WO2016197320A1 - 一种西酞普兰二醇中间体的制备方法 - Google Patents

一种西酞普兰二醇中间体的制备方法 Download PDF

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WO2016197320A1
WO2016197320A1 PCT/CN2015/081054 CN2015081054W WO2016197320A1 WO 2016197320 A1 WO2016197320 A1 WO 2016197320A1 CN 2015081054 W CN2015081054 W CN 2015081054W WO 2016197320 A1 WO2016197320 A1 WO 2016197320A1
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citalopram
reaction
metal salt
auxiliary reagent
magnesium halide
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PCT/CN2015/081054
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French (fr)
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梁尊俊
肖伟烽
彭才华
黄文锋
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 ES15894590T priority Critical patent/ES2827454T3/es
Priority to US15/580,517 priority patent/US10227293B2/en
Priority to EP15894590.7A priority patent/EP3309142B1/en
Priority to CN201580079969.5A priority patent/CN107848958B/zh
Priority to PCT/CN2015/081054 priority patent/WO2016197320A1/zh
Publication of WO2016197320A1 publication Critical patent/WO2016197320A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B49/00—Grignard reactions
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/02—Magnesium compounds
    • 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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  • the invention relates to a preparation method of a key intermediate of citalopram and S-citalopram.
  • Citalopram is an important class of antidepressant drugs. It is a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor with fast onset, antidepressant effect and small side effects. Its single optically active isomer, dextroamphetamine (S-citalopram), is 100 times more antidepressant than its opposite conformation, R-citalopram, and therefore has better efficacy and The small doses used now gradually occupy a large market share of antidepressants.
  • the structure of citalopram (I) and its single optically active isomer S-citalopram (II) is as follows:
  • the main route for the preparation of citalopram is to cyclize citalopram (IV) to obtain citalopram (I).
  • S-citalopram The main route for the preparation of S-citalopram is the chiral separation of citalopram (IV) to give S-citalopram diol (V), followed by cyclization to give S-citalopram (II).
  • citalopram (IV) is a key intermediate in the industrial production process of citalopram and S-citalopram.
  • Patent US 4,650,884 reports the use of 5-cyanobenzoquinone as a starting material, followed by two Grignard addition reactions of the same fluorophenyl halomagnesium and N,N-dimethylpropylamine halomagnesium to obtain citalopram II.
  • Alcohol (IV) the synthetic route is as follows:
  • the present invention provides an efficient method for preparing citalopram diol key intermediate (IV), comprising the steps of:
  • 5-cyanobenzoquinone is subjected to Grignard addition reaction with p-fluorophenyl magnesium halide and N,N-dimethylaminopropyl magnesium halide in an organic solvent; after completion of the reaction, hydrolysis and separation are carried out to obtain the formula IV Citalopram diol free base; alternatively, the compound of formula (IV) is further converted to its acid salt;
  • auxiliary metal M A X B wherein M is selected from Mn, Cu, Zn, Li, or Cs, X is selected from Cl, Br or I, A is 1, B is 1 or 2, preferably MnCl 2 , CuI, ZnCl 2 , LiCl or LiBr.
  • the molar ratio of the auxiliary reagent metal salt M A X B to 5-cyanobenzoquinone is preferably ⁇ 0.2, more preferably 0.2-2.0, still more preferably 0.3-1.8, even more preferably 0.4 to 1.5, further preferably 0.5 to 1.0.
  • the p-fluorophenyl magnesium halide is p-fluorophenyl magnesium bromide.
  • the N,N-dimethylaminopropyl magnesium halide is N,N-dimethylaminopropyl magnesium chloride.
  • the organic solvent is preferably tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diisopropyl ether and diethyl ether, further preferably tetrahydrofuran.
  • the present invention also provides a process for the preparation of citalopram or S-citalopram, which comprises further converting citalopram diol represented by formula IV obtained according to the process of the present invention to citalopram or S-Western Puland.
  • Methods for the conversion of citalopram to citalopram or S-citalopram are described in the prior art, see, for example, EP 0 347 066 B1 and CN 101538257 A.
  • the regioselectivity of the reaction is remarkably improved, and the side reaction is small, for example, the content of the main reaction product in the present invention is >80%;
  • the Grignard reaction conversion rate of the present invention is >90%
  • the temperature was raised to 5 ° C, the temperature was controlled at 5-10 ° C, and 260 ml (1.0 mmol/ml, 1.3 equivalents) of N,N-dimethylaminopropylmagnesium chloride in tetrahydrofuran was slowly added dropwise, and the mixture was stirred and stirred for 0.5 hour.
  • the reaction mixture was poured into 500 mL of a saturated aqueous solution of ammonium chloride, and the mixture was stirred for 2 hr.
