CN103351300A - Preparation method of aliskiren intermediate side chain ((s)-methyl-2-bromoisovalerate) - Google Patents

Preparation method of aliskiren intermediate side chain ((s)-methyl-2-bromoisovalerate) Download PDF

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CN103351300A
CN103351300A CN2013102673853A CN201310267385A CN103351300A CN 103351300 A CN103351300 A CN 103351300A CN 2013102673853 A CN2013102673853 A CN 2013102673853A CN 201310267385 A CN201310267385 A CN 201310267385A CN 103351300 A CN103351300 A CN 103351300A
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acid
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赵月楠
闫起强
马苏峰
王进敏
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北京万全德众医药生物技术有限公司
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Abstract

The invention belongs to the field of medicine chemistry, and relates to a preparation method of aliskiren intermediate side chain ((s)-methyl-2-bromoisovalerate). The preparation method comprises following steps: dimethyl isopropylmalonate hydrolyzes in the presence of alkali and converts to an acid; separated isopropylmalonic acid reacts with diethylamine in a formaldehyde solution and generates isopropyl acrylic acid; isopropyl acrylic acid reacts with hydrogen bromide organic acid solution and generates ethyl 2-bromo-3-methylbutyrate; ethyl 2-bromo-3-methylbutyrate is subjected to the processes of salification and de-salification in sequence and generates (s)-ethyl 2-bromo-3-methylbutyrate; (s)-ethyl 2-bromo-3-methylbutyrate is subjected to an esterification reaction and generates (s)-methyl-2-bromoisovalerate. The preparation method has the advantages of simple operation, extremely high purity, high yield, mild reaction conditions, and no side reactions.

Description

一种制备阿利克仑中间体侧链(S) -2-溴代异戊酸甲酯的方法 A method of Aliskiren side chain intermediate (S) -2-bromo-methyl isoamyl

技术领域 FIELD

[0001] 本发明属于化学领域,涉及制备阿利克仑中间体侧链(S) -2-溴代异戊酸甲酯(式I)的制备方法。 [0001] The present invention belongs to the field of chemistry, relates to the preparation of Intermediate Aliskiren side chains (S) -2- Preparation of methyl (Formula I) bromo isopentyl.

[0002] [0002]

Figure CN103351300AD00031

背景技术 Background technique

[0003] 阿利克仑是诺华公司开发的具有新型药理作用机制的抗高血压药为作用于肾素血管紧张素醛固酮系统的第二代肾素抑制剂。 [0003] Aliskiren Novartis developed novel antihypertensive drugs with pharmacological mechanism of action of the second generation of renin inhibitors in the renin-angiotensin-aldosterone system. 2007年分别在美国和欧盟批准上市。 2007 is listed in the US and EU approval. 2008年I月,由阿利克伦与氢氯噻嗪组成的复方制剂也获得了FDA的上市许可。 In January 2008 I, compound preparation Composition of aliskiren and hydrochlorothiazide is also received marketing approval by the FDA. 与市场上常见的降压药相比,该药具有高度选择性的、加大剂量给药不会导致血压骤降,在众多阿利克伦众多合成路线中,一般来说(S)-2-溴代异戊酸甲酯是必不可少的中间体之一,该中间体的合成引起大量关注,发表的文献较多,通过查阅相关文献,我们在阿利克伦合成工作中,开发出一条合成(S) -2-溴代异戊酸甲酯的方法,该方法操作简单,纯度极高,收率高,反应条件温和,没有副反应的发生。 Compared with the common antihypertensive drugs on the market, highly selective drug, increase the dosage does not lead to drop in blood pressure, many Aliskiren many synthetic route, in general (S) -2- bromo-iso-amyl acetate is one of the essential intermediates, synthetic intermediates that caused a lot of attention, many published literature, through access to relevant literature, we Aliskiren synthesis work, developed a synthesis (S) -2- bromoisobutyrate pentanoate method, the method is simple, high purity, high yield, mild reaction conditions, no side reactions.

