WO2016078107A1 - Method for synthesizing piperazine pharmaceutical intermediate - Google Patents
Method for synthesizing piperazine pharmaceutical intermediate Download PDFInfo
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- WO2016078107A1 WO2016078107A1 PCT/CN2014/092276 CN2014092276W WO2016078107A1 WO 2016078107 A1 WO2016078107 A1 WO 2016078107A1 CN 2014092276 W CN2014092276 W CN 2014092276W WO 2016078107 A1 WO2016078107 A1 WO 2016078107A1
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- Prior art keywords
- piperazine
- hydrochloride
- chlorophenyl
- synthesizing
- reaction
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- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- 239000012450 pharmaceutical intermediate Substances 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 9
- MHXPYWFZULXYHT-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazin-1-ium;chloride Chemical compound Cl.ClC1=CC=CC(N2CCNCC2)=C1 MHXPYWFZULXYHT-UHFFFAOYSA-N 0.000 claims abstract description 8
- QBPISWMTLKTKMK-UHFFFAOYSA-N 1-[(4-aminophenyl)methyl]pyridin-2-one Chemical compound C1=CC(N)=CC=C1CN1C(=O)C=CC=C1 QBPISWMTLKTKMK-UHFFFAOYSA-N 0.000 claims abstract description 8
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims abstract description 7
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 claims abstract description 4
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 claims abstract description 4
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000000543 intermediate Substances 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 230000037361 pathway Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- -1 piperazine compound Chemical class 0.000 description 3
- JVLRNANYLVRULL-UHFFFAOYSA-N 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine;hydrochloride Chemical compound [Cl-].C1CN(CCCCl)CC[NH+]1C1=CC=CC(Cl)=C1 JVLRNANYLVRULL-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VRBKIVRKKCLPHA-UHFFFAOYSA-N nefazodone Chemical compound O=C1N(CCOC=2C=CC=CC=2)C(CC)=NN1CCCN(CC1)CCN1C1=CC=CC(Cl)=C1 VRBKIVRKKCLPHA-UHFFFAOYSA-N 0.000 description 1
- 229960001800 nefazodone Drugs 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- 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
- C07D295/06—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 halogen atoms or nitro radicals
- C07D295/073—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 halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Definitions
- the invention relates to a method for synthesizing piperazine-based pharmaceutical intermediates.
- Piperazines are an important branch of heterocyclic compounds.
- the 1,4-N,N-substituted piperazine compound is an important pharmaceutical intermediate for the synthesis of piperazines such as etalazine, meiperazole, aripiprazole and nefazodone.
- the synthetic route of the 1,4-N,N-substituted piperazine compound is complicated, the reaction conditions are harsh, and the product purity is low.
- the technical scheme of the present invention is: a method for synthesizing a piperazine-based drug intermediate, comprising the following steps:
- Step (1) diethanolamine is reacted with thionyl chloride to prepare bis(2-chloroethyl)methylamine hydrochloride,
- Step (2) 3-chloroaniline and bis(2-chloroethyl)methylamine hydrochloride are reacted to prepare 1-(3-chlorophenyl)piperazine hydrochloride,
- Step (3) 1-(3-chlorophenyl)piperazine hydrochloride and 1-bromo-3-chloropropane are reacted to prepare piperazine intermediate 1-(3-chlorophenyl)-4-(3) -Chloropropyl)piperazine hydrochloride,
- the reaction solvent of the step (1) is CHCl 3 .
- the reaction solvent of the step (2) is xylene.
- the reaction temperature of the step (3) is 0 to 10 °C.
- 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride is prepared by a three-step reaction using diethanolamine and 3-chloroaniline as raw materials.
- the route is simple and easy to operate, the post-treatment operation is also greatly simplified, the reaction conditions are mild, and the product purity is high.
- Step (1) Synthesis of bis(2-chloroethyl)methylamine hydrochloride.
- Step (2) Synthesis of 1-(3-chlorophenyl)piperazine hydrochloride.
- Step (3) Synthesis of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride.
