WO2023005117A1 - 一种普拉洛芬杂质的制备方法 - Google Patents

一种普拉洛芬杂质的制备方法 Download PDF

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WO2023005117A1
WO2023005117A1 PCT/CN2021/139525 CN2021139525W WO2023005117A1 WO 2023005117 A1 WO2023005117 A1 WO 2023005117A1 CN 2021139525 W CN2021139525 W CN 2021139525W WO 2023005117 A1 WO2023005117 A1 WO 2023005117A1
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impurity
pranoprofen
compound
reaction
preparation
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PCT/CN2021/139525
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French (fr)
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陈容
汪国松
徐杨
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海南碧凯药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

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  • the invention belongs to the technical field of organic synthesis, in particular to a preparation method of pranoprofen impurity.
  • Pranoprofen whose chemical name is 2-5H-[1]benzopyran[2,3-b]pyridin-7-ylpropionic acid, has significant analgesic, anti-inflammatory, antipyretic and anti-rheumatic effects.
  • Pranoprofen is a propionic acid derivative, which is a non-steroidal anti-inflammatory analgesic drug, which can mainly inhibit the biosynthesis of prostaglandins to exert antipyretic, analgesic and anti-inflammatory effects.
  • Pranoprofen has a stronger inhibitory effect on rabbit fever than indomethacin, ibuprofen, and aspirin, but has almost no effect on normal body temperature; in the experiment of lipopolysaccharide (LPS) causing fever in rabbits, syrup
  • LPS lipopolysaccharide
  • the antipyretic effect of oral administration was dose-dependent.
  • animal experiments also show that the analgesic effect of pranoprofen is stronger than that of ibuprofen and aspirin.
  • Pranoprofen impurity can be prepared according to the following route:
  • the impurity shown in formula I can be produced, and researching its impurity is crucial to the production of high-purity pranoprofen products.
  • the invention provides a method for preparing the pranoprofen impurity.
  • the preparation method in the invention can prepare the pranoprofen impurity represented by formula I with high purity and high yield.
  • the invention provides a kind of preparation method of pranoprofen impurity, comprises the following steps:
  • step B) adding compound 1 into the reaction solution in step A) for reaction to obtain compound 2;
  • the alkali metal is added in batches to the diol until no bubbles are generated;
  • the diol is ethylene glycol, propylene glycol or pentanediol; the alkali metal is sodium metal or potassium metal.
  • the molar ratio of compound 1 to ethylene glycol is (2-10):1.
  • the reaction time in the step B) is 3-5 hours; the reaction temperature is 20-30°C.
  • step B the temperature is lowered to 0-10° C., and a saturated ammonium chloride solution is added dropwise. After reacting for 1-3 hours, extraction and concentration are performed to obtain compound 2.
  • the sulfonic acid catalyst includes p-toluenesulfonic acid, one or more of methanesulfonic acid, benzenesulfonic acid and p-nitrobenzenesulfonic acid.
  • the molar ratio of the compound 2 to the sulfonic acid catalyst is 1:(1-3).
  • the reaction temperature in step C) is 50-60°C; the reaction time is 2-5 hours.
  • the obtained reaction solution is extracted and concentrated to obtain the crude pranoprofen impurity with the structure shown in formula I.
  • the solvent for recrystallization in the step D) is one or more of ethanol, Virahol, ethyl acetate, n-heptane.
  • the invention provides a method for preparing pranoprofen impurities, comprising the following steps: A) reacting an alkali metal and a diol to obtain a reaction solution; B) adding compound 1 to the reaction solution of the step A), Carry out the reaction to obtain compound 2; C) compound 2, ethylene glycol, p-toluenesulfonic acid and water are mixed, and reacted to obtain the crude product of pranoprofen impurity of the structure shown in formula I; D) the general The crude product of pranoprofen impurity is recrystallized to obtain the pranoprofen impurity of the structure shown in formula I.
  • Fig. 1 is the mass spectrogram of the product of the embodiment of the present invention 1;
  • Fig. 2 is the proton nuclear magnetic spectrum figure of the product of the embodiment of the present invention 1;
  • Fig. 3 is the carbon nuclear magnetic spectrogram of the product of embodiment 1 of the present invention.
