CN102295604A - Preparation method of telmisartan intermediate - Google Patents
Preparation method of telmisartan intermediate Download PDFInfo
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- CN102295604A CN102295604A CN2011101961746A CN201110196174A CN102295604A CN 102295604 A CN102295604 A CN 102295604A CN 2011101961746 A CN2011101961746 A CN 2011101961746A CN 201110196174 A CN201110196174 A CN 201110196174A CN 102295604 A CN102295604 A CN 102295604A
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- benzoglyoxaline
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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 telmisartan intermediates preparation, belong to chemical pharmacy field.
Background technology
Husky smooth class preparation is to be used for clinical antihypertensive drug behind the ACEI inhibitor.Telmisartan is a specific specificity angiotensin-ii receptor (AT I type) antagonist in the husky smooth class preparation.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.Behind the first dose of telmisartan in 3 hours pressure reduction effect obvious gradually.4 weeks can obtain the maximum reducing effect in treatment beginning back, and can in long-term treatment, keep.We can say that 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 synthetic key intermediate I.
The synthetic method of 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline mainly is: one, 2-propyl group-4-methyl-benzoglyoxaline-6-carboxylic acid and N-methyl-O-Phenylene Diamine in polyphosphoric acid, heat 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 heating pass ring in polyphosphoric acid.Because polyphosphoric acid is thickness extremely, therefore there is following defective in density very big (2.1g/cm3): material stirs difficulty in the reaction, mixes inhomogeneous; By product is more in the product; 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 telmisartan intermediates preparation, 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 telmisartan intermediates preparation comprises the steps: that N-methyl-O-Phenylene Diamine and 7-methyl-2-propyl group-3H-benzoglyoxaline-5-carboxylic acid adds the thermal condensation dehydration under condition of no solvent, and its synthetic route is:
Telmisartan intermediates preparation of the present invention adds phase-transfer catalyst in the building-up process.Described phase-transfer catalyst is one or more in tetrabutylammonium chloride (TBAC), tetrabutyl ammonium fluoride (TBAF), the 4-butyl ammonium hydrogen sulfate.
Telmisartan intermediates preparation of the present invention adds or does not add molecular sieve powder in the building-up process.Described molecular sieve powder is 4A or 3A molecular sieve powder.
Telmisartan intermediates preparation of the present invention, mixed system is heated to 180-220 ℃, insulation reaction 1.5-2.5 hour in the building-up process under nitrogen atmosphere.
Telmisartan intermediates preparation of the present invention, in the building-up process after the reacting by heating mixture slowly be added in the 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 intermediates preparation of the present invention, comprise the steps: that specifically with molar ratio be 1.1-1.5: 1 N-methyl-O-Phenylene Diamine and 7-methyl-2-propyl group-3H-benzoglyoxaline-5-carboxylic acid mixes, add 0.5-0.8 doubly to tetrabutylammonium chloride or the 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 reduce to room temperature, solid slowly is added in the 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 used to prepare antihypertensive medicine.
Telmisartan intermediates preparation of the present invention has following beneficial effect: reaction conditions gentleness, environmental friendliness, make things convenient for aftertreatment and adapt to industrial production; Organic synthesis under the condition of no solvent of the present invention has that yield height, selectivity are strong, easy and simple to handle, cost low and superiority such as non-environmental-pollution.
