CN1271068C - Novel method for preparing olmesartan - Google Patents
Novel method for preparing olmesartan Download PDFInfo
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- CN1271068C CN1271068C CNB031159834A CN03115983A CN1271068C CN 1271068 C CN1271068 C CN 1271068C CN B031159834 A CNB031159834 A CN B031159834A CN 03115983 A CN03115983 A CN 03115983A CN 1271068 C CN1271068 C CN 1271068C
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- Prior art keywords
- acid
- formula
- methyl
- phenyl
- alkali
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- 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 present invention discloses a new method for preparing olmesartan. In the present invention, 4, 4-dimethyl-2-propyl-1-{4-[2-(tribenzyl tetrazole-5-radical) phenyl] phenyl} methyl-4, 6-dihydrofuran-[3, 4-d]imidazol-6-one is processed via ring opening so as to obtain a compound B of B, 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tribenzyl tetrazole-5-radical) phenyl] phenyl} methyl imidazol-5-carboxylic acid; under the action of alkali, the compound B condensates with 4-bromo(or chloro)methyl-5-methyl-2-oxo-1, 3-dioxacyclo amylene, and finally, triphenylmethyl protecting groups are removed so as to obtain the purpose products of olmesartan. The olmesartan preparation method of the present invention has the advantages of simple operation, little side reaction, more reasonable method and high yield and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of olmesartan medoxomill.
Background technology
Olmesartan medoxomill is a kind of novel medicine that brings high blood pressure down, and belongs to angiotensin II receptor antagonists, brings into play pressure reduction effect by influencing feritin-Angiotensin-aldosterone system.Its chemical name is: 4-(1-hydroxyl-1-methylethyl)-2-propyl group-1-{4-[2-(tetrazolium-5-yl) phenyl] phenyl } Methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl ester; English name: Olmesartan Medoxomil, CAS accession number: 144689-63-4; Molecular formula: C
29H
30N
6O
6, molecular weight: 558.59, outward appearance: the white powder crystallization, chemical structural formula is as follows:
Day disclosure special permission JP (31) 27098, European patent EP 503785, CN106563A, CN1381453A, Journol of MedicalChemistry, 1996, Vol.39 has reported the preparation method of olmesartan medoxomill on the No:1323-338.Described method is partly to be formed by connecting with biphenyl with the imidazoles part, can produce 4 hydroxyl and biphenyl part etherificates and cause by product on (1-hydroxyl-1-methylethyl) during reaction, and cause poor selectivity, by product is many, follow-up separation difficulty, the defective that yield is lower.
Summary of the invention
The technical problem that the present invention solves is the preparation method who discloses a kind of new olmesartan medoxomill, and is many to overcome the side reaction that prior art exists, severe reaction conditions, operation inconvenience, the defective that yield is lower.
Method of the present invention comprises the steps:
(1) be that compound shown in the formula (I) and pharmacy acceptable salt are hydrolyzed by alkali or acid in solvent with general structure, the acquisition general structure is compound and the pharmacy acceptable salt shown in the formula (II);
Wherein, said alkali preferred alkali metal hydroxide, alkaline carbonate, alkali metal hydrocarbonate.Comprise lithium hydroxide, sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus;
Said acid comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid and phosphoric acid;
The preferred alcohols of said solvent is as methyl alcohol or ethanol; Ethers, as tetrahydrofuran (THF), dioxy six alkane; The sulfoxide class is as methyl-sulphoxide; Amides, as N, dinethylformamide, N, N-diethylformamide, N,N-dimethylacetamide; Ketone is as acetone; Water; Or the mixture of water and one or more above-mentioned organic solvents.
Temperature of reaction can be in the certain width scope, and precise dose is unimportant to this reaction.Usually at-20 ℃～120 ℃, be preferably 0 ℃～100 ℃.Reaction times is as the criterion to react completely, and is generally 30 minutes to 24 hours.
Formula (I) formula (II)
Wherein: R
1Represent propyl group R
2, R
3The difference represent methylidene;
R
4Represent protected tetrazolium-5-base.
The method that compound shown in (I) that is addressed can adopt the contriver to be reported in the Chinese patent 03115940.0 of first to file is prepared, and the preparation method comprises the steps:
Compound shown in the formula (III) is issued living intramolecularly ring-closure reaction in the cyclizing agent effect make the compound shown in the formula (IV), with the compound reaction shown in the formula V, promptly obtain the compound shown in (I) then.
