CN111892556A - 新的卡利拉嗪制备方法 - Google Patents
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- KPWSJANDNDDRMB-QAQDUYKDSA-N cariprazine Chemical compound C1C[C@@H](NC(=O)N(C)C)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 KPWSJANDNDDRMB-QAQDUYKDSA-N 0.000 title description 3
- 229960005123 cariprazine Drugs 0.000 title description 3
- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 12
- LDQCWGIXZGDJNL-IYARVYRRSA-N chembl3085821 Chemical compound C1C[C@@H](NC(=O)OC(C)(C)C)CC[C@@H]1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 LDQCWGIXZGDJNL-IYARVYRRSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- UDQMXYJSNNCRAS-UHFFFAOYSA-N 2,3-dichlorophenylpiperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1Cl UDQMXYJSNNCRAS-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 4
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- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- KPWSJANDNDDRMB-UHFFFAOYSA-N 3-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-1,1-dimethylurea Chemical compound C1CC(NC(=O)N(C)C)CCC1CCN1CCN(C=2C(=C(Cl)C=CC=2)Cl)CC1 KPWSJANDNDDRMB-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims 1
- 239000011230 binding agent Substances 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- -1 2, 3-dichlorophenyl Chemical group 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
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- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
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- 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
- C07D295/12—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
本发明属于药物化学领域，主要涉及一种新的N'‑(反式‑4‑{2‑[4‑(2,3‑二氯苯基)‑1‑哌嗪基]乙基}环己基)‑N,N‑二甲基脲制备方法；
Description
技术领域
本发明属于药物化学领域，主要涉及新的N'-(反式-4-{2-[4-(2,3-二氯苯基)-1-哌嗪基]乙基}环己基)-N,N-二甲基脲制备方法。
背景技术
卡利拉嗪是由美国森林实验室（Forest lab）研发的一种非典型性抗精神病药，属于多巴胺D2、D3受体部分激动剂。根据本发明的反式N-{4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐与三光气是制备卡利拉嗪的一种重要方法。
使用反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙醇与甲磺酰氯反应制得反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙基甲磺酸酯，通过使反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙基甲磺酸酯与2,3-二氯苯基-哌嗪反应制得反式N-叔丁氧羰基-4-｛2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺，通过使反式N-叔丁氧羰基-4-｛2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺脱Boc反应制得反式N-{4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐，是一种安全且工业规模容易控制的方法，通过该方法可以经由简单反应步骤以及良好的产率制备反N-{4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐，而且没有使用极端的反应条件和附加设备，再由N-{4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐与三光气制备得产率高达95%的N'-(反式-4-{2-[4-(2,3-二氯苯基)-1-哌嗪基]乙基}环己基)-N,N-二甲基脲（
），三光气作为剧毒光气和双光气在合成中的替代产物，具有毒性低，使用安全方便，而且反应条件温和，选择性好，收率高等特点，且路线并无特殊要求。
发明内容
在实验过程中，我们发现从反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙醇开始和使用本发明的方法可以通过两个容易进行且经济的合成步骤以高纯度按工业规模合成N'-(反式-4-{2-[4-(2,3-二氯苯基)-1-哌嗪基]乙基}环己基)-N,N-二甲基脲（
），其中进行的所有步骤都可以具有良好的产率。
