CN102079747A - Olmesartan medoxomil key intermediate, synthesis method thereof and method for synthesizing olmesartan medoxomil from same - Google Patents
Olmesartan medoxomil key intermediate, synthesis method thereof and method for synthesizing olmesartan medoxomil from same Download PDFInfo
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- CN102079747A CN102079747A CN 201010583290 CN201010583290A CN102079747A CN 102079747 A CN102079747 A CN 102079747A CN 201010583290 CN201010583290 CN 201010583290 CN 201010583290 A CN201010583290 A CN 201010583290A CN 102079747 A CN102079747 A CN 102079747A
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- 0 CCCc1nc(C(C)(C)*)c(C(OCC(O2)=C(C)[U]C2=O)=O)[n]1Cc1ccc(C(C=CC=C2)N[C@]2C(N)=NN=N)cc1 Chemical compound CCCc1nc(C(C)(C)*)c(C(OCC(O2)=C(C)[U]C2=O)=O)[n]1Cc1ccc(C(C=CC=C2)N[C@]2C(N)=NN=N)cc1 0.000 description 1
Abstract
The invention discloses an olmesartan medoxomil key intermediate, wherein the structural formula is shown as (III). The invention also discloses a synthesis method of the olmesartan medoxomil key intermediate and a method for synthesizing olmesartan medoxomil from the same. The invention has the advantages of simple and convenient operation method, fewer side effects, more reasonable method and high yield and is suitable for industrial production.
Description
Technical field
The invention belongs to chemosynthesis technical field, the method that is specifically related to olmesartan medoxomill key intermediate and synthetic method thereof and synthesizes olmesartan medoxomill by this intermediate.
Background technology
Olmesartan medoxomill is by Japan three company (Sankyo) exploitation altogether, 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 is that the 7th of drugs approved by FDA listing is used for the treatment of hypertensive angiotensin-ii receptor AT
1Antagonist (ARB), it obviously is being better than other like products aspect reduction diastolic pressure general curative effect.In May, 2002 is with trade(brand)name Benicar
TMIn U.S. listing, olmesartan medoxomill is a kind of imidazoles of replacement, August in the same year in Germany granted and at the beginning of 10 months with Olinetec
TMListing.Shown in its structural formula:
About synthesizing of olmesartan medoxomill having carried out big quantity research both at home and abroad; mostly be partly to be formed by connecting with biphenyl with the imidazoles part; imidazoles partly adopts 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid, ethyl ester; be connected with biphenyl posthydrolysis trip provide corresponding free acid again with 4-chloromethyl-5-methyl isophthalic acid; 3-dioxole-2-ketone esterization; take off trityl as protecting group at last and get olmesartan medoxomill; or imidazoles part elder generation and 4-chloromethyl-5-methyl isophthalic acid; 3-dioxole-2-ketone esterization, be connected with biphenyl again olmesartan medoxomill.No matter use the intermediate by-products of which kind of method gained many, the isomer that produces during with the biphenyl condensation is difficult to purifying, and document adopts the method for column chromatography more, has increased industrial difficulty.Shanghai Institute of Pharmaceutical Industry (CN15321195) has reported a kind of new Olmesartan intermediate 4,4-dimethyl-2-propyl group-4,6-dihydrofuran also [3,4-d] imidazoles-6-ketone, effectively reduced the generation of isomer when this intermediate and biphenyl condensation, improved the condensation productive rate, for Olmesartan synthetic provides good selection, but this intermediate is still so that original 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid, ethyl ester is a starting raw material, and synthetic route is longer, has further increased the industrialization difficulty.
Summary of the invention
Technical problem to be solved by this invention provides a kind of olmesartan medoxomill key intermediate, few by the synthetic olmesartan medoxomill side reaction of this intermediate, be easy to separate, the yield height.
The technical problem that the present invention also will solve provides the synthetic method of above-mentioned olmesartan medoxomill key intermediate.
The technical problem that the present invention will solve at last provides the method by the synthetic olmesartan medoxomill of above-mentioned intermediate.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of olmesartan medoxomill key intermediate, chemical name are 4, and 4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-hydroxyl also, and structural formula is shown in (III);
The synthetic method of above-mentioned olmesartan medoxomill key intermediate generates 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-formaldehyde (II) with 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-cyanogen (I) reduction reaction; Compound 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-formaldehyde (II) changes olmesartan medoxomill key intermediate 4 immediately in system, 4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-hydroxyl (III) also.
