WO2023060856A1 - 一种磺吡酮的制备方法 - Google Patents

一种磺吡酮的制备方法 Download PDF

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WO2023060856A1
WO2023060856A1 PCT/CN2022/086078 CN2022086078W WO2023060856A1 WO 2023060856 A1 WO2023060856 A1 WO 2023060856A1 CN 2022086078 W CN2022086078 W CN 2022086078W WO 2023060856 A1 WO2023060856 A1 WO 2023060856A1
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sulfinpyrazone
preparation
solvent
formula
iodide
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PCT/CN2022/086078
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English (en)
French (fr)
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冯宇
钱伟
许燕萍
高莉燕
钟为慧
凌飞
刘涛
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诚达药业股份有限公司
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Priority to US18/128,362 priority Critical patent/US20230242490A1/en
Publication of WO2023060856A1 publication Critical patent/WO2023060856A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/28—Two oxygen or sulfur atoms
    • C07D231/30—Two oxygen or sulfur atoms attached in positions 3 and 5
    • C07D231/32—Oxygen atoms
    • C07D231/36—Oxygen atoms with hydrocarbon radicals, substituted by hetero atoms, attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/01—Products
    • C25B3/09—Nitrogen containing compounds
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
    • C25B3/00—Electrolytic production of organic compounds
    • C25B3/20—Processes
    • C25B3/23—Oxidation

Definitions

  • the invention relates to the field of drug synthesis, in particular to a preparation method of sulfinpyrazone.
  • Sulcopyrazone is a derivative of phenylbutazone, which can inhibit platelet aggregation and release in vivo, and can reversibly inhibit platelet prostate synthetase.
  • Sulfinpyrazone can competitively inhibit the active reabsorption of urate in the proximal convoluted tubule, increase the excretion of uric acid, reduce the concentration of uric acid in the blood, slow down or prevent the formation of gouty nodules and joint gouty lesions.
  • This product can also inhibit platelet aggregation and increase the survival time of platelets. It also has weak anti-inflammatory and analgesic effects.
  • the synthetic route of the prior art not only has long steps and low yield, but also is difficult to control the product retention, so there is an urgent need for an environmentally friendly, simple, efficient and fast method to replace the prior art method for the preparation of sulfinpyrazone .
  • the invention provides a preparation method of sulfinpyrazone.
  • thiophenol is used as a raw material for the first time to prepare sulfinpyrazone through two steps of electrocatalytic oxidation and nucleophilic substitution.
  • the method has short steps, is environmentally friendly, and has high purity.
  • the quality is stable, no oxidant hydrogen peroxide is used, and the shortcoming that sulfide is easily over-oxidized into sulfone in the classical method of the prior art is overcome.
  • the object of the present invention is to provide a kind of preparation method of sulfinpyrazone in order to solve the problems existing in the above-mentioned prior art conditions.
  • a preparation method of sulfinpyrazone, the synthetic route is as follows:
  • electrolyte represents the electrolyte
  • current represents the current
  • temperature represents the temperature
  • salt represents the salt
  • base represents the alkali
  • additive represents the additive
  • solvent represents the solvent
  • the conditions of the electrodes described in step (1) are as follows: the anode is selected from one of graphite felt, platinum, and nickel electrodes, and the cathode is selected from graphite felt, platinum, nickel, and carbon sheet electrodes, and the electrode specifications are all 1 cm ⁇ 1cm.
  • the electrolyte described in step (1) is tetrabutylammonium bromide, tetrabutylammonium tetrafluoroborate, tetra-n-octylammonium bromide, tetrabutylammonium hexafluorophosphate, perchloric acid Any one of lithium, ammonium perchlorate, and tetrabutylammonium iodide, the amount of electrolyte used is 0.5-2 times that of thiophenol.
  • the water described in step (1) is any one of distilled water and deionized water, and the amount used is 0.5-10 times the amount of the thiophenol substance.
  • the current in step (1) is 4-30 mA.