发明内容 SUMMARY

[0004] 本发明提供一种制备阿利克仑中间体侧链(S) -2-溴代异戊酸甲酯的方法,其步骤在于,将异丙基丙二酸二甲酯通过碱水解生成异丙基丙二酸,分离出的异丙基丙二酸在甲醛溶液中与二乙胺反应成异丙基丙烯酸,再与溴化氢有机酸溶液反应得到2-溴代异戊酸,通过拆分剂成盐解盐得到(S)-2-溴代异戊酸,再经过酯化得到(S)-2-溴代异戊酸甲酯。 [0004] The present invention provides a process for preparing Aliskiren side chain of intermediate (S) -2- bromoisobutyrate pentanoate method, comprising the steps, the isopropyl malonate generated by basic hydrolysis isopropyl malonate, isopropyl separated malonic acid in the formaldehyde solution and diethylamine as isopropyl acid, hydrogen bromide and then with a solution of an organic acid to afford 2-bromo-isovaleric acid, by resolving agent to obtain a salt solution of salt (S) -2- bromo-isovaleric acid, and then after esterification (S) -2- bromo-methyl isovalerate. 该方法具有原料简单易得,反应条件温和,易于控制,产品收率高的特点。 This method has the simple raw materials, mild reaction conditions, easily controlled, high yield characteristics.

[0005] [0005]

Figure CN103351300AD00041

其中所述的碱包括氢氧化钠和氢氧化钾,其中优选氢氧化钾。 Wherein said base comprises sodium hydroxide and potassium hydroxide, wherein potassium hydroxide is preferred. 所述有机酸包括甲酸和乙酸,其中优选乙酸。 And the organic acid include formic acid, acetic acid being preferred. 所述拆分剂包括(S)-a-苯乙胺和奎宁,其中首选(S)-a-苯乙胺。 The resolving agent comprises (S) -a- phenethylamine and quinine, wherein the preferred (S) -a- phenethylamine. 所使用的拆分溶剂为乙醚。 Split solvent used is diethyl ether. 所述酯化所用的催化剂为TMSCHN2,溶剂为甲苯。 The catalyst used for the esterification TMSCHN2, solvent is toluene.

具体实施方式 Detailed ways

[0006] 以下通过实施例进一步说明本发明,但不作为对本发明的限制。 [0006] The following examples further illustrate the invention, not limitation of the invention.

实施例1: Example 1:

在IL三口瓶中,加入201.6ml水及201.6g氢氧化钠,配成50%的氢氧化钠水溶液。 In IL three-neck flask, and 201.6g water was added 201.6ml of sodium hydroxide, 50% aqueous sodium hydroxide dubbed. 搅拌加热至80°C,称量174.19g异丙基丙二酸二甲酯于250ml滴液漏斗中,80°C滴加,保持ld/s。 Was stirred and heated to 80 ° C, weighed 174.19g isopropyl malonate in 250ml dropping funnel, 80 ° C was added dropwise, maintaining ld / s. 搅拌反应5小时,经后处理得到异丙基丙二酸,收率52.92%。 The reaction was stirred for 5 hours after treatment isopropyl malonate obtained, yield 52.92%.

[0007] 实施例2: [0007] Example 2:

在IL三口瓶中,加入201.6ml水及201.6g氢氧化钾,配成50%的氢氧化钾水溶液。 In IL three-neck flask, and 201.6g water was added potassium hydroxide 201.6ml, dubbed 50% aqueous potassium hydroxide solution. 搅拌加热至80°C,称量174.19g异丙基丙二酸二甲酯于250ml滴液漏斗中,80°C滴加,保持ld/s。 Was stirred and heated to 80 ° C, weighed 174.19g isopropyl malonate in 250ml dropping funnel, 80 ° C was added dropwise, maintaining ld / s. 搅拌反应5小时,经后处理得到异丙基丙二酸,收率55.69%。 The reaction was stirred for 5 hours after treatment isopropyl malonate obtained, yield 55.69%.

[0008] [0008]

实施例3: Example 3:

在IL单口瓶中,依次加入81.78g异丙基丙二酸,115.38ml 二乙胺及224.9ml甲醛溶液(37%)。 In IL single-neck flask, were added 81.78g isopropyl malonate, 115.38ml 224.9ml diethylamine and formaldehyde solution (37%). 搅拌加热至回流,回流反应5小时,经后处理得到无色透明油状物54.4g,收率85%。 Was stirred and heated to reflux, refluxed for 5 hours, after processing to give 54.4 g of a colorless clear oil, yield 85%.

