CN106008356B - Preparation method of telmisartan - Google Patents
Preparation method of telmisartan Download PDFInfo
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- CN106008356B CN106008356B CN201610400485.2A CN201610400485A CN106008356B CN 106008356 B CN106008356 B CN 106008356B CN 201610400485 A CN201610400485 A CN 201610400485A CN 106008356 B CN106008356 B CN 106008356B
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- organic solvent
- telmisartan
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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
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides an improved telmisartan preparation method, which comprises the following steps: the telmisartan is obtained by carrying out condensation reaction on 2-n-propyl-4-methyl-6- (1 '-methylbenzimidazole-2-yl) benzimidazole and 4' -bromomethyl biphenyl-2-carboxylic ester under alkaline conditions and hydrolyzing under acidic conditions. The invention cancels the process of organic solvent extraction and water washing after the condensation reaction is finished; and after hydrolysis, the pH is directly adjusted by adding alkali into the organic solvent containing water to separate out telmisartan, so that the operation is simplified, the yield is improved, and the use of the organic solvent and acid and alkali and the discharge of waste water are reduced.
Description
Technical Field
The invention relates to a preparation method of telmisartan which is a blood pressure lowering drug.
Background
Telmisartan, a novel antihypertensive drug for the treatment of essential hypertension, is chemically named 4'- { [1,4' -dimethyl-2 '-propyl (2, 6' -bi-1 h-benzoimidazol) -1 '-yl ] methyl } - [1,1' -biphenyl ] -2-carboxylic acid, having the structural formula shown in formula I:
telmisartan can be prepared into an intermediate telmisartan ester (compound IV) through condensation reaction under the action of alkali by using 2-n-propyl-4-methyl-6- (1 '-methylbenzimidazole-2-yl) benzimidazole (compound II) and 4' -bromomethyl biphenyl-2-carboxylic acid alkyl ester (compound III) as raw materials; and hydrolyzing the ester group of the compound IV under strong acid or strong alkaline conditions to obtain telmisartan.
The synthetic route is as follows:
in compounds III and IV, R = Me, et or t-Bu
CN1344712A reports that after the condensation reaction is completed, an organic solvent immiscible with water and a large amount of water are added for extraction and water washing to remove inorganic salts as byproducts. This operation produces a waste water containing a large amount of organic solvent. In the step of ester group hydrolysis, if acid hydrolysis is used, after the hydrolysis is completed, a large amount of alkali is generally added to adjust the solution to be alkaline, then the solution is adjusted to be weakly acidic, and crystallization is performed to obtain the product. The use amount of alkali is large, and more high-salinity wastewater can be generated. The yield of the whole process is 75-85%.
Disclosure of Invention
The invention aims to provide a simple, environment-friendly and low-cost telmisartan preparation method, which comprises the following steps:
(1) 2-n-propyl-4-methyl-6- (1 '-methylbenzimidazole-2-yl) benzimidazole and 4' -bromomethylbiphenyl-2-carboxylic acid ester are subjected to condensation reaction in a first organic solvent in the presence of a base;
the base is selected from: carbonates, alkali metal hydroxides, alkoxides and phosphates;
the 4' -bromomethylbiphenyl-2-carboxylic acid ester is selected from: 4' -bromomethylbiphenyl-2-carboxylic acid methyl ester, 4' -bromomethylbiphenyl-2-carboxylic acid ethyl ester and 4' -bromomethylbiphenyl-2-carboxylic acid tert-butyl ester;
(2) After the condensation reaction is completed, distilling to remove the first organic solvent;
(3) Adding a second organic solvent and hydrochloric acid into the distillation substrate in the step (2) to perform hydrolysis reaction;
(4) After the hydrolysis reaction is finished, distilling to remove the second organic solvent;
(5) Adding a third organic solvent and a certain amount of water, heating to reflux, slowly dripping alkali, adjusting the pH value to 5-6, and crystallizing; wherein the amount of water required to be added is 1/5-1/50, preferably 1/10 of the amount of the third organic solvent;
(6) And (5) carrying out suction filtration, washing and drying.