  • the temperature in step (1) is 30-70° C.; the volume of 1,2-dichloroethane in step (1) is 5-30 times that of compound 3.
  • the solvent is selected from any one or more of acetone, acetonitrile, and n-hexane.
  • the alkali described in step (2) is selected from any one of cesium carbonate, sodium hydroxide, potassium hydroxide, sodium ethylate, potassium ethylate, triethylamine, diisopropylethylamine ;
  • the additive is selected from any one of sodium iodide, potassium iodide, lithium iodide and ammonium iodide; the reaction temperature in step (2) is 50-70°C.
  • the dosage of the compound 1,2-diphenyl-3,5-pyrazolidinedione in step (2) is 1.0-4.0 times that of 2-chloroethylphenyl sulfoxide;
  • the amount of base is 1.0-4.0 times that of 2-chloroethyl phenyl sulfoxide;
  • the amount of additive is 1-5 times that of 2-chloroethyl phenyl sulfoxide;
  • the amount of solvent is 2-chloroethyl phenyl sulfoxide 5-10 times that of sulfone.
  • the present invention has the following beneficial effects:
  • a preparation method of sulfinpyrazone, the synthetic route is as follows:
  • the conditions of the electrodes described in step (1) are as follows: the anode is selected from one of graphite felt, platinum, and nickel electrodes, and the cathode is selected from graphite felt, platinum, nickel, and carbon sheet electrodes, and the electrode specifications are 1cm ⁇ 1cm; step ( 1)
  • the electrolyte described in is tetrabutylammonium bromide, tetrabutylammonium tetrafluoroborate, tetran-octylammonium bromide, tetrabutylammonium hexafluorophosphate, lithium perchlorate, ammonium perchlorate, tetrabutylammonium Any one of ammonium iodide, the consumption of electrolyte is 0.5-2 times of thiophenol; the water described in step (1) is any one of distilled water and deionized water, and its consumption is the amount of thiophenol substance 0.5-10 times of 0.5-10 times; the electric current described
  • the solvent is selected from acetone, acetonitrile, any one or more of normal hexane; the alkali described in step (2) is selected from cesium carbonate, sodium hydroxide, potassium hydroxide, Sodium ethylate, potassium ethylate, any one in triethylamine, diisopropylethylamine; Additive is selected from any one in sodium iodide, potassium iodide, lithium iodide, ammonium iodide; Step (2) reaction temperature 50-70°C; the amount of the compound 1,2-diphenyl-3,5-pyrazolidinedione described in step (2) is 1.0-4.0 times that of 2-chloroethyl phenyl sulfoxide; base The dosage is 1.0-4.0 times of 2-chloroethyl phenyl sulfoxide; the dosage of additive is 1-5 times of 2-chloroethyl phenyl sulfoxide; the dosage
  • 2-Chloroethylphenylsulfoxide 2 (189.0mg, 1.0mmol), 1,2-diphenyl-3,5-pyrazolidinedione 4 (378.2mg, 1.5mmol), carbonic acid Cesium (488.7mg, 1.5mmol), sodium iodide (149.9mg, 1.0mmol), acetone (6mL), one side of the three-necked bottle was inserted with a condenser tube, a three-way balloon, and the other side was covered with a rubber stopper, and the nitrogen gas was replaced. Reflux at 65°C for 12 hours.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • 2-Chloroethylphenylsulfoxide 2 (189.0mg, 1.0mmol), 1,2-diphenyl-3,5-pyrazolidinedione 4 (302.6mg, 1.2mmol), carbonic acid Cesium (391.0mg, 1.2mmol), sodium iodide (149.9mg, 1.0mmol), acetone (6mL), one side of the three-necked bottle was inserted with a condenser tube, a three-way balloon, and the other side was covered with a rubber stopper, and the nitrogen gas was replaced. Reflux at 65°C for 12 hours.
