Note: Descriptions are shown in the official language in which they were submitted.
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New polymers based on N-carbamyl-N'-dimethylsilyl methyl-piperazine
traceless linkers for the solid phase synthesis of phenyl based libraries
The present invention relates to polymers characterised by novel silicon
linkers
based on the carbamyl piperazine moiety, methods of preparing these polymers
and
their use in the solid phase synthesis of compounds or libraries of compounds
embracing a phenyl ring in their structure. Owing to the peculiar chemistry of
the
silicon atom, when breaking this linkage, an hydrogen atom (or other different
groups) substitutes the silicon itself. Therefore the released compounds show
no
trace of the tethering point (in the hydrogen case) or show further diversity
(when
additional groups are inserted).
Background of the invention
Solid phase organic chemistry (SPOC) which was originally developed for
peptide
~5 and oligo nucleotide synthesis, is now widely applied as an organic
synthesis tool in
the preparation of small molecules. The SPOC methods are exploited both by .
academic and pharmaceutical researchers to produce compounds, in limited
number
or as part of large libraries, to be submitted to high throughput screening in
the
search for new leads o address the increasing number of therapeutic targets..
2o The advantages of SPOC over the: solution approach are well recognised
(reacti~~ns
driven.to completion by excess reagent, easy purification by filtration
a:~°~d easy
automation of the processes) and the limitations as well (not all the
reactions .are
amenable to solid phase, e.g. hydrogenation, traditional analytical methods
poorly
amenable for in process control, continuous need of developing new synthetic
25 methods .
In addition to the attach-detach steps which need chemistry development, the
chemical groups involved both in the linkage and in the spacers sometime pose
limitation to the chemistries to be carried out to assemble the desired
campound and
consequently deserve special attention. In former times the attachment relied
on
3o traditional hydrophilic groups such as hydroxy, amine and carboxy taking
advantage
of the knowledge coming from the protective groups chemistry.
Such handles have clear drawbacks as they are stable only under limited
conditions
and as a common feature, upon detaching they leave the precursor groups on the
final molecule as a trace of the attachment point. Moreover when the anchoring
point
35 IS .on a phenyl ring, the presence of hydroxyl, carboxyl or amino groups
may be
detrimental from the biological point of view. In many cases these groups
negatively
affect the interaction with the receptor sites and are responsible for low
absorption
and fast metabolism when compounds of pharmacological interest are tested in
vivo.
If considering that a phenyl ring is present at least in 70% of compounds
endowed
4o with biological activity it is worthwhile developing methods which allow a
phenyl ring
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to be used as an attachment point and in the same time the released compounds
don't show any trace of the anchoring point, unless other groups are desired
to
expand diversity. ,
Detailed description of the invention
The most widely exploited class of traceless linkers are those based on the
silicon
chemistry. These lead to a phenyl ring with no trace of the anchoring point
owing to
an ipso-desilylation process under acidic conditions (TFA) or to a fluoride
mediated
cleavage under basic conditions [tetrabuthyl ammonium fluoride (TBAF)~.
According
9o to a further option other n.on polar functionalities such as nitro, bromo
or acetyl can
be introduced, if desired, during the detachment step.
Now here we describe and, this is tfie object of the present invention,.a new
linker
based on the silicon chemistry as far as the phenyl anchoring point is
concerned but
exploiting an alternative and advantageous linkage on the resin. Th.e handle
or linker
~5 is built around a piperazine moiety: one nitrogen connects the silicon
containing
chain. to the target phenyl ring whereas the second one serves to tether the
whole
structure to the resin. This anchorage relies on a urea type linkage and it,
is simply
F~bfa.ined by reacting the free piperazine nitrogen with a Merrifield
isocyanate resin.
'This very sirnple: process allows Vin. high~-yield=coupl,ing step.avoiding an
excess of the
2,~ ~ ;:precious reagent and an easy.ir~ process control:.(e.g. by following
the disappearance
of the isocyanate signal and the formation of the urea bond by FT IR
technique).
Moreover the generated urea linkage is robust and stable under a uariety of
conditions including acid, basic, reduction and oxydation steps. A broad range
of
chemistry is thus allowed in building up the compounds of interest during the
25 production of complex and diverse libraries. . .
The general usefulness of the new linker is exemplified here by applying it on
phenyl
rings possessing functional groups such as hydroxy, formyl and amino, which
can in
turn; after deprotection, be derivatised. A more complex pattern of
substitution (e.g.
trifluoromethylpiperazine) is amenable as well to the present new linker.
