CN110615744B - 一种布瓦西坦中间体及其制备方法 - Google Patents

一种布瓦西坦中间体及其制备方法 Download PDF

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CN110615744B
CN110615744B CN201810634229.9A CN201810634229A CN110615744B CN 110615744 B CN110615744 B CN 110615744B CN 201810634229 A CN201810634229 A CN 201810634229A CN 110615744 B CN110615744 B CN 110615744B
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杨汉荣
罗宇
李涛
王博
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Shanghai Puyi Chemical Co ltd
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Abstract

本发明提出一种化合物，3‑((((S)‑1‑氨基‑1‑氧代丁‑2‑基)氨基)甲基)己酸(I)，以及其制备方法。该化合物(I)包含(R)‑3‑((((S)‑1‑氨基‑1‑氧代丁‑2‑基)氨基)甲基)己酸(I)‑R，或(S)‑3‑((((S)‑1‑氨基‑1‑氧代丁‑2‑基)氨基)甲基)己酸(I)‑S，或者任意比例的(I)‑R与(I)‑S的混合物。本发明式(I)的化合物，可以用于布瓦西坦的合成，为设计简洁高效的路线合成布瓦西坦提供了新的思路和方法。

Description

一种布瓦西坦中间体及其制备方法
技术领域
本发明涉及布瓦西坦合成技术领域，更具体地，涉及中间体3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)，以及其合成技术领域。
背景技术
布瓦西坦(Brivaracetam)是UCB公司开发的新一代抗癫痫药物，2016年2月，美国FDA批准布瓦西坦上市，布瓦西坦可以作为其他药物的附加药物治疗部分发作性癫痫。
布瓦西坦(S)-2-((R)-2-氧代-4-丙基吡咯啉-1-基)丁酰胺的结构如式1所示，本发明设计了一种新的化合物3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)，该化合物(I)包含(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)-R，或(S)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)-S，或者任意比例的(I)-R与(I)-S的混合物。其中异构体(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)-R可以通过关环反应得到布瓦西坦。
Figure 359783DEST_PATH_IMAGE001
由于布瓦西坦分子中有两个手性中心，对应四个不同的异构体，这给布瓦西坦的合成带来了一定的难度。目前合成布瓦西坦的方法主要有以下报道：
最早的方法是UCB开发的，以正戊醛为原料，先与乙醛酸环合，再与L-氨基丁酰胺反应，得到的产物氢化，生成一对非对映异构体，再通过柱层析分离纯化得到产物布瓦西坦（式2），如专利CN1208319C、CN1882535B所述。该方法步骤虽短，但最后一步只能柱层析分离，成本高而且不适合大量生产，限制了其应用。
Figure 808082DEST_PATH_IMAGE002
CN107663185A报道了以(R)-4-丙基二氢呋喃-2(3H)-酮为中间体与L-氨基丁酰胺反应得到布瓦西坦（式3）。但是手性的(R)-4-丙基二氢呋喃-2(3H)-酮合成路线很长，涉及到金属试剂反应，而且它与L-氨基丁酰胺也需要多步转化才能得到目标产物。这使整个合成方案路线长，操作繁琐。
Figure 181295DEST_PATH_IMAGE003
CN106748950A报道了以差向异构体混合物酸为中间体，通过与R-苯乙胺的成盐纯化的方法得到单一异构体酸，再转化成布瓦西坦的方法（式4）。该方法相对比较简洁，实用性较强。
Figure 107662DEST_PATH_IMAGE004
发明内容
为了探索简洁高效的合成布瓦西坦的方法，本发明提出了一种中间体3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)。
Figure 125297DEST_PATH_IMAGE005
该化合物(I)包含(R)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)-R，或(S)-3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)-S，或者任意比例的(I)-R与(I)-S的混合物。
Figure 603552DEST_PATH_IMAGE006
本发明还提出一种合成中间体3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)的方法，该方法以(2S)-2-(2-羟基-5-氧代-3-丙基-2,5-二氢-1H-吡咯-1-基)丁酰胺(II)为原料，在水中氢化还原，得到式(I)的化合物。
Figure 136164DEST_PATH_IMAGE008
较佳的，所述的氢化还原的催化剂为钯碳，反应温度为10~50oC，压力1~30bar。
本发明还涉及一种合成中间体(2S)-2-(2-羟基-5-氧代-3-丙基-2,5-二氢-1H-吡咯-1-基)丁酰胺(II)的方法，该方法以正戊醛与乙醛酸为原料，先按CN1208319C和CN1882535B中的方法合成中间体5-羟基-4-丙基呋喃-2(5H)-酮(III)，中间体(III)与L-氨基丁酰胺在醇溶剂体系中反应得到中间体(2S)-2-(2-羟基-5-氧代-3-丙基-2,5-二氢-1H-吡咯-1-基)丁酰胺(II)。
较佳的，所述的醇溶剂为异丙醇，反应温度为30~40oC，反应时间2~4小时。
具体实施方式
为更好的理解本发明的内容，下面结合具体实施例作进一步说明。应理解，下列具体实施例仅仅用于说明本发明，而不是对本发明的限制。
实施例1：5-羟基-4-丙基呋喃-2(5H)-酮(III)的制备
Figure 741589DEST_PATH_IMAGE009
将正庚烷125mL和***啉30mL加入三口瓶中，常温下搅拌10min混合均匀，降温至4oC以下滴加50%乙醛酸水溶液25.0g。滴完后升温至25~30oC搅拌反应2h，然后在40oC以下缓慢加入正戊醛30.5g，继续搅拌反应18h。反应完成后降温至20oC，缓慢滴加浓盐酸21.3g搅拌。
降至室温，静置分去正庚烷相。水相中加入乙酸乙酯100mL，缓慢加入碳酸钠固体调pH=4，分层取有机相，再用乙酸乙酯萃取，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥、抽滤、减压浓缩，得棕色油状物5-羟基-4-丙基呋喃-2(5H)-酮(III) 43.9g，收率91.5%。1H NMR (400 MHz, Chloroform-d) δ 0.93-1.00 (t, 3H), 1.56-1.67 (q, 2H),2.31-2.43 (q, 2H), 5.81 (s, 1 H), 6.02 (s, 1 H). MS (ESI) m/z =143 (M++1)。
实施例2：(2S)-2-(2-羟基-5-氧代-3-丙基-2,5-二氢-1H-吡咯-1-基)丁酰胺(II)的制备
Figure 857138DEST_PATH_IMAGE010
将氨基丁酰胺盐酸盐96.2g混溶于异丙醇1000mL中，通氨气进行游离，直至体系pH值为9~10，且pH值不变化为止。过滤除去盐，滤液浓缩至500mL待用。
将5-羟基-4-丙基呋喃-2(5H)-酮(III) 98.4g分批加入上述500mL氨基丁酰胺溶液中，控温30~40oC反应2h以上。反应完成后过滤去除盐，滤液缓慢降温至0~5oC析晶，抽滤，用少量乙酸乙酯漂洗，得白色固体(2S)-2-(2-羟基-5-氧代-3-丙基-2,5-二氢-1H-吡咯-1-基)丁酰胺(II)139.2g，收率88.8%。1H NMR (500 MHz, Chloroform-d) δ 6.45 (s, 1H),5.89 (s, 1H), 5.85 (s, 1H), 5.57 (s, 1H), 3.42 (s, 1H), 2.39 (s, 3H), 1.82(dq, J = 14.4, 7.4, 6.9 Hz, 1H), 1.74 (dt, J = 14.2, 7.2 Hz, 1H), 1.67 (dd, J= 14.6, 7.2 Hz, 2H), 1.02 (dt, J = 11.3, 7.4 Hz, 6H). MS (ESI) m/z =227 (M++1)。
实施例3：3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)的制备
Figure 381661DEST_PATH_IMAGE011
将(2S)-2-(2-羟基-5-氧代-3-丙基-2,5-二氢-1H-吡咯-1-基)丁酰胺(II) 15.0g加入到150mL水中，再加入5%的Pd/C 1.5g, 搅拌均匀，氮气置换。通氢气至20bar，常温搅拌反应过夜。反应完后，过滤去钯碳，旋干滤液得到淡黄色油状物3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)16.3g，收率93.7%。1H NMR (400 MHz, DMSO-d 6) δ 7.34 (s,1H), 7.01 (s, 1H), 2.96 – 2.79 (m, 1H), 2.56 (dd, J = 11.6, 4.9 Hz, 1H), 2.40(d, J = 4.8 Hz, 1H), 2.29 (ddt, J = 28.6, 20.1, 10.3 Hz, 1H), 2.13 (ddd, J =21.1, 11.9, 5.2 Hz, 1H), 1.93 – 1.74 (m, 1H), 1.49 (tt, J = 13.6, 6.5 Hz,2H), 1.41 – 1.07 (m, 4H), 0.82 (dt, J = 29.2, 6.6 Hz, 6H). MS (ESI) m/z =231(M++1)。
在此说明书中，本发明已参照其特定的实施例作了描述。但是，很显然仍可以作出各种修改和变换而不背离本发明的精神和范围。因此，说明书应被认为是说明性的而非限制性的。

