CN1101395C - 头胞氨苄的回收方法 - Google Patents
头胞氨苄的回收方法 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
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P35/00—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin
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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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Abstract
从含头胞氨苄和7-ADCA的混合物回收头胞氨苄的方法，其中将pH大于7，头胞氨苄和7-ADCA的混合物调至pH值小于7.8，除了出现的任何固体头胞氨苄外，此混合物在pH7～8.5时是均匀的，然后回收出现的固体物质。本方法尤其适用于以苯基甘氨酸的衍生物作酰化剂，由7-ADCA的酶酰化反应后所得的反应混合物。这样可以简单的方式回收纯头胞氨苄。
Description
本发明涉及从含有头胞氨苄和7-氨基去乙酸基头胞菌素酸(7-ADCA)的混合物中回收头胞氨苄的方法。
当用以D-苯基甘氨酸衍生物酰化的7-ADCA制备头胞氨苄时，头胞氨苄的回收及反应混合物的加工处理通常较难。因此例如在WO-A-93/12250中所述的酰化反应从来不能完全，并且由于某些成分(尤其如US-A-4003896中所述的7-ADCA和苯基甘氨酸)的酸/碱特性和溶解度与其最终产物的没有多少不同，阻碍了终产物的最终纯化，所以发生共沉降而得到不纯的头胞氨苄。在WO-A-93/12250和US-A-4003896中，提出了采用如萘酚等配位剂是合适的，但是这带来了加入与本方法相异的另外物质的缺点。
本发明的目的是为了提供一种不需使用与本方法相异的有机物质，而使头胞氨苄得到纯化的简单方法。
根据本发明，达到此目的的方法是将pH大于7，含头胞氨苄和7-ADCA的混合物的pH值调至pH小于7.8的较低值，除了任何出现的固体物质，该混合物在pH7～8.5时是均匀的，然后回收出现的固体物质。
另一个从含有头胞氨苄和少量7-ADCA的混合物中分离纯头胞氨苄的方法，描述于JP-A-52111584中。根据此日本公布中所述方法，在有机溶剂，如二氯甲烷、二甲亚砜和低级醇的混合物中，当有一个如二异丙胺的碱性成分存在时，将含有头胞氨苄和7-ADCA的混合物重结晶。此方法也有必须加入与本方法相异物质的缺点。此外头胞氨苄在此纯化方法中发生18％的损失。
申请人发现，根据反应混合物的组成，通过降低混合物的pH值小于7.8，如5～7.8，尤其6.0～7.6，将头胞氨苄以纯度大于90，尤其大于98质量％结晶出来是可能的，既使混合物中存在大量7-ADCA，此后，可以回收头胞氨苄。反应混合物中除含头胞氨苄外，通常还含有其它有用的成分，如7-ADCA。为了得到一个工业上有吸引力的方法，尽量减少7-ADCA和头胞氨苄的损失也是很重要的。另外还发现，如果将该反应混合物的pH值逐渐调小至小于6.5，尤其是在1.5～5.5时，7-ADCA和剩余的头胞氨苄实际上完全结晶出来，此后可以例如通过过滤回收7-ADCA和头胞氨苄的混合物。所得的7-ADCA和头胞氨苄混合物能任选地再利用，这样就得到了生产纯头胞氨苄，而没有7-ADCA和头胞氨苄大量损失的一个方法。
在本发明方法的特定实施案例中，混合物的pH值首先降低至0～3.5，优选地0.5～2.5，接着上升至5～7.8，优选地6.0～7.6。
根据本发明，本方法尤其适用于由酶酰化反应而得的反应混合物的加工处理，其中7-ADCA用D-苯基甘氨酸酰胺(PGA)或D-苯基甘氨酸的酯酰化。这样，根据本发明，本方法例如可应用于通过连续过滤，用(固定化)酶分离而得到的起始混合物，此混合物是在pH值相对高时，如8～10，然后降低至7.0～8.5，进行酶酰化反应的反应混合物。如果需要，首先取决于在较高pH值7～8.5时酰化反应所形成的D-苯基甘氨酸(PG)的数量，可分离出基本上将主要由PG组成的最终固体物质，选择后面哪一个pH值，然后是根据混合物来选择这样使PG结晶出，而头胞氨苄不结晶出来。
在另一实施方案中，所用的起始混合物是在以相对低的pH值，如pH7～8.5，结束的酶酰化反应后，和取决于酰化反应中生成PG的量，对主要含固定化酶和D-苯基甘氨酸的固体物质进行分离后所得到的混合物。
在含7-ADCA和头胞氨苄的起始混合物中，存在大量的7-ADCA。7-ADCA的量多半小于7-ADCA与头胞氨苄总量的75mol％，优选2～60％，尤其5～50％。
在本发明的设计中可以几种方式降低pH值，如化学地加入酸，如无机酸，尤其硫酸，盐酸或硝酸。另一种可能例如是，如果在此酰化反应中已用PGA或者用PG的酯作酰化试剂，而且在酰化反应中用氨滴定，保持pH值稳定，则用物理方法除去氨来降低pH值。适合的物理除去方法如用蒸气或惰性气体气提；在低压下(蒸汽)蒸馏，尤其薄膜蒸发；在喷雾塔中蒸发；气膜分离或电渗析。
回收头胞氨苄的最佳pH值取决于此混合物的组成，选择最佳pH值使7-ADCA和头胞氨苄达到最佳分离。在实际中，最佳pH值是以下两个因素间的折衷：一是回收头胞氨苄的高纯度，其在相对高的pH值时回收头胞氨苄时达到，这样头胞氨苄仍部分在溶液中，7-ADCA仍完全在溶液中；二是高产率，其在相对低的pH值时回收头胞氨苄时达到，这样头胞氨苄实际上完全沉降，同时部分7-ADCA沉降。对于本领域的技术人员，确定某给定情况下的最佳pH值是容易的。
加工处理的温度大部分低于35℃，优选地0～30℃，尤其10～30℃。
