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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- 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 45
- 239000005537 C09CA07 - Telmisartan Substances 0.000 title claims abstract description 23
- 229960005187 telmisartan Drugs 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000005406 washing Methods 0.000 claims abstract description 16
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 238000006482 condensation reaction Methods 0.000 claims abstract description 10
- ILXRSCZVHSZGCS-UHFFFAOYSA-N 4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propyl-1h-benzimidazole Chemical compound C1=CC=C2N(C)C(C3=CC(C)=C4N=C(NC4=C3)CCC)=NC2=C1 ILXRSCZVHSZGCS-UHFFFAOYSA-N 0.000 claims abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- 238000010992 reflux Methods 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 19
- 238000010438 heat treatment Methods 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 238000000967 suction filtration Methods 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- YHXCWNQNVMAENQ-UHFFFAOYSA-N tert-butyl 2-[4-(bromomethyl)phenyl]benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1C1=CC=C(CBr)C=C1 YHXCWNQNVMAENQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 150000004703 alkoxides Chemical class 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 abstract description 10
- 239000002253 acid Substances 0.000 abstract description 4
- 239000002351 wastewater Substances 0.000 abstract description 4
- QQHZAARABFGGBY-UHFFFAOYSA-N 2-[4-(bromomethyl)phenyl]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=C(CBr)C=C1 QQHZAARABFGGBY-UHFFFAOYSA-N 0.000 abstract description 3
- 230000002378 acidificating effect Effects 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 238000000638 solvent extraction Methods 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 39
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- HJCCZIABCSDUPE-UHFFFAOYSA-N methyl 2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]methyl]phenyl]benzoate 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)OC HJCCZIABCSDUPE-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- SCQUWJNTFMIYAV-UHFFFAOYSA-N ethyl 2-[4-(bromomethyl)phenyl]benzoate Chemical compound CCOC(=O)C1=CC=CC=C1C1=CC=C(CBr)C=C1 SCQUWJNTFMIYAV-UHFFFAOYSA-N 0.000 description 2
- RMXGTMRDXKUUDJ-UHFFFAOYSA-N methyl 2-[4-(bromomethyl)phenyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1C1=CC=C(CBr)C=C1 RMXGTMRDXKUUDJ-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000029219 regulation of pH Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- -1 telmisartan ester Chemical class 0.000 description 1
- JSCFLEBEWCTASN-UHFFFAOYSA-N tert-butyl 2-[4-[[4-methyl-6-(1-methylbenzimidazol-2-yl)-2-propylbenzimidazol-1-yl]methyl]phenyl]benzoate Chemical group CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(=O)OC(C)(C)C JSCFLEBEWCTASN-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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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| 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 |
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| 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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