Hans Journal of Chemical Engineering and Technology
Vol.07 No.05(2017), Article ID:21876,6 pages
10.12677/HJCET.2017.75029

Overview on the Synthesis of (S)-3-(Methyl-Amino)-1-(Thiophen-2-yl) Propan-1-ol

Jiajia Wu1, Chengyu Ji1, Tongjie Xie1, Liangxiu Ma2, Zhikui Hao1, Feng Xu1*

1Chemical Pharmaceutical Research Institute, Taizhou Vocational & Technical College, Taizhou Zhejiang

2Neo-Dankong Pharmaceutical Co., Ltd, Taizhou Zhejiang

Received: Aug. 13th, 2017; accepted: Aug. 24th, 2017; published: Aug. 30th, 2017

ABSTRACT

(S)-3-(Methylamino)-1-(thiophen-2-yl)propan-1-ol is a class of important intermediate for antidepressant R-Duloxetine. This paper summarized several methods to synthetize the compound according to its starting materials: starting from acetylthiophene, starting from thiophene, starting from thiophenecarboxaldehyde. The features of each method were analyzed. Finally, the development in the synthesis technology of (S)-3-(Methylamino)-1-(thiophen-2-yl) propan-1-ol was proposed.

Keywords:Enzymic Method, Asymmetry of Homogeneous Catalysts, Synthesis, Duloxetine

度洛西汀中间体(S)-3-甲基氨基-1-(噻吩-2-基)丙醇合成工艺综述

吴佳佳1,季程宇1,谢童杰1,马良秀2,郝之奎1,徐峰1*

1台州职业技术学院化学制药研究所,浙江 台州

2浙江新东港药业股份有限公司,浙江 台州

收稿日期:2017年8月13日;录用日期:2017年8月24日;发布日期:2017年8月30日

摘 要

(S)-3-甲基氨基-1-(噻吩-2-基)丙醇是抗抑郁药度洛西汀的重要中间体。本文根据起始原料的不同,将其合成方法概括为:乙酰噻吩法、噻吩法和噻吩甲醛法,分析了各种方法的工艺特点,并指出了(S)-3-甲基氨基-1-(噻吩-2-基)丙醇未来的发展趋势。

关键词 :酶法,均相不对称催化剂,合成,度洛西汀

Copyright © 2017 by authors and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 引言

度洛西汀(Duloxetine)是由美国礼来公司(Elililly)开发的一种安全有效的抗抑郁剂,是一种5-羟色胺和去甲肾上腺素双重再吸收抑制剂。随着全球抑郁人数越来越多,对于高效低毒的抗抑郁药的需求越来越大。相比于其他抗抑郁药物,如帕罗西汀、氟西汀和瑞波西汀等,度洛西汀具有更好的安全性和耐受性,更少的不良反应,且具有多样的治疗活性,因而销量逐年提高 [1] ,现已占据全球抗抑郁药销量榜的第一的宝座。

为此,众多研究者致力于度洛西汀及其中间体的合成路线的探索,旨在寻找一条经济、环保、操作简单以及高收率的合成路线。其中,(S)-3-甲基氨基-1-(噻吩-2-基)丙醇(I),作为合成度洛西汀的关键中间体(图1),已成为众多研究者近年来关注热点。

2. 度洛西汀关键中间体(S)-3-甲基氨基-1-(噻吩-2-基)丙醇的合成工艺

本文根据不同的起始原料,将(S)-3-甲基氨基-1-(噻吩-2-基)丙醇的合成方法分为乙酰噻吩法、噻吩法以及噻吩甲醛法。

2.1. 乙酰噻吩法

以乙酰噻吩为原料,主要有两种方法:一种是与三聚甲醛或多聚甲醛和胺通过Mannich缩合,再经

Figure 1. The general synthetic route of duloxetine

图1. 度洛西汀的一般合成路线

过不对称还原、进一步脱保护基得到目标产品;或者是通过溴代、还原、水解、环合以及开环得到目标产品。前者根据所用胺分为甲胺盐酸盐法和甲胺保护基法,后者一般为乙酰噻吩溴代法。

2.1.1. 甲胺盐酸盐法

此法将乙酰噻吩、三聚甲醛或多聚甲醛和甲胺盐酸盐通过Mannich法得到(S)-3-甲基氨基-1-(噻吩-2-基)丙酮盐酸盐,再经过不对称催化反应得到目标产品(图2)。其中不对称催化剂常用金属不对称催化剂或酶。常见的金属不对称催化剂有:(1, 5-环辛二烯)四氟硼酸铑(I) [2] ,二氯{(R)-(+)-二[二(3, 5-二甲苯基)膦基]-1, 1'-联萘基}[(1R, 2R)-(+)-1, 2-二苯基乙烯二胺]钌(II) [3] ,二氯双(4-甲基异丙基苯基)钌(II) [4] 等。所报道的酶来源于圆红冬孢酵母菌 [5] 、酿酒酵母(CGMCC No. 2230) [6] 、L-肉碱还原酶 [7] 、羰基还原酶(SEQ ID NO: 28) [8] 、壳聚糖 [9] 等。