Compound shown in formula (III) and the formula V can adopt document Journol of Medicalchemistry, and 1996, Vol.39, the No:1323-338 disclosed method is prepared, or adopts the commercially available prod.
The cyclizing agent of being addressed comprises mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid for general conventional cyclizing agent; Carbodiimide is as dicyclohexylcarbodiimide; Acid and anhydrides: trifluoracetic acid, trifluoroacetic anhydride (TFAA); And thionyl chloride.
(III)
Wherein: R
1, R
2, R
3Representative: the alkyl of a hydrogen atom or 1-6 carbon atom, R
1, R
2, R
3Can be identical also can be different.
Wherein: R
1, R
2, R
3Definition the same; X represents halogen atom, R
4Represent carboxylic acid, tetrazolium-5-base, cyano group, protected hydroxyl, protected tetrazolium-5-base, formamyl or alkyl-carbamoyl.
(2) formula that step 1 is obtained (II) salt or free acid under the catalysis of alkali in inert solvent with 4-bromine (or chlorine) methyl-5-methyl-2-oxo-1,3-dioxole reaction forms ester;
The alkali preferred alkali metal carbonate of being addressed is as yellow soda ash or salt of wormwood; Alkali metal hydrocarbonate is as sodium bicarbonate or saleratus;
The solvent preferred solvent amides of being addressed, as N, dinethylformamide, N,N-dimethylacetamide, N, N-diethylformamide; Ketone is as acetone; Ethers is as tetrahydrofuran (THF) or dioxy six alkane;
Temperature of reaction can be in the scope of certain width, and precise dose is unimportant to this reaction.Usually at 0-120 ℃, be preferably 20-80 ℃.Under optimum condition, the reaction times only needs 15 minutes to 5 hours usually.
Under the effect of acid, slough protecting group on the tetrazyl then.
The character of acid herein is restriction not, as long as have the general function as protonic acid.Organic acid: as acetate, formic acid, oxalic acid; Mineral acid: example hydrochloric acid, sulfuric acid, phosphoric acid.Be preferably acetate, formic acid, hydrochloric acid, sulfuric acid.
Reaction is preferably carried out having under the solvent condition usually.Reaction solvent does not have particular restriction to the character of solvent for use, as long as reaction or agents useful for same are not had side reaction.Solvent for use can dissolve or dissolve to a certain extent used reagent.The suitable solvent has: water; Organic acid is as acetate; Ketone is as acetone or methyl ethyl ketone; Ethers, as tetrahydrofuran (THF), dioxane; Or the mixture of any two or more these solvents.Wherein, be preferably water, organic acid, alcohol or their mixture.
Temperature of reaction can be in the scope of certain width, and precise dose is unimportant to this reaction.Usually at 0 ℃～120 ℃, be preferably 0 ℃～100 ℃.Under optimum condition, the reaction times only needs 30 minutes to 24 hours usually.Be preferably 1～16 hour.
The reaction expression of step (2) is as follows:
Work as R
1=propyl group, R
2, R
3=methyl, R
4=
The time, be purpose product-olmesartan medoxomill.
Adopt method disclosed by the invention to prepare olmesartan medoxomill, by product is few, the selectivity height, and the reaction conditions gentleness, easy to operate, be convenient to industrializing implementation production.
Embodiment
EXAMPLE l
4-(1-hydroxyl-1-methylethyl)-2-propyl group-1-{4-[2-(trityl tetrazole-5-yl) phenyl] phenyl } Methylimidazole-5-carboxylic acid
Magnetic agitation is being housed, in the 100ml three-necked bottle of oil bath heating, add 3.0 grams 4,4-dimethyl-2-propyl group-1-{4-[2-(trityl tetrazole-5-yl) phenyl] phenyl } methyl-4, the 6-dihydrofuran is [3,4-d] imidazoles-6-ketone (compound (A)) also, 10ml l0% sodium hydroxide solution, 30ml acetone, be warming up to backflow, reacted 10 hours, be chilled to room temperature, transfer pH to neutral with concentrated hydrochloric acid, use ethyl acetate 30ml * 4 to extract again, after organic layer merged, saturated common salt was washed once, anhydrous magnesium sulfate drying, remove desolvate 2.85 gram title compounds.
