WO2016074225A1 - 一种拆分西酞普兰中间体5-氰二醇的方法 - Google Patents

一种拆分西酞普兰中间体5-氰二醇的方法 Download PDF

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WO2016074225A1
WO2016074225A1 PCT/CN2014/091139 CN2014091139W WO2016074225A1 WO 2016074225 A1 WO2016074225 A1 WO 2016074225A1 CN 2014091139 W CN2014091139 W CN 2014091139W WO 2016074225 A1 WO2016074225 A1 WO 2016074225A1
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ether
solvent
resolution
peak
ethylene glycol
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PCT/CN2014/091139
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French (fr)
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梁尊俊
胡斯琪
彭才华
黄文峰
芦启锋
涂国良
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浙江华海药业股份有限公司
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Priority to EP14905690.5A priority Critical patent/EP3219702B1/en
Priority to US15/521,776 priority patent/US10287240B2/en
Priority to CN201480081785.8A priority patent/CN107074750B/zh
Priority to PCT/CN2014/091139 priority patent/WO2016074225A1/zh
Priority to ES14905690T priority patent/ES2881105T3/es
Publication of WO2016074225A1 publication Critical patent/WO2016074225A1/zh
Priority to US16/282,922 priority patent/US10508076B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/32—Separation; Purification; Stabilisation; Use of additives
    • C07C253/34—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the present invention relates to a process for the resolution of citalopram intermediate 5-cyanodiol.
  • Citalopram is an important class of antidepressant drugs, a selective 5-hydroxytryptamine (5-HT) reuptake S-constitutive inhibitor, its single optically active isomer, dextroamphetamine (S-citalopram) is 100 times more potent than its anti-depressant effect, R-citalopram, and therefore has better efficacy and less dosage.
  • 5-HT 5-hydroxytryptamine
  • S-citalopram dextroamphetamine
  • R-citalopram anti-depressant effect
  • the S-type isomers are mainly sold in the European and American markets, which are prepared by cyclization and salt formation of S-5-cyanodiol (IV).
  • (S)-5-Cyanamide (IV) is a key starting material for the production of S-citalopram.
  • it is generally composed of racemic 5-cyanodiol (I) and resolving agent D-( +) Di-p-toluoyl tartaric acid (II) (abbreviated as DPTTA), salt-forming and crystallization separation in an alcohol and an alcohol-containing mixed solvent (S)-5-Cyanide diol resolution intermediate (III) ), and then prepared by alkali free preparation.
  • DPTTA Di-p-toluoyl tartaric acid
  • S -5-Cyanide diol resolution intermediate
  • the splitting process can be expressed as follows:
  • the structure of the resolving agent DPTTA is as follows:
  • a first aspect of the present invention provides an efficient method for the resolution of 5-cyanodiol (I) comprising the steps of: crystallizing (S)-4-[4- represented by Formula IV in a solvent to be resolved Dimethylamino-1-(4-fluorophenyl)-1-hydroxybutyl]-3-hydroxymethylbenzonitrile is formed with the resolving agent D-(+) di-p-toluoyl tartaric acid represented by Formula II a salt; wherein the dissolving solvent is an ether solvent;
  • the ether solvent is selected from the group consisting of: tetrahydrofuran, methyltetrahydrofuran, cyclopentyl methyl ether, diisopropyl ether, dioxane, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and ethyl Diol dibutyl ether, diethylene glycol dimethyl ether, propylene glycol dimethyl ether and propylene glycol diethyl ether.
  • the ether solvent preferably contains a certain amount of water, and the volume percentage of water in the solvent is 0.2% to 10%, and the volume percentage of water is further preferably 0.2% to 5%.
  • the crystalline particles of the intermediate are more regular and have a large particle size, which is very easy to filter and is more convenient to handle in production.
  • thermogravimetric analysis (TGA) spectra are shown in Figure 4.
  • the Form C powder X-ray diffraction (PXRD) spectrum is shown in Figure 5.
  • the diffraction peak angle and intensity data are shown in Table 1 below:
  • the (S)-5-cyanodiol-resolved intermediates Form B and Form C prepared by the present invention are different from the crystal structure of the (S)-5-cyanodiol-resolved intermediate obtained by the prior art.
  • a single aqueous or anhydrous solvent can be used, the solvent recovery rate is high, and the production cost is low;
  • D-(+) di-p-toluoyl tartaric acid was added (15.0 g) to n-propanol (118 ml), and the mixture was heated to 40 ° C, stirred and dissolved, and acetic acid (1.2 g) was added.
  • the solution of the above-mentioned resolving agent was added to a solution of racemic 5-cyanodiol base (34.2 g) and n-propanol (32 ml) over 1 hour, kept at 40 ° C, and stirred for 2 hours. Cool down at 20-25 ° C, stir and crystallize for 2 hours. Filtration, the filter cake was rinsed twice with n-propanol to obtain a crude chiral purity of the crude intermediate: S-5-cyanodiol 91% to 98%.
  • the crude product was reintroduced into the flask, n-propanol (86 ml) was added, and the mixture was warmed to 50 ° C and stirred for 2 hours. Then, the mixture was cooled at 20 to 25 ° C, and the mixture was incubated and incubated for 2 hours. Filtration, the filter cake was rinsed once with n-propanol, and the filter cake was vacuum dried at 50 ° C to obtain 18.5 g of the intermediate. The yield was 34.5%. The chiral purity of the obtained split intermediate was: S-5-cyanodiol 99.3%.
  • the racemic 5-cyanodiol (178.1 g) was added, and isopropyl alcohol (1125 ml) was added thereto, and the mixture was heated to 50 to 55 ° C, and stirred to dissolve.
  • the temperature was controlled at 50 to 55 ° C, D-(+) di-p-toluoyl tartaric acid (105 g,) was added, and the temperature was slowly lowered to 25 to 30 ° C, and the mixture was stirred for 10 hours. Filtration, the filter cake was rinsed twice with isopropanol, and the amount of each wash was 110 ml.
  • the filter cake is vacuum dried at 50 ° C to obtain the intermediate
  • the crude product was 185 g, and the chiral purity was: S-5-cyanodiol 96.1%.
  • the crude product was re-introduced into the flask, and isopropyl alcohol (1500 ml) was added thereto, and the mixture was heated to 80 ° C and stirred to dissolve. Then, it was cooled at 20 to 25 ° C, and the mixture was incubated for 1 hour while being kept warm. Filtration, the filter cake was rinsed twice with isopropyl alcohol, 50 ml each time, and the filter cake was vacuum dried at 50 ° C to obtain 101.2 g of the intermediate. The yield was 36.3%, and the chiral purity was: S- 5-cyanodiol 99.1%.