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • 2-Chloroethylphenylsulfoxide 2 (189.0mg, 1.0mmol), 1,2-diphenyl-3,5-pyrazolidinedione 4 (302.6mg, 1.2mmol), carbonic acid Cesium (391.0mg, 1.2mmol), sodium iodide (224.8mg, 1.5mmol), acetone (6mL), one side of the three-necked bottle was inserted with a condenser tube, a three-way balloon, and the other side was covered with a rubber stopper, and nitrogen was replaced. Reflux at 65°C for 12 hours.
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • 2-Chloroethylphenylsulfoxide 2 (189.0mg, 1.0mmol), 1,2-diphenyl-3,5-pyrazolidinedione 4 (378.2mg, 1.5mmol), carbonic acid Cesium (488.7mg, 1.5mmol), potassium iodide (166.0mg, 1.0mmol), acetone (6mL), one side of the three-necked bottle with a condenser tube, a three-way balloon, and a rubber stopper on the other side, nitrogen replacement, at 65°C Reflux for 12 hours.
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • 2-Chloroethylphenylsulfoxide 2 (189.0mg, 1.0mmol), 1,2-diphenyl-3,5-pyrazolidinedione 4 (378.2mg, 1.5mmol), carbonic acid Cesium (488.7mg, 1.5mmol), sodium iodide (149.9mg, 1.0mmol), acetonitrile (6mL), one side of the three-necked bottle was inserted with a condenser tube, a three-way balloon, and the other side was covered with a rubber stopper, and the nitrogen gas was replaced. Reflux at 65°C for 12 hours.
  • embodiments 1 to 4 are the preparation of 2-chloroethyl phenyl sulfoxide in step 1, and in step 2 of embodiments 5 to 9, 2-chloroethyl sulfoxide in step 1 Phenyl sulfoxide to produce sulfinpyrazone.
  • the green and environment-friendly electrochemical method is introduced into the synthesis steps, which not only greatly shortens the reaction steps, but also improves the total yield; avoids the use of strong alkali and oxidant hydrogen peroxide, and improves the atomic It is economical and reduces environmental pollution; fundamentally overcomes the problem that chloroethyl sulfide is easily over-oxidized to chloroethyl sulfone in a hydrogen peroxide system, and improves the selectivity of the reaction.
