CN104016974A - Azilsartan medoxomil intermediates and synthetic methods thereof, as well as synthetic method of azilsartan medoxomil - Google Patents
Azilsartan medoxomil intermediates and synthetic methods thereof, as well as synthetic method of azilsartan medoxomil Download PDFInfo
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- CN104016974A CN104016974A CN201410288572.4A CN201410288572A CN104016974A CN 104016974 A CN104016974 A CN 104016974A CN 201410288572 A CN201410288572 A CN 201410288572A CN 104016974 A CN104016974 A CN 104016974A
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- 0 CC(C)(C)OC(*1C(c2ccccc2-c2ccc(C)cc2)=**C1=O)=* Chemical compound CC(C)(C)OC(*1C(c2ccccc2-c2ccc(C)cc2)=**C1=O)=* 0.000 description 2
- QJFSABGVXDWMIW-UHFFFAOYSA-N CCOc1nc2cccc(C(OCC(O3)=C(C)OC3=O)=O)c2[n]1Cc(cc1)ccc1-c1ccccc1C(N1)=NOC1=O Chemical compound CCOc1nc2cccc(C(OCC(O3)=C(C)OC3=O)=O)c2[n]1Cc(cc1)ccc1-c1ccccc1C(N1)=NOC1=O QJFSABGVXDWMIW-UHFFFAOYSA-N 0.000 description 2
- JEQSUJXHFAXJOW-UHFFFAOYSA-N CC(O1)=C(CO)OC1=O Chemical compound CC(O1)=C(CO)OC1=O JEQSUJXHFAXJOW-UHFFFAOYSA-N 0.000 description 1
- AYDULPUPDJBDDP-JGVFFNPUSA-N CCCCC[C@H](C)[C@H](N)NCl Chemical compound CCCCC[C@H](C)[C@H](N)NCl AYDULPUPDJBDDP-JGVFFNPUSA-N 0.000 description 1
- KGSXMPPBFPAXLY-UHFFFAOYSA-N CCOc1nc2cccc(C(O)=O)c2[n]1Cc(cc1)ccc1-c1ccccc1C(N1)=NOC1=O Chemical compound CCOc1nc2cccc(C(O)=O)c2[n]1Cc(cc1)ccc1-c1ccccc1C(N1)=NOC1=O KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D271/07—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention provides three kinds of azilsartan medoxomil intermediates and synthetic methods thereof. The azilsartan medoxomil intermediates are as shown in formulae 8, 9 and 11, and prepared according to the scheme as shown in the specification. The invention also provides a synthetic method of azilsartan medoxomil, wherein the synthetic method is as shown in the specification. The invention provides three types of azilsartan medoxomil intermediates, and expands the research field of important azilsartan medoxomil intermediates; a compound shown in the formula 11 is adopted and subjected to hydrolysis, condensation and deprotection so as to obtain a final product azilsartan medoxomil; compared with the prior art, the synthetic method has the advantages that the utilization of expensive 4-hydroxymethyl-5-methyl-1,3-dioxo hetercyclopentene-2-ketone is avoided, so that the production cost can be greatly reduced; in the production process of the azilsartan medoxomil intermediates disclosed by the invention, the purity of the intermediates can achieve over 98%, and can meet market demands, and the yields of the compound as shown in the formula 11 to a final product azilsartan medoxomil are high, and is up to 68-75%; the purity of obtained final products azilsartan medoxomil reaches 99.0-99.5%.
Description
Technical field
The present invention relates to the field of chemical synthesis, be specifically related to the synthetic method of Azilsartan intermediate and synthetic method thereof, Azilsartan.
Background technology
Azilsartan, its English name is Azilsartan medoxomil (trade(brand)name: EDARBI), its chemical name is 2-oxyethyl group-1-{[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl }-1H-benzoglyoxaline-7-carboxylic acid (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl ester, CAS863031-21-4, its chemical structural formula is as follows:
Azilsartan is a prodrug.It is Japanese Takeda Pharmaceutical Company Limited research and develop be used for the treatment of hypertensive Angiotensin Ⅱ receptor antagonist (FDA approval on February 25th, 2011 is in U.S.'s listing).This medicine can be used alone or uses together with other Altace Ramipril, is considered the next-generation of Candesartan.Under equal oral metered, efficacy of antihypertensive treatment is better than olmesartan medoxomill.
