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WO1998005640A2 - Process for the preparation of 3,3-disubstituted piperidines - Google Patents

Process for the preparation of 3,3-disubstituted piperidines Download PDF

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Publication number
WO1998005640A2
WO1998005640A2 PCT/EP1997/004275 EP9704275W WO9805640A2 WO 1998005640 A2 WO1998005640 A2 WO 1998005640A2 EP 9704275 W EP9704275 W EP 9704275W WO 9805640 A2 WO9805640 A2 WO 9805640A2
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Prior art keywords
formula
compound
represents hydrogen
methyl
benzoyl
Prior art date
Application number
PCT/EP1997/004275
Other languages
French (fr)
Other versions
WO1998005640A3 (en
Inventor
Mario Grugni
Roberto Rigolio
Karl Francis Erhard
Original Assignee
Smithkline Beecham S.P.A.
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9616417.3A external-priority patent/GB9616417D0/en
Priority claimed from GBGB9617594.8A external-priority patent/GB9617594D0/en
Application filed by Smithkline Beecham S.P.A., Smithkline Beecham Corporation filed Critical Smithkline Beecham S.P.A.
Priority to EP97937554A priority Critical patent/EP0915849A2/en
Priority to JP10507624A priority patent/JP2000515534A/en
Publication of WO1998005640A2 publication Critical patent/WO1998005640A2/en
Publication of WO1998005640A3 publication Critical patent/WO1998005640A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to a novel process and to certain novel compounds prepared by such process.
  • European Patent Application, Publication Number 0673928 discloses certain compounds which are stated to have activity as specific antagonists of the human NK-3 receptor and in the treatment of diseases involving neurokinin B.
  • Example 19 of EP0673928 is the compound (+)-N- ⁇ ⁇ 3-[l-benzoyl-3-(3,4- dichlorophenyl)piperidin-3-yl]prop-l-yl ⁇ -4-phenylpiperidin-4-yl ⁇ -N- methylacetamide, hereinafter also referred to as 'Compound V.
  • EP0673928 also discloses certain intermediates of formula (A), used in the preparation of Compound I, which intermediates are prepared by reduction and subsequent cyclisation of a nitrile intermediate of formula (B):
  • the present invention provides a process for preparing a compound of formula (I):
  • R2 represents hydrogen or benzoyl optionally substituted in the phenyi moiety with halogen, methyl or C 1.4 alkoxy; which process comprises cyclising a compound of formula (II):
  • the cyclisation of the compound of formula (II) is suitably carried out by treating the compound of formula (II) with glacial acetic acid, preferably in the presence of a catalytic amount of sulphuric acid, at any temperature providing a suitable rate of formation of the required product, usually at an elevated temperature such as a temperature in the range of 85°C to 105°C, for example at 100°C.
  • the above mentioned reduction may be carried out using any suitable reducing reagent or procedure, including c a complex metal hydride reagent or a borane reagent.
  • a preferred reducing agent is borane especially when complexed with a dialkysulphide, for example dimethyl sulphide.
  • the reduction is suitably carried our under the conditions conventionally used for the particular reduction method chosen.
  • aprotic solvent such as tetrahydrofuran
  • Ri is a protecting group, such as an acetyl or tetrahydropyran-2-yl group.
  • R2 is benzoyl.
  • the invention provides a process for the preparation of a compound of the above defined formula (III), which process comprises cyclising a compound of the above defined formula (II).
  • the reaction conditions for this process are as described above.
  • the invention provides a process for the preparation of a compound of the above defined formula (I) wherein R2 is hydrogen, which process comprises reducing a compound of the above defined formula (III).
  • the reaction conditions for this process are as described above.
  • the invention provides a process for the preparation of a compound of the above defined formula (I) wherein R2 represents benzoyloptionally substituted with halogen, methyl or C ⁇ .4 alkoxy, which process comprises acylating a compound of formula (I) wherein R2 represents hydrogen.
  • the reaction conditions for this process are as described above.
  • a suitable acylating agent is a benzoyl or an appropriately substituted benzoyl halide, preferably the chloride.
  • the compounds of formula (I) are useful as intermediates for the preparation of Compound I.
  • the compounds of formula (I) are preferably used in an activated form, for example in a tosylated or mesylated form.
  • the activated form of the compound of formula (I) is prepared using the appropriate conventional procedure depending upon its particular nature:
  • a mesylate is prepared by treating the compound of formula (I) with a mesyl haiide, for example mesylchloride, in an inert solvent such as dimethyl chloride.
  • the invention provides a process for the preparation of a compound of formula (IV): 98/05640
  • R2 is as defined in relation to (I)
  • R3 represents phenyl optionally substituted with halogen, methyl or C 1.4 alkoxy
  • R4 represents hydrogen or -CO- C ⁇ _4 alkyl
  • R5 represents C1.4 alkyl; which process comprises reacting a compound of the above defined formula (I), or an activated form thereof, with a compound of formula (V):
  • R3, R4 and R5 are as defined in relation to (IV), and thereafter optionally converting a compound of formula (IV) in to another compound of formula (IV).
  • the reaction between the compounds of formulae (TV) and (V) is suitably carried out in an aprotic solvent, preferably dimethylformamide at any temperature providing a suitable rate of formation of the final product, including temperatures such as room temperature, but usually at an elevated temperature.
  • reaction conditions depend upon the nature of the compound of formula (V):
  • R3 represents the said phenyl group and R4 represents hydrogen
  • the reaction is suitably carried out at ambient temperature.
  • R3 represents the said phenyl group and R4 represents -CO-C 1.4 alkyl
  • the reaction is usually effected at an elevated temperature such as a temperature in the range o 65°C to 100°C, for example 80°C, and preferably in the presence of a base such as a trialkylamine for example triethylamine.
