Note: Descriptions are shown in the official language in which they were submitted.
CA 02341718 2001-02-26
WO 00/12468 PCT/US99/19492
1
An Improved Synthesis of 3-Hydroxy-4-Amino-Benzonitrile
Scope of the Invention
This invention relates to a process for making intermediates useful for
making certain phenyl urea compounds. The end-product phenyl urea compounds
are useful in treating IL-8, GROoc, GROG, GROy and NAP-2 mediated diseases.
Area of the Invention
Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of
T-cells. It is produced by a majority of nucleated cells including
macrophages,
fibroblasts, endothelial and epithelial cells exposed to TNF, IL-la, IL-lb or
LPS,
and by neutrophils themselves when exposed to LPS or chemotactic factors such
as
FMLP. M. Baggiolini et al, J. Clin. Invest. 84, 1045 ( 1989); J. Schroder et
al, J.
Immunol. 139, 3474 ( 1987) and J. Immunol. 144, 2223 ( 1990) ; Strieter, et
al,
Science 243, 1467 ( 1989) and J. Biol. Chem. 264, 10621 ( 1989); Cassatella et
al, J.
Immunol. 148, 3216 ( 1992).
There is a need for treatment in this field, for compounds which are capable
of binding to the IL-8 a or p receptor. Therefore, conditions associated with
an
increase in IL-8 production (which is responsible for chemotaxis of neutrophil
and
T-cells subsets into the inflammatory site) would benefit by compounds which
are
inhibitors of IL-8 receptor binding. Such compounds have been disclosed in
published patent applications exemplified by the likes of PCT/US96/13632,
published 21 August 1997 as WIPO No. W097/29743. This invention provides a
method for making 2-amino-5-cyano-phenol which is a useful intermediate for
synthesising N-[2-hydroxy-4-cyanophenyl]-N'-[2-bromophenyl]urea, a compound
disclosed in PCT application serial number PCT/US96/13632, published 21 August
1997 as WIPO No. W097/29743.
SUMMARY OF THE INVENTION
In a first aspect this invention relates to a method for making compounds of
Formula (A)
R
~ Ri)m
H H ~ ~ A
( )
wherein
CA 02341718 2001-02-26
WO 00/12468 PCT/US99/19492
2
X is oxygen;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or
less;
R1 is independently selected from hydrogen; halogen; nitro; cyano; C1_10
alkyl; halosubstituted CI-10 ~kyl; C2_10 alkenyl; CI-10 alkoxy;
halosubstituted
CI-l0alkoxy; azide; S(O)tRq.; (CRgRg)q S(O)tR4; hydroxy; hydroxy substituted
C 1 _4alkyl; aryl; aryl C 1 _4 alkyl; aryl C2_ 10 alkenyl; aryloxy; aryl C I
_4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2_ 10 alkenyl; heteroaryl C 1 _4
alkyloxy;
heterocyclic, heterocyclic C 1 _4alkyl; heterocyclicC I _4alkyloxy;
heterocyclicC2_ 10
alkenyl; (CRgRg)q NR4R5; (CRgRg)q C(O)NR4R5; C2_ 10 alkenyl C(O)NR4R5;
(CRgRg)q C(O)NR4R10; S(O)3H; S(O)3Rg; (CRgRg)q C(O)R11; C2-10 alkenyl
C(O)RI I; C2-10 ~kenyl C(O)ORI 1; (CRgRg)q C(O)ORI I; (CRgRg)q OC(O)R1 l;
(CRgRg)qNR4C(O)R11; (CRgRg)q C(NR4)NR4R5; (CRgRg)q NR4C(NRS)R11 ,
(CRgRg)q S(O)2NR4R5, or two RI moieties together may form a 5 to 6 membered
unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl,
heterocyclic
moities may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
t is 0 or an integer having a value of 1 or 2;
s is an integer having a value of i to 3;
R4 and RS are independently, optionally substituted C 1 _4 alkyl, optionally
substituted aryl, optionally substituted aryl CI_4alkyl, optionally
substituted
heteroaryl, optionally substituted heteroaryl C1_4alkyl, heterocyclic,
heterocyclic
C I _4 alkyl, or R4 and RS together with the nitrogen to which they are
attached form
a 5 to 7 member ring which may optionally comprise an additional heteroatom
selected from O, N or S;
Y is R1;
q is 0 or an integer having a value of 1 to 10;
m is an integer having a value of 1 to 3;
R6 and R~ are independently hydrogen or a C 1 _4 alkyl group, or R6 and R~
together with the nitrogen to which they are attached form a 5 to 7 member
ring
which ring may optionally contain an additional heteroatom which heteroatom is
selected from oxygen, nitrogen or sulfur;
Rg is hydrogen or C1_4 alkyl;
R I p is C I _ 10 alkyl C(O)2Rg;
R 11 is hydrogen, optionally substituted C 1 _4 alkyl, optionally substituted
aryl, optionally substituted aryl C I _4alkyl, optionally substituted
heteroaryl,
optionally substituted heteroarylC I _4alkyl, optionally substituted
heterocyclic, or
optionally substituted heterocyclicC I _4alkyl;
CA 02341718 2001-02-26
WO 00/12468 PCT/US99/19492
3
R12 is hydrogen, C1-10 ~kYl, optionally substituted aryl or optionally
substituted arylalkyl;
R 13 is suitably C I _4 alkyl, aryl, aryl C 1 _4alkyl, heteroaryl, heteroarylC
1 _
4alkyl, heterocyclic, or heterocyclicC 1 _4alkyl;
Rb is NR6R~, alkyl, aryl, aryl C 1 _4 alkyl, aryl C2~ alkenyl, heteroaryl,
heteroaryl C 1 _q. alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclic C
I ~ alkyl,
heterocyclic C2_4 alkenyl, or camphor, all of which groups may be optionally
substituted;
which process comprises treating a compound of Formula (I) or (Ia)
NH3+A.
