CN116730953A - 一种布瓦西坦中间体的制备方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
- C07D307/60—Two oxygen atoms, e.g. succinic anhydride
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
通过金属钌催化不对称氢化不饱和环丁酮酯,合成了布瓦西坦的关键中间体,具有高收率、高ee值、反应条件温和以及催化剂用量低的特点,并且可以进行克级反应,具有极大的潜在应用价值。
Description
技术领域
本发明涉及医药、有机化工合成技术领域,具体涉及到一种布瓦西坦中间体的制备方法。
背景技术
布瓦西坦(Brivaracetam),化学名称为(S)-2-((R)-2-氧代-4-丙基吡咯烷-1-基)丁酰胺,其结构如下:
布瓦西坦是由优时比(UCB)公司研发,分别于2016年1月14日和2月18日获欧洲药品管理局(EMA)和美国食品药品管理局(FDA)批准上市,该药用于成人及16岁以上青少年癫痫患者的部分发作,伴有或不伴有继发性全身性发作的辅助治疗,并于2021年美国食品药品管理局(FDA)批准用于年龄低至1个月大的患者,治疗部分发作性癫痫,也是近7年FDA批准的唯一一种用于治疗1个月及以上儿科患者部分发作性癫痫的Ⅳ制剂。
布瓦西坦具有高度亲和力,可选择性的结合突触囊泡蛋白2A(SV2A),是AED左乙拉西坦的作用位点。SV2A位于突触前膜,参与调解神经递质的释放和囊泡循环进而维持着突触囊泡的正常功能。AED与SV2A结合可减少兴奋性神经递质的释放,并通过调节脑内兴奋性递质和抑制性递质的平衡达到控制癫痫发作的效果。
(R)-4-正丙基二氢呋喃-2-酮是布瓦西坦合成过程中一个关键的中间体,ArnaudSchule(Org.Process Res.Dev.2016,20,1566-1575)报道了如下的反应路线:
专利CN 108503610 A公布了如下反应路线:
专利CN 108530402 A公布了如下反应路线:
专利CN 109134406 A公布了如下反应路线:
Sinai-Zingde,G.,(J.Org.Chem.1987,52,719.)报道了如下的反应路线:
在以上合成路线中,路线1和路线4均涉及到手性拆分以得到单一构型的产品,这些方法路线长并且收率低,操作繁琐;路线2、路线3和路线5则以手性底物作为起始原料直接构建具有手性中心的产品,尽管这些方法可以避免手性拆分导致的收率低等问题,但手性底物原料价格贵,提高了生产成本。
发明内容
为了克服现有技术的缺点和不足,本发明的目的在于提供一种合成布瓦西坦中间体的制备方法,该方法反应条件温和、产率高、对映选择性好、操作简便,无需手性拆分,无需手性起始原料,成本低。
本发明为解决上述技术问题采用的技术方案为:一种布瓦西坦中间体的制备方法,以4-正丙基呋喃-2(5H)-酮为底物,在氢气和手性催化剂作用下进行反应,包括如下步骤:
1)制备如式(Ⅲ)所示的不饱和环丁内酯化合物:
2)式(Ⅲ)化合物在手性催化剂存在下经过不对称氢化得到如式(Ⅰ)所示的光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮:
所述不对称氢化所用的手性催化剂为醋酸钌与双膦配体的络合物。
所述手性催化剂的双膦配体为(S)-(-)-2,2'-二(二-3,5-二甲基苯基)膦-1,1'-联萘、(S)-(+)-2,2'-双[二(3,5-二叔丁基苯基)磷]-6,6'-二甲氧基-1,1'-联苯、(S)-(+)-2,2'-联[二-(4-甲基苯基)膦基]-1,1'-联萘、(S)-(6,6′-二甲氧基联苯-2,2'-二基)二[双(3,5-二-叔丁基-4-甲氧苯基)膦]、(S)-5,5'-双(二苯基膦)-4,4'-联苯并二恶茂、(S)-(-)-2,2'-双[双(3,5-二叔丁基-4-甲氧基苯基)膦基]-1,1'-联萘,优选(S)-(+)-2,2'-双[二(3,5-二叔丁基苯基)磷]-6,6'-二甲氧基-1,1'-联苯。
所述不对称氢化反应温度为25℃~60℃,优选25℃。
所述不对称氢化反应压力为300kPa~1600kPa,优选500kPa。
所述不对称氢化反应溶剂为三氟乙醇、甲醇、乙醇、异丙醇、叔丁醇、环己醇、苯甲醇、乙酸乙酯、四氢呋喃、乙苯、甲苯、均三甲苯、三氟甲苯、苯、苯甲醚,优选三氟乙醇。