  • the preparation route of the present invention has short steps, the highest yield of step 1) can reach 83%, and the highest yield of step 2) Example 5 can reach 58%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Electrochemistry (AREA)
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  • Metallurgy (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)

Abstract

本发明公开了一种磺吡酮的制备方法，该磺吡酮以苯硫酚为起始物，经电催化与二氯乙烷偶联制得2-氯乙基苯基亚砜，随后与1,2-二苯基-3,5-吡唑烷二酮发生取代反应制得磺吡酮，两步反应，总收率48％。与现有技术相比，本方法具有收率高、步骤短、三废少、化学选择性好、无需使用强碱和氧化剂、操作安全简便、易于实现工业化生产的特点。

Description

一种磺吡酮的制备方法 技术领域
本发明涉及到药物合成领域，尤其涉及一种磺吡酮的制备方法。
背景技术
磺吡酮结构如式I所示。
Figure PCTCN2022086078-appb-000001
磺吡酮为保泰松的衍生物，在体内具有抑制血小板聚集和释放的作用，能可逆性地抑制血小板前列腺合成酶。磺吡酮可竞争性抑制尿酸盐在近曲小管的主动重吸收，增加尿酸的排泄，降低血中尿酸的浓度，减缓或预防痛风结节形成和关节的痛风病变。本品还可抑制血小板聚集，增加血小板存活时间。还具有微弱的抗炎和镇痛作用。
文献Volumen XLIV,Fasciculus I 1961,28,233.和Chin.J.Pharm.,1999,30,100.中报道磺吡酮合成方法如下：苯硫酚为原料和1,2-二氯乙烷反应，再和丙二酸二乙酯发生亲核取代反应，之后和二苯肼发生酯交换反应，最后硫醚被氧化成亚砜，即得磺吡酮。
Figure PCTCN2022086078-appb-000002
图一、原研路线图
Figure PCTCN2022086078-appb-000003
图二、改进路线
上面两条路线步骤长，繁琐，收率低下。此外，更为主要的是，最后一步硫醚容易被双氧水和醋酸体系过度氧化成砜，难以控制产物停留在亚砜这一步。
综上所述，现有技术的合成路线不仅步骤长、收率低，而且难以控制产物停留，所以亟需一种绿色环保、操作简单、高效快速的方法替代现有技术的方法制备磺吡酮。
发明内容
本发明提供了一种磺吡酮的制备方法，本发明首次以苯硫酚为原料，经过电催化氧化、亲核取代两步制得磺吡酮，该方法步骤短，绿色环保，纯度高，质量稳定，没有使用氧化剂过氧化氢，克服了现有技术的经典方法中容易将硫醚过度氧化成砜的缺点。
本发明的目的就是为了解决上述现有技术条件存在的问题，提供一种磺吡酮的制备方法。
为了达到上述目的，本发明采用了以下技术方案：
一种磺吡酮的制备方法，合成路线如下：
Figure PCTCN2022086078-appb-000004
其中，electrolyte表示电解质，current表示电流，temperature表示温度，salt表示盐，base表示碱，additive表示添加剂，solvent表示溶剂。
作为本方案的进一步改进，具体包括以下步骤：
(1)将如式3所示的苯硫酚和电解质溶于1,2-二氯乙烷和水的混合溶液中，通入电流反应1～48小时，得到如式2所示的2-氯乙基苯基亚砜。
(2)将如式2所示的2-氯乙基苯基亚砜、如式4所示的1,2-二苯基-3,5-吡唑烷二酮、碱和添加剂混溶于溶剂中，在氮气氛围下加热反应1～48个小时，反应结束后，反应混合物经柱层析得到如式1所示的磺吡酮。
作为本方案的进一步改进，步骤(1)中所述电极情况如下：阳极选自石墨毡、铂、镍电极之一，阴极选自石墨毡、铂、镍、碳片电极，电极规格均为1cm×1cm。
作为本方案的进一步改进，步骤(1)中所述电解质为四丁基溴化铵、四丁基四氟硼酸铵、四正辛基溴化铵、四丁基六氟磷酸铵、高氯酸锂、高氯酸铵、四丁基碘化铵的任意一种，电解质的用量为苯硫酚的0.5-2倍。
