WO2021259051A1 - 一种羟哌吡酮游离碱的合成工艺改进方法 - Google Patents

一种羟哌吡酮游离碱的合成工艺改进方法 Download PDF

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WO2021259051A1
WO2021259051A1 PCT/CN2021/098608 CN2021098608W WO2021259051A1 WO 2021259051 A1 WO2021259051 A1 WO 2021259051A1 CN 2021098608 W CN2021098608 W CN 2021098608W WO 2021259051 A1 WO2021259051 A1 WO 2021259051A1
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preparation
free base
inorganic base
reaction
formula
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汪有贵
蔡长清
郭攀
朱元勋
颜峰峰
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浙江华海药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • the invention specifically relates to the field of medicine, and relates to a method for improving the synthesis process of piperpirox free base.
  • Hydrochloride hydrochloride English name (Hydione Hydrochloride), chemical name is 1-[(1-benzyl-4-hydroxypiperidin-4-yl)-methyl]-pyridine-2(1H)-one hydrochloride Salt.
  • the structural formula of piperpyrone hydrochloride is as follows:
  • the compound is a dual-target antidepressant independently developed by the Institute of Toxicology and Drugs of the Chinese Academy of Military Medical Sciences. It can be used to prevent or treat central nervous system diseases related to 5-HT system dysfunction, including depression, mania, and cognition. Cognitive deficits, schizophrenia, pain, etc.
  • Patent CN102241667A discloses piperpirox compound and its preparation method:
  • Method 1 Using ethylene glycol monomethyl ether and water as the reaction solvent, using 2-aminopyridine and the epoxy compound represented by formula I as raw materials, reacting for 3 days, adding ethanol and fumaric acid to dissolve After lowering the temperature, adding diethyl ether and evaporating the organic phase to dry the solvent, adding sodium hydroxide and sodium acetate to basify, extracting with dichloromethane, and column chromatography to obtain the free base of piperpyrone represented by formula II.
  • the process uses ethylene glycol monomethyl ether as the reaction solvent, which has a long production reaction time in the workshop, complex column chromatography procedures, difficult to control, and the yield is too low, which is not suitable for large-scale production in the workshop.
  • Method 2 Use DMF as the reaction solvent, 2-hydroxypyridine and epoxy as raw materials, carry out the addition reaction under the action of alkali for 1 day, wash with potassium carbonate aqueous solution, evaporate the solvent, and then add petroleum ether-ethyl acetate The ester crystallized and filtered to obtain the free base of piperpyrone.
  • the process has a long reaction time and low process yield. In view of the defects in the process, the synthesis process is improved.
  • the purpose of the present invention is to provide an improved method for the synthesis of piperpirox free base.
  • the present invention provides a preparation method for improving the free base conversion rate of piperpirox, which comprises subjecting 2-hydroxypyridine and the epoxy compound represented by formula I to a phase transfer catalyst and an inorganic base under the action of an organic
  • the reaction is carried out in a solvent to obtain the free base of piperpirox as shown in formula II, and the reaction formula is shown as follows:
  • the phase transfer catalyst is selected from the group consisting of tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltrimethylammonium chloride, One or more of benzyl trimethyl ammonium bromide, benzyl triethyl ammonium chloride, and benzyl triethyl ammonium bromide.
  • the molar ratio of the epoxy, 2-hydroxypyridine and the inorganic base is 1:0.7 ⁇ 1.3:0.05 ⁇ 0.5, preferably 1:1.0 ⁇ 1.1:0.10 ⁇ 0.15.
  • the inorganic base is selected from potassium carbonate, sodium carbonate, lithium carbonate or cesium carbonate inorganic base aqueous solution or solid, preferably an inorganic base aqueous solution, more preferably potassium carbonate aqueous solution.
  • the organic solvent is selected from toluene or xylene, preferably toluene.
  • the molar ratio of the epoxy compound to the phase transfer catalyst is 1:0.02-0.4, preferably 1:0.05-0.1.
  • the volume ratio of the epoxy compound to the organic solvent is 1:3-12 g/mL, preferably 1:5-7 g/mL.
  • the reaction temperature is 50° C. to 90° C.
  • the reaction time is 6 to 24 hours, and more preferably, the reaction temperature is 55° C. to 65° C., and the reaction time is 8 to 10 hours.
  • the innovations of the method for preparing piperpirox free base provided by the present invention include:
  • phase transfer catalyst greatly improves the reaction efficiency, reduces the reaction time, and improves the reaction yield, which is very suitable for industrial production.
  • the prior art uses DMF as the reaction solvent, which brings about the discharge of a large amount of nitrogen-containing wastewater; the present invention preferably uses toluene or xylene as the solvent, which is easy to post-process and recycle, and is more environmentally friendly.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明提供了一种提高改进的羟哌吡酮游离碱转化率的制备方法，包括将2-羟基吡啶和式（I）所示的环氧物在相转移催化剂和无机碱作用下，在有机溶剂中进行反应得到式（II）所示的羟哌吡酮游离碱。本发明提供的制备，大大提升了反应效率，降低反应时间，提高了反应收率，非常适合工业化生产。