- the route is simple and easy to operate, the post-treatment operation is also greatly simplified, the reaction conditions are mild, and the product purity is high.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Provided is a method for synthesizing a piperazine pharmaceutical intermediate, comprising the following steps: step (1): diethanolamine undergoes a reaction with thionyl chloride to yield bis(2-chloroethyl)methylamine hydrochloride; step (2): 3-chloroaniline undergoes a reaction with bis(2-chloroethyl)methylamine hydrochloride to yield 1-(3-chlorophenyl)piperazine hydrochloride; step (3): 1-(3-chlorophenyl)piperazine hydrochloride undergoes a reaction with 1-bromo-3-chloropropane to yield 1-(3-chlorophenyl)-4-(3-chloropropane)piperazine hydrochloride. The pathway is simple and easy, subsequent processing is greatly simplified, reaction conditions are mild, and product purity is high.
Description
本发明涉及一种哌嗪类药物中间体的合成方法。The invention relates to a method for synthesizing piperazine-based pharmaceutical intermediates.
哌嗪类化合物是杂环化合物的一个重要分支。1，4-N，N取代哌嗪类化合物是依托哌酮，美吡哌唑，阿立哌唑，奈法唑酮等哌嗪类药物合成的重要药物中间体。现有技术中1，4-N，N取代哌嗪类化合物的合成路线复杂，反应条件苛刻，产物纯度较低。Piperazines are an important branch of heterocyclic compounds. The 1,4-N,N-substituted piperazine compound is an important pharmaceutical intermediate for the synthesis of piperazines such as etalazine, meiperazole, aripiprazole and nefazodone. In the prior art, the synthetic route of the 1,4-N,N-substituted piperazine compound is complicated, the reaction conditions are harsh, and the product purity is low.
发明内容Summary of the invention
本发明的目的是提供一种哌嗪类药物中间体的合成方法，以解决现有技术中的上述缺陷。It is an object of the present invention to provide a method for synthesizing piperazine-based pharmaceutical intermediates to solve the above-mentioned drawbacks in the prior art.
为了达到上述目的，本发明的技术方案是：一种哌嗪类药物中间体的合成方法，包括以下步骤：In order to achieve the above object, the technical scheme of the present invention is: a method for synthesizing a piperazine-based drug intermediate, comprising the following steps:
步骤(1)：二乙醇胺与二氯亚砜反应制备二(2-氯乙基)甲胺盐酸盐，Step (1): diethanolamine is reacted with thionyl chloride to prepare bis(2-chloroethyl)methylamine hydrochloride,
(HOCH2CH2)2NH+SOCl2→(ClCH2CH2)2NHHCl+SO2+HCl；(HOCH 2 CH 2 ) 2 NH + SOCl 2 → (ClCH 2 CH 2 ) 2 NHHCl + SO 2 + HCl;
步骤(2)：3-氯苯胺和二(2-氯乙基)甲胺盐酸盐反应制备1-(3-氯苯基)哌嗪盐酸盐，Step (2): 3-chloroaniline and bis(2-chloroethyl)methylamine hydrochloride are reacted to prepare 1-(3-chlorophenyl)piperazine hydrochloride,
步骤(3)：1-(3-氯苯基)哌嗪盐酸盐和1-溴-3-氯丙烷反应制备哌嗪类药物中间体1-(3-氯苯基)-4-(3-氯丙基)哌嗪盐酸盐，
Step (3): 1-(3-chlorophenyl)piperazine hydrochloride and 1-bromo-3-chloropropane are reacted to prepare piperazine intermediate 1-(3-chlorophenyl)-4-(3) -Chloropropyl)piperazine hydrochloride,
作为优选，步骤(1)的反应溶剂是CHCl3。Preferably, the reaction solvent of the step (1) is CHCl 3 .
作为优选，步骤(2)的反应溶剂是二甲苯。Preferably, the reaction solvent of the step (2) is xylene.
作为优选，步骤(3)的反应温度是0～10℃。Preferably, the reaction temperature of the step (3) is 0 to 10 °C.
本发明以二乙醇胺和3-氯苯胺为原料，经过三步反应制备1-(3-氯苯基)-4-(3-氯丙基)哌嗪盐酸盐。该路线简便，易行，后处理操作也大大简化，反应的条件温和，产物纯度高。In the present invention, 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride is prepared by a three-step reaction using diethanolamine and 3-chloroaniline as raw materials. The route is simple and easy to operate, the post-treatment operation is also greatly simplified, the reaction conditions are mild, and the product purity is high.
下面结合具体实施例对本发明作进一步详述。The invention will be further described in detail below with reference to specific embodiments.
