WO2015090160A1 - 用于制备4-(2‐(4‐甲基苯基硫基))苯基哌啶的化合物、其制备方法及应用 - Google Patents

用于制备4-(2‐(4‐甲基苯基硫基))苯基哌啶的化合物、其制备方法及应用 Download PDF

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WO2015090160A1
WO2015090160A1 PCT/CN2014/093695 CN2014093695W WO2015090160A1 WO 2015090160 A1 WO2015090160 A1 WO 2015090160A1 CN 2014093695 W CN2014093695 W CN 2014093695W WO 2015090160 A1 WO2015090160 A1 WO 2015090160A1
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compound
formula
reaction
methylphenylthio
preparation
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PCT/CN2014/093695
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曹龙吉
辛建创
杨相平
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江苏恩华药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide

Definitions

  • the invention belongs to the technical field of drug synthesis.
  • the invention relates to compounds for the preparation of 4-(2-(4-methylphenylthio))phenylpiperidine, to processes for their preparation and to their use.
  • Tedatioxetine chemical name is 4 ⁇ (2 ⁇ (4 ⁇ methylphenylthio))phenyl piperidine, developed by Lingbei for the treatment of severe depression, is a monoamine reuptake inhibitor, monoamine transport reuptake Inhibitors, 5-HT3 antagonists and 5-HT2c receptor antagonists.
  • Tedatioxetine has the following structure:
  • the current synthetic routes mainly include the following:
  • WO 2003/029232 discloses for the first time the preparation method of Tedatioxetine, as shown in the following synthetic route,
  • the method has low yield, the product is not easy to be purified, and requires column chromatography; more importantly, the preparation of the compound N-Boc-piperidin-4-ol requires the use of butyl lithium, and the reaction is carried out at a lower temperature, Conducive to industrial production.
  • WO 2009109541 provides an improved method for the above route, as shown in the following synthetic route,
  • the present invention provides a compound for preparing 4-(2-(4-methylphenylthio))phenyl piperidine, a preparation method thereof and use thereof to overcome the drawbacks existing in the prior art.
  • the present invention relates to a process for the preparation of a compound of the formula VIII or a salt thereof, which comprises the step of preparing a compound of the formula VIII from a compound of the formula VII: a compound of the formula VII is reduced in an organic solvent to give a compound of the formula VIII;
  • the reducing agent is selected from the group consisting of lithium aluminum hydride, borane tetrahydrofuran, and borane dimethyl sulfide.
  • the organic solvent is selected from one or more of tetrahydrofuran, ethylene glycol dimethyl ether or dioxane; and the reflux temperature is from 0 to 100 ° C, preferably from 30 to 80 ° C.
  • the method relates to a process for the preparation of a compound of formula VII, comprising the steps of: melt-condensing a compound VI with urea in the absence of a solvent to give a compound of formula VII:
  • the molar ratio of the urea to the compound VI ranges from 1 to 10:1, preferably from 2 to 6:1; and the temperature of the reaction ranges from 130 to 190 ° C, preferably from 140 to 170. °C, more preferably 140-150 °C.
  • the present invention relates to a process for the preparation of a compound of formula VI, comprising the steps of: reacting compound III with a compound of formula IV under the action of a base;
  • the compound of formula IV is a compound having an active methylene group.
  • the compound having an active methylene group is ethyl acetoacetate, methyl acetoacetate, diethyl malonate, dimethyl malonate, ethyl cyanoacetate or cyanoacetic acid.
  • the base is an organic base
  • the hydrolysis is divided into two steps, first hydrolysis under alkaline conditions, and then hydrolysis under acidic conditions;
  • the solvent used in the hydrolysis reaction is water, methanol or ethanol;
  • the alkali is 20-50% aqueous NaOH solution, the amount of use 10 to 20 volumes (based on the mass of the compound III as a reference), preferably 12 to 15 times the volume;
  • the acid used is concentrated hydrochloric acid or hydrobromic acid, the amount is 13 to 30 times the volume (based on the mass of the compound III) Ratio, preferably 15 to 20 times the volume, the concentration of the concentrated hydrochloric acid is 30 to 37%, hydrobromic acid The concentration is 30 to 48%.
  • the present invention relates to a process for the preparation of the compound of formula III, comprising the steps of: compound I and compound II are condensed under a base to prepare compound III,
  • X is a halogen
  • the base is an inorganic base
  • the reaction solvent is DMF, DME, DMSO or 1,4-dioxane, etc., preferably DMF
  • the halogen in the compound II is Cl, Br or I, preferably Br.