As a preferable scheme:
the first organic solvent is a polar solvent, preferably DMF, THF, acetone, preferably DMF.
The alkali in the step (1) is preferably Na 2 CO 3 、K 2 CO 3 、Cs 2 CO 3 、NaOH、KOH、LiOH、Ba(OH) 2 Sodium methoxide, potassium tert-butoxide and Na 3 PO 4 、Na 2 HPO 4 、K 3 PO 4 Or K 2 HPO 4 Further, naOH is preferable.
The second organic solvent is preferably acetic acid; the hydrolysis reaction condition is preferably 100-110 ℃ for 6h.
The third organic solvent is preferably methanol, ethanol or isopropanol, and more preferably ethanol.
The base in step (5) is preferably 17% (w.t%) aqueous ammonia.
The process improvement of the invention comprises:
1. and (3) eliminating organic solvent extraction and water washing:
after the condensation reaction is finished, the materials are not subjected to extraction and water washing, and hydrochloric acid is directly used for ester group hydrolysis; distilling the acid solution after the reaction is finished, adding a small amount of water into the organic solvent which is mutually soluble with water, and then adjusting the pH value; inorganic salts generated by the condensation reaction are dissolved in water and enter the mother liquor.
2. Because telmisartan is insoluble in water, a proper amount of water is added to play a role in improving the yield.
Directly adjusting the pH value in place:
when the pH adjustment is started, the pH value of the system is about 0-2, and the material is solid. When the pH value is adjusted to be between 3.8 and 4.4, the materials are dissolved and cleaned. The alkali is continuously added, and the material is separated out again along with the rising of the pH value. Adjusting the pH value to 5-6, and crystallizing to obtain the product.
The method simplifies the pH regulation process by eliminating the operation of extraction and washing, reduces the use of organic solvents and acid and alkali, simultaneously reduces the discharge of waste water, can recycle all the used organic solvents, has high yield, and has remarkable economic benefit and environmental protection benefit.
Detailed Description
Example 1
100mL of DMF, compound II (16.25g, 0.05mol) and NaOH (2.56g, 0.06mol) were charged into a 250mL four-necked flask, and the temperature was lowered to 0 to 10 ℃ to slowly add methyl 4' -bromomethylbiphenyl-2-carboxylate (16.23g, 0.05mol). After the feeding is finished, the temperature is kept between 0 and 10 ℃ for reaction for 5 hours. And (3) detecting the reaction liquid, wherein the purity (HPLC) of the telmisartan methyl ester is as follows: 98.42%, compound II residual (HPLC): 0.15%, other max monohetero (HPLC): 0.34 percent. Controlling the temperature to be 50-80 ℃, and distilling under reduced pressure with the vacuum degree being more than or equal to 0.08Mpa to remove DMF.
Adding 32.5g of acetic acid and 12.2g of refined hydrochloric acid, heating to 100-110 ℃ and reacting for 6h. Controlling the temperature to be 70-100 ℃, and distilling under reduced pressure with the vacuum degree being more than or equal to 0.08Mpa to remove the acetic acid.
Adding 162.5g of ethanol and 16.3g of water (1/10 of the amount of the organic solvent), heating to reflux, slowly adding 17% (w.t%) of ammonia water, adjusting the pH to 5.5, keeping the temperature and refluxing for 2 hours, cooling to 25 ℃, crystallizing for 2 hours, performing suction filtration, washing with a small amount of ethanol, controlling the temperature to be 70-90 ℃, and drying for 20-22 hours under the vacuum degree of more than or equal to 0.06 Mpa. Obtaining telmisartan 26.55g, yield 96.7%, purity (HPLC): 99.95%, compound II residue (HPLC): N.D; telmisartan methyl ester residue (HPLC): n.d, other max monohetero (HPLC): 0.02 percent.
Example 2
The hydrolysis was carried out as in example 1 and the acetic acid was distilled off.