所述步骤(1)中制备式(Ⅲ)结构化合物的方法为式(Ⅱ)所示的化合物在还原剂存在的条件下制备式(Ⅲ)所示的4-正丙基呋喃-2(5H)-酮。
所述还原剂为硼氢化钠。
所述式(Ⅱ)化合物与还原剂的摩尔比是1:1。
所述式(Ⅱ)化合物被还原的反应溶剂为甲苯,反应温度为25℃。
所述式(Ⅱ)化合物的制备方法包括如下步骤:
提供市售的正戊醛和乙醛酸水合物作为底物,
使正戊醛和乙醛酸水合物在含有碱性试剂的溶剂中反应,生成式(Ⅱ)所示的化合物,
其中,
反应所用的碱性试剂为吗啡啉。
所述步骤B)中正戊醛与乙醛酸水合物的摩尔比是1:1.3,正戊醛与吗啡啉的摩尔比是1:1.1。
所述反应的溶剂是正己烷,反应温度是48℃。
本发明采用具有前手性的4-正丙基呋喃-2(5H)-酮在手性催化剂存在下,通过不对称氢化的方式得到本发明的目标产物。总反应过程如下:
步骤(1):使正戊醛与乙醛酸水合物在碱性试剂存在下发生反应,生成式(Ⅱ)所示的化合物。
步骤(2):使步骤(1)所得式(Ⅱ)所示化合物在还原剂存在的条件下制备式(Ⅲ)所示化合物。
步骤(3):使步骤(2)所得式(Ⅲ)所示化合物在手性催化剂存在条件下进行不对称氢化反应,制备光学纯(R)-4-正丙基-二氢呋喃-2(3H)-酮。
整个合成路线如下:
本发明的方法适合制备(R)构型的4-正丙基-二氢呋喃-2(3H)-酮。此处所用的术语(R)指的是这样的化合物:它有95%以上的对映异构体组成。
与现有技术相比,本发明所采用的技术方案带来的有益技术效果为:
本发明方法通过采用手性催化剂催化4-正丙基呋喃-2(5H)-酮手性还原为(R)-4-正丙基-二氢呋喃-2(3H)-酮,解决了现有布瓦西坦中间体合成路线中合成路线长,收率低、成本高的问题,该方法反应条件温和,反应效率高,操作简便,对映选择性好,提高了制备(R)-4-正丙基-二氢呋喃-2(3H)-酮的效率和降低了生产成本,具有工业价值。
附图说明
图1是实施例1所得产物氢谱图
图2是实施例1所得产物碳谱图
图3是实施例2所得产物氢谱图
图4是实施例2所得产物氢谱图
图5是实施例3所得产物氢谱图
图6是实施例3所得产物氢谱图
图7是实施例3所得产物气相色谱图
图8是实施例3所得产物气相积分结果图
实施方式
下面结合具体实施例对本发明作进一步详细地描述,但本发明的实施方式不限于此。
实施例
5-羟基-4-正丙基-2-呋喃酮的制备:
取吗啡啉(110mmol,9.6800g,1.1eq.)溶于正己烷(30mL)中,0℃下缓慢滴加50%乙醛酸水溶液(130mmol,19.2504g,1.3eq.),在30℃下反应2小时后滴加正戊醛(100mmol,8.7888g),在48℃下反应20小时,TLC监测直至反应完全。降至室温,缓慢滴加浓盐酸(15mL)淬灭,继续搅拌2小时。分出水相,先用正己烷(30mL′3)洗涤,再用甲基叔丁基醚(30mL′3)萃取,合并有机相,用饱和食盐水洗涤,再用无水硫酸钠干燥,过滤,减压浓缩至干,通过硅胶柱得到10.7225g目标化合物,为无色透明液体,收率75%。
1H NMR(400MHz,CDCl3)δ6.04(s,1H),5.84(s,1H),2.48–2.32(t,2H),1.72–1.56(m,2H),1.01(t,J=5.3Hz,3H).13C NMR(101MHz,CDCl3)δ73.58,35.61,35.33,34.64,20.71,14.08.
根据以上数据推断所得产物的结构如下:
实施例2
4-正丙基呋喃-2(5H)-酮的制备:
在氮气保护下,将5-羟基-4-正丙基-2-呋喃酮(11.0803g,78mmol)溶于甲苯(86mL)中,0℃下缓慢滴加硼氢化钠(78mmol,3.0420g,1.0eq.)水溶液,室温下反应4小时后滴加乙酸淬灭,用甲苯(30mL′3)萃取,10%的碳酸氢钠水溶液(10mL′3)洗涤,饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩,通过硅胶柱得到4.2518g目标化合物,为无色透明液体,收率43%。
1H NMR(400MHz,CDCl3)δ5.84(s,1H),4.74(s,2H),2.39(t,J=6.0Hz,2H),1.67–1.59(m,2H),1.00(t,J=9.0Hz,3H).13C NMR(101MHz,CDCl3)δ73.58,35.61,35.33,34.64,20.71,14.08.