  • the inorganic base is preferably one or more selected from the group consisting of sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate and potassium carbonate.
  • the molar ratio of the inorganic base to the compound of the formula II is preferably from 1 to 5:1, further preferably from 1 to 2:1; the molar ratio of the compound I to the compound II is in the range of from 3.0 to 1.0:1, preferably from 2.0 to 1.0:1, Further preferably 1.2-1.0:1.
  • the formula VIII is further acidified to a salt in an organic solvent, the reaction comprising the steps of:
  • the organic solvent is selected from one or more of acetone, ethanol or ethyl acetate, preferably acetone, and the ratio of the organic solvent to the compound of the formula VIII is 1-20:1, preferably 3:1, and the reaction temperature range is 30-80 ° C, preferably 30-40 ° C, the hydrochloric acid used is hydrogen chloride - ethyl acetate solution or concentrated hydrochloric acid.
  • the raw materials and reagents used in this article are all commercially available.
  • the main raw materials and reagent sources are as follows:
  • the compounds of formula I and formula II are purchased from Shanghai Haoyuan Chemical Co., Ltd.
  • the compound 3-[2(4-tolylthio)phenyl]glutaric acid (19.8 g, 60 mmol) prepared in the above step was mixed with urea (21.6 g, 360 mmol), and heated to 144 ° C for 4 hours; After the TLC monitoring reaction was completed, the temperature was lowered to 100 ° C, and 140 ml of water and 140 ml of ethanol were slowly added and stirred for 30 minutes; cooled to room temperature and stirred for 1 hour.
  • the title compound was recrystallized from EtOAc (EtOAc) (EtOAc) Diketone (melting point: 164-166 ° C), yield 88%.
  • Lithium tetrahydrogen aluminum (5.1 g, 39 mmol) was mixed with 140 ml of tetrahydrofuran, and the mixture was cooled to 8 ° C in an ice water bath. Under the protection of nitrogen, 4 -(2-p-methylphenylindenyl)phenylpiperidine 2,6 2 was added dropwise.
  • a solution of the ketone (7 g) in tetrahydrofuran (140 ml) was allowed to have a temperature of no more than 20 ° C; The reaction solution was cooled in an ice water bath, and 30 ml of water was slowly added dropwise thereto, followed by stirring for 20 minutes.
  • the reaction solution was cooled to 0 ° C, and 1 mol / l HCl (30 mL) was added dropwise, and the mixture was added dropwise, and the mixture was refluxed for 5 hours.
  • the THF was concentrated, washed with 30 ml of ethyl acetate, and saturated aqueous sodium hydrogen carbonate Then, it was extracted by adding 50 ml of ethyl acetate, and the organic phase was dried, and concentrated by filtration to give 1.8 g of a colorless liquid, which was solidified to a white solid 4-[2-(4-methylphenylthio)phenyl] Piperidine.
  • reaction solution was cooled to 0 ° C, and 30 ml of methanol was slowly added dropwise, and the mixture was stirred at room temperature overnight; 4 mol/l HCl/EA (10 ml) was added, and the mixture was heated to 100 ° C for 4 hours; the residue obtained after distillation under reduced pressure was dissolved in 30 ml.
  • Lithium tetrahydroaluminum (19 g, 500 mmol) was mixed with 200 ml of tetrahydrofuran, and 4-(2-p-methylphenylindenyl)phenylpiperidine 2,6-dione (31.1 g, 100 mmol) and tetrahydrofuran were added dropwise at room temperature. 200 ml) solution so that the temperature does not exceed 35 ° C; after the completion of the dropwise addition, the temperature is refluxed for 3 hours.
