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WO2022011948A1 - 制备沃替西汀的方法 - Google Patents

制备沃替西汀的方法 Download PDF

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WO2022011948A1
WO2022011948A1 PCT/CN2020/135640 CN2020135640W WO2022011948A1 WO 2022011948 A1 WO2022011948 A1 WO 2022011948A1 CN 2020135640 W CN2020135640 W CN 2020135640W WO 2022011948 A1 WO2022011948 A1 WO 2022011948A1
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compound
vortioxetine
preparing
reaction
hydrochloric acid
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PCT/CN2020/135640
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French (fr)
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宋雪梅
郭夏
王宇杰
罗米海
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北京万全阳光医学技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the invention relates to a new method for preparing vortioxetine, and relates to the field of chemical medicine.
  • Depression is a psychiatric disorder caused by various reasons and characterized by significant and persistent changes in mood and emotion. Its clinical features are mainly depression as the main, basic and primary symptoms. Patients are often accompanied by corresponding cognitive and behavioral changes, and may have psychotic symptoms such as hallucinations and delusions. Psychotic symptoms can be related to depressive mood. Coordination, such as guilt delusions, accompanied by mocking or condemning auditory hallucinations, can also be inconsistent with depressive mood, such as anger delusions, relationship delusions, auditory hallucinations without emotional color, etc. Most of the attacks can be relieved, and some patients may have residual symptoms or become chronic.
  • Vortioxetine is an antidepressant drug jointly developed by Takeda and Lundbeck for the treatment of major depressive disorder.
  • the new structure category approved by the U.S. Food and Drug Administration (FDA) on September 30, 2013, is listed in the United States under the trade name of Brintellix (vortioxetine).
  • the antidepressant mechanism of Vortioxetine may be the combined action of 5-HT 3 antagonist and 5-HT 1A agonist.
  • Vortioxetine can be prepared in a variety of ways, mainly by the following two methods:
  • Method 1 Suzuki reaction is carried out with 2-bromoiodobenzene and 2,4-dimethylthiophenol under N 2 protection and palladium catalysis to obtain the coupling product, and then Suzuki reaction with piperazine is carried out to obtain vorticil Ting.
  • Method 2 Suzuki reaction of 2-bromoiodobenzene and 2,4-dimethylthiophenol under nitrogen protection, Pd 2 bda 3 and DPEPhos as catalysts to obtain (1-(2-bromo-phenylsulfane) base)-2,4-dimethylbenzene), further react with boc-piperazine, under nitrogen protection, Pd 2 bda 3 and rac-BINAP as catalysts to undergo Suzuki reaction to obtain vortioxetine by deprotection.
  • the present disclosure relates to methods of making vortioxetine.
  • the preparation method of the present disclosure does not need to use heavy metals, the conditions are simple, the method has high yield, convenient post-processing, low production cost, and is suitable for industrial production.
  • the present disclosure provides a method for preparing vortioxetine, which uses commercially available 2,4-dimethylthiophenol as a raw material to synthesize vortioxetine (compound 5) through three steps of docking and deprotection.
  • the step of synthesizing vortioxetine mainly includes three steps, and it is prepared from the following synthetic route: the first step is that 2,4-dimethyl thiophenol (compound IV) is combined with o-difluorobenzene under certain conditions. (Compound V) reacts to generate compound III, the second step is to react compound III with Boc-piperazine to generate compound II, and the third step is to deprotect compound II to generate vortioxetine (compound I).
  • the alkaline reagents are K 2 CO 3 , Na 2 CO 3 , NaOH, triethylamine and the like.
  • the reaction reagents are THF, DMF, DMSO and the like.
  • the reaction temperature is 20-180°C.
  • the alkaline reagents are K 2 CO 3 , Na 2 CO 3 , NaOH, triethylamine, etc.
  • the preferred reaction system is an isopropanol solution of hydrochloric acid, an ethanolic solution of hydrochloric acid, a tetrahydrofuran solution of hydrochloric acid, and the like.
  • the preparation method of the present disclosure has few steps, is suitable for industrial production, does not need harsh reaction conditions, is simple in post-processing and has high purity.
  • relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply that any such relationship exists between these entities or operations. an actual relationship or sequence.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种制备沃替西汀的方法，其包括：2,4-二甲基苯硫酚(化合物IV)与邻二氟苯(化合物V)发生反应生成化合物III，所述化合物III与Boc-哌嗪反应生成化合物II，以及所述化合物II脱保护生成所述沃替西汀(化合物I)。