  • the invention provides a kind of preparation method of pranoprofen impurity, comprises the following steps:
  • reaction solution A) the alkali metal and ethylene glycol are reacted to obtain a reaction solution
  • step B) adding compound 1 into the reaction solution in step A) for reaction to obtain compound 2;
  • alkali metals are first added in batches to diols, and reacted at room temperature until no bubbles are produced.
  • the diols are preferably ethylene glycol, propylene glycol or pentanediol, and the alkali metals are preferably sodium metal or potassium metal;
  • metal sodium is added in batches to ethylene glycol, and reacted at room temperature until no bubbles are generated to obtain disodium ethylene glycol.
  • compound 1 to the above reaction liquid, preferably, compound 1 is dissolved in ethylene glycol in the present invention, and then added to the above reaction liquid for reaction.
  • the molar ratio of compound 1 to ethylene glycol is preferably (2-10): 1, more preferably (3-8): 1; specifically, in an embodiment of the present invention, it may be 3:1.
  • the reaction time in the step B) is 3-5 hours, preferably 3-4 hours; the reaction temperature is 20-30°C, preferably 20-25°C.
  • the present invention lowers the temperature of the obtained reaction solution to 0-10°C, and adds saturated ammonium chloride solution dropwise to the reaction solution to neutralize the lye and facilitate extraction; after the dropwise addition, stir for 1-3 hours to carry out reaction.
  • the extractant is preferably dichloromethane, ethyl acetate or toluene.
  • the present invention has no special requirements for the concentration method, and the concentration method commonly used in the field can be used.
  • the concentration method can be concentrated by rotary evaporation with a rotary evaporator.
  • the present invention preferably dissolves compound 2 in ethylene glycol, adds a sulfonic acid catalyst and water, and reacts under stirring conditions.
  • the ethylene glycol is both a reactant and a reaction solvent, and ethylene glycol is condensed to protect the ketone group, and also serves as a solvent to dissolve the reactant so that the reaction can be carried out in a solution state.
  • the ethylene glycol and compound 2 The molar ratio of the sulfonic acid catalyst to compound 2 is (3 ⁇ 5):1, more preferably (3 ⁇ 4):1; the molar ratio of the sulfonic acid catalyst to compound 2 is (1 ⁇ 3):1, more preferably (1 ⁇ 2 ):1.
  • the reaction temperature is preferably 50-60°C, more preferably 55-60°C; the reaction time is preferably 2-5 hours, more preferably 3-4 hours.
  • reaction solution was cooled to room temperature, water and extractant were added, stirred for 0.5 to 2 hours, left to stand, separated, the organic phase was taken, and the organic phase was concentrated to obtain the pranoprofen impurity of the structure shown in formula I Crude.
  • the extractant is preferably dichloromethane, ethyl acetate or toluene.
  • the present invention has no special requirements for the concentration method, and the concentration method commonly used in the field can be used.
  • the concentration method can be concentrated by rotary evaporation with a rotary evaporator.
  • the present invention uses a solvent to dissolve the crude product and then recrystallizes, and the solvent is preferably one or more of ethanol, isopropanol, ethyl acetate, and n-heptane; the recrystallization The number of times is preferably 1 time.
  • the drying temperature is preferably 50-60°C; the drying time is preferably 12-24 hours.
  • the invention provides a method for preparing pranoprofen impurities, comprising the following steps: A) reacting an alkali metal and a diol to obtain a reaction solution; B) adding compound 1 to the reaction solution of the step A), Carry out reaction, obtain compound 2; C) compound 2, ethylene glycol, sulfonic acid catalyst and water are mixed, react, obtain the pranoprofen impurity crude product of structure shown in formula I; D) described pranoprofen The impurity crude product is recrystallized to obtain the pranoprofen impurity of the structure shown in formula I.
  • the compound 2 concentrate was dissolved in ethylene glycol, 5 g of p-toluenesulfonic acid and 5 g of water were added, and the reaction was stirred for about 2 hours at 50°C, cooled to room temperature, added with water and dichloromethane, and stirred for 0.5 hour, Stand still, separate the liquids, keep the organic phase, and concentrate the organic phase to dryness to obtain the crude product of pranoprofen impurity I.
