CN1148044A - 7-[(2-羰基烷氧基-1-甲基乙烯基)氨基]-3-羟基甲基-3-头孢烯-4-羧酸的制备和应用 - Google Patents
7-[(2-羰基烷氧基-1-甲基乙烯基)氨基]-3-羟基甲基-3-头孢烯-4-羧酸的制备和应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
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Abstract
本发明涉及在水溶液介质中由3-羟基甲基-3-头孢烯-4-羧酸生产3-链烷酰氧基甲基-3-头孢烯-4-羧酸的方法以用于大规模实际生产。而且,本发明还为本方法提供一理想的中间体。
Description
本发明涉及在水溶液介质中由3-羟基甲基-3-头孢烯-4-羧酸生产3-链烷酰氧基甲基-3-头孢烯-4-羧酸的方法以用于大规模实际生产。而且,本发明还为本方法提供一理想的中间体。
Newton和Abraham首先分离出抗菌化合物头孢菌素C(Na-ture,175:548,1955)。头孢菌素C是由发酵得到,一般是用有机体头孢菌属支顶孢属。
7-氨基头孢菌素酸(7-ACA)式1,是合成许多头孢菌素抗菌素的一种重要的中间体。通常,可由头孢菌素C的与7-氨基取代基连接的酰基经化学断裂后得到,
脱乙酰基头孢菌素C是发酵过程的主要副产物,它可在头孢菌素C转化为7-ACA过程中转化为脱乙酰7-ACA,式2。在生产7-ACA中的一个问题是产生这些副产物,美国专利5,221,739和4,908,444提供了可能解决这一问题的方法。更具体讲,它们提出在水溶液介质中将3-羟甲基-3-头孢烯-4-羧酸直接再酰化。
本发明涉及在水溶液介质中由脱乙酰基7-ACA生产7-氨基头孢菌素酸的实用的大规模生产方法。而且,本发明还为此方法提供一理想的中间体。
在游离氨基存在下,羟基的选择酰化一般需要对氨基加以保护。保护基的选择随每种应用而不同,但一般来说,要求保护基容易连接和产率高,能防止同氨基出现不希望的反应,并能很容易地除去和产率高。在许多情况下,在选择最好为保护基时,这些考虑需加以平衡。
对胺类的最通用的保护基是烷氧基羰基,或氨基甲酸酯,特别是,常用苄氧羰基(CBE)和叔丁氧羰基(BOC)这两种。不太常用的保护基是酰基(形成酰胺)、亚烷基(形成亚胺或西佛碱)、水合氢离子(形成盐)、磺酰基(形成氨磺酰),或在某些情况下,甲硅烷基(形成叠氮硅烷)或三苯甲基(形成三苯甲胺)。一般来说,这些不太常用的保护基容易连接,但常缺少足够的保护能力并容易除去。一般来说,善于防止胺的不希望反应的保护基常难于除去,容易除去的保护基常不能提供足够的保护。
在探讨化合物2的氨基的理想保护基中我们发现,将胺作烯胺保护起来,即具有容易连接又容易除去的双重优点,并适于大规模生产,化合物2同乙酰乙酸烷基酯反应得到高产率的过去未知的通式3的烯胺,通式3的化合物可选择地同乙酸酐反应生成通式4的化合物,后者随后可通过酸水解转化为7-ACA。过去,烯胺曾偶然地用于氨基酸和头孢菌素的7-氨基的N-保护,例如,参见P.H.Bentley et al.,Tetrahedron Letters No.41,pp3739-3741(1976),但在本发明中其被使用的能力令人吃惊,特别是,由于Isamu et al,在日本专利公开7825,589(化学文摘Vol89:109529t)中谈到,用酰氯酰化带7-氨基的头孢菌素衍生得到烯胺会生成N-酰化产物,说明烯胺不会防止氮上的酰化。
下面流程说明本发明的方法。在此流程中,在化合物3和4中用~表示的键是指E或Z异构体,R是C1-6烷基,优选为甲基或乙基。步骤(a):步骤(a)需要碱或碱混合物。碱可以是任何无机或有机碱,其pKa值在4-14之间。有机碱指三C1-6烷基胺、吡啶、二甲基氨基吡啶等。MT指优选的碱,其中M是碱金属或碱土金属,优选是钠或钾;T包括碱或碱土金属的氢氧化物,醋酸盐、碳酸盐、碳酸氢盐、磷酸盐。较优选的碱是氢氧化钠或氢氧化钾,或醋酸钠或醋酸钾。在步骤(a)中用过量的乙酰乙酸烷基酯最好,所以使用这种试剂作为溶剂是很方便的,使用或不用其它有机辅助溶剂。此反应优选在无水条件下进行。步骤(a)的可能的温度范围为0°-55℃。当然,优选的温度取决于碱和溶剂的选择。步骤(b):可用作步骤(b)的溶剂***是单独的水或水同有机溶剂的混合物。所要使用的作用物与所用碱的溶解需要一些水,但水也会和作用物竞争醋酸酐,所以水的用量应尽量少。优选的溶剂体系是丙酮溶于水的50%水溶液。步骤(b)需要碱或碱的混合物。无机碱和有机碱都可用。然而,无机碱优于有机碱,因为用叔胺碱会产生较多量的不希望的副产物(内酯)。能够使用的普通碱包括碱金属或碱土金属的氢氧化物,二甲基氨基吡啶等,反应的pH应保持在7-11,优选为9-10。优选的温度范围是-10-40℃,更为优选的是0-5℃。步骤(c):反应混合物的最终的pH应通过加入酸调至3-4。各种酸可用于步骤(c);可以是无机酸,如盐酸、溴化氢、碘化氢;或对-甲苯磺酸等,优选的最终pH是3.5。在调节pH和分离产物时,将温度优选保持在-10-40℃,更优选的是0-5℃。
这里所用的C1-6烷基是指具有1-6个碳原子的直链或支链的饱和碳链;实施例包括甲基、乙基、正-丙基、异丙基、正-丁基、叔丁基、仲丁基、异丁基、正戊基、仲戊基、异戊基和正己基。碱金属是指周期表IA族金属,优选为锂、钠和钾。碱土金属是指周期表IIA族的金属,优选是钙和镁。
下面的具体的实施例可说明本发明,但不应限制本发明。这些方法可以加以修改以生产本发明所包括的化合物,而不会偏离本发明的主旨。而且,以稍为不同的方式生产相同化合物的各种方法的变化对熟悉此技术的人也是明白的。
在-500毫升的三颈圆底烧瓶中,将脱乙酰基-7-氨基头孢菌素酸(20.0克,0.0837摩尔)借助在0°-5℃下剧烈搅拌而悬浮在甲醇(140毫升)中。在约一小时内缓慢加入KOH(5.36克,0.0830摩尔)在甲醇(60毫升)中的溶液,将反应混合物在0°-5℃搅拌30分钟。在0°-5℃下的2-3分钟内以稳定的液流将得到的稀悬浮液加到乙酰乙酸甲酯(100毫升)中。将得到的混合物在0℃搅拌3.5-4小时。然后在减压下除去甲醇,所得到的湿残留物在0°-5℃于醋酸乙酯(100毫升)中搅拌一小时。然后通过真空过滤收集固体,并用醋酸乙酯(2×20毫升)洗滤饼。随之在40℃下真空干燥滤饼,得到约25.48克(80.1%)的7-〔2-羰基甲氧基-1-甲基乙烯)氨基〕-3-羟甲基-3-头孢烯-4-羧酸钾盐。