Description

制备沃替西汀的方法
领域
本发明涉及一种制备沃替西汀的新方法，涉及到化学医药领域。
背景
抑郁症是指由各种原因引起的、以显著而持久的心境和情感改变为主要临床特征的精神疾病。它的临床特征主要为以情感低落为主要的、基本和原发的症状，患者常伴有相应的认知和行为改变，可以有幻觉、妄想等精神病性症状，精神病性症状可以与抑郁心境相协调，如罪恶妄想，伴嘲弄性或谴责性的幻听，也可以与抑郁心境不协调，如出现被害妄想、关系妄想，没有情感色彩的幻听等，多数患者有反复发作的倾向，每次发作多可缓解，部分患者可有残留症状或转化为慢性。沃替西汀是由武田制药公司(Takeda)和灵北制药公司(Lundbeck)共同研发的治疗重度抑郁症的抗抑郁药，其双芳香基硫醚基胺类的结构，是抑郁药中的化学新结构类别，2013年9月30日由美国食品药品监督管理局(FDA)批准在美国上市，商品名为Brintellix(vortioxetine)。Vortioxetine抗抑郁药作用机制可能为5-HT 3拮抗剂和5-HT 1A激动的联合作用。
沃替西汀化学名称：1-[2-(2,4-二甲基苯硫酚)苯基]哌嗪
其结构式：
Figure PCTCN2020135640-appb-000001
沃替西汀可以通过多种方式制备得到，主要由以下两种方法制备：
方法一：以2-溴碘代苯和2,4-二甲基苯硫酚在N 2保护、钯催化下，发生Suzuki反应得到偶联产物，之后与哌嗪再次发生Suzuki反应得到沃替西汀。
Figure PCTCN2020135640-appb-000002
该方法需要使用2B类重金属，对产品的质量有着巨大的考验，同时条件较苛刻，需要无氧条件，并且Pd容易在体系中失活，导致原料反应不完全。
方法二：将2-溴碘代苯和2,4-二甲基苯硫酚在氮气保护下，Pd 2bda 3和DPEPhos作为催化剂发生Suzuki反应得到(1-(2-溴-苯基硫烷基)-2,4-二甲基苯)，进一步与boc-哌嗪，氮气保护下，Pd 2bda 3和rac-BINAP作为催化剂发生Suzuki反应得到再脱保护得到沃替西汀。
该方法需要使用2B类重金属，对产品的质量有着巨大的考验，同时条件较苛刻，需要无氧条件，并且Pd容易在体系中失活，导致原料反应不完全。
Figure PCTCN2020135640-appb-000003
因此，寻找一种步骤少，不使用重金属，产率高，适合工业化生产沃替西汀的合成路线是非常必要的。
概述
一方面，本公开涉及制备沃替西汀的方法。本公开的制备方法无 需使用重金属，条件简便，该方法收率高、后处理简便、生产成本低、适合工业化生产。
一方面，本公开提供了制备沃替西汀的方法，其以市购的2,4-二甲基苯硫酚为原料通过对接、脱保护三步合成沃替西汀(化合物5)。
合成路线：
Figure PCTCN2020135640-appb-000004
合成沃替西汀的步骤主要包括三步，它是由下述合成路线制备而成：第一步是2,4-二甲基苯硫酚(化合物IV)在一定条件下与邻二氟苯(化合物V)发生反应生成化合物III，第二步化合物III与Boc-哌嗪反应生成化合物II，第三步化合物II脱保护生成沃替西汀(化合物I)。
Figure PCTCN2020135640-appb-000005
在合成沃替西汀第一步中，碱性试剂为K 2CO 3、Na 2CO 3、NaOH、三乙胺等。
在合成沃替西汀第一步中，反应试剂为THF、DMF、DMSO等。
在合成沃替西汀第一步中，反应温度为20～180℃。
在合成沃替西汀第二步中，碱性试剂为K 2CO 3、Na 2CO 3、NaOH、三乙胺等
在合成沃替西汀第三步中，优选的反应体系为盐酸的异丙醇溶液、盐酸的乙醇溶液、盐酸的四氢呋喃溶液等。
本公开的制备方法一种步骤少，适合工业化生产，无需苛刻的反应条件，后处理简单，纯度高。
详述
下面通过实施例的方式进一步说明本公开，但并不因此将本公开限制在所述的实施例范围之中。下列实施例中未标明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1
Figure PCTCN2020135640-appb-000006
(1)将化合物IV(50.0g，361.7mmol)和300mL甲苯加入到500mL三口烧瓶中，开启搅拌。加入K 2CO 3(100g，723.4mmol)反应0.5小时，量取化合物V(41.3g，361.7mmol)滴加入体系中，滴加完毕后，加热至回流，反应12小时，TLC检测反应完全，反应停止。降温，降至室温，加入150mL水，搅拌1h，抽滤，收集滤液，分液，收集有机相，有机相用无水硫酸难干燥，抽滤，(70℃，-0.1MPa)浓缩，得到棕褐色油状物(化合物III)74.8g，收率为89.0％。
(2)将化合物III(74.8g，322.0mmol)和450mL甲苯加入到1L三口瓶中，开启搅拌。加入Boc-哌嗪(90.0g，483.0mmol)、K 2CO 3(111.2g，805.4mmol)，加热至回流，反应12小时，TLC检测反应完全，反应停止。降温，降至室温，加入225mL水，搅拌1h，抽滤，收集滤液，分液，收集有机相，有机相用无水硫酸难干燥，抽滤，(70℃，-0.1MPa)浓缩，得到棕褐色固体(化合物II)116.8g，收率为91.0％。
(3)将棕褐色固体(化合物II)(116.8g，293.0mmol)加入到500mL2mol/L的盐酸异丙醇溶液中搅拌6小时，析出大量白色固体，抽滤，收集白色固体71.7g，收率为82％，HPLC检测总杂为0.35％，单杂 最大为0.06％。
实施例2
(1)将化合物IV(50.0g，361.7mmol)和300mL DMF加入到500mL三口烧瓶中，开启搅拌。加入K 2CO 3(125.0g，904.2mmol)反应0.5小时，量取化合物V(41.3g，361.7mmol)滴加入体系中，滴加完毕后，加热至回流，反应8小时，TLC检测反应完全，反应停止。降温，降至室温，加入150mL水，搅拌1h，抽滤，收集滤液，分液，收集有机相，有机相用无水硫酸难干燥，抽滤，(70℃，-0.1MPa)浓缩，得到棕褐色油状物(化合物III)77.3g，收率为92.0％。
(2)将化合物III(77.3g，332.7mmol)和450mL甲苯加入到1L三口瓶中，开启搅拌。加入Boc-哌嗪(92.9g，499.0mmol)、Na 2CO 3(74.0g，698.7mmol)，加热至回流，反应12小时，TLC检测反应完全，反应停止。降温，降至室温，加入225mL水，搅拌1h，抽滤，收集滤液，分液，收集有机相，有机相用无水硫酸难干燥，抽滤，(70℃，-0.1MPa)浓缩，得到棕褐色固体(化合物II)114.3g，收率为86.2％。
(3)将棕褐色固体(化合物II)(114.3g，286.8mmol)加入到500mL2mol/L的盐酸异丙醇溶液中搅拌6小时，析出大量白色固体，抽滤，收集白色固体73.6g，收率为86.0％，HPLC检测总杂为0.39％，单杂最大为0.07％。
在本公开中，诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来，而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。
从前述中可以理解，尽管为了示例性说明的目的描述了本公开的具体实施方案，但是在不偏离本公开的精神和范围的条件下，本领域所述技术人员可以作出各种变形或改进。这些变形或修改都应落入本公开所附权利要求的范围。

