CN111233748B - 合成盐酸替罗非班 - Google Patents

合成盐酸替罗非班 Download PDF

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CN111233748B
CN111233748B CN202010156266.0A CN202010156266A CN111233748B CN 111233748 B CN111233748 B CN 111233748B CN 202010156266 A CN202010156266 A CN 202010156266A CN 111233748 B CN111233748 B CN 111233748B
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pyridin
butylsulfonamido
butylsulfonyl
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CN111233748A (zh
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邱小龙
李冰健
左智伟
张义森
胡林
刘文博
邹平
储玲玲
张新刚
王平
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Jiangsu Huiju Pharmaceutical Co ltd
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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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract

本发明涉及一条制备盐酸替罗非班的方法。该方法涉及4‑吡啶丁醇或4‑(吡啶‑4‑基)丁‑3‑炔‑1‑醇与(S)‑3‑(4‑卤代苯基)‑2‑(正丁基磺酰氨基)‑丙酸酯在铜试剂/碱/添加物/溶剂条件下发生缩合反应，生成(S)‑2‑(正丁基磺酰氨基)‑3‑(4‑(4‑(吡啶‑4‑基)丁基氧)苯基)丙酸酯或(S)‑2‑(正丁基磺酰氨基)‑3‑(4‑((4‑(吡啶‑4‑基)丁‑3‑炔‑1‑基)氧)苯基)丙酸酯。