Description

一种羟哌吡酮游离碱的合成工艺改进方法 技术领域
本发明具体涉及医药领域，涉及一种羟哌吡酮游离碱的合成工艺改进方法。
技术背景
盐酸羟哌吡酮，英文名称(Hydione Hydrochloride)，化学名称为1-[(1-苄基-4-羟基哌啶-4-基)-甲基]-吡啶-2(1H)-酮盐酸盐。盐酸羟哌吡酮结构式如下所示：
Figure PCTCN2021098608-appb-000001
该化合物是中国人民解放军军事医学科学院毒物药物研究所自主研发的双靶点抗抑郁药物，可用于预防或治疗5-HT***功能紊乱相关的中枢神经***疾病，包括抑郁症、躁狂症、认知缺陷、精神***症、疼痛等。
专利CN102241667A公开了羟哌吡酮化合物及其制备方法：
方法一：以乙二醇单甲醚和水做为反应溶剂，以2-氨基吡啶、式I所示所示的环氧物为原料，反应3天，加入乙醇、反式丁烯二酸溶解后降温，再加入***，有机相蒸干溶剂后，再加入氢氧化钠、乙酸钠碱化，二氯甲烷提取，柱层析得到式II所示羟哌吡酮游离碱。
Figure PCTCN2021098608-appb-000002
该工艺采用的乙二醇单甲醚做为反应溶剂，车间生产反应时间长，柱层析工序复杂，不易控制，且收率过低，不适宜车间大规模生产。
方法二：以DMF做为反应溶剂，以2-羟基吡啶、环氧物为原料，在碱作用下进行加成反应1天，碳酸钾水溶液洗涤，蒸干溶剂后，再加入石油醚-乙酸乙酯结晶，过滤得到羟哌吡酮游离碱。
Figure PCTCN2021098608-appb-000003
该工艺反应时间较长，且工艺收率偏低，鉴于上述工艺中存在的缺陷，对上述合成工艺过程进行改进。
发明内容
本发明的目的是提供一种羟哌吡酮游离碱的合成工艺改进方法。
具体而言，本发明提供了一种提高羟哌吡酮游离碱转化率的制备方法，包括将2-羟基吡啶、式I所示的环氧物在相转移催化剂和无机碱作用下，在有机溶剂中进行反应得到式II所示的羟哌吡酮游离碱，反应式如下所示：
Figure PCTCN2021098608-appb-000004
在上述羟哌吡酮游离碱的制备方法中，所述相转移催化剂选自四丁基硫酸氢铵、四丁基氯化铵、四丁基溴化铵、苄基三甲基氯化铵、苄基三甲基溴化铵、苄基三乙基氯化铵、苄基三乙基溴化铵中的一种或多种。
在上述羟哌吡酮游离碱的制备方法中，所述的环氧物、2-羟基吡啶与无机碱的摩尔比为1：0.7～1.3：0.05～0.5，优选1：1.0～1.1：0.10～0.15。
在上述羟哌吡酮游离碱的制备方法中，所述无机碱选自碳酸钾、碳酸钠、碳酸锂或碳酸铯无机碱水溶液或固体，优选为无机碱水溶液，进一步优选为碳酸钾水溶液。
在上述羟哌吡酮游离碱的制备方法中，所述的有机溶剂选自：甲苯或二甲苯，优选为甲苯。
在上述羟哌吡酮游离碱的制备方法中，所述的环氧物与相转移催化剂的摩尔比为1：0.02～0.4，优选1：0.05～0.1。
在上述羟哌吡酮游离碱的制备方法中，所述的环氧物与有机溶剂的体积比为1：3～12g/mL，优选1：5～7g/mL。
在上述羟哌吡酮游离碱的制备方法中，所述的反应温度为50℃～90℃，反应时间为6～24h，进一步优选反应温度55℃～65℃，反应时间为8～10h。
本发明提供的羟哌吡酮游离碱的制备方法，创新点包括：
(1)加入相转移催化剂，大大提升了反应效率，降低反应时间，提高了反应收率，非常适合工业化生产。
(2)本发明得到的羟哌吡酮游离碱纯度高，后续进一步成盐，获得的盐酸羟哌吡酮 纯度可达99.8％。
(3)现有技术采用DMF作为反应溶剂，带来的大量含氮废水的排放；本发明优选使用甲苯或二甲苯作溶剂，且易于后处理及回收，也更加环保。
具体实施方式
以下具体的制备实施例在于详细说明本发明，实施例仅用于更详细具体说明之用，而非以任何形式限制本发明。
实施例1
室温下，称取20.3g环氧物、9.97g 2-羟基吡啶、1.70g四丁基硫酸氢铵，102mL甲苯混合，再加入溶有1.38g碳酸钾的水溶液，升温至55～65℃保温反应8～10h，加入60mL水搅拌，静置分层，甲苯相浓缩至干，再加入61mL乙醇升温溶清后缓慢降温至0℃～10℃，过滤，烘干，得到白色的羟哌吡酮游离碱，收率83.5％，纯度97.1％。
实施例2
室温下，称取20.3g环氧物、9.97g 2-羟基吡啶、1.70g四丁基硫酸氢铵，102mL甲苯混合，再加入1.38g碳酸钾固体，升温至55～65℃保温反应8～10h，加入60mL水搅拌，静置分层，甲苯相浓缩至干，再加入61mL乙醇升温溶清后缓慢降温至0℃～10℃，过滤，烘干，得到白色的羟哌吡酮游离碱，收率77.5％，纯度96.8％。
实施例3
室温下，称取20.3g环氧物、9.97g 2-羟基吡啶、0.64g四丁基溴化铵，61mL二甲苯混合，再加入溶有1.38g碳酸钾的水溶液，升温至55～65℃保温反应8～10h，加入60mL水搅拌，静置分层，甲苯相浓缩至干，再加入21mL乙醇升温溶清后缓慢降温至0℃～10℃，过滤，得到白色的羟哌吡酮游离碱，收率84.2％，纯度96.5％。
实施例4
室温下，称取1.0kg环氧物、491.2g 2-羟基吡啶、83.5g四丁基硫酸氢铵，5.0L甲苯混合，再加入溶有68.0g碳酸钾的水溶液，升温至55～65℃保温反应8～10h，加入2.5L水搅拌，静置分层，甲苯相浓缩至干，再加入3.0L乙醇升温溶清后缓慢降温至0℃～10℃，过滤，烘干，得到白色的羟哌吡酮游离碱，收率84.3％，纯度96.9％。
实施例5
室温下，称取60.0kg环氧物、29.47kg 2-羟基吡啶、5.01kg四丁基硫酸氢铵，300L甲苯混合，再加入溶有4.08kg碳酸钾的水溶液，升温至55～65℃保温反应8～10h，加入200L 水搅拌，静置分层，甲苯相浓缩至干，再加入180L乙醇升温溶清后缓慢降温至0℃～10℃，过滤，烘干，得到白色的羟哌吡酮游离碱，收率84.3％，纯度97.0％。