HO
NH3*A- /
I
HO
li
R1 (I) or N (Ia)
where A' is the anion of an acid addition salt with an isocyanate in the
presence of about an equivalent of an organic base.
This invention also relates to a process for making a 2-aminophenol. In
particular, this process comprises preparing the phenol of Formula (I) or (Ia)
NH3+A_
HO
NH3~A_ /
HO /
R~ (I) or N (Ia)
where A- is the anion of an acid addition saltc by treating a compound of
formula (II) or (IIa) with an acid to remove the t-BOC group.
CA 02341718 2001-02-26
WO 00/12468 PCT/US99/19492
4 O
HN
O ~ HO /~ O 1
HN-
o ~ 1'
HO~
/
~i)
R1
(IIa)
(II) or N
In a third aspect this invention relates to a process for making the nitrite
of
formula (III)
O
HN
O
/ v
(III)
which process comprises treating the halo-substituted compound of formula
(IV)
O
H2N
v
O
(IV )
where X is CI, Br, or I with a cyanide salt and optionally a transition metal
catalyst.
Detailed Description of the Invention
The preferred compounds which can be synthesised by these methods and
using these intermediates are those where RI is halogen, cyano, nitro, CF3,
C(O)NR4R5, alkenyl C(O)NRq.RS, C(O) R~R10, alkenyl C(O)OR12, heteroaryl,
CA 02341718 2001-02-26
WO 00/12468 PCT/US99/19492
heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4RS, and preferably one of R4 or
RS
is phenyl. A preferred ring substitution for R 1 is in the 4-position of the
phenyl ring.
Preferably R 1 is nitro, halogen, cyano, trifluoromethyl group, or
C(O)NR4R5.
S Y is preferably a halogen, C 1-4 alkoxy, optionally substituted aryl,
optionally substituted aryloxy, optionally substituted arylalkoxy, optionally
substituted arylalkyloxy, optionally substituted heteroarylalkyloxy,
methylenedioxy,
NR4RS, thioC 1 _4alkyl, thioaryl, halosubstituted alkoxy, optionally
substituted C 1-4
alkyl, or hydroxy alkyl. Y is more preferably mono-substituted halogen,
disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy,
methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-
substituted in the 2'- position or 2'-, 3'-position.
While Y may be substituted in any of the S ring positions, preferably when R
is OH, or SH, Y is preferably mono-substituted in the 2'-position or 3'-
position, with
1S the 4'- preferably being unsubstituted. If the ring is disubstituted, when
R is OH or
SH other ring substituents are preferably in the 2' or 3' position of a
monocyclic ring.
While both Rl and Y can both be hydrogen, it is prefered that at least one of
the
rings be substituted. Preferably both rings are substituted.
Preferred compounds include:
N-[2-hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea
N-(2-hydroxy-4-cyanophenyl)-N'-(2-(4-pyridylmethyloxy)phenyl)urea , and
N-(2-hydroxy-4-cyanophenyl)-N'-(2-chlorophenyl)urea.
The roadmap for synthesizing compounds of Formula (A) is set out in
2S Scheme I. The compounds given in this scheme are illustrative of the
process and
any of the analogs of these compounds as defined for Formula (A) can be made
by
this processs.
