RU97111801A - Способ получения 1-(2'-деокси-2',2'-дифтор-d-рибофуранозил)-аминопиримидин-2-он гидрохлорида - Google Patents
Способ получения 1-(2'-деокси-2',2'-дифтор-d-рибофуранозил)-аминопиримидин-2-он гидрохлоридаInfo
- Publication number
- RU97111801A RU97111801A RU97111801/04A RU97111801A RU97111801A RU 97111801 A RU97111801 A RU 97111801A RU 97111801/04 A RU97111801/04 A RU 97111801/04A RU 97111801 A RU97111801 A RU 97111801A RU 97111801 A RU97111801 A RU 97111801A
- Authority
- RU
- Russia
- Prior art keywords
- deoxy
- methanol
- ribofuranosyl
- difluoro
- aminopyrimidin
- Prior art date
Links
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims 3
- 238000004519 manufacturing process Methods 0.000 title 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 5
- 239000012296 anti-solvent Substances 0.000 claims 3
- 239000002904 solvent Substances 0.000 claims 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims 2
- 229960005144 Gemcitabine hydrochloride Drugs 0.000 claims 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N Isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 2
- 150000003973 alkyl amines Chemical class 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- OKKDEIYWILRZIA-OSZBKLCCSA-N gemcitabine hydrochloride Chemical compound [H+].[Cl-].O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 OKKDEIYWILRZIA-OSZBKLCCSA-N 0.000 claims 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N Cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims 1
- 229940104302 Cytosine Drugs 0.000 claims 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims 1
- 230000003197 catalytic Effects 0.000 claims 1
- 238000011065 in-situ storage Methods 0.000 claims 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 1
- 230000001681 protective Effects 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
Claims (12)
1. Способ получения гемцитабин гидрохлорида, отличающийся тем, что включает (а) удаление защитной группы у β-1-(2'-деокси-2', 2'-дифтор-3', 5'-ди-O-бензоил-D-рибофуранозил)-4-аминопиримидин-2-она каталитическим количеством алкиламина в присутствии метанола или этанола в, по существу, безводной среде; (б) обработку полученного раствора соляной кислотой и антирастворителем и (в) выделение полученного твердого гемцитабин гидрохлорида.
2. Способ по п. 1, отличающийся тем, что в качестве алкиламина используют диэтиламин.
3. Способ по п. 1, отличающийся тем, что в качестве растворителя на стадии (а) используют метанол.
4. Способ по п. 3, отличающийся тем, что в качестве антирастворителя на стадии (б) используют растворитель, выбранный из ацетона, ацетонитрила, тетрагидрофурана, пропанола, бутанола, изобутанола, втор.-бутанола и изопропанола.
5. Способ по п. 4, отличающийся тем, что в качестве антирастворителя используют изопропанол.
6. Способ по п. 5, отличающийся тем, что соотношение метанола и изопропанола составляет 1: 1.
7. Способ по п. 3, отличающийся тем, что на 1 г β-1-(2'-деокси-2', 2'-дифтор-3', 5'-ди-O-бензоил-D-рибофуранозил)-4-аминопиримидин-2-она используют 15-25 мл метанола.
8. Способ по п. 7, отличающийся тем, что 20 мл метанола используют на 1 г β-1-(2'-деокси-2', 2'-дифтор-3', 5'-ди-O-бензоил-D-рибофуранозил)-4-аминопиримидин-2-она.
9. Способ по п. 1, отличающийся тем, что β-1-(2'-деокси-2', 2'-дифтор-3'-5'-ди-O-бензоил-В-рибофуранозил)-4-аминопиримидин-2-он получают in situ из 2-деокси-2,2-дифтор-3,5-дибензоил-D-рибофуранозил-1-метансульфоната и цитозина.
10. Способ по п. 9, отличающийся тем, что используют 10-20 мл метанола на 1 г 2-деокси-2,2-дифтор-3,5-ди-бензоил-В-рибофуранозил-1-метансульфоната.
11. Способ по п. 10, отличающийся тем, что в качестве антирастворителя используют изопропанол.
