DK1620396T3 - Fremgangsmåde til fremstilling af N-substituerede 2-cyanopyrrolidiner - Google Patents
Fremgangsmåde til fremstilling af N-substituerede 2-cyanopyrrolidiner Download PDFInfo
- Publication number
- DK1620396T3 DK1620396T3 DK04727557.3T DK04727557T DK1620396T3 DK 1620396 T3 DK1620396 T3 DK 1620396T3 DK 04727557 T DK04727557 T DK 04727557T DK 1620396 T3 DK1620396 T3 DK 1620396T3
- Authority
- DK
- Denmark
- Prior art keywords
- alkyl
- halogen
- substituted
- formula
- independently
- Prior art date
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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
- C07D207/10—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Claims (6)
1. Fremgangsmåde til fremstilling af en N-(N'-substitueret glycyl)-2-cyanopyrrolidin med formlen I (i) hvori R er
a) RiRiaN(CH2)m - hvori Ri er en pyridinyl- eller pyrimidinylgruppe, der eventuelt er mono- eller uafhængigt disubstitueret med (Ci^alkyl, (Ci.4)alkoxy, halogen, trifluormethyl, cyano eller nitro; eller phenyl, der eventuelt er mono- eller uafhængigt disubstitueret med (Ci^)alkyl, (Ci^t)alkoxy eller halogen; Ria er hydrogen eller (Ci_8)alkyl; og m er 2 eller 3; b) (C3-i2)cycloalkyl, der eventuelt er monosubstitueret i 1-stillingen med (Ci_3)hydroxyalkyl; c) R2(CH2)n - hvori enten R2 er phenyl, der eventuelt er mono- eller uafhængigt di- eller uafhængigt trisubstitueret med (Ci^)alkyl, (Ci^alkoxy, halogen eller phenylthio, der eventuelt er monosubstitueret i phenylringen med hydroxymethyl; eller er (Ci.e)alkyl; en [3.1.1]bicyclisk carbocyclisk gruppe, der eventuelt er mono- eller plurisubstitueret med (Ci_8)alkyl; en pyridinyl- eller naphthylgruppe, der eventuelt er mono- eller uafhængigt disubstitueret med (Ci^)alkyl, (Ci^)alkoxy eller halogen; cyclohexenyl; eller eventuelt substitueret adamantyl; og n er 1 til 3; eller R2 er phenoxy, der eventuelt er mono- eller uafhængigt disubstitueret med (Ci^)alkyl, (C^Jalkoxy eller halogen; og n er 2 eller 3; d) (R3)2CH(CH2)2- hvori hvert R3 uafhængigt er phenyl, der eventuelt er mono- eller uafhængigt disubstitueret med (Ci^alkyl, (C^alkoxy eller halogen; e) R4(CH2)P - hvori R4 er 2-oxopyrrolidinyl eller (C2^)alkoxy, og p er 2 to 4; f) isopropyl, der eventuelt er monosubstitueret i 1-stillingen med (Ci.3)hydroxyalkyl; eller g) R5, hvori R5 er: indanyl; en pyrrolidinyl- eller piperidinylgruppe, der eventuelt er substitueret med benzyl; en [2.2.1]- eller [3.1.1 ]bicyclisk carbocyclisk gruppe, der eventuelt er mono- eller multi-substitueret med (C1.8)alkyl; adamantyl; substitueret adamantyl; eller (Ci.8)alkyl, der eventuelt er mono- eller uafhængigt pluri-substitueret med hydroxy, hydroxymethyl eller phenyl, der eventuelt er mono- eller uafhængigt disubstitueret med (Ci.4)alkyl, (Ci_4)alkoxy eller halogen; i fri form eller i form af et syreadditionssalt, omfattende i det mindste (a) omsætning i nærvær af dimethylformamid af en forbindelse med formlen V
(V) hvori indbyrdes uafhængigt af hinanden, Xi og X3 er halogen; X2 er halogen, OH, 0-C(=0)-CH2X3, -0-S02-(C-|.8)alkyl eller -0-S02-(aryl), med L-prolinamid, efterfulgt af (b) omsætning af den fremkomne forbindelse uden isolering med et dehydratiserings-middel, efterfulgt af (c) omsætning i nærvær af en base af den fremkomne forbindelse uden isolering med en passende amin og (d) udvinding af den fremkomne forbindelse i fri form eller i form af et syreadditionssalt, idet dehydratiseringsmidlet er et (halogenalkylen)dialkylammoniumhalogenid.