Adding 162.5g of methanol and 32.5g of water (1/5 of the amount of the organic solvent), heating to reflux, slowly adding 17 percent (w.t percent) of ammonia water, adjusting the pH to 5, keeping the temperature and refluxing for 2 hours, cooling to 25 ℃, crystallizing for 2 hours, performing suction filtration, washing with a small amount of methanol, controlling the temperature to be 70-90 ℃, and drying for 20-22 hours under the vacuum degree of more than or equal to 0.06 MPa. Obtaining 21.69g of telmisartan, the yield is 79.0%, and the purity (HPLC): 99.13%, compound II residue (HPLC): n.d, telmisartan methyl ester residue (HPLC): 0.24%, other max monohetero (HPLC): 0.33 percent.
Example 3
The hydrolysis was carried out as in example 1 and the acetic acid was distilled off.
Adding 162.5g of ethanol and 32.5g of water (1/5 of the amount of the organic solvent), heating to reflux, slowly adding 17% (w.t%) of ammonia water, adjusting the pH to 5, keeping the temperature and refluxing for 2 hours, cooling to 25 ℃, crystallizing for 2 hours, performing suction filtration, washing with a small amount of ethanol, controlling the temperature to be 70-90 ℃, and drying for 20-22 hours under the vacuum degree of more than or equal to 0.06 Mpa. Obtaining telmisartan 26.02g, yield 94.8%, purity (HPLC): 99.79%, compound II residual (HPLC): n.d telmisartan methyl ester residue (HPLC): 0.13%, other max monohetero (HPLC): 0.05 percent.
Example 4
The hydrolysis was carried out as in example 1 and the acetic acid was distilled off.
Adding 162.5g of isopropanol and 32.5g of water (1/5 of the dosage of the organic solvent), heating to reflux, slowly adding 17% (w.t%) of ammonia water, adjusting the pH to 5, keeping the temperature and refluxing for 2 hours, cooling to 25 ℃, crystallizing for 2 hours, performing suction filtration, washing with a small amount of isopropanol, controlling the temperature to be 70-90 ℃, and drying for 20-22 hours under the vacuum degree of more than or equal to 0.06 Mpa. Obtaining telmisartan 26.16g, yield 95.3%, purity (HPLC): 95.95%, compound II residual (HPLC): n.d, telmisartan methyl ester residue (HPLC): 1.42%, other max monohetero (HPLC): 1.02 percent.
Example 5
The hydrolysis was carried out as in example 1 and the acetic acid was distilled off.
Adding 162.5g of ethanol and 8.1g of water (1/20 of the amount of the organic solvent), heating to reflux, slowly adding 17 percent (w.t percent) of ammonia water, adjusting the pH to 5, keeping the temperature and refluxing for 2 hours, cooling to 25 ℃, crystallizing for 2 hours, performing suction filtration, washing with a small amount of ethanol, controlling the temperature to be 70-90 ℃, and drying for 20-22 hours under the vacuum degree of more than or equal to 0.06 MPa. Obtaining telmisartan 24.79g, yield 90.3%, purity (HPLC): 99.85%, compound II residue (HPLC): n.d, telmisartan methyl ester residue (HPLC): 0.07%, other max monohetero (HPLC): 0.03 percent.
Example 6
The hydrolysis was carried out as in example 1 and the acetic acid was distilled off.
Adding 162.5g of ethanol and 3.3g of water (1/50 of the amount of the organic solvent), heating to reflux, slowly adding 17% (w.t%) of ammonia water, adjusting the pH to 5, keeping the temperature and refluxing for 2 hours, cooling to 25 ℃, crystallizing for 2 hours, performing suction filtration, washing with a small amount of ethanol, controlling the temperature to be 70-90 ℃, and drying for 20-22 hours under the vacuum degree of more than or equal to 0.06 Mpa. Telmisartan 23.75g was obtained in 86.5% yield and purity (HPLC): 99.90%, compound II residual (HPLC): n.d, telmisartan methyl ester residue (HPLC): 0.02%, other max monohetero (HPLC): 0.05 percent.
