CN112250611B - 一种-2-(2,5-二氟苯基)吡咯烷盐酸盐的合成方法 - Google Patents
一种-2-(2,5-二氟苯基)吡咯烷盐酸盐的合成方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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Abstract
本发明公开一种2‑(2,5‑二氟苯基)吡咯烷盐酸盐的合成方法,属于药物合成领域。本发明以对二氟苯和丁二酸酐为原料经过傅克反应得到中间体I,中间体I经过还原得到中间体II,中间体II经过酯化反应得到中间体III,最后中间体III在液氨作用下关环、成盐得到2‑(2,5‑二氟苯基)吡咯烷盐酸盐。本发明反应条件温和,原料廉价易得,收率高,产品纯度好。
Description
技术领域
本发明属于药物合成领域,涉及一种2-(2,5-二氟苯基)吡咯烷盐酸盐的合成方法。
背景技术
2-(2,5-二氟苯基)吡咯烷是一种医药中间体,经过手性拆分后可以得到(2R)-2-(2,5-二氟苯基)吡咯烷,该手性化合物是合成抗肿瘤药物拉罗替尼的重要中间体。
中国专利CN201810066842.5报道了一种以四氢吡咯为原料的合成路线,四氢吡咯与N-氯代丁二酰亚胺反应生成1-氯代吡咯烷,在甲醇钠作用下消除得到3,4-二氢-2H-吡咯,之后与2,5-二氟溴苯的格式试剂加成得到2-(2,5-二氟苯基)吡咯烷,合成工艺如下:
该路线格式反应条件苛刻,需要无水无氧操作,并且存在一定的危险性,难以实现工业化。
专利US2016168156A1报道了一种合成方法,该路线是2-溴-1,4-二氟苯(L-9)在异丙基氯化镁的作用下与N-Boc-2-吡咯烷酮(L-10)反应,得到开环化合物(L-11);然后用酸关环得到L-12,最后还原得到2-(2,5-二氟苯基)吡咯烷。
该路线所用原料L-10不易获得,同时用到异丙基氯化镁,反应条件苛刻。
发明内容
本发明针对现有技术上的不足,提供了一种2-(2,5-二氟苯基)吡咯烷盐酸盐的合成方法。本发明以对二氟苯和丁二酸酐为原料经过傅克反应得到中间体I,中间体I经过还原得到中间体II,中间体II经过酯化反应得到中间体III,最后中间体III在液氨作用下关环、成盐得到2-(2,5-二氟苯基)吡咯烷盐酸盐,具体合成路线如下所示:
S1:在溶剂中,对二氟苯与丁二酸酐在催化剂作用下发生傅克反应得到中间体I;
S2:中间体I在还原剂还原下得到中间体II;
S3:在缚酸剂作用下中间体II与甲基磺酰氯反应得中间体III;
S4:在一定压力下,中间体III与液氨反应关环、成盐得到2-(2,5-二氟苯基)吡咯烷盐酸盐。
S1步骤中所述溶剂为二氯甲烷;所述催化剂为无水三氯化铝;反应温度为35-38℃。
S2步骤中所述还原剂为硼烷-四氢呋喃、硼氢化钠-碘、硼氢化钠-三氟化硼乙醚、硼氢化钠-三氯化铝、硼氢化钠-氯化锌中的一种,优选为硼烷-四氢呋喃。
S3步骤中所述缚酸剂为碳酸钾、碳酸钠、碳酸氢钠中的一种,优选为碳酸钾。
S4步骤中所述通液氨反应压力为0.4-0.5 MPa。
本发明的有益效果:
(1)反应条件温和、安全性高,本发明避免使用格式试剂和超低温反应,增加了反应的安全性和可操作性;(3)收率和纯度较高,本发明工艺总收率60%以上,每一步中间体纯度≥98%。
具体实施方式
实施例1:
中间体I的合成
向2 L三口烧瓶中加入二氯甲烷(300 mL),搅拌下依次加入三氯化铝(283.4 g,2.5 mol),丁二酸酐(120.1 g,1.2 mol),升温至35℃,将对二氟苯(114.1 g,1 mol)滴加到反应体系,0.5 h滴加完毕,维持35-38℃反应4 h,TLC监控反应完全。然后将反应液缓慢倒入冰水(500 g)中,然后加入浓盐酸(0.9 L,6 M)溶液,搅拌0.5 h,分出有机相,水相用二氯甲烷(100 mL)萃取一次,合并有机相,有机相经水(300 mL)洗一次,用无水硫酸钠干燥有机相,减压浓缩得到粗产品,经甲苯重结晶,得到白色固体183.1 g,即中间体I,产率85.5%,纯度98.4%。
中间体II的合成