Wu Tian company discloses the synthetic method of Azilsartan acid (formula 2 compounds) in patent US05243054: 2-[(2 '-cyanobiphenyl base-4-methyl) amino]-3-nitrobenzene methyl (A1) hydrazine hydrate reduction nitro under Ferric Chloride obtains O-phenylene diamine derivatives A2, under acetic acid catalysis, obtain benzimidizole derivatives A3 with ethyl orthocarbonate cyclization, under sodium methylate exists, reaction obtains A4 with oxammonium hydrochloride, triethylamine exists lower Vinyl chloroformate acidylate hydroxyl to obtain A5, in dimethylbenzene, reflux and slough the methyl esters (formula 3 compounds) that a part ethanol obtains Azilsartan, in LiOH water/methanol solution, be hydrolyzed to obtain Azilsartan acid.
Wu Tian company also discloses the another kind of synthetic method of Azilsartan acid: 2-[(2 '-carbamyl xenyl-4-methyl in patent US05243054) amino]-3-nitrobenzene methyl (B1) obtains O-phenylene diamine derivatives B2 with sodium borohydride reduction nitro, under acetic acid catalysis, obtain benzimidizole derivatives B3 with ethyl orthocarbonate cyclization, react and obtain B4 with Tetrafluoroboric acid triethyl, 2, 6 lutidine exist lower Vinyl chloroformate acidylate imino-to obtain B5, under existing, sodium methylate reacts with oxammonium hydrochloride the methyl esters that obtains Azilsartan, in NaOH water/methanol solution, be hydrolyzed to obtain Azilsartan acid.
Wu Tian company also discloses the another kind of synthetic method of Azilsartan acid in patent US05243054: under triethylamine exists, reaction obtains C1 to compd A 2 with oxammonium hydrochloride; triethylamine exists lower Vinyl chloroformate acidylate hydroxyl to obtain C2; under acetic acid catalysis, obtain benzimidizole derivatives C3 with ethyl orthocarbonate cyclization; under DBU or salt of wormwood existence, in ethyl acetate, reflux; obtain the methyl esters of Azilsartan, in the NaOH aqueous solution, be hydrolyzed to obtain Azilsartan acid.
Wu Tian company also discloses the another kind of synthetic method of Azilsartan acid in patent US05243054: under sodium methylate exists, reaction obtains formula 5 compounds to 2 '-cyano group-4-methyl diphenyl with oxammonium hydrochloride, in benzene, reflux and obtain 5-trichloromethyl-4 with trifluoroacetic anhydride, 5-dihydro-1,2,4-oxadiazole derivative D1, NBS/AIBN benzyl bromide obtains D2, the methyl esters that obtains Azilsartan under sodium methylate exists with the condensation of 2-oxyethyl group benzo imidazoles-7-carboxylate methyl ester, in NaOH water/dioxane solution, hydrolysis obtains Azilsartan acid.
Wu Tian company discloses the synthetic method of Azilsartan in patent US7157584:
A) Azilsartan acid is reacted and is generated mixed acid anhydride under alkali exists with acylating agent (pivaloyl chloride, Tosyl chloride, Benzoyl chloride etc.); then with 4-methylol-5-methyl isophthalic acid, 3-dioxole-2-ketone carries out esterification and obtains Azilsartan under alkali exists.
B) Azilsartan acid is reacted and is generated acyl chlorides under catalyzer exists such as DMF with thionyl chloride or oxalyl chloride, then makes this acyl chlorides and 4-methylol-5-methyl isophthalic acid, and 3-dioxole-2-ketone carries out esterification and obtains Azilsartan under alkali exists.
C) Azilsartan acid and 4-chloromethyl-5-methyl isophthalic acid, 3-dioxole-2-ketone (or corresponding bromo, iodo thing) reaction under alkali exists obtains Azilsartan to carry out esterification.
D) Azilsartan acid and 4-methylol-5-methyl isophthalic acid, 3-dioxole-2-ketone carries out esterification and obtains Azilsartan under the condensing agents such as DCC, WSC, Mitsunobu reagent exist.
Wherein method a) can residual acyl chlorides in product and corresponding hydrolysate carboxylic acid after reaction; Method b) easily makes the oxyethyl group structure deteriorate that replaces on benzoglyoxaline when Azilsartan acid is prepared into acyl chlorides; Method c) is reacted and is lacked selectivity, easily generates N, the disubstituted impurity of O, and reaction yield is low; Method d) condensing agent in reaction, absorb water generate corresponding product can remain in Azilsartan, be difficult to remove.And method a), method b), the 4-methylol-5-methyl isophthalic acid that d) need to use of method, 3-dioxole-2-ketone is difficult to scale operation, price is higher.