Example 7
The hydrolysis was carried out as in example 1 and the acetic acid was distilled off.
Adding 162.5g of ethanol and 16.3g of water (1/10 of the amount of the organic solvent), heating to reflux, slowly adding 17% (w.t%) of ammonia water, adjusting the pH to 6.0, keeping the temperature and refluxing for 2 hours, cooling to 25 ℃, crystallizing for 2 hours, performing suction filtration, washing with a small amount of ethanol, controlling the temperature to be 70-90 ℃, and drying for 20-22 hours under the vacuum degree of more than or equal to 0.06 Mpa. Telmisartan is obtained in 25.67g, yield 93.5% and purity (HPLC): 99.65%, compound II residue (HPLC): n.d, telmisartan methyl ester residue (HPLC): 0.13%, other max monohetero (HPLC): 0.10 percent.
Example 8
100mL of DMF, compound II (16.25g, 0.05mol) and NaOH (2.56g, 0.06mol) were charged into a 250mL four-necked flask, and the flask was cooled to 0 to 10 ℃ and then ethyl 4' -bromomethylbiphenyl-2-carboxylate (16.98g, 0.05mol) was slowly added thereto. After the feeding is finished, the temperature is kept between 0 and 10 ℃ for reaction for 5 hours. Controlling the temperature to be 50-80 ℃, and distilling under reduced pressure with the vacuum degree being more than or equal to 0.08Mpa to remove DMF.
Adding 32.5g of acetic acid and 12.2g of refined hydrochloric acid, heating to 100-110 ℃ and reacting for 6h. Controlling the temperature to be 70-100 ℃, and removing the acetic acid by vacuum distillation under the vacuum degree of more than or equal to 0.08 Mpa.
Adding 162.5g of ethanol and 16.3g of water, heating to reflux, slowly adding 17% (w.t%) of ammonia water, adjusting the pH value to 5.5, keeping the temperature and refluxing for 2h, cooling to 25 ℃, crystallizing for 2h, performing suction filtration, washing with a small amount of ethanol, and drying for 20-22 h at the temperature of 70-90 ℃ and the vacuum degree of more than or equal to 0.06 MPa. Telmisartan is obtained in 25.09g, yield 91.4% and purity (HPLC): 99.80%, compound II residue (HPLC): 0.02%, telmisartan ethyl ester residue (HPLC): n.d, other max monohetero (HPLC): 0.04 percent.
Example 9
100mL of DMF, compound II (16.25g, 0.05mol) and NaOH (2.56g, 0.06mol) were charged into a 250mL four-necked flask, and the temperature was lowered to 0 to 10 ℃ to slowly add tert-butyl 4' -bromomethylbiphenyl-2-carboxylate (18.47g, 0.05mol). After the feeding is finished, the temperature is kept between 0 and 10 ℃ for reaction for 5 hours. Controlling the temperature to be 50-80 ℃, and distilling under reduced pressure with the vacuum degree being more than or equal to 0.08Mpa to remove DMF.
Adding 32.5g of acetic acid and 12.2g of refined hydrochloric acid, heating to 100-110 ℃ and reacting for 6h. Controlling the temperature to be 70-100 ℃, and removing the acetic acid by vacuum distillation under the vacuum degree of more than or equal to 0.08 Mpa.
Adding 162.5g of ethanol and 16.3g of water (1/10 of the amount of the organic solvent), heating to reflux, slowly adding 17 percent (w.t percent) of ammonia water, adjusting the pH to 5.5, keeping the temperature to reflux for 2 hours, cooling to 25 ℃, crystallizing for 2 hours, performing suction filtration, washing with a small amount of ethanol, drying at 70-90 ℃ under the vacuum degree of more than or equal to 0.06MPa for 20-22 hours. Telmisartan was obtained in 26.16g, yield 95.3%, purity (HPLC): 99.97%, compound II residue (HPLC): n.d, telmisartan tert-butyl ester residue (HPLC): 0.01%, other max monohetero (HPLC): 0.01 percent.
