h. The mixture was
cooled to room temperature and the solvents were removed in vacuo.
The residue was dissolved in EtOAc and washed with 10% aqueous
citric acid, H2O, and brine. Drying (MgSO4), filtration, and removal
of the solvent in vacuo gave 7.7 g of 1-nitrophenyl-4-(1,1-dimethyl-
10 ethoxycarbonyl)piperazine as a yellow solid.IH NMR (CDC13): ~ 1.42 (s, 9H), 3.41 (m, 4H), 3.62 (m, 4H), 6.81 (d,
j=8.5Hz, 2H), 8.16 (d, j=8.5Hz, 2H).
4-(4-(1.1 -Dimethylethoxycarbonyl)piperazin- 1 -yl)aniline (14-3)
To a 250 mL Parr haydrogenation bottle was added 1-
nitrophenyl-4-(1,1-dirnethylethoxycarbonyl)piperazine (4.5 g, 16.34
mrnol), EtOAc (81 mL), MeOH (27 mL), and 5% Pd-C (0.18 g). This
mixture was hydrogenated under 45 psig H2 at ambient temperature for
24 h. The mixture was filtered through a celite pad and the solvents
20 were removed in vacuo. The residue was chromatographed on 250 g of
silica gel using 70% EtOAc-hexane as eluant. There was obtained 3.43
g of 4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)aniline as a
yellow solid.
1H NMR (CDC13): ~ 1.49 (s, 9~), 2.98 (m, 4H), 3.49 (br s, 2H), 3.57
25 (m, 4H), 6.66 (d, j=9Hz, 2H), 6.82 (d, j=9Hz, 2H).
N-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -yl)phenyl)-4-
hydroxybenzamide (14-4)
To a 100 mL round bottomed flask with a stirring bar and
30 an argon inlet was added 4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-
yl)aniline (0.868 g, 3.13 mmol), 4-hydroxybenzoic acid (0.525 g, 3.~0
mmol), chloro-N,N,N',N',-bis(pentamethylene)formamidinium
hexafluorophosphate (1.35 g, 3.74 mmol), and CH2C12 (45 mL). This
mixture was cooled in an ice bath and diisopropylethylamine (0.96 mL,
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5.52 mmol) was added. The ice bath was allowed to expire and the
mixture was stirred at ambient temperature 18 h. The mixture was
diluted with EtOAc and washed with 10% aqueous citric acid, water and
brine. Drying (MgS04), filtration and removal of the solvent in vacuo
5 gave an oil. This material was chromatographed on 100 g of silica gel
using 70% EtOAc-hexane as eluant to give 0.57 g of N-(4-(4-(1,1-
dimethylethoxycarbonyl)piperazin-l-yl)phenyl)-4-hydroxybenzamide as
a grey solid.
lH NMR (CDC13): ~ 1.48 (s, 9H), 3.01 (m, 4H), 3.48 (m, 4H), 6.82 (d,
10 J=9Hz, 2H), 6.85 (d, j=9Hz, 2H), 7.58 (d, j=8Hz, 2H), 7.81 (d, p8Hz,
2H), 9.80 (br s, lH), 10.01 (br s, lH).
tert-Butyl 4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-
yl)phenylaminocarbonyl)phenoxyacetate (14-5)
To a 100 mL round bottomed flask with a stirring bar and
an argon inlet was added N-(4-(4-(1,1-dimethylethoxycarbonyl)piper-
azin-l-yl)phenyl)-4-hydroxybenzamide (0.56 g, 1.41 mmol) DMF (35
mL), Cs2C03 (0.49 g, 1.51 mrnol) and tert-butyl bromoacetate (0.28
mL, 1.75 mmol). This mixture was stirred at ambient temperature for
18 h. The mixture was diluted with EtOAc and washed with H2O and
brine. Drying (MgSO4), filtration and removal of the solvent in ~acuo
gave 0.78 g of tert-butyl 4-(4-(4-(1,1-dimethylethoxycarbonyl)piper-
azin-1-yl)phenylaminocarbonyl)phenoxyacetate which was used in the
next step without purification.
1H NMR (DMSO-d6): ~ 1.48 (s, 9H), 1.49 (s, 9H), 3.02 (m, 4H), 3.39
(m, 4H), 4.78 (s, 2H), 6.88 (d, j=9Hz, 2~I), 7.02 (d, j=9Hz, 2H), 7.62 (d,
j=8Hz, 2H), 7.82 (d, j=8Hz, 2H), 9.82 (br s, lH).
4-(4-(Piperazin-l-yl)phenylaminocarbonyl)phenoxyacetic acid (14-6)
To a 100 mL round bottomed flask with a stirring bar and
a gas dispersion tube was added tert-butyl 4-(4-(4-(1,1-dimethylethoxy-
carbonyl)piperazin-l-yl)phenylaminocarbonyl)phenoxyacetate (0.78 g,
1.52 mmol) and EtOAc (40 mL). This solution was cooled in an ice
bath and HCI gas was sparged through the solution for 15 min. The
T
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resulting mixture was aged 90 min. The excess HCl and EtOAc were
removed in vacuo and the crude product was purified by preparative
reverse phase HPLC, There was obtained 0.218 g of 4-(4-(piperazin-1-
yl)phenylaminocarbonyl)phenoxyacetic acid as a crystalline solid.
S lH NMR (0.lN NaoD-D2o): o 2.99 (m, 4H), 3.15 (m, 4H), 4.59 (s,
2H), 7.03 (d, j=9Hz, 2H), 7.16 (d, j=9Hz, 2H), 7.7.37 (d, j=8Hz, 2H),
7.88 (d, j=8Hz, 2H).
.. , .. .. , ~, ., ~ . ..
. . . ,~.,
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- 112-
SCHEME 15
OH 1. HO3S~N2+ Cl-
H3C CH3 2. Na2S2O4
15-1
OH
~ Boc2O, CHCI3
H3C~CH3 reflux
NH2
15-2
OH
~ Br~COOEt
H3C~ Cs2CO3, DMF
NHBoc
15-3
O COOEt O COOEt
HCI (gas) ~b .HCI
H C~CH EtOAc,0~C ~
3 1 3 H3C I CH3
NHBoc NH2
15-4 1 5~5
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SCHEME 15 CONTINUED
~ /=\
Boc--N~ N~COOH 1-5
Cl PF6-
C~NJ~N3 i-Pr2NEt, CH2CI2
A /=\ O CH3 LiOH
Boc--N N~\ /A/ ~ r COOEt
~O DME, H20
CH3
Boc--N N ~N~or COOH
1 5-7 CH3
.HCI
HCI (gas) / \ /~\ O CH~
HN N~\ /r~ r COOH
EtOAc, 0~C \ J w HN~O
15-8 C H3
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- l l 4 -
2-(4-(4-( ~ -Piperazinyl)phenylcarbonylamino)-3 ,S-dimethyl-
phenoxy)acetic acid~ dihydrochloride (15-8)
Using a-sequence essentially the same as described for
compound 12-8, but starting with 3,5-dimethylphenol (15-1), 2-(4-(4-
S ( l -piperazinyl)phenylcarbonylamino)-3 ,S-dimethylphenoxy)acetic acid, dihydrochloride was prepared, mp: >250~C.
1~ NMR (D20): o 2.15 (s, 6H), 3.32 (m, 4H), 3.54 (m, 4H), 4.64 (s,
2H), 6.72 (s, 2H), 7.12 (d, j=8.6, 2H), 7.17 (m, 2H), 7.83 (d, j-8.6Hz,
2H).
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SCHEME 16
N~3~ 1 6-1
KMnO4/H20
N~co2H 1 6-2
1. H2 / PtO2 /HOAc / MeOH
60 psi
2. BOC2O
BOCN~ CO2H 16-3
H2N~O~CO2Et Cl PF -
H3C ~ CH2CI2
t0-4
BOCN~ 1 6-4
H~O~CO2Et
H3C
1. LiOH
2. HCI / EtOAc
HN~}~ 1 6-5
NH~O~CO2H
H3C
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N~ CO2H 16-2
H2N~O~CO2Et J~ PF-
H3C ~ CH2CI2
10-4
N~O O~,CO2Et
16-6
H3C
LiOH
H ~O~,CO2H
16-7 H C
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- 1~7-
N~ CO2H
16-2
4-(4-Pyridinyl)benzoic acid (16-2)
A slurry of 16 1 (5 g, 29.6 mmol, prepared as described in
S Chambron, J.C; Sauvage, J.P., Tetrahedron, 1987, 895 and Comins,
D.L.; Abdullah, A.H., J. Org. Chem., 1982, 47, 431S method B) in 200
mL H20 was treated with 10% HCl until the solids dissolved. The
solution was treated with solid KMnO4 in portions (11.2 g, 888 mmol),
stirred until the KMnO4 hjad dissolved and heated to 90~C for 18hr.
An additional 2 g of KMnO4 was added and the reaction was again
heated to 90~C for 2 hr. The reaction was cooled to ~60~C, filtered and
the solids were washed with warm water. The filtrate was evaporated
and the residue chromatographed (Silica gel, 10: 1: 1 EtOH/H2O/NH4OH)
to give 16-2 as an off-white solid.
1H NMR (400 MHz, DMSO) o 8.61 (m, 2H), 8.0 (m, 2H), 7.72 (m, 4H).
/ \ /=\
BOCN~ CO2H
16-3
4-(1 -(1. I -Dimethylethoxvcarbonyl)piperidin-4-yl)benzoic acid (16-3)
A solution of 16-2 (0.5 g, 2.5 mmol) in 20 mL 20%
HOAc/MeOH was treated with 250 mg PtO2 and hydrogenated at 50 psi
for 4 hr. The solution was filtered through Solka Floc, evaporated and
azeotroped with heptane to remove excess HOAc. The intermediate
amino acid acetic acid salt was obtained as a white solid.
Rf (10:1:1 EtOH/H2O/NH4OH) 0.3.
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lH NMR (400 MHz, CD30D) ~ 8.96 (m, 2H), 7.35 (m, 2H), 3.5 (bd,
2h), 3.4 (m, 2H), 3.2 (m, 2H), 3.0 (m, 2H).
A slurry~of the amino acid (0.5 g, 1.9 mmol) in 30%
H20/dioxane (12 mL) was treated with 1 N NaOH (4.8 mL) and
S ditertbutyldicarbonate (0.564 g, 2.58 rnmol) at room temperature for 6
hr. The reaction was acidified to pH S with 10% KHSO4 and extracted
several times with EtOAc. The EtOAc layers were combined and
evaporated to give 16-3 as a white solid.
Rf (97:3:1 CHC13/MeOH/HOAc) 0.39.
lH NMR (400 MHz, CD30D) ~ 7.95 (d, 2H), 7.33 (d, 2H), 4.2 (bd,
2H), 2.85 (b, 3H), 1.8 (bd, 2H), 1.6 (m, 2H), 1.48 (s, 9H).
BOCN~)~4O O~,CO2Et
16-4 H C
15 Ethyl 2-(4 -(4-( 1-( 1,1 -Dimethylethoxycarbonyl)piperidin-4-
yl)phenylcarbonyl amino)-3-methylphenoxy)acetate (16-4)
A slurry of 16-3 (0.lSg, 0.49 mmol) and 10-4 (0.12g, 0.49
mmol) in CH2C12 was treated with chloro-N,N,N',N',-
bis(pentamethylene)formamidinium hexafluorophosphate (0.194g, 0.54
20 mmol) and diisopropylethyl amine (0.34 mL, 1.96 mmol) and stirred at
room temperature for 24 hours. The solution was diluted with EtOAc
and washed with H2O, 10% citric acid, saturated NaHCO3 and brine,
dried over MgSO4, filtered and evaporated. The residue was
chromatographed (silica gel 50% EtOAc/Hexanes) then triturated with
25 ether~exanes to give 16-4.
Rf(50% EtOAc/Hexanes) 0.33.
lH NMR (400 MHz,CDC13)~ 7.81 (2s,2H), 7.70(d,1H), 7.50 (s, lH),
7.31 (2s, 2H), 6.8 (m, 2H), 4.6 (s, 2H), 4.28 (q, 2H), 2.8 (m, 2H), 2.72
(m, lH), 2.30 (s, 3H), 1.85 (bd, 2H), 1.75 (m,2H), 1.48 (s, 9H) 1.3 (t,
30 3H)-
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H N~)~H ~ Q~,CO2H
16-5
3C
2-(4-(4-(Piperidi~-4-yl)phenylcarbonylamino)-3 -methylphenoxy)
acetate ( 16-5)
A solution of 16-4 (O.lg, 0.2 mmol) in 1:1:1
THF/MeOH/H20 was treated with LiOH (0.084g, 2 mmol) at room
temperature. After 1 hour the reaction was diluted with EtOAc and
10% KHS04 and the layers were separated. The organic layer was
washed with H20, brine, dried with MgS04, filtered and evaporated to
give the acid as a clear oil.
Rf(9: 1:1 CH2C12/MeOH/HOAc) 0.57.
lH NMR (400 MHz,CD30D) ~ 7.94 (2s,2H), 7.44(2s,2H), 7.2 (d, lH),
6.90 (m, lH), 6.8 (m, lH), 4.62 (s, 2H), 4.24 (bd, 2H), 2.9 (b, 2H), 2.83
(m, lH), 2.28 (s, 3H), 1.86 (bd, 2H), 1.7-1.6 (m, 2H), 1.5 (s, 9H).
A slurry of the intermediate acid (0.9 g, 1.19 mmol) was
cooled to -78~C and saturated with HCl gas. The reaction was walmed
to 0~C, then concentrated in vacuo to give 16-5 as the HCl salt.
Rf (10:1:1 EtOH/H20/NH40H) 0.81.
lH NMR (400 MHz, CD30D) ~ 7.94 (2s, 2H), 7.44 (2s, 2H), 7.2 (d,
20 lH), 6.90 (m, lH), 6.8 (m, lH), 4.65 (s, 2H), 3.52 (bd, 2h), 3.15 (bt,
2H), 3.05 (m, lH), 2.12 (bd, 2H), 1.97 (m, 2H).
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~N ~O~,CO2Et
16-6
Ethyl 2-(4-(4-(Pyridin-4-yl)phenylcarbonylamino)-3-methyl-
phenoxy)acetate ( 16-6)
16-2 (0.5 g, 2.5 mmol) and Ethyl 2-acetoxy-4-amino
benzene hydrochloride (13-9) (0.579 g, 2.5 mmol) were coupled as
described for 16-4 to give 16-6 after chromatography (silica gel, 5%
MeOH/EtOAc) followed by reverse phase preparative HPLC.
1H NMR (400 MHz, CD30D) ~ 8.82 (d, 2H), 8.30 (d, 2H), 8.15 (d,
2H), 8.05 (d, 2H), 7.60 (d, 2H), 6.98 (d, 2H), 4.70 (s, 2H), 4.23 (q, 2H),
1.30 (t, 3H).
H~O~,CO2H
16-7
2-(4-(4-(Pyridin-4-yl)phenylcarbonylaminophenoxy)acetic acid (16-7)
16-6 was treated with LiOH as described for 16 5 to give
16-7 after chromatography (silica gel, 10:1: 1 EtOH/H2O/NH4OH)
followed by preparative reverse phase HPLC.
Rf (10:1:1 EtOH/H20/NH40H) 0.76.
lH NMR (400 MHz, DMSO) ~ 8.65 (d, 2H), 8.10 (d, 2H), 7.96 (d, 2H),
7.8 (d, 2H), 7.65 (d, 2H), 6.90 (d, 2H), 4.58 (bs, 2H).
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~ /=\
N~CH3 16-1
NaNH2
Dimethylaniline
1 60~
N~CH3 1 7-1
H2N
~ Cl~ CI
BOC20
/=\ ~
o N~ C H3 1 7-2
tBuO NH
NBS
CCI4
AIBN
o N~ 17-3
tBuO N H
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SCHEME 17 (CONT'D)
17-3
AgNO3
THF/H20
O N~ 17-4
tBuO NH NaCI02
H2~2
~ CH3CN
o N~ 17-5
tBuO N H
~ PYCLU, Et2Ni Pr
HCI- H2N~O~,COOEt
13-9
~ N~<N~O~,COOEt
tBuO NH 17-6
LiOH, THF/H20/MeOH
~I
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SCHEME 17 (CONT'D)
tBuO NH N~O~COOH ~:~
HCI/EtOAc
H2N NH~O~,COOH 17-8
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N~&~ CH3
H2N
17-1
2-Amino-4-(4-methylphenyl)pyridine ( 17- l )
NaNH2 (142 mmol) was prepared in situ as described in
Lemer, M.T. Organic Reactions 1942 Vol. I. Dimethylaniline (20 ml)
5 was added dropwise to the freshly prepared NaNH2. 16-1 (8.0 g, 47.3
mmol) was dissolved in a small amount of dimethylaniline and added to
the mixture. The slurry was heated to 160~ for 2 hours. The reaction
mixture is cooled and diluted with 10% KHSO4 and water. The layers
are separated, and the dimethylaniline layer is washed with 10%
10 KHSO4. The aqueous layers are combined, basified with saturated
NaHCO3, and extracted with EtOAC (3x). The combined organic
layers are washed w/brine and concentrated to yield an oily solid. This
oily solid was purified by flash chromatography (5% MeOH/EtOAc) to
give 17-1 as a tan solid. Rf (5% MeOH/EtOAc) 0.36. lH NMR (400
15 MHz, DMSO-d6) ~ 7.9 (d, lH), 7.5 (d, 2H), 7.3 (d, 2H), 6.7 (d, lH), ~.6
(s, lH), 5.9 (d, lH), 2.3 (s, 3H).
O N~ C H3
tBuO NH
17-2
2-(1, l -Dimethylethoxycarbonylamino-4-(4-methylphenyl)
20 pyridine ( 17-2)
17-l is dissolved in dichloroethane (30 mL) and added
dropwise, rapidly to a refluxing solution of Boc2O in dichloroethane
- (10 mL). After the addition, the reaction is refluxed for 30 min, then
stirred at RT overnight. The reaction mixture is cooled and
. . , . ~
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concentrated to yield a yellow solid, which is purified by
chromatography (silica, 30% EtOAc/Hexane) to give 17-2 as a white
solid. Rf (50% EtOAc/Hex) 0.73. lH NMR (400 MHz, CDCl3) ~ 8.3
(d, lH), 8.2 (s, lH), 7.5-7.6 (m, 4H), 7.3 (bs, lH), 7.1 (d, lH), 2.3 (s,
5 3H), 1.5 (s, 9H)
~ ~Br
tBuO NH
17-3
2-(1, 1 -Dimethylethoxycarbonylamino-4-(4-dibromomethylphenyl)
pyridine ( 17-3)
17-2 (1.0 g, 3.5 mmol) is dissolved in CCl4. NBS (1.3 g;
7.3 mmol) is added, followed by AIBN (28.7 mg, 0.18 rnmol). The
reaction is heated to reflux while shinin~ a white light directly on the
flask. After 2 hours, AIBN (28.7 mg) is added, the light is turned off,
and the reacion is stirred overnight to effect completion to product.
15 The reaction mixture is cooled and the succinimide is filtered off,
washing the solids with CCl4. The filtrate is concentrated to give 17-3
as a brown solid which is used in the next step without further
purification. Rf (50% EtOAc/Hex) 0.70. 1H NMR (400 MHZ, CDCl3)
~ 8.3 (d, lH), 8.2 (S, lH), 7.7 (m, 3H), 7.2 (bs, lH), 7.1 (d, lH), 6.7 (s,
lH), 1.5 (s,9H).
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~ N~OH
tBuO NH
1 7-4
4-(2-(1 ,1 -Dimethylethoxycarbonylamino)pyrid-4-yl)
benzaldehyde ( 17-4)
17 3 (1.5 g, 34 mmol) is dissolved in water/THF (15 rnL/45
mL). AgNO3 (1.1 g, 6.8 mrnol) is added and stirred for 1/2 hour. The
reaction mixture is diluted w/EtOAc and water. The layers are
separated and the organic layer is filtered to remove the solids. The
filtrate is washed w/brine, dried (MgS04), filtered and concentrated to
10 yield a brown solid. The solid is purified on a "plug" of silica, eluting
first w/50% EtOAC/hexane, then 100% EtOAc to elute all of the
product. The fractions are concentrated to give 17-4 as a brown solid.
Rf (50% EtOAc/Hexane)0.62. lH NMR (400 MHz, CDC13) ~ 10.1 (s,
lH), 8.29 (d,lH), 8.26 (s,lH), 8.0 (d,2H), 7.8 (d, 2H), 7.5 (bs, lH), 7.2
15 (d, lH), 1.5 (s, 9H).
o N~lOH
tBuO 1 7-5
4-(2-(1, 1 -Dimethylethoxycarbonylamino)pyrid-4-yl)
20 benzoic acid (17-5)
17-4 (1.0 g, 3.4 mmol) is slurried in CH3CN (40 mL).