Wherein, described reduction reaction is diisobutyl aluminium hydride reduction, Raney's nickel/acidic solution reduction or stephen reduction.Above-mentioned reduction reaction is for well known to a person skilled in the art reduction reaction.Specifically, the diisobutyl aluminium hydride reduction is a reductive agent with the diisobutyl aluminium hydride, and the mole dosage of diisobutyl aluminium hydride is the equivalent of 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-cyanogen (I) molar weight or omits many.Raney's nickel/acidic solution is reduced in the presence of formic acid, adds the Raney's nickel (4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-cyanogen (I) quality about 10%) of catalytic amount, is aldehyde with cyano reduction in the presence of hydrogen.Stephen is reduced to that cyano group changes imine intermediate in the presence of tindichloride, hydrochloric acid, obtains aldehyde after the hydrolysis.Preferred herein Stephen reduction.
Wherein, the temperature of charge of above-mentioned reaction is 0～100 ℃, and preferred temperature is a normal temperature; Described solvent is water, alcohol or ether solvent, is preferably alcoholic solvent.Reaction times is approximately 0.5～2 hour till transforming fully with raw material.
By the method for the synthetic olmesartan medoxomill of above-mentioned olmesartan medoxomill key intermediate, this method comprises the steps:
(1) the olmesartan medoxomill key intermediate 4,4-dimethyl-2-propyl group-4,6-dihydrofuran also [3,4-d] imidazoles-6-hydroxyl (III) under the alkali effect with 4 '-methyl diphenyl-2-nitrile (IV) prepared in reaction 1-(2 '-cyanobiphenyl-4-yl) methyl-4 of replacing, 4-dimethyl-2-propyl group-4, the 6-dihydrofuran is [3,4-d] imidazoles-6-hydroxyl (V) also;
Among the formula IV, X is halogen, trifluoromethane sulfonic acid base, methylsulphonic acid base or tosic acid base.
(2) 1-(2 '-cyanobiphenyl-4-yl) methyl-4,4-dimethyl-2-propyl group-4,6-dihydrofuran also [3,4-d] imidazoles-6-hydroxyl (V) hydrolysis under the acidic conditions in solvent, obtain 1-(2 '-cyanobiphenyl-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-formaldehyde (VI);
(3) 1-(2 '-cyanobiphenyl-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-formaldehyde (VI) is oxidized to 1-(2 '-cyanobiphenyl-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid (VII) under the oxygenant effect;
(4) 1-(2 '-cyanobiphenyl-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid (VII) and 4-chloromethyl-5-methyl-2-oxo-1, the 3-dioxole carries out esterification, then carries out the cyano group ring-closure reaction and obtains olmesartan medoxomill.
In the step (1), described alkali is organic bases, alkaline carbonate (as salt of wormwood, yellow soda ash), alkali metal hydrocarbonate (as sodium bicarbonate), alkalimetal hydride (as sodium hydride, potassium hydride KH) or alkali metal alcoholates (as sodium methylate, sodium ethylate, sodium tert-butoxide).Preferred as alkali hydride, most preferably sodium hydride.
In the step (1), olmesartan medoxomill key intermediate 4,4-dimethyl-2-propyl group-4,6-dihydrofuran also the reaction mol ratio of the methyl diphenyl of [3,4-d] imidazoles-6-hydroxyl (III) and 4 '-replacement-2-nitrile (IV) are 1: 1.
In the step (1), described solvent is water, ethers (for example tetrahydrofuran (THF), dioxane) or other non-proton property polar solvents (for example dimethyl sulfoxide (DMSO), acetone, second eyeball, N, N ' dimethyl formamide, N, N '-N,N-DIMETHYLACETAMIDE, hexamethylphosphoramide), can be preferably acetonitrile for above-mentioned two or more mixes according to any proportioning.The temperature of reaction can be in certain width, and precise dose is to reacting unimportant.Usually at-20～120 ℃, be preferably 0～100 ℃, the reaction times is as the criterion to react completely, and is generally 30 minutes to 24 hours.
In the step (2), described acid is hydrochloric acid or sulfuric acid, and the adding quality of acid is 1-(2 '-cyanobiphenyl-4-yl) methyl-4, and 4-dimethyl-2-propyl group-4,6-dihydrofuran be 1～10 times of [3,4-d] imidazoles-6-hydroxyl (V) quality also, is preferably 4 times.
In the step (2), the temperature of reaction is 0～100 ℃, preferred normal temperature; Described solvent is water, alcohol or ether solvent, is preferably water; Reaction times in reaction times is as the criterion to react completely, and is generally 1 hour to 24 hours.
