EP0270596A1 - A stereoconservative synthesis of 1-substituted (s)- and (r)-2-aminomethylpyrrolidines and intermediates thereto - Google Patents

A stereoconservative synthesis of 1-substituted (s)- and (r)-2-aminomethylpyrrolidines and intermediates thereto

Info

Publication number
EP0270596A1
EP0270596A1 EP87903468A EP87903468A EP0270596A1 EP 0270596 A1 EP0270596 A1 EP 0270596A1 EP 87903468 A EP87903468 A EP 87903468A EP 87903468 A EP87903468 A EP 87903468A EP 0270596 A1 EP0270596 A1 EP 0270596A1
Authority
EP
European Patent Office
Prior art keywords
formula
isomer
compound
formation
group
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP87903468A
Other languages
German (de)
English (en)
French (fr)
Inventor
Hans-Jürgen Federsel
Thomas Högberg
Sten Ingvar RÄMSBY
Hans Eric Peter STRÖM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astra Lakemedel AB
Original Assignee
Astra Lakemedel AB
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
Application filed by Astra Lakemedel AB filed Critical Astra Lakemedel AB
Publication of EP0270596A1 publication Critical patent/EP0270596A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a new method for preparation of the (R)-isomer or (S)-isomer of 1-substituted 2-aminom ⁇ ethylpyrrolidines of the formula
  • Stereocontrolled syntheses have been disclosed by Synthelabo in GB 1 555 890 and by Ravizza in GB 2014 990.
  • the procedures of Synthelabo start with the S-form or R-form of proline (Scheme 1), S-form or R-form of glutamic acid or S-form or R-form of prolinol.
  • the procedures cover compounds of the formula 1 with different R a -groups such as alkyl, cycloalkyl and substituted phenyl.
  • the preferred method using the S-form or the R-form of proline as starting material is a four step synthesis consisting of esterification, aminolysis, acylation and reduction as outlined in Scheme 1. No yields or optical purities besides optical rotations are disclosed.
  • the crude amine obtained in ca 35% yield from proline is not characterized but converted to sulpiride and purified as such.
  • 1-methyl-2-pyrrolidinecarboxamide prepared from L-proline is described in the European Patent Application 0121244.
  • Arch. Pharm. 309 (5) p. 380-85 (1976) is described the preparation of methyl (-)-1-methyl-2- -pyrrolidinecarboxylate from (-)-proline by N-alkylation followed by 0-alkylation.
  • Arch. Pharm 316 (9), p. 771-81 (1983) indicates manufacture of a 1-substituted phenylmethyl-2-pyrrolidinecarboxylate from methyl L-proline by N-alkylation.
  • the present invention is related to a process for preparation of the (R)- or (S)-isomers of 1-substituted 2-aminomethylpyrrolidines of the formul a
  • the process according to the present invention involves a short and efficient synthesis starting from either of the enantiomers of proline.
  • the synthesis from (S)-proline will produce the (S)-isomer of 1-substituted 2-aminomethylpyrrolidines of the formula
  • the new process is generally applicable for 2-aminomethylpyrrolidines containing a wide variety of substituents in the 1-position.
  • R 1 in the formulas 1, (S)-I and (R)-I above may have the following meaning:
  • R 1 is a hydrogen atom, a saturated or unsaturated lower alkyl group, a cycloalkyl group, or a group (CH 2 ) m Ph wherein m is 0-3 and Ph is a phenyl group or a substituted phenyl group; preferably where m is 0;
  • Saturated lower alkyl groups in the formulas are straight or branched alkyl groups with 1 to 4 carbon atoms, e.g. methyl, ethyl, n-propyl, n-butyl and i-butyl;
  • Unsaturated lower alkyl groups in the formulas are lower alkenyl groups having straight or branched hydrocarbon chains with 2 to 3 carbon atoms and a double bond, e.g. vinyl, ally! or isopropenyl, or lower alkynyl groups having hydrocarbon chains with 2 to 3 carbon atoms with a triple bond, that is -C ⁇ CH, -CH 2 -C ⁇ CH and -C ⁇ CCH 3 ; Cycloalkyl groups in the formulas are unsubstituted 3-6 membered cyclomethylene groups C C wherein n is 2-5.
  • Substituted phenyl in the formulas is a phenyl group substituted by for example one or more halo groups such as fluoro, chloro, bromo, trifluoromethyl, lower alkyl such as methyl, ethyl, hydroxy, methoxy or ethoxy in the ortho, meta or para positions, or substituted by methylenedioxy.
  • halo groups such as fluoro, chloro, bromo, trifluoromethyl
  • lower alkyl such as methyl, ethyl, hydroxy, methoxy or ethoxy in the ortho, meta or para positions, or substituted by methylenedioxy.