Consider the market outlook of Azilsartan, and the defect of the intermediate of Azilsartan and the existence of the production technique of Azilsartan, the intermediate to Azilsartan and the preparation method of Azilsartan carry out research and development and are very important.
Summary of the invention
The object of the invention is to overcome above-mentioned deficiency, intermediate of new Azilsartan and preparation method thereof is provided, and adopt intermediate to prepare the synthetic method of Azilsartan.
First aspect of the present invention is to provide a kind of Azilsartan intermediate, described Azilsartan intermediate is 2-oxyethyl group-1-[[2 '-(N-tertbutyloxycarbonyl-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester, as shown in structural formula 11:
Second aspect of the present invention is to provide Azilsartan intermediate 2-oxyethyl group-1-[[2 '-(N-tertbutyloxycarbonyl-5-oxo-4 described in first aspect of the present invention, 5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl] synthetic method of-1H-benzoglyoxaline-7-carboxylate methyl ester, be prepared from according to following proposal:
Wherein,
Formula 7 compounds react the formula of obtaining 8 compounds under the catalysis of alkali with tert-Butyl dicarbonate,
Formula 8 compounds react the formula of obtaining 9 compounds under Diisopropyl azodicarboxylate catalysis with N-bromo-succinimide,
The condensation under alkali exists of formula 9 compounds and formula 10 compounds obtains formula 11 compounds.
Preferably, in the process by formula 7 compound preparation formula 8 compounds, alkali used is selected from the one in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, sodium methylate, potassium tert.-butoxide.
Preferably, in the process by formula 7 compound preparation formula 8 compounds, the molar ratio of tert-Butyl dicarbonate and formula 7 compounds is 1.0-3.0; The molar ratio of alkali and formula 7 compounds is 1.0-3.0.
Preferably, in the process by formula 7 compound preparation formula 8 compounds, reaction solvent is the one in methylene dichloride or tetrahydrofuran (THF), and temperature of reaction is 0-40 DEG C, and the reaction times is 1-5h.
Preferably, in the process by formula 8 compound preparation formula 9 compounds, the molar ratio of N-bromo-succinimide and formula 8 compounds is 1.0-1.2, and the molar ratio of Diisopropyl azodicarboxylate and formula 8 compounds is 0.01-0.1.
Preferably, in the process by formula 8 compound preparation formula 9 compounds, reaction solvent is the one in methylene dichloride or trichloromethane.
Preferably, in the process by formula 8 compound preparation formula 9 compounds, temperature of reaction is 0-40 DEG C.
Preferably, in the process by formula 8 compound preparation formula 9 compounds, the reaction times is 1-5 hour.
Preferably, in the process by formula 9 compound preparation formula 11 compounds, alkali used is selected from the one in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, sodium methylate, potassium tert.-butoxide;
Preferably, in the process by formula 9 compound preparation formula 11 compounds, the molar ratio of formula 10 compounds and formula 9 compounds is 0.9-1.1; The molar ratio of alkali and formula 9 compounds is 0.5-2.0.
Preferably, in the process by formula 9 compound preparation formula 11 compounds, reaction solvent is the one in dimethyl formamide, N,N-DIMETHYLACETAMIDE, toluene.
Preferably, in the process by formula 9 compound preparation formula 11 compounds, temperature of reaction is 20-80 DEG C.
Preferably, in the process by formula 9 compound preparation formula 11 compounds, the reaction times is 2-10 hour.
One preferred embodiment in, formula 7 compounds are prepared from according to following proposal by formula 5 compounds:
Formula 5 compounds and Vinyl chloroformate carry out esterification and obtain formula 6 compounds under alkali exists,
Formula 6 compounds reacting by heating in organic solvent obtains formula 7 compounds.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, alkali used is selected from the one in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, sodium methylate, potassium tert.-butoxide.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, the molar ratio of Vinyl chloroformate and formula 5 compounds is 1.0-1.5; The molar ratio of alkali and formula 5 compounds is 1.0-3.0.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, reaction solvent is the one in methylene dichloride or trichloromethane.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, temperature of reaction is 0-5 DEG C.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, the reaction times is 0.5-2 hour.
