CN101029056A - 聚－3－羟基丁酸酯在制备β－内酰胺化合物中的用途 - Google Patents
聚－3－羟基丁酸酯在制备β－内酰胺化合物中的用途 Download PDFInfo
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Abstract
本发明公开了聚－3－羟基丁酸酯P(3HB)在制备β－内酰胺化合物中的用途，本发明还公开了利用P(3HB)制备具有通式(I)的β－内酰胺化合物的方法，其中R为式（Ⅱ），R1、R2、R3为C1－C4的低级直链或支链烷基。利用本发明公开的方法，可以方便地制备通式(I)所述的化合物。该方法较之以前的方法步骤更短，收率更高，同时也更为避开了对环境污染的试剂及贵重试剂的使用，降低了成本并减少了环境污染。
Description
技术领域
本发明属于β-内酰胺化合物的生产领域，更具体地，本发明公开了聚3-羟基丁酸酯P(3HB)在制备具有通式(I)的β-内酰胺化合物中的应用：
其中R为
R1、R2、R3为C1-C4的低级直链或支链烷基。
背景技术
具有通式(I)的β-内酰胺化合物
其中R为
R1、R2、R3为C1-C4的低级直链或支链烷基是制备碳青霉烯类抗生素的重要中间体(Andrew H.Berks，“Tetrahydron”，第52卷，331页，1996年)。迄今为止，合成上述化合物的方法有很多，例如：由6-氨基青霉烷酸合成(Yoshida，A.；Hayashi，T.；Takeda，N.；Oida，S.；Ohki，E.Chem.Pharm.Bull.1981，29，2899-2909.)；由苏氨酸合成(Shiozaki，M.；Ishida，N.；Maruyama，H.；Hiraoka，T.Tetrahedron 1983，39，2399-2407.)；由(3R)-3-羟基丁酸甲酯合成(Ohashi，T.；Kan，K.；Ueyama，N.；Sada，I.；Miyama，A.；Watanabe，K.U.S.Patent US 4861877，Aug.29，1989.)等等，但这些方法或是在合成过程中使用了易造成污染的重金属化合物，如乙酸汞和四乙酸铅；或是使用了过多的硅试剂以及手性原料和催化剂，导致成本高昂。
因而寻找合适的起始原料，优化合成工艺从而减少成本高昂的试剂的使用或降低污染一直是本领域的技术人员着力解决的问题。
发明内容：
本发明的发明人通过大量实验，找到了制备如通式(I)的化合物
的起始原料聚3-羟基丁酸P(3HB)并开发了适合大规模生产的合成上述化合物的工艺，即由P(3HB)得到取代的(3R)-3-羟基丁酸甲酯，还原后得到取代的(3R)-3-羟基丁醛，烯醇化后与氯磺酰异氰酸酯反应具有上述通式(I)的化合物，
其中R为
R1、R2、R3为C1-C4的低级直链或支链烷基。该方法较之以前的方法步骤更短，收率更高，同时也避开了对环境污染的试剂及贵重试剂的使用，降低了成本并减少了环境污染。其反应路线如下：
其中，R为
R1、R2、R3为C1-C4的低级直链或支链烷基。
更具体地，本发明公开了：
1，P(3HB)在制备通式(I)化合物的用途：
其中R为
R1、R2、R3为C1-C4的低级直链或支链烷基。
2，上述1所述的用途，其中R为1-叔丁基二甲基硅基、异丙基二甲基硅基、三异丙基硅基之一。
3，一种利用P(3HB)制备上述通式(I)化合物的方法，包括：
a：P(3HB)裂解，保护得到(3R)-3-RO-CH(CH3)CH2COOCH3；
b：(3R)-3-RO-CH(CH3)CH2COOCH3还原得到(3R)-3-RO-CH(CH3)CH2CHO；
c：(3R)-3-RO-CH(CH3)CH2CHO烯醇化后与氯磺酰异氰酸酯反应然后再还原得到终产品。
4，上述3所述的方法，其中步骤a为：P(3HB)与无水甲醇和硫酸回流经后处理得到初步产物，然后再和取代的甲硅烷氯进行反应。
5，上述4所述的方法，其中回流时间为三天。
6，上述3所述的方法，其中(3R)-3-RO-CH(CH3)CH2COOCH3为(3R)-3-叔丁基二甲基硅氧基丁酸甲酯。
7，上述3所述的方法，其中步骤c中烯醇化步骤为(3R)-3-RO-CH(CH3)CH2CHO和乙酸异丙烯酯、对甲苯磺酸混合加热回流进行反应。