  • the organic layer was separated, and the aqueous layer was extracted twice with toluene (200 ml ⁇ 2).
  • the organic layer was combined and washed twice with water (200 ml ⁇ 2) and concentrated to dryness.
  • the temperature was raised to 5 ° C, the temperature was controlled at 5-10 ° C, and 260 ml (1.0 mmol/ml, 1.3 equivalents) of N,N-dimethylaminopropylmagnesium chloride in tetrahydrofuran was slowly added dropwise, and the mixture was stirred and stirred for 0.5 hour.
  • the Grignard reaction solution was added to 500 mL of a saturated aqueous solution of ammonium chloride, and the mixture was stirred for 2 hours, and the organic layer was separated. The aqueous layer was extracted twice with toluene (200 ml ⁇ 2), and the organic layer was combined, washed twice with water (200 ml ⁇ 2) and concentrated to dryness.
  • the sample was sent for HPLC, the reaction conversion rate was 77%, and the purity of the main product of the reaction liquid was 69%.
  • the water layer is combined, the temperature is lowered to 5 ° C, a large amount of solids are precipitated, and the mixture is kept warm and stirred. 60 minutes, filtered.
  • the filter cake was vacuum dried at 50 ° C to obtain citalopram diol hydrochloride in a yield of 61%.
  • the aqueous layer was extracted once again with 200 mL of toluene.
  • the combined toluene layer was washed once with 200 ml of hot water at 50 ° C, and the toluene layer was sampled and sent for HPLC.
  • the reaction conversion rate was 75%, and the purity of the main product of the reaction liquid was 65%.
  • the toluene layer was extracted once more with an aqueous solution of acetic acid, 300 ml of toluene was added, the pH was adjusted to 9.0 with aqueous ammonia, and the aqueous layer was extracted once with 200 ml of toluene, and the toluene layer was concentrated to dryness.
  • the concentrate was adsorbed by activated carbon and silica gel, purified, and then salted with HBr to obtain 38.1 g of citalopram hydrobromide product, yield: 45%.
  • the reaction conversion ratio according to Comparative Example 1 is only 77%, and the yield is only 61%, according to Comparative Example 2
  • the reaction conversion rate is only 75%, and the yield is only 45%; and in the case of adding the auxiliary reagent metal salt (M A X B ) according to the present invention, the reaction conversion rate is remarkably increased to 92% or more, even up to 98%.
