CN112724034A - Synthesis method of telmisartan intermediate - Google Patents
Synthesis method of telmisartan intermediate Download PDFInfo
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- CN112724034A CN112724034A CN202110066047.8A CN202110066047A CN112724034A CN 112724034 A CN112724034 A CN 112724034A CN 202110066047 A CN202110066047 A CN 202110066047A CN 112724034 A CN112724034 A CN 112724034A
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- China
- Prior art keywords
- butyrylamino
- reaction
- methyl
- methyl ester
- nitro
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- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 239000005537 C09CA07 - Telmisartan Substances 0.000 title claims abstract description 7
- 229960005187 telmisartan Drugs 0.000 title claims abstract description 7
- 238000001308 synthesis method Methods 0.000 title claims abstract description 5
- IGCBUUTXGYCQAI-UHFFFAOYSA-N methyl 4-(butanoylamino)-3-methyl-5-nitrobenzoate Chemical compound CCCC(=O)NC1=C(C)C=C(C(=O)OC)C=C1[N+]([O-])=O IGCBUUTXGYCQAI-UHFFFAOYSA-N 0.000 claims abstract description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 15
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 12
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 8
- 238000006722 reduction reaction Methods 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 238000001514 detection method Methods 0.000 claims abstract description 3
- 238000001035 drying Methods 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 239000007858 starting material Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 229960002089 ferrous chloride Drugs 0.000 claims description 3
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 3
- 239000011790 ferrous sulphate Substances 0.000 claims description 3
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 3
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 3
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 claims description 3
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910021519 iron(III) oxide-hydroxide Inorganic materials 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- UITANFWKOFOWHF-UHFFFAOYSA-N methyl 3-amino-4-(butanoylamino)-5-methylbenzoate Chemical compound CCCC(=O)NC1=C(C)C=C(C(=O)OC)C=C1N UITANFWKOFOWHF-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 239000010865 sewage Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 1
- 229960004887 ferric hydroxide Drugs 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A synthesis method of a telmisartan intermediate, belonging to the technical field of medicine synthesis. The preparation method comprises the steps of taking 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester as a starting material, carrying out reduction reaction at the dropping temperature of 40-70 ℃ and the reaction temperature of 40-70 ℃ under the participation of a nitro reducing agent and hydrazine hydrate in an alcohol solvent environment, wherein the nitro reduction reaction is carried out for a period of time until the detection reaction is complete, and filtering and spin-drying after the reaction is complete to obtain the 3-methyl-4-butyrylamino-5-aminobenzoic acid methyl ester; the nitro group is reduced by the method, so that the selectivity of the reducing group is high, the raw materials are easy to obtain, the pollution is low, and the requirement on equipment is low; the method has the advantages of low cost, environmental protection, safety, simple and convenient operation and easy realization of industrial production.
Description
Technical Field
The invention relates to a synthesis method of a telmisartan intermediate, belonging to the technical field of medicine synthesis.
Background
The methyl 3-methyl-4-butyrylamino-5-aminobenzoate is an important intermediate of telmisartan, the intermediate takes methyl 3-methyl-4-butyrylamino-5-nitrobenzoate as an initial raw material, and the current main synthetic route comprises the following steps:
the synthetic route reported in the document J.heterocylic.chem., 40,1107(2003) carries out reduction of nitro in the presence of raney nickel and hydrazine hydrate, and has the advantages of high yield and quick reaction, but raney nickel has strong catalytic activity and is often accompanied with reduction of other groups; the raney nickel is inflammable in an exposed air state, has potential safety hazard and is expensive; nickel belongs to heavy metal, and the heavy metal in the sewage is easy to exceed the standard because the conventional sewage biochemical treatment cannot be carried out.
According to a synthetic route reported in a document J.Zhongguo.Xinyao.Zazhi, 19,1726(2010), hydrogen is introduced under high pressure in the presence of Pd/C to reduce a nitro group, the hydrogen is flammable, the hydrogen can be generally carried out under high pressure, and the requirement on equipment is high; and hydrogenation is a hazardous process.
The above routes all have certain limitations, and bring certain difficulties to the industrial production of telmisartan.
Disclosure of Invention
The invention aims to select a nitro reducing agent which is relatively safe, environment-friendly and easily obtained to reduce 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester under the participation of hydrazine hydrate, and the finally obtained product 3-methyl-4-butyrylamino-5-aminobenzoic acid methyl ester has the purity of not less than 97.0 percent, the yield of not less than 92 percent and the appearance of white crystalline powder.
The technical scheme adopted for achieving the purpose of the invention is as follows: taking 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester as a starting material, carrying out reduction reaction at the dropping temperature of 40-70 ℃ and the reaction temperature of 40-70 ℃ under the participation of a nitro reducing agent and hydrazine hydrate in an alcohol solvent environment, wherein the nitro reduction reaction is carried out for a period of time until the detection reaction is complete, and filtering and spin-drying after the reaction is complete to obtain 3-methyl-4-butyrylamino-5-methyl aminobenzoate; the alcohol is methanol or ethanol or butanol or isopropanol; the nitro reducing agent is one or more of carbon, ferrous sulfate, ferrous chloride or ferric oxyhydroxide; the hydrazine hydrate content is 80%; the mass ratio of the alcohol to the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester is 1: 1-1: 20; the mass ratio of the nitro reducing agent to the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester is 1: 1-1: 10; the mass ratio of hydrazine hydrate to 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester is 1: 1-1: 10.