10% KHSO4 (1.3 mL) and 30% H2~2 (0.957 mL) are added and the
solution is cooled in an ice bath. NaClO2 (8.5 mmol, 770 mg) is added
dropwise in 50 mL water over 20 min. The reaction is stirred for 16
25 hrs. The reaction mixture is diluted w/EtOAc and washed with
saturated NaHCO3 (2x). The aqueous layers are combined, acidifed
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with 10% KHSO4, and extracted w/CH2C12 (2x) and EtOAc (2x) to give
17 5 as a yellow solid. lH NMR (400MHz, DMSO-d6) ~ 12.6-12.8 (bs,
lH), 9.9 (s, lH), 8.3-(d, lH), 8.0-8.1 (m, 3H), 7.9 (d, 2H), 7.3 (d, lH),
1.5 (s, 9H).
~ N~N~O~,COOEt
tBuO NH
17-6
Ethyl 2-(4-(4-(2-(1,1-Dimethylethoxycarbonylamino)pyrid-4-
yl)carbonylamino)phenoxy)acetate ( 17-6)
A mixture of 17-5 (300 mg, 0.956 mmol), 13-9 (0.956
mmol, 236 mg), diisopropylethylamine (3.8 mmol, 0.66 mL), PYCLU
(1.05 mrnol, 378 mg), and CH2C12 (10 ml) is stirred at RT for 16
hours. The reaction mixture is diluted with EtOAc and washed with
saturated NaHCO3 and Brine. The Organic layer is dried (MgSO4),
15 filtered and concentrated to yield a pink solid. Triturations with
hexanes followed by flash chromatography (silica, 30% EtOAc/Hex)
affored 17-6 as a white solid. Rf (30% EtOAc/Hexanes) 0.24. 1H NMR
(400 MHz, CDC13) ~ 8.3 (d, lH), 8.2 (s, lH), 7.9 (d, 2H), 7.8 (2d, 3H),
7.4 (bs, lH), 7.6 (bs, lH), 7.2 (d, lH), 6.8 (s, lH), 6.7 (d, lH), 4.6 (s,
20 2H), 4.3 (q, 2H), 2.3 (s, 3H), 1.5 (s, 9H), 0.9 (t, 3H).
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o N~N ~ O~,COOH
tBuO N H
17-7
2-(4-(4-(2-(1,1 -Dimethylethoxycarbonylamino)pyrid-4-
yl)carbonylamino)phenoxy)acetic acid (17-7)
A mixture of 17-6 (0.17 rnmol, 90 mg), LiOH (0.60 mmol,
25 mg), and THF/H2O/MeOH/ (1 rnL/l mL/l mL) is stirred for 2
hours. The reaction mixture is diluted with EtOAc and 10% KHSO4.
The aqueous layer is back-extracted with EtOAc. The organic layers
are combined, washed with brine, dried (MgSO4), filtered and
10 concentrated to yield 17 7 as a white solid. 1H NMR (400 MHz,
CD30D) ~ 8.3 (d, lH), 8.1 (bd, 3H), 7.9 (d, 2H), 7.5 (bs, lH), 7.2 (s,
lH), 6.9 (s, lH), 6.8 (d, lH), 4.7 (s, 2H), 2.3 (s, 3H), 1.5 (s, 9H).
N~ H ~O ~,COO H
17-8
2-(4-(4-(2-Aminopyrid-4-yl)carbonylamino)phenoxy)acetic acid (17-8)
17-7 (0.14 mmol, 70 mg) is dissolved in EtOAC (3 mL)
and cooled to -78~. HCl (g) is bubbled through until the solution is
saturated. The reaction is stirred at 0~ for 3 hours, then at 35~ for 16
20 hours. The reaction mixture is concentrated to yield a tan solid, which
is purified by flash chromatography (10/0.25/0.25 EtOH/NH40H/H20)
to yield 17-8 as an off white solid. Rf (10/0.5/0.5/0.5
EtOH/NH40H/H20) 0.86. lH NMR (400MHz, DMSO-d6) ~ 9.8 (s,
lH), 8.0 (d, 2H), 7.9 (d, lH), 7.7 (d, 2H), 7.2 (d, lH), 6.9 (m, 2H), 6.8
25 (m, 2H), 6.0 (d, lH), 2.2 (s, 3H).
-- .......................... _ .. ..
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SCHEME 1
N H
~ Y
~CN
H
18-1
1.) aq. H2S04/dioxane
2.) CH30H
N~ ~,I~OCH3
H
18-2
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SCHEME 18 (CONT'D)
8 2
1.) H2(9), 10% Pd/C
2.) Boc2O, Et3N
o
tBuO N ~OCH3
18-3
1.) 1 N NaOH
2.) ,~,,O~,CO2Et
CH3 10-4
PYCLU, DIPEA
~N~ J~1~HJ~'
1.) HCI (g)
2.) LiOH
O ~~ ~, CO2H
N '¢~ H J~H3
H 18-5
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~ N J~
/~ H
'~ 1~-1
4-(3(R)-((N-benzyl)pyrrolidinyl)amino)phenylnitrile (18- 1)
A solution of N-benzyl-3-(R)-aminopyrrolidine (TCI, 0.45
S g, 2.27 mmol) in 1 mL acetonitrile was treated with 4-fluoro-
phenylcyanide (Aldrich, 3 g, 25.5 mrnol) and heated to 100~C. The
acetonitrile was allowed to evaporate and the slurry was heated for 18
hours. Additional 4-fluorophenylcyanide (1 g) was added and the
reaction heated for 18 hours. The oily mixture was absorbed onto silica
gel and eluted first with 20% EtOAc/Hexanes, then with 5%
MeOH/CHC13 saturated with NH3 to give 18-1.
Rf (5% MeOH/CHC13 saturated with NH3) 0.55.
lH NMR (400 MHz, CDC13) ~ 7.4 (d, 2H), 7.3 (m, SH), 6.5 (d, 2H),
4.45 (bd, lH), 4.0 (m, lH), 3.64 (s, 2H), 2.83 (m, lH), 2.75 (dd, lH),
2.6 (dd, lH), 2.43(m, lH), 2.34 (m, lH), 1.6 (m, lH).
~N~OCH3
18-2
Methyl 4-(3(R)-((N-benzyl)pyrrolidinyl)amino)benzoate (18-2)
A solution of 18-1 (0.52 g, 1.87 mmol) in dioxane (10 mL)
and 1:1 H20/concentrated H2S04 (10 mL) was heated to 100~C for 18
hours. The solvent was removed in vacuo and the residue dissolved in
MeOH (30 mL) and stirred for 4 days. The solvent was removed and
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the residue taken up in saturated NaHCO3 and lN NaOH to give a pH of
10, then extracted with chloroform. I'he organic extracts were
combined, evaporate~ and the residue chromatographed in a gradient of
20-30% EtOAc/Hexanes to give 1~-2 as a clear oil.
S Rf=(50% EtOAc/Hexanes) 0.31.
1H NMR (400 MHz, CDC13) ~ 7.45 (d, 2H), 7.30 (m, 5H), 4.35 (bd,
lH), 4.05 (m, lH), 3.34 (s, 3H), 3.63 (s, 2H), 2.8 (m, 2H), 2.58 (dd,
lH), 2.45 (dd, lH), 2.84 (m, lH), 1.65 (m, lH).
~ N~ ~OC ~3
tBuO N 18-3
Methyl 4-(3-(R)-(1 -(1,1 -dimethylethoxycarbonyl)pyrrolidinyl)
amino)benzoate (18-3)
A suspension of 18-2 (0.29 g, 0.93 mmol) and 10~o Pd/C
(0.068 g, 23% by weight) in CH30H (7 ml) was stirred under hydrogen
atmosphere for 48 hours. The mixture was filtered through Solka Floc,
and solvent removed. The residue was dissolved in CH2C12 (5 ml) and
treated with Et3N (0.65 ml, 4.7 mmol) and BOC2O (0.45 g, 2.1 mmol).
The reaction mixture was stirred 1 h at room temperature, then diluted
with EtOAc and washed with 10% KHS04 and brine, dried (Na2S04),
and the solvent removed. The residue was purified by flash
chromatography on silica gel, eluting with EtOAc (1)/hexane (1) to
provide 18-3 as an oil.
Rf=0.3 (silica gel, EtOAc (3)/hexane (2)).
lH NMR (400 MHz, CDC13) ~ 1.47 (9H, s), 1.92 (lH, s), 2.20 (lH, q),
3.25 (3H, s), 4.11 (lH, m), 4.19 (lH, m), 6.55 (2H, d), 7.87 (2H, d).
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O ,~O~co2Et
N~ CH3
tBuO H
1 8-4
Ethyl 2-(3-methyl-4-(4-(3-(R)-((1 -(1,1 -dimethylethoxycarbonyl)pyrro-
lidinyl)amino)phenylcarbonylamino)phenyloxy)acetic acid (18-4)
S A solution of 18 3 (0.245 g, 0.76 mmol) in dioxane (4 ml)
was treated with lN NaOH (3.0 ml, 3.0 mmol) at room temperature for
1 h. A second portion of lN NaOH (3.0 ml, 3.0 mmol) was then added,
and the reaction mixture was stiITed for 15 h. The solution was then
adjusted to pH 7 with lN HCl and the solvent removed. The residue was
suspended in CH2C12 (6 ml) and treated with 10-4 (0.19 g, 0.77 mrnol),
diisopropylethylamine (0.53 mrnol, 3.0 mmol), and PYCLU (Fluka,
0.30 g, 0.83 mmol). The reaction mixture was stirred for 48 h at room
temperature, then solvent was removed and the residue was purified by
flash chromatography on silica gel, eluting with EtOAc (3)~exane (2)
to give 18-4 as an oil.
Rf=0.2 (silica gel, ~tOAc (3)/hexane (2)).
1H NMR (400 MHz, CDC13) ~ 1.30 (3H, t), 1.47 (9H, s), 1.93 (lH, s),
2.24 (lH, m), 2.28 (3H, s), 3.27 (lH, m), 3.49 (2H, m), 3.73 (lH, m),
4.11 (2H, m), 4.16 (lH, m), 4.29 (2H, ~), 4.60 (2H, s), 6.62 (2H, d),
6.77 (lH, d), 6.81 (lH, s), 7.41 (lH, s), 7.68 (lH, d), 7.73 (2H, d).
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O ~O~,CO2H
N ~~ H ~H
1 8-5
2-(3-Methyl-4-(4-(3(R)-(pyrrolidinyl)amino)phenylcarbonylamino)
5 phenyloxy~acetic acid (18-5)
A solution of 18s 4 (0.216 g, 0.434 mmol) in EtOAc (10
ml) was cooled to -7~~C and treated with HCI (g) for 1.5 min. The
reaction mixture was stirred at 0~C for 1 h and then solvent was
removed. The residue taken up in THF (1)/CH30H (I)/H20 (1) (6 ml)
10 and treated with LiOH-H2O (0.1 lg, 2.6 mmol) at room temperature for
2.5 h. The solvent was removed and the residue was purified by flash
chromatography on silical gel eluting with EtOH (18)/H20 (1)/NH40H
(1) to afford 18 5 as a white solid.
Rf=0.2 (silica gel, EtOH (18)/H20 (1)/NH40H (1)).
1H NMR (400 MHz, D2O) ~ 1.57 (lH, m), 2.06 (lH, m), 2.08 (3H, s),
2.60 (lH, m), 2.76 (lH, m), 2.86 (lH, m), 3.03 (lH, m), 3.93 (lH, m),
4.38 (2H, s), 6.71 (3H, m), 6.80 (lH, s), 7.05 (lH, d), 7.66 (2H, d).
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SCHEME 19
H2N--C~N--~
Boc20, Et~N
H
tBUO ~ N_C~N
O ~
1g-1
1.) H2 (9), 10% Pd/C
~CN
2 ) ,~J
¢,
tBuO ~
.1 9-2
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SCHEME ~9 (CONT'D)
1 9-2
1.) aq. H2SO4, dioxane
2.) CH30H
3.) Boc20, Et3N
~¢~OCH3
N~N
tBuO~ I 19-3
~ 1.) 1 N NaOH
2.) ~ O~CO2Et
H2N~ 10-4
HCI CH3
PYCLU, DIPEA
O ~~ ~,CO2Et
~N~JJ 19-4
H_~N CH3
tBuO ~ l
0 1.) HCI (g)
2.) LiOH
O ~O~,CO2H
H2N ~ N ~ H ~ 19-5
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H
tBuO ~N~N--
19-1
N-benzyl-3-(R)-(( l 1 -dimethylethoxycarbonyl)amino)pyrrolidine (19- 1)
A solution of N-benzyl-3-(R)-aminopyrrolidine (TCI, 5.00
5 g, 28.4 mmol) in CH2Cl2 (100 ml) was treated with Boc2O (6.80 g,
31.2 mmol) and Et3N (7.9 ml, 57 mmol). The reaction was stirred at
room temperature for 15 h, then solvent was removed. The residue was
purified by flash chromatography on silica gel eluting with EtOAc
(3)/hexane (2) to give 19-1 as an oil.
10 Rf=0.4 (silica gel, EtOAc (1)/ hexane (1)).
lH NMR (400 MHz, CDC13) ~ 1.43 (9H, s), 1.60 (lH, m), 2.27 (2H, m),
2.51 (lH, m), 2.62 (lH, m), 2.76 (lH, m), 3.58 (2H, s), 4.13 (lH, m),
4.89 (lH, m), 7.29 (5H, m).
~ ~CN~CN
19-2
4-((3 -(R)-(1,1 -Dimethylethoxycarbonyl)amino)pyrrolidin- 1-
yl)phenylnitrile (19-2)
A suspension of 19-1 (7.43 g, 26.9 mmol) and 10% Pd/C
20 (2.45 g, 33~o by weight) in CH30H (150 ml) was stirred under H2 (g)
atmosphere for 5 h. The reaction mixture was filtered through a pad of
Solka Floc, and the solvent was removed. The residue was dissolved in
CH3CN (20 ml) and treated with 4-fluorobenzonitrile (16.1 g, 133
mmol) at 70~C for 18 h. The reaction mixture was then cooled to room
25 temperature and the solvent was removed. The residue was purified by
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flash chromatography on silica gel eluting with EtOAc (l)~exane (1) to
afford 19-2 as a white solid.
Rf=0.4 (silica gel, EtoAc (2)/hexane (3)).
lH NMR (400 MHz, CDCl3) ~ 1.45 (9H, s), 1.99 (lH, m), 2.30 (IH, m),
5 3.1~ (lH, m), 3.46 (2H, m), 3.62 (lH, m), 4.36 (lH, b), 4.67 (lH, b),
6.52 (2H, d), 7.47 (2H, d).
~CN ~OCH3
19-3
10 Methyl 4-((3-(R)-( 1,1 -dimethylethoxycarbonyl)amino)pyrrolidin- l -
yl)-benzoate ( 19-3)
A solution of 19 2 (1.48 g) in dioxane (25 ml) and H2S04
(I)/H20 (1) (25 ml) was heated at 70~C for lS h. The reaction mixture
was then concentrated to remove the dioxane, diluted with CH30H (100
lS ml), heated at 60~C for 2 h, and stirred at room temperature for 48 h.
The reaction mixture was concentrated to remove the CH30H, and the
residue adjusted to pH 10 with 6N NaOH and sat. NaHC03. The
aqueous mixture was then extracted with CH2Cl2, and the organic
extracts concentrated to afford an oil. This residue was dissolved in
20 CH2C12 (25 ml) and treated with Boc20 (2.96 g, 13.6 mmol) and Et3N
(2.2 ml, 16 mmol). The reaction mixture was stirred at room
temperature for 15 h. The solvent was then removed and the residue
purified by flash chromatography on silica gel eluting with EtOAc
(2)/hexane (3) to yield 19-3 as an oil.
25 Rf=O.S (silica gel, EtOAc (2), hexane (3)).
lH NMR (400 MHz, CDCl3) o 1.27 (9H, s), 1.99 (lH, m), 2.30 (lH, m),
3.22 (lH, m), 3.42 (2H, m), 3.85 (3H, s), 4.37 (IH, b), 4.69 (lH, b),
- 6.51 (2H, d), 7.91 (2H, d).
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~CN~N~O~co2Et
19-4 CH3
Ethyl 2-(4-((3-(R)-(1,1-dimethylethoxycarbonyl)amino)pyrrolidin-
1-yl)phenylcarbonylamino)-3-methylphenoxy)acetic acid (19-4)
S A solution of 19-3 (0.418 g, 1.30 mmol) in dioxane (10 ml)
was treated with lN NaOH (7.0 ml, 7.0 mmol), and the reaction mixture
was stirred at room temperature for 15 h. A second portion of lN
NaOH (3.0 ml, 3.0 mmol) was then added and the reaction mixture was
stirred an additional 15 h. Solvent was removed, and the residue was
10 taken up in H2O, adjusted to pH 6-7 with 10% KHSO4 and extracted
with EtOAc. The combined organic extracts were dried (Na2S04) and
the solvent was removed. The residue was taken up in CH2C12 (7 ml)
and treated with 10-4 (0.33 g, 1.3 mmol), DIPEA (0.81 mmol, 4.6
mmol) and PYCLU (Fluka, 0.53 g, 1.5 mmol). The reaction mixture
15 was stirred at room temperature for 48 h. The solvent was then
removed and the residue was purified by flash chromatography on silica
gel eluting with EtOAc (1)/hexane (1) to afford 19-4 as a white solid.
Rf=0.3 (silica ge~, EtOAc ( l )~exane ( l )).
1H NMR (400 MHz, CDCl3) ~ 1.30 (3H, t), 1.46 (9H, s), 2.04 (lH, m),
20 2.29 (3H, s), 2.31 (lH, m), 3.23 (lH, m), 3.45 (2H, m), 3.65 (lH, m),
4.27 (2H, q), 4.38 (lH, b), 4.60 (2H, s), 4.72 (l H, b), 6.57 (2H, d),
6.77 (lH, d), 7.67 (lH, s), 7.41 (lH, s), 7.72 (lH, d), 7.77 (2H, d).
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H2N _GN '~O~,CO2H
2-(4-((3(R)-amino)pyrrolidin- 1 -yl)phenylcarbonylamino)-3-
methylphenoxy)acetic acid (19-5)
S A solution of 19-4 (0.306 g, 0.615 mmol) in EtOAc (15
ml) at -78~C was treated with HCl (g) for 1.5 min. The reaction
mixture was then stirred at 0~C for 1 h, and the solvent was removed.
The residue was taken up in THF (l)/CH30H(l)/H20 (1) (6 ml) and
treated with LiOH-H20 at room temperature for 1 h. The solvent was
removed, and the residue was purified by flash chromatography on
silica gel eluting with EtOH (18)/H20 (1)/NH40H (l) to give 19-5 as a
white solid.
Rf=0.4 (silica gel, EtOH (18)/H20 (1)/NH40H.
1H NMR (400 MHz, D2O) ~ 1.74 (lH, m), 2.10 (3H, s), 2.12 (lH, m),
3.00 (lH, m), 3.28 (lH, m), 3.39 (lH, m), 3.47 (lH, m), 3.59 (lH, m),
4.39 (2H, s), 6.61 (2H, d), 6.71 (lH, d), 6.81 (lH, s), 7.07 (lH, d), 7.79
(2H, d).
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SCHEME 20
N3N~o- Li+
MeOH/HOAC
conc. HCI
H2O/PtO2/H2
o
HOAc- HN3N~oH 20-1
BOC20
1 N NaOH/H2O/Dioxane
tBuOJ~ 3 N~OH
PYCLU HCI ~ H2N ~O~,COOCH2CH3
DIPEA CH3 10-4
O O
tBuO~ N3 N~ H~O~,COOEt
CH3
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SCHEME 20 (CONT'D)
20-3
1 ) LiOH
THF/H20/MeOH
2) 1 N HCI
O O
tBuO N3N~ N ~ O~COOH
CH3 20-4
HCI (g)
EtOAc
o
HN~ N~ HN~ O~,COOH
C H3 20-5
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o
HOAc- HN~ N~OH
20-1
4-(Piperidin-4-yl)piperidinyl carboxylic acid, acetic acid salt (20-1)
A suspension of the lithium salt of N-(pyridin-4-yl)-4-
5 piperidine carboxylic acid (prepared as described in Tetrahedron, 1988
44(23) 7095-7108, 1 g, S.SS mmol) in 50 mL 20% HOAc/MeOH, 10
mL H20 and 10 mL concentrated HCI was treated with PtO2 (1.7 g) and
hydrogenated at 65 psi for 24 hrs. The solution was filtered, evaporated
and the residue azeotroped with heptane to yield 20-1 as a white solid.
10 Rf(9: 1:1 EtOH/H2O/NH4OH)=0.39.
lH NMR (400 MHz, D2O) ~ 3.6-3.5 (m, 4H), 3.9 (m, lH), 3.1-3.0 (m,
4H), 2.65 (m, lH), 2.32 (d, 2H), 2.25 (d, 2H), 2.0-1.7 (m, 4H).
tBuO N3N~oH
20-2
4-((1,1-Dimethylethoxycarbonyl)piperidin-4-yl)piperidinyl carboxylic
acid (20-2)
A solution of 20-1 (1.7 g, 5.55 rnrnol) in H20 (10 mL)
was treated with sufficient 1 N NaOH to bring the solution to pH 1 1.
20 Dioxane (20 mL) was added followed by BOC anhydride (1.33 g, 6.2
mmol) dissolved in S mL dioxane. After 1 hr the solvents were
removed and the residue was triturated with acetonitrile and n-butanol,
filtered and the filtrate concentrated. The residue was chromatographed
(silica gel, 9:1:1 EtOH/H2O/NH4OH) to give 20-2 as a white solid.