Preferably, in the process by formula 6 compound preparation formula 7 compounds, reaction solvent is the one in ethanol, methyl alcohol, propyl alcohol.
Preferably, in the process by formula 6 compound preparation formula 7 compounds, temperature of reaction is 50-80 DEG C.
Preferably, in the process by formula 6 compound preparation formula 7 compounds, the reaction times is 15-30 hour.
One preferred embodiment in, formula 5 compounds are reacted and obtain under alkali exists by formula 4 compounds and oxammonium hydrochloride:
The 3rd aspect of the present invention is to provide a kind of synthetic method of Azilsartan, and Azilsartan is as shown in structural formula 1, synthetic according to following proposal:
Wherein, formula 11 compounds are prepared from according to any one synthetic method described in second aspect of the present invention,
The hydrolysis under alkali exists of formula 11 compounds obtains formula 12 compounds,
Formula 12 compounds and 4-chloromethyl-5-methyl isophthalic acid, 3-dioxole-2-ketone in the time that alkali exists under DMAP catalysis condensation obtain formula 13 compounds;
The de-Boc protection under acidic conditions of formula 13 compounds obtains Azilsartan.
Preferably, in the process of formula 11 compound preparation formula 12 compounds, alkali used is selected from the one in lithium hydroxide or salt of wormwood.
Preferably, in the process of formula 11 compound preparation formula 12 compounds, the molar ratio of alkali and formula 11 compounds is 0.5-1.5.
Preferably, in the process of formula 11 compound preparation formula 12 compounds, reaction solvent is the mixed solvent of a kind of and water in methyl alcohol, ethanol.
Preferably, in the process of formula 11 compound preparation formula 12 compounds, temperature of reaction is 0-35 DEG C.
Preferably, in the process of formula 11 compound preparation formula 12 compounds, the reaction times is 2-5 hour.
Preferably, in the process of formula 12 compound preparation formula 13 compounds, alkali used is selected from the one in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide.
Preferably, in the process of formula 12 compound preparation formula 13 compounds, 4-chloromethyl-5-methyl isophthalic acid, the molar ratio of 3-dioxole-2-ketone and formula 12 compounds is 1.0-2.0, the molar ratio of alkali and formula 12 compounds is 1.0-3.0, and the molar ratio of DMAP and formula 12 compounds is≤0.1.
Preferably, in the process of formula 12 compound preparation formula 13 compounds, reaction solvent is selected from the one in methylene dichloride, tetrahydrofuran (THF), dimethyl formamide, N,N-DIMETHYLACETAMIDE.
Preferably, in the process of formula 12 compound preparation formula 13 compounds, temperature of reaction is 0-40 DEG C.
Preferably, in the process of formula 12 compound preparation formula 13 compounds, the reaction times is 1-10 hour.
In a most preferred embodiment, Azilsartan is synthetic according to following proposal:
The 4th aspect of the present invention is to provide another kind of Azilsartan intermediate, N-tertbutyloxycarbonyl-3-(4 '-bromomethylbiphenyl-2-yl)-5-oxo-4, and 5-dihydro-1,2,4-oxadiazole, as shown in structural formula 9:
The 5th aspect of the present invention is to provide Azilsartan intermediate N tertbutyloxycarbonyl-3-(4 '-bromomethylbiphenyl-2-yl)-5-oxo-4 described in the 4th aspect of the present invention, 5-dihydro-1, the synthetic method of 2,4-oxadiazole, is prepared from according to following proposal:
Wherein, formula 7 compounds react the formula of obtaining 8 compounds under the catalysis of alkali with tert-Butyl dicarbonate, and formula 8 compounds react the formula of obtaining 9 compounds under Diisopropyl azodicarboxylate catalysis with N-bromo-succinimide.
Preferably, in the process by formula 7 compound preparation formula 8 compounds, alkali used is selected from the one in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, sodium methylate, potassium tert.-butoxide.
Preferably, in the process by formula 7 compound preparation formula 8 compounds, the molar ratio of tert-Butyl dicarbonate and formula 7 compounds is 1.0-3.0; The molar ratio of alkali and formula 7 compounds is 1.0-3.0.
Preferably, in the process by formula 7 compound preparation formula 8 compounds, reaction solvent is the one in methylene dichloride or tetrahydrofuran (THF), and temperature of reaction is 0-40 DEG C, and the reaction times is 1-5h.