作为本方案的进一步改进，步骤(1)中所述水为蒸馏水、去离子水中的任意一种，其用量为苯硫酚物质的量的0.5-10倍。
作为本方案的进一步改进，步骤(1)中所述电流为4-30毫安。
作为本方案的进一步改进，步骤(1)中所述温度为30-70℃；步骤(1)中所述1,2-二氯乙烷的体积用量为化合物3的5-30倍。
作为本方案的进一步改进，步骤(2)中，所述溶剂选自丙酮，乙腈，正己烷其中的任意一种或多种。
作为本方案的进一步改进，步骤(2)中所述的碱选自碳酸铯，氢氧化钠，氢氧化钾，乙醇钠，乙醇钾，三乙胺、二异丙基乙胺中的任意一种；添加剂选自碘化钠，碘化钾，碘化锂、碘化铵中的任意一种；步骤(2)反应温度为50-70℃。
作为本方案的进一步改进，步骤(2)中所述化合物1,2-二苯基-3,5-吡唑烷 二酮的用量为2-氯乙基苯基亚砜的1.0-4.0倍；碱的用量为2-氯乙基苯基亚砜的1.0-4.0倍；添加剂的用量为2-氯乙基苯基亚砜的1-5倍；溶剂的用量为2-氯乙基苯基亚砜的5-10倍。
与现有技术相比，本发明具备下述有益效果：
a)将绿色环保，环境友好型的电化学方法引入到合成步骤中，大大缩短了反应步骤，提高了总收率；
b)避免了强碱、氧化剂过氧化氢的使用，提高了原子经济性，减少了环境污染；
c)从根源上克服了氯乙基硫醚在过氧化氢体系下容易过度氧化成氯乙基砜的问题，提高了反应的选择性。本方法具有良好的应用价值和潜在的社会经济效益。
具体实施方式
为了使本发明的目的、技术方案和优点更加清楚，以下结合实施例对本发明作进一步说明：
一种磺吡酮的制备方法，合成路线如下：
Figure PCTCN2022086078-appb-000005
具体包括以下步骤：
(1)将如式3所示的苯硫酚和电解质溶于1,2-二氯乙烷和水的混合溶液中，通入电流反应1～48小时，得到如式2所示的2-氯乙基苯基亚砜。
(2)将如式2所示的2-氯乙基苯基亚砜、如式4所示的1,2-二苯基-3,5-吡唑烷二酮、碱和添加剂混溶于溶剂中，在氮气氛围下加热反应1～48小时，反应结 束后，反应混合物经柱层析得到如式1所示的磺吡酮。
其中，步骤(1)中所述电极情况如下：阳极选自石墨毡、铂、镍电极之一，阴极选自石墨毡、铂、镍、碳片电极，电极规格均为1cm×1cm；步骤(1)中所述电解质为四丁基溴化铵、四丁基四氟硼酸铵、四正辛基溴化铵、四丁基六氟磷酸铵、高氯酸锂、高氯酸铵、四丁基碘化铵的任意一种，电解质的用量为苯硫酚的0.5-2倍；步骤(1)中所述水为蒸馏水、去离子水中的任意一种，其用量为苯硫酚物质的量的0.5-10倍；步骤(1)中所述电流为4-30毫安；步骤(1)中所述温度为30-70℃；步骤(1)中所述1,2-二氯乙烷的体积用量为化合物3的5-30倍。
其中，步骤(2)中，所述溶剂选自丙酮，乙腈，正己烷其中的任意一种或多种；步骤(2)中所述的碱选自碳酸铯，氢氧化钠，氢氧化钾，乙醇钠，乙醇钾，三乙胺、二异丙基乙胺中的任意一种；添加剂选自碘化钠，碘化钾，碘化锂、碘化铵中的任意一种；步骤(2)反应温度为50-70℃；步骤(2)中所述化合物1,2-二苯基-3,5-吡唑烷二酮的用量为2-氯乙基苯基亚砜的1.0-4.0倍；碱的用量为2-氯乙基苯基亚砜的1.0-4.0倍；添加剂的用量为2-氯乙基苯基亚砜的1-5倍；溶剂的用量为2-氯乙基苯基亚砜的5-10倍。
实施例1：
2-氯乙基苯基亚砜2的制备方法如下：
反应瓶中依次加入苯硫酚3(220.0mg,2.0mmol)，四丁基四氟硼酸铵(330.0mg,1.0mmol)，加入水(180.0uL,10.0mmol)以及1,2-二氯乙烷(4.0mL)，盖上橡胶塞，塞上插有2根电极，分别是石墨毡阳极，铂片阴极。该体系在恒电流20mA下反应16小时。反应结束后，减压蒸馏除去溶剂，硅胶拌样，上柱分离， 使用石油醚:乙酸乙酯＝5:1组成的洗脱剂，可以成功获得2-氯乙基苯基亚砜2，无色透明油状液体312.0mg，收率83％。
2-氯乙基苯基亚砜2的核磁表征：
1H NMR(400MHz,CDCl 3)δ7.61(dd,J＝7.6,2.0Hz,2H),7.54–7.49(m,3H),4.97–3.90(m,1H),3.65–3.59(m,1H),3.16–3.12(m,2H). 13C NMR(100MHz,CDCl 3)δ142.6,131.3,129.4,123.7,59.2,36.6.HRMS(ESI):calcd for C 8H 10ClOS[M+H] +189.0135,found 189.0126.
