CN102295604B - Preparation method of telmisartan intermediate - Google Patents
Preparation method of telmisartan intermediate Download PDFInfo
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- CN102295604B CN102295604B CN 201110196174 CN201110196174A CN102295604B CN 102295604 B CN102295604 B CN 102295604B CN 201110196174 CN201110196174 CN 201110196174 CN 201110196174 A CN201110196174 A CN 201110196174A CN 102295604 B CN102295604 B CN 102295604B
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Abstract
The invention discloses a preparation method of a telmisartan intermediate. The preparation method of the invention comprises the following steps of heating, condensation and dehydration of N-methyl-o-phenylenediamine and 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid under a solvent-free condition; the synthetic route is as follows; the preparation method of a telmisartan intermediate of the invention has a mild reaction condition, is environment friendly, is convenient for post-treatment, and is applicable to industrial production; The organic synthesis under a solvent-free condition of the invention has the advantages of high yield, strong selectivity, simple operation, low cost, no environmental pollution, and the like. The telmisartan intermediate of the invention can be used to prepare antihypertensive drugs.
Description
Technical field
The present invention relates to a kind of preparation method of telmisartan intermediate, belong to chemical pharmacy field.
Background technology
Husky smooth class preparation is to be used for clinical antihypertensive drug after the ACEI inhibitor.In husky smooth class preparation, telmisartan is a species specificity angiotensin-ii receptor (AT I type) antagonist.Give the 80mg telmisartan at human body and almost can suppress the elevation of blood pressure that Angiotensin II causes fully.Retarding effect continues 24 hours, still can measure at 48 hours.After first dose of telmisartan in 3 hours pressure reduction effect obvious gradually.4 weeks can obtain the maximum reducing effect after the treatment beginning, and can keep in long-term treatment.Can say, telmisartan is the extraordinary medicine of hypertension.
The structure of telmisartan belongs to non-Biphenyltetrazoles, and its synthetic committed step is to be carried out nucleophilic substitution reaction and obtained product by 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline and 4 '-brooethyl-xenyl-2-carboxylicesters.Wherein 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline is the key intermediate I that synthesizes.
The synthetic method of 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline is mainly: one, 2-propyl group-4-methyl-benzoglyoxaline-6-carboxylic acid and N-methyl-O-Phenylene Diamine heat in polyphosphoric acid close ring (DE4103492, DE 4117121, EP 0502314, EP 0543263, JP 1992346978, J.Med.Chem., 1993,36 (25), 4040-51, Drugs Fut., 1997,22 (10), 1112 etc.).
N-(2-methylamino--phenyl)-3-amino-4-butyramide-5-methyl benzamide heats pass ring (WO2006/44754) in polyphosphoric acid.
Above method common feature is that material is mixed in heating pass ring in polyphosphoric acid.Due to polyphosphoric acid thickness extremely, therefore there is following defective in density very large (2.1g/cm3): material stirring difficulty in reaction, mix inhomogeneous; In product, by product is more; Relate to a large amount of acid of neutralization during aftertreatment, generates a large amount of inorganic salt, cause the aftertreatment difficulty, cost rising, seriously polluted to environment.
Summary of the invention
The object of the invention is to provide a kind of preparation method of telmisartan intermediate, and this preparation method can solve the technological deficiency problem that above-mentioned preparation method brings.
The present invention seeks to be achieved through the following technical solutions:
A kind of preparation method of telmisartan intermediate comprises the steps: that N-methyl-O-Phenylene Diamine and 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid adds the thermal condensation dehydration under condition of no solvent, and its synthetic route is:
The preparation method of telmisartan intermediate of the present invention adds phase-transfer catalyst in building-up process.Described phase-transfer catalyst is one or more in tetrabutylammonium chloride (TBAC), tetrabutyl ammonium fluoride (TBAF), 4-butyl ammonium hydrogen sulfate.
The preparation method of telmisartan intermediate of the present invention adds or does not add molecular sieve powder in building-up process.Described molecular sieve powder is 4A or 3A molecular sieve powder.
The preparation method of telmisartan intermediate of the present invention, in building-up process, mixed system under nitrogen atmosphere, is heated to 180-220 ℃, insulation reaction 1.5-2.5 hour.
The preparation method of telmisartan intermediate of the present invention, in building-up process after reacting by heating mixture slowly be added in 10%NaHCO3 solution, disperse to stir 3-5 hour, filter and obtain 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, i.e. telmisartan intermediate.