1H NMR (CDCl
3400MHz): δ 7.4～6.8 (23H, multiplet), 5.38 (2H, singlets), 2.31 (2H, multiplets), 1.3～1.8 (8H, broad peaks), 0.72 (3H, multiplet); MS (Q-Tof micro, ESI
+): 689.30 (M+1), 1377.54 (2M+1)
Embodiment 2
4-(1-hydroxyl-1-methylethyl)-2-propyl group-1-{4-[2-(trityl tetrazole-5-yl) phenyl] phenyl } Methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl ester
Magnetic agitation is being housed, in the 100ml three-necked bottle of oil bath heating, add 2.50 gram 4-(1-hydroxyl-1-methylethyl)-2-propyl group-1-{4-[2-(trityl tetrazole-5-yl) phenyl] phenyl } Methylimidazole-5-carboxylic acid, add 20ml N, dinethylformamide, 0.53 gram salt of wormwood, 0.70 gram 4-brooethyl-5-methyl-2-oxo-1,3-dioxole.In 50 ℃ of reactions 1 hour.Reaction solution is transferred in the separating funnel, adds the 40ml ethyl acetate, 100ml water divides and gets organic layer, and water layer uses ethyl acetate 20ml * 3 to extract again.Organic layer with saturated common salt washing once adds anhydrous magnesium sulfate drying, steam desolventize 2.47 gram title compounds.
1H-NMR (CDCl
3, 400MHz): δ 7.87 (1H, multiplet), 7.60-7.20 (14H, multiplet), (7.12 2H, doublet), 6.98 (5H, doublets), (6.70 1H, doublet), 5.32 (2H, unimodal), (4.73 2H, singlet), 2.60 (2H, multiplets), (1.99 3H, singlet), 1.74 (2H, multiplets), (1.64 6H, singlet), 0.92 (3H, multiplet)
MS(Q-Tof?micro，ESI
+)：243.03，801.07(M+1)EI-MS(M/Z，％)，179(37.38)，244(36.19)，343(27.55)，420(100)，570(35.36)，744(13.00)
Embodiment 3
The preparation of olmesartan medoxomill
4-(1-hydroxyl-1-methylethyl)-2-propyl group-1-{4-[2-(tetrazolium-5-yl) phenyl] phenyl } Methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl ester (olmesartan medoxomill)
Magnetic agitation is being housed, thermometer, in the four-hole boiling flask of oil bath heating, add 1.83 gram 4-(1-hydroxyl-1-methylethyl)-2-propyl group-1-{4-[2-(trityl tetrazole-5-yl) phenyl] phenyl } Methylimidazole-5-carboxylic acid (5-methyl-2-oxo-1, the 3-Dioxol-4-yl) methyl ester, the 20ml75% acetic acid aqueous solution, be warming up to 45 ℃, reacted 6 hours, and be chilled to 5 ℃, suction filtration, filtrate is revolved and is steamed to doing, resistates is through silica gel chromatography, and with 15: 1 methylene dichloride: methanol mixed solution was made eluent, 0.96 gram title compound.Fusing point: 187.0 ℃
1H-NMR (DMSO-d6,400MHz): δ 7.7～7.5 (4H, multiplet), 7.05 (2H, doublet) 6.88 (2H, doublets), 5.42 (2H, singlet), 5.05 (2H, singlets), 2.60 (2H, triplet), 2.07 (3H, singlets), (1.59 2H, sextet), 1.48 (6H, singlet), 0.87 (3H, triplet)
MS(Q-Tof?micro，ESI
+)：559.09(M+1)，581.06(M+Na)597.01(M+K)
Claims (5)
1. the preparation method of an olmesartan medoxomill is characterized in that comprising the steps:
With general structure is that compound shown in the formula (I) and pharmacy acceptable salt thereof are hydrolyzed by alkali or acid in solvent, and the acquisition general structure is compound and the pharmacy acceptable salt thereof shown in the formula (II);
Formula (I) formula (II)
Wherein: R
1Represent propyl group, R
2, R
3The difference represent methylidene;
R
4Represent protected tetrazolium-5-base;
General structure is compound and the pharmacy acceptable salt thereof shown in the formula (II); by known method elder generation and 4-brooethyl-5-methyl-2-oxo-1; 3-dioxole or 4-chloromethyl-5-methyl-2-oxo-1; the 3-dioxole becomes ester, sloughs protecting group again and obtains olmesartan medoxomill.
