CN100497349C - 一种改进的比阿培南的制备方法 - Google Patents
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- 229960003169 biapenem Drugs 0.000 title claims abstract description 20
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Abstract
本发明涉及一种改进的成本低而有效，且工业上有利的制备比阿培南的方法，该方法由双(6，7-二氢-5H-吡唑并[1.2a][1.2.4]三氮唑鎓盐-6-基)二硫醚二氯化物与甲磺酸成盐后，可不需过柱层析得到6，7-二氢-5H-吡唑并[1，2-a][1，2，4]三氮唑鎓的甲磺酸盐，(即侧链甲磺酸盐)，且由侧链甲磺酸盐与双环母核反应制得的缩合物，在氢化制备最终产品时也不用经过柱层析就得到终产品比阿培南。该方法反应条件温和，适合大规模生产。
Description
技术领域
本发明涉及一种改进的、成本低而有效且能工业化大生产的比阿培南的制备方法。
背景技术
碳青霉烯类抗生素(Carbapenems)属于非典型的β-内酰胺类全新结构的抗生素。用于治疗院内严重感染、多重耐药菌感染及混合感染等，近几年来已在我国应用于临床的有默克公司的伊米培南(Imipenem，伊米培南)、日本三共的帕尼培南(Panipenem)以及日本住友的美罗培南(Meropenem)。
比阿培南(Biapenem)是新型1β-甲基碳青霉烯类抗生素，本品是在2位硫上有双环三唑的1β-甲基碳青霉烯，具有广泛的抗菌谱，对革兰氏阴性、革兰氏阳性、需氧菌和厌氧菌均有良好的杀菌作用；对人DHP-I稳定，无须和DHP-I抑制剂联合用药，且对β-内酰胺酶稳定；药物动力学性质优良，毒性低；对并发性腹腔内感染、下呼吸道感染(包括细菌性肺炎)以及并发性尿道感染有良好的治疗效果，耐受性好，不良反应率低。可以预见它将成为治疗重症感染的新的一线药物。
比阿培南是由日本Lederle公司和美国氰胺公司开发的注射用碳青霉烯类抗生素品种，2002年3月由日本Lederle公司和日本明治制果株式会社联合在日本上市。
根据文献报道，比阿培南的合成主要有如下两条路线：
1、以水合肼为原料，同甲酸乙酯缩合，再和丙酮反应，得到1-甲酰基-2-异丙叉联胺。上述产物同丙烯溴进行烷基化反应，得到1-烯丙基-1甲酰基-2-异丙叉联胺，产物和甲酸反应得到1烯丙基-1，2-二甲酰基联胺，该反应物进行溴代、环合，得到4-溴-1，2-二甲酰基吡唑烷。产物利用硫代醋酸钾巯基化反应，然后水解、氧化，在盐酸中成盐。所得盐酸盐同乙基甲酰亚胺盐酸盐反应，环合得到双(6，7-二氢-5H-吡唑并[1，2-a][1，2，4]三氮唑鎓盐-6-基)二硫醚二盐酸盐。双环产物用三丁基磷还原，得到比阿培南侧链6，7-二氢-6-巯基-5H-吡唑并[1，2-a][1，2，4]三氮唑氯化物。该侧链同双环母核β-MEPDE缩合，缩合产物最后还原得到目标产物比阿培南(Toshio Kumagaiet al.，J.Org.Chem.，1998，63：8145～8149)。
2、同样以水合肼为原料，同环氧氯丙烷环合，得到4-羟基-1，2-吡唑烷，然后与PNZ-Cl缩合，将胺基保护。保护后产物用甲磺酰氯氯化，通过硫代醋酸钾巯基化，然后水解得到侧链4-巯基-1，2-二对硝基苄氧酰基吡唑烷。侧链同母核β-MEPDE缩合、氢化，最后和乙基甲酰亚胺盐酸盐反应合环得到目标产物比阿培南。
