CN1522235A - 制备无定形西司他汀钠的方法 - Google Patents
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- 229960003716 cilastatin sodium Drugs 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 239000002904 solvent Substances 0.000 claims description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 239000012296 anti-solvent Substances 0.000 claims description 13
- 229960004912 cilastatin Drugs 0.000 claims description 13
- DHSUYTOATWAVLW-WFVMDLQDSA-N cilastatin Chemical compound CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O DHSUYTOATWAVLW-WFVMDLQDSA-N 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 5
- 230000008021 deposition Effects 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 18
- 239000002002 slurry Substances 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000011345 viscous material Substances 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 235000011121 sodium hydroxide Nutrition 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- -1 2-amino-2-carboxy ethyl Chemical group 0.000 description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GJCSXQWYMSOSDU-UHFFFAOYSA-N 2-aminohept-2-enoic acid Chemical compound CCCCC=C(N)C(O)=O GJCSXQWYMSOSDU-UHFFFAOYSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KIDXYAWWICJAFK-UHFFFAOYSA-N O.[Na].OC Chemical compound O.[Na].OC KIDXYAWWICJAFK-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000027950 fever generation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000005389 magnetism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000004493 neutrocyte Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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Abstract
本发明涉及无定形西司他汀钠的制造方法，该方法费用低且在工业上是有利的。
Description
发明领域
本发明涉及无定形西司他汀钠的制造方法，该方法费用低且在工业上是有利的。
发明背景
西司他汀钠是衍生的庚烯酸的钠盐，其化学名称是[R-[R*，S*-(Z)]]-7-[(2-氨基-2-羧基乙基)硫代]-2-[[(2，2-二甲基环丙基)羰基]氨基-2-庚烯酸单钠盐，它有结构式I所示的结构。
式I
原型碳青霉烯抗菌剂亚胺培南具有式II的结构，
式II
它具有非常广谱的抗菌活性。它与肾脱氢肽酶抑制剂西司他汀一起施用以防止临床使用时它被肾脏代谢。亚胺培南/西司他汀钠组合物是有效的肌肉内用药的广谱抗菌剂。它对败血病、中性粒细胞减少性发热以及腹内、下呼吸道、泌尿生殖器、妇科、皮肤和软组织感染和骨骼及关节感染是一种有效的单一疗法。在这些适应症中，亚胺培南/西司他汀与广谱头孢菌素和其它碳青霉烯通常有类似的效果。
美国专利5,147,868揭示了西司他汀钠，其中描述了获得无定形西司他汀钠的冻干技术。除冻干技术外，还没有其它现有技术描述制造无定形西司他汀钠的方法。用于工业领域时冻干技术不是令人满意的技术/方法。它需要大量溶剂和资金投入以得到冻干所需的基本技术设施，从经济角度看，这一方法没有太大吸引力，且它不适合大规模生产。
发明概要
本发明的目的是提供一种商业上可行的制造无定形西司他汀钠的方法，该方法非常易于在商业规模上操作且不需要使用冻干这种的资金密集型技术。