2. method according to claim 1 is characterized in that, the alkali that hydrolysis is adopted is alkali metal hydroxide, alkaline carbonate or alkali metal hydrocarbonate.
3. method according to claim 2 is characterized in that the alkali of being addressed comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus.
4. method according to claim 1 is characterized in that the acid of being addressed comprises hydrochloric acid, Hydrogen bromide, hydroiodic acid HI or sulfuric acid.
5. method according to claim 1 is characterized in that, said solvent comprises a kind of or water in alcohols, ethers, ketone or the water and the mixture of one or more organic solvents of addressing.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031159834A CN1271068C (en) | 2003-03-25 | 2003-03-25 | Novel method for preparing olmesartan |
| PCT/CN2004/000200 WO2004085428A1 (en) | 2003-03-25 | 2004-03-12 | A new process for preparing olmesartan medoxomil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031159834A CN1271068C (en) | 2003-03-25 | 2003-03-25 | Novel method for preparing olmesartan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1532195A CN1532195A (en) | 2004-09-29 |
| CN1271068C true CN1271068C (en) | 2006-08-23 |
Family
ID=33035139
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB031159834A Expired - Fee Related CN1271068C (en) | 2003-03-25 | 2003-03-25 | Novel method for preparing olmesartan |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1271068C (en) |
| WO (1) | WO2004085428A1 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006029056A1 (en) | 2004-09-02 | 2006-03-16 | Teva Pharmaceutical Industries Ltd. | Preparation of olmesartan medoxomil |
| WO2007017135A2 (en) | 2005-07-29 | 2007-02-15 | Krka | Process for the preparation of olmesartan medoxomil |
| US8048904B2 (en) * | 2006-06-19 | 2011-11-01 | Matrix Laboratories Ltd. | Process for the preparation of olmesartan medoxomil |
| EP2074116A2 (en) | 2006-10-09 | 2009-07-01 | Cipla Limited | Process for preparing trityl olmesartan medoxomil and olmesartan medoxomil |
| KR101400653B1 (en) * | 2006-10-25 | 2014-05-27 | 다이이찌 산쿄 가부시키가이샤 | Packaging material |
| WO2008058402A1 (en) * | 2006-11-17 | 2008-05-22 | Queen's University At Kingston | Compounds and methods for treating protein folding disorders |
| JP5395908B2 (en) * | 2008-11-17 | 2014-01-22 | 浙江海正薬業股▲ふん▼有限公司 | Process for producing 4- (1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid ester |
| CN104583185A (en) | 2012-08-31 | 2015-04-29 | 株式会社Api | Method for producing biaryl compound |
| CN104662008B (en) | 2012-09-26 | 2017-03-08 | 株式会社Api | The deprotection method of tetrazole compound |
| CN103044407A (en) * | 2012-12-20 | 2013-04-17 | 安徽悦康凯悦制药有限公司 | Preparation method of olmesartan ester |
| CN105418593A (en) * | 2015-11-25 | 2016-03-23 | 蚌埠丰原涂山制药有限公司 | Preparation method of key intermediate of olmesartan medoxomil and olmesartan medoxomil |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0753489A (en) * | 1993-06-11 | 1995-02-28 | Sankyo Co Ltd | Production of biphenylcarboxamide |
| JP3671266B2 (en) * | 1996-03-21 | 2005-07-13 | 東洋化成工業株式会社 | Process for producing 5-substituted tetrazoles |
| CN1164587C (en) * | 2002-05-17 | 2004-09-01 | 浙江省医学科学院 | Process for preparing Aomeishatan |
| CN1197866C (en) * | 2003-03-21 | 2005-04-20 | 上海医药工业研究院 | 4,6-dihydrofuran [3,4-d] imidazole-6- ketone derivative and salt and preparation method thereof |
-
2003
- 2003-03-25 CN CNB031159834A patent/CN1271068C/en not_active Expired - Fee Related
-
2004
- 2004-03-12 WO PCT/CN2004/000200 patent/WO2004085428A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| CN1532195A (en) | 2004-09-29 |
| WO2004085428A1 (en) | 2004-10-07 |
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