  • -A- Suitable conversions of a compound of formula (IV) into another compound of formula (TV) includes the conversion of a compound of formula (IV) wherein R4 represents hydrogen into a compound of formula (IV) wherein R4 represents -CO- C ⁇ _4 alkyl by use of an approp ⁇ ate acylating agent; for example treatment with acetic anhydride smoothly converts R4 as hydrogen into R4 as acetyl
  • R3 represents phenyl optionally substituted with halogen, methyl or C 1.4 alkoxy
  • R4 is hydrogen
  • R5 is Ci .4 alkyl
  • R3 is phenyl
  • R4 is acetyl
  • R5 is methyl
  • the compounds of formula (IV) have at least one chiral centre
  • the present process provides either single isomer or racemic products depending upon the stereochemical nature of the starting mate ⁇ als.
  • the compounds of formula (I) can be separated into single isomers using known methodology (for example that disclosed n EP067928) which may then be used in the subsequent process steps disclosed herein.
  • the racemic products prepared by means of the present process can be separated into the component single isomers by using any conventional separation method, for example fractional crystallisation methods.
  • a further aspect the present invention also provides a novel, chiral high pressure liquid (HPLC) chromatographic method for resolving mixtures of optical isomers of compound (TV) which method is characterised m that the mobile phase comp ⁇ ses ethanol, hexane, tnfluoroacetic acid and and t ⁇ ethylamine, in particular 25% ethanol, 75% hexane, 0.5% tnfluoroacetic acid and 0.1% tnethylamine
  • a preferred HPLC column for use in the separation is a Daicel Chiral Cell OD column.
  • R ⁇ is as defined in relation to formula (I), with methylacrylate 98/05640
  • the reaction between the compounds of formula (VI) and methylacrylate is carried out in Triton B (40% in methanol) at any suitable temperature usually an elevated temperature such as the reflux temperature of the solvent.
  • R3 is as defined in relation to formula (V)
  • R4 a represents -CO-C 1.4 alkyl, especially acetyl
  • R5 represesnt C1.4 alkyl:
  • the compounds of formula (V) wherein R3 represents phenyl optionally substituted with halogen, methyl or C]__4 alkoxy, R4 represents hydrogen and R5 represents C1.4 alkyl are prepared from a compound of formula (VIII) wherein R3 and R4 a are as last defined, by removing the group R4 a using for example acid hydrolys, to provide a compound of formula (VII) which is then alkylated using conventional methods to give, after debenzylation of the ring nitrogen, the required compound of formula (V).
  • Any suitable alkylation method may be used, for example methylation is effected by initial formylation, by treatment with ethyl formate, followed by reduction with such as lithium aluminium hydride.
  • Debenzylation is usually effected by catalytic hydrogenolysis, using for example palladium on carbon in ethanol.
  • the compounds of formula (V) wherein R3 represents phenyl optionally substituted with halogen, methyl or C 1.4 alkoxy, R4 represents -CO- C 1.4 alkyl and R5 represents Ci .4 alkyl are prepared from the compound of formula (VIII) by first deprotecting the ring nitrogen, using the procedure described above, reprotecting as a BOC derivative to give the compound of formula (IX), alkylating the exocylic nitrogen of (IX) to give compound (X) using the procedure described above and finally isolating (V) in stabilisd form as the zinc chloride adduct.
  • the compounds of formula (VIII) known compounds prepared according to methods such as those in EP0673928.
  • the compounds of formula (VI) are known compounds or they are prepared according to methods disclosed for the preparation of such compounds, for example those disclosed in EP512901.
  • reaction mixture was quenched with 20% NH4CI, concentrated in vacuo and extracted with ether.
  • the organic phase was extracted with 0.5N NaOH; the aqueous phase was therefore acidified to pH 5 with IN HC1 and extracted with Et2 ⁇ .
  • the organic layer was d ⁇ ed over Na2SO4 and evaporated in vacuo to dryness to give
  • reaction mixture was quenched with 610 ml of 2N HC1, refluxed 2 hours and the solvent evaporated in vacuo to dryness.
  • the residue was treated with cone. NaOH and extracted with Et2 ⁇ ; the organic layer was separated, dried over Na2SO4 and evaporated in vacuo to dryness.
  • the residual oil was purified by gradient chromatography on 70-230 mesh silica gel, eluting with CH2C /MeOH (from 0 to
  • the title compound was prepared starting from 13.55 g (47 mmol) of 3-(3,4- dichIoro)pr ⁇ enyl-3-(3-hydroxypropyl)piperidine (compound of Description 3), 5.5 ml (47 mmol) of benzoyl chloride and 7 ml (50 mmol) of TEA and following the method described in EP 512901.
  • the crude product was purified by 70-230 mesh silica gel gradient column chromatography, eluting with CfoCb MeOH (from 0 to 5%) to afford 18 g of the title compound.
  • C21H23CI2NO2 M.W. 392.327 98/05640
  • reaction was quenched with 50 mi of water.
  • the reaction mixture was evaporated in vacuo to dryness; the residue was dissolved in EtOAc and washed with H2O; the organic layer was separated, dried over Na2SO4 and evaporated in vacuo to dryness.
  • the crude product was purified on 70-230 mesh silica gel gradient column chromatography, eluting with CHiChMeOU (from 0 to 5%) to yield 7.5 g of the title compound as an oil.
  • Daicel Chiralcel OD column (10 ⁇ , 21.2 x 250 mm), using a flux of 10 ml/min with the UV detector fixed at 280 nm, eluting with a unique mobile phase consisting of
  • Controls of the samples were made by analytical HPLC on Daicel Chiralcel OD column (10 ⁇ , 4.6 x 250 mm) using a flux of 1 ml/min with the UV detector fixed at

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

A process for preparing a compound of formula (I), wherein R1 represents hydrogen or a protecting group; and R2 represents hydrogen or benzoyl optionally substituted in the phenyl moiety with halogen, methyl or C1-4 alkoxy; which process comprises cyclising a compound of formula (II), wherein R1 is as defined in relation to (I), to provide a cyclic lactam of formula (III), wherein R1 is as defined in relation to (I); reducing the compound of formula (III) so formed to provide a compound of formula (I) wherein R2 represents hydrogen; and thereafter carrying out one or more of the following optional steps: (a) N-acylating the compound of formula (I) wherein R2 represents hydrogen to provide a compound of formula (I) wherein R2 represents benzoyl wherein the phenyl moiety is optionally substituted with halogen, methyl or C1-4 alkoxy; and (b) removing any protecting group.

