CN104163820B - 一种莫西沙星中间体化合物的制备方法 - Google Patents
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
本发明公开了一种莫西沙星中间体化合物的制备方法。本发明公开的一种如式B所示的莫西沙星中间体化合物的制备方法,其包含下列步骤:有机惰性溶剂中,在硼氢化锌作用下,将如式A所示的化合物进行如下所示的还原反应。本发明的制备方法能够降低生产成本、提高了生产安全性、减少工业排污,产率高,更适用于工业化生产。
Description
技术领域
本发明涉及一种莫西沙星中间体化合物的制备方法。
背景技术
盐酸莫西沙星是第四代8-甲氧基喹咯酮类抗菌药,用于治疗急性窦炎、慢性支气管炎急性发作、社区获得性肺炎以及皮肤和软组织感染。莫西沙星抗菌谱广且半衰期长,组织穿透力强,肝、肾双向排泄,有良好的药代动力学及良好的安全性和耐受性。莫西沙星于1999年在德国和美国上市,2002年在中国上市使用。
德国拜耳公司的专利EP550903中公开了莫西沙星中间体(S,S)-8-苄基-2,8-二氮杂双环[4.3.0]壬烷的合成方法,其采用对8-苄基-7,9-二氧代-2,8-二氮杂双环[4.3.0]壬烷(I)经D-酒石酸或者L-酒石酸化学拆分后得到(1S,6R)-8-苄基-7,9-二氧代-2,8-二氮杂双环[4.3.0]壬烷(II)的D-酒石酸盐,经游离后再用氢化铝锂还原得到(S,S)-8-苄基-2,8-二氮杂双环[4.3.0]壬烷(III)。
专利EP350733和CA1340553公开了用氢化铝锂或硼氢化钠/三氟化硼还原8-苄基-7,9-二氧代-2,8-二氮杂双环[4.3.0]壬烷(I)制备消旋8-苄基-2,8-二氮杂双环[4.3.0]壬烷(IV)的制备方法。德国拜耳公司在专利US6235908中公开用酒石酸化学拆分消旋8-苄基-2,8-二氮杂双环[4.3.0]壬烷(IV)后得到(S,S)-8-苄基-2,8-二氮杂双环[4.3.0]壬烷(III)。
以上所述的两种专利方法都涉及到还原步骤,且都是采用氢化铝锂作为还原剂。由于氢化铝锂价格较贵,易爆易燃,使用存在危险性,不利于产业化生产,从而缺乏市场竞争力。采用金属硼氢化物/三氟化硼·乙醚还原体系进行还原,也因三氟化硼·乙醚的易燃性和较高的价格,不适用于工业化大生产,因此,有必要开发一种新的还原方法。
发明内容
本发明所要解决的技术问题是为了克服了现有的莫西沙星中间体的制备方法中还原步骤需要使用氢化铝锂和金属硼氢化物/三氟化硼·乙醚等易燃易爆且价格昂贵的还原试剂,而提供了一种莫西沙星中间体化合物的制备方法。本发明的制备方法能够降低生产成本、提高了生产安全性、减少工业排污,产率高,更适用于工业化生产。
本发明提供了一种如式B所示的莫西沙星中间体化合物的制备方法,其包含下列步骤:有机惰性溶剂中,在硼氢化锌作用下,将如式A所示的化合物进行如下所示的还原反应;
其中,如式A所示的化合物可以为单一的手性化合物,也可以为外消旋体,本发明中,如式A所示的化合物较佳地为(S,S)-8-苄基-7,9-二氧代-2,8-二氮杂双环[4.3.0]壬烷或者8-苄基-7,9-二氧代-2,8-二氮杂双环[4.3.0]壬烷。所述的硼氢化锌可以硼氢化锌固体或者硼氢化锌溶液的形式参与反应。所述的硼氢化锌可采用本领域常规的制备方法制备得到,所述的硼氢化锌的制备方法,较佳地包含下列步骤:有机惰性溶剂中,将碱金属硼氢化物与ZnX2混合,进行反应;其中,X为氯、溴或碘。所述的碱金属硼氢化物较佳地为硼氢化锂、硼氢化钠或硼氢化钾,更佳地为硼氢化钠。