Figure PCTCN2022086078-appb-000006
Figure PCTCN2022086078-appb-000007
实施例2：
2-氯乙基苯基亚砜2的制备方法如下：
反应瓶中依次加入苯硫酚3(20.0mg,2.0mmol)，四丁基四氟硼酸铵(660.0mg,2.0mmol)，加入水(180.0uL,10.0mmol)以及1,2-二氯乙烷(4.0mL)，盖上橡胶塞，塞上插有2根电极，分别是石墨毡阳极，铂片阴极。该体系在恒电流20mA下反应16小时。反应结束后，减压蒸馏除去溶剂，硅胶拌样，上柱分离，使用石油醚:乙酸乙酯＝5:1组成的洗脱剂，可以成功获得2-氯乙基苯基亚砜2，无色透明油状液体285.7mg，收率76％
实施例3：
2-氯乙基苯基亚砜2的制备方法如下：
反应瓶中依次加入苯硫酚3(220.0mg,2.0mmol)，四丁基溴化铵(332.0mg,1.0mmol)，加入水(180.0uL,10.0mmol)以及1,2-二氯乙烷(4.0mL)，盖上橡胶 塞，塞上插有2根电极，分别是石墨毡阳极，铂片阴极。该体系在恒电流20mA下反应16小时。反应结束后，减压蒸馏除去溶剂，硅胶拌样，上柱分离，使用石油醚:乙酸乙酯＝5:1组成的洗脱剂，可以成功获得2-氯乙基苯基亚砜2，无色透明油状液体203.0mg，收率54％。
实施例4：
2-氯乙基苯基亚砜2的制备方法如下：
反应瓶中依次加入苯硫酚3(220.0mg,2.0mmol)，四丁基四氟硼酸铵(330.0mg,1.0mmol)，加入水(180.0uL,10.0mmol)以及1,2-二氯乙烷(4.0mL)，盖上橡胶塞，塞上插有2根电极，分别是石墨毡阳极，铂片阴极。该体系在恒电流10mA下反应16小时。反应结束后，减压蒸馏除去溶剂，硅胶拌样，上柱分离，使用石油醚:乙酸乙酯＝5:1组成的洗脱剂，可以成功获得中间体2，无色透明油状液体229.3mg，收率61％。
步骤2)中磺吡酮1的制备如实施例5～9所示：
实施例5：
反应瓶中依次加入2-氯乙基苯基亚砜2(189.0mg,1.0mmol)、1,2-二苯基-3,5-吡唑烷二酮4(378.2mg,1.5mmol)、碳酸铯(488.7mg,1.5mmol)、碘化钠(149.9mg,1.0mmol)、丙酮(6mL)，三口瓶一侧插上冷凝管，三通气球，另一侧盖有橡胶塞，置换氮气，于65℃下回流12小时。反应结束，减压蒸除掉丙酮后，加入适量水溶解，10％稀盐酸将溶液pH调至5-6，加入乙酸乙酯(10mL×3)萃取，合并有机层，有机层用无水硫酸钠干燥，减压蒸除有机溶剂，硅胶拌样，上柱分离，使用二氯甲烷:乙酸乙酯＝10:1组成的洗脱剂，可以成功获得磺吡酮1， 白色固体234.6mg，收率58％。
磺吡酮1的核磁表征：
1H NMR(400MHz,CDCl3)δ7.61(dd,J＝7.6,1.6Hz,2H),7.52–7.47(m,3H),7.31–7.24(m,9H),7.16(t,J＝6.8Hz,2H),3.52(t,J＝7.4Hz,1H),3.33–3.26(m,1H),3.09–3.02(m,1H),2.55–2.45(m,1H),2.23–2.20(m,1H). 13C NMR(100MHz,CDCl 3)δ168.8,142.7,135.2,131.1,129.3,129.0,127.0,124.0,122.6,52.2,44.1,20.7.HRMS(ESI):calcd for C 23H 21N 2O 3S[M+H] +405.1267,found405.1261.