25 Rf(9: 1:1 EtOH/H20/NH40H)=0.70
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1H NMR (400 MHz, D2O) ~ 4.12 (bd, 2H), 3.5 (bd, 2H), 3.32 (m, lH),
2.95 (bt, 2H), 2.75 (bt, 2H), 2.9 (m, lH), 2.15 (bd, 2H), 2.0 (bd, 2H),
1.7 (m, 2H), 1.55 (m, 2H), 1.35 (s, 9H).
O O
tBuO N~N~ N~O~,COOEt
20 3 CH3
Ethyl 2-(4-(4-((1,1 -dimethylethoxycarbonyl)piperidin-4-
yl)piperidinylcarboxamido)3-methylphenoxy)acetic acid (20-3)
20-2 (486 mg; 1.6 mmol) and.10-4 (250 mg, 1.6 mmol)
10 were dissolved in CH2C12. PYCLU (1.8 mmol, 634 mg) was added,
followed by diisopropylethylamine (6.4 mmol, 1.1 mL). The reaction is
stirred for 2 days. The reaction mixture is diluted with EtOAc and
washed with H2O, 10% KHS04, sat NaHCO3 and brine. The organic
layer is dried (MgSO4), filtered and concentrated to yield a tan oil.
15 Flash chromatography (10% MeOH/CHC13 sat NH3) yielded desired
product (20-3) plus bis piperidine urea by-product. This material is
triturated with hexane to remove most of the by-product.
Rf (10% MeOH/ CHC13 sat. NH3)=0.20
1H NMR (400 MHz, CdC13) ~ 7.55-7.57 (d, lH), 6.88 (s, lH), 6.74 (s,
lH) 6.71-6.72 (d, lH), 4.6 (s, lH), 4.27-4.29 (q, 2H), 4.23-4.25 (bs,
2H), 2.9-3.0 (d, 2H), 2.6-2.7 (t, 2H), 2.35-2.45 (t, 2H).
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O O
tBuO N~}N~ N~O~,COOH
C H3
2-(-4-(4-((1,1 -Dimethylethoxycarbonyl)piperidin-4-yl)piperidinyl-
5 carboxamido)3-methylphenoxy)acetic acid (20-4)
20-3 (300 mg) was dissolved in THF/H20/MeOH (2 mL/2
mL/2 mL). LiOH (50 mg) was added and the reaction is stirred for 2
hours. lN HCl was added (0.50 mL) and the reaction mixture was
concentrated to yield 20-4 as a tan solid.
10 Rf(9llll CH2cl2lMeoH/HoAc)=o.l6
lH NMR (400 MHz, CD30D) ~ 7.06-7.08 (d,lH), 6.81 (s, lH), 6.75 (d,
lH), 4.88 (s, 2H), 4.12-4.15 (bd, 2H), 3.04-3.07 (bd, 2H), 2.6-2.8 (vbs,
2H), 2.25-2.45 (m, 4H), 2.17 (s, 3H), 1.46-1.56 (m, 6H), 1.45 (9H).
HN3N~ N~O~,COOH
CH3
20-5
2-(4-(4-(Piperidin-4-yl)piperidinylcarboxamido)3-methylphenoxy)
acetic acid (20-5)
20-4 (0.08 mmol) is dissolved in EtOAc and cooled to -78~.
20 HCI (g) is bubbled through until the solution is saturated. The reaction
is warmed to 0~, and stirred for five minutes. The reaction mixture is
concentrated to yield a tan solid. The material was purified by flash
chromatography using 10/1/1 EtOH/NH40H/H20 as an eluent, resulting
in pure 20-5 as a white solid.
25 Rf(10/1/1 EtOH/NH4OH/H20)=0.15
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lH NMR (400 MHz, D2O) 7.0 (d, lH), 6.8 (s, lH), 6.7 (dd, lH), 4.7 (s,
lH), 3.4 (d, 2H), 3.1 (bd, 2H), 2.9 (t, 2H), 2.8 (bt, lH), 2.5 (bs, 3H),
2.10-2.13 (d, 2H), 2.~6 (s, 3H), 1.96-1.99 (d, 2H), 1.65-1.75 (m, 4H).
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SCHEME 2
CH3')~
CH3 OH
2~
Pyridine
NaOH
HO~'O,I CH~OH
2 1-3 ~2
10 % Pd/C
MeOH
o
HOJ~
CH3 OH
21 -3
HCI(g)
MeOH
C H30 ~
CH3 OH
21 -4
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SCHEME 21 (CONT'D)
BrCH2COOEt
CS2C~3
DMF
CH30~
CH3 O~,CO2Et
21 -5
NBS
CCI4
CH30~
O~,CO2Et
21 -6
tBuO N~N~ 2 C6H6
14-3
tBuO N~N~3--N~
21-7 C02Et
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SCHEME 21 (CONT'D)
21 -7
LiOH
~THF/H20/MeOH
tBuO N~N
HCl(g); EtOAc 2
-78~-0~
preparitive
HPLC
o
TFA ~ H N~N~ N~
21 -9 CO2H
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H O ~
C H3 O H
21-3
4-Hydroxy-2-methyl benzoic acid (21-3)
21-3 was prepared in two steps from 4'-hydroxy-2'methyl-
S acetophenone, 21-1, (Aldrich, 18.0 g, 0.120 mol).
The first step employed the procedure found in Merck
Process Patent US 852870-92031, which resulted in a 70/30 mix of 21-3
and 3-iodo-4-hydroxy-6-methyl benzoic acid (21-2)
For the second step, the mixture (7.0 g) of 21-2 and 21-3
10 was reduced in MeOH (200 mL) using 10% Pd/C (700 mg) under a
hydrogen balloon. After 16 hours of stirring, the reaction mixture was
filtered through celite, the celite pad was washed with MeOH and the
filtrate was concentrated to yield pure 21-3 as a tan solid.
lH NMR (400 MHz, CDC13) ~ 7.8 (d, lH), 6.6 (m, 2H), 2.5 (s, 3H).
15 Rf (90 % Ethyl Acetate/Hexane)=0.34
C H30 ~
C H3 O H
~1-4
Methyl 4-hydroxy-2-methylbenzoate (21-4)
21-3 (5.0 g, 32.9 mmol) was redissolved in MeOH (150
mL) and cooled to 0~. HCI (g) was bubbled through for a few minutes,
the cooling bath was removed and the reaction was stirred at RT for 16
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hours. The reaction mixture was then concentrated to yield pure 21-4
as a tan solid.
Rf (50% Ethyl Aceta e/Hexane)=0.83
lH NMR (400 MHz, CDC13) ~ 7.9 (d, lH), 6.7 (m, 2H), 3.85 (s, 3H),
5 2.57 (s, 3H).
CH30 J~
CH3 O~,COOEt
21 -5
Ethyl 2-(3-methyl-4-methoxycarbonylphenoxy)acetate (21-5)
21-4 (1.5 g; 9.0 mmol) was dissolved in DMF (150 mL).
Ethyl bromoacetate (9.0 mmol, 1.0 mL) was added followed by Cs2C03
(9.0 mmol, 2.9 g). The slurry was stirred vigorously for 16 hours.
The reaction mixture was diluted with EtOAc and washed twice with
water, 10% KHSO4 and brine. The organic layer was dried (MgSO4),
15 filtered and concentrated to yield 21-5 which will be used in the next
step without any further purification.
Rf (30 % Ethyl Acetate/Hexane)=0.40
1H NMR (400 MHz, CDCl3) ~ 7.9 (d, lH), 6.7-6.~ (m, 2H), 4.6 (s, 2H~,
4.3-4.3 (q, 2H), 3.9 (s, 3H), 2.6 (s, 3H), 1.3 (t, 3H).
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Br~l'O~COOEt
21 -6
Ethyl 2-(3-bromomethyl-4-methoxycarbonylphenoxy)acetate (21-6)
21-5 (2.1 g; 8.3 mmol) was dissoved in CCl4 (40 mL).
5 NBS (10.3 mmol, 1.9 g) was added followed by dibenzoyl peroxide
(1.66 mmol, 400 mg). The reaction mixture was heated to reflux for 16
hours. The reaction mixture was cooled and filtered through a celite
pad to remove excess succinimide. The filtrate was concentrated to
yield 21-6 as a tan oil, which was used in the next step without any
10 further purification.
Rf (30% Ethyl Acetate/Hexane)=0.52
tBuO N ~N~N~l
COOEt
21 -7
15 Ethyl 1-(4-(1,1-Dimethylethoxycarbonylpiperazin-l-yl)phenyl)-2-oxo-
isoindolin-5-oxy)acetate (2 1-7)
21-6 (8.3 mmol) was dissolved in benzene (100 mL),
followed by 14 3. The mixture was heated to reflux for 32 hours.
Triethylamine (8.3 mmol) was added and the reaction was refluxed for
20 2 more days. The reaction mixture was then concentrated to yield a
brown solid which was absorbed on silica and purified by flash
- chromatography. A small amount of the product was eluted with 50%
EtOAC/Hex. Most of the material was then flushed off the column with
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10% MeOH/CHC13 saturated with NH3. These flushings yielded a brown
solid which was repurified on a column of silica using 10%
MeOH/CHC13 as a eluent to yield 21-7 as a brown solid.
Rf (50% EtOAc/Hex)=0.48
5 1H NMR (400 MHz, CDC13) ~ 7.8 (d, lH), 7.7 (d, 2H), 7.0 (m, 4H),
4.77 (s, 2H), 4.72 (s, 2H), 4.3 (q, 2H), 3.6 (m, 4H), 3.1 (m, 4H), 1.5 (s,
9H), 1.3 (t, 3H).
tBuO N~N--~N~
COOH
21 -8
1-(4-(1, I -Dimethylethoxycarbonylpiperazin- 1 -yl)phenyl)-2-oxo-
i~soindolin-5-oxy)acetic acid (21-8)
2~-7 (1.3 g; 2.6 mmol) was dissolved in THF/H20/MeOH
(5 mL/5/5). LiOH (5.2 mmol, 218 mg) was added and the reaction
lS mixture was stirred for 2 hours. 1 N HCl was added (2.6 mL), and the
reaction mixture was concentrated to yield 21-8 and excess LiCl as a
brown solid.
Rf(9/1/1 CH2CH2/MeOH/HOAc)=0.80
IH NMR (400 MHz, CD30D) ~ 7.7 (m, 3H), 7.0-7.1 (m, 4H), 3.3 (bm,
20 4H), 3.1 (bm, 4H), 1.5 (s, 9H).
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TFA ~ HN - N~N~
21-9 COOH
1-(((4-Piperazin-l-yl)phenyl)-2-oxo-isoindolin-5-oxy)acetic acid (21-9)
21-8 (2.6 mmol) was dissolved in EtOAc and cooled to
5 -78~. HCI was bubbled through until the solution was saturated. The
reaction mixture was then stirred at 0~ for 10 min and concentrated to
yield a brown solid. Flash chromatography (10/0.8/0.8 EtOH/NH40H/
H20) yielded 21-9 as a brown solid. This material was further purified
by preparative HPLC to yield pure 21-9 (TFA salt) as an off-white
1 0 solid.
Rf(10/1/1 EtOH/NH40H/H20)=0.72
lH NMR (400 MHz, DMSO- d6) ~ 7.8 (d, 2H), 7.7 ~d, lH), 7.2 (s, lH),
7.1 (d, 3H), 4.9 (s, 2H), 4.8 (s, 2H), 3.2-3.3 (bd, 8H).
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SCHEME 22
J~ ~CH3 22-1
AlCI3/CH3NO2
o
H3C NH ~ 22-2
1. pyridine
H C~NJ~[~ C 22-3
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SCHEME 22 (CONT'D)
22-3
NaOH
o
~OH 22-4
H2N CH3
HCI/n-butanol
r o
HCI . ~oC4H9 22-5
H2N CH3
.. . , . . ~ .
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SCHEME 22 tCONT'D)
HCI . ~J~OC4H9 22-5
H2N CH3
HN(CH2CH2CI)2
1~l
OC4Hg 22-6
f/~N CH3
HCI . HNJ BOC20
o
~¢~OC4Hg 22-7
~N CH3
tBuO~"N~J
o
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SCHEME 22 (CONT'D)
22-7
NaOH/EtOH/reflux
,~OH 22-8
~N CH3
tBuO~NJ
H2N~O~[~ /PYCLU
/ N~CH, 22-9
tBuO~,N~J
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SCHEME 22 (CONT'D)
~ N C H3 22-9
tBuO~NJ
O nBuLi/CNBr
N 3 0~ 22-10
tBuO N~J
H2/Pd/C/HOAc
~N i ~OH 22-11
tBuO~n,N~J
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SCHEME 22 (CONT'D)
22-1 1
Cs2CO3/BrCH2CO2Et
~N J3~N~O~CO2Et ~-12
tBuO N~J
HCI / EtOAc
~ N~N~O~CO2Et 22-13
HCI ~ HN J
NaOH
~N~N~O~,~CO2H 22-1 4
HNJ
~ ~ .. . .
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H3C H ,¢~CI
l-Chloro-2-(2-methyl-4-acetamidophenyl)ethanone (22-2)
A suspension of 3-acetamido toluene (Aldrich) (33.45 g,
5 0.224 mole) in nitromethane (100 mL) was treated with
chloracetylchloride (69.3 mL, 0.739 mole). The solution became
homogenous. Aluminum trichloride (92.3 g, 0.694 mol) was added in
10 g portions over 40 minutes. The temperature rose to 50~C and the
solution became dark brown. The reaction was heated to 80~C for 2
10 hours, then cooled to room temperature and concentrated to give a thick
green oil that was added to crushed ice and stirred with a overhead
stirrer. The resulting tan solid was collected in a sintered glass funnel
and washed with water and dried to give 22-2 as a tan solid.
Rf (40% EtOAc/Hexanes)=0.14.
lH NMR (300 MHz, CDC13) ~ 7.66 (d, lH), 7.58 (m, lH), 7.43 (s, lH),
7.28 (s, lH), 4.62 (s, 2H), 2.55 (s, 3H), 2.2 (s, 3H).
O ~
o ~N~J
H3C H ~ + Cl- 22-3
.
20 1 -(1 -Pyridinium)-2-(2-methyl-4-acetamidophenyl)
ethanone, chloride (22-3)
A solution of 22-2 (21.8 g, 0.098 mol) in refluxing ethanol
(110 mL) was treated with pyridine (28 mL). A salmon-pink
percipitate formed and after 2 hours of reflux the mixture was cooled to
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room temperature, filtered and rinsed with cold (-20~C) EtOH and dried
to give 22-3 as an off-white solid.
Rf (9: 1: 1 EtOH/H20~H40H) 0.12
lH NMR (400 MHz, D20) ~ 8.66 (d, 2H), ~.5 (m, lH), 8.08 (d, 2H),
5 7.92 (d, lH), 7.5 (d, lH), 7.33 (s, lH), 2.4 (s, 3H), 2.1 (s, 3H).
~OH
H2N ~C~3 22-4
2-Methyl-4-amino-benzoic acid 22-4
To a 60~C solution of 22-3 (23.5 g, 0.077 mol) in H20
(155 rnL) was added 2.5 M NaOH solution (160 mL). An orange
percipitate formed. The reaction was heated to reflux for 2.5 hours,
then the homogenous solution was cooled to room temperature and
treated with 2.5 M HCI (160 mL) and stirred overnight. The pH of the
15 solution was adjusted to pH 4-5 with NaOH solution and the yellow
percipitate that formed was washed with water and dried to give 22-4 as
a gummy yellow solid.
Rf(9: 1: 1 EtOH/H20/NH40H)=0.76.
1H NMR (300 MHz, CD30D) ~ 7.75 (d, lH), 6.43 (m, 2H), 2.42 (s,
20 3H).
~ _ .
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HCI - ,~ OC4Hg
H2N C H3 22-5
n-Butyl 2-methyl-4-amino-benzoate~ hydrochloride (22-5)
A suspension of 22-4 (8.8 g, 58 mmol) in n-butanol (200
5 mL) was cooled to 0~C under argon and saturated with HCl gas. A
salmon-pink percipitate formed. The solution was heated to reflux for
18 hours then evaporated. The residue was dissolved in EtOAc and
saturated NaHCO3 and the layers were separated. The aqueous layer
was washed repeatedly with EtOAc, the EtOAc layers were combined,
10 dried with brine and MgSO4, filtered and evaporated. The oily residue
was dissolved in CHC13 and evaporated to give 22-5 as a brown solid.
Rf (20% EtOAc/Hexanes) 0.5
lH NMR (300 MHz, CDC13) ~ 7.83 (d, IH), 6.48 (m, 2H), 4.23 (t, 2H),
3.9 (bs, 2H), 2.53 (s, 3H), 1.7 (m, 2H), 1.48 (m, 3H), 0.95 (t, 3H).
HCI- HN N~ 22-6
\--/ OC4Hg
CH3
n-Butyl 2-methyl-4-piperizin-1-yl-benzoate. hydrochloride (22-6)
A solution of 22-5 (10.7 g, 52 mmol) in n-butanol (285
20 mL) was treated with bis chloroethylamine hydrochloride (9.22 g, 52
mmol) and refluxed for one week. The ethanol was removed in vacuo
and the residue was diluted with EtOAc. A percipitate formed and was
collected and washed with EtOAc and dried to give 22-6 as tan solid.
Rf (2.5% MeOH/CHC13 saturated with NH3)=0.31
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lH NMR (400 MHz, CD30D) ~ 7.88 (d, lH), 6.88 (m, 2H), 4.24 (t,
2H), 3.55 (m, 4H), 3.36 (m, 4H), 2.56 (s, 3H), 1.73 (m, 2H), 1.5 (m,
2H), 1.0 (t, 3H).
o,~N~N~oc4Hs 22-7
CH~
n-Butyl 2-methyl-4-(4-( 1,1 -dirnethylethoxycarbonylpiperizin- 1 -yl)-
benzoate acid (22-7)
A solution of 22-6 (10.5 g, 33.3 mmol) in CH2Cl2 (100
mL) was cooled to 0~C and treated with triethylamine (18.8 mL, 0.133
10 mol) and di-tert-butyldicarbonate (14.75 g, 66 mmol). The solution was
allowed to warm to room temperature and after 1 hour was washed with
10% KHSO4, brine, dried over MgSO4, filtered and evaporated to give
22-7 as brown oil.
Rf (5% EtOAc/Hexanes)=0.4
15 lH NMR (300 MHz, CDCl3) ~ 7.9 (d, 2H), 6.68 (m, 2H), 4.23 (t, 2H),
3.55 (m, 4H), 3.38 (m, 4H), 2.6 (s, 3H), 1.75 (m, 2H), 1.5 (m, 1 lH),
0.95 (t, 3H).
o,~N ~N~OH 22-8
CH3
2-Methyl-4-(4-( 1, l -dimethylethoxycarbonylpiperizin- 1 -yl)
benzoic acid (22-8)
A solution of 22-7 (2.55 g, 6.78 rnrnol) in 4:1 EtOH/H20
(125 mL) was treated with NaOH (2.7 g, 67.8 rnrnol) and refluxed
- 25 overnight. The solvents were removed and the residue was partitioned
between EtOAc and 10% KHSO4. The layers were separated and the
aqeous layer was washed with EtOAc several times. The organic layers
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were combined, washed with brine, dried over MgSO4, filtered and
evaporated to give 22-8 as a white solid.
lH NMR (400 MHz,-CDC13) ~ 8.0 (d, lH), 6.7 (m, 2H), 3.6 (m, 4H),
3.34 (m, 4H), 2.6 (s, 3H), 1.5 (s, 9H).
N~O~ 22-9
~N CH3
tBuO~NJ
N-(4-Benzyloxyphenyl)-2-methyl-4-(4-( 1,1 -dimethylethoxycarbonyl)
piperizin- 1 -yl)benzamide (22-9)
A solution of 22-8 (2.06 g, 6.43 mmol) in CH2C12 (50 mL)
was treated with p-benzyloxy analine hydrochloride (Aldrich, 1.66 g,
7.08 mmol), diisopropyl amine (5.6 mL, 32 mmol) and PYCLU 93.47
g, 9.6 mrnol). After stirring for 24 hours the volatile components were
removed in vacuo and the residue was dissolved in EtOAc and washed
15 with 10% KHSO4, water, saturated NaHCO3, water and brine, dried
over MgSO4, filtered and evaporated. The residue was
chromatographed in a gradient of 20 to 50% EtOAc/Hexanes to give
22-9 as an oil.
Rf (50% EtOAc/Hexanes)=0.57
20 lH NMR (400 MHz, CDC13) ~ 7.4 (m, 8H), 7.0 (d, 2H), 6.76 (m, 2H),
4.08 (s, 2H), 3.6 (s, 4H), 3.22 (bs, 4H), 2.53 (s, 3H), 1.5 (s, 9H).
, . , , .,, . . , . . ... , . . ~, , .