步骤(1)：二(2-氯乙基)甲胺盐酸盐合成。Step (1): Synthesis of bis(2-chloroethyl)methylamine hydrochloride.
将24克(0.23mol)二乙醇胺加入35mL CHCl3，搅拌，缓慢滴加65mL(0.92mol)二氯亚砜和40mL CHCl3的混合物，1小时滴加完毕，反应2小时，减压除去过量的二氯亚砜和CHCl3，得到浅黄色固体，用丙酮重结晶，得到白色固体二(2-氯乙基)甲胺盐酸盐，25.6克，收率62％。24 g (0.23 mol) of diethanolamine was added to 35 mL of CHCl 3 , stirred, and a mixture of 65 mL (0.92 mol) of thionyl chloride and 40 mL of CHCl 3 was slowly added dropwise, and the mixture was added dropwise for 1 hour, and the reaction was carried out for 2 hours, and excess was removed under reduced pressure. Dichloro sulfoxide and CHCl 3 gave a pale yellow solid which crystallised from EtOAc (EtOAc)
步骤(2)：1-(3-氯苯基)哌嗪盐酸盐的合成。Step (2): Synthesis of 1-(3-chlorophenyl)piperazine hydrochloride.
3-氯苯胺2.2克(17.2mmol)和二(2-氯乙基)甲胺盐酸盐(17.2mmol)溶于20mL二甲苯中。加热回流24小时。二氯甲烷萃取，无水硫酸镁干燥，减压蒸馏除去二氯甲烷，得到粘稠油状物2.5克，收率86％。油状物减压蒸馏，蒸馏出的油状物加少量浓盐酸转变成盐酸盐，盐酸盐可在乙醇中重结晶，得到白色固体。2-Chloroaniline 2.2 g (17.2 mmol) and bis(2-chloroethyl)methylamine hydrochloride (17.2 mmol) were dissolved in 20 mL of xylene. Heat to reflux for 24 hours. The mixture was extracted with methylene chloride, dried over anhydrous magnesium sulfate and evaporated. The oil was distilled under reduced pressure, and the obtained oil was evaporated to ethylamine.
步骤(3)：1-(3-氯苯基)-4-(3-氯丙基)哌嗪盐酸盐的合成。Step (3): Synthesis of 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride.
将2.5克(10.8mmol)1-(3-氯苯基)哌嗪盐酸盐和1-溴-3-氯丙烷1.7
克(10.8mmol)溶于2.2mL水和2.7mL丙酮中，保持0～10℃搅拌滴加25％NaOH溶液3.4mL，加完后在室温搅拌18小时，反应完毕后，有机层分离，减压浓缩，浓缩残留物溶于10mL丙酮中，过滤，滤液减压浓缩，得到油状物溶于稀盐酸中(115mL水加入0.7mL浓盐酸)。分离出油状物质，静止固化，冷水洗涤，空气干燥，得到白色1-(3-氯苯基)-4-(3-氯丙基)哌嗪盐酸盐2.2克，产率65％。2.5 g (10.8 mmol) of 1-(3-chlorophenyl)piperazine hydrochloride and 1-bromo-3-chloropropane 1.7
Ke (10.8mmol) was dissolved in 2.2mL water and 2.7mL acetone, and 3.4mL of 25% NaOH solution was added dropwise while stirring at 0～10°C. After the addition, it was stirred at room temperature for 18 hours. After the reaction was completed, the organic layer was separated and decompressed. After concentration, the residue was dissolved in EtOAc (EtOAc)EtOAc. The oily material was separated, solidified, washed with cold water and dried in vacuo to give white <RTI ID=0.0>#</RTI> <RTIgt; </RTI> <RTIgt;
该路线简便，易行，后处理操作也大大简化，反应的条件温和，产物纯度高。The route is simple and easy to operate, the post-treatment operation is also greatly simplified, the reaction conditions are mild, and the product purity is high.
本领域的技术人员可以对发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包括这些改动和变型在内。
A person skilled in the art can make various modifications and variations to the invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of the invention as claimed.