路线1原料易得，反应条件较温和，采用较多。但它也存在合成难度大，多步反应需过柱层析，收率低等问题。
发明内容
本发明通过由双(6，7-二氢-5H-吡唑并[1，2a][1，2，4]三氮唑鎓盐-6-基)二硫醚二氯化物与甲磺酸反应而得到其甲磺酸盐后，可不经过柱层析得到6，7-二氢-6-巯基-5H-吡唑并[1，2a][1，2，4]三氮唑鎓甲磺酸盐(即侧链甲磺酸盐)，且由侧链甲磺酸盐与双环母核反应制得的缩合物，氢化制备最终产品时也不用经过柱层析就能得到比阿培南，解决现有技术中制备比阿培南需要柱层析，收率低，不能大规模生产的问题，并提供成本低、高效的合成方法。
本发明合成比阿培南包括以下步骤，化合物II可通过文献报道的方法(Toshio Kumagai et al.，J.Org.Chem.，1998，63：8145～8149)制备：
本发明的技术方案如下：
步骤1双(6，7-二氢-5H-吡唑并[1，2a][1，2，4]三氮唑鎓盐-6-基)二硫醚二甲磺酸盐(III)的制备
将双(6，7-二氢-5H-吡唑并[1.2a][1.2.4]三氮唑鎓盐-6-基)二硫醚二氯化物(II)溶解于甲醇中，室温搅拌下加入甲磺酸，减压浓缩后的残留物中加入丙酮析晶，得到类白色固体；
步骤26，7-二氢-6-巯基-5H-吡唑并[1，2a][1，2，4]三氮唑鎓甲磺酸盐的制备
将步骤1中的产物类白色固体，即双(6，7-二氢-5H-吡唑并[1，2-a][1，2，4]三唑-6-基)二硫醚二甲磺酸盐(III)、四氢呋喃和水溶液加入反应瓶中，冰盐水冷却，加入三丁基磷搅拌，反应完毕后，减压除去四氢呋喃，水溶液用乙酸乙酯和二氯甲烷洗涤，水层减压浓缩，干燥，得到类白色固体；
步骤3对硝基苄基(1R，5S，6S)-2-[(6，7-二氢-5H-吡唑并[1，2a][1，2，4]三氮唑鎓-6-基)硫基]-6-[(R)-1-羟乙基]-1-甲基碳代青霉-2-烯-3-羧酸酯甲磺酸盐的制备
将步骤2中的产物类白色固体，即6，7-二氢-6-巯基-5H-吡唑并[1，2a][1，2，4]三氮唑鎓甲磺酸盐(IV)、双环母核1β-甲基青霉烯双环母核即MAP(V)、MeCN混合后在室温条件下滴加二异丙基乙胺/四氢呋喃溶液，反应后将反应液浓缩，除去有机溶剂，加入CH2Cl2，搅拌析出固体，过滤干燥得到缩合物(VI)，为淡黄色固体；
步骤4(1R，5S，6S)-2-[(6，7-二氢-5H-巯基-5H-吡唑并[1，2a][1，2，4]三氮唑鎓-6-基)硫基]-6-[(R)-1-羟乙基]-1-甲基碳代青霉-2-烯-3-羧酸盐(I)即比阿培南的制备
将对硝基苄基(1R，5S，6S)-2-[(6，7-二氢-5H-吡唑并[1，2a][1，2，4]三氮唑鎓-6-基)硫基]-6-[(R)-1-羟乙基]-1-甲基碳代青霉-2-烯-3-羧酸酯甲磺酸盐(VI)、钯炭、正丁醇和水混合，用磷酸盐调节PH值，室温、5atm的氢压下搅拌，反应结束后还原产物不需过柱层析，先蒸去大部分反应溶剂，加入有机溶剂(优选丙酮)，再加吸水剂(如无水硫酸镁、无水硫酸钠等)及吸附剂(优选硅藻土、硅胶、活性炭)以除去水份和杂质，搅拌后过滤，用无水乙醇重结晶，过滤干燥。
发明详述
在以下部分中通过说明本发明方法的实施例来说明一个优选的实施方式。但是它决不用来限制本发明的范围。
制备比阿培南实施例
步骤1 双(6，7-二氢-5H-吡唑并[1，2a][1，2，4]三氮唑鎓盐-6-基)二硫醚二甲磺酸盐的制备
将8g双(6，7-二氢-5H-吡唑并[1.2a][1.2.4]三氮唑鎓盐-6-基)二硫醚二氯化物(II)溶解于20ml甲醇中，室温搅拌下加入5ml甲磺酸，减压浓缩后的残留物中加入7.5ml丙酮析晶，得到类白色固体7.8g。