12. Способ по п. 11, отличающийся тем, что соотношение метанола и изопропанола составляет 1:1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/355,372 | 1994-12-13 | ||
| US08/355,372 US5637688A (en) | 1994-12-13 | 1994-12-13 | Process for preparing 1-(2'-deoxy-2'-difluoro-d-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU97111801A true RU97111801A (ru) | 1999-06-10 |
| RU2154648C2 RU2154648C2 (ru) | 2000-08-20 |
Family
ID=23397211
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU97111801/04A RU2154648C2 (ru) | 1994-12-13 | 1995-11-14 | Способ получения гемцитабин гидрохлорида |
Country Status (31)
| Country | Link |
|---|---|
| US (2) | US5637688A (ru) |
| EP (1) | EP0719788B1 (ru) |
| JP (1) | JPH10510806A (ru) |
| KR (1) | KR100424991B1 (ru) |
| CN (1) | CN1047177C (ru) |
| AR (1) | AR001041A1 (ru) |
| AT (1) | ATE179986T1 (ru) |
| AU (1) | AU689674B2 (ru) |
| BG (1) | BG62738B1 (ru) |
| BR (1) | BR9509979A (ru) |
| CO (1) | CO4520286A1 (ru) |
| CZ (1) | CZ290941B6 (ru) |
| DE (1) | DE69509624T2 (ru) |
| DK (1) | DK0719788T3 (ru) |
| ES (1) | ES2130542T3 (ru) |
| GR (1) | GR3030265T3 (ru) |
| HU (1) | HU219021B (ru) |
| IL (1) | IL115852A (ru) |
| MY (1) | MY112488A (ru) |
| NO (1) | NO306783B1 (ru) |
| NZ (1) | NZ296476A (ru) |
| PE (1) | PE49296A1 (ru) |
| PL (1) | PL181732B1 (ru) |
| RO (1) | RO117327B1 (ru) |
| RU (1) | RU2154648C2 (ru) |
| SI (1) | SI0719788T1 (ru) |
| TW (1) | TW379226B (ru) |
| UA (1) | UA48152C2 (ru) |
| WO (1) | WO1996018637A1 (ru) |
| YU (1) | YU49314B (ru) |
| ZA (1) | ZA959320B (ru) |
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| US5637688A (en) * | 1994-12-13 | 1997-06-10 | Eli Lilly And Company | Process for preparing 1-(2'-deoxy-2'-difluoro-d-ribofuranosyl)-4-aminopyrimidin-2-one hydrochloride |
| EP0870506A1 (en) * | 1997-04-11 | 1998-10-14 | Eli Lilly And Company | Compositions comprising a cryptophycin compound in combination with a synchronizing or activating agent for treating cancer |
| CA2315693C (en) * | 1997-12-22 | 2010-11-30 | Schering Corporation | Combination of benzocycloheptapyridine compounds and antineoplastic drugs for treating proliferative diseases |
| US6376470B1 (en) | 1999-09-23 | 2002-04-23 | Enzon, Inc. | Polymer conjugates of ara-C and ara-C derivatives |
| WO2002028387A1 (en) * | 2000-10-03 | 2002-04-11 | Oncopharmaceutical, Inc. | Inhibitors of angiogenesis and tumor growth for local and systemic administration |
| WO2005014010A1 (en) * | 2003-07-24 | 2005-02-17 | Eli Lilly And Company | Pharmaceutical composition comprising gemcitabine and cyclodextrines |
| US7214791B2 (en) * | 2004-07-01 | 2007-05-08 | Shenzhen Hande Technology Co., Ltd. | Method for preparation of 2′-deoxy-2′, 2′-difluoro-β-cytidine or pharmaceutically acceptable salts thereof by using 1,6-anhydro-β-d-glucose as raw material |
| EP1812457A1 (en) * | 2004-07-30 | 2007-08-01 | Pharmaessentia Corp. | STEREOSELECTIVE SYNTHESIS OF ß-NUCLEOSIDES |
| WO2006070985A1 (en) * | 2004-12-30 | 2006-07-06 | Hanmi Pharm. Co., Ltd. | METHOD FOR THE PREPARATION OF 2#-DEOXY-2#,2#-DIFLUOROCYTIDINE |
| JP2008531680A (ja) * | 2005-03-04 | 2008-08-14 | ダブール・ファーマ・リミテッド | βアノマーが富化された２１−デオキシ−２１，２１−ジフルオロ−Ｄ−リボフラノシルヌクレオシドの調製のための中間体と方法 |
| WO2006095359A1 (en) * | 2005-03-10 | 2006-09-14 | Sms Pharmaceuticals Limited | Synthesis of 2-deoxy-2, 2-di fluoro-d-ribo furanose-3, 5 di(4-methy/4-nitro-chloro)benzoate and its conversion to gemcitabine hydrochloride thereof |
| WO2006119347A1 (en) * | 2005-05-02 | 2006-11-09 | Pharmaessentia Corp. | STEREOSELECTIVE SYNTHESIS OF β-NUCLEOSIDES |
| CN100391966C (zh) * | 2005-06-17 | 2008-06-04 | 华东师范大学 | 一种2’-脱氧-2’，2’-二氟-胞苷合成的方法 |
| EP1940859A1 (en) * | 2005-10-28 | 2008-07-09 | Arch Pharmalabs Limited | An improved process for preparation of gemcitabine hydrochloride |
| KR101259637B1 (ko) * | 2005-12-14 | 2013-04-30 | 주식회사종근당 | 1-(2´-데옥시-2´,2´-디플루오로-디-리보푸라노실)-4-아미노피리미딘-2-온또는 그의 염산염의 제조방법 |