In the step (3), described oxygenant is air, oxygen, hydrogen peroxide, nitric acid, manganese oxygenant (as potassium permanganate, Manganse Dioxide etc.), chromium oxygenant (as dichromate, chromium trioxide etc.) or halogen (as chlorine, bromine, hypohalous acid, hypohalite), preferred manganese oxygenant, most preferably potassium permanganate.
In the step (3), be reflected in the solvent and carry out, temperature of reaction is 0～100 ℃, preferred room temperature; Described solvent is water, alcohol or ether solvent, is preferably water; Reaction times in reaction times is as the criterion to react completely, and is generally 30 minutes to 24 hours.
In the step (4), compound (VII) and 4-chloromethyl-5-methyl-2-oxo-1, the 3-dioxole carries out esterification, then carry out the cyano group ring-closure reaction and obtain olmesartan medoxomill, for well known to a person skilled in the art technology, change compound (VII) into salt or direct and 4-chloromethyl-5-methyl-2-oxo-1, the 3-dioxole carries out esterification, and carboxylate carries out the cyano group cyclization again and becomes the tetrazole reaction to obtain olmesartan medoxomill.
Beneficial effect: by the synthetic Olmesartan of olmesartan medoxomill key intermediate of the present invention, easy and simple to handle, side reaction is few, and method is more reasonable, and the yield height is fit to industrial production.
Embodiment
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand that the described concrete material proportion of embodiment, processing condition and result thereof only are used to illustrate the present invention, and should also can not limit the present invention described in detail in claims.
Embodiment 1:4,4-dimethyl-2-propyl group-4,6-dihydrofuran be the preparation of [3,4-d] imidazoles-6-hydroxyl (III) also.
Anhydrous tindichloride (0.03mol), ether (100mL) place the condenser of being furnished with calcium chloride tube and the there-necked flask of mechanical stirrer, feed the exsiccant hydrogen chloride gas, slowly mix liquid until the solid completely dissolve.Stop logical hydrogenchloride, (2.9g 0.015mol) splashes into also vigorous stirring 1h fast with 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-cyanogen (I).Leave standstill mixed solution and fully separate until solid-liquid, supernatant liquid is inclined to, residuum adds entry (80ml) with ether (30ml * 2) washing in the remaining solid, and sodium bicarbonate transfers pH to neutral.With mixture distillation, stop distillation during the about 50ml of overhead product volume, distillate extracts with ether (30ml * 2), and anhydrous sodium sulfate drying filters the back evaporated under reduced pressure, get oily product 4,4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-hydroxyl (III) also, yield 75%, detect parameters is as follows:
1H NMR (300MHz, CDCl
3+ D
2O) δ ppm:0.95～1.03 (3H, t,
CH 3 CH
2CH
2), 1.64～1.76 (6H, s, 2 CH
3), 1.83～1.95 (2H, m, CH
3 CH 2 CH
2), 2.35～2.55 (2H, m, CH
3CH
2 CH 2 ).
MS(FAB，m/z)：195(M
++1)。
Embodiment 2:4,4-dimethyl-2-propyl group-4,6-dihydrofuran be the preparation of [3,4-d] imidazoles-6-hydroxyl (III) also.
(2.9g 0.015mol) is dissolved in the 30ml anhydrous methylene chloride N with 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-cyanogen (I)
2Protection slowly drips DIBAL-H (0.015mol) down under the normal temperature condition, 30min adds.Solution is flavescence slightly, keeps this temperature 2h, and TLC is to there not being raw material.Drip saturated ammonium chloride solution (20ml) under the room temperature, this moment, solution slowly became muddy, added and continued to stir 0.5 hour, add ethyl acetate (30ml) then and continue to stir 1 hour, tell organic layer, water layer extracts with ethyl acetate (20ml * 2), merge organic layer, anhydrous magnesium sulfate drying filters, decompression screws out organic solvent and gets pale yellow oily liquid body product 4,4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-hydroxyl (III) also, yield 70%, detect parameters is as follows:
1H NMR (300MHz, CDCl
3+ D
2O) δ ppm:0.95～1.03 (3H, t,
CH 3 CH
2CH
2), 1.64～1.76 (6H, s, 2 CH
3), 1.83～1.95 (2H, m, CH
3 CH 2 CH
2), 2.35～2.55 (2H, m, CH
3CH
2 CH 2 ).
MS(FAB，m/z)：195(M
++1)。
Embodiment 3:4,4-dimethyl-2-propyl group-4,6-dihydrofuran be the preparation of [3,4-d] imidazoles-6-hydroxyl (III) also.