According to the present invention, we provide polymers of general formula (l)
I a R'
/-N ~ ~i\
Resin ~--N N Me R2
O
wherein
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Resin denotes polystyrene, optionally cross linked with divinyl benzene or
polyethylenglycol;
R~ denotes hydrogen, C~-C6-alkyl, CZ-Cg-alkenyl, C2-C6-alkynyl C~-Cg-
alkoxy, halogen, N02 or CF3;
s R~ denotes a group selected from hydroxy, amino, preferably
N-C~=Cg-alkylamino, and formyl, being optionally protected by a suitable
protective group,
or
. . a 5 or 6. membered saturated or unsaturated nitrogen heterocycle,
0 optionally containing one or two additional heteroatoms selected from the
group consisfiing.of oxygen, nitrogen and sulfur, and being optionally
substituted by a .group selected from C~-C6-alkyl, C~-C6-alkoxy, halogen,
N02 and a suitable protective group.
~5 I'r~ferred polymers are those of general formula (I),
wherein
Resin denotes polystyrene, optionally cross linked with divinyl benzetle or
polyethylenglycoi. .
R~ ' .denotes hydrogen, C~-Cq.-alkyl, C,-C~.-alkoxy,-flaorlne, chlorine,
bromine,
20 ~ or NO~; .. .
R2 denotes a group selected from hydroxy, amino, preferably
N-C~-C~-alkylamino, and formyl, being op#iorPally protected by a suitable
protective group,
or
2~ a 5 or 6 membered saturated or unsaturated nitrogen heterocycle,
optionally containing one additional nitrogen heteroatom which is
substituted by a protective group selected from fluorenylmethyoxycarbonyl
and t-butoxycarbonyl.
3Q More preferred polymers are those of general formula (I),
wherein
Resin denotes polystyrene cross linked with divinyl benzene;
R~ denotes hydrogen, methyl, methoxy , fluorine, chlorine, bromine, or N02,
preferably hydrogen;
35 R2 denotes hydroxy, being protected by a group selected from
tertbutyldimethylsilyl, methoxy-ethoxymethyl (MEM) and methyl,
or
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N-methylamino, being protected by a group selected from
fluorenylmethyloxycarbonyl (FMOC) and t-butoxycarbonyl (BOC),
or
formyl, being protected to form a dioxolane ring,
or
piperazin-1-yl, being substituted by a protective group selected from
fluarenylmethyoxycarbonyl and t-butoxycarbonyl.
According to the invention the term resin refers to polystyrene, optionally
crosss
linked with divinyl benzene, preferably with high swelling properties or
highly cross
linked macroporous polystyrene beads with low swelling capacity or cross
linked ..
polystyrene - polyethylenglycol. The preferred one,is a resin made with cross
linked
polystyrene - 1 % divinylbenzene, 200-400 mesh of the so called Merrifiefd
type.
~5 The alkyl groups meant, here (including those which are components of other
groups)
are branched and unbranched alkyl groups having 1 to 6 carbon atoms,
preferably 1
vto 4 carbon atoms, such as: methyl, ethyl, n-propyl; iso-propyi, butyl, iso-
butyl, .
ser,=butyl, tert-butyl, pentyl, iso-pentyl and hexyl.
Alkenyl=groups (including those which are components of other groups; are.the
branched and unbranched alkenyl groups with 2 to C carbon atoms, preferably 2
to 4
carbori atoms, provided that they have at leastrone double bond, e.g. the
alkyl groups
mentioned above provided that they have at least one double bond, such as for
example vinyl (provided that no unstable enamines or enolethers are formed),
25 ~ propenyl; iso-propenyl, butenyl, pentenyl and hexenyl.
If not otherwise specified the alkenyl- arid alkenylen-groups mentioned above
are to
be understood as embracing optionally existing stereoisomers. Accordingly,.
for
instance the definition 2-butenyl is to be understood as embracing 2-(Z)-
butenyl and
30 2-(E)-butenyl, etc..
The term alkynyl groups (including those which are components of other groups)
refers to alkynyl groups having 2 to 6, preferably 2 to 4 carbon atoms
provided that
they have at least one triple bond, e.g. ethynyl, propargyl, butynyl, pentynyl
and
35 hexynyl.
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The term amino denotes a group selected from NH2, N-C1-C6-alkylamino,
preferably
N-C1-Cq.-alkylamino, N-di(C1-Cg-alkyl)amino, preferably N-di(C1-C4-
alkyl)amino,
wherein C1-C6-alkyl is as hereinbefore defined. Preferred aminogroups are
selected
from N-methylamino and N-ethylamino, preferably N-methylamino.
5
The suitable protective groups that are applicable according to the invention
may
differ depending on the functional group they protect. For the hydroxy group
the
suitable protective group is preferably selected from methoxymethyl,
benzyloxymeth.yl, t-butoxymethyl, tertbutyldimethylsilyl, tetrahydropyranyl,
To methoxyethoxyethyl and benzyl, preferred protecting group being
tertbutyldimethylsilyl. For the amino group the suitable protective group is
preferably
. selected from fluorenylmethyloxycarbonyl (FMOC), benzyloxycarbonyl, t-
butoxycarbonyl (BOC), allyloxycarbonyl preferred protecting group being FMOC
and
BOC.The formyl group is preferably protected by a protective group to form
a~group
~5 selected from 1,3-dioxolane, 1,3-dithiolane, preferred protecting group
being 1,3- '
dioxolane. . .
