CN108250148B - Refining method of telmisartan key intermediate - Google Patents
Refining method of telmisartan key intermediate Download PDFInfo
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- CN108250148B CN108250148B CN201711469880.7A CN201711469880A CN108250148B CN 108250148 B CN108250148 B CN 108250148B CN 201711469880 A CN201711469880 A CN 201711469880A CN 108250148 B CN108250148 B CN 108250148B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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Abstract
The invention relates to a refining method of a telmisartan key intermediate 2-n-propyl-4-methyl-6-carboxyl benzimidazole, namely a compound (I), which is characterized in that an alcohol and an alkane organic solvent are added into a crude product of the compound (I) in the presence of an inorganic base, the mixture is stirred at a certain temperature, an acidic aqueous solution is added, the pH value is adjusted, the mixture is subjected to suction filtration, and a filter cake is subjected to reduced pressure and vacuum drying to obtain the high-purity compound (I). Compared with the prior art, the method has good refining effect and high yield and purity of refined target products, thereby ensuring the quality of the finished product telmisartan; the solvent used in the refining process is common, which is beneficial to recovery, greatly simplifies the industrial operation and is suitable for industrial mass production.
Description
Technical Field
The invention belongs to the field of chemical engineering and chemical medicine, and particularly relates to a method for refining a telmisartan key intermediate 2-n-propyl-4-methyl-6-carboxybenzimidazole.
Background
Telmisartan, developed by Boehringer Ingelheim, germany, is an angiotensin ii receptor inhibitor for the treatment of hypertension. Because of its obvious antihypertensive effect and good tolerance, it has become one of the most common clinical antihypertensive drugs. It was first marketed in the united states in 2 months 1999 under the trade name Micardis (mecacamin) and subsequently in many countries in germany, uk, etc. Telmisartan, chemically known as 4 '- [ (1, 4' -dimethyl-2 '-propyl [2, 6' -bis-1H-benzimidazole ] -1 '-methyl ] [1, 1' -biphenyl ] -2-carboxylic acid, has the following structural formula:
at present, various synthetic routes of telmisartan exist, wherein the route related to the key intermediate of the invention is to prepare the compound (I), 2-n-propyl-4-methyl-6-carboxyl benzimidazole by one step of cyclization hydrolysis of a compound (VI), 3-methyl-4-methyl aminobenzoate. In the optimization research of telmisartan synthesis process, the pottery fufang et al disclose that 3-methyl-4-methyl aminobenzoate is used as a raw material, and is acylated with n-butyryl chloride in chlorobenzene to generate 3-methyl-4-n-butyrylaminobenzoate, then mixed acid nitration is carried out with fuming nitric acid/sulfuric acid, and 2-n-propyl-4-methyl-6-carboxyl benzimidazole is obtained through hydrogenation reduction, heating cyclization in an acetic acid medium and hydrolysis by sodium hydroxide.
After a plurality of experiments, the compound (I) cannot be obtained in a pure way, and an impurity of a formula (III) is generated at the same time, and the chemical name is as follows: 3-methyl-4-butylamidine benzoic acid is difficult to refine and affects the quality of the telmisartan product, and the structural formula of the impurity in the formula (III) is confirmed as follows:
the 2010 patent of HanseImam (WO2010149360) reported that cheap o-toluidine was used as a starting material and the method comprises n-butyryl chloride acylation, HBr/H2O2System bromination and palladium catalysis introduction of cyano and NaNO3/H2SO4Mixed acid nitration, reduction and ring closing of an iron powder/glacial acetic acid system and hydrolysis reaction of concentrated hydrochloric acid to synthesize the compound (I). The o-toluidine as the starting material of the route is cheap and short, but the method has the defects that the introduction of cyano requires the use of potassium ferrocyanide which is highly toxic, the recovery of a solvent DMF is difficult, and the post-treatment is complicated.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a refining method of telmisartan key intermediate 2-n-propyl-4-methyl-6-carboxybenzimidazole to remove impurities in a formula (III). The specific technical scheme is as follows:
adding an alcohol and alkane organic solvent into a crude compound (I) in the presence of an inorganic base, stirring at the temperature of 10-80 ℃, adding an acidic aqueous solution to adjust the pH, then carrying out suction filtration on the crude compound (I) solution, and carrying out reduced pressure vacuum drying on a filter cake to obtain the high-purity compound (I).
