CN102256955A - 哌嗪衍生物的制备方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000004885 piperazines Chemical class 0.000 title description 2
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 2
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 8
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- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 3
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- 125000003118 aryl group Chemical group 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- 150000005621 tetraalkylammonium salts Chemical group 0.000 claims description 5
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- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
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- 229920006395 saturated elastomer Polymers 0.000 claims description 3
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- 239000012467 final product Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
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- 239000012453 solvate Substances 0.000 description 2
- PPJHVSVDKHKGDT-UHFFFAOYSA-N 1,1-dimethylurea;hydrochloride Chemical compound Cl.CN(C)C(N)=O PPJHVSVDKHKGDT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 241000370738 Chlorion Species 0.000 description 1
- 101150049660 DRD2 gene Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- JVKSIKSGFZZPKX-UHFFFAOYSA-N cyclohexanamine hydrate dihydrochloride Chemical compound O.Cl.Cl.NC1CCCCC1 JVKSIKSGFZZPKX-UHFFFAOYSA-N 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical group CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07D295/12—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 singly or doubly bound nitrogen atoms
- C07D295/135—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 singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Abstract
本发明涉及制备式(I)的反式-N-{4-{2-[4-(2，3-二氯苯基)-哌嗪-1-基]-乙基}-环己基}-脲衍生物的方法，该方法通过使式(III)的化合物与式(II)的氨基甲酰氯反应来进行，该方法包括在40-100℃的温度下、在相转移催化剂的存在下、在溶剂和浓的碱金属氢氧化物水溶液的混合物中进行反应，分离相并洗涤有机相，然后除去溶剂，干燥所得的式(I)的化合物，直至其为恒重。
Description
技术领域
本发明涉及一种新的制备通式(I)的反式-N-{4-{2-[4-(2，3-二氯苯基)-哌嗪-1-基]-乙基}-环己基}-脲衍生物的方法。
背景技术
通式(I)的化合物最初作为D3/D2受体拮抗剂在匈牙利专利No.P0302451的说明书中被公开。在P0302451的说明书中给出了制备式(I)化合物的3个反应路线(A，B，C法)。根据方法“A”，胺衍生物与(硫代)氨基甲酰氯化合物反应。在P0302451的实施例3的方法A中，在三乙胺的存在下、在无水条件下，胺与N，N-二甲基-氨基甲酰氯反应。
从产业的观点来看，上述方法“A”的缺点是反应时间长(48小时)、且收率低(65％)。此外，需要在额外的重结晶步骤中对所得最终产物进行纯化。