  • the preparation proceeds in three steps involving 0,N-dialkylation, aminolysis and reduction as shown in Reaction Schemes 3-6.
  • the reactions are performed with full control and retention of the stereochemistry, i.e. stereoconservative.
  • the overall yield from proline is high and the amines of the formulas (S)-I and (R)-I are obtained with very high optical purities.
  • the wording 'an optical pure compound' in the present invention means material containing at least 95% (S)- or (R)-isomer.
  • L-proline is the same as (S)-proline
  • D-proline is the same as (R)-proline.
  • R 2 is identical to R 1 as defined above. Reaction Scheme 4 OO 2 I) 1
  • R 2 is defined as R 1 above and R 1 and R 2 may be the same or different.
  • R 2 is defined as R 1 above and R 1 and R 2 may be the same or different.
  • R 2 is defined as R 1 above and R 1 and R 2 may be the same or different. The reaction steps are described in more detail in the following.
  • Step 1 involves a 0,N-dialkylation of (S)- and (R)-proline giving the chiral ester of the formula II in optically pure form.
  • the reaction can be done as a stepwise monoalkylation involving isolation of an intermediate N-alkylated product
  • R 1 and R 2 may be identical or different.
  • R 1 CH 2 X wherein X is a leaving group for instance a halogen group such as chlorine (-Cl), bromine (-Br), or a sulfonic acid residue such as toluenesulfonyl (-OTs) or methansulfonyl (-OMs).
  • halogen group such as chlorine (-Cl), bromine (-Br)
  • sulfonic acid residue such as toluenesulfonyl (-OTs) or methansulfonyl (-OMs).
  • reaction is carried out in a suitable solvent such as dimethylformamid (DMF), dimethylsulfoxid (DMSO), hexamethylphosphoric triamid
  • a suitable solvent such as dimethylformamid (DMF), dimethylsulfoxid (DMSO), hexamethylphosphoric triamid
  • HMPT dichloromethane
  • trichloromethane ethanol or acetone
  • a suitable organic or inorganic base such as CO 3 2- ,OH-,F-, tetramethylpiperidine, trialkylamin, 1,5-diazabicyclo [4,3,0] non-5-ene
  • DBN 1,8-diazabicyclo [4,3,0] undec-7-ene
  • a catalyst like iodine (I-) or a phase-transfer catalyst such as quaternary ammonium salts (e.g. Bu 4 N + HSO 4 ) and crown ethers (e.g.
  • Step lb O-alkylation by known methods such as esterification of (R)- or (S)-proline with R 2 CH 2 OH and acid catalyst such as hydrogen chloride, thionylchloride or by reaction of a reactive proline derivative such as prolylchloride hydrochloride with R 2 CH 2 OH or by alkylation with R 2 CH 2 X to give the known intermediate of the formula V followed by N-alkylation by known methods such as reductive alkylation with the corresponding aldehyde R 1 CHO and a reducing agent such as NaBH 3 CN, HCOOH or H 2 -Pd/C in conventional solvents or alkylation with R 1 CH 2 X as described in Step la to give the (R)- or (S)-isomer of the compound of the formula II.
  • R 1 , R 2 and X are defined as above.
  • Step 1c N-alkylation by known methods such as reductive alkylation of
  • R 1 , R 2 and X are defined as above.
  • reaction temperature in the direct O,N-dialkylation step as well as the stepwise monoalkylation steps is below e boiling point of the used solvent, preferably below 50°C.
  • Step 2a involves aminolysis of the (R)- or (S)-isomer of the ester of the formula II producing the amide of the formula III by conventional procedures such as reaction with ammonia in hydroxylic solvents or by reaction with Me 2 AlNH 2 .
  • the reaction can preferably be done in an alcoholic ammonia solution at elevated temperature in a pressure bottle or at lower temperature at atmospheric pressure.
  • the reaction can be done without or with a suitable catalyst such as inorganic salt and especially preferred anions are iodide and cyanide. Cyanide being most preferred.
  • the reaction should be carried out at temperatures below 100°C. The racemization diminishes with decreasing temperature and is practically eliminated at about 50°C, which is the preferred temperature for optimal conditions.
  • N-alkylation of the known amide of the formula VI in optically pure form by known methods such as reductive alkylation with the corresponding aldehyde R 1 CHO and a reducing agent such as NaBH 3 CN, HCOOH or H 2 -Pd/C or alkylation with R 1 CH 2 X, wherein X is a leaving group, e.g. a halogen or a sulfonic acid residue such as -Cl, -Br, -OTs or -OMs to give a (R)- or (S)-isomer of the compound of the formula III.