根据以上数据推断所得产物的结构如下:
实施例3
(R)-4-正丙基-二氢呋喃-2(3H)-酮的制备(毫克级反应):
在氮气氛围下,取手性催化剂(0.006mmol,6.2mg)于反应釜中,加入三氟乙醇(0.25mL)于室温下搅拌20分钟,然后缓慢加入溶于三氟乙醇(0.5mL)的4-正丙基呋喃-2(5H)-酮(1mmol,126.2mg),将氮气置换为氢气(500kPa′7次),在500kPa,25℃下反应20小时,GC-MS监测反应完全后用硅藻土和硅胶过滤,二氯甲烷洗涤,取滤液减压浓缩,蒸馏得到96.2mg目标化合物,为无色透明液体,GC收率99%,分离收率75%,ee值96%。
1H NMR(400MHz,CDCl3)δ4.42(dd,J=8.6,7.7Hz,1H),3.93(dd,J=8.7,7.4Hz,1H),2.67–2.51(m,2H),2.19(dd,J=16.5,7.5Hz,1H),1.49–1.42(m,2H),1.40–1.30(m,2H),0.94(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ73.58,35.61,35.33,34.64,20.71,14.08.[α]D 17+4.08°(c=0.02646g/mL,CH2Cl2).
根据以上数据推断所得产物的结构如下:
实施例4
(R)-4-正丙基-二氢呋喃-2(3H)-酮的制备(克级反应):
在氮气氛围下,取手性催化剂(0.016mmol,16.5mg)于反应釜中,加入三氟乙醇(0.67mL)于室温下搅拌20分钟,然后缓慢加入溶于三氟乙醇(4.0mL)的4-正丙基呋喃-2(5H)-酮(8.0mmol,1.000g),将氮气置换为氢气(500kPa′7次),在1000kPa,25℃下反应20小时,GC-MS监测反应完全后用硅藻土和硅胶过滤,二氯甲烷洗涤,取滤液减压浓缩,蒸馏得到0.7867g目标化合物,为无色透明液体,GC收率99%,分离收率78%,ee值96%。
上述手性催化剂及溶剂均为市售,其中三氟乙醇通过冻融法除杂后使用,其余溶剂均通过标准处理后使用。
Claims (13)
1.一种布瓦西坦中间体的制备方法:以4-正丙基-2(5H)-呋喃酮为底物,在手性催化剂的作用下进行反应,具体包括:
1)制备如式(Ⅲ)所示的不饱和环丁内酯化合物:
2)式(Ⅲ)化合物在手性催化剂存在下经过不对称氢化得到如式(Ⅰ)所示的光学纯的(R)-4-正丙基-二氢呋喃-2(3H)-酮:
2.根据权利要求1所述的方法,其特征在于,所述不对称氢化所用的手性催化剂为醋酸钌与双膦配体的络合物。
3.根据权利要求1所述的方法,其特征在于,所述手性催化剂的双膦配体为(S)-(+)-2,2'-双[二(3,5-二叔丁基苯基)磷]-6,6'-二甲氧基-1,1'-联苯。
4.根据权利要求1所述的方法,其特征在于,所述不对称氢化反应温度为25℃。
5.根据权利要求1所述的方法,其特征在于,所述不对称氢化反应压力为500kPa。
6.根据权利要求1所述的方法,其特征在于,所述不对称氢化反应溶剂为三氟乙醇。
7.根据权利要求1所述的方法,所述步骤1)中制备式(Ⅲ)结构化合物的方法为式(Ⅱ)所示的化合物在还原剂存在的条件下制备式(Ⅲ)所示的4-正丙基呋喃-2(5H)-酮:
8.根据权利要求7所述的方法,所述还原剂为硼氢化钠。
9.根据权利要求7所述的方法,所述式(Ⅱ)化合物被还原的反应溶剂为甲苯,反应温度为25℃,所述式(Ⅱ)化合物与还原剂的摩尔比是1:1。
10.根据权利要求7所述的方法,所述式(Ⅱ)化合物的制备方法包括如下步骤:
A)提供市售的正戊醛和乙醛酸水合物作为底物,
B)使正戊醛和乙醛酸水合物在含有碱性试剂的溶剂中反应,生成式(Ⅱ)所示的化合物。
11.根据权利要求10所述的方法,所述的反应所用的碱性试剂为吗啡啉。
12.根据权利要求10所述的方法,所述的反应溶剂为正己烷,反应温度为25℃。
13.根据权利要求10所述的方法,所述步骤B)中正戊醛与乙醛酸水合物的摩尔比是1:1.3,正戊醛与吗啡啉的摩尔比是1:1.1。
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