实施例2由7-〔2-羰基甲氧基-1-甲基乙烯基)氨基〕-3-羟甲基-3-头孢烯-4-羧酸钾盐制备7-氨基头孢菌素酸
在0°-5℃在搅拌下将7-〔2-羰基甲氧基-1-甲基乙烯)氨基-3-羟甲基-3-头孢烯-4-羧酸钾盐(10.00克,0.0273摩尔)溶于丙酮(25毫升)和水(25毫升)中,并在pH 9-10下加入二甲基氨基吡啶(33毫克,0.27毫摩尔)。然后在约15分钟内逐滴加入醋酸酐(6.44毫升,0.0682摩尔),同时通过定时加入20%的KOH将pH保持在9-10。在这些条件下将反应搅拌30分钟,加入醋酸乙酯(10毫升)。在0°-5℃下通过加入6N的盐酸使pH降至3.5。所得到的淤浆搅拌1小时。然后经真空过滤收集固体,并用丙酮(15毫升)洗固体。固体饼在真空下40℃干燥,得到约7.00克(94.2%)的7-氨基头孢菌素酸。
Claims (9)
1.下面通式的化合物
式中M是选自周期表Ia或IIa族的金属,R是C1-6烷基。
2.权利要求1的化合物,式中R是甲基或乙基,M是钾或钠。
3.权利要求2的化合物,式中R是甲基,M是钾。
5.权利要求4的方法,式中M是钾或钠,R是甲基或乙基。
6.权利要求5的方法,式中M是钾,R是甲基。
8.权利要求7的方法,其中R是甲基或乙基,M是钾或钠。
9.权利要求8的方法,其中R是甲基,M是钾。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/438,322 US5552542A (en) | 1995-05-10 | 1995-05-10 | Preparation and use of 7-[(2-carboalkoxy-1-methylethenyl)amino]-3-hydroxymethyl-3-cephem-4-carboxylic acids |
US438322 | 1995-05-10 | ||
US438,322 | 1995-05-10 |
Publications (2)
Publication Number | Publication Date |
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CN1148044A true CN1148044A (zh) | 1997-04-23 |
CN1055692C CN1055692C (zh) | 2000-08-23 |
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Application Number | Title | Priority Date | Filing Date |
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CN96106218A Expired - Fee Related CN1055692C (zh) | 1995-05-10 | 1996-05-09 | 7-[(2-羰基烷氧基-1-甲基乙烯基)氨基]-3-羟基甲基-3-头孢烯-4-羧酸的制备和应用 |
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US (2) | US5552542A (zh) |
EP (1) | EP0742219B1 (zh) |
JP (1) | JPH08301874A (zh) |
KR (1) | KR960041184A (zh) |
CN (1) | CN1055692C (zh) |
AT (1) | ATE203540T1 (zh) |
AU (1) | AU697524B2 (zh) |
CA (1) | CA2173829A1 (zh) |
DE (1) | DE69614030T2 (zh) |
ES (1) | ES2158971T3 (zh) |
HU (1) | HUP9601246A3 (zh) |
IL (1) | IL118038A (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US5917032A (en) * | 1997-10-30 | 1999-06-29 | Bristol-Myers Squibb Company | Chemical acetylation of desacetyl-cephalosporins |
JP2016537965A (ja) | 2013-10-11 | 2016-12-08 | ジェネンテック, インコーポレイテッド | Nsp4阻害剤及び使用方法 |
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DK159154C (da) * | 1975-02-24 | 1991-02-11 | Takeda Chemical Industries Ltd | Fremgangsmaade til fremstilling af cephalosporinderivater eller salte deraf |
JPS5325589A (en) * | 1976-08-03 | 1978-03-09 | Toyama Chem Co Ltd | Novel process for preparation of penicillins and cephalosporins |
JPS5687584A (en) * | 1979-12-20 | 1981-07-16 | Nikken Kagaku Kk | Preparation of 7-methoxycephem compound |