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,¢~ ~ 22-10
tBuO~N~J
O
1 -(4-Benzyloxyphenyl)-5-(4-(1,1 -dimethylethoxycarbonyl)piperizin- 1 -
yl)isoindolin-2-one (22- 10)
A solution of 22-9 (0.66 g, 1.31 mmol) in THF (65 mL)
was cooled to -78~C under argon. n-Butyllithium (2.2M in hexanes, 2.4
mL) was added dropwise to give a deep red solution. The reaction was
stirred for 20 minutes, then rapidly transferred via wide bore canulla to
a -78~C THF solution of cyanogen bromide (2.77 g, 26.2 mmol in 65
mL). The resulting colorless solution was stirred for 25 minutes, then
quenched with methanol. The solution was diluted with water, the
volatile solvents were removed in vacuo and the rem~ining water layer
was extracted with EtOAc. The EtOAc layer was washed with brine,
dried over MgSO4, filtered and evaporated. The residue was
chromatographed in a gradient of 20 to 30% EtOAc/Hexanes to give
22-10 as an oil.
Rf (40% EtOAc/Hexanes)=0.25
lH NMR (400 MHz, CDC13) ~ 7.77 (s, lH),7.7 (d, 2H), 7.44 (m, 2H),
7.4 (m, 2H), 7.34 (m, lH), 7.0 (m, 3H), 6.9 (s, lH), 5.1 (s, 2H), 4.73 (s,
2H), 3.6 (m, 4H), 3.3 (m, 4H), 1.5 (s, 9H).
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~N~ OH
tBuO~,N~J 22-1 1
1 -(4-Hydroxyphenyl)-5-(4-( l ,1 -dimethylethoxycarbonyl)piperizin- 1-
5 yl)isoindolin-2-one (22-1 1 )
A solution of 22-10 (0.155 g, 0.31 mmol) in 10 mL glacial
acetic acid was treated with 10% Pd/C (0.3 g) and hydrogenated at 60
psi for S hours. The solution was decanted from the catalyst,
concentrated and the residue chromatographed using a gradient of 60 to
10 90% EtOAc/Hexanes to give 22-11 as an oil.
Rf(50% EtOAc/Hexanes)=0.19
lH NMR (300 MHz, CDC13) ~ 7.79 (d, lH), 7.55 (d, 2H), 7.0 (m, lH),
6.92 (bs, lH), 6.86 (m, 2H), 4.72 (s, 2H), 3.6 (m, 4H), 3.3 (m, 4H), 1.5
(s, 9H)-
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~N~N~O~CO2Et
tBuO~ N~J 22-12
Ethyl 4-(2-oxo-5-(4-( 1,1 -dimethylethoxycarbonyl)piperizin- 1 -yl)iso-
indolin-- 1 -yl)phenoxyacetate (22-12)
S A solution of 22-1 1 (0.045 g, 0.11 mmol) in DMF (5 ml)
was treated with cesium carbonate (23 mg, 0.07 mmol) and ethyl
bromoacetate (15 uL, 0.011 mmol). After 3 hours the solvents were
removed in vacuo and the residue was dissolved in EtOAc and washed
with water, brine, dried over MgSO4, filtered and evaporated. The
10 residue was chromatographed in a gradient of 30 to 50%
EtOAc/Hexanes to give 22-12 as an oil.
Rf(40~7O EtOAc/Hexanes)=0.36
lH NMR (400 MHz, CDC13) ~ 7.74 (m, 3H), 7.0 (m, 2H), 6.95 (m, 2H),
4.73 (s, 2H), 4.62 (s, 2H), 4.28 (q, 2H), 3.6 (m, 4H), 3.3 (m, 4H), 1.5
15 (s, 9H).
.. . .. ... .
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~ N'~N~O~CO2Et
tlNJ. HCI 22-13
Ethyl 4-(2-oxo-5-piperizin- l -yl)isoindolin- l -yl)phenoxyacetate,
hydrochloride (22- 13)
A solution of 22-12 (0.04 g, 0.08 mmol) in EtOAc (10 mL)
was cooled to -78~C, saturated with HCI gas, warmed to 0~C and
evaporated at ambient temperature to give 22- 13 as a white solid.
lH NMR (300 MHz, D2O) ~ 7.54 (d, lH), 7.4 (d, 2H), 7.03 (m, 3H),
6.89 (d, 2H), 4.6 (s, 2H), 4.15 (q, 2H), 3.43 (m, 4H), 3.23 (m, 4H), 1.15
10 (t, 3H).
~N~N~ O~CO2H
HNJ ~2-14
4-(2-Oxo-5-piperizin-1-yl)isoindolin-l-yl)phenoxyacetic acid (22-143
A solution of 22-13 (0.04 g, 0.08 mmol) in 1:1 THF/H20
(6 mL) was treated with lN NaOH solution (0.4 rnL). The reaction was
concentrated and the residue chromatographed in 9:1:1
EtOH/H20/NH40H to give 22-14 as a white solid.
Rf(9: 1: l EtOH/H20/NH40H)=0.62
IH NMR (400 MHz, D2O + deutero trifluoroacetic acid) ~ 7.49 (d, lH),
7.44 (d, 2H), 6.95 (m, 3H), 6.74 (d, 2H), 4.33 (bs, 4H), 3.42 (bs, 4H),
3.25 (bs, 4H).
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SCHEME 23
Il I
H2N NO2
BOC20
tBuOJ~ N~No2 23-1
Cs2CO3/BrCH2CO2Et
o f~~~C~2Et
tBuO NH ~ No2 23-2
1. H2 Pd/C
2. CH3SO2CI
tBuO H J~O~CO2Et ~ ,~N O
23-3 HCI /EtOAc 23-3a
HCI ,~O~,CO2Et
. H2N NHSO2CH3 23-4
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SCHEME 23 (CONT'D)
23-4
tBuO~ r~ ~o 1-5
O --/ OH
o~N~N~3~N~o 23-5
H ~ CO2Et
NHSO2CH3
/ 1. HCI/ EtOAc
/ 2. LiOH
~ H ~NHSO2CH3
/--N
HN J 23-6
, . . ., ~ . . ,
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SCHEME 23 (CONT'D)
o ~O~,C02Et
tBuO HN J~ N~2
23-2
o,~N~ ~N~H~ ~CO2Et
23-7 N~2
HN N~ ~
H ~ CO2H
23-8 N~2
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O ~O~co2Et
tB OJ~ N~No2 23-2
1. H2 Pd/C
2. 3-pyridylSO2CI
O ~O~,CO2Et
tBuONH~ NHSO2~ 23-9
HCI /EtOAc
~O~,CO2Et 23-1 0
HCI . H2N~NHSO2~ 1-5
tBUO~ r~N~ PYCLU
O ~O~co2Et
N~Jl N~NHSO2~ 23-11
tBuO~N~J 1 HCUEtOAc
O ~O~,CO2H
~ NHJ~ NHSO
HNJ
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'¢~~~2
23-1
2-Nitro-4-(1. I -dimethylethoxycarbonylamino)phenol (23- 1)
A solution of 2-nitro-4-amino phenol (Aldrich) (20 g, 130
S mmol) in THF (500 mL) was cooled to 0~C and treated with di-
tertbutyldicarbonate (64 g, 293 mmol) and triethylamine (37 mE, 265
rnmol). After 24 hours the solution was concentrated and the residue
dissolved in EtOAc, washed with 10% KHSO4, saturated NaHCO3, and
brine, dried over Na2SO4, filtered and evaporated. The crude bis-
10 protedted material (Rf (40% EtOAc/Hexanes) 0.69) was then dissolvedin 400 mL 1 :1 THF/H2O and treated with LiOH-H2O (38 g, 1.3 mol).
After stirring at room temperature overnight the solvent was removed
and the residue was dissolved in EtOAc and washed with brine, dried
with Na2SO4, filtered and concentrated to give 23-1 as a reddish oily
15 solid.
Rf(20% EtOAc/Hexanes)=0.41
1H NMR (400 MHz, CDC13) ~ 10.35 (s, lH), 8.18 (s, lH), 7.58 (d, lH),
7.13 (d, lH), 6.45 (bs, lH), 1.55 (s, 9H).
o ~O~,C02Et
tBuO H ~ NO2
23-2
Ethyl 2-(2-nitro-4-(1,1 -dimethylethoxycarbonylamino)phenoxy)acetic
acid (23-2)
A solution of 23-1 (5 g, 19.7 mmol) in DMF (125 mL) w~s
25 treated with cesium carbonate (3.17 g, 9.73 mmol), stirred for 10
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minutes and treated with ethyl bromoacetate (2.2 mL, 19.8 mrnol) at
room temperature. After 1.5 hours the solution was concentrated under
high vacuum and the-residue was absorbed to silica gel and
chromatographed in a gradient of 20 to 30% EtOAc/Hexanes to give
5 23-2 as a bright yellow solid.
Rf(30% EtOAc/Hexanes)=0.26
1H NMR (400 MHz, CDC13) ~ 7.95 (s, lH), 7.5 (d, lH), 6.97 (d, lH),
6.62 (bs, lH), 4.72 (s, 2H), 4.25 (q, 2H), 1.5 (s, 9H), 1.28 (t, 3H).
~O~,CO2Et
HCI 11 1
H2N ~ NHSO2CH3
23-4
Ethyl 2-(2-methanesulfonamido-4-aminophenoxy)acetic acid
hydrochloride (23-4)
A solution of 23-2 (2 g, 5.88 mmol) in EtOAc (25 mL) was
15 treated with 10% Pd/C (0.67 g), and hydrogenated under balloon
pressure for 1.5 hours. The solution was filtered through SolkaFloc,
and the cake rinsed with EtOAc. The ~iltrate was not concentrated but
was treated directly with methanesulfonyl chloride (3.0 mL, 39 mmol)
and pyridine (5.0 mL, 62 mmol) and stirred overnight. The solution
20 was concentrated and the residue was dissolved in EtOAc and washed
with 10% KHS04, saturated Na2CO3, and brine, dried with Na2SO4,
filtered and concentrated to give a yellow oil that was chromatographed
(40% EtOAc/Hexanes) to give 23-3 (Rf 30% EtOAc/Hexanes) 0.19)
cont~min~ted with 23-3a. The mixture (1.7 g) was dissolved in EtOAc
25 (75 mL), cooled to -78~C and saturated with HCl gas, warmed to 0~C
for 1 hour and concentrated. The residue was partitioned between
CH2C12 and saturated NaCO3, the layers separated and the aqueous
layer extracted with CH2C12. The organic layer was dried over
.... ... .. .
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Na2SO4, filtered and evaporated and the residue chromatographed
(60% EtOAc/Hexanes) to give 23-4 as an off-white solid.
Rf(60% EtOAc/Hexanes) 0.3
1H NMR (400 MHz, CDC13) ~ 7.7 (bs, lH), 6.95 (s, lH), 6.74 (d, lH),
5 6.4 (d, lH), 4.6 (s, 2H), 4.33 (q, 2H), 2.98 (s, 3H), 1.3 (t, 3H).
o,~N~N~3--~H~ ~CO2Et
NHSO2CH3
Ethyl 2-(4-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -yl)phenyl-
10 carbonylamino)-2-methanesulfonamidophenoxy)acetate (23-5)
A suspension of 23-4 (0.125 g, 0.433 mmol) and 1 5 (0.136
g, 0.444 mmol) in CH2C12 (4 mL) was treated with diisopropylamine
(0.3 mL, 1.7 mmol) and PYCLU (0.173 g, 0.48 mmol) and stirred at
room temperature for three days. The solution was concentrated and
15 the residue was absorbed to silica gel and chromatographed in a gradient
of 20 to 60% EtOAc/Hexanes to give 23-5 as a pale yellow oil.
Rf (60% EtOAc/Hexanes)=0.27
1H NMR (400 MHz, CDC13) ~ 7.82 (dd, lH), 7.79 (s, lH), 7.77 (s, lH),
7.54 (bs, lH), 7.48 (s, lH), 6.90 (m, 3H), 4.7 (s, 2H), 4.25 (q, 2H), 3.6
20 (m, 4H), 3.3 (m, 4H), 3.03 (s, 3H), 1.5 (s, 9H), 1.3 (t, 3H).
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O ~0 ,C02H
'' N ~ NHSO2CH3
~N
HNJ
2-(4-(4-(Piperazin- 1 -yl)phenylcarbonylamino)-2-methane-
S sulfonamidophenoxy)acetic acid (23-6)
A solution of 23-5 (0.093 g, 0.16 mmol) was dissolved in
EtOAc (10 mL), cooled to -78~C and saturated with HCl gas, waImed to
0~C for 1 hour and concentrated. The resulting white solid was
dissolved in 1:1:1 H20/THF/MeOH, treated with LiOH-H20 (0.038 g,
10 0.9 mmol) and stirred at room temperature for 1 hour. The reaction
was concentrated and chromatographed (18:1:1 EtOH/H2O/NH4OH) to
give a yellow oil that was diluted with CH2C12 and evaporated to give
23-6 as white solid.
Rf(9:1:1 E~tOH/H2OtNH40H)=0.48
lH NMR (400 MHz, D2O + NaOD) ~ 7.74 (s, lH), 7.72 (s, lH), 7.21 (s,
lH), 7.07 (s, lH), 7.05 (s, lH), 6.9 (d, lH), 6.74 (d, lH), 4.38 (s, 2H),
3.15 (m, 4H), 2.85 (m, 7H).
.. , . ., . . ., .. , . .. ~ ......
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o,~N~N~H~ ~CO2Et
23-7 NO2
Ethyl 2-(4-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-
S yl)phenylcarbonylamino)-2-nitrophenoxy)acetate t23-7)
A solution of 23-2 (0.3 g, 0. 88 mmol) was dissolved in
EtOAc (10 mL), cooled to -78~C and saturated with HCI gas, warmed to
0~C for 1 hour and concentrated to give Ethyl 2-(2-nitro-4-
aminophenoxy)acetic acid as a white solid that was coupled immediately
10 (0.26 g, 0.88 mmol) to 1 S (0.29 g, 0.95 mmol) as described for 23-S to
give 23-7 as a yellow solid after chromatography in a gradient of 40 to
100% EtOAc/Hexanes.
Rf(50% EtOAc/Hexanes)=0.22
HN N~N~ ~CO2H
23-8 N~2
2-(4-(4-(Piperazin- 1 -yl)phenylcarbonylamino)-2-nitrophenoxy)-
acetic acid (23-8)
A solution of 23-7 (0.186 g, 0.352 mmol) in EtOAc was
20 treated first with HCl gas then with LiOH-H20 as described for 23-6 to
give 23-8 as a yellow solid after chromatography in 18:1:1
EtOH/H20/NH40H) .
Rf(l 8:1:1 EtOH/H20/NH40H)=0.47
- lH NMR (400 MHz, D20) ~ 8.0 (s, lH), 7.68 (2s, 2H), 7.52 (d, lH), 7.0
25 (m, 2H), 3.12 (bs, 4H), 2.85 (bs, 4H).
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~BuO~ ~
H \=( ~ CO2Et
NHSO23-pyridyl
23-9
Ethyl 2-(2-(3-pyridyl)sulfonamido-4-(1,1 -dimethylethoxycarbonyl)-
5 aminophenoxy)acetate (23-9)
A solution of 23-2 (2 g, 5.88 mrnol) in EtOAc (25 mL) was
treated with 10% Pd/C and 3-pyridylsulfonyl chloride (JOC, 1989, 54,
389-393) as described for 23-3 to give 23-9 after chromatography in a
gradient of 30 to 50% EtOAc/Hexanes as a white solid.
10 Rf(40% EtOAc/Hexanes)=0.11
lH NMR (400 MHz, CDC13) ~ 9.02 (s, lH), 8.71 (d, lH), 8.1 (m, 2H),
7.4 (s, lH), 7.33 (m, 2H), 6.69 (d, lH), 6.58 (s, lH), 4.4 (s, 2H), 4.23
(q, 2H), 1.5 (s, 9H), 1.25 (t, 3H).
tBuO~N~N ~ Q
O H ~ CO2Et
23-11 NHSO23-pyridyl
Ethyl 2-(4-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -yl)phenyl-
carbonylamino)-2-(3-pyridylsulfonamido)phenoxy)acetate (23- 11)
A solution of 23-9 (0.318 g, 0.704 mrnol) in EtOAc (10
20 mL) was treated with HCl gas as described for 23-4 to give 23-10 as a
white solid that was coupled directly with 1 5 as described for 23-5 to
give 23-11 as a oily yellow solid after chromatography in a gradient of
20 to 40% acetone/Hexanes.
Rf(50% EtOAc/Hexanes)=0.41
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H NMR (400 MHz, CDC13)
HN N~ ~
H ~CO2H
NHSO23-pyridyl
23-1 2
5 2-(4-(4-(Piperazin- 1 -yl)phenylcarbonylamino)-2-(2-(3-pyridyl-
sulfonamido)phenoxy)acetic acid (23-12)
A solution of 23-1 1 (0.047 g, 0.087 mmol) in EtOAc was
treated first with HCI gas then with LiOH-H20 as described for 23-6 to
give 23-12 as a yellow solid after chromatography in 18
10 EtOH/H20/NH40H).
Rf(18:1:1 EtOH/H20/NH40H)=0.38
lH NMR (400 MHz, D20 + NaOD) ~ 8.76 (s, lH), 8.5 (m, lH), 8.13
(m, lH), 7.7 (m, 2H), 7.45 (m, lH), 7.12 (s, lH), 7.08 (m, 2H), 6.84
(m, lH), 6.67 (d, lH), 4.13 (s, 2H), 3.25 (m, 4H), 2.87 (m, 4H).
~O~,CO2Et
02N OCH3
23-13
Ethyl 2-(2-methoxy-4-nitrophenoxy)acetic acid (23-13)
2-methoxy-4-nitro phenol (Aldrich) (1.0 g, 5.9 mmol) was
20 treated with cesium carbonate and ethylbromoacetate as described for
23-2 to give crude 23-13 after removal of DMF. The crude material
was partitioned between water and EtOAc, the organic layer was dried
with brine and MgS04, filtered and evaporated to give 23-13 as a
yellow solid.
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Rf(50% EtOAc/Hexanes)=0.54
1H NMR (400 MHz, CDC13) ~ 7.8 (d, lH), 7.76 (s, lH), 6.75 (d, lH),
4.71 (s, 2H), 4.2 (q, ~H), 3.9 (s, 3H), 1.21 (t, 3H).
O~,CO2Et
H2NJ~ocH3
23-14
Ethyl 2-(2-methoxy-4-aminophenoxy)acetic acid (23-14~
A solution of 23-13 (0.7 g, 2.7 mmol) in EtOH (10 mL)
was treated with 10% Pd/C (0.14 g) and hydrogenated at balloon
pressure. The solution was filtered through Solka-Floc and evaporated
10 to give 23-14 as a tan oil.
1H NMR (400 MHz, CDCl3) ~ 6.78 (d, lH), 6.33 (s, lH), 6.21 (d, lH),
4.59 (s, 2H), 4.21 (q, 2H), 3.8 (s, 3H), 3.45 (bs, 2H), 1.28 (t, 3H).
tBuO~N~N~ ~
O H ~ CO2Et
23-15 OCH3
Ethyl 2-(4-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -
yl)phenylcarbonylamino)-2-methoxyphenoxy)acetate (23-15)
Acid 1 5 and amine 23-14 were coupled as described for
23-5 to give 23-15 as brown solid after chromatography in 50%
20 EtOAc/Hexanes.
Rf(50% EtOAc/Hexanes)=0.13
lH NMR (400 MHz, CDCl3) ~ 7.8s (d, 2H), 7.6 (d, lH), 6.92 (d, 2H),
6.86 (m, 2H), 4.64 (s, 2H), 4.24 (q, 2H), 3.9 (s, 3H), 3.6 (m, 4H), 3.3
(m, 4H), 1.5 (s, 9H), 1.25 (t, 3H).
... . , . .. ,, . , .. , . ~ ...
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HN N~N ~0 23-16
H ~ CO2H
OC H3
2-(4-(4-(4-Piperazin- 1 -yl)phenylcarbonylamino)-2-methoxy-
phenoxy)acetic acid (23 - 16)
S Compound 23-15 was treated with LiOH and HCl gas as
described for 23-6 to give 23-16 as a white solid after chromatography
in 10:1:1 EtOH/H20/NH40H.
Rf (10:1:1 EtOH/H2O/NH40H)=0.15
1H NMR (400 MHz, D2O) ~ 7.78 (d, 2H), 7.15 (s, lH), 7.08 (d, 2H),
6.9 (m, lH), 6.78 (d, lH), 4.4 (s, 2H), 3.8 (s, 3H), 3.18 (bs, 4H), 2.88
(bs, 4H).
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SCHEME 24
~Br
HN N 24-1
H J. Am. Chem. Soc., 1987,109, 3378
BOC20
tBuO~ N H Br 24-2
1. CH3MgBr
2. tert-BuLi
3. C ~2
~OH 24-3
H2N~O~,CO2Et PYCLU/i-Pr2NEt
HCI . CH3 10-4
tBuO~N ¦,-- N~o~CO2Et 24-4
1 . HCI/EtOAc
2. LiOH
H ~O~CO2H 24-5
- CH3
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tBu~N~3Br 24-2
o
2-( l, l -Dimethylethoxycarbonyl)-7-bromo- 1,2,3,4-tetrahydro-9H-
pyridor3~4-blindole (24-2)
A suspension of 24-1, prepared by the method of Rinehard
et al. (J. Am. Chem. Soc., 1987, 109, p 3378-3387) (0.366 g, 1.46
mmol) in CH2C12 (8 mL) was treated with triethyl~mine (0.61 mL, 4.4
mmol) followed by di-tert-butyldicarbonate (0.38 g 1.7 rr~mol) for 1
hour at room temperature. The so}ution was concentrated and the
residue chromatographed (20% EtOAc/Hexanes) to give 24-2 as a white
solid.
