CN102079747B - 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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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, be specifically related to olmesartan medoxomill key intermediate and compound method thereof and reach method by the synthetic olmesartan medoxomill of this midbody.
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 to treat hypertensive angiotensin-ii receptor AT
1Antagonist (ARB), it obviously is being superior to 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 substituted imidazoles, 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 earlier with 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 OLM-Mod midbody 4; 4-dimethyl--2-propyl group-4,6-dihydrofuran-be [3,4-d] imidazoles-6-ketone also; Effectively reduced the generation of isomer when this midbody and biphenyl condensation; Improved the condensation productive rate, for the synthetic of OLM-Mod provides good selection, but this midbody 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 industriallization 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 midbody, be easy to separate, yield is high.
The technical problem that the present invention also will solve provides the compound 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 midbody.
For solving the problems of the technologies described above, the technical scheme that the present invention adopts is following:
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 compound 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, in the presence of hydrogen, is aldehyde with cyano reduction.Stephen is reduced to that cyanic acid changes imine intermediate in the presence of tindichloride, hydrochloric acid, obtains aldehyde after the hydrolysis.Preferred here 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; The 6-dihydrofuran-also [3,4-d] imidazoles-6-hydroxyl (III) under the alkali effect with 4 '-substituted methyl diphenyl-2-nitrile (IV) prepared in reaction 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 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 cyanic acid ring-closure reaction and obtains olmesartan medoxomill.
In the step (1), described alkali is organic bases, alkaline carbonate (like salt of wormwood, yellow soda ash), alkali metal hydrocarbonate (like sodium hydrogencarbonate), alkalimetal hydride (like sodium hydride, potassium hydride KH) or alkali metal alcoholates (like sodium methylate, sodium ethylate, sodium tert-butoxide).Preferred as alkali hydrogenate, 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 [3,4-d] imidazoles-6-hydroxyl (III) and 4 '-substituted methyl diphenyl-2-nitrile (IV) are 1: 1.
In the step (1); Said solvent is water, ethers (for example THF, dioxane) or other aprotic polar solvents (for example DMSO 99.8MIN., acetone, second eyeball, N; N ' dimethyl formamide, N; N '-N,N-DIMETHYLACETAMIDE, hexamethylphosphoramide), can mix according to any proportioning for above-mentioned two or more, be preferably acetonitrile.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, ydrogen peroxide 50, nitric acid, manganese oxygenant (like potassium permanganate, Manganse Dioxide etc.), chromium oxygenant (like dichromate, chromium trioxide etc.) or halogen (like 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 carries out the cyanic acid ring-closure reaction and obtains 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 cyanic acid cyclization again and becomes the tetrazole reaction to obtain olmesartan medoxomill.
Beneficial effect: by the synthetic OLM-Mod of olmesartan medoxomill key intermediate of the present invention, easy and simple to handle, side reaction is few, and method is more reasonable, and yield is high, is fit to industrial production.
Embodiment
According to following embodiment, can understand the present invention better.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 explain the present invention, and the present invention that should also can not limit in claims to be described in detail.
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 condensing surface 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 hydrogencarbonate transfers pH to neutral.With mixture distillation, stop distillation during the about 50ml of overhead product volume, distillate extracts with ether (30ml * 2); Anhydrous sodium sulfate drying filters the back evaporated under reduced pressure, gets 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 following:
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, added ETHYLE ACETATE (30ml) then and continued to stir 1 hour; Tell organic layer, water layer extracts with ETHYLE ACETATE (20ml * 2), merges organic layer, anhydrous magnesium sulfate drying; Filter, decompression screws out organic solvent and gets pale yellow oily liquid body product 4,4-dimethyl--2-propyl group-4,6-dihydrofuran-also [3; 4-d] imidazoles-6-hydroxyl (III), yield 70%, detect parameters is following:
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 absolute ethyl 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 filtrating, 4-dimethyl--2-propyl group-4,6-dihydrofuran-be [3,4-d] imidazoles-6-hydroxyl (III) also, yield 79%, detect parameters is following:
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) are dissolved in the anhydrous acetonitrile (50ml); Normal temperature adds sodium hydride (0.11mol) and 4 '-bromomethylbiphenyl-2-nitrile (IV) (0.1mol) down, makes system be warming up to 60 ℃ gradually, keeps stirring reaction 2h under this temperature, filters; Filter cake removes solvent under reduced pressure with acetonitrile (20ml) washing, and residuum is dissolved in ETHYLE ACETATE (60ml), and water (20 * 2) is washed; Anhydrous magnesium sulfate drying filters, and removes 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 following:
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, and 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 ETHYLE ACETATE (50ml * 3) extracts.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 following:
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 and steams to half the, adds and waits water gaging, ETHYLE 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 following:
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-4,6-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, and 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 ETHYLE ACETATE (50ml * 3) extracts.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 following:
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 DMAC N,N, 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 DMAC N,N, and is added drop-wise in the top solution, and mixture stirred 3 hours down at 50 ℃.In mixture, add ETHYLE ACETATE (50ml) and water (50ml), tell ethyl acetate layer, vacuum concentration gets solid, and this solid is dissolved in YLENE (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, the acetic acid modulation pH of water layer use 50% under the ice bath is about 5, adds ETHYLE 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 following:
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 (2)
1. the compound method of an olmesartan medoxomill key intermediate 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-ketone (III) also;
Wherein, described olmesartan medoxomill key intermediate, chemical name are 4, and 4-dimethyl--2-propyl group-4,6-dihydrofuran-be [3,4-d] imidazoles-6-ketone also, and structural formula is shown in (III);
Wherein, described reduction reaction is diisobutyl aluminium hydride reduction, Raney's nickel/acidic solution reduction or stephen reduction.
2. the compound method of olmesartan medoxomill key intermediate according to claim 1 is characterized in that being reflected in the solvent and carries out, and temperature of charge is 0～100 ℃; Described solvent is water, ethers or alcoholic solvent.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
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| 徐彩丽等.奥美沙坦酯的研究进展.《化学与生物工程》.2005,(第4期),第7-8页. * |
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