本发明的目的是提供一个没有以往方法缺点的方法，即，通过易于进行后处理的方式来制备式(I)的化合物，该方式的反应时间短且收率高。
发明内容
在试验过程中，我们惊奇地发现，当使式(III)的化合物
或其盐和/或水合物和/或溶剂合物与通式(II)的氨基甲酰氯
其中
R1和R2独立地表示：
任选被芳基取代的直链或支链的C1-6烷基，或
包含1-3个双键的C2-7烯基，或
任选被一个或多个C1-6烷氧基、三氟-C1-6烷氧基、C1-6烷氧羰基、C1-6烷酰基、芳基、C1-6烷硫基、卤素或氰基取代的单环、二环或三环芳基，或
任选被取代的单环、二环或三环环烷基，或
R1和R2可与相邻的氮原子一起形成任选被取代的、饱和或不饱和的、单环或二环杂环，其可以包含选自氧、氮或硫原子的另外的杂原子，
在作为相转移催化剂的四烷基铵盐的存在下、在溶剂和浓的碱性水溶液的混合物中反应，得到通式(I)的化合物，
其中R1和R2的定义如上所述，
该方法的收率高(90％以上)、且反应时间短。
采用根据本发明的方法，后处理方法变得更加容易：分离有机相和水相，然后水洗有机相，再通过蒸馏除去溶剂，得到最终产物。
具体实施方式
本发明涉及制备通式(I)的化合物的新的方法，
其中
R1和R2独立地表示：
任选被芳基取代的直链或支链的C1-6烷基，或
包含1-3个双键的C2-7烯基，或
任选被一个或多个C1-6烷氧基、三氟-C1-6烷氧基、C1-6烷氧羰基、C1-6烷酰基、芳基、C1-6烷硫基、卤素或氰基取代的单环、二环或三环芳基，或
任选被取代的单环、二环或三环环烷基，或
R1和R2可与相邻的氮原子一起形成任选被取代的、饱和或不饱和的、单环或二环杂环，其可以包含选自氧、氮或硫原子的另外的杂原子。
本发明的优点在于，反应时间变短，而且可以从反应混合物中以高纯度回收最终产物而无需进一步的纯化，其收率超过90％。
当R1和R2表示芳基时，该芳基部分可选自苯基、甲苯基、萘基和菲基。
在本发明的方法中，使式(III)的化合物
或其盐和/或水合物和/或溶剂合物与通式(II)的氨基甲酰氯
其中，R1和R2的定义如上所述，
在相转移催化剂的存在下、在溶剂和浓的碱性溶液的混合物中反应。在本发明方法中，可在较短的反应时间(9-10小时)内获得高收率(90％以上)的最终产物。
在本发明的优选实施方式中，浓的碱为碱金属氢氧化物例如NaOH或KOH的水溶液。
相转移催化剂为四烷基铵盐，其中烷基部分可具有C1-6的直链或支链。在适当的相转移催化剂的选择中，易于操作可以是很重要的因素。优选的相转移催化剂为四正丁基铵盐或四甲基铵盐，其中用于形成盐的阴离子可为硫酸根、氯离子或溴离子。
可用于本发明方法的合适的溶剂包括中性水不混溶性溶剂，例如甲苯、二氯甲烷、氯苯或二甲苯。在本发明的一个优选实施方式中，可优选二氯甲烷作为溶剂。
根据本发明方法的后处理步骤，分离有机相和水相，然后水洗有机相，再通过蒸馏除去溶剂，得到目标的最终产物。
实施例
通过以下的非限制性实施例进一步阐明本发明。
实施例1
反式-4-{2-[4-(2，3-二氯苯基)-哌嗪-1-基]-乙基}-N，N-二甲基氨甲酰基-环己胺的制备
向500ml四颈瓶中加入180ml的二氯甲烷、40ml的40％氢氧化钠、0.54g(0.002mol)的四正丁基溴化铵和3.12g(0.029mol)的N，N-二甲基氨基甲酰氯。在20-25℃的温度下搅拌混合物30分钟，然后加入6.24g(0.0145mol)的反式-4-{2-[4-(2，3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐。在氮气气氛下，在剧烈搅拌下将反应混合物置于预热至45-50℃的油浴中，并加热至沸腾温度10小时。然后将反应混合物冷却至室温，分离各相，有机层用3×80ml的水洗涤、再用80ml的10％氯化钠溶液洗涤。真空除去溶剂，将所得剩余物在最高50℃的温度下进一步干燥，直至其为恒重。
干燥重量：5.7g(92％)
熔点：212-214℃
实施例2
反式-4-{2-[4-(2，3-二氯苯基)-哌嗪-1-基]-乙基}-N，N-二甲基氨甲酰基-环己胺的制备
向500ml四颈瓶中加入180ml的二氯甲烷、40ml的40％氢氧化钠、0.54g(0.002mol)的四正丁基溴化铵和3.12g(0.029mol)的N，N-二甲基氨基甲酰氯。在20-25℃的温度下搅拌混合物30分钟，然后加入6.50g(0.0145mol)的反式-4-{2-[4-(2，3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐一水合物。在氮气气氛下，在剧烈搅拌下将反应混合物置于预热至45-50℃的油浴中，并加热至沸腾温度10小时。然后将反应混合物冷却至室温，分离各相，有机层用3×80ml的水洗涤、再用80ml的10％氯化钠溶液洗涤。真空除去溶剂，将所得剩余物在最高50℃的温度下进一步干燥，直至其为恒重。
干燥重量：5.7g(92％)
熔点：212-214℃
实施例3
反式-N-{4-{2-[4-(2，3-二氯苯基)-哌嗪-1-基]-乙基}-环己基}-吗啉-4-甲酰胺的制备