The crude compound (i) of the present invention can be prepared by the prior art, for example, according to the synthetic route of the crude compound (i) disclosed in the above-mentioned taffy et al, "optimization research of telmisartan synthesis process", that is: compound (VI) is hydrolyzed by cyclization to prepare compound (I) in one step, but crude compound (I) contains 10-15 wt% of impurity compound (III). The synthetic route is as follows:
the inorganic alkali is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide monohydrate, sodium carbonate or ammonia water with the mass percent of 18%; preferably 50 percent by mass of sodium hydroxide aqueous solution and 18 percent by mass of ammonia water.
The alcohol organic solvent is methanol or ethanol; the alkane solvent is dichloromethane or trichloromethane, and the preferable organic solvent combination is ethanol/dichloromethane system.
The volume consumption of the organic solvent is 3-20 times of the mass (mL/g) of the compound (I).
The volume usage amount of the organic solvent is preferably 5-10 times of the mass (mL/g) of the compound (I).
The reaction temperature is 10-80 ℃, and the preferable temperature is 30-70 ℃.
The acidic aqueous solution is hydrochloric acid aqueous solution or glacial acetic acid aqueous solution, and preferably the hydrochloric acid aqueous solution with the mass percentage of 18% and the glacial acetic acid aqueous solution with the mass percentage of 75% are selected.
The pH range is 1-8, and the preferable pH range is 6-7.
The process for purifying the compound (I) of the present invention is substantially as follows: adding an alcohol and an alkane organic solvent into the crude product of the compound (I), stirring and dissolving, then adding an inorganic base, heating for reaction, controlling the temperature at 30-70 ℃, slowly dropwise adding an acidic solution, adjusting the pH value to 6-7, carrying out suction filtration to obtain a filter cake, and carrying out vacuum drying on the filter cake at 50 ℃ for 8 hours under reduced pressure to obtain a white solid, namely the high-purity compound (I).
Compared with the prior art, the invention has the advantages that: the refining effect is good, and the yield and the purity of the refined target product are high, so that the quality of the finished product telmisartan is ensured; the solvent used in the refining process is common, which is beneficial to recovery, greatly simplifies the industrial operation and is suitable for industrial mass production.
Detailed Description
The technical solutions of the present invention are described in the following embodiments, but the scope of the present invention is not limited to the following embodiments, and any modifications and/or changes made to the present invention will fall within the scope of the present invention.
Example 1
Adding 20.0g of the crude product of the compound (I) into a 250mL four-mouth reaction bottle, adding 60mL of methanol, stirring for accelerating dissolution, preparing a 50% sodium hydroxide aqueous solution from 3.7g of sodium hydroxide, adding the sodium hydroxide aqueous solution into the reaction bottle, heating to 60 ℃ after the system is clear, slowly dropwise adding an 18% hydrochloric acid aqueous solution, adjusting the pH to 6-7, cooling to 30 ℃ after a large amount of white solids are separated out, stirring for 1-2 h, performing suction filtration, and performing vacuum drying on a filter cake at 50 ℃ under reduced pressure for 8h to obtain 17.3.g of white solids, namely the high-purity compound (I), wherein the purity is 98.0%, and the yield is 86.5%.
Example 2
Adding 20.0g of the crude product of the compound (I) into a 250mL four-mouth reaction bottle, adding 60mL of ethanol, stirring, preparing a 50% sodium hydroxide aqueous solution from 3.7g of sodium hydroxide, adding the sodium hydroxide aqueous solution into the reaction bottle, heating to 60 ℃ after the system is clear, slowly dropwise adding an 18% hydrochloric acid aqueous solution, adjusting the pH to 6-7, cooling to 30 ℃ after a large amount of white solid is separated out, stirring for 1-2 h, performing suction filtration, and performing vacuum drying on a filter cake at 50 ℃ under reduced pressure for 8h to obtain 17.5g of white solid, namely the high-purity compound (I), wherein the purity is 98.2%, and the yield is 87.4%.
