CN1035672C - 3－(甲基咪唑基)－甲基－四氢－咔唑酮新的制备方法 - Google Patents
3－(甲基咪唑基)－甲基－四氢－咔唑酮新的制备方法 Download PDFInfo
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- CN1035672C CN1035672C CN94112257A CN94112257A CN1035672C CN 1035672 C CN1035672 C CN 1035672C CN 94112257 A CN94112257 A CN 94112257A CN 94112257 A CN94112257 A CN 94112257A CN 1035672 C CN1035672 C CN 1035672C
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- WHWJWUXBTCMWAS-UHFFFAOYSA-N 2-methyl-3-(5-methyl-1H-imidazol-2-yl)-2,3,4,4a-tetrahydrocarbazol-1-one Chemical compound CC=1N=C(NC1)C1C(C(C2=NC3=CC=CC=C3C2C1)=O)C WHWJWUXBTCMWAS-UHFFFAOYSA-N 0.000 title description 2
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- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 6
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- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 3
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 description 5
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- 238000002844 melting Methods 0.000 description 5
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 4
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
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- 150000001298 alcohols Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
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- 238000006555 catalytic reaction Methods 0.000 description 2
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- 125000001424 substituent group Chemical group 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- HHJUJCWZKJMCLC-UHFFFAOYSA-N 9-methyl-2,3-dihydro-1h-carbazol-4-one Chemical compound C12=CC=CC=C2N(C)C2=C1C(=O)CCC2 HHJUJCWZKJMCLC-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
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- 125000000217 alkyl group Chemical group 0.000 description 1
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- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及一种医药用杂环化合物新的制备方法。
本发明是用化学结构式(II)为原料，一步反应，
制备化学结构式(I)化合物的方法。
本发明所涉及的方法，缩短了反应步骤，简化了工序，减少了操作程序，降低成本，提高得率，有利于工业生产。
Description
本发明是一种医药用杂环化合物新的制备方法。
已有文献报道(Eur.J.Cancer Cim Onca1 Vol.25，Suppl 1pp s61；中国医药工业杂志，1993，24(4)，145)，是用通式IV化合物为原料，与式(III)2-甲基咪唑或其盐反应，
制备成式(I)化合物。
若通式IV中Y＝-CH2N(CH3)2，即式(V)的化合物。
已有文献报道制备式(V)化合物的方法(J.Med，Chem，Vo115，No.8，P875，1972)，是用式(II)的化合物与盐酸甲胺和多聚甲醛反应制备成式(V)的化合物。
本发明提供一种3-(甲基咪唑基)-甲基-四氢-咔唑酮新的制备方法，式(I)化合物的制备可以不通过有一个活性取代基的式(IV)化合物，而是用没有Y活性取代基的式(II)化合物。用式(II)化合物与仲胺类盐、甲醛溶液或它的聚合物及式(III)2-甲基咪唑或它的盐直接一步反应制备成式(I)的化合物。本发明新的制备方法在生产上可缩短反应步骤，简化溶剂萃取分离，分步精制纯化等工序，由此，减少了溶剂的用量40％，降低了生产成本，而且产量提高30％左右。用酸性离子交换树脂催化此类反应是一种新的方法，反应条件缓和，而且可方便地用过滤方法从反应体系中除去，生成的产物颜色较浅，容易精制纯化。
在本发明所涉及的方法中，仲胺类用通式为R1R2NH表示：R1R2可以相同或者不相同，各代表低级烷基、芳基或芳烷基，或R1和R2和氮原子一起相互连结成一个5个原子或6个原子的环。其中以盐酸二甲胺为好。
在本发明所涉及的方法中，甲醛溶液或它的聚合物，其中以多聚甲醛为好。