If not otherwise specified preferred examples of 5- or 6-membered nitrogen
heterocycles are as follows: piperazine, pyrrolidine, piperidine, morpholine,
20 ~ benzimidazole, benzoxazole, imidazole, pyrazoie~, preferably piperazine,
morpholine,
piperidin~e.
Halogen, stands for fluorine, chlorine, bromine or iodine, preferably chlorine
or
bromine.
"=O" means an oxygen atom linked by a double bond.
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The compounds of general formula (I) may be conveniently prepared following
the
method described in scheme 1.
Me Me R~
Br ~ ~ ~Si
R B r-~ R2
(II) (III)
Me Me R~ ~ Me Me _ R~
. O ~ ~Si ~ E ~ wSi
Resins ~-N N-/ R2. . HN N-/ R2
N
H (I) (lV)
Scheme 1:
The bromo-derivatives of formula (II) are obtainable via conventional methods
known
in the art. Those derivatives of formula (II) wherein R2 denotes a functional
group
being protected as hereinbefore defined are obtainable from the unprotected
starting
materials according to well known methods in the art, pertaining to the
introduction of
To , known protective groups. Starting from the appropriate bromo-derivatives
of formula
(II) the silyl-derivatives of formula (III) are available as follows. After
activation by
suitable organometallic reagents, prqferably lithium alkyl reagents, more
preferably
branched or unbranched butyllithium reagents, at low temperature, preferably
between -78°C and -20°C, most preferably between - 40 °C
and - 60 °C, in an
~5 appropriate organic solvent, preferably in a solvent selected from the
group
consisting of tetrahydrofurane and diethylether, the dimethyl silyl
bromomethyl chain
is introduced to by addition of the appropriate chlorosilane to generate
compound of
formula (II I). To obatin the compounds of formula (IV) on the compounds of
formula
(III) a piperazine spacer is added by reaction with excess piperazine or using
a Fmoc
20 or Boc monoprotected piperazine in the presence of a base selected from the
group
triethylamine, pyridine, diisopropylethylamine, with diisopropylethylamine
being the
most preferred base to catch the generated acid. The reaction is preferably
conducted under heating, preferably between 40-120°C, more preferred
between 60-
100°C in an organic solvent selected from the group consisting of
dimethylsulfoxide,
25 N-methyl-pyrrolidone (NMP), ethanol wherein dimethylsulfoxide is most
preferred.
The compounds of formula (I) are obtained by reacting a slight excess (1.5
equivalent) of the compounds of formula (IV) with a polymeric resin being
functionalized by isocyanate-groups. The reaction is preferably conducted in
an
apolar solvent selected from the group consisting of tetrahydrofurane, DMF,
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dichloromethane, with tetrahydrofurane being the most preferred solvent at
moderate
temperatures (between 0-40°C, preferably between 20-30°C).
Optionally the addition
of a base, preferably of an organic base selected from the amines mentioned
hereinbefore may be advisable. The most preferred base is
disiopropylethylamine.
As apparent from scheme 1 the intermediate products of formula (IV) are key
intermediates for the synthesis of the compounds of formula (i). Therfore, a
further
aspect of the invention relates to intermediate compounds of formula (IV)
R~
Mew Me
Si
-/ R2
U
(IV)
wherein
R1 denotes hydrogen, C1-Cg-alkyl, C2-Cg-alkenyl, C2-C6-alkynyl C1-Cg-
alkoxy, halogen, N02 or CF3;
R2 denotes a group selected from hydroxy, amino, preferably
N-C1-Cg-alkylamino, and formyl, being optionally protected by a suitable
~5 protective group,
or
a 5 or 6 membered saturated or unsaturated nitrogen heterocycle,
optionally containing~one or two additional heteroatoms selected .from the
group consisting of oxygen, nitrogen and sulfur, and being optionally
2o substituted by a group selected from C1-C6-alkyl, C1-Cg-alkoxy, halogen,
NO2 and a suitable protective group.
Preferred intermediates are those of general formula (IV),
wherein
25 R1 denotes hydrogen,. C1-C4-alkyl, C1-Cq.-alkoxy, fluorine, chlorine,
bromine,
or N02;
R2 denotes a group selected from hydroxy, amino, preferably
N-C1-Cq.-alkylamino, and formyl, being optionally protected by a suitable
protective group,
30 or
a 5 or 6 membered saturated or unsaturated nitrogen heterocycle,
optionally containing one additional nitrogen heteroatom which is
substituted by a protective group selected from fluorenylmethyoxycarbonyl
and t-butoxycarbonyl.