[0009] 实施例4: [0009] Example 4:

在500ml圆底烧瓶中加入122.18ml溴化氢甲酸溶液(含溴化氢0.68mol ),(TC下向溴化氢的甲酸溶液中滴加54.4g异丙基丙烯酸,室温下搅拌反应一天,经处理得到82.26g淡橘色油状物。 122.18ml acid was added hydrogen bromide solution (containing 0.68 mol of hydrogen bromide) in a 500ml round-bottom flask (the TC isopropyl acrylate was added dropwise to 54.4g of formic acid solution of hydrogen bromide, the reaction was stirred at room temperature for one day, dried processing to give 82.26g pale orange oil.

[0010] 实施例5:在500ml圆底烧瓶中加入122.18ml溴化氢乙酸溶液(含溴化氢0.68mOl),0°C下向溴化氢的乙酸溶液中滴加54.4g异丙基丙烯酸,室温下搅拌反应一天,经处理得到87.33g淡橘色油状物。 [0010] Example 5: 122.18ml added hydrogen bromide in acetic acid 500ml round bottomed flask (with hydrogen bromide 0.68mOl), 0 ° C under isopropyl acrylate was added dropwise to 54.4g solution of hydrogen bromide in acetic acid , the reaction was stirred at room temperature for one day, to give 87.33g processed pale orange oil.

[0011] 实施例6: [0011] Example 6:

在IL三口瓶中加入30.7g2-溴代异戊酸,加入307ml无水乙醚,40°C回流条件下搅拌。 IL three-neck flask was added 30.7g2- bromo isovaleric acid, 307ml of anhydrous diethyl ether was added, stirred 40 ° C under reflux conditions. 称量51g奎宁加至瓶内,搅拌2小时,停止搅拌,加入少量晶种,冷却至室温静置过夜。 Weighing bottle to 51g Kuining Jia, stirred for 2 hours, stirring was stopped, a small amount of seed crystals was added, cooled to stand at room temperature overnight. 第二天有针状白色固体析出,5°C析晶2小时,抽滤得16.24g固体,乙醚重结晶三次,得光学合格的(S) -2-溴代异戊酸奎宁盐,累计收率20.3%。 The next day acicular precipitate a white solid, 5 ° C crystallization for 2 hours to obtain 16.24g solid was filtered off with suction, recrystallized three times to obtain optically acceptable (S) -2- bromo-isovaleric acid quinine salt, total yield 20.3%.

[0012] 实施例7: [0012] Example 7:

在IL三口瓶中加入30.7g2-溴代异戊酸,加入307ml无水乙醚,40°C回流条件下搅拌。 IL three-neck flask was added 30.7g2- bromo isovaleric acid, 307ml of anhydrous diethyl ether was added, stirred 40 ° C under reflux conditions. 称量19.06gS-a-苯乙胺于恒压滴液漏斗中,缓慢滴加至瓶内,滴毕,搅拌5分钟,停止搅拌,加入少量晶种,冷却至室温静置过夜。 Weighing 19.06gS-a- phenethylamine in a constant pressure dropping funnel, was slowly added dropwise to the flask dropwise, stirred for 5 minutes, stirring was stopped, a small amount of seed crystals was added, cooled to stand at room temperature overnight. 第二天有针状白色固体析出,5°C析晶2小时,抽滤得12.98g固体,乙醚重结晶三次,得光学合格的(S) -2-溴代异戊酸苯乙胺盐,累计收率21.13%。 The next day acicular precipitate a white solid, 5 ° C crystallization for 2 hours to obtain 12.98g solid was filtered off with suction, recrystallized three times to obtain optically acceptable (S) -2- bromo-isovaleric acid phenethylamine salt, the cumulative yield of 21.13%.

[0013] 实施例8: [0013] Example 8:

在50ml三口瓶中,加入0.2g (S)-2-溴代异戊酸苯乙胺盐,加入2.258ml IN HC1,室温下搅拌反应3小时,经处理得到0.121g无色油状物(S) -2-溴代异戊酸,收率98%。 In 50ml 3-necked flask, 0.2g (S) -2- bromo-isovaleric acid phenethylamine salt, was added 2.258ml IN HC1, the reaction was stirred at room temperature for 3 hours, treated to give 0.121g as a colorless oil (S) 2-bromomethyl isovaleric acid, 98% yield.