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Abstract

提供了一种拆分式4-[4-二甲氨基-1-(4-氟苯基)-1-羟基丁基]-3-羟甲基苯腈为其对映异构体的方法，包括以下步骤：在拆分溶剂中结晶出(S)-4-[4-二甲氨基-1-(4-氟苯基)-1-羟基丁基]-3-羟甲基苯腈与拆分剂D-(+)二对甲苯甲酰酒石酸形成的盐；其特征在于所述的拆分溶剂为醚类溶剂。还提供了拆分中间体的新晶型。

Description

一种拆分西酞普兰中间体5-氰二醇的方法 技术领域
本发明涉及一种拆分西酞普兰中间体5-氰二醇的方法。
背景技术
西酞普兰是一类重要的抗抑郁药物，是一种选择性的5-羟基色胺(5-HT)再摄取S-构抑制剂，其单一光学活性的异构体-右旋西酞普兰(S-西酞普兰)是其相反构型异构体-R-西酞普兰抗抑郁作用的100倍，因此具有更好的疗效，更少的使用剂量。目前欧美市场上主要销售的是S-型异构体，它是由S-5-氰二醇(IV)经过环合、成盐反应制备得到。
(S)-5-氰二醇(IV)是生产S-西酞普兰的关键起始原料，工业生产中一般是由外消旋的5-氰二醇(I)与拆分剂D-(+)二对甲苯甲酰酒石酸(II)(简称DPTTA)，在醇类及含醇类的混合溶剂中进行成盐、析晶分离出(S)-5-氰二醇拆分中间体(III)，然后再经碱游离制备得到。拆分过程可表示如下：
Figure PCTCN2014091139-appb-000001
拆分剂DPTTA结构如下：
Figure PCTCN2014091139-appb-000002
US 4943590和WO2007012954中描述了使用DPTT在异丙醇中拆分外消旋的4-(4-二甲胺基-1-对氟苯基-1-羟基丁基)-3-(羟甲基)氰基苯，得到(S)-5-氰二醇拆分中间体(III)。该方法制得的(S)-5-氰二醇拆分中 间体(III)结晶颗粒较细，十分难过滤，不适合于工业化大生产的需要，而且得到的(S)-5-氰二醇拆分中间体(III)粗品手性纯度较低，生产中需要用异丙醇重精制，才能合格，操作繁琐。
US20090069582报道了使用DPTT为拆分剂，含1-丙醇的溶剂体系中拆分外消旋的5-氰二醇(I)，来制备(S)-5-氰二醇拆分中间体(III)。该方法手性纯度普遍较低，生产中需要两次精制才能得到手性纯度合格的(S)-5-氰二醇拆分中间体(III)，并且该方法目前收率普遍小于38％。
发明内容
本发明的第一个方面提供了一种高效的拆分5-氰二醇(I)方法，包括以下步骤：在拆分溶剂中结晶出式IV所示的(S)-4-[4-二甲氨基-1-(4-氟苯基)-1-羟基丁基]-3-羟甲基苯腈与式II所示的拆分剂D-(+)二对甲苯甲酰酒石酸形成的盐；其特征在于：所述的拆分溶剂为醚类溶剂，
Figure PCTCN2014091139-appb-000003
所述醚类溶剂选自：四氢呋喃、甲基四氢呋喃、环戊基甲醚、异丙醚、二氧六环、乙二醇单甲醚、乙二醇二甲醚、乙二醇二乙醚、乙二醇二丁醚、二乙二醇二甲醚、丙二醇二甲醚和丙二醇二乙醚。
所述的醚类溶剂优选含有一定量的水，所述溶剂中水的体积百分比含量为0.2％-10％，水的体积百分比含量进一步优选为0.2％-5％。在含水条件下，拆分中间体的结晶颗粒更规整、且粒径大，非常容易过滤，生产中操作更方便。
本发明的第二个方面，发现当使用没有加水的醚类溶剂中，得到一种新的式(III)所示的拆分中间体的晶型form B，该晶型的差示描述量热法 (加热速度10℃/分钟)得到的DSC图谱表现为吸热峰初始值(onset)135.20℃、峰值(peak)为150.85℃。
Figure PCTCN2014091139-appb-000004