Description

PROCESS FOR THE PREPARATION OF 3,3-DISUBSTrTUTED PIPERIDINES
This invention relates to a novel process and to certain novel compounds prepared by such process.
European Patent Application, Publication Number 0673928 discloses certain compounds which are stated to have activity as specific antagonists of the human NK-3 receptor and in the treatment of diseases involving neurokinin B.
Example 19 of EP0673928 is the compound (+)-N-{ {3-[l-benzoyl-3-(3,4- dichlorophenyl)piperidin-3-yl]prop-l-yl}-4-phenylpiperidin-4-yl}-N- methylacetamide, hereinafter also referred to as 'Compound V.
EP0673928 also discloses certain intermediates of formula (A), used in the preparation of Compound I, which intermediates are prepared by reduction and subsequent cyclisation of a nitrile intermediate of formula (B):
H2/ Raney Nickel
Figure imgf000003_0001
Figure imgf000003_0002
(B) (A)
In our hands the preparation of intermediate (A) proved to be difficult, mainly due to problems encountered in the reduction/cyclisation of (B). We have now found a novel and efficient method of preparing Compound I which avoids this troublesome conversion of (B) to (A) and proceeds , via a novel intermediate to give superior yields to that disclosed in EP673928. This method also utilises a novel, stereochemicaliy efficient and high yielding resolution step to provide Compound I. Accordingly, in a first aspect the present invention provides a process for preparing a compound of formula (I):
Figure imgf000003_0003
Cl (I) 98/05640 wherein R[ represents hydrogen or a protecting group; and
R2 represents hydrogen or benzoyl optionally substituted in the phenyi moiety with halogen, methyl or C 1.4 alkoxy; which process comprises cyclising a compound of formula (II):
Figure imgf000004_0001
wherein Ri is as defined in relation to (I), to provide a cyclic lactam of formula (III):
Figure imgf000004_0002
wherein Ri is as defined in relation to (I); reducing the compound of formula (III) so formed to provide a compound of formula (I) wherein R2 represents hydrogen; and thereafter carrying out one or more of the following optional steps:
(a) N-acylating the compound of formula (I) wherein R2 represents hydrogen to provide a compound of formula (I) wherein R2 represents benzoyl wherein the phenyl moiety is optionally substituted with halogen, methyl or C 1.4 alkoxy; and
(b) removing any protecting group.
The cyclisation of the compound of formula (II) is suitably carried out by treating the compound of formula (II) with glacial acetic acid, preferably in the presence of a catalytic amount of sulphuric acid, at any temperature providing a suitable rate of formation of the required product, usually at an elevated temperature such as a temperature in the range of 85°C to 105°C, for example at 100°C.
The above mentioned reduction may be carried out using any suitable reducing reagent or procedure, including c a complex metal hydride reagent or a borane reagent. A preferred reducing agent is borane especially when complexed with a dialkysulphide, for example dimethyl sulphide.
The reduction is suitably carried our under the conditions conventionally used for the particular reduction method chosen. For example when borane/ dimethyl sulphide is used the reaction is carried out in an aprotic solvent, such as tetrahydrofuran, usually at an elevated temperature and conveniently at the reflux temperature of the solvent.
Suitably, Ri is a protecting group, such as an acetyl or tetrahydropyran-2-yl group. Suitably, R2 is benzoyl.
The compounds of formula (III) are novel and are considered to form a further part of the present invention.
Accordingly, in a particular aspect the invention provides a process for the preparation of a compound of the above defined formula (III), which process comprises cyclising a compound of the above defined formula (II). The reaction conditions for this process are as described above.
In a further particular aspect, the invention provides a process for the preparation of a compound of the above defined formula (I) wherein R2 is hydrogen, which process comprises reducing a compound of the above defined formula (III). The reaction conditions for this process are as described above.
In yet a further aspect the invention provides a process for the preparation of a compound of the above defined formula (I) wherein R2 represents benzoyloptionally substituted with halogen, methyl or C \ .4 alkoxy, which process comprises acylating a compound of formula (I) wherein R2 represents hydrogen. The reaction conditions for this process are as described above.
A suitable acylating agent is a benzoyl or an appropriately substituted benzoyl halide, preferably the chloride.
As aforementioned, the compounds of formula (I) are useful as intermediates for the preparation of Compound I. When used as intermediates the compounds of formula (I) are preferably used in an activated form, for example in a tosylated or mesylated form.
The activated form of the compound of formula (I) is prepared using the appropriate conventional procedure depending upon its particular nature: Thus, a mesylate is prepared by treating the compound of formula (I) with a mesyl haiide, for example mesylchloride, in an inert solvent such as dimethyl chloride.
Accordingly, in a further aspect, the invention provides a process for the preparation of a compound of formula (IV): 98/05640
Figure imgf000006_0001
wherein R2 is as defined in relation to (I), R3 represents phenyl optionally substituted with halogen, methyl or C 1.4 alkoxy, R4 represents hydrogen or -CO- Cι_4 alkyl and R5 represents C1.4 alkyl; which process comprises reacting a compound of the above defined formula (I), or an activated form thereof, with a compound of formula (V):
Figure imgf000006_0002
wherein R3, R4 and R5 are as defined in relation to (IV), and thereafter optionally converting a compound of formula (IV) in to another compound of formula (IV). The reaction between the compounds of formulae (TV) and (V) is suitably carried out in an aprotic solvent, preferably dimethylformamide at any temperature providing a suitable rate of formation of the final product, including temperatures such as room temperature, but usually at an elevated temperature.
Generally the reaction conditions depend upon the nature of the compound of formula (V): Thus, when R3 represents the said phenyl group and R4 represents hydrogen, the reaction is suitably carried out at ambient temperature. Alternatively, when R3 represents the said phenyl group and R4 represents -CO-C 1.4 alkyl, then the reaction is usually effected at an elevated temperature such as a temperature in the range o 65°C to 100°C, for example 80°C, and preferably in the presence of a base such as a trialkylamine for example triethylamine.