由此，本发明提供了一种制造纯净形式的无定形西司他汀钠的方法，该方法包括通过溶剂沉淀从其溶液中回收西司他汀钠，所述溶液含有有机溶剂、有机溶剂的均匀混合物或有机溶剂和水的均匀混合物。
用来回收西司他汀钠的溶液是通过将粗制西司他汀钠溶于溶剂获得的，或获自含有已溶解的粗制西司他汀钠的反应混合物。术语“溶剂”用在这里包括有机溶剂、有机溶剂的均匀混合物或有机溶剂和水的均匀混合物。无定形形式的西司他汀钠是通过加入合适的对钠盐的反溶剂(anti-solvent)，或通过将溶于溶剂的粗制西司他汀钠溶液加到反溶剂中，并通过溶剂沉淀、分离和干燥产物而回收的。
通常，可用此领域已知的任何标准方法来分离产物，如过滤、离心或倾析。通常，当使用该方法范围内的任何溶剂时都可通过过滤来分离产物。
或者，将西司他汀游离酸悬浮于溶剂，尤其是水或甲醇中，并在溶剂中加入氢氧化钠在溶剂中的溶液，优选是水溶液或甲醇溶液，以得到澄清溶液，用这种方法也可获得西司他汀钠。在以水作为溶剂的情况下将所得澄清溶液浓缩，，以得到粘性的含有粗制西司他汀钠的物质。再将粘性物质溶于溶剂，优选甲醇，在真空下将其浓缩以除去痕量的水并再次得到含有粗制西司他汀钠的粘性物质。
所述溶剂选自可溶解西司他汀钠的溶剂，其中包括甲醇。合适的反溶剂可以是任何西司他汀钠不溶于其中但可与溶解西司他汀钠的溶剂混溶的溶剂。在本发明优选的实施方案中，所述溶剂是甲醇，反溶剂是丙酮。
更具体的，将粗制西司他汀钠溶于甲醇并在所得溶液中加入丙酮，或者将所得溶液加到丙酮中，温度为0℃-50℃，优选25-30℃以得到浆液。在真空下蒸馏此浆液以在减压下回收一定量的溶剂，同时在加入新鲜反溶剂丙酮后在室温下通过过滤回收产物。
过滤操作快且平稳，它是用真空吸滤过滤(nutsche filtration)或离心过滤进行的。优选在大规模操作时采用真空吸滤过滤。将滤出的物质，一种半干粉末，在真空盘式干燥机、盘式烘干机、流化床干燥机或旋转式真空干燥机中进一步干燥以除去表面的溶剂，以得到无定形物质。优选地，将所述物质在真空盘式干燥机中以20℃-约80℃的温度干燥约6-24小时。更优选地，干燥在35-约40℃下进行约8小时。
通常，在室温下将西司他汀钠溶于溶剂，如甲醇，其浓度为约20％w/v-约80％w/v，优选为约30％w/v-约60％w/v。
反溶剂的体积可以是加入的西司他汀重量的约5-100倍。优选的是，所用反溶剂的体积是加入的西司他汀重量的约20-60倍。
按本发明方法制造的无定形西司他汀钠，通过X-射线衍射图(图1)表征，显示它具有无定形性质。
发明详述
通过以下实施例阐述了本发明，这些实施例不能理解为以任何方式限制本发明的有效范围。
实施例1
(A)制备粗制西司他汀钠
在约25-30℃下，在西司他汀游离酸(15gm)的水(80ml)悬液中加入2N氢氧化钠水溶液，以将pH调至约7.35。在真空下浓缩所得澄清溶液以除去水得到粘性物质。将所得粘性物质溶于甲醇(150ml)以得到澄清溶液，将此溶液在真空下浓缩以得到粘性残余物。
(B)制备无定形西司他汀钠
将所得粗制的西司他汀钠溶于甲醇(30ml)，边搅拌边并将此溶液加入丙酮(300ml)。在真空下浓缩所得浆液以回收约100ml溶剂。在浆液中加入新鲜的丙酮(100ml)并在20-25℃下搅拌约30分钟。滤出分离的固体，用丙酮(75ml)洗涤并于35-40℃下在真空中干燥产物以得到干燥的无定形西司他汀钠(15.5gm，色谱纯度；98.96％；pH：6.94)。
实施例2
(A)制备粗制西司他汀钠
将西司他汀(5gm)悬浮于甲醇(15ml)，并搅拌边在其中缓慢加入氢氧化钠甲醇溶液(将0.558gm氢氧化钠溶于15ml甲醇制成)以得到澄清溶液。
(B)制备无定形西司他汀钠
边搅拌边在所得溶液中加入丙酮(300ml)以得到浆液，将此浆液在25-30℃下搅拌约30分钟。滤出分离的固体并用丙酮(100ml)洗涤。在35-40℃下在真空中干燥以得到干燥的无定形西司他汀钠(5gm，色谱纯度：99％)。
由于用特定的实施方案描述了本发明，精通这一技术的技术人员可以对它进行修改和等效改变，这应理解为包括在本发明的范围之内。
Claims (15)
1.制造无定形纯净的西司他汀钠的方法，其特征在于，所述方法包括通过溶剂沉淀从其溶液中回收西司他汀钠，所述溶液含有有机溶剂、有机溶剂的均匀混合物或有机溶剂和水的均匀混合物。
2.如权利要求1所述的方法，其特征在于，所述方法包括通过在溶于溶剂的西司他汀钠溶液中加入反溶剂以回收纯净的无定形的西司他汀钠。
3.如权利要求1所述的方法，其特征在于，所述方法包括通过将西司他汀钠溶液加到反溶剂中以回收纯净的无定形的西司他汀钠。
4.如权利要求1所述的方法，其特征在于，所述西司他汀钠溶液是通过将粗制西司他汀钠溶于溶剂而获得的，或者直接获自反应混合物。
5.如权利要求1所述的方法，其特征在于，所述溶剂有溶解西司他汀钠的特性。
6.如权利要求5所述的方法，其特征在于，所述溶剂是甲醇。
7.如权利要求2所述的方法，其特征在于，所述反溶剂是丙酮。
8.如权利要求1所述的方法，其特征在于，所述西司他汀钠是通过使西司他汀游离酸与氢氧化钠反应获得的。
9.如权利要求8所述的方法，其特征在于，所述西司他汀钠是通过使悬浮于水的西司他汀游离酸与氢氧化钠水溶液反应获得的。
10.如权利要求9所述的方法，其特征在于，所述氢氧化钠水溶液浓度为2N，
11.如权利要求8所述的方法，其特征在于，所述西司他汀钠是通过使悬浮于甲醇的西司他汀游离酸与氢氧化钠的甲醇溶液反应获得的。
12.如权利要求5所述的方法，其特征在于，所述西司他汀钠溶于溶剂，浓度为约20％w/v-约80％w/v。