Preferably, in the process by formula 8 compound preparation formula 9 compounds, the molar ratio of N-bromo-succinimide and formula 8 compounds is 1.0-1.2, and the molar ratio of Diisopropyl azodicarboxylate and formula 8 compounds is 0.01-0.1.
Preferably, in the process by formula 8 compound preparation formula 9 compounds, reaction solvent is the one in methylene dichloride or trichloromethane.
Preferably, in the process by formula 8 compound preparation formula 9 compounds, temperature of reaction is 0-40 DEG C.
Preferably, in the process by formula 8 compound preparation formula 9 compounds, the reaction times is 1-5 hour.
One preferred embodiment in, formula 7 compounds are prepared from according to following proposal by formula 5 compounds:
Formula 5 compounds and Vinyl chloroformate carry out esterification and obtain formula 6 compounds under alkali exists,
Formula 6 compounds reacting by heating in organic solvent obtains formula 7 compounds.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, alkali used is selected from the one in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, sodium methylate, potassium tert.-butoxide.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, the molar ratio of Vinyl chloroformate and formula 5 compounds is 1.0-1.5; The molar ratio of alkali and formula 5 compounds is 1.0-3.0.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, reaction solvent is the one in methylene dichloride or trichloromethane.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, temperature of reaction is 0-5 DEG C.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, the reaction times is 0.5-2 hour.
Preferably, in the process by formula 6 compound preparation formula 7 compounds, reaction solvent is the one in ethanol, methyl alcohol, propyl alcohol.
Preferably, in the process by formula 6 compound preparation formula 7 compounds, temperature of reaction is 50-80 DEG C.
Preferably, in the process by formula 6 compound preparation formula 7 compounds, the reaction times is 15-30 hour.
One preferred embodiment in, formula 5 compounds are reacted and obtain under alkali exists by formula 4 compounds and oxammonium hydrochloride:
The 6th aspect of the present invention is to provide another kind of Azilsartan intermediate, N-tertbutyloxycarbonyl-3-(4 '-methyl diphenyl-2-yl)-5-oxo-4, and 5-dihydro-1,2,4-oxadiazole, as shown in structural formula 8:
The 7th aspect of the present invention is to provide Azilsartan intermediate N tertbutyloxycarbonyl-3-(4 '-methyl diphenyl-2-yl)-5-oxo-4 described in the 6th aspect of the present invention, 5-dihydro-1, the synthetic method of 2,4-oxadiazole, is prepared from according to following proposal:
Wherein, formula 7 compounds react the formula of obtaining 8 compounds under the catalysis of alkali with tert-Butyl dicarbonate.
Preferably, in the process by formula 7 compound preparation formula 8 compounds, alkali used is selected from the one in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, sodium methylate, potassium tert.-butoxide.
Preferably, in the process by formula 7 compound preparation formula 8 compounds, the molar ratio of tert-Butyl dicarbonate and formula 7 compounds is 1.0-3.0; The molar ratio of alkali and formula 7 compounds is 1.0-3.0.
Preferably, in the process by formula 7 compound preparation formula 8 compounds, reaction solvent is the one in methylene dichloride or tetrahydrofuran (THF), and temperature of reaction is 0-40 DEG C, and the reaction times is 1-5h.
One preferred embodiment in, formula 7 compounds are prepared from according to following proposal by formula 5 compounds:
Formula 5 compounds and Vinyl chloroformate carry out esterification and obtain formula 6 compounds under alkali exists,
Formula 6 compounds reacting by heating in organic solvent obtains formula 7 compounds.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, alkali used is selected from the one in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, sodium methylate, potassium tert.-butoxide.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, the molar ratio of Vinyl chloroformate and formula 5 compounds is 1.0-1.5; The molar ratio of alkali and formula 5 compounds is 1.0-3.0.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, reaction solvent is the one in methylene dichloride or trichloromethane.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, temperature of reaction is 0-5 DEG C.
Preferably, in the process by formula 5 compound preparation formula 6 compounds, the reaction times is 0.5-2 hour.
Preferably, in the process by formula 6 compound preparation formula 7 compounds, reaction solvent is the one in ethanol, methyl alcohol, propyl alcohol.
Preferably, in the process by formula 6 compound preparation formula 7 compounds, temperature of reaction is 50-80 DEG C.
Preferably, in the process by formula 6 compound preparation formula 7 compounds, the reaction times is 15-30 hour.
