CA2431927A1 - New polymers based on n-carbamyl-n'-dimethylsilyl methyl-piperazine traceless linkers for the solid phase synthesis of phenyl based libraries - Google Patents
New polymers based on n-carbamyl-n'-dimethylsilyl methyl-piperazine traceless linkers for the solid phase synthesis of phenyl based libraries Download PDFInfo
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- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B80/00—Linkers or spacers specially adapted for combinatorial chemistry or libraries, e.g. traceless linkers or safety-catch linkers
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/42—Introducing metal atoms or metal-containing groups
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33303—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group
- C08G65/3331—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group cyclic
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- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/336—Polymers modified by chemical after-treatment with organic compounds containing silicon
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- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
- C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support
- C40B50/18—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support using a particular method of attachment to the solid support
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Abstract
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 librarie s of compounds embracing a phenyl ring in their structure.
Description
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 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 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 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.
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.
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 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 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 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.
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.
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.
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.
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, 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 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.
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 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 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).
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 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.
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 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
Description 2 tent-Butyl-4-[3-bromo-5-(trifluoromethyl)-phenyl]-1-piperazine carboxylate 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 ~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 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 °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 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) 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) 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 , 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) 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) 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 ~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 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 ~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 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) Description 9 7 1-[3-(Trifluoromethyl)-phenyl-piperazine H N
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.
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.
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, 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 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.
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 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 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).
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 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.
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 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
Description 2 tent-Butyl-4-[3-bromo-5-(trifluoromethyl)-phenyl]-1-piperazine carboxylate 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 ~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 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 °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 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) 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) 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 , 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) 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) 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 ~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 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 ~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 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) Description 9 7 1-[3-(Trifluoromethyl)-phenyl-piperazine H N
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.
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.
Claims (7)
1) Compounds of general formula (I) wherein Resin denotes polystyrene, optionally cross linked with divinyl benzene or polyethylenglycol;
R1 denotes hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl C1-C6-alkoxy, halogen, NO2 or CF3;
R2 denotes a group selected from hydroxy, amino, preferably N-C1-C6-alkylamino, and formyl, being optionally protected by a suitable 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 substituted by a group selected from C1-C6-alkyl, C1-C6-alkoxy, halogen, NO2 and a suitable protective group.
R1 denotes hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl C1-C6-alkoxy, halogen, NO2 or CF3;
R2 denotes a group selected from hydroxy, amino, preferably N-C1-C6-alkylamino, and formyl, being optionally protected by a suitable 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 substituted by a group selected from C1-C6-alkyl, C1-C6-alkoxy, halogen, NO2 and a suitable protective group.
2) Compounds of general formula (I) according to claim 1, wherein Resin denotes polystyrene, optionally cross linked with divinyl benzene or polyethylenglycol;
R1 denotes hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, bromine, or NO2;
R2 denotes a group selected from hydroxy, amino, preferably N-C1-C4-alkylamino, and formyl, being optionally protected by a suitable protective group, 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.
R1 denotes hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, bromine, or NO2;
R2 denotes a group selected from hydroxy, amino, preferably N-C1-C4-alkylamino, and formyl, being optionally protected by a suitable protective group, 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.
3) Compounds of general formula (I) according to claim 1 or 2, wherein Resin denotes polystyrene cross linked with divinyl benzene;
R1 denotes hydrogen, methyl, methoxy , fluorine, chlorine, bromine, or NO2, 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), 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.
R1 denotes hydrogen, methyl, methoxy , fluorine, chlorine, bromine, or NO2, 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), 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.
4) Process for the preparation of compounds of formula (I) wherein resin, R1 and R2 are as defined in one of claims 1, 2 or 3, characterised in that a compound of formula (IV) wherein R1 and R2 are as defined in one of claims 1, 2 or 3 is reacted with the polymeric isocyanate compound Resin-N=C=O, wherein Resin is as defined in one of claims 1, 2 or 3.
5) Compounds of formula (IV) wherein R1 and R2 are as defined in one of claims 1, 2 or 3.
6) Compounds of formula (I') wherein Resin and R1 are as defined in one of claims 1, 2 or 3 and R3 denotes a group selected from -O-CO-C1-C4-alkyl, -N(C1-C4-alykl)2, -NH-CO-C1-C4-alkyl, -NH-CO-OC1-C4-alkyl, -NH-CO-NH-C1-C4-alkyl, -COOH, -COOC1-C4-alkyl and -CONHC1-C4-alkyl and -CH2OH.
7) Use of compounds of formula (I) or (I') for the synthesis of compounds of formula (V) wherein R1 is as defined. in one of claims 1, 2 or 3, R4 denotes R2 as defined in one of claims 1, 2 or 3 or R4 denotes R3 as defined in claim 6 and X denotes hydrogen, halogen, preferably Br, F or I, or -COMe.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01101946.0 | 2001-01-29 | ||
| EP01101946 | 2001-01-29 | ||
| PCT/EP2002/000312 WO2002060960A2 (en) | 2001-01-29 | 2002-01-15 | New polymers based on n-carbamyl-n'-dimethylsilyl methyl-piperazine traceless linkers for the solid phase synthesis of phenyl based libraries |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2431927A1 true CA2431927A1 (en) | 2002-08-08 |
Family
ID=8176316
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002431927A Abandoned CA2431927A1 (en) | 2001-01-29 | 2002-01-15 | New polymers based on n-carbamyl-n'-dimethylsilyl methyl-piperazine traceless linkers for the solid phase synthesis of phenyl based libraries |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1360211A2 (en) |
| JP (1) | JP2004518015A (en) |
| CA (1) | CA2431927A1 (en) |
| MX (1) | MXPA03006718A (en) |
| WO (1) | WO2002060960A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102122470B1 (en) | 2016-12-08 | 2020-06-12 | 주식회사 엘지화학 | Modified agent and modified conjugated diene polymer comprising functional group derived from the same |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69727374T2 (en) * | 1996-05-20 | 2004-11-11 | Smithkline Beecham Corp. | SILYL LINKER FOR ORGANIC SYNTHESIS IN THE SOLID PHASE OF MOLECULES CONTAINING ARYL GROUPS |
| WO1999017869A2 (en) * | 1997-10-03 | 1999-04-15 | Argonaut Technologies | Compositions for organic synthesis on solid phase and methods of using the same |
-
2002
- 2002-01-15 MX MXPA03006718A patent/MXPA03006718A/en active IP Right Grant
- 2002-01-15 EP EP02703549A patent/EP1360211A2/en not_active Withdrawn
- 2002-01-15 WO PCT/EP2002/000312 patent/WO2002060960A2/en not_active Application Discontinuation
- 2002-01-15 CA CA002431927A patent/CA2431927A1/en not_active Abandoned
- 2002-01-15 JP JP2002561527A patent/JP2004518015A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002060960A2 (en) | 2002-08-08 |
| WO2002060960A3 (en) | 2002-10-17 |
| MXPA03006718A (en) | 2004-05-31 |
| EP1360211A2 (en) | 2003-11-12 |
| JP2004518015A (en) | 2004-06-17 |
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