  • the crude product of the impurity I of pranoprofen was dissolved with 5 times the amount of ethanol as a solvent, recrystallized, filtered, and dried to obtain the refined product of the impurity I.
  • the molecular formula of pranoprofen impurity I is C 15 H 13 NO 3 , and the molecular weight is 255.27.
  • Mass spectrum shows (accompanying drawing 1), compound molecular ion peak 256.2 (M+1), shows that compound molecular weight is about 255.2, accords with the molecular weight of pranoprofen impurity I.
  • the H NMR spectrum shows (accompanying drawing 2), the compound has 9 sets of NMR hydrogen signals, a total of 13 hydrogens, and the chemical shifts ( ⁇ , ppm) are 8.20 ⁇ 8.21 (1H, Ar-H), 7.79 ⁇ 7.84 (2H, Ar-H), 7.58(1H, Ar-H), 7.22 ⁇ 7.30(1H, Ar-H), 7.10 ⁇ 7.12(1H, Ar-H), 5.11 ⁇ 5.13(1H, CHOH), 4.18(2H, CH2 ), 3.76 (1H, CHOH), 1.45 ⁇ 1.47 (3H, CHCH3), which is consistent with the number of 13 hydrogens contained in the molecular formula of pranoprofen impurity I, and the hydrogen signals of each group are compared one by one, which is also consistent with the structural information of the compound .
  • the compound 2 concentrate was dissolved in ethylene glycol, 6 g of p-toluenesulfonic acid and 6 g of water were added, and the reaction was stirred for about 2 hours at 50°C, cooled to room temperature, added with water and dichloromethane, and stirred for 0.5 hour, Stand still, separate the liquids, keep the organic phase, and concentrate the organic phase to dryness to obtain the crude product of pranoprofen impurity I.
  • the crude product of the impurity I of pranoprofen was dissolved with 5 times the amount of ethanol as a solvent, recrystallized, filtered, and dried to obtain the refined product of the impurity I.
  • the compound 2 concentrate was dissolved in ethylene glycol, 5 g of p-toluenesulfonic acid and 5 g of water were added, and the reaction was stirred for about 2 hours at 50°C, cooled to room temperature, added with water and dichloromethane, and stirred for 0.5 hour, Stand still, separate the liquids, keep the organic phase, and concentrate the organic phase to dryness to obtain the crude product of pranoprofen impurity I.
  • the crude product of the impurity I of pranoprofen was dissolved with 6 times the amount of ethanol as a solvent, recrystallized, filtered, and dried to obtain the refined product of the impurity I.
  • the compound 2 concentrate was dissolved in ethylene glycol, 7 grams of p-toluenesulfonic acid and 7 grams of water were added, and the reaction was stirred for about 2 hours at 50°C, cooled to room temperature, added with water and dichloromethane, and stirred for 0.5 hours. Stand still, separate the liquids, keep the organic phase, and concentrate the organic phase to dryness to obtain the crude product of pranoprofen impurity I.