Form B的DSC图谱如图2所示。
本发明的第三个方面，发现使用含水的体积百分比为0.2％-10％的醚类溶剂作为拆分溶剂时，得到式(III’)所示的拆分中间体的晶型form C，
Figure PCTCN2014091139-appb-000005
Form C的差示描述量热法(加热速度10℃/分钟)得到的DSC图谱表现为两个吸热峰，分别为初始值(onset)107.40℃、峰值(peak)114.11℃，以及初始值(onset)144.44℃、峰值(peak)154.55℃。
Form C的DSC图谱如图3所示。
Form C热重分析(TGA)图谱分别如图4所示。
从Form C的TGA图上能明显看出先失去1份子水的数据(1.66％)，失水温度：120-130℃，随后再失去一分子水的时候，图上显示3.05％，失水温度：140-150℃，失水温度同物质的融化后分解吸热峰有一定重合，干扰较大，所以失重数据有偏差。卡尔费休法检测form C水含量为3.0％，接近于含二个结晶水。
Form C粉末X-射线衍射(PXRD)图谱如图5所示，衍射峰角度及强度数据见下表1：
表1
衍射角度(2θ，°) 强度(I/I0，％)
6.99791 100.00
7.2123 45.07
7.7337 3.65
9.5913 3.26
10.2215 2.07
11.1993 1.16
13.2329 1.37
14..0106 3.21
14.6793 1.62
15.4477 1.47
16.1794 5.38
17.3132 4.74
17.8285 5.88
18.3324 3.39
18.9355 4.97
20.3996 9.00
21.1254 8.22
21.7329 6.48
23.2205 2.61
24.0681 3.77
26.6347 2.17
本发明制备的(S)-5-氰二醇拆分中间体Form B和Form C，不同于已有方法得到的(S)-5-氰二醇拆分中间体晶体结构。
重复WO2007012954和US20090069582的拆分方法，得到的(S)-5-氰二醇拆分中间体的结晶形式均为同一种晶型，在本说明书中将其命名为form A。form A的差示描述量热法(加热速度10℃/分钟)得到的DSC图谱如图1所示，表现为吸热峰为初始值(onset)131.20℃、峰值(peak)142.90℃。
本发明提供的拆分方法优势在于：
(1)拆分效果较好，收率较高，手性纯度高，普遍大于99.0％，后 处理操作简单，不需要二次精制，效率高；
(2)可以使用单一的含水或者无水溶剂，溶剂回收率高，生产成本低；
(3)结晶性好，晶体颗粒大，离心甩料快速简单，效率高。
附图说明
图1(S)-5-氰二醇拆分中间体(III)form A的DSC图谱。
图2(S)-5-氰二醇拆分中间体(III)form B的DSC图谱。
图3(S)-5-氰二醇拆分中间体二水合物(III’)form C DSC图谱。
图4(S)-5-氰二醇拆分中间体二水合物(III’)form C TGA图谱。
图5(S)-5-氰二醇拆分中间体二水合物(III’)form C PXRD图谱。
具体实施方式
实施例一
Figure PCTCN2014091139-appb-000006
投入外消旋5-氰二醇(34.2g，1.0当量)，D-(+)二对甲苯甲酰酒石酸(20.1g，0.52当量)，加入醚类溶剂(513ml)，升温至50～60℃，搅拌反应2小时。缓慢降温至30℃，大量固体析出，保温搅拌60分钟。过滤，滤饼用醚类溶剂30ml淋洗一次。滤饼于50℃下真空烘干，得拆分中间体(III)。
使用不同的醚类溶剂，结果如表2所示：
表2
溶剂 收率 手性纯度
四氢呋喃 48.5％ 99.8％