8，上述3所述的方法，其中步骤c中使用的还原剂为亚硫酸氢钠。
本发明中使用的起始原料聚3-羟基丁酸酯P(3HB)是一种热塑性树酯，有良好的生物分解性和生物适应性，主要作为生物降解材料使用。本发明利用其作为合成具有通式(I)的β-内酰胺化合物的起始原料，可以方便地得到3-羟基被RO取代的(3R)-3-RO-CH(CH3)CH2COOCH3，与利用(3R)-3-羟基丁酸甲酯合成的取代的(3R)-3-RO-CH(CH3)CH2COOCH3相比，具有价格低廉的优点。更进一步，其反应条件为P(3HB)与甲醇、硫酸回流经后处理得到初步产物，然后再和取代的甲硅烷氯进行反应得到(3R)-3-RO-CH(CH3)CH2COOCH3。
利用P(3HB)得到的(3R)-3-RO-CH(CH3)CH2COOCH3可以在常规的反应条件下得到(3R)-3-RO-CH(CH3)CH2CHO，例如在低温下利用二异丁基氢铝进行反应后加入酒石酸钾钠饱和溶液当中，再加入乙醚经萃取、干燥、蒸干然后过硅胶柱即可。
(3R)-3-RO-CH(CH3)CH2CHO经过烯醇化得到稳定的烯醇化物以后和氯磺酰异氰酸酯反应后得到的产物利用温和的还原剂亚硫酸氢钠进行还原再经硅胶柱纯化后可得ee值99％以上的终产品。
具体实施方式：
以下实施例仅对本发明进行进一步的说明，不应理解为对本发明的任何限制。本发明中如果没有特别说明，产率均为摩尔收率，试剂如果没有言明，均为市售化学纯试剂。
P(3HB)天津国韵生物科技有限公司产品
旋光仪型号：WZZ-1 上海精密仪器仪表有限公司
核磁共振仪型号：Bruker AVANCE DRX-500 布鲁克光谱仪器公司
熔点仪型号：WRS-2A 上海精密仪器仪表有限公司
实施例1：(3R)-3-叔丁基二甲基硅氧基丁酸甲酯的制备
将80克P(3HB)溶于1升无水二氯乙烷中，回流一个小时后，加入20毫升浓硫酸以及400毫升无水甲醇，再回流三天后冷却至室温，向反应混合物中投入200毫升饱和食盐水，搅拌30分钟后，分出水相，并用500毫升氯仿分三次洗涤水相，合并有机相并分别用200毫升饱和食盐水，200毫升饱和碳酸氢钠溶液，200毫升饱和食盐水分三次洗涤有机相。有机相用硫酸镁干燥，减压蒸除溶剂后，残留物减压蒸馏，收集61-62摄氏度/18毫米汞柱馏分，得产物104克，将以上产物投入三口瓶中，加入400毫升二氯甲烷，50克咪唑，搅拌均匀后缓慢加入3-叔丁基二甲基甲硅烷氯120克，反应5小时后过滤，将滤液分别用饱和碳酸氢钠，盐酸以及饱和食盐水洗涤，分出有机相无水硫酸镁干燥过夜，减压浓缩后得到(3R)-3-叔丁基二甲基硅氧基丁酸甲酯200克，产率92.5％。
实施例2(3R)-三异丙基硅氧基丁酸甲酯的制备
同实施例1，只是用三异丙基甲硅烷氯替代3-叔丁基二甲基甲硅烷氯，得到(3R)-三异丙基硅氧基丁酸甲酯223克，产率87.2％。
实施例3(3R)-3-叔丁基二甲基硅氧基丁醛的制备
(3R)-3-叔丁基二甲基硅氧基丁酸甲酯46.4克，溶于200毫升正己烷中，冷却至-78摄氏度，缓缓滴入240毫升1mol/L的二异丁基氢铝的正己烷溶液，加完之后，在此温度下继续反应2个小时，反应完成后，缓慢升温，将反应液倒入1升的酒石酸钾钠饱和溶液当中，再加入乙醚1.5升，水0.5升激烈搅拌1个小时，分液，有机相用饱和食盐水洗，水相分三次用1.2升乙醚萃取，合并有机相，硫酸钠干燥过夜，减压蒸除溶剂，粗品经硅胶柱色谱纯化(洗脱液的配比：乙酸乙酯∶己烷＝1∶1)得(3R)-3-叔丁基二甲基硅氧基丁醛39.7克，产率98.3％。
实施例4(3R)-三异丙基硅氧基丁醛的制备
同实施例3，只是将(3R)-3-叔丁基二甲基硅氧基丁酸甲酯改为(3R)三异丙基硅氧基丁酸甲酯，投料量为54.8克得到(3R)-三异丙基硅氧基丁醛44克，产率90.2％
实施例5(3R，4R)-4-乙酰氧基-3-[(R)-1-叔丁基二甲基甲硅烷氧基乙基]-氮杂环丁-2-酮的制备
将20.2克(3R)-3-叔丁基二甲基硅氧基丁醛，15克乙酸异丙烯酯，1克对甲苯磺酸混合加热回流，上置韦氏精馏柱，将体系中生成的丙酮蒸馏干净以后，残液用饱和碳酸氢钠溶液调至中性，减压蒸除水和原料的共沸混合物后，得烯醇化产物17.2克，产率70.5％。