根据本发明，结合进一步降低pH值后得到的7-ADCA和头胞氨苄的混合物的再循环来回收纯头胞氨苄的方法应用于用PGA使对7-ADCA的酶酰化后而得到的混合物，能对7-ADCA达到全面的高选择性，尤其是高于80％。主要含少量残余PGA的残余滤液可进一步任选加工处理，例如将其置于pH大于8，尤其8～10，回收沉降的PGA。如果需要，进一步浓缩和冷却至温度小于10℃，尤其0～8℃是可能的。用这种办法，就可获得7-ADCA和PGA均可高效应用的一个方法。在酶酰化反应中，例如PGA或PGA的酯可用作酰化剂。
原则上，在偶合反应中适于作催化剂的任何酶均可采用。这些酶例如通常是被命名为‘青霉素酰胺酶’和‘青霉素酰化酶’的酶。合适的酶的实例由下列酶衍生而来：醋酸杆菌属、气单胞菌属，产碱杆菌属，Aphanocladium，芽孢杆菌属
sp.，头孢霉属，埃希氏杆菌属，黄杆菌属，Kluyvera，
Mycoplana，
Protaminobacter，假单胞菌属和Xanthomonas，尤其是醋酸杆菌属
pasteurianum，产碱杆菌属
faecalis，芽孢杆菌属
megaterium，埃希氏杆菌属
coli和
Xanthomonas citrii。
优选采用固定化酶，因为此酶易于分离，然后再利用。固定化酶以此而闻名且商业上可得。合适的酶的实例为：Boehringer MannheimGmbH的商业名为‘Enzygel’的大肠杆菌，Recordati的固定化青霉素-G酰化酶，Pharma Biotechnology Hannover的固定化青霉素-G酰化酶，和如WO-A-92.12782中所述分离和如EP-A-222462中所述固定化的大肠杆菌青霉素酰化酶。
酶酰化反应大多数在温度低于35℃进行，优选在0～28℃，进行酶酰化反应时的pH值大多数在6-10，优选在6.5～9。
在实际中，酶酰化反应和反应混合物的加工处理大多数在水中进行。任选地，反应混合物还可含有机溶剂或有机溶剂混合物，优选小于30 vot％。可以使用的有机溶剂的实例为带1～7个碳原子的醇，例如单醇，尤其甲醇或乙醇；二醇，尤其1，2-亚乙基二醇或三醇，尤其甘三醇。
在本发明的设计中，各组分以游离形式或盐存在于反应混合物中。所指的pH值都是在室温时测定的pH值。
本发明将用以下实例进一步评价，但不限于此。缩写：CEX＝头胞氨苄CEX·H2O＝一水头胞氨苄7-ADCA＝7-氨基去乙酸基头胞菌素酸PGA＝D-苯基甘氨酸酰胺PG＝D-苯基甘氨酸
实施例I
550mM的PGA·1/2H2SO4与410mM 7-ADCA在5℃下，酶偶合后得到的混合物的加工处理。
将80g PGA·1/2H2SO4，64.2g 7-ADCA和425ml水的混合物冷却至5℃，然后用25ml 25wt.％的液态NH4OH调其pH值至7.6，将Recordati(Milan)得到的湿固定化青霉素-G-酰化酶190g，加至所得的悬浮液(‘进料’)中。此酶在水和甘三醇的混合物中商业可得(‘湿酶’)；使用前用100ml水洗涤三次。
反应混合物经搅拌2小时后(pH值现在升至8.35)，用G-3玻璃滤器过滤；滤渣用50ml水洗涤两次。此滤渣是酶与反应中形成的PG的混合物。
用浓硫酸(共4ml)小心酸化滤液(黄色溶液)至pH＝7.2。30分钟后过滤，用3×30ml的水洗涤，干燥。产生化学纯度(去水基础上)＞99.5％的CEX·H2O 40.8g。
CEX结晶母液再用浓硫酸(共3.7ml)酸化。搅拌17小时后，过滤，用3×20ml水洗涤，产生在去水基础上计算的固体物质30.2g，此固体物质含摩尔比60∶40的CEX和7-ADCA的混合物。
实施例II
500mM PGA和500mM 7-ADCA在5℃时的酶偶合，接着加工处理。
由75.0g游离PGA，109.2g 7-ADCA，10.0g PG和750ml水组成的进料，冷却至5℃，然后加入Recordati(Milaan)的湿酶青霉素-G酰化酶150g。(先洗涤)。5℃下搅拌2小时10分钟后，(用G-3玻璃滤器)过滤此混合物，并用1×100ml水洗涤。所得的滤液含以下组分：CEX＝328mmol7-ADCA＝161mmolPG＝75mmolPGA＝46mmol这样相对于7-ADCA转化率达66％。此混合物如下加工处理：通过旋转薄膜蒸发器在20℃蒸馏360ml(971.4g)总混合物(约45～60分钟)，然后加入360ml新鲜水，重复一次此操作，所得的悬浮液用G-3玻璃滤器过滤，滤渣用冷水(1×50ml)和丙酮(2×30ml)洗涤，接着干燥一夜。产量：57.0g白色物质；无水基础上的CEX含量＞99％。由CEX过滤的滤液(包括洗涤用水)再冷却至5℃，用12N液态硫酸酸化至pH＝4.5。悬浮液经2小时搅拌后，用G-3玻璃滤器过滤。产量：淡黄色物质78.4g(以无水基础上计算)；此物质含有以摩尔比75∶25的CEX和7-ADCA的混合物。
Claims (10)
1.从含头胞氨苄和7-氨基去乙酸基头胞菌素酸(7-ADCA)的混合物中回收头胞氨苄的方法，其特征在于将pH大于7，含头胞氨苄和7-ADCA的混合物的pH值调至pH5～7.8的较低值，除了出现的任何固体头胞氨苄外，此混合物在pH7～8.5时是均匀的，然后回收出现的固体物质。
2.根据权利要求1的方法，其特征在于将pH降低至6～7.6。
3.根据权利要求1或2的方法，其特征在于首先将pH值降低至0～3.5，接着升高pH值至6～7.6。
4.根据权利要求3的方法，其中将pH值降低至0.5～2.5。
5.根据权利要求1或2的方法，其特征在于起始混合物含有相对于7-ADCA和头胞氨苄总量计算的2～60mol％7-ADCA。
6.根据权利要求1或2的方法，其特征在于将剩余液相的pH降至小于6.5，然后回收出现的固体物质。
7.根据权利要求6的方法，其特征在于将剩余液相的pH降至1.5～5.5。
8.根据权利要求1或2的方法，其中头胞氨苄和7-ADCA的混合物是由pH值8～10时进行的酶酰化反应的反应混合物，通过降低pH值至7.0～8.5，和分离固体物质制备。