  • the N-alkylation is performed under the same reaction conditions as described in Step la. Step 3.
  • the reduction of the (R)- or (S)-isomer of the amide III can be performed using a hydride reagent such as LiAlH. NaBH 4 with or without addition of a catalyst e.g. AlCl 3 , BF 3 , TiCl., COC1 2, CH 3 COOH and CF 3 C00H or metal hydride complexes such as NaAlH 2 (OCH 2 CH 2 OCH 3 ) 2, NaBH 2 S 3 or borane and borane complexes such as B 2 H 6 and BH 3 S(CH 3 ) 2 .
  • a hydride reagent such as LiAlH. NaBH 4 with or without addition of a catalyst e.g. AlCl 3 , BF 3 , TiCl., COC1 2, CH 3 COOH and CF 3 C00H or metal hydride complexes such as NaAlH 2 (OCH 2 CH 2 OCH 3 ) 2, NaBH 2 S 3 or borane and borane complex
  • the amides can also be reduced by catalytic hydrogenation procedures at elevated temperature and pressure using catalysts such as copper chromite in solvents such as dioxane.
  • the reduction can be performed by conversion of the amides to reactive intermediates such as imino ethers, imino chlorides, nitriles using e.g. (C 2 H 5 ) 3 0BF 4 , PCl 5 , POCl 3 or dehydrating agents in inert solvents e.g CH 2 Cl 2 .
  • reactive intermediates such as imino ethers, imino chlorides, nitriles using e.g. (C 2 H 5 ) 3 0BF 4 , PCl 5 , POCl 3 or dehydrating agents in inert solvents e.g CH 2 Cl 2 .
  • These intermediates are preferably not isolated but reduced directly with hydride reagents or metals e.g. Zn in alcoholic solvents.
  • R 1 and R 2 are the same or different and represent a hydrogen atom, a saturated or unsaturated lower alkyl group, a cycloalkyl group, or a group (CH 2 ) m Ph wherein m is 0-3 and Ph is an unsubstituted or substituted phenyl group with the proviso that when R 2 is hydrogen then
  • R 1 and R 2 are different and with the further proviso that when R 2 is hydrogen and R 1 is a group (CH 2 ) m Ph ' wherein m is O then Ph is unsubstituted or substituted with one or more groups selected from halo, trifluoromethyl, hydroxy, lower alkyl, ethoxy or methylendioxy, and salts of said compounds constitute a further aspect of the invention.
  • Especially preferred compounds are those wherein R 1 is methyl, enthyl, cyclopropyl, vinyl or halophenyl, particularly 4-fluorophenyl.
  • Acceptable salts of compounds of the invention are prepared by methods known in the art.
  • the salts are novel compounds and comprise a further aspect of the invention.
  • Metal salts can be prepared by reacting a metal hydroxide with an acidic compound of the invention. Examples of metal salts which can be prepared in this way are salts containing Li + , Na + , K + and Ca 2+ . A less soluble metal salt can be precipitated from a solution of a more soluble salt by addition of a suitable metal compound. Also amine salts eg. trialkylamine or onium salts eg. Bu 4 N + ,
  • Ph 3 P + can be prepared.
  • Acid salts can be prepared by treating a compound of the invention with an acid such as HCl, HBr, H 2 SO 4 , or an organic sulphonic acid, carboxylic acid, phenols such as picric acid.
  • the ester (16.5 g, 0.10 mol) was transferred to a flask containing propionaldehyde (36 ml, 0.50 mol), 10% Pd/C (1.5 g) and 100 ml MeOH. The mixture was shaken in a Parr apparatus overnight at a hydrogen pressure of 55 psi at room temperature. Filtration and evaporation in vacuo gave 22.0 g of the crude title ester (94% purity by GLC) as a hydrochloride salt, which was used in the aminolysis in Example 11B.
  • Methyl (S)-2-pyrrolidinecarboxylate hydrochloride (1.65 g, 0.01 mol) was added to a hydrogenation flask containing a mixture of propionaldehyde (2.4 g, 0.04 mol), 5% Pd/C (0.3 g) and 30 ml MeOH. The mixture was shaken an a Parr apparatus at 40 psi hydrogen pressure for 2 h at room temperature. After filtration and evaporation the residue was mixed with 10 ml 2M HCl and 40 ml ice-water and then extracted twice with Et 2 O. Solid NaCl was added to the aqueous phase which was made alkaline with 20 ml 2M NH 3 during addition of ice.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
EP87903468A 1986-05-22 1987-05-19 A stereoconservative synthesis of 1-substituted (s)- and (r)-2-aminomethylpyrrolidines and intermediates thereto Pending EP0270596A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8602339A SE8602339D0 (sv) 1986-05-22 1986-05-22 An efficient stereoconservative synthesis of 1-substituted (s)- and (r)-2-aminomethylpyrrolidines
SE8602339 1986-05-22