It will be appreciated that those compounds of formula (V) wherein R4 represents hydrogen may have been expected to react at either the ring nitrogen atom or the alkylamino nitrogen atom. It is a particularly surprising feature of the present process that reaction occurs almost exclusively at the ring nitrogen to provide the said compounds of formula (IV).
-A- Suitable conversions of a compound of formula (IV) into another compound of formula (TV) includes the conversion of a compound of formula (IV) wherein R4 represents hydrogen into a compound of formula (IV) wherein R4 represents -CO- Cι_4 alkyl by use of an appropπate acylating agent; for example treatment with acetic anhydride smoothly converts R4 as hydrogen into R4 as acetyl
The compounds of formula (IV) wherein R3 represents phenyl optionally substituted with halogen, methyl or C 1.4 alkoxy, R4 is hydrogen and R5 is Ci .4 alkyl are novel compounds and are considered to form a further aspect of this invention. Preferably, R3 is phenyl
Preferably, R4 is acetyl.
Preferably, R5 is methyl.
As indicated the compounds of formula (IV) have at least one chiral centre The present process provides either single isomer or racemic products depending upon the stereochemical nature of the starting mateπals. For example, the compounds of formula (I) can be separated into single isomers using known methodology (for example that disclosed n EP067928) which may then be used in the subsequent process steps disclosed herein.
The racemic products prepared by means of the present process can be separated into the component single isomers by using any conventional separation method, for example fractional crystallisation methods. However, m a further aspect the present invention also provides a novel, chiral high pressure liquid (HPLC) chromatographic method for resolving mixtures of optical isomers of compound (TV) which method is characterised m that the mobile phase compπses ethanol, hexane, tnfluoroacetic acid and and tπethylamine, in particular 25% ethanol, 75% hexane, 0.5% tnfluoroacetic acid and 0.1% tnethylamine
A preferred HPLC column for use in the separation is a Daicel Chiral Cell OD column.
The compounds of formula (II) are known compounds and are prepared according to literature methods, for example those disclosed in EP0673928
Alternatively the compounds of formula (II) are prepared by reacting compounds of formula (VI)
Figure imgf000007_0001
wherein R\ is as defined in relation to formula (I), with methylacrylate 98/05640
The reaction between the compounds of formula (VI) and methylacrylate is carried out in Triton B (40% in methanol) at any suitable temperature usually an elevated temperature such as the reflux temperature of the solvent.
The compounds of formula (V) may be prepared according to the procedures set out in Scheme I:
Scheme I
r
Figure imgf000008_0001
wherein R3 is as defined in relation to formula (V), R4a represents -CO-C 1.4 alkyl, especially acetyl, and R5 represesnt C1.4 alkyl:
In particular the compounds of formula (V) wherein R3 represents phenyl optionally substituted with halogen, methyl or C]__4 alkoxy, R4 represents hydrogen and R5 represents C1.4 alkyl are prepared from a compound of formula (VIII) wherein R3 and R4a are as last defined, by removing the group R4a using for example acid hydrolys, to provide a compound of formula (VII) which is then alkylated using conventional methods to give, after debenzylation of the ring nitrogen, the required compound of formula (V). Any suitable alkylation method may be used, for example methylation is effected by initial formylation, by treatment with ethyl formate, followed by reduction with such as lithium aluminium hydride. Debenzylation is usually effected by catalytic hydrogenolysis, using for example palladium on carbon in ethanol. Also the compounds of formula (V) wherein R3 represents phenyl optionally substituted with halogen, methyl or C 1.4 alkoxy, R4 represents -CO- C 1.4 alkyl and R5 represents Ci .4 alkyl are prepared from the compound of formula (VIII) by first deprotecting the ring nitrogen, using the procedure described above, reprotecting as a BOC derivative to give the compound of formula (IX), alkylating the exocylic nitrogen of (IX) to give compound (X) using the procedure described above and finally isolating (V) in stabilisd form as the zinc chloride adduct.
The compounds of formula (V) wherein R3 represents phenyl optionally substituted with halogen, methyl or C 1.4 alkoxy, R4 represents hydrogen and R5 represents Ci .4 alkyl are novel compounds and form a further part of the present invention.
The compounds of formula (V) wherein R3 represents phenyl optionally substituted with halogen, methyl or C 1.4 alkoxy, R4 represents represents -CO-C1.4 alkyl and R5 represents C1.4 alkyl in the form of a stabilised aduct, with such as zinc chloride aduct are novel compounds and form a further part of the present invention. However, the non-complexed compounds are prepared according to methods disclosed in EP0673928.
The compounds of formula (VIII) known compounds prepared according to methods such as those in EP0673928. The compounds of formula (VI) are known compounds or they are prepared according to methods disclosed for the preparation of such compounds, for example those disclosed in EP512901.
The following Examples illustrate the invention but do not limit it in any way.
98/05640
DESCRIPTION 1 4-Cyano-4-(3,4-dichloro)pheny!-7-(tetrahydropyran-2-yloxy)heptanoic acid
54.2 g (165.1 mmol) of 2-(3,4-dichloro)phenyl-5-(tetrahydropyran-2-yloxy) pentanenitrile (EP 512901) and 18.54 g (215.3 mmol) of methyl acrylate were dissolved in 90 ml (215.2 mmol) of Triton B (40% in MeOH) and the solution was refluxed for 8 hours; 1.85 g (21.53 mmol) of methyl acrylate and 9 ml (21.52 mmol) of Triton B were added again and the reaction refluxed for additional 4 hours.
The reaction mixture was quenched with 20% NH4CI, concentrated in vacuo and extracted with ether. The organic phase was extracted with 0.5N NaOH; the aqueous phase was therefore acidified to pH 5 with IN HC1 and extracted with Et2θ. The organic layer was dπed over Na2SO4 and evaporated in vacuo to dryness to give
48.0 g of the title compound as an orange oil.