The preparation method of telmisartan intermediate of the present invention, comprise the steps: that specifically with molar ratio be 1.1-1.5: N-methyl-O-Phenylene Diamine of 1 and 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid mix, add 0.5-0.8 doubly to tetrabutylammonium chloride or tetrabutyl ammonium fluoride or the 4-butyl ammonium hydrogen sulfate of N-methyl-O-Phenylene Diamine mass parts, add or do not add 0.1-0.2 doubly to the molecular sieve powder of N-methyl-O-Phenylene Diamine mass parts, mix; With the nitrogen flooding deacration, be heated to 180-220 ℃, insulation reaction 1.5-2.5 hour, slowly be down to room temperature, solid slowly is added in 10%NaHCO3 solution, disperse to stir 3-5 hour, filter and obtain 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, i.e. telmisartan intermediate.
Telmisartan intermediate of the present invention is for the preparation of antihypertensive medicine.
The preparation method of telmisartan intermediate of the present invention has following beneficial effect: reaction conditions gentleness, environmental friendliness, facilitate aftertreatment and adapt to industrial production; Organic synthesis under condition of no solvent of the present invention has that yield is high, selectivity is strong, easy and simple to handle, cost low and the superiority such as non-environmental-pollution.
Embodiment
Embodiment 1:
with N-methyl-O-Phenylene Diamine (50g, 0.409mol) and 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid (59.6g, 0.273mol) add respectively 500 milliliters of there-necked flasks, then add successively tetrabutylammonium chloride (TBAC) (30g), 4A or 3A molecular sieve powder (8g), stir, be heated to 200 ℃, insulation reaction 2 hours, slowly be down to room temperature, solid slowly is added in 10%NaHCO3 solution, disperse to stir 4 hours, filtration obtains 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline (telmisartan intermediate) 68.1g, yield 82%,
1HNMR(DMSO-d6)：0.91-1.02ppm(t，3H)，1.60-1.70ppm(m，2H)，2.45(s，3H)，2.63ppm(t，2H)，3.75ppm(s，3H)，5.12-5.35ppm(br，1H)，7.33ppm(m，3H)，7.70-7.85ppm(m，3H).。
Embodiment 2:
with N-methyl-O-Phenylene Diamine (50g, 0.409mol) and 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid (59.6g, 0.273mol) add respectively 500 milliliters of there-necked flasks, then add successively tetrabutyl ammonium fluoride (TBAF) (30g), 4A or 3A molecular sieve powder (8g), stir, be heated to 180 ℃, insulation reaction 2 hours, slowly be down to room temperature, solid slowly is added in 10%NaHCO3 solution, disperse to stir 4 hours, filtration obtains 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline (telmisartan intermediate) 65.5g, yield 78.9%.
Embodiment 3:
with N-methyl-O-Phenylene Diamine (50g, 0.409mol) and 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid (59.6g, 0.273mol) add respectively 500 milliliters of there-necked flasks, then add successively 4-butyl ammonium hydrogen sulfate (30g), 4A or 3A molecular sieve powder (8g), stir, be heated to 220 ℃, insulation reaction 2 hours, slowly be down to room temperature, solid slowly is added in 10%NaHCO3 solution, disperse to stir 3.5 hours, filtration obtains 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline (telmisartan intermediate) 63.8g, yield 76.8%.
Embodiment 4:
with N-methyl-O-Phenylene Diamine (50g, 0.409mol) and 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid (59.6g, 0.273mol) add respectively 500 milliliters of there-necked flasks, then add tetrabutylammonium chloride (TBAC) (35g), stir, be heated to 200 ℃, insulation reaction 2 hours, slowly be down to room temperature, solid slowly is added in 10%NaHCO3 solution, disperse to stir 4.5 hours, filtration obtains 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline (telmisartan intermediate) 60.5g, yield 72.9%.
Embodiment 5:
with N-methyl-O-Phenylene Diamine (50g, 0.409mol) and 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid (59.6g, 0.273mol) add respectively 500 milliliters of there-necked flasks, then add tetrabutyl ammonium fluoride (TBAF) (30g), stir, be heated to 180 ℃, insulation reaction 2.5 hours, slowly be down to room temperature, solid slowly is added in 10%NaHCO3 solution, disperse to stir 4 hours, filtration obtains 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline (telmisartan intermediate) 64.7g, yield 78%.