Publications (1)

Publication Number Publication Date
EP0270596A1 true EP0270596A1 (en) 1988-06-15

Family

ID=20364616

Family Applications (2)

Application Number Title Priority Date Filing Date
EP87903468A Pending EP0270596A1 (en) 1986-05-22 1987-05-19 A stereoconservative synthesis of 1-substituted (s)- and (r)-2-aminomethylpyrrolidines and intermediates thereto
EP87850165A Expired - Lifetime EP0253785B1 (en) 1986-05-22 1987-05-19 Efficient stereoconservative syntheses of 1-substituted (s)- and (r)-2-aminomethylpyrrolidines and intermediates therein

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP87850165A Expired - Lifetime EP0253785B1 (en) 1986-05-22 1987-05-19 Efficient stereoconservative syntheses of 1-substituted (s)- and (r)-2-aminomethylpyrrolidines and intermediates therein

Country Status (12)

Country Link
EP (2) EP0270596A1 (enrdf_load_stackoverflow)
JP (1) JPH07103098B2 (enrdf_load_stackoverflow)
KR (1) KR950011407B1 (enrdf_load_stackoverflow)
AT (1) ATE82259T1 (enrdf_load_stackoverflow)
DE (2) DE3782566T2 (enrdf_load_stackoverflow)
DK (1) DK11788A (enrdf_load_stackoverflow)
ES (1) ES2044974T3 (enrdf_load_stackoverflow)
FI (1) FI95028C (enrdf_load_stackoverflow)
GR (1) GR3006609T3 (enrdf_load_stackoverflow)
IE (1) IE59896B1 (enrdf_load_stackoverflow)
SE (1) SE8602339D0 (enrdf_load_stackoverflow)
WO (1) WO1987007271A1 (enrdf_load_stackoverflow)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4425070A1 (de) * 1994-07-15 1996-01-18 Degussa Verfahren zur Herstellung optisch aktiver l-substituierter 2-(Aminomethyl)pyrrolidine
CN1298702C (zh) * 2005-03-15 2007-02-07 江苏省原子医学研究所 一种(s)－1－烯丙基－2－胺甲基四氢吡咯的制备方法
JP6359365B2 (ja) * 2014-07-09 2018-07-18 国立研究開発法人産業技術総合研究所 アミノ酸のアミノ基及びカルボキシル基を対象としたプレカラム誘導体化ｌｃ−ｍｓ分析法
CN107641092A (zh) * 2017-10-30 2018-01-30 广东肇庆星湖生物科技股份有限公司 一种l‑脯氨酰胺的合成方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3718688A (en) * 1967-10-18 1973-02-27 Radio Carbon Lab Alkylidine and arylidine amino acid esters, and alkyl and aryl amino acid esters
US3947408A (en) * 1974-08-05 1976-03-30 American Cyanamid Company Pyrrolo-benzodiazepines, method of preparation and method of use
IL52645A (en) * 1976-08-05 1980-02-29 Synthelabo Optically active 1 substituted 2 aminomethyl pyrrolidines stereospecifics synthesis thereof and process for the preparation of optically active 2 methoxy n pyrrolidylmethyl benzamides
IT1095415B (it) * 1978-02-16 1985-08-10 Ravizza Spa Processo per la produzione di una benzamide otticamente attiva,benzamide otticamente attiva cosi'ottenuta e composizioni
FR2452482A1 (fr) * 1979-03-28 1980-10-24 Synthelabo Derives de benzamides et leur application en therapeutique
US4525473A (en) * 1983-03-30 1985-06-25 Bristol-Myers Company Cephalosporins
US4698336A (en) * 1985-01-30 1987-10-06 Eisai Co., Ltd. 3-(pyrrolidinio)methyl-3-cephem derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8707271A1 *