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More preferred intermediates are those of general formula (IV),
wherein
R1 denotes hydrogen, methyl, methoxy , fluorine, chlorine, bromine, or N02,
preferably hydrogen;
R2 denotes hydroxy, being protected by a group selected from
tertbutyldimethylsilyl, methoxy-ethoxymethyl (MEM) and methyl,
or
N-methylamino, being protected by a group selected from
fluorenylmethyloxycarbonyl (FMOC) and t-butoxycarbonyl (BOC),
~o or
formyl, being protected to form a dioxolane ring,
or
piperazin-1-yl, being substituted by a protective group selected from
fluorenylmethyoxycarbonyl and t-butoxycarbonyl.
The compounds of formula (I) wherein R2 denotes a suitably protecfied hydroxy,
amino or formy! group can be deprotected via conventional methods. The methods
for the cleavage of the protective groups being applicable according to the
invention
are well known in the art. After cleavage of the protective group the hydroxy,
amino.
or formyl group can be further derivatised via conventional methods to lead to
compounds of formula (I')
I a R,
N
Resins N-~ I Me~
R
O
(I')
wherein
Resin and R1 are as hereinbefore defined and
R3 denotes a group selected from -O-CO-C1-Cq.-alkyl, -N(C1-C4-alykl)2,
-NH-CO-C1-Cq.-alkyl, -NH-CO-OC1-Cq.-alkyl, -NH-CO-NH-C1-Cq.-alkyl,
-COOH, -COOC1-Cq.-alkyl and -CONHC1-Cq.-alkyl and -CH20H.
Compounds of formula (l') wherein R3 denotes -O-CO-C1-Cq.-alkyl are obtainable
via
conventional ester syntheses either under acid or basic reaction conditions
starting
from compounds of formula (I) wherein R~ denotes hydroxy. Compounds of formula
(I') wherein R3 denotes -N(C1-Cq.-alykl)2 are obtainable from the compounds of
formula (I) wherein R2 denotes NH2 or -NHC1-C4-alkyl via conventional methods
by
treatment with C1-Cq.-alkyl-halides, -triflates, -mesylates or -p-
toluenesulfonates
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under basic reaction conditions. Compounds of formula (I') wherein R3 denotes -
NH-
CO-C~-Cq.-alkyl are obtainable from the compounds of formula (I) wherein R~
denotes NH2 via conventional methods by treatment with
C~-Cq.-alkyl-carboxylic acid esters, anhydrides or acyl halydes under basic
reaction
conditions. Compounds of formula (I') wherein R3 denotes -NH-CO-OCR-Cq.-alykl
are
obtainable from the compounds of formula (I) wherein R2 denotes NH2 via
conventional methods by treatment with C~-Cq.-alkyl-chloroformates under basic
reaction conditions. Compounds of formula (I') wherein R3 denotes
-NH-CO-NH-C~-Cq.-alkyl are obtainable via conventional methods by treatment
with
-C~-Cq.-alkyl-isocyanates. Compounds of formula (!') wherein R3 denotes -COOH
are
obtainable from the compounds of formula (!) wherein R2 denotes formyl via
conventional oxidation methods. Compounds of formula (I') wherein R3 denotes
.'
-CO-OCR-Cq.-alkyl are obtainable via conventional ester syntheses either under
acid
or basic reaction conditions starting from compounds of formula (I') wherein
R3
denotes -COOH. Compounds of formula (I') wherein R3 denotes -CONHC~-Cq.-alkyl
are obtainable from the compounds of formula (I') wherein R3 denotes
-CO-OCR-Cq.-alkyl via conventional methods by treatment with amines of formula
-
~NHC~-C4-alkyl under basic reaction conditions. Compounds of formula'(I')
wherein.
R3 denotes -CH20H are obtainable from the compounds of formula (I) wherein R2
' w .
2o denotes formyl via conventional reductive methods.
The compounds of formula (I) (or (I')) can be easily cleaved from the resin
under mild
reaction conditions to lead to the products of formula (V) (scheme 2).
1
Mew Me R 1
O Si \ R
Resin ~- N-~ Rn --~ X
~N ~ R4
H
(I) (with R~ = R2) (V) (With R4 =R2 or R3)
(I') (with Rn =, R3)
Scheme 2:
Depending on the reaction conditions for the cleavage step according to~scheme
2
X may either denote hydrogen, halogens (Br, F, I) or -COMB.
Compounds (V) wherein X denotes hydrogen are obtainable by reacting compounds
so of formula (I) or (I') with tetrabutylammonium fluoride (TBAF), Cesium
fluoride, KF,
trifluoroacetic acid or triflic acid, preferably with TBAF under the reaction
conditions
that are usually applied for analogous cleavage reactions known in the art.