3S
CA 02341718 2001-02-26
WO 00/12468 PCT/US99/19492
6
Scheme 1
O O
HN~ HN-~/
O Br2, AcOH O CuCN (l.7eq)
AcONa, 90% ~ DMF, 150 °C
/ : ~ / 88%
Br
O
O Hv
HN-~ N O
p 1 a. t-Boc20 THF HO 20%TFA/CH2CI2
DMAP, Et N
71%
b. MeOH, iCzC03
66%
CN RCN
Br
NH2
NH302CCF3
OH / ~ TiCl4, PhCH~ NC ~ /
O
v
j
/ C~NH N N
CH3CN, 25% °C H H
CN OH Br
63%
The benzoxazolinone starting material (formula 1-a) is commercially
available. See for example Aldrich. It is halogenated, bromine is illustrated,
by
mixing it with a solution of an organic acid, and a the alkali metal salt of
that acid in
a molar amount about equal to that of the benzoxazolinone to give the compound
of
formula b. Glacial acetic acid and its sodium salt are the preferred organic
acid/salt
combination. In the case of the illustrated benzoxazolinone, a suspension
forms.
That suspension is cooled to below ambient temperature, somewhere between 0-20
°C and then bromine is added slowly; a slight molar excess of bromine
with
reference to the benzoxazolinone is preferred. This mixture is stirred at
ambient
temperature for a period sufficient to effect the reaction, usually about 12
hours to
overnight. No special conditions are required to work up the halogenated
product
illustrated by formula b.
The nitrite of formula 1-c is prepared by treating the brominated
benzoxazolinone with CuCN at a moderately elevated temperature under an inert
gas
CA 02341718 2001-02-26
WO 00/12468 PCT/US99/19492
7
in a polar solvent such as dimethyl formamide, N-methyl pyrrolidinone or
dimethylsulfoxide. Alternatively Zn(CN)2 or an alkali metal salt of the
cyanide ion
can be used to effect this cyanation reaction. In addition a transition metal
catalyst
such as Pd(0) or Ni(0) can be used with Zn(CN)2 and an alkali metal salt of
the
cyanide ion respectively. As illustrated herein the benzoxazolinone is added
to the
solvent followed by the CuCN (in about a 75% molar excess). This mixture is
heated to a temperature which is in the range of 120 - 175 °C. The
reaction is carried
out under an inert gas, preferably nitrogen. The reaction mixture is heated to
the
noted temperature range for about 4-8 hours. Then the reaction is cooled to
about
100 °C, a 3 to 4-fold molar excess of an alkali metal cyanide, e.g.
NaCN, is added
and the resulting suspension is stirred for a couple of more hours at ambient
temperature. No special workup is required to recover the nitrite.
The carbamate (formual 1-d) is prepared by treating the
benzoxolecarbonitrile with an alkyl dicarbonate in a polar non-protic solvent
in the
presence of a nucleophilic addition catalyst such as dimethylaminopyridine.
The
reaction is run at about ambient temperature for a couple of hours or so.
To remove the t-BOC group and form the NH2-acid form of the compound
(formula 1-e) the I,l-dimethylethylcarbamate is treated with an organic or
mineral
acid. While trifluoroacetic acid is illustrated, HCl or H2S04 or an organic
acid such
as methansulfonic acid can be used in this reaction as well. The carbamate is
dissolved in a polar aprotic solvent, cooled, acid added, and the mixture
stirred for
several hours at a temperature between 0 °C and room temperature.
Workup can
involve precipitating the product by adding an organic solvent, cooling the
resulting
suspension to below freezing, and holding it at that temperature for up to 12
hours or
so as a means for isolating the product.
The compound designated formula 1-f is made by treating the acid salt form
of the amine with an isocyanate in the presence of about an equivalent of a
base to
scavenge the acid release when the isocyanate reacts with the amine to form
the urea
moiety. As a preferred practice the salt is dissolved in a suitable solvent
such as
acetonitrile to which is added a base. Piperidine is an example of a base that
can be
used as an acid scavenger. Then an isocyanate is added. The reaction proceeds
at
room temperature and is complete in the course of 1 to 3 hours or thereabouts.
Workup and recovery of the product is conventional.
An experimental procedure for each stage of the reaction set out in Scheme I
is detailed below. These experimentals are set out solely for the purpose of
illustrating the invention. What is reserved to the inventors is to be
determined by
reference to the claims, not to the following examples.
CA 02341718 2001-02-26
WO 00/12468 PCT/US99/19492
8
Examples
Example 1
6-Bromo-2(3H)-benzoxazolone
To a solution of glacial acetic acid ( 1500 ml) was added sodium acetate (222
g, 2.70 mole) and 2-benzoxazolinone (300 g, 2.22 mole). The suspension was
cooled to 15 °C, bromine ( 118 ml, 2.29 mole) added dropwise over 1 h
and the
mixture stirred for 12 h at ambient temperature. The solids were then
filtered,
washed with H:O (3 x 500 ml) and dried under vacuum to give the captioned
compound as a white solid (374 g, 89.7%): mp 186.0-187.0 °C; 'H NMR
(DMSO-dfi)
811.8 (s, 1 H), 7.6 (s, 1 H), 7.3 (d, J=8.0 Hz, 1 H), 7.0 (d, J=8.0 Hz, 1 H).