Also Published As

Publication number Publication date
IE871320L (en) 1987-11-22
FI880265A0 (fi) 1988-01-21
DE3782566T2 (de) 1993-03-25
DE3782566D1 (de) 1992-12-17
JPS63503384A (ja) 1988-12-08
EP0253785A1 (en) 1988-01-20
FI95028B (fi) 1995-08-31
DE270596T1 (de) 1988-10-13
WO1987007271A1 (en) 1987-12-03
IE59896B1 (en) 1994-04-20
KR880701226A (ko) 1988-07-26
KR950011407B1 (ko) 1995-10-04
ATE82259T1 (de) 1992-11-15
ES2044974T3 (es) 1994-01-16
GR3006609T3 (enrdf_load_stackoverflow) 1993-06-30
JPH07103098B2 (ja) 1995-11-08
SE8602339D0 (sv) 1986-05-22
DK11788D0 (da) 1988-01-12
DK11788A (da) 1988-01-12
EP0253785B1 (en) 1992-11-11
FI880265A7 (fi) 1988-01-21
FI95028C (fi) 1995-12-11

Similar Documents

Publication Publication Date Title
Bailey et al. A short synthesis of (S)-2-(diphenylmethyl) pyrrolidine, a chiral solvating agent for NMR analysis
JP2011508751A (ja) アセナピンの調製方法および前記方法において使用される中間生成物
US6809214B2 (en) Shortened synthesis of 3,3-diarylpropylamine derivatives
CA2693843A1 (en) Process for the enantioselective preparation of pregabalin
EP1863761A1 (en) Process for preparing levetiracetam
Alcaide et al. Preparation of. alpha.-Methylene and. alpha.-Ethylidene. beta.-Lactams via the Ester Enolate-Imine Condensation Using. beta.-(Dialkylamino) Esters as Starting Materials: Scope and Synthetic Applications
EP0253785B1 (en) Efficient stereoconservative syntheses of 1-substituted (s)- and (r)-2-aminomethylpyrrolidines and intermediates therein
US5468876A (en) Intermediates for the stereoconservative synthesis of 1-substituted (S)-and (R)-2-aminomethylpyrrolidines
US5585500A (en) Method of producing optically active pyrrolidines with high enantiomeric purity
KR20060070485A (ko) 프로키랄 및 메소 사이클릭 무수물의 촉매적 비대칭탈대칭화
US20020169323A1 (en) Practical syntheses of chiral trans-3, 4-disubstituted piperidines and the intermediates
Högberg et al. Efficient stereoconservative syntheses of 1-substituted (S)-and (R)-2-aminomethylpyrrolidines
US6414180B1 (en) Synthesis of chiral β-amino acids
KR100743617B1 (ko) 고광학순도를 갖는 키랄 3-히드록시 피롤리딘 및 그유도체를 제조하는 방법
US5502210A (en) 1H-isoindole-1,3-dione compounds
US5670666A (en) Process for preparing intermediates for the synthesis of D1 antagonists
JP2002537394A (ja) パロキセチンの製造方法
Sugiyama et al. A Three-Step Synthesis of Optically Active 5-Halomethyl-2-oxazolidinones; Asymmetric Desymmetrizatlon of Prochiral 1, 3-Dihalo-2-propyl Carbamates
Mellin et al. Stereoselective synthesis of methoxy substituted 1, 2, 3, 4, 4a, 5, 10, 10a-octahydrobenzo [g] quinolines
US6172234B1 (en) Optically active cyclic amino acid ester derivatives and processes for producing the same
US5223646A (en) Process for producing optically active atenolol and intermediate thereof
Dong et al. An Asymmetric Reductive Amination Synthesis of Ritlecitinib Using (S)‐α‐Methylbenzylamine as Chiral Auxiliary
US20010053862A1 (en) Process for preparing arylpiperidine carbinol intermediates and derivatives
JP2703048B2 (ja) プロリン誘導体の製法
KR0127750B1 (ko) 피톨리돈 유도체의 제조방법

Legal Events

Date Code Title Description
ITCL It: translation for ep claims filed

Representative=s name: BARZANO' E ZANARDO ROMA S.P.A.

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 19880111

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

DET De: translation of patent claims
XX Miscellaneous (additional remarks)

Free format text: VERFAHREN ABGESCHLOSSEN INFOLGE VERBINDUNG MIT 87850165.9/0253785 (EUROPAEISCHE ANMELDENUMMER/VEROEFFENTLICHUNGSNUMMER) VOM 06.04.90.

RIN1 Information on inventor provided before grant (corrected)

Inventor name: STROEM, HANS, ERIC, PETER

Inventor name: RAEMSBY, STEN, INGVAR

Inventor name: HOEGBERG, THOMAS

Inventor name: FEDERSEL, HANS-JUERGEN