  • the reaction liquid was cooled in an ice water bath, and 100 ml of a saturated aqueous sodium sulfate solution was gradually added dropwise, and the mixture was stirred for 60 minutes.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了用于制备4-(2‐(4‐甲基苯基硫基))苯基哌啶的化合物、其制备方法及应用。本发明提供了两种制备4-(2‐(4‐甲基苯基巯基))苯基哌啶的中间体：3-(2‐(4‐甲基苯基巯基))苯基戊二酸和4-(2‐(4‐甲基苯基巯基))苯基哌啶‐2，6‐二酮及其制备与应用。该方法收率高，操作安全、方便，对环境污染小且利于工业化生产。

Description

用于制备4-(2‐(4‐甲基苯基硫基))苯基哌啶的化合物、其制备方法及应用 技术领域
本发明属于药物合成技术领域。具体地，本发明涉及用于制备4-(2‐(4‐甲基苯基硫基))苯基哌啶的化合物、其制备方法及应用。
背景技术
Tedatioxetine化学名为4‐(2‐(4‐甲基苯基硫基))苯基哌啶，由灵北公司开发用于治疗重症抑郁，是一单胺重摄取抑制剂，单胺转运重摄取抑制剂、5‐HT3拮抗剂和5‐HT2c受体拮抗剂。用于治疗重症抑郁及广泛性焦虑，处于II期临床研究。Tedatioxetine具有以下结构：
Figure PCTCN2014093695-appb-000001
根据文献报道，目前的合成路线主要有以下几种：
WO 2003/029232首次公开了Tedatioxetine的制备方法，如以下合成路线所示，
Figure PCTCN2014093695-appb-000002
该方法收率低，产物不易纯化，需要柱层析；更主要的是化合物N-Boc-哌啶-4-醇的制备需要用到丁基锂，且在较低的温度下进行反应，不利于工业化生产。
WO 2009109541提供一种针对上述路线的改进方法，如以下合成路线所示，
Figure PCTCN2014093695-appb-000003
用Bn-代替Boc-，脱羟基改用到TFA和Et3SiH,改进后的收率虽然有所提高。但也存在许多不足之处。不足之处主要体现在如下几个方面：化合物3的合成用到了价格昂贵的原料2‐碘溴代苯和催化剂钯源和膦二齿配位体，增加了制备成本；制备化合物4时需要用到较危险试剂丁基锂，需要在低温下反应。这在生产中会带来较大的安全隐患，也不利于操作；脱羟基制备2‐(4‐甲基苯基巯基)苯基哌啶氢溴酸盐时，要用到大量的三氟乙酸(15eq)，后处理比较麻烦且对环境有较大污染。
鉴于4-[2-(4-甲基苯基硫基)苯基]哌啶及其盐所具有的良好的药理学特性，以及现有工艺的不足，十分有必要开发一种适合工业生产，操作方便且环境友好的制备工艺。
发明内容
本发明提供一种制备4-(2‐(4‐甲基苯基硫基))苯基哌啶的化合物、其制备方法及应用，以克服现有技术中存在的缺陷。
在第一方面，本发明涉及一种制备式VIII化合物或其盐的方法，包括以式VII化合物为原料制备式VIII化合物的步骤：式VII化合物在有机溶剂中，还原得式VIII化合物；
Figure PCTCN2014093695-appb-000004
所述式VIII的制备方法中，所述的还原剂选自氢化铝锂、硼烷四氢呋喃，硼烷二甲硫醚中的 一种或几种；所述的有机溶剂选自四氢呋喃、乙二醇二甲醚或者二氧六环中的一种或几种；回流的反应温度为0～100℃，优选30～80℃。
在第二方面，本法涉及一种式VII化合物的制备方法，包括如下步骤：化合物VI与尿素在无溶剂条件下熔融缩合反应得式VII化合物：
Figure PCTCN2014093695-appb-000005
所述式VII化合物的制备方法中，所述的尿素和化合物VI的摩尔比范围为1～10：1优选2～6：1；所述反应的温度范围在130～190℃，优选140～170℃，更优选140‐150℃。
在第三方面，本发明涉及一种式VI化合物的制备方法，包括如下步骤：化合物III与式IV化合物在碱的作用下反应，经过水解制备化合物VI，
