WO1998005640A2 - Process for the preparation of 3,3-disubstituted piperidines - Google Patents
Process for the preparation of 3,3-disubstituted piperidines Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- represents hydrogen
- methyl
- benzoyl
- Prior art date
Links
- FBLGCZZUECSACN-UHFFFAOYSA-N COC(CCC(CC1)(CNC1=O)c(cc1)cc(Cl)c1Cl)=O Chemical compound COC(CCC(CC1)(CNC1=O)c(cc1)cc(Cl)c1Cl)=O FBLGCZZUECSACN-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP10507624A JP2000515534A (en) | 1996-08-05 | 1997-08-04 | Method for producing 3,3-disubstituted piperidine |
EP97937554A EP0915849A2 (en) | 1996-08-05 | 1997-08-04 | Process for the preparation of 3,3-disubstituted piperidines |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9616417.3A GB9616417D0 (en) | 1996-08-05 | 1996-08-05 | Process |
GB9616417.3 | 1996-08-22 | ||
GB9617594.8 | 1996-08-22 | ||
GBGB9617594.8A GB9617594D0 (en) | 1996-08-22 | 1996-08-22 | Process |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1998005640A2 true WO1998005640A2 (en) | 1998-02-12 |
WO1998005640A3 WO1998005640A3 (en) | 1998-05-22 |
Family
ID=26309818
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/004275 WO1998005640A2 (en) | 1996-08-05 | 1997-08-04 | Process for the preparation of 3,3-disubstituted piperidines |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0915849A2 (en) |
JP (1) | JP2000515534A (en) |
WO (1) | WO1998005640A2 (en) |
Cited By (3)
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 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0512901A1 (en) * | 1991-05-03 | 1992-11-11 | Sanofi | Aminated polycyclic compounds and their enantiomers, process for their preparation and pharmaceutical compositions containing them |
EP0673928A1 (en) * | 1994-03-18 | 1995-09-27 | Sanofi | Novel N-(3,4-dichlorophenyl-propyl)-piperidine derivatives as selective human NK3-receptor antagonists |
-
1997
- 1997-08-04 JP JP10507624A patent/JP2000515534A/en not_active Ceased
- 1997-08-04 EP EP97937554A patent/EP0915849A2/en not_active Withdrawn
- 1997-08-04 WO PCT/EP1997/004275 patent/WO1998005640A2/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0512901A1 (en) * | 1991-05-03 | 1992-11-11 | Sanofi | Aminated polycyclic compounds and their enantiomers, process for their preparation and pharmaceutical compositions containing them |
EP0673928A1 (en) * | 1994-03-18 | 1995-09-27 | Sanofi | Novel N-(3,4-dichlorophenyl-propyl)-piperidine derivatives as selective human NK3-receptor antagonists |
Non-Patent Citations (3)
Title |
---|
E. TAGMANN ET AL.: "]ber in 3-Stellung basisch substituierte Pyrrolidin-, Piperidin- und Hexamethylenimin-Derivate" HELVETICA CHIMICA ACTA, vol. 35, no. 4, 16 June 1952, BASEL, CH, pages 1235-49, XP002048798 * |
G.A.M. GIARDINA ET AL: "A reliable and efficient synthesis of SR 142801" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 6, no. 19, October 1996, OXFORD, GB, pages 2307-2310, XP002043892 * |
H.G. CHEN ET AL.: "A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 7, no. 5, March 1997, OXFORD, GB, pages 55-60, XP002055505 * |
Cited By (10)
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 |
Also Published As
Publication number | Publication date |
---|---|
EP0915849A2 (en) | 1999-05-19 |
JP2000515534A (en) | 2000-11-21 |
WO1998005640A3 (en) | 1998-05-22 |
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