JPS5690089A (en) * | 1979-12-25 | 1981-07-21 | Nikken Kagaku Kk | Synthesis of 7-methoxycephem compound |
JPS56150095A (en) * | 1980-04-24 | 1981-11-20 | Nikken Kagaku Kk | Preparation of 7-methoxy-7-acylaminocephem compound |
JPS5758690A (en) * | 1980-09-25 | 1982-04-08 | Nikken Kagaku Kk | Preparation of 7-amino-7alpha-methoxycephem compound |
JPS57188595A (en) * | 1981-05-14 | 1982-11-19 | Meiji Seika Kaisha Ltd | 7alpha-methoxycephem compound and its preparation |
US4584371A (en) * | 1984-03-01 | 1986-04-22 | The Upjohn Company | Catalytic process for preparing 3-ester-methyl cephalosporins from desacetyl-7-aminocephalosporanic acid |
US4908444A (en) * | 1986-01-23 | 1990-03-13 | Takeda Chemical Industries, Ltd. | Method of producing cephem compounds |
US5221739A (en) * | 1992-01-09 | 1993-06-22 | Eli Lilly And Company | Acetylation of 3-hydroxymethyl cephalosporins |
-
1995
- 1995-05-10 US US08/438,322 patent/US5552542A/en not_active Expired - Lifetime
-
1996
- 1996-04-05 US US08/628,426 patent/US5637694A/en not_active Expired - Lifetime
- 1996-04-10 CA CA002173829A patent/CA2173829A1/en not_active Abandoned
- 1996-04-26 IL IL11803896A patent/IL118038A/xx not_active IP Right Cessation
- 1996-05-07 AT AT96107189T patent/ATE203540T1/de not_active IP Right Cessation
- 1996-05-07 EP EP96107189A patent/EP0742219B1/en not_active Expired - Lifetime
- 1996-05-07 ES ES96107189T patent/ES2158971T3/es not_active Expired - Lifetime
- 1996-05-07 DE DE69614030T patent/DE69614030T2/de not_active Expired - Lifetime
- 1996-05-08 KR KR1019960014943A patent/KR960041184A/ko not_active Application Discontinuation
- 1996-05-09 CN CN96106218A patent/CN1055692C/zh not_active Expired - Fee Related
- 1996-05-09 JP JP8114855A patent/JPH08301874A/ja active Pending
- 1996-05-09 AU AU52175/96A patent/AU697524B2/en not_active Ceased
- 1996-05-09 HU HU9601246A patent/HUP9601246A3/hu unknown
Also Published As
Publication number | Publication date |
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DE69614030D1 (de) | 2001-08-30 |
ES2158971T3 (es) | 2001-09-16 |
DE69614030T2 (de) | 2002-05-29 |
IL118038A (en) | 2000-01-31 |
HU9601246D0 (en) | 1996-07-29 |
HUP9601246A3 (en) | 2001-04-28 |
CA2173829A1 (en) | 1996-11-11 |
AU697524B2 (en) | 1998-10-08 |
ATE203540T1 (de) | 2001-08-15 |
KR960041184A (ko) | 1996-12-19 |
US5552542A (en) | 1996-09-03 |
AU5217596A (en) | 1996-11-21 |
US5637694A (en) | 1997-06-10 |
HUP9601246A2 (en) | 1997-02-28 |
IL118038A0 (en) | 1996-08-04 |
CN1055692C (zh) | 2000-08-23 |
EP0742219A1 (en) | 1996-11-13 |
JPH08301874A (ja) | 1996-11-19 |
EP0742219B1 (en) | 2001-07-25 |
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