Claims (1)

1.一种制备化合物3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)的方法，该化合物有如下结构；
Figure 489742DEST_PATH_IMAGE001
所述的一种制备化合物3-((((S)-1-氨基-1-氧代丁-2-基)氨基)甲基)己酸(I)的方法，包括将(2S)-2-(2-羟基-5-氧代-3-丙基-2,5-二氢-1H-吡咯-1-基)丁酰胺(II)在水中氢化还原，得到式(I)的化合物；
Figure 672462DEST_PATH_IMAGE002
所述氢化还原方法的催化剂为钯碳，反应温度为10~50℃，压力20~30bar；
所述的(2S)-2-(2-羟基-5-氧代-3-丙基-2,5-二氢-1H-吡咯-1-基)丁酰胺(II)的制备方法，包括将5-羟基-4-丙基呋喃-2(5H)-酮(III)与L-氨基丁酰胺在醇类溶剂中反应得到式(II)的化合物；
Figure 858724DEST_PATH_IMAGE003
所述的醇类溶剂为异丙醇，反应温度为30~40℃，反应时间2~4小时。
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EP18923290.3A EP3812377A4 (en) 2018-06-20 2018-10-30 BRIVARACETAM INTERMEDIATE, METHOD OF PRODUCTION AND METHOD OF PRODUCTION OF BRIVARACETAM
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