  • the crude product of impurity I of pranoprofen was dissolved with 7 times the amount of ethanol as a solvent, recrystallized, filtered, and dried to obtain the fine product of impurity I.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明提供了一种普拉洛芬杂质的制备方法，包括以下步骤：A)将碱金属和二醇进行反应，得到反应液；B)将化合物1加入所述步骤A)的反应液中，进行反应，得到化合物2；C)将化合物2、乙二醇、磺酸催化剂和水混合，进行反应，得到式I所示结构的普拉洛芬杂质粗品；D)将所述普拉洛芬杂质粗品重结晶，得到式I所示结构的普拉洛芬杂质。以7-2-(氯丙酰基)-5H-[1]苯并吡喃[2,3-b]吡啶为起始物，经过两步合成反应步骤得到普拉洛芬杂质I粗品，经过重结晶纯化得到终产物普拉洛芬杂质I，经质谱和核磁检测，检测数据结果与杂质I结构信息相符合，并且具有较高的纯度和收率。

Description

一种普拉洛芬杂质的制备方法
本申请要求于2021年07月28日提交中国专利局、申请号为202110857573.6、发明名称为“一种普拉洛芬杂质的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于有机合成技术领域，尤其涉及一种普拉洛芬杂质的制备方法。
背景技术
普拉洛芬，化学名为2-5H-[1]苯并吡喃[2,3-b]吡啶-7-基丙酸，具有显著的镇痛、消炎、解热和抗风湿作用。
普拉洛芬系丙酸衍生物，为非甾体类抗炎镇痛药，主要能抑制前列腺素的生物合成而发挥解热、镇痛、抗炎作用。普拉洛芬对家兔发热的抑制作用比吲哚美辛、布洛芬、阿司匹林更强，而对正常体温几乎没有任何影响；在脂多糖(LPS)引起家兔发热的实验中，使用糖浆剂进行口服给药，其解热作用呈剂量依赖性。此外，动物实验还表明，普拉洛芬的镇痛作用较布洛芬及阿司匹林强。
普拉洛芬杂质可按照以下路线制备：
Figure PCTCN2021139525-appb-000001
在第一步反应时，会产生如式I所示的杂质，研究其杂质对生产高纯度的普拉洛芬产品至关重要。
Figure PCTCN2021139525-appb-000002
发明内容
本发明提供了一种普拉洛芬杂质的制备方法，本发明中的制备方法能够制备得到具有式I所示的普拉洛芬杂质，且纯度高，收率高。
本发明提供一种普拉洛芬杂质的制备方法，包括以下步骤：
A)将碱金属和二醇进行反应，得到反应液；
B)将化合物1加入所述步骤A)的反应液中，进行反应，得到化合物2；
C)将化合物2、乙二醇、磺酸催化剂和水混合，进行反应，得到式I所示结构的普拉洛芬杂质粗品；
D)将所述普拉洛芬杂质粗品重结晶，得到式I所示结构的普拉洛芬杂质；
Figure PCTCN2021139525-appb-000003
优选的，所述步骤A)中，向二醇中分批加入碱金属，直至无气泡产生；
所述二醇为乙二醇、丙二醇或戊二醇；所述碱金属为金属钠或金属钾。
优选的，所述化合物1与乙二醇的摩尔比为(2～10)：1。
优选的，所述步骤B)中反应的时间为3～5小时；反应的温度为20～30℃。
优选的，所述步骤B)的反应完毕后，降温至0～10℃，滴加饱和氯化铵溶液，反应1～3小时后，萃取、浓缩，得到化合物2。
优选的，所述磺酸催化剂包括对甲基苯磺酸，甲磺酸、苯磺酸和对硝基苯磺酸中的一种或几种。
优选的，所述化合物2和磺酸催化剂的摩尔比为1：(1～3)。
优选的，所述步骤C)中反应的温度为50～60℃；反应的时间为2～5小时。
优选的，所述步骤C)反应完毕后，对得到的反应液进行萃取和浓缩，得到式I所示结构的普拉洛芬杂质粗品。