步骤2 6，7-二氢-6-巯基-5H-吡唑并[1，2a][1，2，4]三氮唑鎓甲磺酸盐的制备
将步骤1中的产物类白色固体，即双(6，7-二氢-5H-吡唑并[1，2-a][1，2，4]三唑-6-基)二硫醚二甲磺酸盐(III)6g、30ml四氢呋喃和30ml水溶液加入反应瓶中，冰盐水冷却到0℃，加入三丁基磷6.85g然后于0℃搅拌2小时，反应完毕，减压除去四氢呋喃，水溶液用乙酸乙酯和二氯甲烷洗两次，水层减压浓缩，五氧化二磷真空干燥，得到类白色固体1.9g。
步骤3 对硝基苄基(1R，5S，6S)-2-[(6，7-二氢-5H-巯基-5H-吡唑并[1，2a][1，2，4]三氮唑鎓-6-基)硫基]-6-[(R)-1-羟乙基]-1-甲基碳代青霉-2-烯-3-羧酸酯甲磺酸盐的制备
将(IV)1.5g、1β-甲基青霉烯双环母核双环母核(V)即MAP 3.3g、20ml MeCN混合后在室温条件下滴加5ml二异丙基乙胺/5ml四氢呋喃溶液，反应3-4小时后将反应液浓缩，除去有机溶剂，加入25mlCH2Cl2，搅拌析出固体，过滤干燥得到缩合物VI，为淡黄色固体2.1g。
步骤4 (1R，5S，6S)-2-[(6，7-二氢-5H-巯基-5H-吡唑并[1，2a][1，2，4]三氮唑鎓-6-基)硫基]-6-[(R)-1-羟乙基]-1-甲基碳代青霉-2-烯-3-羧酸盐(I)即比阿培南的制备
将1.5g(VI)、0.3g 10％Pd-C，30ml正丁醇及30ml水混合后用磷酸氢二钠调节pH在4.5～5.5，然后在室温、5atm的氢压下搅拌1小时。过滤除去催化剂，并再次调节pH在4.5～5.5，减压浓缩到约5ml体积，加入20ml丙酮，加入无水硫酸镁、硅藻土。搅拌2小时，过滤，蒸去丙酮，用无水乙醇重结晶，过滤干燥，得比阿培南0.52g。
Claims (4)
1.一种制备式I所示比阿培南的方法，由下列步骤构成：
式I
步骤一，将双(6，7-二氢-5H-吡唑并[1.2a][1.2.4]三氮唑鎓盐-6-基)二硫醚二氯化物溶解于甲醇中，室温搅拌下加入甲磺酸，减压浓缩后的残留物中加入丙酮析晶，得到类白色固体；
步骤二，将步骤一中的类白色固体产物，即双(6，7-二氢-5H-吡唑并[1，2-a][1，2，4]三唑-6-基)二硫醚二甲磺酸盐、四氢呋喃和水溶液加入反应瓶中，冰盐水冷却，加入三丁基磷搅拌，反应完毕后除去杂质，减压浓缩干燥，得到类白色固体；
步骤三，将步骤二中的类白色固体产物，即6，7-二氢-6-巯基-5H-吡唑并[1，2a][1，2，4]三氮唑鎓甲磺酸盐、1β-甲基青霉烯双环母核即MAP、MeCN混合后在室温条件下滴加二异丙基乙胺/四氢呋喃溶液，反应后将反应液浓缩，除去有机溶剂，加入CH2Cl2，搅拌析出固体，过滤干燥得到淡黄色固体；
步骤四，将步骤三中的淡黄色固体，即对硝基苄基(1R，5S，6S)-2-[(6，7二氢-5H-吡唑并[1，2a][1，2，4]三氮唑鎓-6-基)硫基]-6-[(R)-1-羟乙基]-1-甲基碳代青霉-2-烯-3-羧酸酯甲磺酸盐溶于正丁醇和水的混合溶剂中，加入催化剂钯炭，用磷酸盐调节反应溶液的pH值为弱酸性，室温、5atm的氢压下反应，将产物蒸去大部分反应溶剂，加入有机溶剂，再加吸水剂及吸附剂以除去水份和杂质，搅拌后过滤，用无水乙醇重结晶，过滤干燥。
2.根据权利要求1的方法，其中步骤四中的磷酸盐为磷酸氢二钠。
3.根据权利要求1的方法，其中步骤四中加入的有机溶剂为丙酮。
4.根据权利要求1的方法，其中步骤四中吸附剂为硅藻土或硅胶或活性炭。
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