甲基四氢呋喃 47.3％ 99.7％
环戊基甲醚 48.2％ 99.2％
乙醚 44.7％ 98.7％
异丙醚 45.5％ 99.1％
二氧六环 45.1％ 99.5％
二乙二醇二甲醚 46.0％ 99.3％
乙二醇单甲醚 42.5％ 98.4％
乙二醇二甲醚 45.7％ 99.2％
乙二醇二乙醚 46.1％ 99.1％
乙二醇二丁醚 45.8％ 99.4％
丙二醇二甲醚 45.1％ 99.0％
丙二醇二乙醚 46.2％ 99.2％
实施例二
Figure PCTCN2014091139-appb-000007
投入外消旋5-氰二醇(34.2g，1.0当量)，D-(+)二对甲苯甲酰酒石酸加入(20.1g，0.52当量)，加入醚类溶剂(513ml)和一定量的水，升温至50～60℃，搅拌反应2小时。缓慢降温至30℃，大量固体析出，保温搅拌60分钟。过滤，滤饼用醚类溶剂30ml淋洗一次。滤饼于50℃下真空烘干，得拆分中间体III’。
使用不同的醚类溶剂及含水量的体积百分比，结果如表3所示：
表3
溶剂(V/V) 收率 手性纯度
四氢呋喃/水(99.8∶0.2) 48.2％ 99.5％
四氢呋喃/水(99.5∶0.5) 47.5％ 99.7％
四氢呋喃/水(95.0∶5.0) 41.5％ 99.4％
四氢呋喃/水(90.0∶10.0) 38.5％ 99.5％
甲基四氢呋喃/水(99.0∶1.0) 46.3％ 99.3％
环戊基甲醚/水(99.0∶1.0) 46.0％ 99.1％
异丙醚/水(99.0∶1.0) 45.1％ 99.0％
二氧六环/水(99.0∶1.0) 46.2％ 99.6％
二氧六环/水(90∶10) 36.2％ 99.6％
二乙二醇二甲醚/水(99.0∶1.0) 46.0％ 99.5％
乙二醇单甲醚/水((99.0∶1.0) 40.0％ 97.9％
乙二醇二甲醚/水((99.0∶1.0) 44.7％ 99.0％
乙二醇二丁醚/水((99.0∶1.0) 46.5％ 99.3％
丙二醇二甲醚/水((99.0∶1.0) 45.0％ 99.5％
丙二醇二乙醚/水((99.0∶1.0) 46.1％ 99.4％
对比实施例一(US20090069582实施例一)
取D-(+)二对甲苯甲酰酒石酸加入(15.0g)加入正丙醇(118ml)，升温至40℃，搅拌溶清，加入醋酸(1.2g)。1小时内，将上述拆分剂的溶液加入到外消旋5-氰二醇碱(34.2g)和正丙醇(32ml)的溶液中，保温40℃，搅拌反应2小时。降温20-25℃，保温搅拌析晶2小时。过滤，滤饼用正丙醇淋洗两次，得到拆分中间体粗品手性纯度为：S-5-氰二醇91％～98％。
粗品重新投入烧瓶中，加入正丙醇(86ml)，升温至50℃，搅拌2小时。然后冷却20-25℃，保温搅拌析晶2小时。过滤，滤饼用正丙醇淋洗一次，滤饼于50℃下真空烘干，得拆分中间体18.5g，收率：34.5％。得到拆分中间体手性纯度为：S-5-氰二醇99.3％。
对比实施例二(WO2007012954实施例5)
取外消旋5-氰二醇(178.1g)，加入异丙醇(1125ml)，升温至50～55℃，搅拌溶清。控温50～55℃，加入D-(+)二对甲苯甲酰酒石酸(105g，)，缓慢降温至25～30℃，保温搅拌10小时。过滤，滤饼用异丙醇淋洗两次，每次洗涤用量110ml。滤饼于50℃下真空烘干，得拆分中间体 粗品185g，手性纯度为：S-5-氰二醇96.1％。
粗品重新投入烧瓶中，加入异丙醇(1500ml)，升温至80℃，搅拌溶清。然后冷却20-25℃，保温搅拌析晶1小时。过滤，滤饼用异丙醇淋洗两次，每次洗涤用量50ml，滤饼于50℃下真空烘干，得拆分中间体101.2g，收率：36.3％，手性纯度为：S-5-氰二醇99.1％。