2. Fremgangsmåde ifølge krav 1, ved hvilken dehydratiseringsmidlet i trin (b) er (chlormethylen)dimethylammoniumchlorid.
3. Fremgangsmåde ifølge krav 1, ved hvilken aminen i trin (c) er en forbindelse med formlen VI H2NR (VI) hvori R er som defineret for formlen I i krav 1.
4. Fremgangsmåde ifølge krav 1 omfattende (a) omsætning i nærvær af dimethylformamid af en forbindelse med formlen V
(V) hvori Xi er halogen; X2 er halogen, OH, 0-C(=0)-CH2X, -0-S02-(Ci_8)alkyl eller -0-S02-(aryl), med L-prolinamid, efterfulgt af (b) omsætning af den fremkomne forbindelse uden isolering med (chlormethylen)-dimethylammoniumchlorid, efterfulgt af (c) omsætning i nærvær af en base af den fremkomne forbindelse uden isolering med en forbindelse med formlen VI H2NR (VI) hvori R er som defineret for formlen I og (d) udvinding af den fremkomne forbindelse i fri form eller i form af et syreadditionssalt.
5. Fremgangsmåde ifølge krav 4, ved hvilken R er R2(CH2)n-, og R2 er substitueret adamantyl; og n er 0, 1,2 eller 3.
6. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 5, hvori N-(N'-substitueret glycyl)-2-cyanopyrrolidinen med formlen I er pyrrolidin, 1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-, (S).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0308854A GB0308854D0 (en) | 2003-04-16 | 2003-04-16 | Organic compounds |
| GB0311836A GB0311836D0 (en) | 2003-05-22 | 2003-05-22 | Process for the manufacture of organic compounds |
| PCT/EP2004/003980 WO2004092127A1 (en) | 2003-04-16 | 2004-04-15 | Process for the preparation of n-substituted 2-cyanopyrrolidines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK1620396T3 true DK1620396T3 (da) | 2015-02-23 |
Family
ID=33301223
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK04727557.3T DK1620396T3 (da) | 2003-04-16 | 2004-04-15 | Fremgangsmåde til fremstilling af N-substituerede 2-cyanopyrrolidiner |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US7375238B2 (da) |
| EP (1) | EP1620396B1 (da) |
| JP (1) | JP4672647B2 (da) |
| KR (1) | KR101192538B1 (da) |
| AR (1) | AR044019A1 (da) |
| AU (2) | AU2004230245B2 (da) |
| BR (1) | BRPI0409471B8 (da) |
| CA (1) | CA2520128C (da) |
| CL (1) | CL2004000804A1 (da) |
| CO (1) | CO5700735A2 (da) |
| CY (1) | CY1116008T1 (da) |
| DK (1) | DK1620396T3 (da) |
| EC (1) | ECSP056093A (da) |
| ES (1) | ES2531084T3 (da) |
| HK (1) | HK1087695A1 (da) |
| HR (1) | HRP20150163T1 (da) |
| IL (1) | IL170887A (da) |
| IS (1) | IS2979B (da) |
| MA (1) | MA27765A1 (da) |
| MX (1) | MXPA05011073A (da) |
| MY (1) | MY139476A (da) |
| NO (1) | NO333251B1 (da) |
| NZ (1) | NZ542899A (da) |
| PE (2) | PE20081293A1 (da) |
| PL (1) | PL1620396T3 (da) |
| PT (1) | PT1620396E (da) |
| RU (1) | RU2369598C2 (da) |
| SG (1) | SG160212A1 (da) |
| SI (1) | SI1620396T1 (da) |
| TW (1) | TWI359135B (da) |
| WO (1) | WO2004092127A1 (da) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR044019A1 (es) | 2003-04-16 | 2005-08-24 | Novartis Ag | Proceso para la preparacion de 2-cianopirrolidinas n-sustituidas |