| US20090069354A1 (en) * | 2007-09-12 | 2009-03-12 | Protia, Llc | Deuterium-enriched gemcitabine |
| JO2778B1 (en) | 2007-10-16 | 2014-03-15 | ايساي انك | Certain vehicles, installations and methods |
| AU2008323923A1 (en) * | 2007-11-06 | 2009-05-14 | Pharmaessentia Corporation | Novel synthesis of beta-nucleosides |
| IT1393062B1 (it) * | 2008-10-23 | 2012-04-11 | Prime Europ Therapeuticals | Procedimento per la preparazione di gemcitabina cloridrato |
| ES2628609T3 (es) * | 2009-04-06 | 2017-08-03 | Otsuka Pharmaceutical Co., Ltd. | Combinación de fármacos antineoplásicos a base de citidina con inhibidor de citidina deaminasa y uso del mismo en el tratamiento de cáncer |
| US8324180B2 (en) * | 2009-04-06 | 2012-12-04 | Eisai Inc. | Compositions and methods for treating cancer |
| CA2757744C (en) * | 2009-04-06 | 2018-02-13 | Eisai Inc. | Combination of decitabine with cytidine deaminase inhibitor and use thereof in the treatment of cancer |
| US8609631B2 (en) | 2009-04-06 | 2013-12-17 | Eisai Inc. | Compositions and methods for treating cancer |
| CN101525361B (zh) * | 2009-04-21 | 2010-11-17 | 济南圣鲁金药物技术开发有限公司 | 基于吉西他滨结构的前药及其合成方法及应用 |
| EP2431376B2 (en) * | 2009-05-15 | 2024-02-07 | Delta-Fly Pharma, Inc. | Novel stable crystal of 1-(2'-cyano-2'-deoxy-beta -d-arabinofuranosyl)cytosine monohydrochloride |
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| CN102453064B (zh) * | 2011-06-30 | 2014-07-09 | 江苏豪森药业股份有限公司 | 制备吉西他滨盐酸盐的方法 |
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-
1994
- 1994-12-13 US US08/355,372 patent/US5637688A/en not_active Expired - Lifetime
-
1995
- 1995-11-01 AR AR33407495A patent/AR001041A1/es unknown
- 1995-11-02 IL IL11585295A patent/IL115852A/xx not_active IP Right Cessation
- 1995-11-02 PE PE1995283631A patent/PE49296A1/es not_active IP Right Cessation
- 1995-11-03 ZA ZA959320A patent/ZA959320B/xx unknown
- 1995-11-09 DK DK95308030T patent/DK0719788T3/da active
- 1995-11-09 AT AT95308030T patent/ATE179986T1/de active
- 1995-11-09 DE DE69509624T patent/DE69509624T2/de not_active Expired - Lifetime
- 1995-11-09 SI SI9530272T patent/SI0719788T1/xx unknown
- 1995-11-09 ES ES95308030T patent/ES2130542T3/es not_active Expired - Lifetime
- 1995-11-09 EP EP95308030A patent/EP0719788B1/en not_active Expired - Lifetime
- 1995-11-10 CO CO95053319A patent/CO4520286A1/es unknown
- 1995-11-13 YU YU70895A patent/YU49314B/sh unknown
- 1995-11-14 NZ NZ296476A patent/NZ296476A/xx not_active IP Right Cessation
- 1995-11-14 KR KR1019970703880A patent/KR100424991B1/ko not_active IP Right Cessation
- 1995-11-14 WO PCT/US1995/014864 patent/WO1996018637A1/en active IP Right Grant
- 1995-11-14 JP JP8518835A patent/JPH10510806A/ja active Pending
- 1995-11-14 CN CN95196792A patent/CN1047177C/zh not_active Expired - Fee Related
- 1995-11-14 RO RO97-01060A patent/RO117327B1/ro unknown
- 1995-11-14 TW TW084112041A patent/TW379226B/zh not_active IP Right Cessation
- 1995-11-14 HU HU9800673A patent/HU219021B/hu not_active IP Right Cessation
- 1995-11-14 BR BR9509979A patent/BR9509979A/pt not_active Application Discontinuation
- 1995-11-14 UA UA97062781A patent/UA48152C2/ru unknown
- 1995-11-14 PL PL95321046A patent/PL181732B1/pl unknown
- 1995-11-14 RU RU97111801/04A patent/RU2154648C2/ru not_active IP Right Cessation
- 1995-11-14 AU AU41101/96A patent/AU689674B2/en not_active Ceased
- 1995-11-14 CZ CZ19971798A patent/CZ290941B6/cs not_active IP Right Cessation
- 1995-11-16 MY MYPI95003490A patent/MY112488A/en unknown
-
1997
- 1997-04-11 US US08/837,071 patent/US5808048A/en not_active Expired - Lifetime
- 1997-06-10 BG BG101591A patent/BG62738B1/bg unknown
- 1997-06-11 NO NO972679A patent/NO306783B1/no not_active IP Right Cessation
-
1999
- 1999-05-19 GR GR990401358T patent/GR3030265T3/el unknown
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