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Compounds (V) wherein X denotes bromine are obtainable by reacting compounds
of formula (I) or (I') with N-bromo succinimide (NBS) or Br2, preferably with
NBS
under the reaction conditions that are usually applied for analogous cleavage
reactions known in the art. Compounds (V) wherein X denotes fluorine are
obtainable
by reacting compounds of formula (I) or (I') with BF3 under the reaction
conditions
that are usually applied for analogous cleavage reactions known in the art.
Compounds (V) wherein X denotes iodine are obtainable by reacting compounds of
formula (I) or (I') with I-CI under the reaction conditions that are usually
applied for
analogous cleavage reactions known in the art. Compounds (V) wherein X denotes
-
COMB are obtainable by reacting compounds of formula (I) or (I') with acethyl
chloride in the presence of AICI3 under the reaction conditions that are
usually
applied for analogous cleavage reactions known in the art.
The following examples illustrate the preparation of all the new compounds
included
95 in the. present invention. It should be understood that the invention is
not limited to
the given examples of chemical methods and processes for the preparation of
the
substances, as other conventional methods well known to those skilled in the
art, are
suitable too.
2o Description 7
1-(3-Bromo-5-trifluoromethyl-phenyl)-piperazine
CF3
H N
U
Br
A solution of 1-bromo-3-fluoro-5-(trifluoromethyl)-benzene (100 g, 0.41
moles),
25 piperazine (194.9 g, 2.26 moles) in DMSO (800 ml) was heated at 100
°C for 5
hours, cooled at room temperature and stirred overnight. The mixture was
poured
into water and the yellow solid which separeted was filtered. The solid was
suspended in a 5% THF solution in water (300 ml) water/THF, stirred for 1 hour
and
filtered again.
30 120 g, light beige solid, m.p. 74-77°C
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Description 2
tent-Butyl-4-[3-bromo-5-(trifluoromethyl)-phenyl]-1-piperazine carboxylate
CF3
O
--N N
O
Br
A solution of 1-(3-bromo-5-trifluoromethyl-phenyl)-piperazine (115 g, 0.37
moles) in
THF (550 ml) was added dropwise to a solution of di-tert butyl dicarbonate
(81.2 g,
0.37 moles) in THF (250 ml) at 20 °C. The reaction mixture was stirred
overnight at
room temperature. The reaction mixture was taken to dryness and from the
residue,
after crystallisation from water/THF, the title compound was obtained.
151 g, beige solid, m.p 100-103 °C
According to the above described procedure, the following compounds were
prepared:
tert-Butyl 3-bromophenyl-carbamate
N
O_
O Br
6.7 g, yellowish solid, m.p. 88-91 °C
Description 3
20 (3-Bromophenoxy)-(tert-butyl)-dimethylsilane
Me
Si-O
I
Me
Br
A suspension of 3-bromo-phenol (5.5 g, 31.8 mmoles), imidazole (4.3 g, 63.6
mmoles) in CH2CI2 (70 ml) was added dropwise to a solution of tent-butyl-
chloro-
dimethylsilane (5.3 g, 35 mmoles) in CH2CI2 (5 ml) at 0 °C. The
reaction mixture was
25 stirred for 3 hours at room temperature then evaporated to dryness under
vacuum.
The residue was partitioned between water and ethyl acetate and from the
organic
solution after essiccation over MgS04, filtration and evaporation the title
compound
was obtained.
7.5 g, yellow oil
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~H-NMR (CDC13; 200 MHz) 7.05-7.11 (ov, 2H); 7.00 (m, 1 H); 6.76 (m, 1 H); 0.97
(s,
9H): 0.20 (s, 6H)
Description 4
Tert butyl-3-bromophenyl IV-methyl carbamate
CH3
N~Boc
8r
A solution of tertbutyl-3-bromo-phenyl-carbamate (14g, 51.4 mmoles) in DMF (90
ml)
were added dropwise to a suspension of 80% NaH (1.858, 67.7 mmoles) in DMF
(30'
ml) al 10 °C. The reaction mixture was stirred 'for 1 h at room
temperature then a
solution of CH31 (6.4 ml, 102.88 mmoles) in DMF (30 ml) was added dropwise at
10
°C. The reaction mixture was stirred overnight at room temperature then
evaporated
95 to dryness under vacuum. The residue. was partitioned between water and
diethyl-
ether and the title compound was obtained by evaporating organic layer.
14.28g; yellow oil.
~H-NMR (CDCI3; 200 MHz) 7.43 (m, 1 H); 7.34 (m, 1 H); 3.61 (m, 4H); 7.1-702
(ov,
20 2H); 3.25 (s, 3H); 1.46 (s, 9H)
Description 5
tent-Butyl-4-[3-[(bromomethyl)-(d.imethyl)silyl]-5-(trifluoromethyl)-phenyl]-1-
25 piperazine carboxylate
CF3
O
N N.