C19H23CI2NO4 M.W. = 400.307
LR. (nujol): 3160; 2930; 2220; 1720 cm"1.
300 MHz 1H-NMR (CDCI3): δ 7.52 (d, 1H); 7 49 (d, 1H); 7.28 (dd, 1H); 4.51 (m,
1H); 3.87-3.65 (m, 2H); 3.53-3.32 (m, 2H); 2.61- 2.50 (m, 1H); 2.45-2.32 (m, 1H); 2.28-1.98 (m, 4H); 1.85-1.65 (m, 2H); 1.60-1.40 (m, 6H).
MS (El, TSQ 700, source 180 °C, 70 V, 200 uA): 399 (M+); 315; 256; 210; 197;
101; 85.
DESCRIPTION 2 3-(3,4-DιchIoro)phenyl-3-(3-acethoxy)propylpiperidin-2,6-dione
52.4 g (131 mmol) of 4-cyano-4-(3,4-dichloro)phenyl-7-(tetrahydropyran-2-yloxy) heptanoic acid (compound of Descπption 1) were dissolved in 262 ml of acetic acid, 1.2 ml of 98% H2SO4 were added dropwise and the solution was heated at 100°C for 16 hours.
The reaction mixture was concentrated in vacuo and the residue made alkaline with aqueous 2CO3 and extracted with Et2θ; the organic layer was separated, dπed over Na2SO4 and evaporated in vacuo to dryness to yield 42 g of the title compound as an oil (punty: 85% by GC). C16H17CI2NO4 M.W = 358.219
I.R. (KBr): 3180;3100; 2980; 1740; 1720; 1700 cm'1.
300 MHz !H-NMR (CDCI3): δ 8.05 (s br, 1H); 7.47 (d, 1H); 7.39 (d, 1H); 7.14 (dd,
1H); 4.02 (t, 2H); 2.66 (ddd, 1H); 2.45-2.20 (m, 3H); 2.08-1.89 (m, 2H); 2.03 (s, 3H); 1.73-1.47 (m, 2H). MS (El, TSQ 700, source 180 °C, 70 V, 200 uA): 357 (M+); 297.
DESCRIPTION 3
3-(3,4-Dichloro)phenyl-3-(3-hydroxypropyl)piperidine
36.2 g (101.0 mmol) of 3-(3,4-dichloro)phenyl-3-(3-acethoxy)propylpiperidin-2,6- dione (compound of Description 2) were dissolved, under nitrogen atmosphere, in 1000 ml of dry THF; 95.9 ml (1.01 mol) of borane dimethylsulfide complex, dissolved in 1000 ml of dry THF, were added dropwise and the solution was refluxed for 5 hours.
The reaction mixture was quenched with 610 ml of 2N HC1, refluxed 2 hours and the solvent evaporated in vacuo to dryness. The residue was treated with cone. NaOH and extracted with Et2θ; the organic layer was separated, dried over Na2SO4 and evaporated in vacuo to dryness. The residual oil was purified by gradient chromatography on 70-230 mesh silica gel, eluting with CH2C /MeOH (from 0 to
20%) to afford 18.8 g of the title compound as a yellow oil.
Cι4Hι9Cl2NO M.W. = 288.215
LR. (neat): 3300; 2920; 2880; 1555 cm"1.
300 MHz 1H-NMR (CDCI3): δ 7.40 (d, 1H); 7.39 (d, 1H); 7.16 (dd, 1H); 3.48 (t,
2H); 3.19 (d, 1H); 2.91 (d, 1H); 2.81 (m, 2H); 2.10 (s br, 2H); 2.03 (m, 1H); 1.75 (ddd, 1H); 1,70-158 (m, 1H); 1.64 (t, 2H); 1.55-1.45 (m, 1H).
MS (El, TSQ 700, source °180 C, 70 V, 200 uA): 288 (M+); 229.
DESCRIPTION 4 l-Benzoyl-3-(3,4-dichloro)phenyl-3-(3-hydroxypropyl)piperidine
The title compound was prepared starting from 13.55 g (47 mmol) of 3-(3,4- dichIoro)prιenyl-3-(3-hydroxypropyl)piperidine (compound of Description 3), 5.5 ml (47 mmol) of benzoyl chloride and 7 ml (50 mmol) of TEA and following the method described in EP 512901. The crude product was purified by 70-230 mesh silica gel gradient column chromatography, eluting with CfoCb MeOH (from 0 to 5%) to afford 18 g of the title compound. C21H23CI2NO2 M.W. = 392.327 98/05640
DESCRIPTION 5
4-Acetylamino-4-phenyl-l-(/-?rr-buthoxycarbonyI)piperidine
15.8 g (72.5 mmol) of 4-acetylamιno-4-phenylpiperidine (EP 474561 and EP 512901) were dissolved in 200 ml of dry DMF and 21.8 ml (157 mmol) of TEA were added.
The solution was cooled at 0°C and 18.3 g (84 mmol) of di-t -butyl dicarbonate
(BOC2O), dissolved in 30 ml of dry DMF, were added dropwise; after 30 minutes at
0°C, the reaction was quenched with 50 mi of water. The reaction mixture was evaporated in vacuo to dryness; the residue was dissolved in EtOAc and washed with H2O; the organic layer was separated, dried over Na2SO4 and evaporated in vacuo to dryness.
The residual oil was chromatographed on 70-230 mesh silica gel, eluting with a mixture of hexane/EtOAc 6:4 to afford 20.6 g of the title compound as a yellow oil. C18H26N2θ3
M.W. = 318.421
I.R. (neat): 3300; 3060; 2980; 1695; 1655; 1550 cm"1.
300 MHz iH-NMR (CDCI3): δ 7.40-7.20 (m, 5H); 5.78 (s br, 1H); 3.81 (d br, 2H);
3.09 (ddd, 2H); 2.38 (d br, 2H); 1.99 (ddd, 2H); 1.99 (s, 3H); 1.47 (s, 9H).
MS (El, TSQ 700, source 180 °C, 70 V, 200 uA): 261; 202; 158.