优选的，所述步骤D)中重结晶的溶剂为乙醇、异丙醇、乙酸乙酯、正庚 烷中的一种或几种。
本发明提供了一种普拉洛芬杂质的制备方法，包括以下步骤：A)将碱金属和二醇进行反应，得到反应液；B)将化合物1加入所述步骤A)的反应液中，进行反应，得到化合物2；C)将化合物2、乙二醇、对甲基苯磺酸和水混合，进行反应，得到式I所示结构的普拉洛芬杂质粗品；D)将所述普拉洛芬杂质粗品重结晶，得到式I所示结构的普拉洛芬杂质。以7-2-(氯丙酰基)-5H-[1]苯并吡喃[2,3-b]吡啶(1)为起始物，经过两步合成反应步骤得到普拉洛芬杂质I粗品，粗品经过重结晶纯化得到终产物普拉洛芬杂质I(7-2-(羟基丙酰基)-5H-[1]苯并吡喃[2,3-b]吡啶)，经质谱和核磁检测，检测数据结果与杂质I结构信息相符合，并且具有较高的纯度和收率。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图获得其他的附图。
图1为本发明实施例1的产物的质谱图；
图2为本发明实施例1的产物的核磁氢谱图；
图3为本发明实施例1的产物的核磁碳谱图。
具体实施方式
本发明提供了一种普拉洛芬杂质的制备方法，包括以下步骤：
A)将碱金属和乙二醇进行反应，得到反应液；
B)将化合物1加入所述步骤A)的反应液中，进行反应，得到化合物2；
C)将化合物2、乙二醇、对甲基苯磺酸和水混合，进行反应，得到式I所示结构的普拉洛芬杂质粗品；
D)将所述普拉洛芬杂质粗品重结晶，得到式I所示结构的普拉洛芬杂质；
Figure PCTCN2021139525-appb-000004
本发明中的制备路线如式II所示：
Figure PCTCN2021139525-appb-000005
本发明首先在二醇中分批加入碱金属，室温下反应直至无气泡产生为止，所述二醇优选为乙二醇、丙二醇或戊二醇，所述碱金属优选为金属钠或金属钾；具体的，在本发明的实施例中，在乙二醇中分批加入金属钠，室温下反应直至无气泡产生为止，得到乙二醇二钠。
然后在上述反应液中加入化合物1，优选的，本发明将化合物1溶于乙二醇中，再加入上述反应液中，进行反应。
在本发明中，所述化合物1与乙二醇的摩尔比优选为(2～10)：1，更优选为(3～8)：1；具体的，在本发明的实施例中，可以是3:1。
所述步骤B)中反应的时间为3～5小时，优选为3～4小时；反应的温度为20～30℃，优选为20～25℃。
完成上述反应之后，本发明将得到的反应液降温至0～10℃，向反应液中滴加饱和氯化铵溶液，中和碱液并利于萃取；滴加完毕之后，搅拌1～3小时进行反应。
得到的反应液中加入萃取剂，搅拌0.5～2小时后静置，分层，取有机相，将有机相浓缩，得到化合物2。
在本发明中，所述萃取剂优选为二氯甲烷、乙酸乙酯或甲苯。
本发明对于浓缩的方法没有特殊的要求，采用本领域常用的浓缩方法即可，具体的，在本发明的实施例中，可以是旋转蒸发仪旋蒸浓缩。
得到化合物2后，本发明优选将化合物2溶于乙二醇中，加入磺酸催化剂和水，搅拌条件下进行反应。
在本发明中，所述乙二醇即是反应物也是反应溶剂，乙二醇缩合保护酮基，同时也作为溶剂溶解反应物使得反应能在溶液状态中进行，所述乙二醇与化合物2的摩尔比为(3～5):1，更优选为(3～4)：1；所述磺酸催化剂与化合物2的摩尔比为(1～3)：1，更优选为(1～2):1。
所述反应的温度优选为50～60℃，更优选为55～60℃；所述反应的时间优选为2～5小时，更优选为3～4小时。
反应完毕后，将反应液降温至室温，加入水和萃取剂，搅拌0.5～2小时，静置、分液，取有机相，将有机相浓缩，得到式I所示结构的普拉洛芬杂质粗品。
在本发明中，所述萃取剂优选为二氯甲烷、乙酸乙酯或甲苯。
本发明对于浓缩的方法没有特殊的要求，采用本领域常用的浓缩方法即可，具体的，在本发明的实施例中，可以是旋转蒸发仪旋蒸浓缩。