该工艺是目前研究较热门的方向,其具有收率高、步骤短、反应温和,具有潜在的工业化价值。但问题在于采用酶或者金属不对称催化剂会导致成本较高。

2.1.2. 甲胺保护基法

此法将乙酰噻吩、三聚甲醛或多聚甲醛和甲胺衍生物通过Mannich法合成相应的(S)-3-甲基氨基-1-(噻吩-2-基)丙酮衍生物,通过不对称催化剂还原得到相应的(S)-3-甲基氨基-1-(噻吩-2-基)丙醇衍生物,再通过水解或还原得到目标产物(图3)。其中R保护基为甲酸乙酯基、三氟乙酰基、羟基、甲氧基或者苯乙基,所用的不对称催化剂是(S, S)-N-(对甲苯磺酰)-1, 2-二苯乙烷二胺(对异丙基苯)氯化钌(II) [10] 、二氯(对甲基异丙苯)钌(II) [4] 、R-2-甲基-CBS-恶唑硼烷 [11] 或Ni[(R)-2, 2'-双(二苯基磷)-1, 1'-联苯]二氧化钌 [12] 。当R基是甲酸乙酯基、三氟乙酰基或苯乙基时,可用氢氧化钾 [10] 或者碳酸钠 [4] 进行脱保护;当R是羟基或者甲氧基,可用锌粉/醋酸 [13] 或者镍粉 [14] 进行脱保护基。

此法具有较好的专一性,副产物较少,但是由于保护基的存在,使得原料成本和步骤增长,成本增加。

2.1.3. 乙酰噻吩溴代法

此法将乙酰噻吩先与N-溴代琥珀酰亚胺(NBS) [15] 、液溴 [16] 或者溴化亚铜 [17] 反应得到溴代乙酰噻吩,在不对称催化剂氯化(均三甲苯)[(S, S)-N-(对甲苯磺酰基)-1, 2-二苯乙烯基二胺]钌(II) (RhCl[(S, S)- TsDPEN])的作用下得到具有R构型的醇,然后用硼烷二甲硫醚络合物还原得到噻吩丙胺醇,通过N'N-

Figure 2. The synthetic route from methylamine hydrochloride

图2. 以甲胺盐酸盐为原料的合成路线

Figure 3. The synthetic route from methylamine derivatives

图3. 以甲胺衍生物为原料的合成路线

羰基二咪唑(CDI)发生分子内缩合得到相应内酰胺化合物,其可以在氢化钠作用下与碘甲烷反应得到目标产物 [18] [19] [20] [21] (图4)。

2.2. 噻吩法

以噻吩为原料,先与3-氯丙酰氯发生傅克反应得到2-(氯丙酰基)噻吩 [22] [23] [24] ,以此为原料有两条合成路线,分别是叠氮转化法和直接还原法。

2.2.1. 叠氮转化法

此法在合成2-(氯丙酰基)噻吩的基础上,通过与叠氮化钠和硼氢化钠还原得到噻吩叠氮醇,再在脂肪酶作用下转化为立体异构体,然后在10%Pd-C还原下得到噻吩氨基醇,再与氯甲酸乙酯反应将氨基酯化,最后再四氢铝锂作用下得到目标产物 [24] (图5)。

2.2.2. 直接还原法

2-(氯丙酰基)噻吩直接用脂肪酶还原为噻吩氯代丙醇,然后再与甲胺反应得到目标产品 [23] [25] [26] [27] [28] [29] (图6)。

Figure 4. The synthetic route from acetylthiophene

图4. 以乙酰噻吩为原料的合成路线

Figure 5. The synthetic route I from thiophene

图5. 以噻吩为原料的合成路线I

Figure 6. The synthetic route II from thiophene

图6. 以噻吩为原料的合成路线II

Figure 7. The synthetic route from thiophenecarboxaldehyde

图7. 以噻吩甲醛为原料的合成路线

2.3. 噻吩甲醛法

此合成路线是以噻吩甲醛为原料,与N, N-二烯丙基硫代乙酰胺通过组合催化剂[六氟磷酸四乙腈铜(Cu(CH3CN)4PF6), 1, 2-双((2S, 5S)-2, 5-二苯基膦)乙烷((S, S)-Ph-BPE)和对甲氧基苯氧基锂(Li(OC6H4-p-OMe))]得到R构型的硫代烯丙基胺噻吩醇,再通过四氢铝锂还原,氯甲酸甲酯酯化和四氢铝锂还原三步得到目标产物 [30] (图7)。

3. 总结

本文基于合成(S)-3-甲基氨基-1-(噻吩-2-基)丙醇起始原料,将其合成方法分为乙酰噻吩法、噻吩法和噻吩甲醛法。由于噻吩法和噻吩甲醛法按照现有的工艺由于成本高,收率较低(20%~50%),因而离工业化还较远;而乙酰噻吩法由于路线短,收率较高(60%~80%),将是今后工业化的发展方向。而所有方法关键点都在于如何将羰基直接转化成手性羟基的方法。一般用到的不对称催化剂有两大类,分别是金属不对称催化剂和酶催化剂,前者由于成本较高,还未有大范围的工业化;而后者由于反应温和又环保,且随着生物技术的提高,其工业化的潜力将越来越大。

基金项目

2016年台州市科技计划项目(162gy57);台州市“211”人才工程资助项目。

文章引用

吴佳佳,季程宇,谢童杰,马良秀,郝之奎,徐 峰. 度洛西汀中间体(S)-3-甲基氨基-1-(噻吩-2-基)丙醇合成工艺综述
Overview on the Synthesis of (S)-3-(Methyl-Amino)-1-(Thiophen-2-yl) Propan-1-ol[J]. 化学工程与技术, 2017, 07(05): 199-204. http://dx.doi.org/10.12677/HJCET.2017.75029

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  31. NOTES

    *通讯作者。

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