O ~ Br
Me~si
Me
A solution of tent butyl 4-[3-bromo-5-(trifluoromethyl)-phenyl]-1-piperazine
carboxylate
(75 g, 183 mmoles) in diethyl ether, previously dried on molecular sieves,
(1000 ml)
was cooled to -65 °C and a 1.7M solution of tent butyl lithium (215,6
ml, 366 mmoles)
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was added. After 30 minutes stirring bromomethyl-dimethyl-chlorosilane (49.9
ml,
366 mmoles) was added dropwise. After 2 hours stirring at -65 °C, the
reaction
mixture was left at room temperature overnight. Water (600 ml) was added and
the
organic layer was washed with water, dried on MgS04, filtered and evaporated.
114 g, yellowish oil
~H-NMR (CDC13; 200 MHz) 7.2-7.3 (ov, 2H); 7.13 (b, 1H); 3.61 (m,~4H); 3.19 (m,
4H); .
2.63 (s, 2H); 1.49 (s, 9H); 0.45 (s, 6H)
According to the above described procedure, the following compounds were
prepared:
Bromomethyl-[3-(1,3-dioxolan-2-yl)-phenyls-dimethylsilane
C
0 Br
Me~Si
Me
The crude compound was purified by flash chromatography (Silica-gel, eluent n-
hexane-ethyl acetate 90-10). , . .
'~ 5.7 g yellowish oil . .
MS (ABCI+) [M+H~+= 302
The compound was pure enough to be used in the following step, without further
characterization.
Bromomethyl-(3-~[tert-butyl-(dimethyl)-silyl]-oxy}-phenyl)-dimethylsilane
Me
Si-O
Me Br
Me~~i
Me
The crude compound was purified by flash chromatography (Silica-gel, eluent n-
hexane-ethyl acetate 97-3).
700 mg, yellow oil
~H-NMR (CDCI3 ; 200 MHz) 7.25 (m, 1 H); 7.10 (m, 1 H); 7.00 (m, 1 H); 6.86 (m,
1 H);
2.61 (s, 2H); 0.99 (s, 9H); 0.41 (s, 6H); 0.20 (s, 6H)
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tert-Butyl-3-[(bromomethyl)-(dimethylsilyl)]-phenyl]-N-methyl carbamate
Hs
N
O Br
O Me~Si
Me
The crude compound was purified by flash chromatography (silica-gel; eluent
hexane-ethyl acetate 98:2). 12.1 g.
MS (APCI+) (M+Hj+w 359
1o
Description G
tert-Butyl-4-[3-[dimethyl-("I -piperazinylmethyl)-silyl]-5-(trifluoromethyl)-
phenyl]=
'I-piperazine carboxylaxe ,
CF3
O
J // N N
O
Me'I
Me
A solution of tent butyl 4-[3-((bromomethyl)-dimethylsilyl]-5-
(trifluoromethyl)-phenyl]-1-
piperazine carboxylate (114.7 g, 0.24 moles) piperazine (205.2 g, 2.38 moles)
and
DIPEA (203.7 ml, 1.19 moles) in DMSO (1000 ml) was heated to 80 °C for
6 hours,
cooled to room temperature and stirred overnight. The reaction was poured in
water
20~ (6 I) and the separeted orange oil was extracted into ethyl acetate. The
organic layer
was washed with a saturated NaCI water solution, dried on MgS04, filtered and
evaporated. From the oily residue, after a flash chromatography purification
(Silica-
gel, eluent CH~C12 - MetOH - NH40H 90-10-1 ) the pure title compound was
obtained.
25 24 g, ivory solid, m.p. 179-180°C
~H-NMR: (CDCI3 ; 200 MHz) 7.2-7.4 (ov, 2H); 7.09 (b, 1 H); 3.61 (m, 4H); 3.19
(m,
4H); 2.84 (m, 4H); 2.35 (m, 4H); 2.14 (s, 2H); 1.93 (b, 1 H+HDO); 1.49 (s,
9H); 0.34
(s, 6H)
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According to the above described procedure, the following compounds were
prepared:
5 1-{([3-(1,3-Dioxolan-2-yl)-phenyl]-dimethylsilyl]-methyl}-piperazine
H
O / \ N
C
O N
Me~Si
Me
The compound was obtained after traditional work-up (acid and basic
extraction).with
a purity good enough to be used without any further purification.
1.4 g, thick oil
1o MS (APCI+) [M+H]+ = 307
1-~[(3-~([tert-Butyl-dimethylsilyl]-oxy}-phenyl)-dimethylsilyl]-methyl-
piperazine
Me . H .