向500ml四颈瓶中加入400ml的二氯甲烷、40ml的40％氢氧化钠、1.2g(0.0036mol)的四正丁基溴化铵和11g(0.074mol)的N，N-二甲基氨基甲酰氯。在20-25℃的温度下搅拌混合物30分钟，然后加入15.5g(0.036mol)的反式-4-{2-[4-(2，3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐。在氮气气氛下，在剧烈搅拌下将反应混合物置于预热至45-50℃的油浴中，并加热至沸腾温度4小时。然后将反应混合物冷却至室温，分离各相，有机层用3×80ml的水洗涤、再用150ml的10％氯化钠溶液洗涤。真空除去溶剂，将所得剩余物在最高50℃的温度下进一步干燥，直至其为恒重。
干燥重量：15.2g(90％)
熔点：203-205℃
Claims (7)
1.通式(I)的化合物的制备方法，
其中
R1和R2独立地表示：
任选被芳基取代的直链或支链的C1-6烷基，或
包含1-3个双键的C2-7烯基，或
任选被一个或多个C1-6烷氧基、三氟-C1-6烷氧基、C1-6烷氧羰基、C1-6烷酰基、芳基、C1-6烷硫基、卤素或氰基取代的单环、二环或三环芳基，或
任选被取代的单环、二环或三环环烷基，或
R1和R2可与相邻的氮原子一起形成任选被取代的、饱和或不饱和的、单环或二环杂环，其可以包含选自氧、氮或硫原子的另外的杂原子，
通过使式(III)的化合物
与通式(II)的氨基甲酰氯反应来进行，
其中R1和R2的定义如上所述，
该方法包括：
在40-100℃的温度下、在相转移催化剂的存在下、在溶剂和浓的碱金属氢氧化物水溶液的混合物中进行反应，
分离相并洗涤有机层，然后除去溶剂，干燥所得的式(I)的化合物，直至其为恒重。
2.根据权利要求1的方法，其特征在于，所述相转移催化剂为四烷基铵盐。
3.根据权利要求2的方法，其特征在于，所述四烷基铵盐为四正丁基卤化铵。
4.根据权利要求3的方法，其特征在于，所述四烷基铵盐为四烷基溴化铵。
5.根据权利要求1的方法，其特征在于，所述溶剂为惰性水不相混溶溶剂。
6.根据权利要求1的方法，其特征在于，所述溶剂为甲苯、二氯甲烷、氯苯或二甲苯。
7.根据权利要求1的方法，其特征在于，所述反应在45-50℃的温度下进行。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP0800766 | 2008-12-18 | ||
| HU0800766A HUP0800766A2 (en) | 2008-12-18 | 2008-12-18 | Process for the preparation of piperazine derivatives |
| PCT/HU2009/000110 WO2010070371A1 (en) | 2008-12-18 | 2009-12-18 | Process for the preparation of piperazine derivatives |
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| CN102256955B CN102256955B (zh) | 2014-03-12 |
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| US (1) | US8569497B2 (zh) |
| EP (1) | EP2367807B1 (zh) |
| JP (1) | JP5583689B2 (zh) |
| CN (1) | CN102256955B (zh) |
| EA (1) | EA019521B1 (zh) |
| HK (1) | HK1160847A1 (zh) |
| HU (1) | HUP0800766A2 (zh) |
| TW (1) | TWI454464B (zh) |
| WO (1) | WO2010070371A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020042876A1 (zh) * | 2018-08-29 | 2020-03-05 | 浙江华海药业股份有限公司 | 一种卡利拉嗪的合成方法 |
| CN111320593A (zh) * | 2018-12-13 | 2020-06-23 | 江苏恩华药业股份有限公司 | 一种高纯度卡利拉嗪的精制方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0700353A2 (en) * | 2007-05-18 | 2008-12-29 | Richter Gedeon Nyrt | Metabolites of (thio)carbamoyl-cyclohexane derivatives |
| US7875610B2 (en) * | 2007-12-03 | 2011-01-25 | Richter Gedeon Nyrt. | Pyrimidinyl-piperazines useful as D3/D2 receptor ligands |
| EA023972B1 (ru) * | 2008-02-21 | 2016-08-31 | Рихтер Гедеон Нирт. | Стабильный твёрдый препарат карипразина для перорального введения и способ его получения |
| DK2317852T3 (en) | 2008-07-16 | 2015-03-23 | Richter Gedeon Nyrt | PHARMACEUTICAL FORMULATIONS CONTAINING dopamine receptor ligands |