Figure PCTCN2022086078-appb-000008
Figure PCTCN2022086078-appb-000009
实施例6：
反应瓶中依次加入2-氯乙基苯基亚砜2(189.0mg,1.0mmol)、1,2-二苯基-3,5-吡唑烷二酮4(302.6mg,1.2mmol)、碳酸铯(391.0mg,1.2mmol)、碘化钠(149.9mg,1.0mmol)、丙酮(6mL)，三口瓶一侧插上冷凝管，三通气球，另一侧盖有橡胶塞，置换氮气，于65℃下回流12小时。反应结束，减压蒸除掉丙酮后，加入适量水溶解，10％稀盐酸将溶液pH调至5-6，加入乙酸乙酯(10mL×3)萃取，合并有机层，有机层用无水硫酸钠干燥，减压蒸除有机溶剂，硅胶拌样，上柱分离，使用二氯甲烷:乙酸乙酯＝10:1组成的洗脱剂，可以成功获得磺吡酮1，白色固体165.8mg，收率41％。
实施例7：
反应瓶中依次加入2-氯乙基苯基亚砜2(189.0mg,1.0mmol)、1,2-二苯基-3,5-吡唑烷二酮4(302.6mg,1.2mmol)、碳酸铯(391.0mg,1.2mmol)、碘化钠 (224.8mg,1.5mmol)、丙酮(6mL)，三口瓶一侧插上冷凝管，三通气球，另一侧盖有橡胶塞，置换氮气，于65℃下回流12小时。反应结束，减压蒸除掉丙酮后，加入适量水溶解，10％稀盐酸将溶液pH调至5-6，加入乙酸乙酯(10mL×3)萃取，合并有机层，有机层用无水硫酸钠干燥，减压蒸除有机溶剂，硅胶拌样，上柱分离，使用二氯甲烷:乙酸乙酯＝10:1组成的洗脱剂，可以成功获得磺吡酮1，白色固体202.2mg，收率50％。
实施例8：
反应瓶中依次加入2-氯乙基苯基亚砜2(189.0mg,1.0mmol)、1,2-二苯基-3,5-吡唑烷二酮4(378.2mg,1.5mmol)、碳酸铯(488.7mg,1.5mmol)、碘化钾(166.0mg,1.0mmol)、丙酮(6mL)，三口瓶一侧插上冷凝管，三通气球，另一侧盖有橡胶塞，置换氮气，于65℃下回流12小时。反应结束，减压蒸除掉丙酮后，加入适量水溶解，10％稀盐酸将溶液pH调至5-6，加入乙酸乙酯(10mL×3)萃取，合并有机层，有机层用无水硫酸钠干燥，减压蒸除有机溶剂，硅胶拌样，上柱分离，使用二氯甲烷:乙酸乙酯＝10:1组成的洗脱剂，可以成功获得磺吡酮1，白色固体194.2mg，收率48％。
实施例9：
反应瓶中依次加入2-氯乙基苯基亚砜2(189.0mg,1.0mmol)、1,2-二苯基-3,5-吡唑烷二酮4(378.2mg,1.5mmol)、碳酸铯(488.7mg,1.5mmol)、碘化钠(149.9mg,1.0mmol)、乙腈(6mL)，三口瓶一侧插上冷凝管，三通气球，另一侧盖有橡胶塞，置换氮气，于65℃下回流12小时。反应结束，减压蒸除掉丙酮后，加入适量水溶解，10％稀盐酸将溶液pH调至5-6，加入乙酸乙酯(10mL×3) 萃取，合并有机层，有机层用无水硫酸钠干燥，减压蒸除有机溶剂，硅胶拌样，上柱分离，使用二氯甲烷:乙酸乙酯＝10:1组成的洗脱剂，可以成功获得磺吡酮1，白色固体125.4mg，收率48％。