Rf (20% EtOAc/Hexanes)=0.28.
lH NMR (400 MHz, CDCl3) ~ 8.0-7.6 (m, lH), 7.46 (s, lH), 7.33 (d,
lH), 7.2 (d, lH), 4.6 (bs, 2H), 3.78 (bs, 2H), 2.76 (bs, 2H), 1.5 (s, 9H).
tBuO~N~ 24-3
o
2-(1, l -Dimethylethoxycarbonyl)- 1,2,3,4-tetrahydro-9H-pyrido[3,4-
blindol-7-yl carboxylic acid (24-3)
A solution of 24-2 (0.26 g, 0.734 mmol) in THF (10 mL)
was cooled to 0~C and treated with methylmagnesium chloride (3.0 M in
THF, 0.29 mL, 0.87 mmol) to give a pale yellow solution. After 15
minutes the solution was cooled to -78~C and treated with tBuLi (1.7M
in pentane, 4.35 mL, 7.39 mmol) to give a bright yellow solution.
After 10 minutes CO2 gas was bubbled vigorously through the solution
for 10 minutes. Saturated NH4Cl, water and enough 6N NaOH to reach
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pH12 were added and the solution extracted with EtOAc. The EtOAc
layer was back extracted with 0.5 NaOH and the aqueous layers
combined, acidified to pH 7 and extracted with EtOAc, the EtOAc layer
was dried (Na2SO4) filtered and concentrated to give 24-3 as an off-
5 white solid.
Rf(75 :25: 1 CHC13/MeOH/HOAc)=0.48.
1H NMR (400 MHz, DMSO-d6) ~ 12.0 bs, lH), 11.2 (s, lH), 7.93 (s,
lH), 7.6 (d, lH), 7.45 (d, lH), 4.6 (s, 2H), 3.68 (m, 2H), 2.7 (m, 2H),
1.4 (s, 9H).
tBuO~ ~O~CO2Et 24-4
Ethyl 4-(2-(1,1 -dimethylethoxycarbonyl)- 1,2,3,4-tetrahydro-9H-
pyridor3~4-blindol-7-yl)carbonylamino)-3-methylphenoxyacetate (24-4)
A solution of 24-3 (0.078 g, 0.25 mmol) and .10-4 (0.303 g,
1.23 mmol) in CH2C12 were treated with diisopropylamine and PYCLU
as described for 23-5 to give.24-4 as a white solid after chromatography
in a gradient of 40 to 60% EtOAc/Hexanes.
Rf (40% EtOAc/Hexanes)=0.11
20 lH NMR (400 MHz, CDC13) ~ 8.5-8.2 (m, lH), 8.0 (s, lH), 7.75 (d,
lH), 7.63 (s, lH), 7.52 (s, 2H), 6.83 (s, lH), 6.80 (d, lH), 4.7 (bs, 2H),
4.6 (s, 2H), 4.28 (q, 2H), 3.8 (bs, 2H), 2.83 (bs, 2H), 2.82 (s, 3H), 1.5
(s, 9H), 1.3 (t, 3H).
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HN~O O~CO2H 24-5
CH ~
3-Methyl-4-((1,2,3,4-tetrahydro-9H-pyrido[3,4-b3indol-7-
S yl)carbonylamino)phenoxyacetic acid (24-5)
A solution of 24-4 (0.082 g, 0.16 mmol) in EtOAc (10 mL)
was treated first with HC~l gas, then with LiOH-H20 as described for 23-
6 to give 24-5 as a white solid after chromatography in 18:1:1
EtOH/H201NH40H.
10 Rf (18: 1: 1 EtOH/H20/NH40H)=0.48
1H NMR (400 MHz, D2O) ~ 7.9 (s, lH), 7.54 (m, 2H), 7.13 (d, lH),
6.84 (s, lH), 6.75 (d, lH), 4.40 (s, 2H), 3.8 (s, 2H), 3.0 (m, 2H), 2.7
(m, 2H), 2.15 (s, 3H).
....
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SCHEME 25
tBuO NH~OH 10-2
H3C
NBS/THF
O Br
tBuOJ~ N~OH 25-1
H3C Br
Cs2CO3/BrC H2CO2Et
O Br
tBuO~ ~O~CO2Et
H3C Br 25-2
HCI/EtOAc
., . . , . , , ~ ~ ... .. .. . . .
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SCHEME 25 (CONT'D)
Br
HCI- H2N~O
~ CO2Et
H3C Br 25-3
tBuO,~ A ~OH 1-5
o~N~ N~ ~l 25-4
~ CO2Et
H3C Br
~N N~3~ Br
oO --/ N~ 25-4a
~ N N~ )=~ CO2Et
tBuO \ / O H3C Br
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SCHEME 25 (CONT'D)
-
25-4 + 25-4a
LiOH
.
tBuO~ ~o Br 25-5
~ HN ~ O
)==~ ~ C02H
H3C Br
HN N~ ~
CO2H
H3C Br
.
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O Br
tBu~ H~OH 25-1
H3C Br
2,6-Dibromo-3 -methyl-4-(1,1 -dimethylethoxycarbonyl)amino-
phenol (25- 1)
S A solution of 10-2 (1.0 g, 450 mmol) in 20 mL THF under
argon was treated with N-Bromosuccinimide (1.6 g, 9 mmol) for 2 hr.
The solution was concentrated and the residue was resuspended in
carbontetrachloride and filtered. The filtrate was concentrated and
chromatographed (15% EtOAc/Hexanes) to give 25-1 as a white solid.
Rf(20% EtOAc/Hexanes)=0.56
1H NMR (400 MHz, CDCl3) ~ 7.79 (bs, lH), 6.08 (bs, lH), 5.8 (s, lH),
2.33 (s, 3H), 1.43 (s, 9H).
O Br
tBuO~ ~ ~ CO2~t
H3C Br 25-2
Ethyl 2-(2,6-dibromo-3-methyl-4-(1,1-dimethylethoxycarbonyl)-
aminophenoxy)acetate (25-2)
A solution of 25- l (0.6 g, 1.57 mmol) in DMF was treated
with cesium carbonate and ethyl bromo acetate as described for 10-3 to
give 25-2 as a tan solid
Rf(20% EtOAc/Hexanes)=0.56
1H NMR (400 MHz, CDC13) o 8.0 (bs, lH), 6.21(bs, lH), 4.56 (s, 2H),
4.3 (q, 2H), 2.35 (s, 3H), 1.5 (s, 9H), 1.33 (t, 3H).
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Br
H2N ~0
- >=< ~CO2Et
H3C Br ~
Ethyl 2-(2.6-dibromo-3-methyl-4-arninophenoxy)acetate (25-3)
A solution of 25-2 (0.6 g, 1.29 mmol) in EtOAc (10 mL)
5 was treated with HCl gas as described for 16-10 to give 25-3 as a tan
solid.
1H NMR (400 MHz, DMSO) ~ 7.0 (s, lH), 4.8-4.4 (b, 2H), 4.41 (s, 2H),
4.2 (q, 2H), 2.18 (s, 3H), 1.2 (t, 3H).
0~ N~N~N ~0 25-4
~CO2Et
H3C Br
Ethyl 2-(2,6-dibromo-3-methyl-4-(4-(N-(1,1-dimethylethoxycar-
bonyl)piperizin-4-yl)phenylcarboxamide)phenoxy) acetate (25-4)
A solution of 25-3 (0.520 g, 1.29 mmol) and 1 5 (0.395 g,
1.29 mmol) in CH2C12 was treated with chloro-N,N,N'N',-bis(penta-
methylene)formamidinium hexafluorophosphate (0.504 g, 0.1.4 mmol)
and diisopropylethyl amine (0.9 mL, 5.16 mmol) and stirred at room
temperature for 24 hours. The solution was diluted with EtOAc and
washed with H2O, 10% KHS04, saturated NaHCO3 and brine, dried
20 over MgS04, filtered and evaporated. The residue was
chromatographed (silica gel 30% EtOAc/Hexanes) to give a mixture of
25-4 and 25-4a.
Rf25-4a(50% EtOAc/Hexanes)=0.45.
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lH NMR (400 MHz, CDC13) ~ 8.0 (m, 2H), 7.8 (d, 2H), 7.5 (s, lH),
6.93 (d, 2H), 6.85 (d, lH), 4.6 (s, 2H), 4.3 (q, 2H), 3.6 (bs, 8H), 3.35
(m, 8H), 2.4 (s, 3H),-1.45 (s, 9H), 1.35 (t, 3H).
Rf25-4(50% EtOAc/Hexanes)=0.37.
lH NMR (400 MHz, CDC13) ~ 7.6 (d, 2H), 6.7 (d, 2H), 4.6 (s, 2H), 4.3
(q, 2H), 3.55 (bs, 4H), 3.3 (bs, 4H), 2.38 (s, 3H), 1.45 (s, 9H), 1.33 (t,
3H).
~N N~ Br
~ \ J ~N ~0 25-5
)=~ ~C02H
H3C Br
2-(2,6-Dibromo-3 -methyl-4-(4-(4-(1,1 -dimethylethoxycarbonyl)-
piperizin-4-yl)phenylcarbonylamino)phenoxy) acetic acid (25-5)
A solution of 25-4 and 25-4a (0.3 g) in 1:1:1
THF/MeOH/H2O was treated with LiOH (0.084 g, 2 mmol) at 60~C.
After 1 hour the reaction was diluted with EtOAc and 10% KHSO4 and
the layers were separated. The organic layer was washed with H20,
brine, dried with MgSO4, filtered and evaporated to give 25-5 as a clear
oil after chromatography in 9:0.5:0.5 CH2C12/MeOH/HOAc.
Rf(9:0.5:0.5 CHC13/MeOH/HOAc)=0.6.
1H NMR (400 MHz, CD30D) ~ 7.90 (d, 2H), 7.6 (s, 2H), 7.05 (d, 2H),
4.55 (s, 2H), 3.6 (bs,- 4H), 3.3 (bs, 4H), 2.35 (s, 3H), 1.5 (s, 9H).
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HN N~HN~O 25-6
HCI ~CO2H
H3C Br
2-(2,6-Dibromo-3 -methyl-4-(4-piperizin-4-yl)phenylcarbonylamino)
S phenoxy) acetic acid. hydrochloride (25-6)
A slurry of the intermediate acid (0.4 g, 0.6 mrnol) in
EtOAc was cooled to -78~C and saturated with HCl gas. The reaction
was warmed to 0~C, then concentrated in vacuo to give 25-6 as the HCl
salt.
10 Rf(10:0.5:0.5 EtOH/H20/NH40H) 0.18.
1H NMR (400 MHz, D2O) ~ 7.73 (d, 2H), 7.23 (s, lH), 7.02 (d, 2H),
4.3 (s, 2H), 3.1 (bs, 4H), 2.82 (bs, 4H), 2.1 (s, 3H).
.. ... . .
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SCHEME 26
H2N¢~ OH
02N
BOC20/TEA/T H F
O
H2N~O OtBu 26-1
02N
1. BOC20/DMAP
2. LiOH
tBuO H~OH ;2
02N
Cs2CO~/BrCH2CO2Et
o
tB oJ~ N~30 CO2Et 26-3
02N
HCI/EtOAc
HCI . H2N¢~O~CO2Et 26-4
>=/
02N
I
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SCHEME 26 (CONT'D)
tBuO,~ A ~ 1-5
0,~ N~N ~NH ~O~CO2Et 26-5
02N
o,~ N~N ~N ~0~ C~2 Et
~N~N3~oo2N 26-5a
10% Pd/C H2
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SCHEME 26 (CONT'D)
o,~N~N~HN~O CO2Et 26-6
NH2
clso2C6H5
,~N~N~3~HN~30 CO2Et 26-7
NHS02 C6H5
1. LiOH
2. HCI/EtOAc
HN N~HN~O CO2H 26-8
NHS02 C6H5
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H2N ~O~OtBu 2Ç- 1
02N
1 -(1.1 -dimethylethoxycarbonyloxy)-3-nitro-4-aminophenol (26-1)
A solution of 3-nitro-4-amino phenol (Aldrich) (8 g, 52.6
5 mmol) in THF (250 mL) was cooled to 0~C and treated with di-
tertbutyldicarbonate (24 g, 110 mmol) and triethylamine (14 mL, 105
mmol). The solution was allowed to warm slowly and after 24 hours
was concentrated and the residue dissolved in EtOAc, washed with 10%
KHSO4, saturated NaHCO3, and brine, dried over Na2SO4, filtered and
10 evaporated to give 26- 1 as a brown oil.
lH NMR (400 MHz, CDC13) ~ 7.94 (s, lH), 7.21 (dd, lH), 6.8 (d, lH),
6.04 (bs, 2H), 1.5 (s, 9H).
tBuO N~OH 2~~
02N
3-Nitro-4-(1,1-dimethylethoxycarbonylamino)phenol (26-2)
A solution of 26-1 (52.6 mmol) in dichloroethane (150 mL)
was added at a rapid drip to a refluxing solution of di-tert-
butyldicarbonate (12 g, 52.6 mmol) in dicloroethane (100 mL) and the
20 resulting mixture was refluxed for 20 minutes, then cooled to room
temperature and stirred overnight. Triethylamine (52.6 mmol) and 2,6-
dimethylaminopyridine (1.3 g, 10.5 mmol) were added and the solution
refluxed for 2 hours and stirred at room temperature overnight. The
solvents were removed and the residue was dissolved in 240 mL 1: 1: 1
25 THF/MeOH/H2O and treated with LiOH-H2O (22 g, 526 mmol) for 48
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hours. The solution was diluted with water, 10% KHSO4 and EtOAc
and the layers separated. The organic layer was washed with water and
brine, dried over Mg~04, filtered and evaporated. The residue was
chromatographed (20% EtOAc/Hexanes) to give 26-2 as a yellow solid.
S Rf (20% EtOAc/Hexanes)=0.26
lH NMR (400 MHz, CDC13) ~ 9.5 (bs, lH), 8.35 (d, lH), 7.61 (s, lH),
7.13 (d, lH), 5.33 (s, lH), 1.55 (s, 9H).
tBuO N ~0 CO2Et 26-3
02N
Ethyl 2-(3-nitro-4-(1,1-dimethylethoxycarbonylamino)phenoxy)
acetate (26-3)
A solution of 26-2 (2 g, 7.87 mmol) in DMF (75 mL)
treated with cesium carbonate (1.28 g, 3.93 mmol), stirred for 10
minutes and treated with ethyl bromoacetate (0.8 mL, 7.92 mmol) at
room temperature. After 1.5 hours the solution was concentrated under
high vacuum and the residue was absorbed to silica gel and
chromatographed in 10% EtOAc/Hexanes to give 26-3 as a yellow solid.
Rf(30% EtOAc/Hexanes) 0.18
lH NMR (400 MHz, CDC13) ~ 9.4 (bs, lH), 8.44 (d, lH), 7.65 (s, lH),
7.26 (m, lH), 4.63 (s, 2H), 4.24 (q, 2H), 1.55 (s, 9H), 1.3 (t, 3H).
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HCI .
H2N~30~Co2Et .2~.
02N
Ethyl 2-(3-nitro-4-aminophenoxy)acetate~ hydrochloride (26-4)
A solution of 26-3 (0.5 g, 0.2.5 mmol) was dissolved in
EtOAc (15 mL), cooled to -78~C and saturated with HCl gas, warmed to
0~C for 1 hour and concentrated to give 26-4 as an orange solid.
Rf (10% MeOH/CHC13 saturated with NH3)=0.13
H NMR (400 MHz, CD30D) ~ 7.51 (d, lH), 7.18 (dd, lH), 7.0 (d,
lH), 4.68 (s, 2H), 4.24 (q, 2H), 1.15 (t, 3H).
o ~ N~ N ~ N ~ O ~''C 02Et 26-~
02N
Ethyl 2-(3-nitro-4-(4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -
yl)phenylcarbonylamino)phenoxy)acetate (26-5)
A solution of 26-4 (0.65 g, 2.46 mmol) and 1-5 (1.5 g, 4.9
mmol) were treated with PYCLU and diisopropylamine as described for
23-5 to give 26-5 and 26-5a after chromatography in 30%
EtOAc/Hexanes.
Rf(30% EtOAc/Hexanes)=0.16
lH NMR 26-5 (400 MHz, CDC13) o 8.95 (d, lH), 7.9 (d, 2H), 7.75 (s,
- lH), 6.95 (d, 2H), 4.65 (s, 2H), 4.28 (q, 2H), 3.6 (m, 4H), 3.35 (m, 4H),
1.5 (s, 9H), 1.3 (t, 3H).
.. . .~ ... .. ~ .. . ..
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o~N~N~H~O CO2Et 26-7
NHS02 C6H5
Ethyl 2-(3-phenylsulfonamido-4-(4-(4-(1,1-dimethylethoxycar-
bonyl)piperazin-l-yl)phenylcarbonylamino)phenoxy)acetate (26-7)
SA solution of 26-5 (0.4 g, 0.76 mmol) in EtOH (10 mL)
was treated with 10% Pd/C (0.070 g), and hydrogenated under balloon
pressure for 1.5 hours. The solution was filtered through SolkaFloc,
and the cake rinsed with EtOAc. The filtrate was concentrated to give
26-6.
10 Rf(10% MeOH/CHC13 saturated with NH3)=0.72
The crude arnine was dissolved in pyridine (3 mL) and
treated with phenylsulfonyl chloride (0.10 mL, 0.83 mmol) and stirred
for four hours. The solution was diluted-with EtOAc and washed with
water and brine, dried with MgS04, filtered and concentrated to give a
15 yellow oil that was chromatographed (gradient 30% EtOAc/Hexanes to
100% EtOAc) to give 26-7 as an oil.
(Rf 30% EtOAc/Hexanes) 0.85)
lH NMR 26-5(400 MHz, CDC13) ~ 8.04 (s, lH), 7.7 (d, 2H), 7.65 (d,
2H), 7.5 (s, 2H), 7.42 (d, lH), 7.38 (m, 2H), 6.9 (m, 2H), 6.8 (d, lH),
20 6.6 (s, lH), 4.46 (s, 2H), 4.25 (q, 2H), 3.6 (m, 4H), 3.3 (m, 4H), 1.5 (s,
9H), 1.28 (t, 3H).
.. . . .
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HN~N~H ~O~CO2H
NHS02 C6H5
2-(3-Phenylsulfonamido-4-(4-(4-piperazin- 1 -yl)phenylcarbonyl-
5 amino)phenoxy)acetic acid (26-8)
A solution of 26-7 (0.18 g, 0.28 mmol) was treated with
LiOH and HCl gas as described for 23-6 to give 26-8 as a white solid
after chromatography (10:0.5:0.5 EtOH/NH4OH/H2O) and further
purification via reverse phase HPLC.
10 lH NMR (400 MHz, D2O) ~ 7.6 (m, 3H), 7.48 (d, 2H), 7.23 (m, lH),
7.18 (m, 2H), 7.1 (d, 2H), 6.59 (s, lH), 6.5 (d, lH), 4.23 (s, 2H), 3.2
(m, 4H), 2.9 (m, 4H).
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SCHEME 27
BOC-N~N~N ~ r COOH
1 0-6 H3C
o
Ci~J~ (27-1 )
Cs2CO3, DMF, Nal, 60~C
BOC-N N ~H ~ 4'~
HCI (g) H3C 27-2 O
EtOAc, 0~C
HN N~ o
27-3
r ~0-6 H ~ r COOH
H3C
Cl'J~ ~27-
NHCH3
Cs2CO3, DMF, Nal, 60~C
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SCHEME 27 (CONT'D)
BOC-N~N~ ~ ~
H ~NHCH3
H3C 2~ ~
HCI (g)
EtOAc, 0~C
HN ~N~O O
~HCI H3C ~NHCH3
27-6
5 4-[4-(4-(1,1 -dimethylethoxycarbonyl)piperazin- 1 -yl)phenyl-
carbonylamino]-3-methylphenoxyacetic acid; N,N-diethylglycolamide
ester (27-2)
A solution of carboxylic acid 10-6 (500 mg, 1.07 mmol),
N,N-diethyl chloroacetamide 27-1 (0.154 mL, 1.12 mmol), NaI (5 mg,
10 0.03 mmol), Cs2C03, (173 mg, 0.535 mmol) and DMF (5 mL) was
heated at 60~C for 20 h. The reaction mixture was diluted with EtOAc
and washed with water, 10% aqueous KHS04 and brine. Drying
(MgS04), ~lltration, removal of the solvent in vacuo, and
chromatography on silica gel using a gradient of 50 to 90% EtOAc in
15 hexane as eluant gave 4-[4-(4-(l,l-dimethylethoxycarbonyl)piperazin-1-
- yl)phenylcarbonylamino]-3-methylphenoxyacetic acid N,N-diethyl-
glycolamide ester (27-2) as a white solid. 1H NMR (CD30D): ~ 1.23 (t,
J=7Hz, 6H), 1.48 (s, 9H), 2.25 (s, 3H), 3.32 (m, 8H), 3.58 (m, 2H), 4.83
~s, 2H), 4.92 (s, 2H), 6.83 (dd, J=3Hz, 9Hz, lH), 6.90 (s, lH), 7.03 (d,
20 J=9Hz, 2H), 7.19 (d, J=(Hz, lH), 7.78 (d, J=9Hz, 2H).
, ... . .