| HU230067B1 (hu) | 2008-12-17 | 2015-06-29 | Richter Gedeon Nyrt | Új piperazin só és eljárás előállítására |
| HUP0800765A2 (en) | 2008-12-18 | 2010-11-29 | Richter Gedeon Nyrt | A new process for the preparation of piperazine derivatives and their hydrochloric salts |
| HUP0900790A2 (en) * | 2009-12-17 | 2011-09-28 | Richter Gedeon Nyrt | A new process for the preparation of piperazine and their hydrochloric salts |
| US11274087B2 (en) | 2016-07-08 | 2022-03-15 | Richter Gedeon Nyrt. | Industrial process for the preparation of cariprazine |
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- 2009-12-15 TW TW098142940A patent/TWI454464B/zh active
- 2009-12-18 US US13/140,261 patent/US8569497B2/en active Active
- 2009-12-18 CN CN200980150721.8A patent/CN102256955B/zh active Active
- 2009-12-18 JP JP2011541615A patent/JP5583689B2/ja active Active
- 2009-12-18 EA EA201170809A patent/EA019521B1/ru not_active IP Right Cessation
- 2009-12-18 EP EP09797147A patent/EP2367807B1/en active Active
- 2009-12-18 WO PCT/HU2009/000110 patent/WO2010070371A1/en active Application Filing
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| WO2008142461A1 (en) * | 2007-05-18 | 2008-11-27 | Richter Gedeon Nyrt. | Metabolites of (thio)carbamoyl-cyclohexane derivatives |
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| WO2020042876A1 (zh) * | 2018-08-29 | 2020-03-05 | 浙江华海药业股份有限公司 | 一种卡利拉嗪的合成方法 |
| US11420948B2 (en) | 2018-08-29 | 2022-08-23 | Zhejiang Huahai Pharmaceutical Co., Ltd. | Synthesis method for cariprazine |
| CN111320593A (zh) * | 2018-12-13 | 2020-06-23 | 江苏恩华药业股份有限公司 | 一种高纯度卡利拉嗪的精制方法 |
| CN111320593B (zh) * | 2018-12-13 | 2022-04-22 | 江苏恩华药业股份有限公司 | 一种高纯度卡利拉嗪的精制方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0800766A2 (en) | 2010-11-29 |
| HK1160847A1 (zh) | 2012-08-17 |
| EA201170809A1 (ru) | 2011-12-30 |
| JP2012512862A (ja) | 2012-06-07 |
| TWI454464B (zh) | 2014-10-01 |
| TW201035057A (en) | 2010-10-01 |
| WO2010070371A1 (en) | 2010-06-24 |
| HU0800766D0 (en) | 2009-03-02 |
| EP2367807B1 (en) | 2013-02-13 |
| EP2367807A1 (en) | 2011-09-28 |
| US20110269959A1 (en) | 2011-11-03 |
| WO2010070371A8 (en) | 2011-04-28 |
| CN102256955B (zh) | 2014-03-12 |
| US8569497B2 (en) | 2013-10-29 |
| JP5583689B2 (ja) | 2014-09-03 |
| EA019521B1 (ru) | 2014-04-30 |
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