Description

合成盐酸替罗非班
技术领域
本发明涉及盐酸替罗非班的合成。
背景技术
盐酸替罗非班(Tirofiban Hydrochloride Monohydrate,商品名Aggrastat)化学名为(N-正丁基磺酰基-O-4-(4-哌啶基)丁基)-L-络氨酸盐酸盐单水合物,是一种可逆性非肽类血小板GPIIb/IIa受体拮抗剂，由国际制药巨头Merck公司于上世纪90年代开发，并于1998年5月成功通过美国FDA批准上市，目前该血小板拮抗剂已在瑞士、中国、德国以及荷兰等国广泛上市使用。该药适用于不稳定型心绞痛或非Q波心肌梗塞病人，预防心脏缺血事件，同时也适用于冠脉缺血综合症病人进行冠脉血管成形术或冠脉内斑块切除术，以及预防与经治冠脉突然闭塞有关的心脏缺血并发症。盐酸替罗非班结构式如下：
Figure BDA0002404156230000011
迄今为止，已有多条盐酸替罗非班的合成路线得以报道：
专利US750647描述了盐酸替罗非班的原始合成路线，该路线从4-哌啶-2-乙醇出发，经11步反应完成盐酸替罗非班的合成，路线中涉及Swern氧化、Wittig反应、硼烷还原等反应，该路线由于步骤长、总产率低等原因导致不易工业化放大生产。
专利CN1844099公开了制备盐酸替罗非班的新工艺。该工艺包括4-(4-吡啶基)-丁基氯还原生成4-(4-哌啶基)丁基氯，随后4-(4-哌啶基)丁基氯原位转化为4-(4-哌啶基)丁基碘。4-(4-哌啶基)丁基碘和N-丁基磺酰基-L-络氨酸在碱性条件下缩合制备替罗非班自由碱，后者再成盐得到目标产物。该路线对于起始原料4-(4-哌啶基)丁基氯的制备，专利人提供了两条路线，一是4-(4-吡啶基)丁基氯用Pd/C氢化制备；二是4-(4-吡啶基)丁基氯用金属钠在乙醇做溶剂条件下进行还原。第一条路线重现性差；第二条路线由于要使用非常活泼的金属钠，安全性问题难以放大。加之关键物料4-(4-哌啶基)丁基氯(碘)容易发生自身分子间缩合，该专利同样存在工业放大生产的局限性。
Merck公司专利US5206373(Tetrahedron,1993,49,5767；中国专利CN1050832)使用L-络氨酸在BSTFA(N,O-双(三甲基硅烷基)三氟乙酰胺)作用下与丁基磺酰氯反应得到N-丁基磺酰基-L-络氨酸。N-丁基磺酰基-L-络氨酸在碱性条件下和4-吡啶丁基氯缩合制备中间体N-正丁基磺酰基-O-(4-(4-吡啶基)-丁基)-L-络氨酸，后者进一步经氢化、盐酸化以及精制等工序完成盐酸替罗非班的制备。中国专利CN1415606的关键点和专利US5206373几乎一样，唯一区别是专利US5206373是使用N-丁基磺酰基-L-络氨酸和4-吡啶丁基氯在碱性条件下进行缩合，而专利CN1415606使用的是N-丁基磺酰基-L-络氨酸甲酯和4-吡啶丁基氯在碱性条件下进行缩合。这些专利都涉及中间体4-(4-吡啶基)-丁基氯的制备，专利US5206373使用了正丁基锂，需在-70℃低温且无水条件下反应，反应条件苛刻，实际工业化大生产难度大；而专利CN1415606由于使用了LiAlH4还原，同样难以放大生产。这些专利的路线如下：
Figure BDA0002404156230000021
Merck公司专利CN1040534则提供了一条较为可行的方法。该方法关键反应为N-丁基磺酰基-L-络氨酸甲酯和4-吡啶丁醇在三苯基膦和偶氮二甲酸二异丙酯(DIAD)作用下发生Mitsunobu反应，制备关键中间体N-正丁基磺酰基-O-(4-(4-吡啶基)-丁基)-L-络氨酸甲酯,然后该中间体经过酯基水解、Pd/C/HOAc还原吡啶基团为哌啶基，最后成盐酸盐完成盐酸替罗非班的制备。该路线虽然比较适合于产业化，但是Mitsunobu反应操作复杂,反应后处理时会产生大量的三苯氧膦副产物。专利CN1040534相关合成路线如下：
Figure BDA0002404156230000031
发明内容
本发明新开发出一条制备盐酸替罗非班的合成路线，该路线操作简单,易于实现产业化。
本发明的合成路线如下：
Figure BDA0002404156230000032