其制备步骤包括：反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙醇（I）与甲磺酰氯反应制得反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙基甲磺酸酯（II），通过使反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙基甲磺酸酯（II）与2,3-二氯苯基-哌嗪反应制得反式N-叔丁氧羰基-4-｛2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺（III），通过使反式N-叔丁氧羰基-4-｛2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺（III）脱Boc反应制得反式N-{4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐（IV），反式N-{4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐（IV）与三光气脲化得N'-(反式-4-{2-[4-(2,3-二氯苯基)-1-哌嗪基]乙基}环己基)-N,N-二甲基脲（
）。
具体实施方式
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1：
反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙基甲磺酸酯的制备
称取反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙醇37.0g（0.15mol）溶于二氯甲烷370mL冰浴条件下缓慢滴加甲磺酰氯22.6g(0.20mol)溶于100mL二氯甲烷的溶液，控温0-5℃。保温搅拌至TLC监控反应完毕，加入100mL水，搅拌30分钟，分液，有机相水洗一次，饱和食盐水洗一次，无水硫酸钠干燥，抽滤浓缩，旋余物加入石油醚打浆。过滤得白色固体，固体放置于50℃鼓风干燥箱干燥，得到固体产物44.1g，收率为90.2%。
实施例2：
反式N-叔丁氧羰基-4-｛2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺的制备
称取反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙基甲磺酸酯24.3g(0.076mol)与195mL乙腈混合搅拌30分钟，缓慢滴加1-(2,3二氯苯基)哌嗪21.0g（0.087mol）溶于60mL乙腈的溶液，加热回流4小时。TLC监控反应完毕，冷却至室温，冰浴析晶1小时，抽滤，固体于50℃下鼓风干燥箱干燥，得到29.4g固体产物，收率为83.1%。
实施例3：
反式N-{4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐的制备
称取22.8g（0.05mol）反式N-叔丁氧羰基-4-｛2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺加入反应瓶，加入250mL甲醇，冰浴冷却至0-5℃，缓慢通入HCl气体搅拌5h，然后缓慢加热至35℃，搅拌2h，TLC监控反应完毕后减压旋蒸除去溶剂，残余物加入150mL异丙醚搅拌1h，过滤，得到固体于50℃下鼓风干燥箱干燥，得到反式N-{4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐固体20.0g，收率为93.19%。
实施例4：
称取反式N-{4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐6.45g（0.015mol）加入到125ml二氯甲烷和12.25ml三乙胺的混合物中。将得到的三乙胺和浓稠悬浮液在20-25℃的温度下搅拌1小时。将该悬浮液加入到4.9g三光气有50ml二氯甲烷的溶液中，温度为-5-（-10）℃，时间为1小时。将得到的反应混合物加入到13g二甲胺在含100ml异丙醇（IPA）（40ml，0.12mol）的溶液中，该溶液在0-（-10）℃的温度下冷却，在此期间反应混合物的温度保持在0°C以下。在0-（ - 8）℃的温度下搅拌40分钟后，在搅拌下加入120ml蒸馏水。然后通过加入浓盐酸将水相的pH调节至8-9，并将体积的反应混合物在真空下浓缩至100ml。向所得反应混合物中加入另外的80ml蒸馏水，并将混合物在真空下浓缩至150ml。将悬浮液在18-27℃搅拌1小时，过滤分离所得产物。这样得到6.6g标题化合物。产率：95％熔点：208-211℃。
Claims (5)
1.N'-(反式-4-{2-[4-(2,3-二氯苯基)-1-哌嗪基]乙基}环己基)-N,N-二甲基脲的制备方法，其特征在于：
使反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙醇（I）与甲磺酰氯（2）在一定温度下反应制得反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙基甲磺酸酯（II）。
2.在酸结合剂的存在下，使反式2-｛1-[4-(N-叔丁氧羰基)-氨基]环己基｝-乙基甲磺酸酯（II）与2,3-二氯苯基-哌嗪反应，得到反式N-叔丁氧羰基-4-｛2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺（III）；
在含水盐酸/甲醇的混合物中，将得到的反式N-叔丁氧羰基-4-｛2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺加热至40-100℃的温度得到反式N-{4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐（IV）；
将反式N-{4-{2-[4-(2,3-二氯苯基)-哌嗪-1-基]-乙基}-环己胺二盐酸盐(
)与三光气经脲化，调PH至8~9，浓缩后过滤分离得N'-(反式-4-{2-[4-(2,3-二氯苯基)-1-哌嗪基]乙基}环己基)-N,N-二甲基脲（V）；
3.根据权利要求1的方法，其特征在于步骤a)中化合物的制备方法，所述的一定温度为-20~15℃，优选-5~5℃。
4.根据权利要求1的方法，其特征在于步骤a)中，化合物（1）与化合物（2）的摩尔比为1:1.1~1:2.0，优选1:1.2~1:1.5。
5.根据权利要求1的方法，其特征在于步骤d）中，脲化试剂为三光气和二甲氨基，反应温度为0℃以下，PH调到8~9。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102256953A (zh) * | 2008-12-17 | 2011-11-23 | 吉瑞工厂 | 哌嗪盐及其制备方法 |
| CN102256954A (zh) * | 2008-12-18 | 2011-11-23 | 吉瑞工厂 | 哌嗪化合物及其盐酸盐的制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102256953A (zh) * | 2008-12-17 | 2011-11-23 | 吉瑞工厂 | 哌嗪盐及其制备方法 |
| CN102256954A (zh) * | 2008-12-18 | 2011-11-23 | 吉瑞工厂 | 哌嗪化合物及其盐酸盐的制备方法 |
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