Claims (8)
1. A preparation method of telmisartan is characterized by comprising the following steps:
(1) 2-n-propyl-4-methyl-6- (1 '-methylbenzimidazole-2-yl) benzimidazole and 4' -bromomethylbiphenyl-2-carboxylic acid tert-butyl ester are subjected to condensation reaction in a first organic solvent in the presence of alkali;
the base is selected from: carbonates, alkali metal hydroxides, alkoxides and phosphates;
(2) After the condensation reaction is finished, distilling to remove the first organic solvent;
(3) Adding a second organic solvent and hydrochloric acid into the distillation substrate in the step (2) to perform hydrolysis reaction;
(4) After the hydrolysis reaction is finished, distilling to remove the second organic solvent;
(5) Adding a third organic solvent and a certain amount of water, heating to reflux, slowly dripping alkali, adjusting the pH value to 5-6, and crystallizing; wherein the amount of water needed to be added is 1/5 to 1/10 of the amount of the third organic solvent;
the third solvent is ethanol;
(6) And (5) carrying out suction filtration, washing and drying.
2. The method of claim 1, wherein the first organic solvent is a polar solvent.
3. The process according to claim 2, the polar solvent is selected from DMF, THF, acetone.
4. The process of claim 1, step (1) the base is selected from Na 2 CO 3 、K 2 CO 3 、Cs 2 CO 3 、NaOH、KOH、LiOH、Ba(OH) 2 Sodium methoxide, potassium tert-butoxide and Na 3 PO 4 、Na 2 HPO 4 、K 3 PO 4 、K 2 HPO 4 。
5. The method of claim 4, wherein the base is NaOH.
6. The method of claim 1, wherein the second organic solvent is acetic acid.
7. The method of claim 1, wherein the base of step (5) is 17% (w.t%) ammonia.
8. The method according to claim 1, wherein the amount of water to be added in the step (5) is 1/10 of the amount of the third organic solvent.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005108375A1 (en) * | 2004-05-11 | 2005-11-17 | Cipla Limited | Process for the preparation of telmisartan |
| CN101550107A (en) * | 2009-04-02 | 2009-10-07 | 宁波经济技术开发区九胜创新医药工艺开发有限公司 | Method for preparing telmisartan |
| US20100197924A1 (en) * | 2008-12-22 | 2010-08-05 | Millennium Pharmaceuticals, Inc. | Preparation of aminotetralin compounds |
| CN102267949A (en) * | 2011-06-14 | 2011-12-07 | 张长利 | New process for telmisartan preparation |
| WO2012028925A2 (en) * | 2010-09-03 | 2012-03-08 | Ogene Systems (I) Pvt Ltd | An improved process for the preparation of telmisartan |
| CN103319414A (en) * | 2013-07-01 | 2013-09-25 | 北京理工大学 | Improved telmisartan preparation process |
-
2016
- 2016-06-07 CN CN201610400485.2A patent/CN106008356B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005108375A1 (en) * | 2004-05-11 | 2005-11-17 | Cipla Limited | Process for the preparation of telmisartan |
| US20100197924A1 (en) * | 2008-12-22 | 2010-08-05 | Millennium Pharmaceuticals, Inc. | Preparation of aminotetralin compounds |
| CN101550107A (en) * | 2009-04-02 | 2009-10-07 | 宁波经济技术开发区九胜创新医药工艺开发有限公司 | Method for preparing telmisartan |
| WO2012028925A2 (en) * | 2010-09-03 | 2012-03-08 | Ogene Systems (I) Pvt Ltd | An improved process for the preparation of telmisartan |
| CN102267949A (en) * | 2011-06-14 | 2011-12-07 | 张长利 | New process for telmisartan preparation |
| CN103319414A (en) * | 2013-07-01 | 2013-09-25 | 北京理工大学 | Improved telmisartan preparation process |
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