9.根据权利要求8的方法，其中首先从酰化反应所得的反应混合物中分离出现的固体物质。
10.根据权利要求1或2的方法，其中头胞氨苄和7-ADCA的混合物是由分离出现的固体物质，从pH7～8.5的酶酰化反应的反应混合物制备得来。
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BE9500081 | 1995-02-02 | ||
| BE9500081A BE1009071A3 (nl) | 1995-02-02 | 1995-02-02 | Werkwijze voor de bereiding van een beta-lactam antibioticum. |
| BE9500205A BE1009194A3 (nl) | 1995-03-09 | 1995-03-09 | Werkwijze voor de winning van cefalexine. |
| BE9500205 | 1995-03-09 | ||
| BE9500290 | 1995-03-31 | ||
| BE9500290A BE1009263A3 (nl) | 1995-03-31 | 1995-03-31 | Werkwijze voor de winning van cefalexine. |
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| Publication Number | Publication Date |
|---|---|
| CN1179779A CN1179779A (zh) | 1998-04-22 |
| CN1101395C true CN1101395C (zh) | 2003-02-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96192915A Expired - Lifetime CN1101395C (zh) | 1995-02-02 | 1996-02-01 | 头胞氨苄的回收方法 |
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| Country | Link |
|---|---|
| US (1) | US5874571A (zh) |
| EP (1) | EP0869961B1 (zh) |
| JP (1) | JPH11503408A (zh) |
| KR (1) | KR100439322B1 (zh) |
| CN (1) | CN1101395C (zh) |
| AT (1) | ATE204580T1 (zh) |
| AU (1) | AU4846196A (zh) |
| CZ (1) | CZ241997A3 (zh) |
| DE (1) | DE69614711T2 (zh) |
| ES (1) | ES2163002T3 (zh) |
| MX (1) | MX9705917A (zh) |
| PL (1) | PL321626A1 (zh) |
| WO (1) | WO1996023796A1 (zh) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2195024T3 (es) * | 1995-12-08 | 2003-12-01 | Dsm Ip Assets Bv | Procedimiento para la preparacion de antibioticos. |
| BE1010651A3 (nl) * | 1996-09-27 | 1998-11-03 | Dsm Nv | Werkwijze voor het zuiveren van cefalexine. |
| NL1007076C2 (nl) * | 1997-09-19 | 1999-03-22 | Dsm Nv | Werkwijze voor de winning van een ß-lactam antibioticum. |
| NL1007077C2 (nl) * | 1997-09-19 | 1999-03-22 | Dsm Nv | Werkwijze voor de winning van een ß-lactam antibioticum. |
| US20040033262A1 (en) * | 2002-08-19 | 2004-02-19 | Orchid Health Care | Sustained release pharmaceutical composition of a cephalosporin antibiotic |
| EP1761328A1 (en) * | 2004-06-30 | 2007-03-14 | DSMIP Assets B.V. | Product comprising a beta-lactam antibiotic |
| US20140200342A1 (en) | 2011-06-23 | 2014-07-17 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Process for preparing 3'-thiosubstituted cephalosporins employing a pencillin g acylase |