With 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-cyanogen (I) (2.9g 0.015mol) is dissolved in the 50ml dehydrated alcohol, adds Raney's nickel 0.3g, drips 1ml formic acid, normal temperature and pressure down with hydrogen reaction till do not have a hydrogen absorption.Reaction is finished, filters, and the dense dried oily product 4 of filtrate, 4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-hydroxyl (III) also, yield 79%, detect parameters is as follows:
1H NMR (300MHz, CDCl
3+ D
2O) δ ppm:0.95～1.03 (3H, t,
CH 3 CH
2CH
2), 1.64～1.76 (6H, s, 2 CH
3), 1.83～1.95 (2H, m, CH
3 CH 2 CH
2), 2.35～2.55 (2H, m, CH
3CH
2 CH 2 ).
MS(FAB，m/z)：195(M
++1)。
Embodiment 4:1-(2 '-cyanobiphenyl-4-yl) methyl-4,4-dimethyl-2-propyl group-4,6-dihydrofuran be the preparation of [3,4-d] imidazoles-6-hydroxyl (V) also.
4,4-dimethyl-2-propyl group-4,6-dihydrofuran also [3,4-d] imidazoles-6-hydroxyl (III) (0.1mol) is dissolved in the anhydrous acetonitrile (50ml), normal temperature adds sodium hydride (0.11mol) down and 4 '-bromomethylbiphenyl-2-nitrile (IV) (0.1mol), make system be warming up to 60 ℃ gradually, keep stirring reaction 2h under this temperature, filter, filter cake washs with acetonitrile (20ml), remove solvent under reduced pressure, residuum is dissolved in ethyl acetate (60ml), and water (20 * 2) is washed anhydrous magnesium sulfate drying, filter, remove solvent under reduced pressure.Get faint yellow oily product 1-(2 '-cyanobiphenyl-4-yl) methyl-4,4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-hydroxyl (V) also, yield 78%, and detect parameters is as follows:
1H NMR (300MHz, CDCl
3+ D
2O) δ ppm:0.90～0.98 (3H, t,
CH 3 CH
2CH
2), 1.52～1.63 (6H, s, 2 CH
3), 1.68～1.87 (2H, m, CH
3 CH 2 CH
2), 2.14～2.35 (2H, m, CH
3CH
2 CH 2 ), 5.24 (H, s,
CH-OH), 7.15～7.73 (8H, m, 7 H on the phenyl ring).
MS(FAB，m/z)：375(M
++1)。
The preparation of embodiment 5:1-(2 '-cyanobiphenyl-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid (VII).
1-(2 '-cyanobiphenyl-4-yl) methyl-4,4-dimethyl-2-propyl group-4,6-dihydrofuran also [3,4-d] imidazoles-6-hydroxyl (V) (0.1mol) spends the night with 2N hydrochloric acid (200ml) normal-temperature reaction, and TLC detects raw material and disappears, need not to separate, system is cooled to room temperature, adds potassium permanganate (0.1mol), room temperature reaction 5h, TLC follows the tracks of reaction and finishes, and ethyl acetate (50ml * 3) is extracted.Merge organic layer, anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure and gets faint yellow oily product (VII).Yield 85%, detect parameters is as follows:
1H NMR (300MHz, CDCl
3+ D
2O) δ ppm:0.95～1.02 (3H, t,
CH 3 CH
2CH
2), 1.59～1.65 (6H, s, 2 CH
3), 1.70～1.83 (2H, m, CH
3 CH 2 CH
2), 2.19～2.31 (2H, m, CH
3CH
2 CH 2 ), 7.20～7.81 (8H, m, 7 H on the phenyl ring).
MS(FAB，m/z)：390(M
++1)。
The preparation of embodiment 6:1-(2 '-cyanobiphenyl-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid (VII).