本发明第一步涉及4-吡啶丁醇(式I)或4-(吡啶-4-基)丁-3-炔-1-醇(式I)与(S)-3-(4-卤代苯基)-2-(正丁基磺酰氨基)-丙酸酯(式II)在铜试剂/碱/添加物/溶剂条件下发生缩合反应，生成(S)-2-(正丁基磺酰氨基)-3-(4-(4-(吡啶-4-基)丁基氧)苯基)丙酸酯(式III)或(S)-2-(正丁基磺酰氨基)-3-(4-((4-(吡啶-4-基)丁-3-炔-1-基)氧)苯基)丙酸酯(式III)。
式I中的R2为
Figure BDA0002404156230000041
式II中的X为Cl,Br,I。
式II中的R1为Me,Et,nPr,iPr,nBu。
式III中的R2为
Figure BDA0002404156230000042
式III中的R1为Me,Et,nPr,iPr,nBu。
第一步反应使用的铜试剂为CuO,Cu(OAc)2,CuI,CuBr,Cu2O,Cu(acac)2。
第一步反应使用的碱为K3PO4,tBuOK,tBuONa。
第一步反应使用的添加物为草酰二胺化合物,包括N1,N2-二(2,4,6-三甲氧基苯基)草酰二胺,N1,N2-二(2-苯基-4-甲基苯基)草酰二胺，N1-(1-萘基)-N2-烷基类草酰二胺,N1-苄基-N2-(5-甲基-[1,1'-联苯]-2-基)草酰二胺，N1,N2-双(苯基乙基)草酰二胺，N1,N2-二([1,1'-联苯]-2-二基)草酰二胺,N1-苄基-N2-([1,1'-联苯]-2-基)草酰二胺,N1,N2-双(萘-1-基甲基)草酰二胺。
第一步反应使用的溶剂为叔丁醇，1,4-二氧六环，DMF,乙腈，DMSO。
反应第二步涉及式III化合物在碱的作用下，酯基发生水解反应，制备得到式IV化合物。
式IV中的R2为
Figure BDA0002404156230000043
反应第二步使用的碱为LiOH、NaOH、KOH、CsOH。
反应第三步为式IV化合物在以醋酸作为溶剂的条件下，在含Pd催化剂条件下发生氢化反应，生成N-正丁基磺酰基-O-(4-(哌啶-4-基)丁-1-基)-L-络氨酸(式V)。
反应第三步所使用的含Pd催化剂为Pd/C、Pd(OH)2。
反应第四步为式V化合物在溶剂存在下加入盐酸成盐，完成盐酸替罗非班的制备。
具体实施方式
通过下面的实施例可以更具体的理解本发明，但其是举例说明而不是限制本发明的范围。
实施例
1.制备(S)-2-(正丁基磺酰氨基)-3-(4-(4-(吡啶-4-基)丁基氧)苯基)丙酸乙酯(式III,R1＝Et,R2＝
Figure BDA0002404156230000044
)。
将(S)-3-(4-氯苯基)-2-(正丁基磺酰氨基)-丙酸乙酯(139.0g,0.40mol)，4-吡啶丁醇(181.5g,1.20mol),CuI(3.80g,19.95mmol)，K3PO4(127.4g,0.60mol)和N1,N2-双(萘-1-基甲基)草酰二胺(14.8g,39.96mmol)加入到反应瓶中，随后氮气置换三次，然后向反应瓶中加入无水DMSO(500mL),反应体系再次氮气置换三次。随后，反应体系搅拌下加热至100℃反应24h。反应结束后，体系自然降至室温。反应体系加入乙酸乙酯(1.5L)稀释，然后通过硅藻土过滤。滤液减压下脱溶去除有机溶剂。残余物加入二氯甲烷(2.5L)和H2O(600mL),体系搅拌10分钟，分出有机相，水相使用二氯甲烷萃取3次(3×1.0L),合并有机相，有机相减压脱除溶剂，残余物加入丙酮(500mL)剧烈搅拌过夜，过滤，所得固体化合物干燥后无需纯化，直接用于下一步(类白色固体，136.2g,73.6％)。
2.制备(S)-2-(正丁基磺酰氨基)-3-(4-((4-(吡啶-4-基)丁-3-炔-1-基)氧)苯基)丙酸正丙酯(式III,R1＝nPr,R2＝
Figure BDA0002404156230000051
)。