| CN103635586A (zh) | 2011-06-23 | 2014-03-12 | 中化帝斯曼制药有限公司荷兰公司 | 结晶头孢氧哌唑中间体、其制备方法及其制药用途 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4003896A (en) * | 1974-12-17 | 1977-01-18 | Novo Industri A/S | Method of preparing a sparingly soluble complex of cephalexin |
| WO1993012250A1 (en) * | 1991-12-19 | 1993-06-24 | Novo Nordisk A/S | AN IMPROVED METHOD FOR THE PREPARATION OF CERTAIN β-LACTAM ANTIBIOTICS |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1001615A (en) * | 1971-12-04 | 1976-12-14 | Takeda Chemical Industries Ltd. | Method for purification of cephalexin |
| JPS52111589A (en) * | 1976-03-16 | 1977-09-19 | Sangyo Kagaku Kenkyu Kyokai | Purification of antibiotics |
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1996
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- 1996-02-01 AU AU48461/96A patent/AU4846196A/en not_active Abandoned
- 1996-02-01 DE DE69614711T patent/DE69614711T2/de not_active Expired - Fee Related
- 1996-02-01 ES ES96904336T patent/ES2163002T3/es not_active Expired - Lifetime
- 1996-02-01 KR KR1019970705249A patent/KR100439322B1/ko not_active IP Right Cessation
- 1996-02-01 CZ CZ972419A patent/CZ241997A3/cs unknown
- 1996-02-01 JP JP8523436A patent/JPH11503408A/ja active Pending
- 1996-02-01 PL PL96321626A patent/PL321626A1/xx unknown
- 1996-02-01 AT AT96904336T patent/ATE204580T1/de active
- 1996-02-01 EP EP96904336A patent/EP0869961B1/en not_active Expired - Lifetime
- 1996-02-01 CN CN96192915A patent/CN1101395C/zh not_active Expired - Lifetime
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- 1997-07-31 US US08/903,879 patent/US5874571A/en not_active Expired - Lifetime
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4003896A (en) * | 1974-12-17 | 1977-01-18 | Novo Industri A/S | Method of preparing a sparingly soluble complex of cephalexin |
| WO1993012250A1 (en) * | 1991-12-19 | 1993-06-24 | Novo Nordisk A/S | AN IMPROVED METHOD FOR THE PREPARATION OF CERTAIN β-LACTAM ANTIBIOTICS |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH11503408A (ja) | 1999-03-26 |
| DE69614711D1 (de) | 2001-09-27 |
| KR100439322B1 (ko) | 2005-08-04 |
| AU4846196A (en) | 1996-08-21 |
| PL321626A1 (en) | 1997-12-08 |
| MX9705917A (es) | 1998-07-31 |
| KR19980701852A (ko) | 1998-06-25 |
| DE69614711T2 (de) | 2002-06-27 |
| CZ241997A3 (cs) | 1998-01-14 |
| ES2163002T3 (es) | 2002-01-16 |
| EP0869961B1 (en) | 2001-08-22 |
| CN1179779A (zh) | 1998-04-22 |
| ATE204580T1 (de) | 2001-09-15 |
| US5874571A (en) | 1999-02-23 |
| EP0869961A1 (en) | 1998-10-14 |
| WO1996023796A1 (en) | 1996-08-08 |
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