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4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]-3-methylphenoxyacetic
acid; N.N-diethylglycolamide ester~ hydrochloride (27-3)
To a stirred solution of EtOAc (7 mL) saturated with HCI
gas was added ester 27-2 (500 mg, 0.86 mmol), suspended in EtOAc (3
5 mL). The mixture was stirred for 1 h at ambient temperature, purged
with dry argon for 30 min and concentrated in vacuo to give 4-[4-
(piperazin-1-yl)phenylcarbonylamino]-3-methylphenoxyacetic acid N,N-
diethylglycolamide ester, hydrochloride (27-3) as a white solid. lH
NMR (D20): ~ 1.11 (t, ~=7Hz, 3H), 1.21 (t, J=7Hz, 3H), 2.23 (s, 3H),
10 3.37 (t, J=7Hz, 4H), 3.44 (m, 4H), 3.62 (m, 4H), 4.96 (s, 2H), 5.01 (s,
2H), 6.92 (d, J=9Hz, IH), 7.00 (s, lH), 7.21 (m, 3H), 7.90 (d, J=9~z,
2H).
4-[4-(4-(1, l -Dimethylethoxycarbonyl)piperazin- l -yl)phenylcarbonyl-
15 aminol-3-methylphenoxyacetic acid: N-methylglycolamide ester (27-5)
A solution of carboxylic acid 10-6 (500 mg, 1.07 mmol),
N-methyl chloroacetamide 27-4 (0.121 mg, 1.12 mmol), NaI (5 mg,
0.03 mmol), Cs2C03, (173 mg, 0.535 mrnol) and DMF (5 mL) was
heated at 60~C for 20 h. The reaction mixture was diluted with EtOAc
20 and washed with water, 10% aqueous KHS04 and brine. Drying
(MgS04), filtration, removal of the solvent in vacuo, and
chromatography on silica gel using EtOAc as eluant gave 4-[4-(4-(1,1-
dimethylethoxycarbonyl)piperazin- 1 -yl)phenylcarbonylamino] -3 -
methylphenoxyacetic acid N-methylglycolamide ester (~) as a white
25 solid. lH NMR (CD30D): ~ 1.49 (s, 9H), 2.31 (s, 3H), 2.77 (d, J=5Hz,
3H), 3.29 (m, 4H), 3.61 (m, 4H), 4.67 (s, 2H), 4.75 (s, 2H), 5.85 (br s,
lH), 6.87 (m, 2H), 6.95 (d, J=(Hz, 2H), 7.47 (s, lH), 7.78 (m, lH), 7.79
(d, J=9Hz, 2H).
30 4-[4-(Piperazin- 1 -yl)phenylcarbonylamino]-3-methylphenoxyacetic
acid: N-methylglycolamide ester. hydrochloride (27-6)
HCI gas was rapidly bubbled through a solution of 4-[4-(4-
( l ,1 -dimethylethoxycarbonyl)piperazin- l -yl)phenylcarbonylamino]-3-
methylphenoxyacetic acid N-methylglycolamide ester (27-5) (325 mg,
T ~
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0.60 mmol) in EtOAc (30 mL) at 0~C for 20 min. The mixture was
aged 40 min., purged wityh argon and concentrated in vac~o. The solid
was triturated with E~OAc and Et2O to give 4-[4-(piperazin-1-
yl)phenylcarbonylarnino]-3-methylphenoxyacetic acid N-
S methylglycolamide ester, hydrochloride (27-6) as a white solid. lH
NMR (D20): ~ 2.23 (s, 3H), 2.78 (s, 3H), 3.43 (m, 4H), 3.62 (m, 4H),
4.75 (s, 2H), 4.95 (s, 2H), 6.90 (d, J=8Hz, lH), 6.99 (s, lH), 7.21 (m,
3H), 7.90 (d, J=9Hz, 2H).
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SCHEME 2
OH 1. HO3S ~ N2+ Cl- ~
OCH 2. Na2S2O4 OCH3
NH2
OH
Boc20, CHCI3 ~ Br~COOEt
reflux ~OCH3 Cs2CO3, DMF
NHBoc
28-3
O~COOEt O COOEt
HCI (gas) ~b ~HCI
~OCH3 EtOAc, 0~C ~OCH3
NHBoc NH2
28-4 28-5
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SCHEME 28 (CONT'D)
Boc--N N~COOH 1-5
Cl PF6-
C~N N~ i-Pr2NEt, CH2C12
/=\ ~ LiOH
Boc--N\ N~H~o DME, H20
~ OC H3
Boc--N N~ COOH HCI (gas)
HN~O EtOAc, 0~C
OC H3
HCI
HN N~N ~Or COOH
28-8 OCH3
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4-[4-( 1 -Piperazinyl)phenylcarbonylamino~-3-methoxyphenoxyacetic
acid. hydrochloride (28-8)
Using asequence essentially the same as described for
compound 15-8, but starting with 3-methoxyphenol (28-1), 4-~4-(1-
S piperazinyl)phenylcarbonylamino]-3-methoxyphenoxyacetic acid,
hydrochloride (28-8) as prepared. lH NMR (D2O): ~ 3.33 (d, J=3.9Hz,
4H), 3.51 (t, J=3.9Hz, 4H), 3.75 (s, 3H), 4.62 (s, 2H), 6.51 (d, J=8.6Hz,
lH), 6.64 (s, lH), 7.05 (d, J=7.4Hz, 2H), 7.32 (d, J=8.6Hz, lH), 7.75 (d,
J= 7.4Hz, 2H).
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SCHEME 29
o~,CH3
~,CH3 12, pyridine, 1 00~C
OH
29-1
O~OH
,CH3
OH
~2
BOCN /N~NH2
Cl PF6-
C~+~N~ pr2NEt~ CH2CI2
/=\ H
BOCN\ N~ N~
29-3 H3C
BrCH2COOBut, Cs2CO3, DMF
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SCHEME 29 (CONT'D)
BOCN~N~ N~ r COO~ut
29-4 H3C
HCI (gas)
EtOAc, 0~C
HN N ~ Nh~ r COOH
2~-5 H3C
5 4-Hydroxy-2-methylbenzoic acid (29-2)
Following the procedure described in US 92-852870
920317, 4-hydroxy-2-methylbenzoic acid was prepared from 4-
hydroxy-2-methylacetophenone 29-1. lH NMR (CD30D): ~ 2.52 (s,
3H), 6.64 (m, 2H), 7.84 (d, J=8.4 Hz, lH).
4-[4-(1 -Piperazinyl)phenylaminocarbonyl] -3-methylphenoxyacetic
acid. hydrochloride (29-5)
Using a sequence essentially the same as described for
compound 14-6, but starting with 4-hydroxy-3-methylbenzoic acid
15 (29-2), 4- [4-(1 -piperazinyl)phenylarninocarbonyl] -3 -
methylphenoxyacetic acid, hydrochloride (29-5) was prepared. lH
NMR (DMSO-D6): ~ 2.36 (s, 3H), 3,26 (d, J=7.3Hz, 8H), 3.80 (br s,
4H), 4.73, (s, 2H), 6.81 (dd, J= 2.4, 8.4 Hz, 2H), 6.84 (d, J=2.4Hz, lH),
6.97 (d, J=8.7Hz, 2H), 7.39 (d, J=8.4 Hz, lH), 7.62 (d, J=8.7Hz, 2H),
20 8.72 (br s, lH), 9.99 (s, lH).
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SCHE~/IE 30
OH
1. HO3S~N2+ Cl-
CF3
30-1 2. Na2S2O4
OH
Boc20, CHCI3
CF3 reflux
NH2
30-~
OH
Br~ COO Et
~CF3 KN(TMS)2
NHBoc 1 8-CROWN-6
30-3
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SCHEME 30 (CONT'D)
O~COOEt O~COOEt
[~ HCI (9aS)
NHBOC NH2
30 4 30 5
BOC N N~ COOH 1-5
Cj PF6-
GNJ~N~ ;-Pr2NEt CH2CI2
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SCHEME 30 (CONT'D)
/=\ ~ LiOH
Boc--N N (~\ /)~ ~ r COOEt
H~ DME, H2O
30-6 CF~
~ ~ O
Boc--N\JN~ ~ rCOOH
CF3
30-7
HCI (gas)
EtOAc, 0~C
HCI
HN N~N ~Or COOH
CF3
30-8
5 4-(1,1-Dimethylethoxycarbonyl)amino-3-trifluoromethylphenol (30-3)
Using a method similar to that described for compound
15 3, starting with 3-trifluorophenol, 4-(l,l-dimethylethoxycarbonyl)-
amino-3-trifluoromethylphenol (30-3) was prepared. lH NMR
(CDC13): o 1.55 (s, 9H), 4.12 (m, 2H), 6.72 (d, lH), 7.12 (m, lH), 7.26
10 (m, lH).
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Ethyl 4-(1,1-dimethylethoxycarbonyl amino-3-trifluoromethyl-
phenoxyacetate (30-5)
To a 200 mL round bottomed flask with a stirring bar and
an argon inlet was added 4-(l,1-dimethylethoxycarbonyl)amino-3-
S trifluorophenol (4.80 g, 17.3 mmol), 18-crown-6 (4.63 g, 17.5 mmol),
and THF (69 mL). This mixture was cooled to 0~C in an ice-water bath,
then a solution of potassium hexamethyl disilylazide in toluene (34.7
mL, 17.4 mmol) was added followed by ethyl bromoacetate (1.93 mL,
17.4 mmol). This mixture was stirred under argon for 16 h, allowing
10 the cooling bath to expire. This mixture was transferred to a separatory
funnel, acidified with 10% aqueous citric acid and extracted with
EtOAc. The organic layer was washed with water and brine, dried
(MgSO4), filyered and concentrated in vacuo. The BOC group was
removed as described for 29-9. This material was chromatographed on
15 silica gel to give ethyl 4-(1,1-dimethylethoxy-carbonyl amino-3-
trifluoromethylphenoxyacetate (30-5) as an oil. lH NMR (CDCl3):
1.58 (t, 3H), 3.93 (br s, 2H), 4.27 (q, 2H), 4.56 (s, 2H), 6.69 (d, lH),
6.95 (dd, lH), 7.00 (d, lH).
20 4-[4-(1-Piperazinyl)phenylcarbonylamino]-3-trifluoromethylphenoxy-
acetic acid (30-8)
Using a sequence similar to that described for compound
12-8 but starting with ethyl 4-(1,1-dimethylethoxycarbonyl amino-3-
trifluoromethylphenoxyacetate (30-5), 4-[4-(1-piperazinyl)phenyl-
25 carbonylamino]-3-trifluoromethylphenoxyacetic acid (30-8) was
prepared. 1H NMR (DMSO-d6): ~ 3.25 (s, 4H), 3.50 (s, 4H), 4.84 (s,
2H), 7.09 (d, J=8.0 Hz, 2H), 7.25 (m, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.88
(d, J= 8.0 Hz, 2H), 8.82 (br s, lH), 9.72 (s, lH).
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SCHEME 3
H2N~ CO2Et
HCI H3C HN~NH
10-4
~2HCI
O2N~O~fCI 31-2
pyridine, CH2C12
Boc2O, NaOH
o EtOH/H20
O2N~OJ~ NH ~ CO2Et
H3C A
BocN~(~N H
31-1 31-3
\/
Et3N ,C H2C12
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SCHEME 31 (CONT'D)
BocN3{~N H~O~ COzEt
H3
31 -4
LiOH, THF/H20/MeOH
BocN~ ~N~r N~O~,CO2H
31 -5
HCI (gas)
EtOAc, 0~
H N~Nlr N~O~,CO2H
~HCI H3C
31 -6
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Ethyl 4-(4-nitrophenylcarbamate)-3-methylphenoxyacetate (31-1)
A solution of ethyl 4-amino-3-methylphenoxyacetate
hydrochloride (10-4) (300 mg, 1.22 mmol) in CH2cl2 (30 mL) was
placed in a 50 mL flask. To this solution 4-nitrophenyl chloroformate
5 (246 mg, 1.22 mmol) and pyridine (0.22 mL) were added at room
temperature. The reaction was stirred at ambient temperature 18 h,
then concentrated in vacuo to yield ethyl 4-(4-nitrophenylcarbarnate)-3-
methylphenoxyacetate (32- 1). l H NMR (CDC13): o 1.30 (t, j=7.0 Hz,
3H), 2.34 (s, 3H), 4.28 (q, j=7.0 Hz, 2H), 4.59 (s, 2H), 6.70 (dd, j=8.3,
10 2.0 Hz, lH), 6.7 (d, j=2.0 Hz, lH), 7.40 (d, j=8.3 Hz, lH), 8.05 (d,
j=7.0 Hz, IH), 8.28 (d, j=7.0 Hz, 2H).
4-(1,1 -Dimethylethoxycarbonyl)-4~4'-bipiperidine (31 -3)
A solution of bipiperidine dihydrochloride (Aldrich 31 -2)
15 (25 g, 0.1 mol) in H2O (100 mL) was placed in a 2L round bottomed
flask. A solution of 6N NaOH was added dropwise to adjust the pH to
8-9. The solution was diluted with EtOH (1200 mL) and stirred
vigorously at ambient temperature. The resulting mixture was treated
with a solution of di-t-butyl dicarbonate (24 g, 0.11 mol) in EtOH (800
20 mL). Periodically, 6N NaOH was added to maintain pH 8-9. After
stirring at ambient temperature 18 h, the reaction was concentrated in
vacuo. The residue was dissolved in 1:1 ether:H20 (1000 mL) and the
pH adjusted to 12 with 6N NaOH. The aqueous phase was separated and
extracted again with ether. The ether phases were combined and washed
25 with brine, 10% citric acid, and H2O. The citric acid and H2O washes
were combined and the pH adjusted to 12-13 with 6N NaOH, then
extracted in 3 portions with ether (600 mL). The ether extract was
washed (brine), dried (Na2S04) and concentrated in vacuo to a clear oil
which solidified on standing to yield 4-(1,1-dimethylethoxycarbonyl)-
30 4,4'-bipiperidine (31-3). lH NMR (CDCl3): ~ 1.25 (br m, 7H), 1.45
(s, 9H), 1.66 (br d, 4H), 2.60 (dd, 4H), 3.1(d, j=12 Hz, 2H), 4.21(br s,
2H).
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Ethyl-4-[(4-( 1,1 -dimethylethoxycarbonyl)-4,4'-bipiperidinyl- 1-
carbonyl)aminol-3-methylphenoxyacetate (31-4)
A soluti~n of ethyl 4-(4-nitrophenylcarbamate)-3-
methylphenoxyacetate (31-1), (457 mg, 1.22 rnmol), 4-(1,1-dimethyl-
5 ethoxycarbonyl)-4,4'-bipiperidine (31-3) 327 mg, 1.22 mmol), and
triethylamine (0.34 mL, 2.44 mmol) in CH2cl2 (20 mL). The solution
was refluxed 4 h, cooled and diluted with CH2C12 (10 mL). The
reaction was extracted with H2O (15 mL). The CH2C12 extract was
washed (1% NaOH, H2O, 10% KHSO4, brine), dried (Na2SO4),
10 filtered, ~en concentrated in vacuo to an oil. The oil was
chromatographed on silica using 50% EtOAc/hexane to obtain ethyl-4-
[(4-(1, l -dimethylethoxycarbonyl)-4,4'-bipiperidinyl- 1 -carbonyl)amino] -
3-methylphenoxyacetate (31-4) lH NMR (CDCl3): ~ 1.27 (br m, 7H),
1 30 (t, j= 7.0 Hz, 3H), 1.46 (s, 9H), 1.68 (d, j=12 Hz, 2H), 1.75 (d,
15 j=10 Hz, 2H), 2.22 (s, 3H), 2.65 (t, j=12 Hz, 2H), 2.83 (t, j=12 Hz, 2H),
4.08 (d, j=12 Hz, lH), 4.25 (br s, 2H), 4.27 (q, j=7 Hz, 2H), 4.58 (s,
2H), 5.97 (s, lH), 6.70 (dd, j=8.3, 2 Hz, lH), 6.73 (d, j=2 Hz, lH), 7.40
(d, j=8.3 Hz, lH),
20 4- [(4-(1 ,1 -Dimethylethoxycarbonyl)-4 ,4'-bipiperidinyl- 1 -carbonyl)-
aminol-3-methylphenoxyacetic acid (31-5)
In a 25 mL round bottomed flask a solution of ethyl-4-[(4-
( 1,1 -dimethylethoxycarbonyl)-4,4'-bipiperidinyl- 1 -carbonyl)amino]-3-
methylphenoxyacetate (31-4) (100 mg, 0.2 mmol), lM LiOH, (0.6 mL,
25 0.6 mmol), H20 (5 mL), THF (5 mL), and MeOH (5 mL) was stirred at
ambient temperature 3 h. The reaction was concentrated in vacuo, then
dissolved in CHC13 (20 mL). The CHCl3 extract was washed (lN HCI,
H2O, and brine), dried (NaSO4), filtered, and concentrated to yield 4-
[(4-(1 ,1 -dimethylethoxycarbonyl)-4,4'-bipiperidinyl- l -carbonyl)amino]-
30 3-methylphenoxyacetic acid (31-5). lH NMR (CDCl3): ~ 1.22 (br m,
6H), 1.46 (s, 9H), 1.6 (br m, 4H), 2.2 (s, 3~), 2.6 (br t, 2H), 2.79 (t,
j=l 1 Hz, 2H), 4.0 (br m, 5H), 4.58 (s, 2H), 6.1 (dd, j=9, 2 Hz, lH), 6.75
(d, j=2 Hz, lH), 7.21 (d, j=9Hz, lH), 8.1 (s, lH).
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4-[(4-[4,4']-Bipiperidinyl-1 -carbonyl)amino~-3-methylphenoxyacetic
acid~ hydrochloride (31 -6)
In a 35 mL round bottomed flask 4-[(4-(1,1-dimethyl-
ethoxycarbonyl)-4,4'-bipiperidinyl- l -carbonyl)amino]-3-methylphen-
S oxyacetic acid (31-5) (83 mg, 0.17 mmol) was dissolved in CH2Cl2 (10
mL) and cooled to 0~. Anhydrous HCI was bubbled through the solution
for S min. The reaction was stirred at 0~ 4 h, then concentrated in
vacuo to yield 4-[(4-[4,4']-bipiperidinyl-1-carbonyl)amino]-3-
methylphenoxyacetic acid, hydrochloride C~) lH NMR (DMSO-d6):
10 ~ 1.04 (br d, j=l l Hz, 3H), 1.3 (br s, 3H), 1.62 (d, j=12 Hz, 2H), 1.79
(d, j=l l Hz, 2H), 2.07 (s, 3H), 2.67 (t, j=12 Hz, 2H), 2.74 (br m, 2H),
4.07 (d, j=12 Hz, 2H), 4.59 (s, 2H), 6.62 (dd, j=9, 2 Hz, lH), 6.70 (d,
j=2 Hz, lH), 6.95 (d, j=9 Hz, lH), 7.87 (s, lH), 8.2 (br s, lH), 8.5 (br s,
lH).
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SCHEME 32
Cl-PF6-
N N +
HO2C(CH2)~0H + BocN~NH
i-Pr2NEt, DMF
31 -3
32-1a (n=O)
32-1 b (n=1 )
BocN~N~f(C H2)n ~0 H
32-2a (n=O)
32-2b (n=1)
BrCH2CO2t-Bu
Cs2CO2, DMF
BocN~ N~(CH2)n~0 CO2t-Bu
32-3a (n=O)
32-3b (n=1)
TFA, CH2CI2, 0
HN~N~f(CH2)n~0 CO2H
~T FA O
32-4a (n=O)
32-4b (n=1
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4-(2-(4-Dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl- 1 -
carbonyl)phenol (32-2a)
In a 50 ~nL round bottomed flask a solution of 4-(1,1-
dimethylethoxcarbonyl)-4,4'-bipiperidine (31-3) (400 mg, 1.49 mm), 4-
hydroxybenzoic acid (206 mg, 1.49 mm), (32-la), chloro-N,N,N',N'-
bis(pentamethyl)formamidinium hexafluorophosphate (537 mg, 1.49
mm) and diisopropylethylamine (0.52 mL, 2.98 mm) in 25 mL DMF
was stirred at ambient temperature 48 h. The reaction was concentrated
in vacuo, then partitioned between EtOAc and H2O. The EtOAc extract
was washed (H2O, sat'd NaHCO3, H2O, 10% KHSO4 and brine), dried
(Na2SO4), filtered and concentrated in vacuo. The resulting oil was
chromatographed on silica using 5% MeOH/CHC13 as eluent to yield 4-
(2-(4-dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl)- 1 -carbonyl)-
phenol (32-2a). 1H NMR (CDC13): o 1.2 (br m, 6H), 1.4 (s, 9H), 1.58
(br m, 4H), 4.1 (m, 2H), 4.3 (m, lH), 6.83 (d, j=8.5 Hz, 2H), 7.31 (d,
j=8.5 Hz, 2H).