N
Si-O
ale N
Me~Si
Me
230 mg yellowish oil '
~5 'H-NMR (CDCI3 ; 200 MHz) 7.22 (m, 1 H); 7.10 (m, 1 H); 7.00 (m, 1 H); 6.83
(m, 1 H);
3.52 (b, 1 H+HDO); 2.95 (m, 4H); 2.46 (m, 4H); 2.15 (s, 2H); 0.99 (s, 9H);
0.31 (s,
6H); 0.19 (s, 6H)
tert-Butyl-3-[dimethyl-(1-piperazinylmethyl)-silyl]-phenyl] t~-methyl
carbari~ate
H
N
N
6..8g; yellow oil
~H-NMR (CDC13 ; 200 MHz) 7.2-7.4 (ov, 4H); 4.1 (b, 1 H); 3.26 (s, 3H); 3.00
(m, 4H);
2.51 (m, 4H); 2.18 (s, 2H); 1.44 (s,9H); 0.33 (s, 6H)
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Description 7
Piperazin, 1-carbamylmethyl-polistyren resin-4-{[3-trifluororiiethyl-5-(4-t-
s butoxycarbonylpiperazin-1-yl)]-phenyl)-dimethylsilylmethyl
O H
CF3 ~-N
O ~ / \ N ~-Polystyrene
-N N
U
O N
/Si-~
A solution of tert-butyl 4-[3-[dimethyl-(1-piperazinylmethyl)-silyl]-5-
(trifluoromethyl)-
phenyl]-1-piperazine carboxylate (15.2 g, 31.2 mmoles), DIPEA (5.35 ml, 31.2
mmoles) in THF (250 ml) was added to (isocyanate)-polystyrene resin (11.5 g,
20.8
mmoies,, loading 1.91 mrnoUg) and left at room temperature overnight under
gently
stirring. The resin was rinsed with ~THF (X 5 ml), DMF (x 5 rnl), THF (x 5 ml)
and
CH2CI2 (x 5 ml) and then dried under vacuum at room temperature.
18.4 g orange resin ~ .
t5 'H-NMI~ (solid state; gel phase in CD2CI2 ; 300 MHz) 3.51 (4H); 3.24 (4W);
3.12 (4H);
2.29 (4H); 2.12 (2H); 1.41 (9H); 0.30 (5H) ..
According to the above described procedure, the following compounds were
prepared:
Piperazin, 1-carbamylmethyl-polistyren resin-4-[3-(1,3-Dioxolan-2-yl)-phenyl]-
dirr~ethylsilylmethyl
O H
--N
O / \ N Polystyrene
C
O N
Me~si
Me
The resin bound compound was obtained starting from 150 mg of (isocyanate)-
polystyrene resin.
150 mg, yellowish resin
CA 02431927 2003-06-12
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17
~H-NMR (solid state; gel phase in CD2C12 ; 300 MHz) 5.72 (1 H); 3.9-4.1 (4h);
3.26
(4H); 2.31 (4H); 2.16 (2H); 0.37 (6H)
Piperazin, 1-carbamylmethyl-polistyren resin-4-[3-(ferf-Butyl-dimethylsilyl-
oxy)-
s phenyl]-methyl-dimethylsilyl
O H
N
I / , \ N ~--Polystyrene
Si-O
I
N
,Si-~
wThe resin bound compound was obtained starting from 300 mg of (isocyanate)-
polystyrene resin.
~0 300 mg, resin
1H-NMR (solid state; gel phase in CD2C12 300 MHz) 3.24 (4H); 2.29 (4H); 2.11
(2H);'
0.96=(9H); 0.29 (5H); 0.17 (6H)' . ' ' . '
Piperazin; 1-carbamylrinethyl-polistyren resin-4-{[3-(N-methyl-N-tert-
9~- butoxycarbonyl)-amino])-methyl-dimethylsilylphenyt
O H
-N
CH3 / \ N ~-polystyrene
N
O
N
O ,Si-~
The resin bound compound was obtained starting from 1 g of (isocyanate)-
2o polystyrene resin.
1 g, resin
~H-NMR (solid state; gel phase in CD2CI2 ; 300 MHz) 3.2 (4H); 3.19 (3H); 2.30
(4H);
2.13 (2H);1.41 (9H); 0.32 (6H)
2.5
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Description 8
Piperazin, 1-carbamylmethyl-polistyren resin-4-{[3-trifluoromethyl-5-
(piperazin-
1-yl)]-phenyl}-methyl-dimethylsilyl
O H
CF3 ~-N
N ~---Polystyrene
HN N
U
N
Me~Si
Me
Piperazin, 1-carbamylmethyl-polistyren resin-4-{[3-trifluoromethyl-5-(4-t-
butoxycarbonylpiperazin-1-yl)]-phenyl}-methyl-dimethylsilyi (14g, 13.9 mmoles)
was
added to a 30% TFA solution in CH2CI2 (200 ml). The slurry was gently stirred
for 1.5
hour at room temperature, filtered and the resin was added to a 30% DBU
solution in
CH2CI2 and the slurry was stirred for 1 hour at room temperature. The solvent
was
removed by filtration and the resin was rinsed with CH2C12, MetOH and CH2CIz-
and
then dried under vacuum.