由上述可知本发明的技术方案中，实施例1～4为步骤1中2-氯乙基苯基亚砜的制备，实施例5～9位步骤2中由步骤1中的2-氯乙基苯基亚砜制得磺吡酮。对比现有技术将绿色环保，环境友好型的电化学方法引入到合成步骤中，不仅大大缩短了反应步骤，而且提高了总收率；避免了强碱、氧化剂过氧化氢的使用，提高了原子经济性，减少了环境污染；从根源上克服了氯乙基硫醚在过氧化氢体系下容易过度氧化成氯乙基砜的问题，提高了反应的选择性。本发明的制备路线步骤短，步骤1)的收率最高可达到83％，步骤2)实施例5的收率最高可达到58％。
以上所述仅为本发明的优选实施方式，并非因此限制本发明的专利范围，凡是利用本发明所作的等效变换，均在本发明的专利保护范围内。

Claims (10)

  1. 一种磺吡酮的制备方法，其特征在于，合成路线如下：
    Figure PCTCN2022086078-appb-100001
    其中，electrolyte表示电解质，current表示电流，temperature表示温度，salt表示盐，base表示碱，additive表示添加剂，solvent表示溶剂。
  2. 如权利要求1所述的一种磺吡酮的制备方法，其特征在于，具体包括以下步骤：
    (1)将如式3所示的苯硫酚和电解质溶于1,2-二氯乙烷和水的混合溶液中，通入电流反应1～48小时，得到如式2所示的2-氯乙基苯基亚砜。
    (2)将如式2所示的2-氯乙基苯基亚砜、如式4所示的1,2-二苯基-3,5-吡唑烷二酮、碱和添加剂混溶于溶剂中，在氮气氛围下加热反应1～48小时，反应结束后，反应混合物经柱层析得到如式1所示的磺吡酮。
  3. 如权利要求1或2所述的一种磺吡酮的制备方法，其特征在于，步骤(1)中所述电极情况如下：阳极选自石墨毡、铂、镍电极之一，阴极选自石墨毡、铂、镍、碳片电极，电极规格均为1cm×1cm。
  4. 如权利要求2所述的一种磺吡酮的制备方法，其特征在于，步骤(1)中所述电解质为四丁基溴化铵、四丁基四氟硼酸铵、四正辛基溴化铵、四丁基六氟磷酸铵、高氯酸锂、高氯酸铵、四丁基碘化铵的任意一种，电解质的用量为苯硫酚的0.5-2倍。
  5. 如权利要求2所述的一种磺吡酮的制备方法，其特征在于，步骤(1)中所述水为蒸馏水、去离子水中的任意一种，其用量为苯硫酚物质的量的0.5-10倍。
  6. 如权利要求2所述的一种磺吡酮的制备方法，其特征在于，步骤(1)中所述电流为4-30毫安。
  7. 如权利要求2所述的一种磺吡酮的制备方法，其特征在于，步骤(1)中所述温度为30-70℃；步骤(1)中所述1,2-二氯乙烷的体积用量为化合物3的5-30倍。
  8. 如权利要求1或2所述的一种磺吡酮的制备方法，其特征在于，步骤(2)中，所述溶剂选自丙酮，乙腈，正己烷其中的任意一种或多种。
  9. 如权利要求2所述的一种磺吡酮的制备方法，其特征在于，步骤(2)中所述的碱选自碳酸铯，氢氧化钠，氢氧化钾，乙醇钠，乙醇钾，三乙胺、二异丙基乙胺中的任意一种；添加剂选自碘化钠，碘化钾，碘化锂、碘化铵中的任意一种；步骤(2)反应温度为50-70℃。
  10. 如权利要求2所述的一种磺吡酮的制备方法，其特征在于，步骤(2)中所述化合物1,2-二苯基-3,5-吡唑烷二酮的用量为2-氯乙基苯基亚砜的1.0-4.0倍；碱的用量为2-氯乙基苯基亚砜的1.0-4.0倍；添加剂的用量为2-氯乙基苯基亚砜的1-5倍；溶剂的用量为2-氯乙基苯基亚砜的5-10倍。
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