Figure PCTCN2014093695-appb-000006
式IV化合物为具有活性亚甲基的化合物。
式VI化合物的制备方法中，所述的具有活性亚甲基的化合物为乙酰乙酸乙酯、乙酰乙酸甲酯、丙二酸二乙酯、丙二酸二甲酯、氰乙酸乙酯、氰乙酸甲酯或者氰乙酰胺；优选乙酰乙酸乙酯；式IV化合物与化合物III的摩尔比范围为1～8:1，优选2～5：1，进一步优选2.5：1；所述的碱为有机碱哌啶、吡啶、胺、甲醇钠、乙醇钠或者叔丁醇中的一种或几种，优选哌啶、甲醇钠。
所述的水解分为两步，先在碱性条件下水解，再在酸性条件下水解；水解反应时所用溶剂为水、甲醇或乙醇等；所用到碱为20～50％的NaOH水溶液，用量为10～20体积(以化合物III质量数为参比)，优选12～15倍体积；用到的酸为浓盐酸或氢溴酸，用量为13～30倍体积(以化合物III质量数为参比)，优选15～20倍体积，所述的浓盐酸的浓度为30～37％，氢溴酸的 浓度为30～48％。
在第四方面，本发明涉及一种所述式III化合物的制备方法，包括如下步骤：化合物I与化合物II在碱作用下缩合制备化合物III,
Figure PCTCN2014093695-appb-000007
式II化合物中X为卤素。
所述式III化合物的制备方法中，所述的碱为无机碱，反应溶剂为DMF、DME、DMSO或者1，4-二氧六环等，优选DMF；化合物II中的卤素为Cl、Br或者I，优选Br。
所述的无机碱优选自碳酸钠、碳酸钾、氢氧化钾、氢氧化钠、碳酸铯和碳酸钾中的一种或几种。所述的无机碱与式II化合物的摩尔比优选1～5：1，进一步优选1～2:1；化合物I与化合物II的摩尔比范围为3.0～1.0：1，优选2.0～1.0:1，进一步优选1.2‐1.0：1。
在第五方面，式VIII在有机溶剂中进一步加酸成盐，反应包括如下步骤：
Figure PCTCN2014093695-appb-000008
所述的有机溶剂选自丙酮，乙醇或者乙酸乙酯等中的一种或几种，优选丙酮，有机溶剂与式VIII化合物的比例为1‐20：1，优选3：1，反应温度范围为30‐80℃，优选30‐40℃，所用的盐酸为氯化氢‐乙酸乙酯溶液或者浓盐酸。
式VII化合物，式VI化合物：
Figure PCTCN2014093695-appb-000009
本发明的有益效果：与现有工艺比较：通过本发明所提供的新化合物3‐[2(4‐甲苯硫基)苯基]戊二酸或4‐[2‐(4‐甲基苯基硫基)苯基]哌啶2，6‐二酮来制备4-[2-(4-甲基苯基硫基)苯基]哌啶及其盐，所用原料及试剂均低毒且廉价易得，产生的三废较少，同时操作简单，收率良好，适合于工业化生产。
具体实施方式
下文对本发明方法的优选实施方案进行更详细的描述。本领域技术人员应当理解，这些优选实施方案仅仅是为了示例本发明而不是构成对其的限制。
本文中所用的原料及试剂均为市售，主要原料及试剂来源如下：式I和式II化合物均购于上海彤源化工有限公司。
实施例1制备2‐(4‐甲基苯硫基)苯甲醛
Figure PCTCN2014093695-appb-000010
向Na2CO3(11g，105mmol)和30mlDMF的搅拌混合物中加入4‐甲基苯硫酚(12.4g，100mmol)，搅拌20分钟。再向混合物中慢慢加入2‐溴苯甲醛(18.4g，100mmol)；一待加入完毕，氮气保护下，加热到100℃反应6小时。反应完毕后，反应液冷却到室温，加入100ml水并搅拌30分钟。过滤，用水(30ml)洗涤滤饼并真空干燥得到20.5g浅绿色固体；经过在正己烷中重结晶得到18.5g淡黄色固体2‐(4‐甲基苯硫基)苯甲醛(熔点：52‐54℃)，收率81％。 实施例2制备2‐(4‐甲基苯硫基)苯甲醛
Figure PCTCN2014093695-appb-000011
向K2CO3(15g，110mmol)和30mlDMA的搅拌混合物中加入4‐甲基苯硫酚(12.6g，102mmol)，搅拌20分钟。再向混合物中慢慢加入2‐氯苯甲醛(14g，100mmol)；一待加入完毕，氮气保护下，加热到100℃反应7小时。反应完毕后，反应液冷却到室温，加入100ml水并搅拌30分钟。过滤，用水(30ml)洗涤滤饼并真空干燥得到19.7g浅绿色固体；经过在正己烷中重结晶得到17g淡黄色固体2‐(4‐甲基苯硫基)苯甲醛(熔点：51-53℃)，收率77.5％，