| PT1715893E (pt) | 2004-01-20 | 2009-10-20 | Novartis Pharma Ag | Formulação para compressão directa e processos |
| GT200600008A (es) | 2005-01-18 | 2006-08-09 | Formulacion de compresion directa y proceso | |
| BRPI0614610A2 (pt) * | 2005-08-04 | 2011-04-05 | Novartis Ag | compostos |
| WO2008066083A1 (fr) * | 2006-11-29 | 2008-06-05 | Mitsubishi Tanabe Pharma Corporation | Procédé de production d'un dérivé de n-(n'-glycyle substitué)-2-cyanopyrrolidine |
| WO2008084383A2 (en) * | 2007-01-10 | 2008-07-17 | Medichem, S.A. | Process for preparing vildagliptin |
| CZ2008512A3 (cs) | 2008-08-26 | 2010-03-10 | Zentiva, A. S | Zpusob prípravy vysoce cistého vildagliptinu |
| EA034049B1 (ru) * | 2009-07-31 | 2019-12-23 | КРКА, д.д., НОВО МЕСТО | Гранулят, включающий вилдаглиптин, способ его получения и фармацевтическая композиция |
| HUP0900638A2 (en) * | 2009-10-07 | 2011-05-30 | Egyt Gyogyszervegyeszeti Gyar | Adducts of inorganic salts basea on vildaelitpin applicable for preparation of pharmaceutical compositions |
| IT1400714B1 (it) | 2010-07-06 | 2013-06-28 | Chemelectiva S R L | Processo ed intermedi per la preparazione di un principio attivo. |
| HU231050B1 (hu) | 2010-08-19 | 2020-02-28 | Egis Gyógyszergyár Nyrt. | Eljárás gyógyszerhatóanyag előállítására |
| ITMI20112224A1 (it) * | 2011-12-06 | 2013-06-07 | Chemelectiva S R L | Nuovo processo ed intermedi per la sintesi di vildagliptin |
| IN2012MU01383A (da) * | 2012-05-04 | 2014-02-28 | ||
| CN103922986B (zh) * | 2013-01-16 | 2017-02-15 | 上海彩迩文生化科技有限公司 | 维大列汀及其类似物、中间体及其制备方法和应用 |
| WO2015145467A1 (en) * | 2014-03-28 | 2015-10-01 | Laurus Labs Private Limited | An improved process for preparing vildagliptin |
| WO2021234430A1 (en) | 2020-05-17 | 2021-11-25 | Lotus International Pte. Ltd. | Modified release dosage form comprising vildagliptin and process for manufacturing the same |
| WO2022003405A1 (en) | 2020-07-03 | 2022-01-06 | Savoi Guilherme | One-pot process to obtain a pyrrolidine-2-carbonitrile intermediate compound and industrial scale telescopic process to prepare (2s)-1-[n-(3-hydroxyadamantan-1-yl)glycyl]-2-pyrrolidinecarbonitrile (vildagliptin) using same |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5510369A (en) * | 1994-07-22 | 1996-04-23 | Merck & Co., Inc. | Pyrrolidine thrombin inhibitors |
| TW492957B (en) * | 1996-11-07 | 2002-07-01 | Novartis Ag | N-substituted 2-cyanopyrrolidnes |
| CO5150173A1 (es) | 1998-12-10 | 2002-04-29 | Novartis Ag | Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv |
| US6380398B2 (en) * | 2000-01-04 | 2002-04-30 | Novo Nordisk A/S | Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
| EP1254113A1 (en) * | 2000-01-24 | 2002-11-06 | Novo Nordisk A/S | N-substituted 2-cyanopyroles and -pyrrolines which are inhibitors of the enzyme dpp-iv |