取上述粗产品4.90克溶于25毫升二氯甲烷，冰水冷却到0摄氏度，将氯磺酰异氰酸酯3.40克缓慢加入，使体系温度低于0摄氏度，反应两个小时后，得红棕色反应混合物，随即将其冷却到-40摄氏度，将冷却后的溶液慢慢滴入激烈搅拌的200毫升0摄氏度的饱和亚硫酸钠溶液中，用饱和氢氧化钠溶液调溶液pH值8-10，薄层色谱监控反应进程，待原料反应完全后，分出有机相，硫酸镁干燥过夜，减压蒸除溶剂后，硅胶柱色谱纯化(洗脱液的配比：乙酸乙酯∶己烷＝1∶10)得到(3R，4R)-4-乙酰氧基-3-[(R)-1-叔丁基二甲基甲硅烷氧基乙基]-氮杂环丁-2-酮，正己烷中重结晶，得白色针状晶体3.40克，产率59.0％。此白色针状晶体即为最终产物，本路线共计三步，总产率37.8％。
产品旋光度：53-57°(c＝0.5，CHCl3)
核磁共振谱(500MHz，CDCl3)
δ(ppm)：0.08(6H，s)，0.84(9H，s)，1.20(3H，d)，2.01(3H，s)，3.04(1H，dd)，4.12(1H，m)，5.76(1H，d)，6.73(NH)
熔点：106-110℃
实施例6(3R，4R)-4-乙酰氧基-3-[(R)-三异丙基硅烷氧基乙基]-氮杂环丁-2-酮的制备
同实施例5，只是将(3R)-3-叔丁基二甲基硅氧基丁醛改为(3R)-三异丙基硅氧基丁醛，投料量为24.4克得到终产品10.9克，总产率33.1％。
本发明得到的终产品的熔点、旋光度以及核磁数据和中国发明专利申请号85105097公开的产品的数据一致。
Claims (8)
1.P(3HB)在制备通式(I)化合物的用途：
其中R为
，R1、R2、R3为C1-C4的低级直链或支链烷基。
2.权利要求1所述的用途，其中R为1-叔丁基二甲基硅基、异丙基二甲基硅基、三异丙基硅基之一。
3.一种利用P(3HB)制备上述通式(I)化合物的方法，包括：
a.将P(3HB)裂解，保护得到(3R)-3-RO-CH(CH3)CH2COOCH3；
b.将(3R)-3-RO-CH(CH3)CH2COOCH3还原得到(3R)-3-RO-CH(CH3)CH2CHO；
c.将(3R)-3-RO-CH(CH3)CH2CHO烯醇化后与氯磺酰异氰酸酯反应然后再还原得到终产品。
4.权利要求3所述的方法，其中步骤a为P(3HB)与无水甲醇和硫酸回流经后处理得到初步产物，然后再和取代的甲硅烷氯进行反应。
5.权利要求4所述的方法，其中回流时间为三天。
6.权利要求3所述的方法，其中(3R)-3-RO-CH(CH3)CH2COOCH3为(3R)-3-叔丁基二甲基硅氧基丁酸甲酯。
7.权利要求3所述的方法，其中步骤c中烯醇化步骤为(3R)-3-RO-CH(CH3)CH2CHO和乙酸异丙烯酯、对甲苯磺酸混合在加热回流的条件下进行。
8.权利要求3所述的方法，其中步骤c中使用的还原剂为亚硫酸氢钠。
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| CN2006100132237A CN101029056B (zh) | 2006-02-28 | 2006-02-28 | 聚-3-羟基丁酸酯在制备β-内酰胺化合物中的用途 |
| US12/280,781 US7985857B2 (en) | 2006-02-28 | 2006-10-16 | Usage of poly-3-hydroxybutyrates in preparation of β-lactam compounds |
| KR1020087023768A KR101071440B1 (ko) | 2006-02-28 | 2006-10-16 | β-락탐 화합물의 제조에서의 폴리-3-히드록시부티레이트의용도 |
| JP2008556632A JP5042243B2 (ja) | 2006-02-28 | 2006-10-16 | ポリ−３−ヒドロキシブチレートを用いてβ−ラクタム化合物を調製する方法 |
| EP06804931A EP1990334B1 (en) | 2006-02-28 | 2006-10-16 | Usage of poly-3-hydroxyalkanoates in preparation of beta-lactam compounds |