Example 2
2,3-Dihydro-4-hydroxy-2-oxo-6-benzoxazolecarbonitrile
To a solution of DMF ( 110 ml) was added 6-bromo-2(3H)-benzoxazolone
1 S (50 g, 0.234 mole) and CuCN (89.6 g, 0.398 mole) and the mixture heated to
150 °C
for 6 h under nitrogen. The reaction was then cooled to 100 °C, Hz0
(200 ml) and
NaCN (36 g, 0.734 mole) added, the suspension stirred for 2h at ambient
temperature and partitioned with EtOAc at 70 °C. The organic phase was
washed
with H,O (2 x 150 ml) and concentrated in vacuo to give the captioned compound
as
a tan solid (33.2 g, 88.5%): mp >220 °C; 'H NMR (DMSO-d~) 8 7.8 (s, 1
H), 7.6 (d,
J=8.0 Hz, 1 H), 7.2 (d, J=8.0 Hz, 1 H).
Example 3
1,1-Dimethylethyl (4-cyano-2-hydroxyphenyl) carbamate
To a solution of THF (500 ml) was added 2,3-dihydro-4-hydroxy-2-oxo-6-
benzoxazolecarbonitrile (25 g, 0.156 mole), Et,N (26 ml, 0.187 mole) and DMAP
(3.81 g, 0.031 mole). To the solution was added di-tert-butyl dicarbonate
(44.3 g,
0.202 mole) in three portions over 10 minutes and the mixture stirred at room
temperature for 2 h. The reaction mixture was then concentrated in vacuo to
give a
brown oil (40 g) which was diluted with MeOH (500 ml) and stirred for 1 h at
room
temperature. K.,CO, (21.5 g, O.I56 mole) was added and stirring continued for
1.5 h.
The inorganic solids were then filtered, the filtrate partitioned with EtOAc
and H,O,
and the organic phase filtered through SiOz ( I 50 g). The filtrate was
concentrated in
vacuo to give the captioned compound as a light yellow solid (24 g, 66%
yield): mp
170.0-171.0 °C; 'H NMR (DMSO-d~) s 8.1 (s, 1H), 7.9 (d, J=8.0 Hz, 1 H),
7.2 (d,
J=8.0 Hz, 1 H), 7.1 (s, 1 H).
Example 4
4-Amino-3-hydroxybenzonitrile, Trifluoroacetic Acid Salt
CA 02341718 2001-02-26
WO 00/12468 PCT/US99/19492
9
To a solution of CH=Cl, ( 1000 ml) was added 1,1-dimethylethyl (4-cyano-2-
hydroxyphenyl) carbamate (24 g, 0.102 mole) and the suspension cooled to 0
°C.
Trifluoroacetic acid ( 100 ml, 1.29 mole) was added in one portion, the
solution
stirred for 0.5 h at 0 °C and for 4 h at room temperature. The reaction
mixture was
then partially concentrated to 750 ml total volume and EtOAc (250 ml) added to
cause immediate precipitation. The suspension was cooled for 12 h at -10
°C,
filtered and dried to give the captioned compound as a white solid ( 18 g, 71
°lo): mp
164.0-166.0 °C; 'H NMR (DMSO-d~) s 7.0 (d, J=8.0 Hz, 1 H), 6.9 (s, 1
H), 6.65 (d,
J=8.0 Hz, 1 H).
Example 5
N-(2-Bromophenyl)-N'-(2-hydroxy-4-cyanophenyl) urea
To a solution of CH,CN (360 ml) was added 4-amino-3-hydroxybenzonitrile
trifluoroacetic acid salt ( 18 g, 0.072 mole) and piperidine (7.2 ml, 0.072
mole). The
solution was stirred at room temperature for 15 minutes followed by the
addition of
2-bromophenyl isocyanate (9.85 ml, 0.079 mole). After 2 h of stirring at room
temperature, a precipitate formed which was cooled to -10 °C for 12 h.
The
precipitate was filtered and dried to give the title compound as a white solid
(15.2 g,
63%): mp 203.5-205.0 °C; 'H NMR (DMSO-d~) 810.8 (bs, 1 H), 9.35 (s, 1
H), 9.1
(s, 1 H), 8.3 (d, J=8.5 Hz, 1 H), 7.9 (dd, J=8.3, 1.5 Hz, 1 H), 7.6 (dd,
J=8.3, 1.5 Hz, 1
H), 7.3 (t, J=8.3 Hz, 1 H), 7.2 (dd, J=8.3, 1.5 Hz, 1 H), 7.15 (s, 1 H), 7.0
(t, J=8.3
Hz, 1 H).