实施例3制备2‐(4‐甲基苯硫基)苯甲醛
Figure PCTCN2014093695-appb-000012
向NaOH(4.2g，105mmol)和50ml 1，4二氧六环的搅拌混合物中加入4‐甲基苯硫酚(12.4g，100mmol)，搅拌30分钟。再向混合物中慢慢加入2‐碘苯甲醛(23.1g，100mmol)；一待加入完毕，氮气保护下，加热回流反应5小时。反应完毕后，反应液冷却到室温，加入50ml水，萃取分离；有机相用50ml乙酸乙酯萃取，合并有机相并分别用20％氯化铵水溶液和饱和食盐水洗涤，无水硫酸镁干燥，过滤并浓缩得到21g粘稠状液体，冷却后固化；经过在正己烷中重结晶得到18.1g淡黄色固体2‐(4‐甲基苯硫基)苯甲醛(熔点：53‐54℃)，收率79％。
实施例4制备3‐[2(4‐甲基苯硫基)苯基]戊二酸
Figure PCTCN2014093695-appb-000013
1)制备乙基‐2‐氰基‐3‐(2‐(4‐甲基苯硫基)苯基)丙烯酸酯
Figure PCTCN2014093695-appb-000014
向2‐(4‐甲苯硫基)苯甲醛(4g，17.5mmol)、氰乙酸乙酯(2.4g 21mmol)和甲苯(30ml)的混合溶液中加入冰醋酸(5ml)和哌啶(0.3ml)搅拌10分钟；加热回流，并用分水器分离出生成的水。反应完毕，冷却到室温；反应液依次用30ml水和30ml饱和碳酸氢钠溶液洗涤，无水硫酸镁干燥；过滤并浓缩得到5.0g黄色液体(冷却后固化)，收率86％。不用纯化直接用于下一步反应。
2)制备二乙基-2，4-二乙酰基-3-(2-(4-甲基苯硫基)苯基)戊二酸酯
Figure PCTCN2014093695-appb-000015
将甲醇钠(1.9g，35mmol)和干燥的THF(30ml)混合搅拌并降温到0-5℃，滴加丙二酸二乙酯(4.6g，35mmol)，滴毕室温搅拌15分钟；滴加上述步骤所得的乙基‐2‐氰基‐3‐(2‐(4‐甲基苯硫基)苯基)丙烯酸酯(5g，15.4mmol)和干燥的四氢呋喃(40ml)溶液；滴毕，室温搅拌13小时。反应完毕，反应液中加入150ml20％的氯化铵水溶液，然后萃取分离；水相用乙酸乙酯萃取，合并有机相，无水硫酸镁干燥；过滤并浓缩得到粘稠状液体5.4g，收率78％。不用纯化直接用于下一步反应。
向上述步骤所得的物质(5.4g)中加入6N盐酸(70ml)，加热回流3天；反应完毕，慢慢冷却到室温，加入50ml乙酸乙酯，搅拌30分钟固体从溶液中析出，过滤并用20ml乙酸乙酯洗涤，于50℃真空干燥10小时得到2.7g白色固体3‐[2(4‐甲苯硫基)苯基]戊二酸(熔点：191‐195℃)，收率58％。
实施例5制备3‐[2‐(4‐甲基苯硫基)苯基]戊二酸
Figure PCTCN2014093695-appb-000016
向乙酰乙酸乙酯(13g,100mmol)和哌啶(1.7g，10mmol)的混合溶液中加入2‐(4‐甲基苯硫基)苯甲醛(11.5g，50mmol)，室温反应1天，得到一黄色粘稠状半固体，加入2.7g甲醇钠，搅拌1小时后固化，放置2天。向上述混合物中加入乙醇(180ml)和40％氢氧化钠水溶液(140ml)搅拌并加热到回流，反应4‐5小时。反应完毕停止加热，待冷却到室温后，减压蒸馏出溶剂；蒸馏后的残余物在冰水浴下降温，并滴加浓盐酸(150ml)调pH到1‐2。加入300ml乙酸乙酯萃取，水相用300ml乙酸乙酯萃取，合并有机相并用300ml水洗涤；有机相用无水硫酸钠干燥，过滤并浓缩出500ml溶剂。残余物冷却到室温，搅拌2小时。标题化合物经过过滤分离，用乙酸乙酯(20ml)洗涤和于50℃真空彻夜干燥，得到21.5g白色固体3‐[2(4‐甲苯硫基)苯基]戊二酸(熔点：194‐196℃)收率65％。
1HNMR(DMSO‐d6):δ2.28(S,3H),2.54‐2.65(m,4H),4.09‐4.16(m,1H),7.08‐7.17(m,4H),7.21‐7.26(m,3H),7.39(d,J＝8.1Hz,1H),12.15(s,2H).ESI‐MS(m/z):353.10[M+Na]+.
