2α-甲基-2β-溴甲基青霉烷酸二苯甲酯的合成
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摘要
以6,6-二氢青霉烷酸二苯甲酯-1-氧化物(Ⅰ)和2-巯基苯并噻唑为原料,通过热裂解开环反应和溴代环合反应,制备得到了β-内酰胺酶抑制剂他唑巴坦关键中间体2α-甲基-2β-溴甲基青霉烷酸二苯甲酯(Ⅲ)。考察了反应温度、反应时间、物料比、催化剂用量对目标产物的影响。结果表明,在n(Ⅱ)∶n(HBr)∶n(Na NO_2)=1∶3∶6,催化剂质量分数为4%,-5℃反应2. 5h的条件下,收率为85. 4%。产物结构经1HNMR、FTIR、MS等技术手段得到验证。
Benzhydryl 2α-methyl-2β-bromomethyl-penicillanate( Ⅲ),a key intermediate of the β-lactamase inhibitor tazobactam,was synthesized via pyrolysis ring-opening reaction and bromo-cyclization reaction between benzhydryl 6,6-dihydropenicillanate-1-oxide( Ⅰ) and 2-mercaptobenzothiazole.The effects of reaction temperature,reaction time,material ratio and catalyst dosage on the target product were investigated. The results showed that the yield was 85. 36% under the conditions of n( II) ∶ n( HBr) ∶ n( Na NO_2) = 1 ∶ 3 ∶ 6,catalyst mass fraction of 4%,and reaction at-5°C for 2. 5h.Its structure was characterized by1 HNMR,FTIR and MS.
Benzhydryl 2α-methyl-2β-bromomethyl-penicillanate( Ⅲ),a key intermediate of the β-lactamase inhibitor tazobactam,was synthesized via pyrolysis ring-opening reaction and bromo-cyclization reaction between benzhydryl 6,6-dihydropenicillanate-1-oxide( Ⅰ) and 2-mercaptobenzothiazole.The effects of reaction temperature,reaction time,material ratio and catalyst dosage on the target product were investigated. The results showed that the yield was 85. 36% under the conditions of n( II) ∶ n( HBr) ∶ n( Na NO_2) = 1 ∶ 3 ∶ 6,catalyst mass fraction of 4%,and reaction at-5°C for 2. 5h.Its structure was characterized by1 HNMR,FTIR and MS.
引文
[1]徐卫良,李云政,张青山,等. 1-羟基-1,2-苯碘酰-3(1H)-酮-1-氧化物(IBX)的合成及在他唑巴坦合成中的应用[J].精细化工,2004,21(4):304-306.
[2]丁成荣,夏光华,沈方烈,等.他唑巴坦的合成新方法[J].中国药物化学杂志,2012,22(2):117-119.
[3]Liu H C.Preparation of ampicillin from 6-aminopenicillanic acid(6-APA)and D-phenylglycine methyl ester or hydrochloride salt with ampicillin synthetase[P]. CN:103937866A,2014-07-23.
[4]江虹,张华,谢虹.阿莫西林与维多利亚蓝B的显色反应及应用[J].化学研究与应用,2010,22(04):483-486.
[5]Wen S J,Wang C Y,Duan Y J,et al.OAT1 and OAT3 also mediate the drug-drug interaction between piperacillin and tazobactam[J]. Int J Pharm,2018,537(1/2):172-182.
[6]Senthilkumar U P,Sivasankaran V,Rajamanickam K.Process for the preparation of tazobactam[P]. WO:2014037893A1,2014-03-13.
[7]刘毅,陈喜,谢国云.一种他唑巴坦的制备方法[P].CN:104031065A,2014-09-10.
[8]胡月华,胡益民.β-内酰胺酶抑制剂-他唑巴坦新的合成方法[J].合成化学,2003,(3):243-245.
[9]Gujral R S,Vig A.Method for preparation of comparation of piperacillin sodium and tazobactam[P]. WO:2013/0145441A,2013-01-31.
[10]Senthilkumar U P,Mohan S.Process for the preparation of tazobactam[P].IN:2012CH03690A,2014-03-07.
[11]Isao W,Yoshihisa T,Akihiro S.Process for producing penam compound useful for preparing tazaobactam[P].US:7714125B2,2010-05-11.
[12]白国义,陈立功,李阳,等.他唑巴坦合成中1,3-偶极环加成反应的研究[J].精细化工,2001(11):634-637.
[13]Senthikumar U P,Mohan S,Sivasankaran V,et al.Process for the preparation of tazobactam[P]. US:20150246931A1,2015-09-03.
[14]杨庆坤,孙政军,张小勇,等.一种他唑巴坦的合成方法[P].CN:102643292A,2012-08-22.
[15]徐栋栋,张超,康从民.4-(4-吗啉基)-1H-吲唑-3-胺合成方法的改进[J].化学研究与应用,2018,30(3):456-459.
[16]夏洋峰,姜翠玉,安高军,等.Prins缩合反应合成4-丁基-1,3-二氧六环的研究[J].化学研究与应用,2017,29(8):1 111-1 115.
[2]丁成荣,夏光华,沈方烈,等.他唑巴坦的合成新方法[J].中国药物化学杂志,2012,22(2):117-119.
[3]Liu H C.Preparation of ampicillin from 6-aminopenicillanic acid(6-APA)and D-phenylglycine methyl ester or hydrochloride salt with ampicillin synthetase[P]. CN:103937866A,2014-07-23.
[4]江虹,张华,谢虹.阿莫西林与维多利亚蓝B的显色反应及应用[J].化学研究与应用,2010,22(04):483-486.
[5]Wen S J,Wang C Y,Duan Y J,et al.OAT1 and OAT3 also mediate the drug-drug interaction between piperacillin and tazobactam[J]. Int J Pharm,2018,537(1/2):172-182.
[6]Senthilkumar U P,Sivasankaran V,Rajamanickam K.Process for the preparation of tazobactam[P]. WO:2014037893A1,2014-03-13.
[7]刘毅,陈喜,谢国云.一种他唑巴坦的制备方法[P].CN:104031065A,2014-09-10.
[8]胡月华,胡益民.β-内酰胺酶抑制剂-他唑巴坦新的合成方法[J].合成化学,2003,(3):243-245.
[9]Gujral R S,Vig A.Method for preparation of comparation of piperacillin sodium and tazobactam[P]. WO:2013/0145441A,2013-01-31.
[10]Senthilkumar U P,Mohan S.Process for the preparation of tazobactam[P].IN:2012CH03690A,2014-03-07.
[11]Isao W,Yoshihisa T,Akihiro S.Process for producing penam compound useful for preparing tazaobactam[P].US:7714125B2,2010-05-11.
[12]白国义,陈立功,李阳,等.他唑巴坦合成中1,3-偶极环加成反应的研究[J].精细化工,2001(11):634-637.
[13]Senthikumar U P,Mohan S,Sivasankaran V,et al.Process for the preparation of tazobactam[P]. US:20150246931A1,2015-09-03.
[14]杨庆坤,孙政军,张小勇,等.一种他唑巴坦的合成方法[P].CN:102643292A,2012-08-22.
[15]徐栋栋,张超,康从民.4-(4-吗啉基)-1H-吲唑-3-胺合成方法的改进[J].化学研究与应用,2018,30(3):456-459.
[16]夏洋峰,姜翠玉,安高军,等.Prins缩合反应合成4-丁基-1,3-二氧六环的研究[J].化学研究与应用,2017,29(8):1 111-1 115.