Example 3
Adding 20.0g of the crude product of the compound (I) into a 250mL four-mouth reaction bottle, adding 60mL of methanol and 20mL of dichloromethane, stirring, preparing a 50% sodium hydroxide aqueous solution from 3.7g of sodium hydroxide, adding the sodium hydroxide aqueous solution into the reaction bottle, heating to 60 ℃ after the system is clear, slowly dropwise adding an 18% hydrochloric acid aqueous solution, adjusting the pH to 6-7, cooling to 30 ℃ after a large amount of white solid is separated out, stirring for 1-2 h, carrying out suction filtration, and carrying out vacuum drying on a filter cake at 50 ℃ under reduced pressure for 8h to obtain 17.6g of white solid, namely the high-purity compound (I), wherein the purity is 99.3%, and the yield is 88.2%.
Example 4
Adding 20.0g of the crude product of the compound (I) into a 250mL four-mouth reaction bottle, adding 60mL of ethanol and 20mL of dichloromethane, stirring, preparing a 50% sodium hydroxide aqueous solution from 3.7g of sodium hydroxide, adding the sodium hydroxide aqueous solution into the reaction bottle, heating to 60 ℃ after the system is clear, slowly dropwise adding an 18% hydrochloric acid aqueous solution, adjusting the pH to 6-7, cooling to 30 ℃ after a large amount of white solid is separated out, stirring for 1-2 h, carrying out suction filtration, and carrying out vacuum drying on a filter cake at 50 ℃ under reduced pressure for 8h to obtain 18.1g of white solid, namely the high-purity compound (I), wherein the purity is 99.9%, and the yield is 90.2%.
Example 5
Adding 20.0g of the crude product of the compound (I) into a 250mL four-mouth reaction bottle, adding 60mL of ethanol and 20mL of dichloromethane, stirring, slowly dropwise adding 18% ammonia water into the reaction bottle, heating to 60 ℃ after the system is clear, slowly dropwise adding 18% hydrochloric acid aqueous solution, adjusting the pH to 6-7, cooling to 30 ℃ after a large amount of white solid is separated out, stirring for 1-2 h, performing suction filtration, and performing vacuum drying on a filter cake at 50 ℃ under reduced pressure for 8h to obtain 17.9g of white solid, namely the high-purity compound (I), wherein the purity is 99.6% and the yield is 89.3%.
Example 6
Adding 20.0g of the crude product of the compound (I) into a 250mL four-mouth reaction bottle, adding 60mL of ethanol and 20mL of dichloromethane, stirring, slowly dropwise adding 18% ammonia water into the reaction bottle, heating to 60 ℃ after the system is clear, slowly dropwise adding 75% glacial acetic acid aqueous solution, adjusting the pH to 6-7, cooling to 30 ℃ after a large amount of white solid is separated out, stirring for 1-2 h, performing suction filtration, and performing vacuum drying on a filter cake at 50 ℃ under reduced pressure for 8h to obtain 17.5g of white solid, namely the high-purity compound (I), wherein the purity is 17.5% and the yield is 87.2%.
Example 7
Adding 20.0g of the crude product of the compound (I) into a 250mL four-mouth reaction bottle, adding 60mL of ethanol and 20mL of dichloromethane, stirring, preparing 50% aqueous solution from 3.7g of sodium hydroxide, adding the aqueous solution into the reaction bottle, heating to 60 ℃ after the system is clear, slowly dropwise adding 75% glacial acetic acid aqueous solution, adjusting the pH to 6-7, cooling to 30 ℃ after a large amount of white solid is separated out, stirring for 1-2 h, performing suction filtration, and performing vacuum drying on a filter cake at 50 ℃ under reduced pressure for 8h to obtain 17.2g of white solid, namely the high-purity compound (I), wherein the purity is 99.6%, and the yield is 86.1%.
Example 8
Adding 20.0g of the crude product of the compound (I) into a 250mL four-mouth reaction bottle, adding 100mL of ethanol and 20mL of dichloromethane, stirring, slowly dropwise adding 18% ammonia water into the reaction bottle, heating to 60 ℃ after the system is clear, slowly dropwise adding 75% glacial acetic acid aqueous solution, adjusting the pH to 6-7, cooling to 30 ℃ after a large amount of white solid is separated out, stirring for 1-2 h, performing suction filtration, and performing vacuum drying on a filter cake at 50 ℃ under reduced pressure for 8h to obtain 17.1g of white solid, namely the high-purity compound (I), wherein the purity is 99.5% and the yield is 85.2%.