1-(2 '-cyanobiphenyl-4-yl) methyl-4,4-dimethyl-2-propyl group-4,6-dihydrofuran also [3,4-d] imidazoles-6-hydroxyl (V) (0.1mol) with 50 ℃ of 2N hydrochloric acid (200ml) reaction 9h, TLC detects raw material and disappears, and is cooled to room temperature, revolves to add 30%H after excessive hydrochloric acid is removed in steaming
2O
2(0.5mol), room temperature reaction spends the night, and TLC follows the tracks of reaction and finishes, and revolves steaming to half, adds to wait water gaging, ethyl acetate (50ml * 3) extraction.Merge organic layer, anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure and gets faint yellow oily product (VII).Yield 80%, detect parameters is as follows:
1H NMR (300MHz, CDCl
3+ D
2O) δ ppm:0.95～1.02 (3H, t,
CH 3 CH
2CH
2), 1.59～1.65 (6H, s, 2 CH
3), 1.70～1.83 (2H, m, CH
3 CH 2 CH
2), 2.19～2.31 (2H, m, CH
3CH
2 CH 2 ), 7.20～7.81 (8H, m, 7 H on the phenyl ring).
MS(FAB，m/z)：390(M
++1)。
The preparation of embodiment 7:1-(2 '-cyanobiphenyl-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid (VII).
1-(2 '-cyanobiphenyl-4-yl) methyl-4,4-dimethyl-2-propyl group-4, the 6-dihydrofuran also [3,4-d] imidazoles-6-hydroxyl (V) (0.1mol) with 2N hydrochloric acid (200ml) back flow reaction 5h, TLC detects raw material and disappears, need not to separate, system is cooled to room temperature, adds sodium dichromate 99 (0.12mol), room temperature reaction 5h, TLC follows the tracks of reaction and finishes, and ethyl acetate (50ml * 3) is extracted.Merge organic layer, anhydrous magnesium sulfate drying filters, and removes solvent under reduced pressure and gets faint yellow oily product (VII).Yield 82%., detect parameters is as follows:
1H NMR (300MHz, CDCl
3+ D
2O) δ ppm:0.95～1.02 (3H, t,
CH 3 CH
2CH
2), 1.59～1.65 (6H, s, 2 CH
3), 1.70～1.83 (2H, m, CH
3 CH 2 CH
2), 2.19～2.31 (2H, m, CH
3CH
2 CH 2 ), 7.20～7.81 (8H, m, 7 H on the phenyl ring).
MS(FAB，m/z)：390(M
++1)。
Embodiment 8: the preparation of olmesartan medoxomill.
Compound (VII) (0.01mol) is dissolved in the 60ml N,N-dimethylacetamide, adds 6.08g (0.04mol) salt of wormwood.Get 4-chloromethyl-5-methyl isophthalic acid, 3-dioxane penta-2-ketone (12g) is dissolved in the 25ml N,N-dimethylacetamide, and is added drop-wise in the top solution, and mixture stirred 3 hours down at 50 ℃.Add ethyl acetate (50ml) and water (50ml) in mixture, tell ethyl acetate layer, vacuum concentration gets solid, and this solid is dissolved in dimethylbenzene (60ml), adds NaN
3(0.01mol) and triethylamine hydrochloride (0.01mol).Back flow reaction to raw material disappears, and is cooled to room temperature, adds water (100ml), tell organic layer, water layer is about 5 with 50% acetic acid modulation pH under the ice bath, adds ethyl acetate (50ml * 3) and extracts, anhydrous magnesium sulfate drying filters, and screws out solvent and gets off-white color solid product olmesartan medoxomill.Yield 82%, detect parameters is as follows:
1HNMR (300MHz, CDCl
3+ D
2O) δ ppm:0.85 (3H, t,
CH 3 CH
2CH
2), 1.50 (6H, s, 2 methyl), 1.61 (2H, m, CH
3 CH 2 CH
2), 2.14 (3H, s, CH
3), 2.73 (2H, t, CH
3CH
2 CH 2 ), 5.13 (2H, s, CH2), 7.15～7.72 (8H, m, H on the phenyl ring).
MS(FAB，m/z)：545(M
++1)。
Claims (11)
1. olmesartan medoxomill key intermediate, chemical name is 4, and 4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-hydroxyl also, and structural formula is shown in (III);
2. the synthetic method of the described olmesartan medoxomill key intermediate of claim 1 is characterized in that 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-cyanogen (I) reduction reaction is generated 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-formaldehyde (II); 4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-formaldehyde (II) changes olmesartan medoxomill key intermediate 4 immediately in system, 4-dimethyl-2-propyl group-4,6-dihydrofuran be [3,4-d] imidazoles-6-hydroxyl (III) also.
3. the synthetic method of olmesartan medoxomill key intermediate according to claim 2 is characterized in that described reduction reaction is diisobutyl aluminium hydride reduction, Raney's nickel/acidic solution reduction or stephen reduction.
4. according to the synthetic method of any described olmesartan medoxomill key intermediate in the claim 2～3, it is characterized in that being reflected in the solvent and carry out, temperature of charge is 0～100 ℃; Described solvent is water, ethers or alcoholic solvent.