得到杂质的粗品之后，本发明使用溶剂将所述粗品溶解后进行重结晶，所述溶剂优选为乙醇、异丙醇、乙酸乙酯、正庚烷中的一种或几种；所述重结晶的次数优选为1次。
重结晶后过滤干燥，得到式I所示结构的普拉洛芬杂质。
在本发明中，所述干燥的温度优选为50～60℃；所述干燥的时间优选为12～24小时。
本发明提供了一种普拉洛芬杂质的制备方法，包括以下步骤：A)将碱金属和二醇进行反应，得到反应液；B)将化合物1加入所述步骤A)的反应液中，进行反应，得到化合物2；C)将化合物2、乙二醇、磺酸催化剂和水混合，进行反应，得到式I所示结构的普拉洛芬杂质粗品；D)将所述普拉洛芬杂质粗品 重结晶，得到式I所示结构的普拉洛芬杂质。以7-2-(氯丙酰基)-5H-[1]苯并吡喃[2,3-b]吡啶(1)为起始物，经过两步合成反应步骤得到普拉洛芬杂质I粗品，粗品经过重结晶纯化得到终产物普拉洛芬杂质I，经质谱和核磁检测，检测数据结果与杂质I结构信息相符合，并且具有较高的纯度和收率。
为了进一步说明本发明，以下结合实施例对本发明提供的一种普拉洛芬杂质的制备方法进行详细描述，但不能将其理解为对本发明保护范围的限定。
实施例1
向500毫升反应瓶中加入乙二醇50毫升，然后分批加入切成小块状的金属钠0.5克，室温反应至无气泡产生为止起始物料5克化合物1溶于25毫升乙二醇后，加入上述反应瓶中，室温搅拌反应3小时，降温至0～10℃，向反应瓶中滴加饱和氯化铵溶液，滴加完毕，继续搅拌1小时左右，加入二氯甲烷，室温搅拌0.5小时，静置，分液，留取有机相，有机相浓缩至干，得到化合物2浓缩物，直接用于下一步反应。
化合物2浓缩物溶于乙二醇，加入5克对甲基苯磺酸和5克水，50℃条件下，搅拌反应2小时左右，降温至室温，加入水和二氯甲烷，搅拌0.5小时，静置，分液，留取有机相，有机相浓缩至干，得到普拉洛芬杂质I粗品。
上述普拉洛芬杂质I粗品，用5倍量乙醇作为溶剂溶解后重结晶，过滤，干燥后得到杂质I精品。
普拉洛芬杂质I结构确证，
普拉洛芬杂质I分子式为C 15H 13NO 3，分子量为255.27。
质谱显示(附图1)，化合物分子离子峰256.2(M+1)，表明化合物分子量为255.2左右，与普拉洛芬杂质I的分子量相符合。
核磁氢谱显示(附图2)，化合物有9组核磁氢信号，共13个氢，化学位移(δ，ppm)分别是，8.20～8.21(1H，Ar-H)，7.79～7.84(2H，Ar-H)，7.58(1H，Ar-H)，7.22～7.30(1H，Ar-H)，7.10～7.12(1H，Ar-H)，5.11～5.13(1H，CHOH)，4.18(2H，CH2)，3.76(1H，CHOH)，1.45～1.47(3H，CHCH3)，与普拉洛芬杂质I分子式所含13个氢数目相符合，逐一比对各组氢信号，与化合物结构信息也相符合。
核磁碳谱显示(附图3)，化合物有15个核磁碳信号，化学位移(δ，ppm)
分别是，200.75，157.52，155.86，146.98，138.64，129.93，129.12，128.94，120.67，120.16，117.54，114.75，69.09，27.77，22.45，与普拉洛芬杂质I分子式所含15个碳数目相符合，逐一比对各个碳信号，与化合物结构信息也相符合。
综合上述信息推断，所合成化合物为普拉洛芬杂质I，化学结构如图1所示。
实施例2
向500毫升反应瓶中加入乙二醇50毫升，然后分批加入切成小块状的金属钠0.6克，室温反应至无气泡产生为止，起始物料5克化合物1溶于25毫升乙二醇后，加入上述反应瓶中，室温搅拌反应4小时，降温至0～10℃，向反应瓶中滴加饱和氯化铵溶液，滴加完毕，继续搅拌1小时左右，加入二氯甲烷，室温搅拌0.5小时，静置，分液，留取有机相，有机相浓缩至干，得到化合物2浓缩物，直接用于下一步反应。
化合物2浓缩物溶于乙二醇，加入6克对甲基苯磺酸和6克水，50℃条件下，搅拌反应2小时左右，降温至室温，加入水和二氯甲烷，搅拌0.5小时，静置，分液，留取有机相，有机相浓缩至干，得到普拉洛芬杂质I粗品。