  • the yield is significantly increased to more than 70%, even as high as 84%, and such results are completely unexpected to those skilled in the art.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及一种式IV所示西酞普兰二醇的制备方法，包括以下步骤：在辅助试剂金属盐的存在下，使5-氰基苯酞先后与对氟苯基卤化镁和N，N-二甲基氨基丙基卤化镁在有机溶剂中进行格氏加成反应；反应结束后水解并分离得到式IV所示的西酞普兰二醇。本发明通过添加一种辅助试剂金属盐，显著地改善了格氏反应的活性和选择性，反应收率明显提高。

Description

一种西酞普兰二醇中间体的制备方法 技术领域
本发明涉及一种西酞普兰和S-西酞普兰二醇关键中间体的制备方法。
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)再摄取抑制剂，具有起效快，抗抑郁作用明显，同时副作用小等优点。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，目前逐渐占据较大的抗抑郁药物市场份额。西酞普兰(I)及其单一光学活性异构体S-西酞普兰(II)的结构如下：
Figure PCTCN2015081054-appb-000001
制备西酞普兰主要途径是将西酞普兰二醇(IV)环合得到西酞普兰(I)。
制备S-西酞普兰的主要途径是将西酞普兰二醇(IV)经手性拆分得到S-西酞普兰二醇(V)，再经环合得到S-西酞普兰(II)。
西酞普兰二醇(IV)和S-西酞普兰二醇(V)的结构式如下所示：
Figure PCTCN2015081054-appb-000002
可见，西酞普兰二醇(IV)是西酞普兰和S-西酞普兰工业生产工艺的一个关键中间体。
专利US4650884报道了以5-氰基苯酞为起始原料，经过同对氟苯基卤代镁和N，N-二甲基丙胺卤代镁两次格氏加成反应，得到西酞普兰二醇(IV)，合成路线如下所示：
Figure PCTCN2015081054-appb-000003
上述专利报道的方法主要存在的问题是：反应转化率低、副反应多、收率偏低、而且产物纯度不高，其可能原因有：(1)格氏加成反应位点多，反应选择性差；(2)首先进行的对氟苯基卤代镁加成的中间态为酮，接着进行N，N-二甲基丙胺卤代镁格氏加成时，存在较大的位阻，转化率不高；(3)两个格氏试剂存在着竞争反应，副产物多。
发明内容
本发明提供了一种高效的制备西酞普兰二醇关键中间体(IV)的方法，包括以下步骤：
Figure PCTCN2015081054-appb-000004
5-氰基苯酞先后与对氟苯基卤化镁和N，N-二甲基氨基丙基卤化镁在有机溶剂中进行格氏加成反应；反应结束后水解并分离得到式IV所示的西酞普兰二醇游离碱；可选择地，进一步将式(IV)化合物转化为其酸式盐；
上述格氏反应在辅助试剂金属盐MAXB的存在下进行，所述辅助试剂金属盐MAXB，其中M选自Mn、Cu、Zn、Li或Cs，X选自Cl、Br或I，A为1，B为1或2，优选为MnCl2、CuI、ZnCl2、LiCl或LiBr。
在一个实施方案中，所述辅助试剂金属盐MAXB与5-氰基苯酞的摩尔比优选为≥0.2，更优选为0.2-2.0，还更优选为0.3-1.8，甚至更优选为0.4-1.5，进一步优选为0.5-1.0。
在另一个实施方案中，对氟苯基卤化镁为对氟苯基溴化镁。
在又一个实施方案中，N，N-二甲基氨基丙基卤化镁为N，N-二甲基氨基丙基氯化镁。在另一个实施方案中，所述有机溶剂优选为：四氢呋喃、2-甲基四氢呋喃、环戊基甲醚、甲基叔丁醚、异丙醚和乙醚，进一步优选为四氢呋喃。
本发明还提供了一种制备西酞普兰或S-西酞普兰的方法，该方法包括将按照本发明所述的方法获得的式IV所示的西酞普兰二醇进一步转化为西酞普兰或S-西酞普兰。现有技术中记载了西酞普兰二醇转化为西酞普兰或S-西酞普兰的方法，参见文献例如EP0347066B1以及CN101538257A。
不受任何理论束缚，本发明人出人意料地发现了在5-氰基苯酞先后与对氟苯基卤化镁和N，N-二甲基氨基丙基卤化镁在有机溶剂中进行格氏加成反应时，通过加入辅助试剂金属盐(MAXB)，可以显著地改善格氏反应的活性和选择性，例如：
(1)反应的区域选择性明显提高，副反应少，例如，本发明中主反应产物含量＞80％；
(2)可以显著提高二甲基氨基丙基格氏试剂加成反应的活性，从而提高格氏反应的转化率，例如本发明中格氏反应转化率＞90％；和
(3)收率显著提高等。
具体实施方式
为使本发明的目的、技术方案、及优点更加清楚明白，通过实施例对本发明进一步进行详细说明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1-15
Figure PCTCN2015081054-appb-000005