13.如权利要求12所述的方法，其特征在于，所述西司他汀钠溶于溶剂，浓度为约30％w/v-60％w/v。
14.如权利要求2或3所述的方法，其特征在于，所述反溶剂的体积约为加入的西司他汀重量的5-100倍。
15.如权利要求14所述的方法，其特征在于，所述反溶剂的体积约为加入的西司他汀重量的20-60倍。
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| EP2402312B1 (en) | 2005-11-09 | 2013-07-17 | Orchid Chemicals&Pharmaceuticals Limited | An improved process for the preparation of cilastatin acid |
| WO2011080648A1 (en) * | 2010-01-01 | 2011-07-07 | Orchid Chemicals And Pharmaceuticals Limited | An improved process for the preparation of cilastatin sodium |
| CN102675175B (zh) * | 2011-03-08 | 2014-02-19 | 深圳市海滨制药有限公司 | 一种西司他丁的分离纯化方法 |
| US11324804B2 (en) | 2016-11-18 | 2022-05-10 | Sepsia Therapeutics, S.L. | Combined CD6 and imipenem therapy for treatment of infectious diseases and related inflammatory processes |
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|---|---|---|---|---|
| US5147868A (en) * | 1978-07-24 | 1992-09-15 | Merck & Co., Inc. | Thienamycin renal peptidase inhibitors |
| US4292436A (en) * | 1980-06-25 | 1981-09-29 | Merck & Co., Inc. | Process for the preparation of N-protected N-formimidoyl 2-aminoethanethiol |
| EP0441371B1 (en) * | 1990-02-08 | 1995-01-25 | Sumitomo Chemical Company, Limited | Process for preparing haloketo acid derivatives |
| US5166417A (en) * | 1990-09-04 | 1992-11-24 | Lonza Ltd. | Process for resolution of racemates of 2,2-dimethylcyclopropanecarboxylic acid |
| CA2056840A1 (en) * | 1990-12-17 | 1992-06-18 | Thomas Meul | Process for the production of dimethylcyclopropanecarboxylic acid |
| DE59209523D1 (de) * | 1991-07-26 | 1998-11-19 | Lonza Ag | Gentechnologisches Verfahren zur Herstellung von S-(+)-2,2-Dimethylcyclopropancarboxamid mittels Mikroorganismen |
| US5245069A (en) * | 1992-10-27 | 1993-09-14 | Merck & Co., Inc. | Process for the preparation of bis(aryl)-phosphorohalidates |
| IN191798B (zh) * | 2000-11-03 | 2004-01-03 | Ranbaxy Lab Ltd |
-
2002
- 2002-05-17 BR BR0209843-1A patent/BR0209843A/pt not_active IP Right Cessation
- 2002-05-17 OA OA1200300301A patent/OA12607A/en unknown
- 2002-05-17 WO PCT/IB2002/001696 patent/WO2002094742A1/en not_active Application Discontinuation
- 2002-05-17 PL PL02367937A patent/PL367937A1/xx not_active Application Discontinuation
- 2002-05-17 CN CNA028131096A patent/CN1522235A/zh active Pending