将(S)-3-(4-溴苯基)-2-(正丁基磺酰氨基)-丙酸正丙酯(81.3g,0.20mol)，4-(吡啶-4-基)丁-3-炔-1-醇(59.0g,0.40mol),Cu(OAc)2(1.82g,10.02mmol)，叔丁醇钾(27.0g,0.24mol)和N1,N2-双(苯基乙基)草酰二胺(3.0g,10.06mmol)加入到反应瓶中，氮气置换三次，随后向反应瓶中加入无水1,4-二氧六环(450mL),反应体系再次氮气置换三次。随后，反应体系搅拌下加热至80℃反应24h。反应结束后，体系自然降至室温。反应体系加入乙酸乙酯(1.0L)稀释，然后通过硅藻土过滤。滤液减压下脱溶去除有机溶剂。残余物加入二氯甲烷(1.5L)和H2O(600mL),体系搅拌10分钟，分出有机相，水相使用二氯甲烷萃取3次(3×600mL),合并有机相，有机相减压脱除溶剂，残余物加入正丙醇/丙酮(1:1，500mL)剧烈搅拌过夜，过滤，所得固体化合物干燥后无需纯化，直接用于下一步(浅黄色固体，77.0g,81.5％)。
3.制备N-正丁基磺酰基-O-(4-(吡啶-4-基)丁-3-炔-1-基)-L-络氨酸(式IV,R2＝
Figure BDA0002404156230000052
)。
三口反应瓶配备磁力搅拌和温度计。向反应瓶中加入(S)-2-(正丁基磺酰氨基)-3-(4-((4-(吡啶-4-基)丁-3-炔-1-基)氧)苯基)丙酸正丙酯(式III,R1＝nPr,R2＝
Figure BDA0002404156230000053
)(60.0g,127.0mmol)、THF(310mL)和乙醇(85mL)。加入完毕后体系搅拌溶解，然后向反应体系中加入LiOH(3.19g,133mmol)的H2O(80mL)溶液。加入完毕后，体系室温搅拌至TLC跟踪起始物料式III基本完全消失。体系加入稀HCl调节pH值至8-9，高真空减压脱除溶剂，残余物加入H2O(100mL)稀释，体系使用乙酸乙酯(100mL)萃取，去除有机相，水相使用稀HCl调节pH值至5-6，然后体系用乙酸乙酯(3×150mL)萃取，无水硫酸钠干燥，过滤，滤液高真空脱除溶剂，残余物使用异丙醇重结晶得N-正丁基磺酰基-O-(4-(吡啶-4-基)丁-3-炔-1-基)-L-络氨酸(式IV)(38.5g,70.4％)。
4.制备N-正丁基磺酰基-O-(4-(哌啶-4-基)丁-1-基)-L-络氨酸(式V)。
2L小型高压反应釜中加入N-正丁基磺酰基-O-(4-(吡啶-4-基)丁-3-炔-1-基)-L-络氨酸(式IV，R2＝
Figure BDA0002404156230000061
(33.0g,76.7mmol)和醋酸(400mL)。随后，氮气保护下将含有Pd/C(含Pd 5％)(2.0g)的醋酸(25mL)的稀浆状物加入到高压釜中。关闭高压釜，氮气置换三次后，反应体系在氢气压力(10atm)和60℃条件下进行氢化2.5小时。降温至室温，体系过滤，残余物高真空减压脱除溶剂(体系最后残留少量醋酸即可，不需要全部脱干)，随后向残余物中加入H2O(400mL)，室温搅拌过夜。过滤，固体使用H2O(200mL)洗涤，所得湿品干燥得N-正丁基磺酰基-O-(4-(哌啶-4-基)丁-1-基)-L-络氨酸(式V)(28.8g,85.1％)。
5.制备盐酸替罗非班
三口圆底烧瓶中配备磁力搅拌和温度计，然后向反应瓶中加N-正丁基磺酰基-O-(4-(哌啶-4-基)丁-1-基)-L-络氨酸(式V)(25.5g,56.9mmol)和醋酸异丙酯(600mL)。小心搅拌至体系中固体完全溶解，然后在20℃下向反应体系中通过滴液漏斗缓慢加入浓HCl(9.7mL)。加入完毕后体系保温搅拌5小时，然后体系氮气保护下过滤，所得固体使用醋酸异丙酯洗涤(2×50mL)。所得固体减压干燥得盐酸替罗非班一水合物(25.0g,88.7％)。

Claims (2)

1.制备(S)-2-(正丁基磺酰氨基)-3-(4-(4-(吡啶-4-基)丁基氧)苯基)丙酸酯或(S)-2-(正丁基磺酰氨基)-3-(4-((4-(吡啶-4-基)丁-3-炔-1-基)氧)苯基)丙酸酯的方法，反应式如下：
Figure FDA0003686151820000011
反应所使用的铜试剂为Cu(OAc)2,CuI,CuBr,
反应所使用的碱为K3PO4,tBuOK或tBuONa；
反应所使用的添加物为N1,N2-双(苯基乙基)草酰二胺；或N1,N2-双(萘-1-基甲基)草酰二胺。
2.根据权利要求1所述方法，其特征在于，反应所使用的溶剂为叔丁醇，1,4-二氧六环，DMF,乙腈或DMSO。
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