上述普拉洛芬杂质I粗品，用5倍量乙醇作为溶剂溶解后重结晶，过滤，干燥后得到杂质I精品。
实施例3
向500毫升反应瓶中加入乙二醇50毫升，然后分批加入切成小块状的金属钠0.7克，室温反应至无气泡产生为止，起始物料5克化合物1溶于25毫升乙二醇后，加入上述反应瓶中，室温搅拌反应5小时，降温至0～10℃，向反应瓶中滴加饱和氯化铵溶液，滴加完毕，继续搅拌1小时左右，加入二氯甲烷，室温搅拌0.5小时，静置，分液，留取有机相，有机相浓缩至干，得到化合物2浓缩物，直接用于下一步反应。
化合物2浓缩物溶于乙二醇，加入5克对甲基苯磺酸和5克水，50℃条件下，搅拌反应2小时左右，降温至室温，加入水和二氯甲烷，搅拌0.5小时，静置，分液，留取有机相，有机相浓缩至干，得到普拉洛芬杂质I粗品。
上述普拉洛芬杂质I粗品，用6倍量乙醇作为溶剂溶解后重结晶，过滤，干燥后得到杂质I精品。
实施例4
向500毫升反应瓶中加入乙二醇50毫升，然后分批加入切成小块状的金属钠0.5克，室温反应至无气泡产生为止，起始物料5克化合物1溶于25毫升乙二醇后，加入上述反应瓶中，室温搅拌反应5小时，降温至0～10℃，向反应瓶中滴加饱和氯化铵溶液，滴加完毕，继续搅拌1小时左右，加入二氯甲烷，室温搅拌0.5小时，静置，分液，留取有机相，有机相浓缩至干，得到化合物2浓缩物，直接用于下一步反应。
化合物2浓缩物溶于乙二醇，加入7克对甲基苯磺酸和7克水，50℃条件下，搅拌反应2小时左右，降温至室温，加入水和二氯甲烷，搅拌0.5小时，静置，分液，留取有机相，有机相浓缩至干，得到普拉洛芬杂质I粗品。
上述普拉洛芬杂质I粗品，用7倍量乙醇作为溶剂溶解后重结晶，过滤，干燥后得到杂质I精品。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 一种普拉洛芬杂质的制备方法，包括以下步骤：
    A)将碱金属和二醇进行反应，得到反应液；
    B)将化合物1加入所述步骤A)的反应液中，进行反应，得到化合物2；
    C)将化合物2、乙二醇、磺酸催化剂和水混合，进行反应，得到式I所示结构的普拉洛芬杂质粗品；
    D)将所述普拉洛芬杂质粗品重结晶，得到式I所示结构的普拉洛芬杂质；
    Figure PCTCN2021139525-appb-100001
  2. 根据权利要求1所述的制备方法，其特征在于，所述步骤A)中，向二醇中分批加入碱金属，直至无气泡产生；
    所述二醇为乙二醇、丙二醇或戊二醇；所述碱金属为金属钠或金属钾。
  3. 根据权利要求1所述的制备方法，其特征在于，所述化合物1与乙二醇的摩尔比为(2～10)：1。
  4. 根据权利要求1所述的制备方法，其特征在于，所述步骤B)中反应的时间为3～5小时；反应的温度为20～30℃。
  5. 根据权利要求1所述的制备方法，其特征在于，所述步骤B)的反应完毕后，降温至0～10℃，滴加饱和氯化铵溶液，反应1～3小时后，萃取、浓缩，得到化合物2。
  6. 根据权利要求1所述的制备方法，其特征在于，所述磺酸催化剂包括对甲基苯磺酸，甲磺酸、苯磺酸和对硝基苯磺酸中的一种或几种。
  7. 根据权利要求1所述的制备方法，其特征在于，所述化合物2和磺酸催化剂的摩尔比为1：(1～3)。
  8. 根据权利要求1所述的制备方法，其特征在于，所述步骤C)中反应的温度为50～60℃；反应的时间为2～5小时。
  9. 根据权利要求1所述的制备方法，其特征在于，所述步骤C)反应完毕后，对得到的反应液进行萃取和浓缩，得到式I所示结构的普拉洛芬杂质粗品。
  10. 根据权利要求1所述的制备方法，其特征在于，所述步骤D)中重结晶的溶剂为乙醇、异丙醇、乙酸乙酯、正庚烷中的一种或几种。
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