- 2002-05-17 CA CA002447788A patent/CA2447788A1/en not_active Abandoned
- 2002-05-17 EP EP02727916A patent/EP1395530A4/en not_active Withdrawn
- 2002-05-17 EA EA200301225A patent/EA005947B1/ru not_active IP Right Cessation
- 2002-05-17 MX MXPA03010547A patent/MXPA03010547A/es not_active Application Discontinuation
- 2002-05-17 CZ CZ20033352A patent/CZ20033352A3/cs unknown
- 2002-05-17 HU HU0400825A patent/HUP0400825A2/hu unknown
- 2002-05-17 AP APAP/P/2003/002913A patent/AP1511A/en active
- 2002-05-17 IL IL15894502A patent/IL158945A0/xx unknown
- 2002-05-17 JP JP2002591417A patent/JP2004526805A/ja not_active Withdrawn
- 2002-05-17 AP APAP/P/2003/002912A patent/AP2003002912A0/en unknown
- 2002-05-17 KR KR10-2003-7015042A patent/KR20040044409A/ko not_active Application Discontinuation
- 2002-05-17 NZ NZ529625A patent/NZ529625A/en unknown
- 2002-05-17 US US10/478,081 patent/US20040152780A1/en not_active Abandoned
- 2002-05-17 SK SK1508-2003A patent/SK15082003A3/sk unknown
- 2002-05-17 EE EEP200300567A patent/EE200300567A/xx unknown
- 2002-05-20 AR ARP020101853A patent/AR036017A1/es not_active Application Discontinuation
-
2003
- 2003-11-18 NO NO20035138A patent/NO20035138D0/no not_active Application Discontinuation
- 2003-11-28 ZA ZA200309287A patent/ZA200309287B/en unknown
- 2003-12-12 BG BG108447A patent/BG108447A/xx unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| EA005947B1 (ru) | 2005-08-25 |
| MXPA03010547A (es) | 2004-05-27 |
| EA200301225A1 (ru) | 2004-06-24 |
| AR036017A1 (es) | 2004-08-04 |
| PL367937A1 (en) | 2005-03-07 |
| EE200300567A (et) | 2004-04-15 |
| EP1395530A1 (en) | 2004-03-10 |
| US20040152780A1 (en) | 2004-08-05 |
| SK15082003A3 (sk) | 2004-06-08 |
| NO20035138D0 (no) | 2003-11-18 |
| CA2447788A1 (en) | 2002-11-28 |
| BG108447A (en) | 2005-03-31 |
| AP2003002913A0 (en) | 2003-12-31 |
| OA12607A (en) | 2006-06-08 |
| CZ20033352A3 (en) | 2004-06-16 |
| HUP0400825A2 (hu) | 2004-08-30 |
| IL158945A0 (en) | 2004-05-12 |
| EP1395530A4 (en) | 2006-01-18 |
| BR0209843A (pt) | 2004-08-24 |
| HRP20031052A2 (en) | 2004-06-30 |
| KR20040044409A (ko) | 2004-05-28 |
| AP2003002912A0 (en) | 2002-05-17 |
| JP2004526805A (ja) | 2004-09-02 |
| ZA200309287B (en) | 2004-07-22 |
| NZ529625A (en) | 2006-02-24 |
| WO2002094742A1 (en) | 2002-11-28 |
| AP1511A (en) | 2005-12-20 |
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