CN110437137A - 一种阿维巴坦中间体化合物的合成方法 - Google Patents
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 35
- 239000000243 solution Substances 0.000 claims description 17
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- 239000002253 acid Substances 0.000 claims description 7
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- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 238000005516 engineering process Methods 0.000 claims description 6
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- NENDHUHGFRLXEN-UHFFFAOYSA-N acetic acid;rhodium Chemical compound [Rh].CC(O)=O NENDHUHGFRLXEN-UHFFFAOYSA-N 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- NDCUAPJVLWFHHB-UHNVWZDZSA-N avibactam Chemical compound C1N2[C@H](C(N)=O)CC[C@@]1([H])N(OS(O)(=O)=O)C2=O NDCUAPJVLWFHHB-UHNVWZDZSA-N 0.000 description 1
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- 239000012954 diazonium Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- LVCDXCQFSONNDO-UHFFFAOYSA-N n-benzylhydroxylamine Chemical compound ONCC1=CC=CC=C1 LVCDXCQFSONNDO-UHFFFAOYSA-N 0.000 description 1
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- 229910052710 silicon Inorganic materials 0.000 description 1
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- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种阿维巴坦中间体化合物的合成方法，具体合成路线为：
Description
技术领域
本发明属于药物制备领域，具体涉及一种阿维巴坦中间体化合物的合成方法。
背景技术
阿维巴坦(Avibactam)，是一个可以与酶可逆性共价结合的新型β内酰胺酶抑制剂。阿维巴坦作为一个新型的酶抑制剂，抑酶作用显著且广泛，能恢复或增强联用抗生素的活性，对临床细菌性尤其是耐药菌感染的治疗具有重要意义。
化合物E1为合成阿维巴坦关键中间体，其结构式为：
现有技术制备E1的合成方法或多或少存在着一些缺陷，如专利文件WO2013149136记载的合成路线为：
该路线需要使用金属铱[Ir(COD)Cl]2催化剂导致成本高、重金属污染；过程用到三苯基磷、偶氮二甲酸二乙酯所进行的Mitsnobu反应，对环境不友好。工艺路线长。
又如专利文件WO2012086241记载的合成路线为：
该方法中，合成化合物15，为叔丁酯，过程不但用到了贵金属催化剂[Ir(COD)Cl]2导致高昂的生产成本，在苄氧基胺取代三氟甲磺酸酯(14到15)的反应需要长达3.5天，生产效率极低，难以工业化。
另一篇专利文件US2014275001记载的合成路线为：
上述过程中获得化合物3的路线，先在低温无水的条件下获得重氮17，然后用醋酸铑催化环合得到化合物3。苛刻的工艺条件及昂贵的催化方式使其很难商业化生产。
综上所述，现有技术制备阿维巴坦关键中间体化合物E1存在反应路线长，或者原料昂贵，或者对环境不友好等等缺陷。
发明内容
为了解决上述问题，本发明提供一种阿维巴坦中间体化合物的合成方法。
为了实现上述目的，本发明采用如下技术方案：
一种阿维巴坦中间体化合物的合成方法，其特征在于，合成路线为：
其中，P为氨基保护基，R1为羧基保护基，R2为肟羟基保护基，X为卤素元素。
进一步的，P为Boc基，R1为OBzl、Et或Me，R2为Bn，X为Br、I。
进一步的，当R1为Et时，X为I。
进一步的，通过碱作用使化合物V11成环得到化合物V12，所述碱为二(三甲基硅基) 氨基钠或者二(三甲基硅基)氨基锂。