Claims (10)

  1. 一种羟哌吡酮游离碱的制备方法，其特征在于，将式I所示的环氧物和2-羟基吡啶在相转移催化剂和无机碱作用下，在有机溶剂中进行反应得到式II所示的羟哌吡酮游离碱，反应式如下所示：
    Figure PCTCN2021098608-appb-100001
  2. 根据权利要求1所述的制备方法，其特征在于，所述的相转移催化剂选自四丁基硫酸氢铵、四丁基氯化铵、四丁基溴化铵、苄基三甲基氯化铵、苄基三甲基溴化铵、苄基三乙基氯化铵、苄基三乙基溴化铵中的一种或多种。
  3. 根据权利要求1所述的制备方法，其特征在于，所述的有机溶剂选自甲苯或二甲苯，优选为甲苯。
  4. 根据权利要求1所述的制备方法，其特征在于，所述的无机碱选自无机碱水溶液或无机碱固体，优选无机碱水溶液。
  5. 根据权利要求1所述的制备方法，其特征在于，所述无机碱选自碳酸钾、碳酸钠、碳酸锂或碳酸铯，优选为碳酸钾。
  6. 根据权利要求1所述的制备方法，其特征在于，所述的环氧物、2-羟基吡啶与无机碱的摩尔比为1：0.7～1.3：0.05～0.5，优选1：1.0～1.1：0.10～0.15。
  7. 根据权利要求1所述的制备方法，其特征在于，所述的环氧物与相转移催化剂的摩尔比为1：0.02～0.4，优选1：0.05～0.1。
  8. 根据权利要求1所述的制备方法，其特征在于，所述的环氧物质量与有机溶剂的体积比为1：3～12g/mL，优选1：5～7g/mL。
  9. 根据权利要求1所述的制备方法，其特征在于，反应温度为50℃～90℃，反应时间为6～24h。
  10. 根据权利要求9所述的制备方法，其特征在于，反应温度为55℃～65℃，反应时间为8～10h。
PCT/CN2021/098608 2020-06-23 2021-06-07 一种羟哌吡酮游离碱的合成工艺改进方法 WO2021259051A1 (zh)

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