[0014] 实施例9: [0014] Example 9:

在50ml单口瓶中,加入0.1lg (S)-2-溴代异戊酸,加入1.138ml甲醇,3.983ml甲苯,室温下搅拌反应。 In 50ml single-neck flask, was added 0.1lg (S) -2- bromo-isovaleric acid, methanol was added 1.138ml, 3.983ml of toluene, the reaction was stirred at room temperature. 移取0.427ml TMSCHN2,滴加至反应液中,室温搅拌反应I小时,经处理后得到淡黄色油状物。 Pipetted 0.427ml TMSCHN2, added dropwise to the reaction mixture, the reaction was stirred for I h at room temperature, after processing to give a pale yellow oil.

Claims (10)

1.一种制备阿利克仑中间体侧链(S)-2-溴代异戊酸甲酯的方法,其特征在于,(I)异丙基丙二酸二甲酯在碱的存在下水解生成异丙基丙二酸,(2)异丙基丙二酸在甲醛溶液中与二乙胺反应成异丙基丙烯酸,(3)异丙基丙烯酸与溴化氢有机酸溶液反应得到2-溴代异戊酸,(4) 2-溴代异戊酸通过拆分剂成盐解盐得到(S)-2-溴代异戊酸,(5) (S)-2-溴代异戊酸经过酯化得到(S) -2-溴代异戊酸甲酯。 A Aliskiren side chain intermediate (S) -2-bromo-iso-pentanoate method, wherein, (the I) isopropyl malonate in the presence of a base hydrolysis of isopropanol and malonic acid, (2) isopropyl malonic acid in a formaldehyde solution into the reaction with diethylamine isopropyl acrylate, (3) isopropyl acrylate, an organic acid solution is reacted with hydrogen bromide to give 2- bromo isovaleric acid, (4) 2-bromo-isovaleric acid obtained by resolution agent salt solution into the salt (S) -2- bromo-isovaleric acid, (. 5) (S) -2- bromo-isopentyl after esterification of the acid to give (S) -2- bromo-methyl isovalerate.
Figure CN103351300AC00021
2.根据权利要求1的方法,其特征在于,第(I)步水解反应用的碱选自氢氧化钠和氢氧化钾。 2. The method according to claim 1, characterized in that the first (I) by base hydrolysis step is selected from sodium hydroxide and potassium hydroxide.
3.根据权利要求1的方法,其特征在于,第(I)步水解反应用的碱为氢氧化钾。 3. The method according to claim 1, characterized in that the first (I) with a base hydrolysis step is potassium hydroxide.
4.根据权利要求1的方法,其特征在于,第(3)步用的有机酸选自甲酸和乙酸。 4. A method according to claim 1, wherein, the step (3) with an organic acid selected from formic acid and acetic acid.
5.根据权利要求1的方法,其特征在于,第(3)步用的有机酸为乙酸。 The method according to claim 1, wherein, the step (3) with the organic acid is acetic acid.
6.根据权利要求1的方法,其特征在于,第(4)步用的拆分剂选自(S)-a-苯乙胺和奎宁。 6. The method according to claim 1, characterized in that the section (4) with a resolving agent in step is selected from (S) -a- phenethylamine and quinine.
7.根据权利要求1的方法,其特征在于,第(4)步用的拆分剂为(S)-a-苯乙胺。 7. A method according to claim 1, characterized in that the section (4) with a resolving agent of step (S) -a- phenethylamine.
8.根据权利要求1的方法,其特征在于,第(4)步用的拆分的溶剂为乙醚。 8. The method according to claim 1, characterized in that the first (4) the solvent used is resolved step diethyl ether.
9.根据权利要求1的方法,其特征在于,第(5)步酯化所用的催化剂为TMSCHN2。 9. The method according to claim 1, characterized in that the catalyst (5) was used in the esterification step TMSCHN2.
10.根据权利要求1的方法,其特征在于,第(5)步酯化所用的溶剂为甲苯。 10. The method according to claim 1, characterized in that the section (5) esterification step solvent used is toluene.
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