4-(2-(4-Dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl- 1 -yl-2-oxo-
ethyl)phenol (32-2b)
In a manner similar to the preparation of compound 32-2a,
4-(2-(4-dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl- 1 -yl-2-oxo-
ethyl)-phenol (32-2b) was prepared. 1H NMR (CDC13): o 0.89 (m,
lH), 1.1 (m, 3H), 1.45 (s, 9H), 1.5 (br m, 6H) 2.49 (t, j=12 Hz, lH),
2.62 (m, 2H), 2.91 (t, j=12 Hz, lH), 3.64 (s, 2H). 3.90 (d, j=12 Hz, lH),
4.1 (m, 2H), 4.68 (d, j=12 Hz, lH), 6.12 (br m~ lH), 6.77 (d, j=8 Hz,
2H), 7.07 (d, j=8 Hz, 2H).
t-Butyl-4-(2-(4-Dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl- 1 -
carbonyl)phenoxyacetate (32-3a)
In a 50 mL round bottomed flask a mixture o~ 4-(2-(4-
dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl- 1 -carbonyl)-phenol (32-
2a) (378 mg, 0.97 mm), t-butyl bromoacetate (0.16 mL, 1.067 mm) and
cesium carbonate (348 mg, 1.067 mm) in 50 mL DMF was stirred at
ambient temperature 18 h. The reaction was concentrated in vacu(~,
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then partitioned between CHC13 and H20. The CHCl3 extract was
washed (10% KHSO4, H20, NaHCO3 and brine), dried (Na2SO4),
filtered and concentrated in vacllo to yield t-butyl-4-(2-(4-dimethoxy-
ethoxycarbonyl)-(4,4')-bipiperidinyl-1-carbonyl)-phenoxyacetate (32-
3a). 1~ NMR (CDC13): o 1.2 (m, 6H), 1.42 (s, 9H), 1.45 (s, 9H), 2.68
(m, 4H), 2.61 (t, 2H), 2.8 (m, 2H), 4.18 (m, 4H), 4.5 (s, 2H), 6.9 (d, j=8
Hz, 2H), 7.35 (d, j=8 Hz, 2H).
t-Butyl-4-(2-(4-dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl- 1 -yl-
2-oxo-ethyl)phenoxyacetate (32-3b)
In a manner similar to the preparation of 32-3a, t-butyl-4-
(2-(4-dimethoxyethoxycarbonyl)-(4,4')-bipiperidinyl- 1 -yl-2-oxo-ethyl)-
phenoxyacetate (32-3b) was prepared. lH NMR (CDC13): ~ 0.88 (m,
lH), 1.11 (m, SH), 1.45 (s, 9H) 1.48 (s, 9H), 1.61 (m, 4H), 2.48 (t,
j=12Hz, lH), 2.61 (br t, 2H), 2.88 (t, j=13 Hz, lH), 3.66 (s, 2H), 3.88
(d, j=13 Hz, lH) 4.1 (m, 2H), 4.49 (s, 2H), 4.68 (d, j=13 Hz, lH), 6.84
(d, j=8.8 Hz, 2H), 7.15 (d, j=8.8 Hz, 2H).
~4-(r4.4'-1-Bipiperidinyl-l-carbonyl)phenoxylacetic acid (32-4a)
In a round bottomed flask, t-butyl-4-(2-(4-dimethoxy-
ethoxycarbonyl)-(4,4')-bipiperidinyl- 1 -carbonyl)-phenoxyacetate
(32-3a) (56 mg, 0.11 mm) was stirred with trifluoracetic acid (2.5 mL)
and CH2C12 (5 mL) at 0~ 18 h. The reaction was concentrated in vacuo
to yield [4-([4,4'-]-bipiperidinyl-1-carbonyl)phenoxy]-acetic acid (35-
4a). 1H NMR (DMSO-d6) ~ 1.11 (m, 2H), 1.32 (m, 4H), 1.78 (m, 2H),
1.80 (d, j=12 Hz, 2H), 2.81 (dd, j=11 Hz, 4H), 3.28 (d, j=11 Hz, 2H),
4.73 (s, 2H), 6.94 (d, j=8.5 Hz, 2H), 7.32, J=8.5, 2H), 8.16 (br s, lH),
8.47 (br s, lH).
[4-(2-[4,4'] -Bipiperidinyl- 1 -yl-2-oxo-ethyl)phenoxy]acetic acid
(32-4b)
In a manner similar to the preparation of (32-4a), 4-(2-
[4,4']-bipipe;idinyl-1-yl-2-oxo-ethyl)-phenoxy]-acetic acid (32-4b) was
prepared. 1H NMR (CDC13): ~ 0.~1 (m, lH), 1.07 (m, lH), 1.36 (br s,
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2H),1.62 (d, j=13 Hz, lH),1.74 (d, j=12 Hz, lH),1.87 (br s,2H),2.56
(t, j=l l Hz, lH),2.94 (m,3H),3.36 (d, j=12 Hz,2H),3.70 (m,3H),4.0
(d, j=13 Hz, lH),4.57 (d, j=13 Hz, lH),4.64 (s,2H),6.89 (d, j=8.5 Hz,
2H),7.17 (d, j=8.5 Hz,2H).
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SC~ME 33
N3CI
NMM, HN '~
NMP ~ J~
1 10~ '' CO2Et
/=\ r~
N~ N~ CO2Et
33-1
N3 N3 CO2H
33-2
PYCLU, iPr2NEt, H2N~O - R
H3C 1 0-4
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SCHEME 33 (CONT'D)
N~ N~' N ~O C02Et
33-3
KOH,
TH F/H20
N~N~'H~O C02H
H3C
33-4
N3 N~ CO2Et
33-1
Ethyl 4-pyridylpiperidin-4-ylcarboxylate (33-1)
Ethyl isonipecotate (6.0 g 38.66 mmol), 4-chloropyridine
10 hydrochloride (5.9 g, 38.66 mmol) and N-methylmorpholine (9.3 g mL,
85.00 mmol), were dissolved in N-methylpyrrolidine (50 mL) and the
resulting solution was heated at 100~C for 48 h. The solution was
concentrated in vacuo and the residue was dissolved in EtOAc and
washed with water and brine (2 x 100 mL), then dried (Na2SO4) and
15 evaporated. The resulting residue was purified by flash
chromatography (5% MeOH/CHC13) to afford 33-1 as a crystalline
solid. 1H NMR (CDC13) ~ 8.21 (d, J=6.8 Hz, 2H), 6.78 (d, J=6.8 Hz,
2H), 4.18 (q, J=7.0 Hz, 2H), 3.85 (m, 2H), 3.10 (m, 2H), 2.61 (m, IH),
2.05 (m, 2H), 1.85 (m, 2H), 1.23 (t, J=7.0 Hz, 3H).
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N~ N~ CO2H
33-2
4-Pyridylpiperidin-4-ylcarboxylic acid (33-2)
A solution of 33-1 (l0 g, 42.7 mmol) in THF (50 mL) was
5 treated with lN LiOH (47 mL, 47.0 mmol) and water (50 mL). The
resulting solution was stirred at ambient temperature for 12 h. The
solution was concentrated and the aqueous residue was cooled to 0~C,
then adjusted to pH = 6 with lN HCI. The resulting solid was collected
by filtration and dned in vacuo to afford 33-2 as a white solid. lH
10 NMR (D2O) ~ 7.95 (d, ~=6.8 Hz, 2H0, 6.73 (d, J=6.8 Hz, 2h), 3.76 (d,
J=12.8 Hz, 2H0, 2.81 (m, 2H), 2.20 (m, lH), l.gS (d, J=12.9 Hz, 2H),
1.55 (m, 2H).
N~ N~ N ~O cO2Et
H3C
33-3
15 Ethyl 4-(Pyridyl)(piperidin-4-yl)-carbonylamino-3-methylphenoxy-
acetate (33-3)
Ethyl 4-amino-3-methylphenoxyacetate hydrochloride
(10-4) (0.35 g, 1.41 mmol), 4-(Pyridyl)(piperidin-4-yl)-carboxylic acid
(0.30 g, 1.41 mmol), chloro-N, N, N', N'-bis(pentamethylene)folm-
20 amidinium hexafluorophosphate (0.50 g, 1.41 mmol), and
diisopropylethylamine (0.25 mL, 1.41 mmol) were dissolved in
dimethylformamide (15 mL). The solution was stirred at ambient
temperature for 48 h and the solvent removed in vacuo to give an oil.
This material was chromatographed on silica gel using 5:95 methanol-
25 ammonia saturated chloroforrn as eluant to afford 33-3 as a beige solid.
1H NMR (CDC13): â 8.27 (d, j=5.6 Hz, 2H), 7.53 (d, j=8.8 Hz, lH),
7.03 (s, lH), 6.78 (s, lH), 6.73 (d, j=8.8 Hz, lH) k, 6.68 (d, j=6.1 Hz,
2H), 4.59 (s, 2H), 4.27 (q, j=7.1 Hz, 2H), 3.97 (d, j=13.2 Hz, 2H), 2.95
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(t, j=11.7 Hz, 2H), 2.53 (m, lH), 2.06 (d, j=10.7 Hz, 2H), 1.92 (m, 2H),
1.73 (s, 3H), 1.30 (t, j=7.1 Hz, 3H).
o
N~N~ H3C O CO2H
33-4
4-(Pyridyl)(piperidin-4-yl)-carbonylamino -3 -methylphenoxyacetate
(33-4)
A solution of Ethyl 4-(Pyridyl)(piperidin-4-yl)-carbonyl-
amino-3-methylphenoxyacetate (33-3) (O.OS g, 0.126 mmol) in
10 tetrahydrofuran (10 mL) was treated with 1 N lithium hydroxide (0.13
mL, 0.132 mmol) and H20 (10 mL). The resulting solution was stirred
at ambient temperature and the solvent removed in vacuo to give 33-4 as
a colorless glass. 1H NMR (CD30D) ~ 8.09 (d, j=6.6 Hz, 2H), 7.09 (d,
j=8.6 Hz, 2H), 6.87 (d, 6.8 Hz, lH), 6.81 (s, lH), 6.75 (d, j=8.6 Hz,
lH), 4.34 (s, 2H), 4.10 (d, j=13.2 Hz, 2H), 3.02 (t, lO.0 Hz, 2H), 2.82
(m, lH), 2.18 (s, 3H), 1.98 (d, J=10.3 Hz, 2H), 1.83 (m, 2H).
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SCHEME 34
OH 1. HO3S~N2+ Cl
Cl 2. Na2S204
34-1
OH OH
Boc20, CHCI3 ~ Br~COOEt
reflux ~CI 1/2 eq Cs2CO3
NH2 NHBoc DMF
.34-2 34-3
O COOEt ~ COOEt
HCI (gas) ~b HCI
Cl EtOAc, 0~C ~f Cl
NHBoc NH2
34-4 34-5
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SCHEME 34 (CONT'D)
Boc--N N~COOH 1-5
Cl PF6
C~N N~ i-Pr2NEt, CH2C12
Boc--N N ~ r COOEt
H~ THF, H20
34-6 Cl
o HCI (gas)
Boc--N N~\ ,)~ ~ r COOH r
~/ ~ HN~~ EtOAc, 0~C
34 7 Cl
HCI
HN N~ ~ Or COOH
34-8 Cl
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3-Chloro-4-arninophenol (34-2)
Using a procedure similar to that described for compound
12 2 but starting with 3-chlorophenol (~), 3-chloro-4-aminophenol
(34-2) was prepared. 1H NMR (CDCl3): o 6.57 (dd, J= 2.8, 8.6 Hz,
lH), 6.73 (m, 2H).
4-(1 ~ 1 -Dimethylethoxycarbonyl)amino-3-chlorophenol (34-3)
To a 100 mL round bottomed flask with a stirring bar and
an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-
10 chlorophenol (1.91 g, 13.3 mmol), di-tert-butyldicarbonate (3.14 g,
14.4 mmol) and THF (50 mL). To this mixture was added
triethylamine (2.23 mL, 16.0 mmol) and the mixture was stirred at
room temperature for 98 h. The solvent was removed in vacuo. The
residue was acidified with 10% aqueous citric acid and extracted with
15 EtOAc. The EtOAc extract was washed with water and brine. Drying
(MgSO4), filtration, removal of the solvent in vacuo and
chromatography on silica gel using EtOAc-hexane as eluant gave an oil.
This material was dissolved in THF (25 mL) and MeOH (8 mL) and lN
LiOH (25 mL) were added. This solution was stirred at ambient
20 temperature 4 h. This mixture was acidif1ed with 10% citric acid and
extracted with EtOAc. The organic layer was dried (MgS04), filtered
and concentrated in vacuo to give 34-3 as an oil. 1H NMR (CDC13): ~
1.53 (s, 9H), 6.69 (dd, J= 2.8, 8.9 Hz, 2H), 6.85 (d, J= 2.8 Hz, lH), 7.80
(d, J= 8.9 Hz, lH).
Ethyl 4-(1, l -dimethylethoxycarbonyl)amino-3 -chlorophenoxyacetate
(34-4)
To a 50 mL round bottomed flask with a stirring bar and
an argon inlet was added 4-(1,1-dirnethylethoxycarbonyl)amino-3-
30 chlorophenol (0.831 g, 3.41 mmol) and DMF (16 mL). This mixturewas cooled in an ice bath then Cs2CO3 (0.552 g, 1.69 mmol) and ethyl
bromoacetate (0.37 mL, 3.34 mmol) were added. The resulting mixture
was stirred for 6 h, during which time the cooling bath was allowed to
expire. The mixture was filtered through a frit and the DMF was
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removed in vacuo. The residue was dissolved in EtOAc and washed
with water (12X) and brine. Drying (MgSO4), filtration and removal
of the solvent in vac~o gave an oil which was purified by silica gel
chromatography (EtOAc-hexane) to give ethyl 4-(1,1-dimethyl-
5 ethoxycarbonyl)amino-3-chlorophenoxyacetate (34-4) as an oil. 1H
NMR (CDC13): ~ 1.30 (m, 3H), 1.53 (s, 9H), 4.27 (m, 2H), 4.57 (s,
2H), 6.78 (br s, lH), 6.83 (dd, J= 2.8, 8.8 Hz, lH), 6.96 (d, J=2.8 Hz,
lH), 8.02 (br d, J= 8.8 Hz, lH).
10 4-[4-(1 -Piperazinyl)phenylcarbonylamino] -3-chlorophenoxyacetic
acid (34-8)
Using a sequence similar to that described ~or compound
12-8, but starting with ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-
chlorophenoxyacetate (~), 4-[4-(1-piperazinyl)phenylcarbonyl-
15 amino]-3-chlorophenoxyacetic acid was prepared. lH NMR (DMSO-d6,
HCI salt): ~ 3.22 (t, J= 5.0 Hz, 4H), 3.53 (t, J= 5.0 Hz, 4H), 4.75 (s,
2H), 6.94 (dd, J= 2.9, 8.8 Hz, lH), 7.08 (d, J= 8.9 Hz, 2H), 7.11 (d,
J=2.9 Hz, lH), 7.40 (d, J=8.8 Hz, lH), 7.91 (d, J= 8.9 Hz, 2H), 9.12 (br
s, lH), 9.69 (s, lH).
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SCHEME 35
A /=\ B2H6 ~ THF
Boc--N N~, ,~COOH
\J ~ TH F/0~C
1 -5
~ ~ OH MnO2/CHCI3/RT
Boc--N N~--
35-1
Boc--N~N~CHO
35-2
OH O~COOEt
BrCH2COOEt
Cs2CO3 / DMF [~1
OH OH
35-3
35-4
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SCHEME 35 (CONT'D)
35-4
Ph3P/CBr4 CH2CI2/0~C
O COOEt O, COOEt
Ph3P/PhH ~
Br P+Ph3 Br~
35-5 35-6
O~COOEt
NaH/DMSO/THF/35-2 ~J
[~
N
Boc
35-7
. . .
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SCHEME 35 (CONT'D)
1. 10% Pd-C /H2
2. 1 N NaOHfrHF
3. HCI (g)/EtOAc
H--N N~-- ~COOH
35-8
\ 1.1NNaOH/THF
2. HCI (g)/1,4-dioxane
H--N N~-- ~COOH
3~-9
5 1 -Hydroxymethyl-4-(4-( 1,1 -dimethylethoxycarbonyl)piperazinyl)-
benzene (35-1 )
To an oven dried 500 mL round bottomed flask with a
stirring bar and an argon inlet was added acid 1 5 (5.00 g, 16.32 mmol)
and distilled, dry, THF (80 mL). This solution was cooled in an ice bath
10 and borane-THF complex (125 mL of a lM solution in THF, 125 mmol)
was added with a syringe. The resulting solution was maintained at 0~C
for 3.5 h. The reaction was ql:lenched by addition of MeOH (50 mL),
slowly, with a syringe over 5 min. This mixture was stirred at ambient
temperature for 18 h. The solvents were removed in vacuo and the
15 residue was dissolved in EtOAc (300 mL). This solution was washed
with saturated aqueous NaHCO3 and brine. Drying (MgSO4), filtration
and removal of the solvent in vacuo gave 4.86 g of 1-hydroxymethyl-4-
(4-(1,1-dirnethylethoxycarbonyl)piperazinyl)benzene, 35-1, as a white
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solid. 1H NMR (CDC13): ~ 1.48 (s, 9H), 3.11 (m, 4H), 3.59 (m, 4H),
4.61 (s, 2H), 6.91 (d, J=7 Hz, 2H), 7.27 (d, J=7 Hz, 2H).
4-(4-(1,1-Dimethylethoxycarbonyl)piperazinyl)benzaldehyde (35-2)
To a 50 mL round bottomed flask with a stirring bar and
an argon inlet was added l-hydroxymethyl-4-(4-(1,1-dimethylethoxy-
carbonyl)piperazinyl)benzene, 35-1 (2.15 g, 7.35 mmol), CHC13 (100
mL), and MnO2 (12.0 g, 138 mmol). This mixture was stirred at
arnbient temperature for 24 h. The salts were removed by filtration and
the solvent was removed in vacuo. The residue was chromatographed
on 90 g of silica gel using 30/70 EtOAc-hexane as eluant. There was
obtained 4-(4-(1,1-dimethylethoxycarbonyl)piperazinyl)benzaldehyde
35-2 (2.10 g, 99%) as a crystalline solid. lH NMR (CDC13): ~ 1.49 (s,
9H), 3.39 (m, 4H), 3.59 (m, 4H), 6.89 (d, J=9 Hz, 2H), 7.75 (d, J=9 Hz,
2H),9.79(s,1H).
Ethyl 2-(4-hydroxymethvlphenoxy)acetate (35-4)
To a 500 mL round bottomed flask with a stirring bar and
an argon inlet was added 4-hydroxybenzyl alcohol (7.50 g, 60.42
mmol), Cs2CO3 (29.53 g, 90.63 mmol), DMF (100 mL), and ethyl
bromoacetate (11.09 g, 66.46 mmol). This mixture was stirred at
ambient temperature for 2 h. The mixture was filtered and the filtrate
was concentrated in vacuo. The residue was partitioned between EtOAc
and water. The layers were separated and the organic phase was washed
with two additional portions of water. Drying (MgSO4), filtration and
removal of the solvent in vacuo, gave an oi~. This material was
chromatographed on 250 g of silica gel using 1: 1 EtOAc-hexane as
eluant. There was obtained ethyl 2-(4-hydroxymethyl-phenoxy)acetate
35-4 (7.47 g, 59%) as an oil. 1H NMR (CDC13): o 1.29 (t, J=7 Hz,
3H), 2.07 (br s, lH), 4.26 (q, J=7 Hz, 2H), 4.58 (s, 2H), 4.60 (s, 2H),
6.88 (d, J=9 Hz, 2H), 7.27 (d, J=9 Hz, 2H).
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Ethyl 2-(4-bromomethylphenoxy)acetate (35-S)
To a lL round bottomed flask with a stirring bar, addition
funnel and an argon inlet was added ethyl 2-(4-hydroxymethyl-
phenoxy)acetate 35-4 (7.47 g, 35.53 mmol), CBr4 (13.26 g, 39.97
S mmol) and dry CH2cl2 (300 mL). This solution was cooled in an ice
bath and and a solution of triphenyl phosphine (10.48 g, 39.97 mmol) in
CH2C12 (100 rnL) was added dropwise over 1 h. The ice bath was
allowed to expire and and the mixture was stirred at ambient
temperature 18 h. The solvent was removed in vacuo and the residue
10 was chromatographed directly on 200 g of silica gel useing 15% EtOAc-
hexane as eluant. There was obtained ethyl 2-(4-bromomethyl-
phenoxy)acetate 35-5 (7.2 g, 74%) as a low melting solid~ mp.: 44-
45~C. 1H NMR (CDC13): ~ 1.29 (t, J=7 Hz, 3H), 4.26 (q, J=7 Hz, 2H),
4.48 (s, 2H), 4.61 (s, 2H), 6.86 (d, J=9 Hz, 2H), 7.32 (d, J=9 HZ, 2H).