实施例6制备4‐[2‐(4‐甲基苯基硫基)苯基]哌啶2，6‐二酮
Figure PCTCN2014093695-appb-000017
将上步骤制备出的化合物3‐[2(4‐甲基苯硫基)苯基]戊二酸(10g，30mmol)与尿素(5.4g，90mmol)混合搅拌，并加热到146℃反应4小时；TLC监控反应完毕后，降温到80℃，慢慢加入70ml水和70ml乙醇搅拌30分钟；冷却到室温，搅拌1小时。标题化合物经过滤无水乙醇(170ml)重结晶和50℃真空彻夜干燥，得到8.0g类白色固体4‐[2‐(4‐甲基苯基硫基)苯基]哌啶2，6‐二酮(熔点：164‐166℃)，收率86％
1HNMR(CDCl3):δ2.33(S,3H),2..86(dd,J＝17.2,4.4Hz,2H),2.69‐2.76 (m,2H),3.99‐4.08(m,1H),7.10‐7.15(m,4H),7.18‐7.30(m,4H),8.78(brs,1H).ESI‐MS(m/z):312.1[M+H]+.
实施例7制备4‐[2‐(4‐甲基苯基硫基)苯基]哌啶2，6‐二酮
Figure PCTCN2014093695-appb-000018
在250ml装有冷凝管的四口反应瓶中，加入3‐[2(4‐甲基苯硫基)苯基]戊二酸(10g，30mmol)和尿素(14.4g，240mmol)并搅拌，加热到146℃反应4小时；TLC监控反应完毕后，降温到100℃，慢慢加入70ml水和70ml乙醇搅拌30分钟；冷却到室温，搅拌1小时。标题化合物经过滤无水乙醇(170ml)重结晶和50℃真空彻夜干燥，得到7.8g类白色固体4‐[2‐(4‐甲基苯基硫基)苯基]哌啶2，6‐二酮(熔点：165‐166℃)，收率84％。
实施例8制备4‐[2‐(4‐甲基苯基硫基)苯基]哌啶2，6‐二酮
Figure PCTCN2014093695-appb-000019
在250ml装有冷凝管的四口反应瓶中，加入3‐[2(4‐甲基苯硫基)苯基]戊二酸(5g，15mmol)和尿素(1.8g，30mmol)并搅拌，加热到143℃反应4小时；降温到100℃，慢慢加入35ml水和35ml乙醇搅拌30分钟；冷却到室温，搅拌1小时。标题化合物经过滤无水乙醇(70ml)重结晶和50℃真空彻夜干燥，得到2.9g灰白色固体4‐[2‐(4‐甲基苯基硫基)苯基]哌啶2，6‐二酮(熔点：163‐166℃)，收率63％。
实施例9制备4‐[2‐(4‐甲基苯基硫基)苯基]哌啶2，6‐二酮
Figure PCTCN2014093695-appb-000020
将上步骤制备出的化合物3‐[2(4‐甲基苯硫基)苯基]戊二酸(10g，30mmol)与尿素(3.6g，60mmol)混合搅拌，并加热到146℃反应4小时；TLC监控反应完毕后，降温到80℃，慢慢加入70ml水和70ml乙醇搅拌30分钟；冷却到室温，搅拌1小时。标题化合物经过滤、无水乙醇(45ml)重结晶和50℃真空彻夜干燥，得到8.0g类白色固体4‐[2‐(4‐甲基苯基硫基)苯基]哌啶2，6‐二酮(熔点：164‐166℃)，收率86％。
实施例10制备4‐[2‐(4‐甲基苯基硫基)苯基]哌啶2，6‐二酮
Figure PCTCN2014093695-appb-000021
将上步骤制备出的化合物3‐[2(4‐甲苯硫基)苯基]戊二酸(19.8g，60mmol)与尿素(21.6g，360mmol)混合搅拌，并加热到144℃反应4小时；TLC监控反应完毕后，降温到100℃，慢慢加入140ml水和140ml乙醇搅拌30分钟；冷却到室温，搅拌1小时。标题化合物经过滤、无水乙醇(350ml)重结晶和50℃真空彻夜干燥，得到16.5g类白色固体4‐[2‐(4‐甲基苯基硫基)苯基]哌啶2，6‐二酮(熔点：164‐166℃)，收率88％。
实施例11制备4-[2-(4-甲基苯基硫基)苯基]哌啶
将四氢铝锂(5.1g，39mmol)与140ml四氢呋喃混合搅拌，冰水浴降温到8℃，氮气保护下，滴加4‐(2‐对甲基苯基巯基)苯基哌啶2,6二酮(7g)的四氢呋喃(140ml)溶液，使温度不超过20℃；滴毕，室温反应5小时。冰水浴中冷却反应液，慢慢滴加30ml水，搅拌20分钟。反应液中加入硫酸钠(20g)，搅拌30分钟。过滤并浓缩滤液，得到的无色液体(4.5g)， 冷却后固化成白色固体4-[2-(4-甲基苯基硫基)苯基]哌啶。