DESCRIPTION 6
4-(N-Methyl-N-acetylamino)-4-phenyl-l-(tt?rr-buthoxycarbonyl) piperidine
10.35 g (32.5 mmol) of 4-acetylamιno-4-phenyl-l-(tert-buthoxycarbonyl)piperidine (compound of Description 5), 1.08 g (3.25 mmol) of tetrabutylammoniurn bromide and 5.62 g (85.24 mmol) of 85% powdered potassium hydroxide were dissolved in 100 ml of dry THF; 6.47 ml (104.0 mmol) of iodomethane, dissolved in 20 ml THF, were added dropwise and the reaction mixture was warmed at 40°C for 24 hours.
The precipitate was filtered off and the mixture was evaporated in vacuo to dryness; the residue was dissolved in EtOAc, washed with H2O and sat. sol. NaCl; the organic layer was separated, dried over a2SO4 and evaporated in vacuo to dryness. The residue was tπturated in hexane and recrystallized from Et2θ to yield 7.2 g of the title compound.
C19H28N2O3
M.P. = 127-128°C
M.W. = 332.447
I.R. (KBr): 3000-2860; 1695; 1640 cm* 1. 98/05640
300 MHz iH-NMR (CDCI3) δ 7.40-7.20 (m, 5H); 3.84 (d br, 2H); 3.10 (dd br, 2H);
2.90-2.70 (m br, 2H); 2.82 (s,3H); 2.11 (s, 3H); 2.04
(ddd, 2H); 1.45 (s, 9H). MS (CI, isobutane, P 4000 mTorr, source °150 C): 333 (MH+); 277; 260; 204.
DESCRIPTION 7
4-(N-MethyI-N-acetylamino)-4-phenyIpiperidine zinc chloride complex
15.0 g (45.14 mmol) of 4-(N-methyl-N-acetylamino)-4-phenyl-l-(tert-buthoxy carbonyI)piperidine (compound of Description 6) were dissolved in 900 ml of CH2CI2; 12.30 g (90.28 mmol) of ZnCb were added and the reaction mixture was stirred at room temperature for 10 days.
The solvent was evaporated in vacuo to dryness; the residue was dissolved in 400 ml of Et2θ and powdered with mechanical stirring. The solid was filtered, washed with E-2O and dried to yield 27 g of a white powder. C 14H2oN2O - 2.5 ZnCl2 M.W. = 573.023
Elemental analysis: Calcd. C, 29.34; H, 3.52; N, 4.89; Cl, 30.93;
Found C, 27.67; H, 3.95; N, 4.58; Cl, 29.43. I.R. (KBr): 3500; 3060-3100; 1600 cm"1.
300 MHz iH-NMR (CDCI3): δ 7.38-7.12 (m, 5H); 3.20 (ddd, 2H); 3.06 (ddd, 2H);
3.00-2.85 (m, 2H); 2.79 (s, 3H); 2.28-2.14 (m, 2H); 2.14 (s, 3H). MS (CI, isobutane, P 4000 mTorr, source °150 C): 233 (MH+).
EXAMPLE 1 - Method A l-Benzoyl-3-(3,4-dichlorophenyl)-3-{3-[4-(N-methyl-N-acetylamino)-4- pheny Ipiperidin-1 -yl] propyl} piperidine
8.8 g (22.5 mmol) of l-benzoyl-3-(3,4-dichloro)phenyl-3-(3-hydroxypropyl) piperidine (compound of Description 4) were treated with 4.2 ml (31.25 mmol) of TEA and 2.34 ml (30.0 mmol) of methanesulfonyl chloride, according to the procedure described in EP 512901. The crude methanesulfonyl derivative obtained and 12.5 ml (90 mmol) of TEA were dissolved in 100 ml of dry DMF and the solution was warmed at 50°C; 27 g of crude 4-(N-methyl-N-acetylamino)-4-phenylpiρeridine zinc chloride complex (compound of Description 7) were added portionwise and the mixture heated at 80°C for 16 hours. 98/05640
The solvent was evaporated in vacuo to dryness and the residue dissolved in EtOAc; the organic phase was washed with 1% HC1, 10% K2CO3, separated, dπed over Na2SO4 and evaporated in vacuo to dryness.
The residue was purified on 70-230 mesh silica gel gradient column chromatography, eluting with C^C^/MeOH (from 0 to 5%) to yield 2.6 g of the title compound. 35H41 I2 3O2 M.P. * 77-80°C. M.W = 606.644 Elemental analysis: Calcd. C, 69.27; H, 6.81 ; N, 6.93; Cl, 1 1.69;
Found C, 67.77; H, 6.88; N, 6.55; Cl, 12.46. I.R. (KBr): 3060; 2940-2760; 1630 cm"1.
300 MHz iH-NMR (CDCI3): δ 7.40-7.20 ( , I3H); 3.60-3.20 (m, 2H); 2.80 (s, 3H);
2.75 (m, 2H); 2.60 (m, 2H); 2.25-2.05 (m, 4H); 2.10 (s, 3H); 1.85 (m, 1H); 1 70-1.10 (m, 11H)
75.47 MHz 13C-NMR (CDCI3): δ 173.3, 171.3, 145.4, 137.0, 133.4, 131.1, 130.3,
129.6, 129.2, 129.2, 129.2, 129.1, 129.1, 127.6,
127.3, 127.1, 126.8, 126.8, 64.4, 59.3, 51.6, 51.4,
50.3, 49.0, 42.9, 38.9, 36.6, 36.4, 34.6, 30.3, 26.4, 22.6, 21.7 (2 aromatic quaternary carbon atoms are hidden). MS [A) ESI POS, solvent MeOH/H2O; B) DAU 606 ESI POS, Ar]: A) 606 (MH+);
B) 606; 533; 403, 268; 105.
DESCRIPTION 8
4-Formylamino-4-pheπyl-l-benzylpiperidine
10 g (37.54 mmol) of 4-amιno-4-phenyl- 1 -benzylpiperidine (EP 673928) were dissolved in 250 ml of ethyl formate, in the presence of a catalitic amount of p- toluenesulfonic acid, and the solution was refluxed for 3 days.