Embodiment 6:
With N-methyl-O-Phenylene Diamine (50g, 0.409mol) and 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid (59.6g, 0.273mol) add respectively 500 milliliters of there-necked flasks, then add 4-butyl ammonium hydrogen sulfate (30g), stir, be heated to 220 ℃, insulation reaction 1.5 hours, slowly be down to room temperature, solid slowly is added in 10%NaHCO3 solution, disperse to stir 4 hours, filter and obtain 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline (telmisartan intermediate) 59.5g, yield 71.7%.
Claims (2)
1. the preparation method of a telmisartan intermediate, is characterized in that comprising the steps: that N-methyl-O-Phenylene Diamine and 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid adds the thermal condensation dehydration under condition of no solvent, and its synthetic route is:
Add phase-transfer catalyst in building-up process: one or more in tetrabutylammonium chloride, tetrabutyl ammonium fluoride, 4-butyl ammonium hydrogen sulfate;
Add or do not add molecular sieve powder in building-up process;
In building-up process, mixed system under nitrogen atmosphere, is heated to 180-220 ℃, insulation reaction 1.5-2.5 hour;
In building-up process after reacting by heating mixture slowly be added to 10%NaHCO
3In solution, disperse to stir 3-5 hour, filter and obtain 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, i.e. telmisartan intermediate.
2. the preparation method of a kind of telmisartan intermediate as claimed in claim 1, it is characterized in that specifically comprising the steps: that N-methyl-O-Phenylene Diamine and 7-methyl-2-propyl-3H-benzimidazole-5-carboxylic acid with molar ratio is 1.1-1.5:1 mix, the tetrabutylammonium chloride or tetrabutyl ammonium fluoride or the 4-butyl ammonium hydrogen sulfate that add 0.5-0.8 times of N-methyl-O-Phenylene Diamine mass parts, add or do not add the molecular sieve powder of 0.1-0.2 times of N-methyl-O-Phenylene Diamine mass parts, mix; With the nitrogen flooding deacration, be heated to 180-220 ℃, insulation reaction 1.5-2.5 hour, slowly be down to room temperature, solid slowly is added to 10%NaHCO
3In solution, disperse to stir 3-5 hour, filter and obtain 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, i.e. telmisartan intermediate.
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| CN104610161A (en) * | 2015-01-05 | 2015-05-13 | 河南师范大学 | Preparation method for telmisartan |
| CN105237457A (en) * | 2015-10-22 | 2016-01-13 | 威特(湖南)药业有限公司 | Preparation method for 2-n-propyl-4-methyl-6-(1-methylbenzimidazole-2-yl)benzimidazole |
| CN114573513B (en) * | 2022-03-25 | 2023-05-16 | 济南大学 | Synthesis method of telmisartan intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101717370A (en) * | 2009-11-30 | 2010-06-02 | 常州亚邦制药有限公司 | New method for preparing 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101717370A (en) * | 2009-11-30 | 2010-06-02 | 常州亚邦制药有限公司 | New method for preparing 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole |
Non-Patent Citations (5)
| Title |
|---|
| Development》.2006,第11卷(第1期),81-85. * |
| Kikkuru Srirami Reddy, et al..An Efficient and Impurity-Free Process for Telmisartan: An Antihypertensive Drug.《Organic Process Research & Development》.2006,第11卷(第1期),81-85. |
| Kikkuru Srirami Reddy, et al..An Efficient and Impurity-Free Process for Telmisartan: An Antihypertensive Drug.《Organic Process Research & * |
| 肖时俊 等.降血压药物替米沙坦的合成.《中国新药杂志》.2010,第19卷(第18期),1726-1728. |
| 降血压药物替米沙坦的合成;肖时俊 等;《中国新药杂志》;20101231;第19卷(第18期);1726-1728 * |
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Address after: 611138 Sichuan science and Technology Development Zone, Wenjiang District, Chengdu City, Xinhua Road, the central section of the two paragraph Patentee after: SICHUAN KELUN DRUG RESEARCH INSTITUTE CO., LTD. Address before: 610500, No. two, No. 520, South Road, Xindu satellite Industrial Development Zone, Sichuan, Chengdu Patentee before: Kelun Pharmaceutical Research Co., Ltd. |