Example 9
Adding 20.0g of the crude product of the compound (I) into a 250mL four-mouth reaction bottle, adding 100mL of methanol and 20mL of dichloromethane, stirring, slowly dropwise adding 18% ammonia water into the reaction bottle, heating to 60 ℃ after the system is clear, slowly dropwise adding 75% glacial acetic acid aqueous solution, adjusting the pH to 6-7, cooling to 30 ℃ after a large amount of white solid is separated out, stirring for 1-2 h, performing suction filtration, and performing vacuum drying on a filter cake at 50 ℃ under reduced pressure for 8h to obtain 17.6g of white solid, namely the high-purity compound (I), wherein the purity is 99.7% and the yield is 88.2%.
Claims (11)
1. A refining method of a telmisartan key intermediate compound (I) is characterized in that an alcohol and alkane organic solvent is added into a crude product of the compound (I) in the presence of an inorganic base, the mixture is stirred and reacted at the temperature of 10-80 ℃, an acidic aqueous solution is added, the pH is adjusted to 1-8, the mixture is subjected to suction filtration, and a filter cake is subjected to reduced pressure vacuum drying to obtain a high-purity compound (I); wherein the volume consumption of the organic solvent is 3-20 times of the mass ml/g of the crude intermediate product; the crude compound (I) contains 10-15 wt% of impurity compound (III);
2. the refining process according to claim 1, wherein the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide monohydrate, sodium carbonate and aqueous ammonia.
3. The refining process according to claim 2, wherein the inorganic base is selected from the group consisting of sodium hydroxide and aqueous ammonia.
4. The refining method according to claim 3, wherein the inorganic base is selected from the group consisting of 50 wt% sodium hydroxide and 10 wt% aqueous ammonia.
5. The purification method according to claim 1, wherein the alcoholic organic solvent is methanol or ethanol; the alkane organic solvent is dichloromethane or trichloromethane.
6. The purification process according to claim 1, wherein the organic solvent of the alcohol type and the alkane type is a mixed solvent of ethanol and methylene chloride.
7. The refining method according to claim 1, wherein the volume usage of the organic solvent is 5 to 10 times of the mass ml/g of the crude intermediate product.
8. The refining process according to claim 1, wherein the temperature is 30 to 70 ℃.
9. The refining method according to claim 1, wherein the acidic aqueous solution is an aqueous hydrochloric acid solution or an aqueous glacial acetic acid solution.
10. The refining method according to claim 9, characterized in that the acidic aqueous solution is an 18 wt% aqueous hydrochloric acid solution or a 75 wt% aqueous glacial acetic acid solution.
11. The purification process according to claim 1, wherein the pH is in the range of 6 to 7.
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| CN201711469880.7A CN108250148B (en) | 2017-12-29 | 2017-12-29 | Refining method of telmisartan key intermediate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006044754A2 (en) * | 2004-10-18 | 2006-04-27 | Dr. Reddy's Laboratories Ltd. | Process for preparing telmisartan |
| WO2012028925A2 (en) * | 2010-09-03 | 2012-03-08 | Ogene Systems (I) Pvt Ltd | An improved process for the preparation of telmisartan |
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- 2017-12-29 CN CN201711469880.7A patent/CN108250148B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006044754A2 (en) * | 2004-10-18 | 2006-04-27 | Dr. Reddy's Laboratories Ltd. | Process for preparing telmisartan |
| WO2012028925A2 (en) * | 2010-09-03 | 2012-03-08 | Ogene Systems (I) Pvt Ltd | An improved process for the preparation of telmisartan |
Non-Patent Citations (2)
| Title |
|---|
| N-苯基-1H-吡咯取代的双苯并咪唑类衍生物的合成及其AT1受体拮抗活性研究;徐进宜等;《中国药科大学学报》;20051231;第36卷(第4期);第296-301页 * |
| 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);第1726-1728页 * |
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