The reaction mixture was evaporated in vacuo to dryness to afford 10.8 g of the title compound, used in the subsequent reaction without further puπfication. 19H22N2O
M.P. = 1 16-118°C. M.W. = 294.399
I.R. (KBr): 3300; 3090-3010; 2940-2760; 1670 cm"1.
300 MHz !H-NMR (C6D6): δ 7.83 (s, 1H); 7.35-7.00 (m, 10H); 4.80 (s br, 1H);
3.30 (s, 2H); 2.50 (m, 2H); 2.20-1.90 (m, 5H), 1.60 (m, 1H). MS (El, TSQ 700, source 180 C, 70 V, 200 uA): 294 (M+); 158. DESCRIPTION 9
4-Methylamino-4-phenyl-l-benzylpiperidine
10.5 g (35.7 mmol) of 4-formylamino-4-phenyl-l-benzylpiperidine (compound of Description 8), dissolved in 150 ml of dry THF, were added dropwise, under nitrogen atmosphere, to a suspension of 3 g (80 mmol) of LiAlH4 in 200 ml of dry THF. The reaction mixture was stirred at room temperature for 1 hour and then refluxed for 4 hours. 25 ml of H2O and 7.5 ml of 10% NaOH were added to the reaction mixture; the resulting slurry stirred 1 hour and then extracted with EtOAc; the organic layer was washed with sat. sol. NaCl, dried over Na ≤θ4 and evaporated in vacuo to dryness, to afford 9.8 g of the title compound as an oiL 9H24N2 M.W. = 280.415
LR. (KBr): 3090-3020; 2940; 2800; 1500 cm-1.
300 MHz H-NMR (C6D6): δ 7.39 (d, 2H); 7.25-7.15 (m, 8H); 3.40 (s, 3H); 2.48
(ddd, 2H); 2.38 (ddd, 2H); 1.97 (ddd, 2H); 1.87 (s, 3H); 1.69 (ddd, 2H). MS (El, TSQ 700, source °180 C, 70 V, 200 uA): 280 (M+); 248; 172; 158.
DESCRIPTION 10
4-Methyiamino-4-phenyl-piperidine
1.4 g (5 mmol) of 4-methylamino-4-phenyl-l-benzylpiperidine (compound of Description 9) were dissolved in 38 ml of abs. EtOH and hydrogenated, in the presence of 1.4 g of 10% palladium on activated charcoal, at 30 psi for 24 hours. The reaction mixture was evaporated in vacuo to dryness to afford 1.0 g of the crude title compound as an oil, used in the subsequent reaction without further purification. Cι2H18N2
M.W. = 190.287
DESCRIPTION 1 1 l-Beπzoyl-3-(3,4-dichlorophenyl)-3-(3-(4-methylamino-4-phenylpiperidin-l-yl) propyl] piperidine
5 g (26.3 mmol) of 4-methylamino-4-pheny!-piperidine (compound of Description 10), 7.5 g (15.94 mmol) of l-benzoyl-3-(3,4-dichlorophenyl)-3-(3-mesyloxypropyl) 98/05640 piperidine (EP 512901) and 2.1 ml (15 mmol) of TEA were dissolved in 60 ml of dry DMF and the solution was stirred at room temperature for 5 days.
The solvent was evaporated in vacuo to dryness and the residue dissolved in EtOAc; the organic phase was washed with H2O, separated, dried over Na2≤θ4 and evaporated in vacuo to dryness.
The crude product was purified on 70-230 mesh silica gel gradient column chromatography, eluting with CHiChMeOU (from 0 to 5%) to yield 7.5 g of the title compound as an oil.
C33H39CI2N3O M.W. = 564.598
I.R. (KBr): 3440; 3080; 2940-2780; 1630 cπr*.
MS (El, TSQ 700, source °180 C, 70 V, 200 uA): 533; 200; 172; 158; 105.
EXAMPLE 1 - Method B l-Benzoyl-3-(3,4-dιchlorophenyl)-3-{3-[4-(N-methyI-N-acetylamino)-4- phenylpiperidin-l-yl]propyI}piperidiπe
7.5 g (13.7 mmol) of l-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-methylamino-4- phenylpiperidin-l-yl)propyI]piperidine (compound of Description 1 1) were dissolved in 30 ml of acetic anhydride and the solution was stirred at room temperature for 20 hours.
30 ml of H2O were added and the solution was made alkaline with solid K2CO3 and extracted with EtOAc; the organic layer was washed with IN HC1, sat. sol. K2CO3 and sat. sol. NaCl, separated, dried over Na2≤θ4 and evaporated in vacuo to dryness.
6.6 g of the crude product were purified on 70-230 mesh silica gel gradient column chromatography, eluting with CH2Cl2/MeOH (from 0 to 5%) to yield 5 g of the title compound. 35H41 I2N3O2 M.W. = 606.644
Melting point, I.R. and N.M.R. spectroscopic data were identical to those obtained for Example 1 - Method A.
EXAMPLE 2 (+)-l-BenzoyI-3-(3,4-dichIorophenyl)-3-{3-(4-(N-methyl-N-acety!amino)-4- pbenylpiperidiπ-l-yI]ρropyl}piperidine
The pure (+) enantiomer of (±)-l-benzoyl-3-(3,4-dichloroρhenyl)-3-{3-[4-(N- methyl-N-acetylamino)-4-phenylpiperidin-l -yljpropyl} piperidine (compound of Example 1) was obtained by automated preparative chiral HPLC separation on
Daicel Chiralcel OD column (10 μ, 21.2 x 250 mm), using a flux of 10 ml/min with the UV detector fixed at 280 nm, eluting with a unique mobile phase consisting of
25% EtOH, 75% hexane, 0.5% TFA and 0.1% TEA. As an example, 2.5 g of the racemate (injection of 200 mg in 4 ml of mobile phase) gave 1.05 g of (-) stereoisomer and 1.15 g of (+) stereoisomer, both with e.e. > 99%.