One preferred embodiment in, formula 5 compounds are reacted and obtain under alkali exists by formula 4 compounds and oxammonium hydrochloride:
The present invention compares the preparation technology of existing Azilsartan, has following beneficial effect:
(1) the invention provides three kinds of new Azilsartan intermediates (formula 8 compounds, formula 9 compounds and formula 11 compounds), opened up the research field of Azilsartan important intermediate;
(2) the present invention uses intermediate 2-oxyethyl group-1-[[2 '-(N-tertbutyloxycarbonyl-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester, through hydrolysis, condensation, separates protection, obtains final product Azilsartan, compared with prior art, avoid using expensive 4-methylol-5-methyl isophthalic acid, 3-dioxole-2-ketone, can significantly reduce production costs;
(3) in production process of the present invention, the purity of intermediate can reach more than 98%, all can meet market demands, and high to the yield of final product Azilsartan by formula 11 compounds, is 68%-75%; The finished product Azilsartan purity obtaining reaches 99.0%-99.5%.
Embodiment
Below with reference to concrete embodiment, the invention will be further described, to understand better the present invention.
Embodiment 1: preparation formula 5 compounds
The chemical name of formula 5 compounds: N '-hydroxyl-4 '-methyl diphenyl-2-amidine hydrochloride
38.6g (0.20mol) 2 '-cyano group-4-methyl diphenyl (formula 4 compounds) adds 200mL ethanol, 40mL water, 83.4g (1.20mol) oxammonium hydrochloride, 68.9g (0.65mol) sodium carbonate, back flow reaction 12 hours, filter, filtrate decompression is sloughed ethanol, residuum adds 150mL ethyl acetate and 100mL water, stir layering, water layer adds 50mL ethyl acetate to extract, merge organic layer, be cooled to 0-5 DEG C, drip 15% hydrochloric acid and regulate PH=1, separate out white solid, stir 1 hour, filter, filter cake is through vacuum-drying, obtain white solid 46.6g, yield 88.7%.
This white solid is through the formula of being accredited as 5 compounds, and appraising datum is as follows:
Mp223-224℃
1H-NMR(400MHz，CDCl
3)δ：7.575(td，J
1＝7.6Hz，J
2＝1.2Hz，1H，ArH)，7.473(dd，J
1＝7.6Hz，J
2＝1.2Hz，1H，ArH)，7.407(qd，J
1＝7.6Hz，J
2＝1.2Hz，2H，ArH)，7.186(s，4H，ArH)，4.701(br?s，4H，OH?and?NH
2)，2.229(s，3H，ArCH
3)。
13C-NMR(100MHz，CDCl
3)δ：161.593，140.983，138.707，135.315，132.818，130.699，129.383，129.142，128.286，127.742，123.698，20.182。
MS(ESI
+)：m/z227.0(M-Cl)。
Embodiment 2: preparation formula 6 compounds
The chemical name of formula 6 compounds: N '-(ethoxycarbonyl) oxygen base-4 '-methyl diphenyl-2-amidine
78.8g (0.30mol) formula 5 compounds add 500mL methylene dichloride, be cooled to 0-5 DEG C, add 65.8g (0.65mol) triethylamine, drip the 120mL dichloromethane solution that contains 35.8g (0.33mol) Vinyl chloroformate at 0-5 DEG C.Dropwise, stirring at room temperature 1 hour, adds 250mL water to stir, and drip 15% hydrochloric acid and adjust PH=6-7, layering, organic layer is after 2 × 250mL water washing, and solvent is sloughed in decompression, obtains off-white color solid 89.3g, yield 99.8%.