The invention has the positive effects that: the nitro group is reduced by the method, so that the selectivity of the reducing group is high, the raw materials are easy to obtain, the pollution is low, and the requirement on equipment is low; the method has the advantages of low cost, environmental protection, safety, simple and convenient operation and easy realization of industrial production.
Detailed Description
Chemical reaction formula of the invention
The invention is further illustrated by the following examples, which are not intended to limit the practice of the invention.
Example 1
Adding 5.6g of 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, 100ml of ethanol, 6.8g of ferrous sulfate and 1.7g of activated carbon into a 250ml four-neck flask, heating to 60 ℃, stirring for 30min, slowly dropwise adding 8g of hydrazine hydrate, keeping the temperature for continuously reacting for 6 hours after dropwise adding is completed, detecting that raw materials are completely reacted by TLC, cooling to 40 ℃, filtering, decompressing and evaporating filtrate to dryness to obtain 4.60g of white solid 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, wherein the content is detected by HPLC (high performance liquid chromatography) and the yield is 92.0%.
Example 2
Adding 5.6g of 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, 50ml of methanol, 5.7g of ferrous chloride and 1.7g of activated carbon into a 250ml four-neck flask, heating to 60 ℃, stirring for 30min, slowly dropwise adding 8g of hydrazine hydrate, keeping the temperature for continuously reacting for 6 hours after dropwise adding is completed, detecting that raw materials are completely reacted by TLC, cooling to 40 ℃, filtering, decompressing and evaporating filtrate to dryness to obtain 4.62g of white solid 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, wherein the content is 97.2 percent by HPLC (high performance liquid chromatography), and the yield is 92.4 percent.
Example 3
Adding 5.6g of 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, 50ml of methanol, 4g of ferric hydroxide and 1.7g of activated carbon into a 250ml four-neck flask, heating to 65 ℃, stirring for 30min, slowly dropwise adding 8g of hydrazine hydrate, keeping the temperature for continuously reacting for 6 hours after dropwise adding is completed, detecting that raw materials are completely reacted by TLC (thin layer chromatography), cooling to 40 ℃, filtering, decompressing and evaporating filtrate to dryness to obtain 4.69g of white solid 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester, wherein the content is 98.1% by HPLC (high performance liquid chromatography), and the yield is 93.8%.
Claims (1)
1. A synthesis method of a telmisartan intermediate is characterized by comprising the following steps: taking 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester as a starting material, carrying out reduction reaction at the dropping temperature of 40-70 ℃ and the reaction temperature of 40-70 ℃ under the participation of a nitro reducing agent and hydrazine hydrate in an alcohol solvent environment, wherein the nitro reduction reaction is carried out for a period of time until the detection reaction is complete, and filtering and spin-drying after the reaction is complete to obtain 3-methyl-4-butyrylamino-5-methyl aminobenzoate; the alcohol is methanol or ethanol or butanol or isopropanol; the nitro reducing agent is one or more of carbon, ferrous sulfate, ferrous chloride or ferric oxyhydroxide; the hydrazine hydrate content is 80%; the mass ratio of the alcohol to the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester is 1: 1-1: 20; the mass ratio of the nitro reducing agent to the 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester is 1: 1-1: 10; the mass ratio of hydrazine hydrate to 3-methyl-4-butyrylamino-5-nitrobenzoic acid methyl ester is 1: 1-1: 10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110066047.8A CN112724034A (en) | 2021-01-19 | 2021-01-19 | Synthesis method of telmisartan intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110066047.8A CN112724034A (en) | 2021-01-19 | 2021-01-19 | Synthesis method of telmisartan intermediate |
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| Publication Number | Publication Date |
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| CN112724034A true CN112724034A (en) | 2021-04-30 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202110066047.8A Pending CN112724034A (en) | 2021-01-19 | 2021-01-19 | Synthesis method of telmisartan intermediate |
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| Country | Link |
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| CN (1) | CN112724034A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002193899A (en) * | 2000-12-27 | 2002-07-10 | Nippon Kayaku Co Ltd | Method for producing aminobenzyl alcohols using water as solvent |
| WO2014075403A1 (en) * | 2012-11-16 | 2014-05-22 | 浙江工业大学 | 4-(5-amino-6-hydroxybenzoxazol-2-yl)ammonium benzoate and preparation method and use thereof |
-
2021
- 2021-01-19 CN CN202110066047.8A patent/CN112724034A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002193899A (en) * | 2000-12-27 | 2002-07-10 | Nippon Kayaku Co Ltd | Method for producing aminobenzyl alcohols using water as solvent |
| WO2014075403A1 (en) * | 2012-11-16 | 2014-05-22 | 浙江工业大学 | 4-(5-amino-6-hydroxybenzoxazol-2-yl)ammonium benzoate and preparation method and use thereof |
Non-Patent Citations (2)
| Title |
|---|
| YANG, LC 等: "Facile synthesis of novel nonpeptide angiotensin-II-Receptor antagonists", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
| 陶锋 等: "3-甲基-4-丁酰氨基-5-氨基苯甲酸甲酯的合成", 《江苏化工》 * |
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Application publication date: 20210430 |
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