| TW583185B (en) * | 2000-06-13 | 2004-04-11 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines and pharmaceutical composition for inhibiting dipeptidyl peptidase-IV (DPP-IV) or for the prevention or treatment of diseases or conditions associated with elevated levels of DPP-IV comprising the same |
| JP2002265439A (ja) * | 2001-03-08 | 2002-09-18 | Mitsubishi Pharma Corp | シアノピロリジン誘導体およびその医薬用途 |
| AR044019A1 (es) | 2003-04-16 | 2005-08-24 | Novartis Ag | Proceso para la preparacion de 2-cianopirrolidinas n-sustituidas |
-
2004
- 2004-04-14 AR ARP040101251A patent/AR044019A1/es not_active Application Discontinuation
- 2004-04-14 PE PE2007000421A patent/PE20081293A1/es not_active Application Discontinuation
- 2004-04-14 PE PE2004000370A patent/PE20050021A1/es not_active Application Discontinuation
- 2004-04-15 EP EP04727557.3A patent/EP1620396B1/en not_active Expired - Lifetime
- 2004-04-15 CL CL200400804A patent/CL2004000804A1/es unknown
- 2004-04-15 SG SG200716949-3A patent/SG160212A1/en unknown
- 2004-04-15 MY MYPI20041383A patent/MY139476A/en unknown
- 2004-04-15 RU RU2005135331/04A patent/RU2369598C2/ru active
- 2004-04-15 WO PCT/EP2004/003980 patent/WO2004092127A1/en active Application Filing
- 2004-04-15 AU AU2004230245A patent/AU2004230245B2/en not_active Ceased
- 2004-04-15 BR BRPI0409471A patent/BRPI0409471B8/pt not_active IP Right Cessation
- 2004-04-15 ES ES04727557T patent/ES2531084T3/es not_active Expired - Lifetime
- 2004-04-15 PT PT04727557T patent/PT1620396E/pt unknown
- 2004-04-15 JP JP2006505132A patent/JP4672647B2/ja not_active Expired - Lifetime
- 2004-04-15 MX MXPA05011073A patent/MXPA05011073A/es active IP Right Grant
- 2004-04-15 NZ NZ542899A patent/NZ542899A/en not_active IP Right Cessation
- 2004-04-15 US US10/552,835 patent/US7375238B2/en not_active Expired - Fee Related
- 2004-04-15 PL PL04727557T patent/PL1620396T3/pl unknown
- 2004-04-15 SI SI200432220T patent/SI1620396T1/sl unknown
- 2004-04-15 CA CA2520128A patent/CA2520128C/en not_active Expired - Fee Related
- 2004-04-15 KR KR1020057019568A patent/KR101192538B1/ko active IP Right Review Request
- 2004-04-15 DK DK04727557.3T patent/DK1620396T3/da active
- 2004-04-15 TW TW093110566A patent/TWI359135B/zh not_active IP Right Cessation
-
2005
- 2005-09-15 IL IL170887A patent/IL170887A/en active IP Right Grant
- 2005-10-12 EC EC2005006093A patent/ECSP056093A/es unknown
- 2005-10-19 MA MA28559A patent/MA27765A1/fr unknown
- 2005-11-03 CO CO05112189A patent/CO5700735A2/es not_active Application Discontinuation
- 2005-11-07 NO NO20055226A patent/NO333251B1/no not_active IP Right Cessation
- 2005-11-10 IS IS8122A patent/IS2979B/is unknown
-
2006
- 2006-07-11 HK HK06107769.8A patent/HK1087695A1/xx not_active IP Right Cessation
-
2008
- 2008-05-22 AU AU2008202278A patent/AU2008202278A1/en not_active Abandoned
-
2015
- 2015-02-10 HR HRP20150163TT patent/HRP20150163T1/hr unknown
- 2015-02-18 CY CY20151100168T patent/CY1116008T1/el unknown
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