5. by the method for the synthetic olmesartan medoxomill of the described olmesartan medoxomill key intermediate of claim 1, it is characterized in that this method comprises the steps:
(1) the olmesartan medoxomill key intermediate 4,4-dimethyl-2-propyl group-4,6-dihydrofuran also [3,4-d] imidazoles-6-hydroxyl (III) under the alkali effect with 4 '-methyl diphenyl-2-nitrile (IV) of replacing carries out condensation reaction and prepares 1-(2 '-cyanobiphenyl-4-yl) methyl-4,4-dimethyl-2-propyl group-4, the 6-dihydrofuran is [3,4-d] imidazoles-6-hydroxyl (V) also;
Among the formula IV, X is halogen, trifluoromethane sulfonic acid base, methylsulphonic acid base or tosic acid base.
(2) 1-(2 '-cyanobiphenyl-4-yl) methyl-4,4-dimethyl-2-propyl group-4,6-dihydrofuran also [3,4-d] imidazoles-6-hydroxyl (V) hydrolysis under the acidic conditions in solvent, obtain 1-(2 '-cyanobiphenyl-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-formaldehyde (VI);
(3) 1-(2 '-cyanobiphenyl-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-formaldehyde (VI) is oxidized to compound 1-(2 '-cyanobiphenyl-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid (VII) under the oxygenant effect;
(4) compound 1-(2 '-cyanobiphenyl-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5-carboxylic acid (VII) and 4-chloromethyl-5-methyl-2-oxo-1, the 3-dioxole carries out esterification, and the cyano group cyclization becomes tetrazole to obtain olmesartan medoxomill then.
6. the method by the synthetic olmesartan medoxomill of olmesartan medoxomill key intermediate according to claim 5 is characterized in that in the step (1), described alkali is organic bases, alkaline carbonate, alkali metal hydrocarbonate, alkalimetal hydride or alkali metal alcoholates.
7. according to claim 5 or 6 described methods by the synthetic olmesartan medoxomill of olmesartan medoxomill key intermediate, it is characterized in that being reflected in the organic solvent and carrying out in the step (1), temperature of reaction is-20～120 ℃; Described organic solvent is acetonitrile, N, dinethylformamide or N,N-dimethylacetamide.
8. the method by the synthetic olmesartan medoxomill of olmesartan medoxomill key intermediate according to claim 5 is characterized in that in the step (2), described acid is hydrochloric acid or sulfuric acid.
9. according to claim 5 or 8 described methods by the synthetic olmesartan medoxomill of olmesartan medoxomill key intermediate, it is characterized in that being reflected in the organic solvent and carrying out in the step (2), temperature of reaction is 0～100 ℃; Described solvent is water, alcoholic solvent, nitrile solvents or ether solvent.
10. the method by the synthetic olmesartan medoxomill of olmesartan medoxomill key intermediate according to claim 5 is characterized in that in the step (3) that described oxygenant is air, oxygen, hydrogen peroxide, nitric acid, manganese oxygenant, chromium oxygenant or halogen.
11., it is characterized in that in the step (3), temperature of reaction is 0～100 ℃ according to claim 5 or 10 described methods by the synthetic olmesartan medoxomill of olmesartan medoxomill key intermediate; Described solvent is water, alcoholic solvent or ether solvent.
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| WO2004083213A1 (en) * | 2003-03-21 | 2004-09-30 | Shanghai Institute Of Pharmaceutical Industry | 4,6-dihydrofuro[3,4-d]imidazole-6-one derivatives and their salts and process for the preparation of the same |
| CN101311168A (en) * | 2007-05-21 | 2008-11-26 | 上海医药工业研究院 | Method for preparing 4-(1-hydroxyl-1-methyl ethyl)-2-propyl glyoxaline-5-carboxylic ether |
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| WO2004083213A1 (en) * | 2003-03-21 | 2004-09-30 | Shanghai Institute Of Pharmaceutical Industry | 4,6-dihydrofuro[3,4-d]imidazole-6-one derivatives and their salts and process for the preparation of the same |
| CN101311168A (en) * | 2007-05-21 | 2008-11-26 | 上海医药工业研究院 | Method for preparing 4-(1-hydroxyl-1-methyl ethyl)-2-propyl glyoxaline-5-carboxylic ether |
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| 《化学与生物工程》 20051231 徐彩丽等 奥美沙坦酯的研究进展 第7-8页 1-10 , 第4期 2 * |
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