| PCT/CN2006/002707 WO2007098651A1 (fr) | 2006-02-28 | 2006-10-16 | UTILISATION DE POLY-3-HYDROXYALCANOATES POUR LA PRÉPARATION DE COMPOSÉS DE β-LACTAME |
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| CN115850065A (zh) * | 2022-10-14 | 2023-03-28 | 东莞理工学院 | 一种以硫酸氢钠为催化剂催化聚3-羟基丁酸酯降解制备r-3-羟基丁酸酯的方法 |
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| EP0003960B1 (de) * | 1978-02-02 | 1983-06-29 | Ciba-Geigy Ag | 6-Substituierte Thia-Azaverbindungen, ihre Herstellung und diese enthaltende pharmazeutische Präparate |
| US4680391A (en) * | 1983-12-01 | 1987-07-14 | Merck & Co., Inc. | Substituted azetidinones as anti-inflammatory and antidegenerative agents |
| US4791198A (en) * | 1984-07-05 | 1988-12-13 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Beta-lactam compound and preparation thereof |
| JPS6118791A (ja) * | 1984-07-05 | 1986-01-27 | Kanegafuchi Chem Ind Co Ltd | 新規β−ラクタム化合物及びその製造法 |
| US4861877A (en) | 1984-07-05 | 1989-08-29 | Kanegafuchi Kagaku Kogyo Kabushiki Kaisha | Process for preparing 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives |
| JPS6118758A (ja) * | 1985-01-14 | 1986-01-27 | Kanegafuchi Chem Ind Co Ltd | ４−アセトキシ−ヒドロキシエチルアゼチジン−２−オン誘導体の製造法 |
| EP0259268A1 (de) * | 1986-09-04 | 1988-03-09 | Ciba-Geigy Ag | Verfahren zur Herstellung optisch aktiver Beta-Lactame |
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| JP2009528300A (ja) | 2009-08-06 |
| US20090088566A1 (en) | 2009-04-02 |
| US7985857B2 (en) | 2011-07-26 |
| KR101071440B1 (ko) | 2011-10-10 |
| JP5042243B2 (ja) | 2012-10-03 |
| EP1990334B1 (en) | 2013-03-06 |
| KR20080098444A (ko) | 2008-11-07 |
| EP1990334A1 (en) | 2008-11-12 |
| EP1990334A4 (en) | 2011-02-23 |
| WO2007098651A1 (fr) | 2007-09-07 |
| CN101029056B (zh) | 2011-06-08 |
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