Claims (4)
- 一种哌嗪类药物中间体的合成方法，其特征在于，包括以下步骤：A method for synthesizing piperazine-based pharmaceutical intermediates, comprising the steps of:步骤(1)：二乙醇胺与二氯亚砜反应制备二(2-氯乙基)甲胺盐酸盐，(HOCH2CH2)2NH+SOCl2→(ClCH2CH2)2NHHCl+SO2+HCl；Step (1): Diethanolamine is reacted with thionyl chloride to prepare bis(2-chloroethyl)methylamine hydrochloride, (HOCH 2 CH 2 ) 2 NH + SOCl 2 → (ClCH 2 CH 2 ) 2 NHHCl + SO 2 + HCl;步骤(2)：3-氯苯胺和二(2-氯乙基)甲胺盐酸盐反应制备1-(3-氯苯基)哌嗪盐酸盐，Step (2): 3-chloroaniline and bis(2-chloroethyl)methylamine hydrochloride are reacted to prepare 1-(3-chlorophenyl)piperazine hydrochloride,
步骤(3)：1-(3-氯苯基)哌嗪盐酸盐和1-溴-3-氯丙烷反应制备哌嗪类药物中间体1-(3-氯苯基)-4-(3-氯丙基)哌嗪盐酸盐，Step (3): 1-(3-chlorophenyl)piperazine hydrochloride and 1-bromo-3-chloropropane are reacted to prepare piperazine intermediate 1-(3-chlorophenyl)-4-(3) -Chloropropyl)piperazine hydrochloride,
- 根据权利要求1所述的哌嗪类药物中间体的合成方法，其特征在于，步骤(1)的反应溶剂是CHCl3。The method for synthesizing a piperazine-based pharmaceutical intermediate according to claim 1, wherein the reaction solvent of the step (1) is CHCl 3 .
- 根据权利要求1所述的哌嗪类药物中间体的合成方法，其特征在于，步骤(2)的反应溶剂是二甲苯。The method for synthesizing a piperazine-based drug intermediate according to claim 1, wherein the reaction solvent in the step (2) is xylene.
- 根据权利要求1所述的哌嗪类药物中间体的合成方法，其特征在于，步骤(3)的反应温度是0～10℃。 The method for synthesizing a piperazine-based pharmaceutical intermediate according to claim 1, wherein the reaction temperature in the step (3) is 0 to 10 °C.
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| CN201410663127.1 | 2014-11-19 | ||
| CN201410663127.1A CN104402842A (en) | 2014-11-19 | 2014-11-19 | Synthetic method of piperazidines drug intermediate |
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| CN115557902A (en) * | 2022-11-09 | 2023-01-03 | 武汉海特生物创新医药研究有限公司 | Preparation method of N- (2-pyrimidine) piperazine hydrochloride |
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| CN108299337A (en) * | 2018-01-15 | 2018-07-20 | 吴江信凯医药科技有限公司 | The preparation method of one kind 2,3- dichlorophenylpiperazine hydrochlorides |
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| US5900485A (en) * | 1996-07-29 | 1999-05-04 | Apotex, Inc. | Methods for the manufacture of neofazodone |
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| JPS60202883A (en) * | 1984-03-26 | 1985-10-14 | Yamanouchi Pharmaceut Co Ltd | Pyrimidone derivative and its preparation |
| US5256664A (en) * | 1992-04-28 | 1993-10-26 | Bristol-Myers Squibb Company | Antidepressant 3-halophenylpiperazinylpropyl derivatives of substituted triazolones and triazoldiones |
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|---|---|---|---|---|
| US4252806A (en) * | 1979-09-24 | 1981-02-24 | Mead Johnson & Company | Triazoloquinolones |
| US4338317A (en) * | 1981-03-16 | 1982-07-06 | Mead Johnson & Company | Phenoxyethyl-1,2,4,-triazol-3-one antidepressants |
| US5900485A (en) * | 1996-07-29 | 1999-05-04 | Apotex, Inc. | Methods for the manufacture of neofazodone |
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| CHEN, XIN ET AL.: "Synthesis of 1- (3-phthalimido-2-oxobutyl) -4-substituted-phenylpiperazines and their Anti-HIV Reverse Transcriptase Activity", ACTA PHARMACEUTICA SINICA, vol. 37, no. 5, 28 May 2002 (2002-05-28), pages 344, XP008066433 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115557902A (en) * | 2022-11-09 | 2023-01-03 | 武汉海特生物创新医药研究有限公司 | Preparation method of N- (2-pyrimidine) piperazine hydrochloride |
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