向2 L三口烧瓶中加入中间体I(107.1 g,0.5 mol),加入四氢呋喃(80 mL)搅拌,降温至0℃滴加硼烷-四氢呋喃(1050 mL,1 M),滴加完毕后,升温至60℃,回流4 h,TLC监控反应完全,降至室温,浓缩反应液,然后向残余液中加入浓盐酸(60 g,12 M),50℃搅拌两小时,降至室温用20%氢氧化钠溶液调节体系pH=6-7,用乙酸乙酯(2×200 mL)萃取,合并有机相,有机相经水洗1次,用无水硫酸钠干燥有机相,减压浓缩得到粗产品,经甲醇重结晶得到白的固体92.1 g,收率91.1%,纯度98.6%。
向2 L三口瓶中加入中间体II(101.1 g,0.5 mol),向体系中加入二氯甲烷(300mL),加入碳酸钾(276.4 g,2 mol),降温至0~5℃,滴加甲磺酰氯(126.0 g,1.1 mol),0.5 h滴加完毕,在室温下反应3 h,TLC监控反应完全。加入水(300 mL),搅拌0.5 h,分液,水相用二氯甲烷(100 mL)萃取一次,合并有机相,用无水硫酸钠干燥有机层,减压浓缩,再经精馏得到淡黄色液体158.2 g,收率88.3%,纯度99.2%。
2-(2,5-二氟苯基)吡咯烷盐酸盐的合成
向500 mL反应釜中加入中间体(71.7 g,0.2 mol),加入甲醇(150 mL),通入液氨,加压到0.5 MPa,升温到60℃,反应3 h,降温到室温,压力降为常压,浓缩反应液,再加入甲醇(140 mL),滴加浓盐酸(40 mL,6 M,0.24 mol),析出固体,过滤得到固体33.0g,收率90.1%,纯度98.2%。
实施例2:
中间体I的合成
向5 L三口烧瓶中加入二氯甲烷(600 mL),搅拌下依次加入三氯化铝(566.8 g,5.0 mol),丁二酸酐(240.2 g,2.4 mol),升温至35℃,将对二氟苯(228.2 g,2 mol)滴加到反应体系,0.5 h滴加完毕,维持35-38℃反应4 h,TLC监控反应完全。然后将反应液缓慢倒入冰水(1000 g)中,然后加入浓盐酸(1.8 L,6 M)溶液,搅拌0.5 h,分出有机相,水相用二氯甲烷(200 mL)萃取一次,合并有机相,有机相经水(600 mL)洗一次,用无水硫酸钠干燥有机相,减压浓缩得到粗产品,经甲苯重结晶,得到白色固体382.1 g,即中间体I,产率89.2%,纯度98.8%。
中间体II的合成
向2 L三口烧瓶中加入中间体I(214.2 g,1 mol),加入四氢呋喃(800 mL)搅拌,分批加入硼氢化钠(113.5 g,3 mol),降温至0℃,滴加三氟化硼乙醚(425.8 g,3 mol),滴加温度不超过10℃,加完自然升温至室温,反应6 h,TLC监控反应完全,浓缩反应液,然后向残余液中加入浓盐酸(120 g,12 M),50℃搅拌两小时,降至室温用20%氢氧化钠溶液调节体系pH=6-7,用乙酸乙酯(2×400 mL)萃取,合并有机相,有机相经水洗1次,用无水硫酸钠干燥有机相,减压浓缩得到粗产品,经甲苯重结晶得到白的固体178.9 g,收率88.5%,纯度98.1%。
向5 L三口瓶中加入中间体II(202.2 g,1 mol),向体系中加入二氯甲烷(600mL),加入碳酸钠(424.0 g,4 mol),降温至0~5℃,滴加甲磺酰氯(252.2 g,2.2 mol),0.5 h滴加完毕,在室温下反应3 h,TLC监控反应完全。加入水(600 mL),搅拌0.5 h,分液,水相用二氯甲烷(200 mL)萃取一次,合并有机相,用无水硫酸钠干燥有机层,减压浓缩,再经精馏得到淡黄色液体312.1 g,收率87.1%,纯度99.0%。
2-(2,5-二氟苯基)吡咯烷盐酸盐的合成
向1000 mL反应釜中加入中间体(143.4 g,0.4 mol),加入甲醇(300 mL),通入液氨,加压到0.45 MPa,升温到60℃,反应3 h,降温到室温,压力降为常压,浓缩反应液,再加入甲醇(280 mL),滴加浓盐酸(80 mL,6 M,0.48 mol),析出固体,过滤得到固体65.5g,收率89.4%,纯度98.0%
上述虽然对本发明的具体实施方式进行了描述,但并非对本发明保护范围的限制,所属领域技术人员应该明白,在本发明的技术方案的基础上,本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。
Claims (2)
2.根据权利要求1中所述的一种2-(2,5-二氟苯基)吡咯烷盐酸盐的合成方法,其特征在于,S1步骤中所述溶剂为二氯甲烷;反应温度为35-38℃。
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