4-(Ethoxycarbonylmethoxy)benzyltriphenylphosphonium bromide
(35-6)
To a 100 mL round bottomed flask with a stirring bar and
a reflux condenser topped with an argon inlet was added ethyl 2-(4-
20 bromomethylphenoxy)acetate 35-5 (2.73 g, 10 mmol), triphenyl-
phosphine (2.62 g, 10 mmol) and dry benzene (50 mL). This solution
was warmed to 50~C for 20 h. The mixture was cooled to room
temperature and the product was collected by filtration. The white solid
was washed with a little benzene and dried in vacuo to give 4-(ethoxy-
25 carbonylmethoxy)benzyltriphenyl-phosphonium bromide 35-6 as a
white, crystalline solid (4.79 g, 89%). lH NMR (CDC13): ~ 1.2~ (t,
J=7 Hz, 3H), 4.27 (q, J=7 Hz, 2H), 4.53 (s, 2H), 5.38 (d, J=14 Hz, 2H),
6.66 (d, J=9 Hz, 2H), 7.06 (d, J=9 Hz, 2H), 7. 62 (m, 6H), 7.76 (m, 9H).
30 (E) Ethyl 4-(2-(4-(4-(1,1-dimethylethoxycarbonyl)piperazinyl)phenyl)-
ethenyl)phenoxyacetate (35-7)
To an oven dried 100 mL round bottomed flask with a
stirring bar and an argon inlet was added 4-(ethoxycarbonyl-
methoxy)benzyltriphenyl-phosphonium bromide (1.106 g, 2.07 mmol)
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and drs THF (50 mL). To this well stirred mixture was added a
solution of lithium hexamethyldisilylazide (2.20 mL of a lM solution in
THF). The deep red solution was stirred 1 h at ambient temperature
then cooled in an ice bath to 0~C. To this mixture was added a solution
5 of 4-(4-(1,1-dimethylethoxycarbonyl)piperazinyl)benzaldehyde (0.60 g,
2.07 mmol) in 10 mL of THF. The ice bath was removed and the
solution was stirred at ambient temperature for 3 h. The reaction
mixture was diluted with EtOAc and washed with water and brine.
Drying (MgSO4), filtration and removal of the solvent in vacuo gave 1
10 g of an oil. This material was chromatographed on 80 g of silica gel
using 25% EtOAc-hexane as eluant. There was obtained (E)-ethyl 4-(2-
(4-(4-(1,1 -dimethylethoxycarbonyl)piperazinyl)phenyl)-
ethenyl)phenoxyacetate 35-7 as an oil. 1H NMR (CDCl3): ~ 1.26 (t,
j=7 Hz, 3H), 1.49 (s, 9H), 3.16 (m, 4H), 3.57 (m, 4H), 4.27 (q, j=7 Hz,
15 2H), 4.60 (s, 2H), 6.90 (m, 6H), 7.40 (m, 4H), and 175 mg of a mixture
of E,Z isomers.
4-(2-(4-(l-Piperazinyl)phenyl)ethyl)phenoxyacetic acid (35-8)
To a 25 mL round bottomed flask with a stirring bar and a
20 balloon hydrogenation adaptor was added (E,Z) ethyl 4-(2-(4-(4-(1,1-
dimethylethoxycarbonyl)piperazinyl)phenyl)ethenyl)phenoxyacetate
(175 mg, 0.36 mmol), absolute EtOH (10 mL) and 10% Pd-C. This
mixture was hydrogenated at 1 atmosphere at ambient temperature for
1~3 h. The cataylst was removed by filtration and the filtrate was
25 concentrated in vacuo. The residue was chromatographed on 40 g of
silica gel using 20% EtOAc-hexane as eluant. The purified
hydrogenation product was hydrolyzed in THF (2 mL) with lN NaOH
(1 mL) for 3 h at ambient temperature. The reaction mixture was
diluted with EtOAc and washed with 10% aqueous citric acid, water,
30 and brine. Drying (MgSO4), filtration and removel of the solvent in
vacuo gave the corresponding acid as a white solid. This material was
dissolved in EtOAc (20 mL) and cooled to 0~C in an ice bath. The
solution was saturated with dry HCl gas for lS min. The resulting
suspension was aged 30 min at 0~C, then the solvent and excess HCl
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were removed in vac~o. The solid product was triturated with fresh
EtOAC and collected on a frit. After drying at 60~C/0.05 torr there
was obtained 103 m~ of 4-(2-(4-(1-piperazinyl)phenyl)ethyl)phenoxy-
acetic acid 35-8 as the hydrochloride salt. mp > 250~C. lH NMR
5 (DMSO-D6): ~ 2.76 (s, 4H), 3.20 (m, 4H), 3.33 (m, 4H), 4.61 (s, 2H),
6.80 (d, J=8 Hz, 2H), 6.90 (d, J-8 Hz, 2H), 7.12 (m, 4H), 9.21 (br s,
2H).
(E) 4-(2-(4-(1-Piperazinyl)phenyl)ethenyl)phenoxyacetic acid (35-9)
To a 25 mL round bottomed flask with a stirring bar and
an argon inlet was added (E) ethyl 4-(2-(4-(4-(1,1-dimethylethoxy-
carbonyl)piperazinyl)phenyl)ethenyl)phenoxyacetate (57 mg, 0.12
mmol), THF (2.0 mL) and lN NaOH (1.00 mL). This mixture was
stirred at ambient temperature 18 h. The reaction was neutralized with
15 lN HCI (1.00 mL) and extracted with several portions of EtOAc. The
combined EtOAc extracts were washed with water and brine. Drying
(MgSO4), filtration and removal of the solvent in vacuo gave 45 mg of
a solid. This solid was dissolved in 4N HCI-1,4-dioxane. The mixture
was stirred 18 h at ambient temperature. The milky suspension was
20 concentrated in vacuo. The crude product was triturated with a little
EtOAc and collected on a frit. This material was dried in vacllo to
provide 24 mg of (E) 4-(2-(4-(1-piperazinyl)phenyl)ethenyl)phenoxy-
acetic acid 35-9 as the hydrochloride salt, mp > 250~C. lH NMR
(DMSO-D6): ~ 3.2 (m, 4H), 3.45 (m, 4H), 4.69 (s, 2H), 6.89 (d, J=9
25 Hz, 2H), 6.98 (d, J=9 Hz, 2H), 7.02 (s, 2H), 7.48 (m, 4H), 9.15 (br s,
2H), 13.02 (br s, 1 H).
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SCHEME 36
NaH2PO4/H20
H~ 30% H2~2 , HO ~NO HCI (gas)
o CH3CN S MeOH
36- 1 -
5% PtSon C
MeO ~ MeO~ ~NH
36-3 36-4
- (Cl ~ 2 ~N~OMe NaOH, H20
n~BuOH, reflux BOCN J S
r ~ MeOH/ THF
2. BOC20, Et3N, CH2C1236-5
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SCHEME 36 (CONT'D)
/~\N~b~ Cl~ , cat. DMF, CH2CI2
30CN O /=\
36-6 H2N <~\ /~0 0
2. ~)~ ~4 , DMAP, pyridine,
H3C . HCI OEt 80~C
10-4
~--N N~O~O 1. NaOH, H20, MeOH
30CN ~ H3C OEt 2. TFA, CHzCI2
36-7
N) S~N~0~40
HN H3C OH
36-8
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HO ~ N~2
36-2
5-Nitrothiophene-2-carboxylic acid (36-2)
To a 500 mL round bottomed flask with a stirring bar, was
5 added 5-nitrothiophene-2-carboxaldehyde (7.86 g, 50.00 mmol) in CH
3CN (50 mL), NaH2PO4 (1.86 g, 13.50 mmol) in water (20 mL), and
30% H2~2 (aq) (6 mL). To this mixture, cooled in an ice bath, was
added NaClO2 (8 g, 70.80 mmol) in water (70 mL) dropwise over a
period of an hour. The reaction was stirred at room temperature for 5
10 hours. It was worked up by addition of Na2SO3 (500 mg), acidified
with lM HCI, and then extracted with ethyl acetate (3X). The combined
organic layers were washed with water (lX), and brine (lX). Drying
(MgSO4), filtration and removal of the solvents in vacuo yielded 5-
Nitrothiophene-2-carboxylic acid as a yellow powder.
lH NMR (300 M~Iz, CDC13) o 7.91(d, J= 4.4 Hz, lH), 7.80(d, J= 4.4
Hz, lH)
MeO ~ NO2
36-3
20 Methyl 5-nitrothiophene-2-carboxylate (36-3)
To a 500 mL round bottomed flask with a stirring bar, was
added 5-nitrothiophene-2-carboxylic acid (4.62 g, 26.68 mmol) and
MeOH (100 mL). This solution was cooled in an ice bath and dry HCI
gas was bubbled through the solution till saturated. The reaction was
25 equipped with a condensor and a drying tube and refluxed overnight.
The solvent was then removed in vacuo to a yellow solid, which was
, . .
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then dissolved in EtOAc. This solution was washed with NaHCO3 (sat,
aq) (3X), and bline (2X), dried (MgSO4), and filtered. Removal of the
solvents in vac~o an~d drying of the product in vacuo yielded methyl 5-
nitrothiophene-2-carboxylate as a tan solid.
lH NMR (300 MHz, CDC13) ~ 7.8~(d, J= 4.4 Hz, lH), 7.70(d, J= 4.4
Hz, lH), 3.96(s, 3H)
MeO ~N1~2
36-4
Methyl 5-aminothiophene-2-carboxylate (36-4)
To a Parr flask was added methyl 5-nitrothiophene-2-
carboxylate (5.00 g, 26.71 mmol) and MeOH (100 mL). The solution
was purged with a stream of Ar, and 5% platinum on sulfide carbon
(2.00 g) was added. The mixture was hydrogenated on a Parr apparatus
set at 50 psi for 6.5 hours. The reaction was then filtered through celite
and the solvents removed in vacuo to yield methyl 5-aminothiophene-2-
carboxylate as an olive green oil.
lH NMR (300 MHz, CDC13) ~ 7.45(d, J= 4.0 Hz, lH), 6.09(d, J= 4.0
Hz, lH), 4.31(br s, 2H), 3.81(s, 3H)
BOCN ~OMe
36-5
5-(4-(1,1 -Dimethylethoxycarbonyl)-piperazin- 1 -yl)-thiophene-2-
carboxylate. (36-5)
To a 500 mL round bottomed flask equipped with a
condenser, stirring bar, and argon inlet was added methyl 5-
aminothiophene-2-carboxylate (4.27 g, 27.16 mmol), bis(2-
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chloroethyl)amine, hydrochloride (5.82 g, 32.59 mmol) and n-BuOH
(90 mL, previously purged with Ar). This solution was reluxed for 7
days under Ar, and the reaction was followed by HPLC. The solvents
were then removed in vacllo, and the residue partitioned between EtOAc
S and NaHCO3 (aq). Extracted aqueous with EtOAc (3X), and ~en
washed the combined organics with brine (lX), dried (Na2S04),
filtered, and concentrated in vacuo. The residue was azeotroped with
toluene (3X), and dried in vacuo overnight.
The dried product was dissolved in CH2C12 (80 mL), and
triethylamine (4.2 mL, 30.13 mmol), di-tert-butylpyrocarbonate (6.53
g, 29.90 mmol), and CH2C12 (20 mL) were added and the reaction was
stirred at room temperature for 2 hours. The reaction was then
concentrated in vacuo. This yielded 490 mg of n-butyl 5-(4-(1,1-
dimethylethoxycarbonyl)-piperazin-1-yl)-thiophene-2-carboxylate and
700 mg of 5-(4-(1,1-dimethylethoxycarbonyl)-piperazin-1-yl)-
thiophene-2-carboxylate as a mixture of the methyl and n-butyl esters.
lH NMR of n-butyl ester (300 MHz, CDC13) o 7.55(d, ~= 4.4 Hz, lH),
6.06(d, J= 4.4 Hz, lH), 4.24(t, 2H), 3.58(t, 4H), 3.22(t, 4H), 1.69(m,
2H), 1.48(s, 9H), 1.42(m, 2H), 0.95(t, 3H)
/--\ N--~ OH
BOCN S
36-6
5-(4-(1,1 -Dimethylethoxycarbonyl)-piperazin- 1 -yl)-thiophene-2-
carboxylic acid. (36-6)
To a 50 ml round bottomed flask with a stirring bar was
added n-butyl 5-(4-(1,1 -dimethylethoxycarbonyl)-piperazin- 1 -yl)-
thiophene-2-carboxylate (490 mg, 1.33 mmol) and 4.2 mL of a 2.5M
NaOH solution in 3:1 MeOH/H20. THF (2 mI,) was added to keep the
- reaction homogeneous. The reaction was stirred at room temperature
and followed by HPLC. After 2 dayst the reaction was concentrated in
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vacuo, acidified with 10% citric acid and extracted with EtOAc (3X3.
The combined organics were washed with water (lX), brine (lX), dried
(Na2S04), filtered, and the solvents removed in vacuo. The product
was azeotroped with benzene (3X) and dried in vacuo over 2 days to
5 yield 5-(4-(1,1 -dimethylethoxycarbonyl)-piperazin- l -yl)-thiophene-2-
carboxylic acid as a dark green solid.
1H NMR (300 MHz, CD30D) ~ 7.51(d, J= 4.4 Hz, lH), 6.19(d, J= 4.4
Hz, lH), 3.57(t, 4H), 3.24(t, 4H), 1.47(s, 9H)
~--N) S~N~O~O
BOC N H3C OEt
1 0 36-7
Ethyl 2-(4-(S-(4-( 1,1 -dimethylethoxycarbonyl)-piperazin- 1 -yl)-2-
thienylcarbonylamino)-3-methylphenoxy)-acetate (36-7)
To a 100 ml round boKomed flask with a stirring bar and
an argon inlet was added 5-(4-(1,1-dimethylethoxycarbonyl)-piperazin-
l-yl)-thiophene-2-carboxylic acid (428 mg, 1.370 mmol), anhydrous
CH2C12 (10 mL), DMF (.05 mL), and distilled oxalyl chloride (.180
mL, 2.06 mmol). It was stirred l.S hours at room temperature. The
acid chloride was concentrated in vacuo, azeotroped with benzene (3X),
and stored under a blanket of Ar.
To another 100 mL round bottomed flask with a stirring
bar and an argon inlet was added ethyl 4-amino-3-methylphenoxyacetate
hydrochloride, anhydrous pyridine (7 mL), and dimethylaminopyridine
(34 mg, 0.278 mmol).
Cooled in an ice bath. A solution of the acid chloride in
pyridine (3 mL) was added. The ice bath was removed and the reaction
was stirred at 80~C overnight.
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The reaction was concentrated in vacuo, dissolved in
EtOAc, washed with aq. KHSO4 (3X), aq. NaHCO3 (2X), brine (lX),
dried (Na2SO4), filt~red, and the solvents removed in vacuo. This
material was chromatographed on silica gel in 18% EtOAc-hexane as
eluant yielding ethyl 2-(4-(5-(4-(1,1-dimethylethoxycarbonyl)-
piperazin- 1 -yl)-2-thienylcarbonylamino)-3-methylphenoxy)-acetate.
lH NMR (300 MHz, DMSO-d6) o 9.42(s, IH), 7.67(d, J= 4.3 Hz, lH),
7.13(d, J= 8.8 Hz, lH), 6.83(d, J=2.7 Hz, lH), 6.74(dd, J= 8.8, 2.7 Hz,
lH), 6.24(d, J= 4.3 Hz, lH), 4.76(s, 2H), 4.17(q, J= 7.1, 2H), 3.47(t,
4H), 3.16(t, 4H), 2.15(s, 3H), 1.42(s, 9H), 1.22(t, ~= 7.1 Hz, 3H)
--N) S~N~O O
N H3C OH
36-8
2-(4-(5-(4-(1 ,1 -Dimethylethoxycarbonyl)-piperazin- 1 -yl)-2-
thienylcarbonylamino)-3-methylphenoxy)-acetic acid (36-8)
To a 100 mL round bottomed flask with a stirring bar was
added ethyl 2-(4-(5-(4-(1,1-dimethylethoxycarbonyl)-piperazin-1-yl)-2-
thienylcarbonylamino)-3-methylphenoxy)-acetate (250mg, 0.496 mmol),
MeOH (8 mL), and lM NaOH (1 mL). The reaction was stirred
overnight at room temperature.
The reaction was concentrated in vacuo, acidified with aq.
KHSO4 and extracted with EtOAc (2X). The organic extracts were
washed with brine (lX), dried (Na2S04), filtered, and the solvents
removed in vacuo.
This product was dissolved in CH2C12 (~ mL), and
trifluoroacetic acid (2 mL) was added. The reaction was stirred for 2
hours at room temperature and then concentrated in vacuo. The residue
was subjected to HPLC on a C-l~ reverse-phase column eluting with
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100% H20 -50% H2o/cH3cN (with 0.1% TFA) over 40 minutes.
Collection and lyophilization of the appropriate fractions yielded 2-(4-
(5-(4-(1,1 -Dimethyl~thoxycarbonyl)-piperazin- 1 -yl)-2-
thienylcarbonylamino)-3-methylphenoxy)-acetic acid as a white fluffy
S solid.
lH NMR (300 MHz, CD30D) o 7.62(d, J= 4.1 Hz, lH), 7.16(d, J= 8.5
Hz, lH), 6.86(d, J=2.7 Hz, lH), 6.79(dd, J= 8.5, 2.7 Hz, lH), 6.34(d, J=
4.1 Hz, lH), 4.65(s, 2H), 3.50(m, 4H), 3.40(m, 4H), 2.24(s, 3H)
EXAMPLE 37
Tablet Preparation
Tablets cont~ining 25.0, 50.0, and 100.0 mg., respectively,
15 of the active compound 3-(4-(4-piperazin-1-ylphenylcarbonylamino)-
phenyl)-propanoic acid are prepared as illustrated below:
TABLE FOR DOSES CONTAINING
FROM 25-lOOMG OF THE ACTIVE COMPOUND
Amount-mg
Active Compound 25.0 50.0 100.0
Microcrystalline cellulose 37.25 100.0 200.0
Modified food corn starch 37.25 4.25 8.5
Magnesium stearate 0.50 0.75 1.5
All of the active compound, cellulose, and a portion of the
corn starch are mixed and granulated to 10% corn starch paste. The
resulting granulation is sieved, dried and blended wi~h the remainder of
25 the corn starch and the magnesium stearate. The resulting granulation is
then compressed into tablets containing 25.0, 50.0, and 100.0 mg,
respectively, of active ingredient per tablet.
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EXAMPLE 3~
Intravenous formulations
An intravenous dosage form of the above-indicated active
compound is prepared as follows:
Active Compound 0.5-lO.Omg
Sodium Citrate 5-50mg
Citric Acid I -I5mg
Sodium Chloride 1 -8mg
Water for Injection (USP) q.s. to 1 L
Uti1i7.in~ the above quantities, the active compound is
10 dissolved at room temperature in a previously prepared solution of
sodium chloride, citric acid, and sodium citrate in Water for Injection
(USP, see page 1636 of United States Pharmacopeia/National Formulary
for 1995, published by United States Pharmacopeial Convention, Inc.,
Rockville, Maryland, copyright 1994.
EXAMPLE 39
Intravenous formulation
A phalmaceutical composition was prepared at room
temperature using 3-(4-(4-piperazin-1-ylphenylcarbonylamino)phenyl)
propanoic acid, a citrate buffer, and sodium chloride, to obtain a
concentration of of 0.25 mg/ml.
800 grams of water was introduced into a standard
pharmaceutical mixing vessel. 0.25 grams of 4-(N-piperazine)benzoyl-
N-(aminophen-4-yl)propionic acid was dissolved in the water. 2.7
grams sodium citrate and 0.16 grams citric acid were added to obtain a
finished citrate concentration of 10 mM. 8 grams of sodium chloride
was added. 200 grams of water was then added to achieve the desired
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final concentrations of ingredients. The resulting aqueous formulation
had the following concentrations:
In~redient Amount
3-(4-(4-piperazin- 1 -ylphenylcarbonylamino)phenyl)
propanoic acid 0.25 mg/ml
citrate buffer 10 rnM
sodium chloride 8 mg/ml
The finished concentrated formulation is stored in a
standard USP Type I borosilicate glass container at 30-40 degrees C.
Prior to compound ~dmini.stration, the concentrated formulation is
15 diluted in a 4:1 ratio resulting in a finished concentration of 0.05 mg/ml
and transfered to an infusion bag.
Therapeutic Treatment
Compounds of the invention may be ~mini~tered to
20 patients where inhibition of hl~mAn or m~mm~lian platelet aggregation
or adhesion is desired.
Compounds of the invention are useful in inhibiting platelet
aggregation and thus, they may find utility in surgery on peripheral
arteries (arterial grafts, carotid endaterectomy) and in cardiovascular
25 surgery where manipulation of arteries and organs, and/or the interation
of platelets with artificial surfaces, leads to platelet aggregation and
consumption. The aggregated platelets may forrn thrombi and
thromboemboli. Compounds of the invention may be administered to
these surgical patients to prevent the formation of thrombi and
30 thromboemboli.