实施例12制备4-[2-(4-甲基苯基硫基)苯基]哌啶
100ml四口反应瓶中加入1mol/l硼烷四氢呋喃溶液(40ml，40mmol)，冰水浴降温到5℃；氮气保护下，滴加4‐(2‐对甲基苯基巯基)苯基哌啶2,6二酮(3.1g)的四氢呋喃(40ml)溶液，使温度不超过10℃；滴毕，室温反应20小时。反应液冷却到0℃，慢慢滴加1mol/l HCl(30mL)，滴毕，升温回流5小时；浓缩除去THF，水溶液中用30ml乙酸乙酯洗涤，加入饱和碳酸氢钠水溶液调pH>10，随后加入50ml乙酸乙酯萃取，有机相经过干燥，过滤浓缩的到得到的1.8g无色液体，冷却后固化成白色固体4-[2-(4-甲基苯基硫基)苯基]哌啶。
实施例13制备4-[2-(4-甲基苯基硫基)苯基]哌啶
将2mol/l BH3.CH3SCH3(20mL)与20ml二乙二醇二甲醚混合搅拌，冰水浴降温到10℃，滴加4‐(2‐对甲基苯基巯基)苯基哌啶2,6二酮(3.1g)的二乙二醇二甲醚(60ml)溶液，使温度不超过20℃；滴毕，室温反应0.5小时，然后慢慢升温到120℃反应10小时。反应液冷却到0℃，慢慢滴加30ml甲醇，滴毕，室温搅拌过夜；加入4mol/l HCl/EA(10ml)，加热到100℃反应4小时；减压蒸馏后所得残余物溶于30ml水，加入饱和碳酸氢钠水溶液调pH>10，随后加入50ml乙酸乙酯萃取，有机相经过干燥，过滤浓缩得到的淡红色液体；经过柱层析(洗脱剂为己烷—醋酸—乙醇10:1.5:0.5)纯化后得到白色固体(0.9g)4-[2-(4-甲基苯基硫基)苯基]哌啶。
实施例14制备4-[2-(4-甲基苯基硫基)苯基]哌啶盐酸盐
将上步骤所得4-[2-(4-甲基苯基硫基)苯基]哌啶(4g，14mmol)加入到无水乙醇(30ml)中，加热到50℃溶解；慢慢滴加4mol/l的氯化氢‐乙酸乙酯溶液(4ml)，同温反应40分钟；降温到5‐10℃搅拌2小时，过滤出的滤饼经过乙醇(5ml)洗涤和44℃时真空彻夜干燥，得到3.2g白色固体4-[2-(4-甲基苯基硫基)苯基]哌啶盐酸盐(熔点：222‐225℃)，收率75％。
实施例15制备4-[2-(4-甲基苯基硫基)苯基]哌啶盐酸盐
将4-[2-(4-甲基苯基硫基)苯基]哌啶(4g，14mmol)加入到丙酮(20ml)中，加热到50℃溶解；慢慢滴加37％的浓盐酸(1.5ml)，同温反应40分钟；降温到5‐10℃搅拌2小时， 过滤出的滤饼经过丙酮(5ml)洗涤和44℃时真空彻夜干燥，得到3.6g白色固体4-[2-(4-甲基苯基硫基)苯基]哌啶盐酸盐(熔点：224‐227℃)，收率80％。
实施例16制备4-[2-(4-甲基苯基硫基)苯基]哌啶盐酸盐
将四氢铝锂(19g，500mmol)与200ml四氢呋喃混合搅拌，室温下滴加4‐(2‐对甲基苯基巯基)苯基哌啶2,6二酮(31.1g，100mmol)和四氢呋喃(200ml)溶液，使温度不超过35℃；滴毕，升温回流反应3小时。冰水浴中冷却反应液，慢慢滴加100ml饱和硫酸钠水溶液，搅拌60分钟。反应液中加入乙酸乙酯(200ml)和无水硫酸镁(50g)搅拌60分钟。过滤并浓缩滤液，得到的无色液体。加入到80ml丙酮并加热到40℃溶解，快速加入4mol/l的氯化氢‐乙酸乙酯溶液(10ml)，加入晶种，搅拌20分钟析出白色固体。40℃时，慢慢滴加余下的氯化氢‐乙酸乙酯溶液(20ml)。滴毕，5‐10℃搅拌3小时。过滤出的滤饼经过丙酮(30ml)洗涤和44℃时真空彻夜干燥，得到20.8g白色固体4-[2-(4-甲基苯基硫基)苯基]哌啶盐酸盐(熔点：225‐228℃)，收率66％。
TLC:Rf 0.15(chloroform:methanol＝9:1)；1HNMR(CDCl3):δ6.83(d,J＝8.1Hz,1H),6.74(d,J＝1.9Hz,1H),6.68(dd,J＝8.1,1.9Hz,1H),4.75(m,1H),3.68(s,3H),3.36(m,1H),3.31(br,2H),3.02‐2.94(m,2H),2.58‐2.52(m,2H),1.94‐1.39(m,12H).