14 g yellowish resin .
~H-NMR (solid state; gel phase in CDaCl2 ; 300 MHz) 3.18 (8H); 3.00 (4H); 2.30
(4H);
~5 2.13 (2H); 0.31 (6H)
Description 9
Piperazin, 1-carbamylmethyl-polistyren resin-4-[3-(Formyl)-phenyl]-methyl- .
2o dimethylsilyl
O H
~N
O / \ N ~-Polystyrene
H N
Me~Si
Me
Piperazin, 1-carbamylmethyl-polistyren resin-4-[3-(1,3-Dioxolan-2-yl)-phenyl]-
methyl-
dimethylsilyl (130 mg) was added to a 5% solution of HCI in THF. The slurry
was
gently strirred at room temperature overnigth, filtered and the resin was
rinsed with
25 THF, CH2CI2, 5% DIPEA, MetOH and CH2CI2.
120 mg, yellowish resin
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19
~H-NMR (solid state; gel phase in CD2C12 ; 300 MHZ) 9.97 (1 H); 3.27 (4H);
2.31 (4H);
2.17 (2H); 0.38 (6H)
Description 10
Piperazin, 1-carbamylmethyl-polistyren resin-4-[3-(hydroxy)-phenyl]-methyl-
dimethylsilyl .
O H
-N
N ~--Polystyrene
HO ,
N
Me~Si
Me
Piperazin,.1-carbamylmethyl-polistyren resin-4-[3-(tert-Butyl-dimethylsilyl-
oxy)-
phenyl-methyl-dimethylsilyl (230 mg) was added to a 5% solution of TFA in
CH2Ch
and the suspension was gently stirred for 1 hour at room temperature. The
slurry was
rinsed with CH2CI~ , 5% DIPEA in CH2Cl2 (x 5), MetOH (x 5) and CH2CI2 (x 5). '
200 mg yellowish resin ' . .' .
~5 ~H-NMR (solid state; gel phase in CD2Cl2; 300 MHz) significative features:
.
disappareance of peak at 0.96 ppm (9H); peak at 2.26 ppm (6H)
According to the above described procedure, using 20% solution of TFA in
CHZCI2
the following compound was prepared:
Piperazin, 1-carbari~ylmethyl-polistyren resin-4-~[3-(N-methylamino])-methyl-
dimethylsilylphenyl
O H
-N
H3 N ~-Polystyrene
N
i
H N
,Si-~
100 mg resin
'H-NMR (solid state; gel phase in CD2CI2; 300 MHz): 3.22 (b, 4H); 2.69 (b,
3H); 2.28
(b, 4H); 2.09 (b, 2H); 0.27 (b, 6H)
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WO 02/060960 PCT/EP02/00312
Description 9 7
1-[3-(Trifluoromethyl)-phenyl-piperazine
CF3
H N
5
Piperazin, 1-carbamylmethyl-polistyren resin-4-~[3-trifluoromethyl-5-
(piperazin-1-yl)]-
phenyl}-methyl-dimethylsilyl (50 mg, 0.035 mmoles) was added to a solution of
tetrabutyl ammonium fluoride (22 mg, 0.07 mmoles) in DMF (1 ml). The slurry
was
heated to 60 °C under stirring for 5 hours and filtered. To this
solution Amberlyst 1.5 .
resin (100 mg), and a calcium sulfonate resin (100 mg) were added and the
mixture
was stirred for 8 hours at room temperature. After filtration, the solution
was
evaporated to dryness into a speed-vac apparatus to give the title compound
3.5 mg, oily
~H-NMR (CDCI3 ; 200 MHz) 7.34 (m, 1 H); 7.0-7.2 (ov, 2H); 3.16,(m, 4H); 3.05
(m,
15 4H); 1.66 (b, 1 H)
According to the above described procedure, the following compounds were
prepared:
2o Benzaldehyde
The title compound was obtained starting from 140 mg of Piperazin, 1-
carbamylmethyl-polistyren resin-4-[3-(Formyl)-phenyl]-methy-dimethylsilyll
4.5 mg yellowish oil
.. , The identity of the product was confirmed by GC-MS in comparison to an
authentical
commercial sample.
Phenol
The title compound was obtained starting from 140 mg of Piperazin, 1-
carbamylmethyl-polistyren resin-4-[3-(hydroxy)-phenyl]-methyl-dimethylsilyl
so 3.8 mg yellowish oil
The identity of the product was confirmed by GC-MS in comparison to an
authentical
commercial sample.
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N-Methyl-aniline
The title compound was obtained starting from 140 mg of Piperazin, 1-
carbamylmethyl-polistyren resin-4-{[3-(N-methylamino]}-methyl-
dimethylsilylphenyl
4.2 mg yellowish oil.
The identity of the product was confirmed by GC-MS in comparison to an
authentical
commercial sample.