在本发明所涉及的方法中，用极性或非极性溶剂，包括醇(甲醇、乙醇等低级脂肪醇)；酮(丙酮、甲乙酮等)；酯(醋酸乙酯)；酰胺(二甲基甲酰胺)；卤代链烷烃(氯仿、二氯甲烷等)；或它们的混合物，其中以醇类为好。
在本发明所涉及的方法中，用无机酸(盐酸、磷酸、硫酸等)；有机酸(甲酸、乙酸、丙酸等)，或用离子交换树脂，优选用酸性离子交换树脂(磺酸型、羧酸型、磷酸型)进行催化，其中以磺酸型离子交换树脂催化为好。用离子交换树脂进行催化，反应后能方便地用过滤方法除去，便于生产操作，且反应液的颜色较浅，容易精制纯化。
在本发明所涉及的方法中，反应温度可选择在20-140℃范围内进行。其中以80-130℃为好。反应时间在80-200小时，其中以100-150小时为好。
本发明制备成式(I)的化合物用常规成盐的方法，用盐酸在溶剂中制备成式(I)含结晶水的盐酸盐。该化合物可用于治疗肿瘤病人由于化疗、放疗引起的恶心、呕吐的副作用。
下列实例说明本发明，但本发明不受实例所限制，温度用摄氏度(℃)表示。熔点测定用毛细管法。
实例1：
2，3二氢-9-甲基-1H-咔唑-4-酮(式II)3.0克、多聚甲醛3.0克、盐酸二甲胺6.0克、2-甲基咪唑3.0克及732型号离子交换树脂6.0克于138毫升乙醇中，加热搅拌反应。加热温度在50-140℃范围内，反应时间在80-200小时的范围内。反应完成后，析出固体，经分离纯化，干燥，得式(I)化合物1.8克，熔点229-30℃。
实例2：
式(II)化合物1.0克、多聚甲醛1.0克、盐酸二甲胺2.0克、2-甲基咪唑1.0克、浓盐酸1.0毫升于46毫升乙醇中，加热搅拌反应。加热温度在50-140℃范围内，反应时间在80-200小时的范围内。反应完成后，析出固体，经分离纯化，干燥，得式(I)化合物0.4克，熔点230-31℃。
实例3：
式(II)化合物0.5克、多聚甲醛1.0克、盐酸二甲胺2.0克、2-甲基咪唑0.5克于23毫升乙醇中，加热温度在50-140℃范围内，反应时间在80-200小时的范围内。反应完成后，析出固体，经分离纯化，干燥，得式(I)化合物0.1克，熔点229-30℃。
实例4：
式(I)化合物0.1克、异丙醇7毫升，在室温搅拌状态下，逐渐滴加浓盐酸10滴。继续搅拌2小时，抽滤干燥，得式(I)化合物含结晶水盐酸盐白色结晶0.1克，熔点175-6℃。
Claims (3)
1、一种制备式(I)化合物的方法，
其特征是用式(II)的化合物为原料，在仲胺盐和甲醛溶液或它的聚合物作用下，以酸性离子交换树脂作催化剂，与式(III)的化合物或它的盐进行反应，生成式(I)的化合物。
2、根据权利要求1的方法， 其中酸性离子交换树脂为磺酸型离子交换树脂。
3、根据权利要求1的方法，其反应在极性或非极性的有机溶剂中进行。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94112257A CN1035672C (zh) | 1994-08-08 | 1994-08-08 | 3－(甲基咪唑基)－甲基－四氢－咔唑酮新的制备方法 |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94112257A CN1035672C (zh) | 1994-08-08 | 1994-08-08 | 3－(甲基咪唑基)－甲基－四氢－咔唑酮新的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1105994A CN1105994A (zh) | 1995-08-02 |
| CN1035672C true CN1035672C (zh) | 1997-08-20 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN94112257A Expired - Fee Related CN1035672C (zh) | 1994-08-08 | 1994-08-08 | 3－(甲基咪唑基)－甲基－四氢－咔唑酮新的制备方法 |
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| CN (1) | CN1035672C (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2398071B (en) | 2003-01-24 | 2006-06-07 | Synthon Bv | Process for making ondansetron and intermediate thereof |
| WO2006046253A1 (en) * | 2004-10-26 | 2006-05-04 | Ipca Laboratories Limited | A one-pot process for the preparation of antiemetic agent, 1,2,3,9-tetrahydro-9-methyl-3[(2-methyl)-1h-imidazole-1-yl)methyl]-4h-carbazol-4-o |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85105643A (zh) * | 1984-01-25 | 1987-05-06 | 格拉克索公司 | 杂环化合物的制备 |
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- 1994-08-08 CN CN94112257A patent/CN1035672C/zh not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85105643A (zh) * | 1984-01-25 | 1987-05-06 | 格拉克索公司 | 杂环化合物的制备 |
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| Publication number | Publication date |
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| CN1105994A (zh) | 1995-08-02 |
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