Claims (13)

  1. 一种制备式VIII化合物或其盐的方法，包括以式VII化合物为原料制备式VIII化合物的步骤，其特征在于，式VII化合物在有机溶剂中，还原得式VIII化合物；
    Figure PCTCN2014093695-appb-100001
  2. 根据权利要求1所述的方法，其特征在于，所述的还原剂选自氢化铝锂、硼烷四氢呋喃，硼烷二甲硫醚中的一种或几种；所述的有机溶剂选自四氢呋喃、二乙二醇二甲醚或者二氧六环中的一种或几种。
  3. 根据权利要求1或2所述的方法，其特征在于，所述式VII化合物的制备方法，包括如下步骤：化合物VI与尿素在无溶剂条件下熔融缩合反应得式VII化合物：
    Figure PCTCN2014093695-appb-100002
  4. 根据权利要求3所述的方法，其特征在于，所述的尿素和化合物VI的摩尔比范围为1～10：1，优选2～6：1；所述反应的温度范围在130～190℃，优选140～170℃。
  5. 根据权利要求4所述的方法，其特征在于，所述式VI化合物的制备方法，包括如下步骤：化合物III与式IV化合物在碱的作用下反应，然后经过水解制备化合物VI，
    Figure PCTCN2014093695-appb-100003
    式IV化合物为具有活性亚甲基的化合物。
  6. 根据权利要求5所述的方法，其特征在于，所述的活性亚甲基化合物为乙酰乙酸乙酯、乙酰乙酸甲酯、丙二酸二乙酯、丙二酸二甲酯、氰乙酸乙酯、氰乙酸甲酯或者氰乙酰胺；优选乙酰乙酸乙酯；式IV化合物与式III化合物的摩尔比范围为1～8：1，优选2～5：1；所述的碱选自哌啶、吡啶、胺、甲醇钠、乙醇钠或者叔丁醇中的一种或几种，优选哌啶、甲醇钠。
  7. 根据权利要求5所述的方法，其特征在于，所述的水解分为两步，先在碱性条件下水解，再在酸性条件下水解；水解反应时所用溶剂为乙醇、甲醇或者水中的一种或几种；所用到的碱为氢氧化钠或者氢氧化钾水溶液，浓度为20～50％；用到的酸为浓盐酸或氢溴酸。
  8. 根据权利要求5‐7任一所述的方法，其特征在于，所述式III化合物的制备方法，包括如下步骤：化合物I与化合物II在碱作用下缩合反应制备化合物III,
    Figure PCTCN2014093695-appb-100004
    式II化合物中X为卤素。
  9. 根据权利要求8所述的方法，其特征在于，所述的碱为无机碱，反应溶剂为DMF、DMA、DMSO或者1，4二氧六环，优选DMF；化合物II中的卤素为Cl、Br或者I，优选Br。
  10. 根据权利要求9所述的方法，其特征在于，所述的无机碱选自碳酸钠、碳酸钾、碳酸铯、氢氧化钾和氢氧化钠中的一种或几种；所述的无机碱与式II化合物的摩尔比为1～5：1，优选1～2:1；化合物I与化合物II的摩尔比范围为3.0～1.0：1，优选2.0～1.0:1。
  11. 根据权利要求1所述的方法，其特征在于，所述的式VIII进一步酸加成盐为式IX，反应包括如下步骤：在有机溶剂中,式VIII与盐酸反应得式IX，
    Figure PCTCN2014093695-appb-100005
  12. 根据权利要求11所述的方法，其特征在于所述的有机溶剂选自丙酮，乙醇或者乙酸乙酯等中的一种或几种，优选丙酮，溶剂与式VIII化合物的比例为1～20：1，优选3～10：1，反应温度范围为30～80℃，优选30～40℃，所用的盐酸为氯化氢的有机溶液或者浓盐酸，氯化氢的有机溶剂选自HCl/EA，HCl/EtOH，HCl/Et2O中的一种或几种。
  13. 式VII化合物，式VI化合物：
    Figure PCTCN2014093695-appb-100006
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