所述的有机惰性溶剂可为本领域此类反应常规的有机惰性溶剂。所述的有机惰性溶剂较佳地为醚类溶剂、烷烃类溶剂和芳香烃类溶剂中的一种或多种。所述的醚类溶剂较佳地为乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、乙二醇二甲醚和2-甲基四氢呋喃中一种或多种,更佳地为四氢呋喃、2-甲基四氢呋喃和乙二醇二甲醚中的一种或多种。所述的烷烃类溶剂较佳地为正庚烷、环己烷和石油醚中的一种或多种。所述的芳香烃类溶剂较佳地为苯、甲苯和二甲苯中的一种或多种,更佳地为甲苯。所述的有机惰性溶剂的用量以不影响反应的进行即可,较佳地与如式A所示的化合物的体积质量比为1mL/g~50mL/g,更佳地为4mL/g~20mL/g。所述的如式A所示的化合物与硼氢化锌的摩尔比较佳地为1:1~1:10,更佳地为1:2~1:5。所述的还原反应的温度可为本领域此类反应常规的温度,较佳地为-10~150℃,更佳地为-1~120℃,最佳地为1~85℃。所述的反应的时间较佳地为1~24小时。
所述的如式B所示的莫西沙星中间体化合物制备方法,较佳地,其包含下列步骤:将硼氢化锌与所述的有机惰性溶剂混合后,再与如式A所示的化合物混合,进行所述的还原反应。
所述的如式B所示的莫西沙星中间体化合物制备方法,更佳地,其包含下列步骤:所述的有机惰性溶剂中,将碱金属硼氢化物、ZnX2和如式A所示的化合物混合,进行所述的还原反应。其中,所述的有机惰性溶剂和ZnX2均同前所述。所述的如式A所示的化合物与碱金属硼氢化物的摩尔比较佳地为1:1~1:10,更佳地为1:2~1:5。所述的如式A所示的化合物与ZnX2的摩尔比较佳地为1:1~1:10,更佳地为1:1~1:5。
所述的还原反应结束后,较佳地还可包含后处理步骤。所述的后处理步骤的方法和条件可为本领域常规的后处理步骤的方法和条件,较佳地,所述的后处理步骤包含下列步骤:将还原反应的反应液淬灭,与水和有机溶剂混合,萃取,得有机相后浓缩,即可;更佳地为将还原反应的反应液用酸性水溶液淬灭、过滤、得滤液后浓缩;然后将浓缩液与有机溶剂和碱性水溶液混合,萃取,得有机相后,浓缩,即可;最佳地为将还原反应的反应液滴加到盐酸溶液中,搅拌、过滤、滤液减压浓缩,然后向浓缩液中加入甲苯和氢氧化钠水溶液,搅拌、静置、分去水层,甲苯层经洗涤、干燥、过滤、滤液浓缩,蒸馏,即可。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
本发明的制备方法能够降低生产成本、提高了生产安全性、减少工业排污,产率高,更适用于工业化生产。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1
向500mL三口反应瓶中加入(S,S)-8-苄基-7,9-二氧代-2,8-二氮杂双环[4.3.0]壬烷24.4g(0.1mol)、四氢呋喃200mL,加入硼氢化锌19.0g(0.2mol),然后升温至回流,保温反应6小时,反应完毕,冷却到室温,将反应液加到100mL2N HCl溶液中,过滤,去除固体,滤液减压浓缩,然后向其中加入甲苯200mL和用2N氢氧化钠水溶液调到pH值为10,静置,分去水层,甲苯层用去离子水50mL洗涤一次,用无水硫酸钠搅拌干燥,过滤,滤液减压浓缩至干,然后减压精馏(108~110℃/0.1毫巴)得到(S,S)-8-苄基-2,8-二氮杂双环[4.3.0]壬烷20.0g,收率为93.0%,[a]D23=+18.0°(未稀释)。