Embodiment
Embodiment 1:
With N-methyl-O-Phenylene Diamine (50g, 0.409mol) and 7-methyl-2-propyl group-3H-benzoglyoxaline-5-carboxylic acid (59.6g, 0.273mol) add 500 milliliters of there-necked flasks respectively, add tetrabutylammonium chloride (TBAC) then successively (30g), 4A or 3A molecular sieve powder (8g), stir, be heated to 200 ℃, insulation reaction 2 hours, slowly reduce to room temperature, solid slowly is added in the 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 group-3H-benzoglyoxaline-5-carboxylic acid (59.6g, 0.273mol) add 500 milliliters of there-necked flasks respectively, add tetrabutyl ammonium fluoride (TBAF) then successively (30g), 4A or 3A molecular sieve powder (8g), stir, be heated to 180 ℃, insulation reaction 2 hours, slowly reduce to room temperature, solid slowly is added in the 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 group-3H-benzoglyoxaline-5-carboxylic acid (59.6g, 0.273mol) add 500 milliliters of there-necked flasks respectively, add 4-butyl ammonium hydrogen sulfate (30g) then successively, 4A or 3A molecular sieve powder (8g), stir, be heated to 220 ℃, insulation reaction 2 hours, slowly reduce to room temperature, solid slowly is added in the 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 group-3H-benzoglyoxaline-5-carboxylic acid (59.6g, 0.273mol) add 500 milliliters of there-necked flasks respectively, add tetrabutylammonium chloride (TBAC) then (35g), stir, be heated to 200 ℃, insulation reaction 2 hours, slowly reduce to room temperature, solid slowly is added in the 10%NaHCO3 solution, disperse to stir 4.5 hours, filter and obtain 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 group-3H-benzoglyoxaline-5-carboxylic acid (59.6g, 0.273mol) add 500 milliliters of there-necked flasks respectively, add tetrabutyl ammonium fluoride (TBAF) then (30g), stir, be heated to 180 ℃, insulation reaction 2.5 hours, slowly reduce to room temperature, solid slowly is added in the 10%NaHCO3 solution, disperse to stir 4 hours, filter and obtain 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 group-3H-benzoglyoxaline-5-carboxylic acid (59.6g, 0.273mol) add 500 milliliters of there-necked flasks respectively, add 4-butyl ammonium hydrogen sulfate (30g) then, stir, be heated to 220 ℃, insulation reaction 1.5 hours, slowly reduce to room temperature, solid slowly is added in the 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 (10)
1. a telmisartan intermediates preparation is characterized in that comprising the steps: that N-methyl-O-Phenylene Diamine and 7-methyl-2-propyl group-3H-benzoglyoxaline-5-carboxylic acid adds the thermal condensation dehydration under condition of no solvent, and its synthetic route is:
2. a kind of telmisartan intermediates preparation as claimed in claim 1 is characterized in that adding in the building-up process phase-transfer catalyst.
3. a kind of telmisartan intermediates preparation as claimed in claim 2 is characterized in that phase-transfer catalyst is one or more in tetrabutylammonium chloride, tetrabutyl ammonium fluoride, the 4-butyl ammonium hydrogen sulfate.
4. as claim 1,2 or 3 described a kind of telmisartan intermediates preparation, it is characterized in that adding or not adding in the building-up process molecular sieve powder.
5. a kind of telmisartan intermediates preparation as claimed in claim 4 is characterized in that mixed system is heated to 180-220 ℃, insulation reaction 1.5-2.5 hour in the building-up process under nitrogen atmosphere.
6. a kind of telmisartan intermediates preparation as claimed in claim 5, it is characterized in that in the building-up process that mixture slowly is added in the 10%NaHCO3 solution after the reacting by heating, disperse to stir 3-5 hour, filtration obtains 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, i.e. telmisartan intermediate.
7. as claim 1,2,3,5 or 6 arbitrary described a kind of telmisartan intermediates preparation, it is characterized in that specifically comprising the steps: that with molar ratio be 1.1-1.5: 1 N-methyl-O-Phenylene Diamine and 7-methyl-2-propyl group-3H-benzoglyoxaline-5-carboxylic acid mixes, 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 reduce to room temperature, solid slowly is added in the 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.
8. a telmisartan intermediate is characterized in that this intermediates preparation comprises the steps: that N-methyl-O-Phenylene Diamine and 7-methyl-2-propyl group-3H-benzoglyoxaline-5-carboxylic acid add the thermal condensation dehydration under condition of no solvent, and its synthetic route is:
9. a kind of telmisartan intermediate as claimed in claim 8, it is characterized in that this intermediates preparation comprises the steps: that specifically with molar ratio be 1.1-1.5: 1 N-methyl-O-Phenylene Diamine and 7-methyl-2-propyl group-3H-benzoglyoxaline-5-carboxylic acid mixes, 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 reduce to room temperature, solid slowly is added in the 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.
10. the application in the preparation antihypertensive drug as claim 9 or 8 described a kind of telmisartan intermediates.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114573513A (en) * | 2022-03-25 | 2022-06-03 | 济南大学 | Synthesis method of telmisartan intermediate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (2)
| Title |
|---|
| KIKKURU SRIRAMI REDDY, ET AL.: "An Efficient and Impurity-Free Process for Telmisartan: An Antihypertensive Drug", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| 肖时俊 等: "降血压药物替米沙坦的合成", 《中国新药杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114573513A (en) * | 2022-03-25 | 2022-06-03 | 济南大学 | Synthesis method of telmisartan intermediate |
| CN114573513B (en) * | 2022-03-25 | 2023-05-16 | 济南大学 | Synthesis method of telmisartan intermediate |
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