Controls of the samples were made by analytical HPLC on Daicel Chiralcel OD column (10 μ, 4.6 x 250 mm) using a flux of 1 ml/min with the UV detector fixed at
254 nm. Using these conditions, the retention time of the (+) stereoisomer was 13.0 min. and the retention time of the (-) stereoisomer was 9.8 min. 35H41CI2N3O2
M.W. = 606.644
[α]D 25 = + 20.0 (c = 0.3, EtOH); [α]D 25 of the (-) enantiomer = -19.9 (c = 0.3, EtOH).

Claims

98/05640 Claims
1. A process for preparing a compound of formula (I):
Figure imgf000018_0001
wherein R\ represents hydrogen or a protecting group; and
R2 represents hydrogen or benzoyl optionally substituted in the phenyl moiety with halogen, methyl or Ci .4 alkoxy; which process comprises cyclising a compound of formula (II):
Figure imgf000018_0002
wherein R\ is as defined in relation to (I), to provide a cyclic lactam of formula (III):
Figure imgf000018_0003
wherein Ri is as defined in relation to (I); reducing the compound of formula (III) so formed to provide a compound of formula (I) wherein R2 represents hydrogen; and thereafter carrying out one or more of the following optional steps:
(a) N-acylating the compound of formula (I) wherein R2 represents hydrogen to provide a compound of formula (I) wherein R2 represents benzoyl wherein the phenyl moiety is optionally substituted with halogen, methyl or C 1.4 alkoxy; and
(b) removing any protecting group.
2. A process according to claim 1, wherein the cyclisation of the compound of formula (II) is carried out by treating with glacial acetic acid.
3. A process according to claim 1 or claim 2, wherein the reduction is carried out using borane
4. A process according to claim 3, wherein the borane is complexed with a dialkysulphide.
5. A process according to any one of claims 1 to 4, wherein R\ is an acetyl or tetrahydropyran-2-yl group.
6. A process according to any one of claims 1 to 5, wherein R2 is benzoyl.
7. A process for the preparation of a compound of formula (IV):
R.
Figure imgf000019_0001
wherein R2 is as defined in relation to formula (I) in claim 1, R3 represents phenyl optionally substituted with halogen, methyl or C 1.4 alkoxy, R4 represents hydrogen or -CO-C1.4 alkyl and R5 represents C1.4 alkyl; which process comprises reacting a compound of the above defined formula (I), or an activated form thereof, with a compound of formula (V):
Figure imgf000019_0002
wherein R3, R4 and R5 are as defined in relation to (IV), and thereafter optionally convening a compound of formula (IV) in to another compound of formula (IV).
8. A chiral high pressure liquid (HPLC) chromatographic method for resolving mixtures of optical isomers of a compound of formula (IV) as defined in claim 7, which method is characterised in that the mobile phase comprises 25% ethanol, 75% hexane, 0.5% trifluoroacetic acid and 0.1% triethylamine.
PCT/EP1997/004275 1996-08-05 1997-08-04 Process for the preparation of 3,3-disubstituted piperidines WO1998005640A2 (en)

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Publication number Priority date Publication date Assignee Title
WO2000007987A1 (en) * 1998-08-05 2000-02-17 Sanofi-Synthelabo Crystalline forms of osanetant
WO2000035879A1 (en) * 1998-12-15 2000-06-22 Sanofi-Synthelabo 3-phenyl-2,6-dioxopiperidin-3-yl propionamide derivatives and method for preparing same
WO2000037445A1 (en) * 1998-12-18 2000-06-29 Sanofi-Synthelabo Alkyl esters of 3-(3,4-dihalogenophenyl)-2,6-dioxopiperidine-3-propionic acid useful as intermediates

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FR2676055B1 (en) * 1991-05-03 1993-09-03 Sanofi Elf AMINO POLYCYCLIC COMPOUNDS AND THEIR ENANTIOMERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR2719311B1 (en) * 1994-03-18 1998-06-26 Sanofi Sa Compounds that are selective antagonists of the human NK3 receptor and their use as drugs and diagnostic tools.

Cited By (10)

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Publication number Priority date Publication date Assignee Title
WO2000007987A1 (en) * 1998-08-05 2000-02-17 Sanofi-Synthelabo Crystalline forms of osanetant
AU748177B2 (en) * 1998-08-05 2002-05-30 Sanofi-Aventis Crystalline forms of osanetant
US7041679B2 (en) 1998-08-05 2006-05-09 Sanofi-Aventis Crystalline forms of osanetant
WO2000035879A1 (en) * 1998-12-15 2000-06-22 Sanofi-Synthelabo 3-phenyl-2,6-dioxopiperidin-3-yl propionamide derivatives and method for preparing same
US6342607B1 (en) 1998-12-15 2002-01-29 Sanofi-Synthelabo 3-phenyl-2, 6-dioxopiperidin-3-yl propionamide derivatives and method for preparing same
US6452012B1 (en) 1998-12-15 2002-09-17 Sanofi-Synthelabo 3-phenyl-2,6-dioxopiperidin-3-ylpropionamide derivatives and method for preparing same
WO2000037445A1 (en) * 1998-12-18 2000-06-29 Sanofi-Synthelabo Alkyl esters of 3-(3,4-dihalogenophenyl)-2,6-dioxopiperidine-3-propionic acid useful as intermediates
US6469173B1 (en) 1998-12-18 2002-10-22 Sanofi-Synthelabo Alkyl esters of 3-(3,4-dihalogenophenyl)-2,6-dioxopiperidine-3-propionic acid of use as intermediates
US6686182B2 (en) 1998-12-18 2004-02-03 Sanofi-Synthelabo Alkyl esters of 3-(3,4-dihalophenyl)-2,6-dioxopiperidine-3-propionic acid of use as intermediates
US6946269B2 (en) 1998-12-18 2005-09-20 Sanofi-Aventis Alkyl esters of 3-(3,4-dihalophenyl)-2,6-dioxopiperidine-3-propionic acid of use as intermediates

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