Claims (6)

  1. 制备沃替西汀的方法，其包括：2,4-二甲基苯硫酚(化合物IV)与邻二氟苯(化合物V)发生反应生成化合物III，所述化合物III与Boc-哌嗪反应生成化合物II，以及所述化合物II脱保护生成所述沃替西汀(化合物I)。
  2. 如权利要求1所述的方法，其中在制备所述化合物III的步骤中，使用选自K 2CO 3、Na 2CO 3、NaOH、三乙胺或其混合物的碱性试剂。
  3. 如权利要求1或2所述的方法，其中在制备所述化合物III的步骤中，反应试剂选自THF、DMF、DMSO或其混合物。
  4. 如权利要求1至3中任一权利要求所述的方法，其中在制备所述化合物III的步骤中，反应温度为20至180℃。
  5. 如权利要求1至4中任一权利要求所述的方法，其中在制备所述化合物II的步骤中，使用选自K 2CO 3、Na 2CO 3、NaOH、三乙胺或其混合物的碱性试剂。
  6. 如权利要求1至5中任一权利要求的方法，其中在制备所述化合物I的步骤中，反应体系为盐酸的异丙醇溶液、盐酸的乙醇溶液、盐酸的四氢呋喃溶液或其混合物。
PCT/CN2020/135640 2020-07-15 2020-12-11 制备沃替西汀的方法 WO2022011948A1 (zh)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115368318A (zh) * 2022-06-22 2022-11-22 山东辰龙药业有限公司 一种伏硫西汀的合成方法及应用
CN115368318B (zh) * 2022-06-22 2023-11-03 山东辰龙药业有限公司 一种伏硫西汀的合成方法及应用

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