Claims (8)

  1. 一种拆分式I所示的4-[4-二甲氨基-1-(4-氟苯基)-1-羟基丁基]-3-羟甲基苯腈为其对映异构体的方法，包括以下步骤：在拆分溶剂中结晶出式I’所示的(S)-4-[4-二甲氨基-1-(4-氟苯基)-1-羟基丁基]-3-羟甲基苯腈与式II所示的拆分剂D-(+)二对甲苯甲酰酒石酸形成的盐；其特征在于：所述的拆分溶剂为醚类溶剂，
    Figure PCTCN2014091139-appb-100001
  2. 根据权利要求1所述的方法，其中所述醚类溶剂选自：四氢呋喃、甲基四氢呋喃、环戊基甲醚、异丙醚、二氧六环、乙二醇单甲醚、乙二醇二甲醚、乙二醇二乙醚、乙二醇二丁醚、二乙二醇二甲醚、丙二醇二甲醚和丙二醇二乙醚。
  3. 根据权利要求1所述的方法，其特征在于醚类溶剂中水的体积百分比含量为0.2％-10％。
  4. 根据权利要求3所述的方法，其特征在于醚类溶剂中水的体积百分比含量为0.2％-5％。
  5. 式III所示的拆分中间体的晶型，
    Figure PCTCN2014091139-appb-100002
    其特征在于：差示描述量热法(加热速度10℃/分钟)得到的DSC图谱表现为吸热峰初始值135.20℃，峰值为150.85℃。
  6. 式III’所示的拆分中间体的晶型，
    Figure PCTCN2014091139-appb-100003
    其特征在于：差示描述量热法(加热速度10℃/分钟)得到的DSC图谱表现为两个吸热峰，分别为初始值107.40℃、峰值114.11℃，和初始值144.44℃、峰值154.55℃。
  7. 根据权利要求6所述的晶型，其特征在于热重分析图如图4所示。
  8. 根据权利要求6所述的晶型，其特征在于X-射线粉末衍射图如图5所示。
PCT/CN2014/091139 2014-11-14 2014-11-14 一种拆分西酞普兰中间体5-氰二醇的方法 WO2016074225A1 (zh)

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