进一步的，用还原剂、酸与V12接触并与草酸作用得到E1，所述还原剂为三乙酰氧基硼氢化钠或氰基硼氢化钠。
进一步的，所述酸为三氟醋酸、甲基磺酸或硫酸。
上述阿维巴坦中间体化合物的合成方法合成方法，具体包括如下步骤：
(1)化合物V11合成工艺为：
氮气保护下，向反应釜中加入化合物B1、乙酸乙酯，氮气保护，加入O-苄基羟胺氢卤酸盐，升温到50℃搅拌反应2小时，降温到常温，反应液水洗、减压浓缩得到V11；
(2)化合物V12合成工艺为：
将所得化合物V11加入到DMF中，然后加入碱，常温反应8小时，向反应液加入水后，用乙酸乙酯萃取，将萃取液进行水洗，将水洗后的萃取液用硫酸钠干燥备用，得到化合物V12 的乙酸乙酯溶液；
(3)化合物E1合成工艺为：
将所得化合物V12的乙酸乙酯溶液降温至-5～0℃，搅拌下缓慢加入酸，控制温度-5～0℃加入还原剂，反应至化合物V12转化完全；向反应液中加入碳酸氢钠水溶液中，分去水相，加入草酸，搅拌析晶过滤、干燥得化合物E1。
使用本方法所得到的式V11、V12为新化合物，是制备式E1所需中间体，亦构成本发明的目的之一。
与现有技术相比，本发明的有益效果在于：
(1)采用本发明的技术方案制备阿维巴坦，由于未用到贵金属催化剂，因而没有重金属污染。
(2)利用V11的溴化物或碘化物制备V12，反应活性较氯化物高；V11反应活性按X的卤素取代物氯、溴、碘的顺序一次增加，V12的产率也相应增加。
(3)成环过程中采用二(三甲基硅基)氨基钠比采用碳酸铯、叔丁醇钾的转化率更好，总收率增加约50％，达到65％以上。采用碳酸铯、叔丁醇钾为非均相反应，以二(三甲基硅基)氨基钠做碱反应体系为均相，而因此成环收率更高。
(4)反应条件温和，对环境友好，能够实现大规模地工业化生产。
具体实施方式
下面结合实施例对本发明作进一步的描述，所描述的实施例仅仅是本发明一部分实施例，并不是全部的实施例。基于本发明中的实施例，本领域的普通技术人员在没有做出创造性劳动前提下所获得的其他所有实施例，都属于本发明的保护范围。
其中，B1-1、B1-2的制备参考文献Journal of the Chemical Society,ChemicalCommunications 1993，issue 18,P.1434。
实施例一：E1-2制备
1.中间体V11-2制备：
氮气保护下，向1500反应釜中加入159kg B1-2、776kg乙酸乙酯，氮气保护，加入O-苄基羟胺氢溴酸盐78kg,升温到50℃搅拌反应2小时。降温到常温，反应液用300kg水洗，然后减压浓缩得到V11-2。1H NMR(400MHz,CDCl3)δ7.232(w,10H,PhH)；5.177～4.966 (m,5H,2PhCH2,NH)；4.272(w,1H,NCH)；3.843～3.781(m,2H,BrCH2)；2.405～2.268(m,2H,NCCH2)；2.036(w,1H,CH2)；1.866(w,1H,CH2).
1H NMR(400MHz,CDCl3,D2O)δ7.232(w,10H,PhH),5.276～4.949(m,4H,2PhCH2)；4.257(w,1H,NCH)；3.841～3.766(m,2H,BrCH2)；2.396～2.268(m,2H,NCCH2)；2.034(w,1H,CH2)；1.843(w,1H,CH2).
2.中间体V12-2的制备：
上步V11-2加入到500kgDMF中，然后加入85kg二(三甲基硅基)氨基钠,常温反应8小时。向反应液加入1000kg水，用300kg乙酸乙酯萃取两次，合并乙酸乙酯相，水洗，硫酸钠干燥备用，得到V12-2的乙酸乙酯溶液。1H NMR(400MHz,CDCl3)δ7.218(s,10H,PhH)； 5.133～4.935(m,4H,PhCH2)；4.753～4.195(m,2H,NCH2)；3.769(dd,1H,J1＝15,J2＝16,COCH)；2.442～1.781(m,4H,2CH2)；1.355～1.243(w,9H,3CH3)
3.E1-2的制备：
上步V12-2的乙酸乙酯溶液降温至-5-0℃，搅拌下缓慢加入23kg三氟醋酸，控制温度-5-0℃分批加入三乙酰氧基硼氢化钠共60kg。继续反应6小时至V12转化完全。
将反应液滴加至碳酸氢钠溶液。分去水相，有机相经水洗后，加入30kg草酸，搅拌析晶 5小时。离心过滤、干燥得到112kg E，以B1-2计，摩尔收率67％。1H NMR(400MHz,DMSO-d6)δ9.584～8.078(w,4H,2NH,2COOH)；7.404～7.330(m,10H,2ArH)；5.227(s,2H,PhCH2O)；4.577(s,2H,PhCH2O)；4.013(dd,1H,J1＝3.3,J2＝9.2,COCH)；3.407～3.120(m,2H, NCH2)；2.642(t,1H,J＝11.2,NCH)；2.100(ABq,2H,J＝17.2,COCCH2)；1.545(ABq,2H,J＝13.2, NCCH2)
实施例二：E1-1制备
1.中间体V11-3的制备。制备过程同于实施例1.