向500mL三口反应瓶中加入(S,S)-8-苄基-7,9-二氧代-2,8-二氮杂双环[4.3.0]壬烷24.4g(0.1mol)、四氢呋喃150mL,加入硼氢化锌9.5g(0.1mol)的THF溶液,然后升温至回流,保温反应20小时,反应完毕,冷却到室温,将反应液加到100mL2N HCl溶液,过滤,去除固体,滤液减压浓缩,然后向其中加入甲苯200mL和用2N氢氧化钠水溶液调到pH值为10,静置,分去水层,甲苯层用去离子水50mL洗涤一次,用无水硫酸钠搅拌干燥,过滤,滤液减压浓缩至干,然后减压精馏(108~110℃/0.1毫巴)得到(S,S)-8-苄基-2,8-二氮杂双环[4.3.0]壬烷19.9g,收率为91.0%,[a]D23=+18.0°(未稀释)。
实施例3
向500mL三口反应瓶中加入四氢呋喃300mL,硼氢化钠11.4g(0.3mol),氯化锌20.6g(0.15mol),(S,S)-8-苄基-7,9-二氧代-2,8-二氮杂双环[4.3.0]壬烷24.4g(0.1mol),然后升温至回流,保温反应20小时,反应完毕,冷却到室温,将反应液加到100mL2N HCl溶液,过滤,去除固体,滤液减压浓缩,然后向其中加入甲苯200mL和用2N氢氧化钠水溶液调到pH值为10,静置,分去水层,甲苯层用去离子水50mL洗涤一次,用无水硫酸钠搅拌干燥,过滤,滤液减压浓缩至干,然后减压精馏(108~110℃/0.1毫巴)得到(S,S)-8-苄基-2,8-二氮杂双环[4.3.0]壬烷19.7g,收率为90.0%,[a]D23=+18.0°(未稀释)。
实施例4
将实施例3中硼氢化钠替换为硼氢化钾,其他操作均相同,亦得到(S,S)-8-苄基-2,8-二氮杂双环[4.3.0]壬烷17.4g(0.801mol),收率为80.2%,[a]D23=+18.0°(未稀释)。
实施例5
将实施例3中溶剂四氢呋喃替换为乙二醇二甲醚,其他操作均相同,亦得到(S,S)-8-苄基-2,8-二氮杂双环[4.3.0]壬烷19.4g,收率为90.0%,[a]D23=+18.3°(未稀释)。
实施例6
将实施例3中溶剂四氢呋喃替换为2-甲基四氢呋喃和甲苯的混合溶剂(v:v=1:0.3),85℃保温24h,得(S,S)-8-苄基-2,8-二氮杂双环[4.3.0]壬烷17.4g,收率为81.0%,[a]D23=+18.0°(未稀释)。
实施例7
向500mL三口反应瓶中加入四氢呋喃200mL,冷却至0℃,加入硼氢化钠7.6g(0.2mol),氯化锌13.7g(0.1mol),8-苄基-7,9-二氧代-2,8-二氮杂双环[4.3.0]壬烷24.4g(0.1mol),然后升温至回流,保温反应15小时,反应完毕,冷却到室温,将反应液加到100mL2N HCl溶液,过滤,去除固体,滤液减压浓缩,然后向其中加入甲苯200mL和用2N氢氧化钠水溶液调到pH值为10,静置,分去水层,甲苯层用去离子水50mL洗涤一次,用无水硫酸钠搅拌干燥,过滤,滤液减压浓缩至干,然后减压精馏(108~110℃/0.1毫巴)得到8-苄基-2,8-二氮杂双环[4.3.0]壬烷20.5g,收率为95.0%,纯度(GC)99.5%。
Claims (1)
1.一种如式B所示的莫西沙星中间体化合物的制备方法,其特征在于包含下列步骤:向500mL三口反应瓶中加入四氢呋喃200mL,冷却至0℃,加入硼氢化钠7.6g,氯化锌13.7g,8-苄基-7,9-二氧代-2,8-二氮杂双环[4.3.0]壬烷24.4g,然后升温至回流,保温反应15小时,反应完毕,冷却到室温,将反应液加到100mL 2N HCl溶液,过滤,去除固体,滤液减压浓缩,然后向其中加入甲苯200mL和用2N氢氧化钠水溶液调到pH值为10,静置,分去水层,甲苯层用去离子水50mL洗涤一次,用无水硫酸钠搅拌干燥,过滤,滤液减压浓缩至干,然后减压精馏,108~110℃/0.1毫巴,得到8-苄基-2,8-二氮杂双环[4.3.0]壬烷20.5g;
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