投入5-氰苯酞(31.8g，1.0当量)，加入四氢呋喃(300ml)，加入一定量的金属盐MAXB，降温至-5℃，搅拌反应0.5小时。控温-5到0℃，缓慢滴加对氟苯基溴化镁的四氢呋喃溶液300ml(0.8mmol/ml，1.2当量)，滴完，保温搅拌反应1小时。升温至5℃，控温5-10℃，缓慢滴加N，N-二甲基氨基丙基氯化镁的四氢呋喃溶液260ml(1.0mmol/ml，1.3当量)，滴完，保温搅拌反应0.5小时，将反应液加入到500mL饱和氯化铵水溶液中，搅拌2小时，分出有机层，水层用甲苯200ml×2提取两次，合并有机层，用水200ml×2洗涤两次，浓缩至干。取样送检HPLC，得到反应转化率和反应液主产物纯度。加入甲苯400ml，升温至50℃，搅拌溶清，加入水100ml，用浓盐酸调节水层pH＝4.0-5.0，分出水层，甲苯层再用水50ml提取一次。合并水层，降温至5℃，大量固体析出，保温搅拌60分钟，过滤。滤饼于50℃下真空烘干得西酞普兰二醇盐酸盐，计算收率。
使用不同当量和种类的金属盐MAXB、不同有机溶剂进行上述实验，结果如下表所示：
Figure PCTCN2015081054-appb-000006
Figure PCTCN2015081054-appb-000007
对比实施例一(不加金属盐)
投入5-氰苯酞(31.8g，1.0当量)，加入四氢呋喃(300ml)，降温至-5℃，搅拌反应0.5小时。控温-5-0℃，缓慢滴加对氟苯基溴化镁的四氢呋喃溶液300ml(0.8mmol/ml，1.3当量)，滴完，保温搅拌反应1小时。升温至5℃，控温5-10℃，缓慢滴加N，N-二甲基氨基丙基氯化镁的四氢呋喃溶液260ml(1.0mmol/ml，1.3当量)，滴完，保温搅拌反应0.5小时，将格氏反应液加入到500mL饱和氯化铵水溶液中，搅拌2小时，分出有机层，水层用甲苯200ml×2提取两次，合并有机层，用水200ml×2洗涤两次，浓缩至干，取样送检HPLC，反应转化率77％，反应液主产物纯度：69％。加入甲苯400ml，升温至50℃，搅拌溶清，加入水100ml，用浓盐酸调节水层pH＝4.0-5.0，分出水层，甲苯层再用水50ml提取一次。合并水层，降温至5℃，大量固体析出，保温搅拌 60分钟，过滤。滤饼于50℃下真空烘干得西酞普兰二醇盐酸盐，收率：61％。
对比实施例二(US4650884)
投入5-氰苯酞(31.8g，1.0当量)，加入四氢呋喃(300ml)，降温至-3℃，搅拌反应0.5小时。控温-3-0℃，缓慢滴加对氟苯基溴化镁的四氢呋喃溶液300ml(0.8mmol/ml，1.3当量)，滴完，保温搅拌反应0.5小时，撤去冷冻，搅拌过夜。控温10-12℃，缓慢滴加N，N-二甲基氨基丙基氯化镁的四氢呋喃溶液200ml(1.0mmol/ml，1.0当量)，滴完，撤去冷冻，于室温下搅拌反应过夜，将格氏反应液加入到冰水中，再用醋酸调节pH＝6.5-7.0，蒸出四氢呋喃，加入甲苯300mL，用饱和氯化铵水溶液节pH＝9.0，分出甲苯层，水层再用甲苯200mL提取一次，合并甲苯层用50℃的热水200ml洗涤1次，甲苯层取样送检HPLC，反应转化率为75％，反应液主产物纯度为65％。甲苯层再用醋酸水溶液提取一次，加入甲苯300ml，氨水调节pH＞9.0，水层用甲苯200ml提取一次，合并甲苯层浓缩至干。浓缩物经过活性炭和硅胶吸附，提纯，再用HBr成盐后，得到西酞普兰二醇氢溴酸盐产品38.1g，收率：45％。
通过比较以上实施例和对比例，可以看出，在5-氰基苯酞先后与对氟苯基卤化镁和N，N-二甲基氨基丙基卤化镁在有机溶剂中进行格氏加成反应时，通过加入辅助试剂金属盐(MAXB)，显著地改善了该特定格氏加成反应的活性和选择性，从而显著地提高了产物的收率。例如，在不加入根据本发明的辅助试剂金属盐(MAXB)的情况下，根据对比实施例一的反应转化率仅为77％，收率仅为61％，根据对比实施例二的反应转化率仅为75％，收率仅为45％；而在根据本发明加入辅助试剂金属盐(MAXB)的情况下，反应转化率显著提高到92％以上，甚至高达98％，同时收率显著提高到70％以上，甚至高达84％，这样的结果是本领域技术人员完全预料不到的。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明保护的范围之内。

Claims (9)

  1. 一种式IV所示西酞普兰二醇的制备方法，
    Figure PCTCN2015081054-appb-100001
    包括以下步骤：5-氰基苯酞先后与对氟苯基卤化镁和N，N-二甲基氨基丙基卤化镁在有机溶剂中进行格氏加成反应；反应结束后水解并分离得到式IV所示的西酞普兰二醇游离碱；可选择地，进一步将式IV化合物转化为其酸式盐；其特征在于：上述格氏反应在辅助试剂金属盐MAXB的存在下进行，对于所述辅助试剂金属盐MAXB，M选自Mn、Cu、Zn、Li或Cs，X选自Cl、Br或I，A为1，B为1或2。
  2. 根据权利要求1所述的方法，其中所述辅助试剂金属盐MAXB为MnCl2、CuI、ZnCl2、LiCl和LiBr。
  3. 根据权利要求1所述的方法，其中所述辅助试剂金属盐MAXB与5-氰基苯酞的摩尔比为≥0.2。
  4. 根据权利要求3所述的方法，其中所述辅助试剂金属盐MAXB与5-氰基苯酞的摩尔比为0.5-1.0。
  5. 根据权利要求1所述的方法，其中对氟苯基卤化镁为对氟苯基溴化镁。
  6. 根据权利要求1所述的方法，其中N，N-二甲基氨基丙基卤化镁为N，N-二甲基氨基丙基氯化镁。
  7. 根据权利要求1所述的方法，其中有机溶剂选自：四氢呋喃、2-甲基四氢呋喃、环戊基甲醚、甲基叔丁醚、异丙醚或乙醚。
  8. 根据权利要求7所述的方法，其中有机溶剂为四氢呋喃。
  9. 一种制备西酞普兰或S-西酞普兰的方法，其特征在于将按照权利要求1～8中任一项所述的方法获得的式IV所示的西酞普兰二醇进一步转化为西酞普兰或S-西酞普兰。
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