V11-3:1H NMR(400MHz,CDCl3)δ7.268(w,5H,ArH)；5.084～5.020(m,3H,PhCH2O,NH)；4.217(w,1H,COCH)；4.152～4.016(m,2H,CH3CH2O)；3.839～3.576(m,2H,ICH2)；2.385～1.787(m,4H,2CH2)；1.369(s,9H,3CH3)；1.176(q,3H,J＝8,CH3)；1H NMR(400MHz,CDCl3,D2O)δ7.268(w,5H,ArH)；5.084～4.975(m,2H,PhCH2O)；4.206(w,1H,COCH)； 4.135～4.015(m,2H,CH3CH2O)；3.839～3.609(m,2H,ICH2)；2.400～1.850(m,4H,2CH2)；1.368(s, 9H,3CH3)；1.176(q,3H,J＝8,CH3)
2.中间体V12-1制备：
制备过程同于实施例1.
V12-1 1H NMR(400MHz,CDCl3)δ7.281～7.216(m,5H,PH)；5.007(s,2H,PhO-CH2)；4.720～4.241(m,2H,NCH2)；4.138～4.105(m,2H,OCH2)；3.795(dd,1H,J1＝15.2,J2＝19.2,COCH)； 2.774～1.941(m,4H,2CH2)；1.408～1.351(w,9H,3CH3)；1.213～1.176(t,J＝6.4,3H,CH3)
3.中间体E1-1的制备：
制备过程同于实施例1.得到E1-1 118kg,以B1-1计，摩尔收率71％。
E1-1 1H NMR(400MHz,CDCl3)δ10.238～8.527(w,3H,COOH、NH)；7.368～7.268(m,5H,ArH)；4.580(s,2H,PhCH2)；4.188(q,2H,J＝6.8,OCH2)；3.922(dd,1H,J1＝3.2,J2＝9.2,COCH) 3.240(ABq,2H,J＝18.4,NCH2)；2.640(t,1H,J＝11.6,NCH)；1.996(ABq,2H,J＝10.4,ONCCH2)； 1.517(ABq,2H,J＝8,COCCH2)；1.217(t,3H,J＝7.2,CH3)
以上揭露的仅为本发明的较佳实施例而已，当然不能以此来限定本发明之权利范围，因此依本发明权利要求所作地等同变化，仍属本发明所涵盖的范围。
Claims (9)
1.一种阿维巴坦中间体化合物的合成方法，其特征在于，合成路线为：
其中，P为氨基保护基，R1为羧基保护基，R2为肟羟基保护基，X为卤素元素。
2.如权利要求1所述阿维巴坦中间体化合物的合成方法，其特征在于：P为Boc基，R1为OBzl、Et或Me，R2为Bn，X为Br、I。
3.如权利要求1或2所述阿维巴坦中间体化合物的合成方法，其特征在于：当R1为Et时，X为I。
4.如权利要求1-3任一项所述阿维巴坦中间体化合物的合成方法，其特征在于，通过碱作用使化合物V11成环得到化合物V12，所述碱为二(三甲基硅基)氨基钠或者二(三甲基硅基)氨基锂。
5.如权利要求4所述阿维巴坦中间体化合物的合成方法，其特征在于，用还原剂、酸与V12接触并与草酸作用得到E1，所述还原剂为三乙酰氧基硼氢化钠或氰基硼氢化钠。
6.如权利要求5所述阿维巴坦中间体化合物的合成方法，其特征在于，所述酸为三氟醋酸、甲基磺酸或硫酸。
7.如权利要求1所述阿维巴坦中间体化合物的合成方法，其特征在于，具体包括如下步骤：
(1)化合物V11合成工艺为：
氮气保护下，向反应釜中加入化合物B1、乙酸乙酯，氮气保护，加入O-苄基羟胺氢卤酸盐，升温到50℃搅拌反应2小时，降温到常温，反应液水洗、减压浓缩得到V11；
(2)化合物V12合成工艺为：
将所得化合物V11加入到DMF中，然后加入碱，常温反应8小时，向反应液加入水后，用乙酸乙酯萃取，将萃取液进行水洗，将水洗后的萃取液用硫酸钠干燥备用，得到化合物V12的乙酸乙酯溶液；
(3)化合物E1合成工艺为：
将所得化合物V12的乙酸乙酯溶液降温至-5～0℃，搅拌下缓慢加入酸，控制温度-5～0℃加入还原剂，反应至化合物V12转化完全；向反应液中加入碳酸氢钠水溶液，分去水相，加入草酸，搅拌析晶过滤、干燥得化合物E1。
8.如权利要求1所述阿维巴坦中间体化合物的合成方法，其特征在于，所述化合物V11的结构式为：
其中，P为任意氨基保护基，R1为羧基保护基，R2为任意肟羟基保护基，X为溴或碘。且当R1为Et时，X为I。
9.如权利要求1所述阿维巴坦中间体化合物的合成方法，其特征在于，所述化合物V12的结构式为：
其中，P为任意氨基保护基，R1为羧基保护基，R2为任意肟羟基保护基。
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