Such white solid is through the formula of being accredited as 6 compounds, and appraising datum is as follows:
Mp125℃
1H-NMR(400MHz，CDCl
3)δ：7.632(dd，J
1＝7.6Hz，J
2＝1.2Hz，1H，ArH)，7.480(td，J
1＝7.6Hz，J
2＝1.2Hz，1H，ArH)，7.405-7.334(m，4H，ArH)，7.206(d，J＝7.6Hz，2H，ArH)，4.608(br?s，2H，NH
2)，2.382(s，3H，ArCH
3)，1.351(t，J＝7.2Hz，3H，OCH
2 CH 3 )。
13C-NMR(100MHz，CDCl
3)δ：157.644，153.833，140.501，137.628，136.757，130.625，130.572，130.420，129.713，129.322，128.488，127.311，64.443，21.221，14.337。
MS(ESI
+)：m/z299.0(M+H)，321.0(M+Na)。
Embodiment 3: preparation formula 7 compounds
The chemical name of formula 7 compounds: 3-(4 '-methyl diphenyl-2-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole
89.5g (0.30mol) formula 6 compounds are dissolved in 450mL ethanol, back flow reaction 20 hours.Solvent is sloughed in decompression, obtains orange red oily matter, adds 100mL methylene dichloride to dissolve, add again 250mL water, be cooled to below 20 DEG C, drip 15% sodium hydroxide solution to PH=10, layering, water layer adds after 5 × 50mL dichloromethane extraction, and water layer is cooled to below 20 DEG C, drip 15% hydrochloric acid to PH≤7, separate out white solid, continue to drip 15% hydrochloric acid to PH=2, be cooled to 0-5 DEG C, stir 1 hour, filter, filter cake, through vacuum-drying, obtains white solid 65.9g, yield 87.1%.
This white solid is through the formula of being accredited as 7 compounds, and appraising datum is as follows:
Mp148-149℃
1H-NMR(500MHz，CDCl
3)δ：7.756(d，J＝7.5Hz，1H，ArH)，7.595(t，J＝8.0Hz，1H，ArH)，7.465(t，J＝7.5Hz，1H，ArH)，7.420(d，J＝7.5Hz，1H，ArH)，7.218(quint，J＝8.0Hz，4H，ArH)，4.306(q，J＝7.2Hz，2H，O
CH 2 CH
3)，2.382(s，3H，ArCH
3)。
13C-NMR(125MHz，CDCl
3)δ：159.788，157.791，141.434，138.713，135.457，132.169，131.174，129.730，129.593，128.782，127.932，121.556，21.257。
Embodiment 4: preparation formula 8 compounds
The chemical name of formula 8 compounds: N-tertbutyloxycarbonyl-3-(4 '-methyl diphenyl-2-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole
25.2.g (0.10mol) formula 7 compounds are dissolved in 150mL methylene dichloride, be cooled to below 10 DEG C, add 20.2g (0.20mol) triethylamine, the DMAP of 0.12g (0.001mol), at 0-5 DEG C, drip the 50mL dichloromethane solution that contains 43.7g (0.20mol) tert-Butyl dicarbonate, dropwise stirring at room temperature 2 hours.Be cooled to below 10 DEG C, add 100mL water, stir, drip acetic acid to PH=4-5, layering, organic layer is after 100mL saturated sodium bicarbonate solution, 100mL water washing, and solvent is sloughed in decompression, the oily matter obtaining, with ethyl acetate and normal hexane crystallization, obtains colourless prism 31.5g, yield 89.5%.
This colourless prism is through the formula of being accredited as 8 compounds, and appraising datum is as follows:
Mp89℃
1H-NMR(400MHz，CDCl
3)δ：7.526(d，J＝7.6Hz，1H，ArH)，7.382(t，J＝8.4Hz，3H，ArH)，7.233(d，J＝8.0Hz，2H，ArH)，7.131(d，J＝7.6Hz，2H，ArH)，2.286(s，3H，ArCH
3)，0.946(s，9H，CH
3)。
13C-NMR(100MHz，CDCl
3)δ：157.691，157.185，141.172，137.166，135.143，130.708，129.818，129.122，128.600，126.173，124.524，58.410，26.599，20.096。
Embodiment 5: preparation formula 9 compounds
The chemical name of formula 9 compounds: N-tertbutyloxycarbonyl-3-(4 '-bromomethylbiphenyl-2-yl)-5-oxo-4,5-dihydro-1,2,4-oxadiazole
35.2g (0.10mol) formula 8 compounds are dissolved in 200mL methylene dichloride, add 1.60g (0.01mol) 2,2'-Azobis(2,4-dimethylvaleronitrile), stir 5 minutes, add 18.7g (0.105mol) N-bromo-succinimide, 37-39 DEG C is reacted 6 hours.Be cooled to 0-5 DEG C, filter, filtrate is used after 2 × 100mL saturated sodium bicarbonate solution, the washing of 100mL saturated nacl aqueous solution successively, and solvent is sloughed in decompression, and the oily matter obtaining, with ethyl acetate and normal hexane crystallization, obtains light yellow solid 33.8g, yield 78.6%.
This light yellow solid is through the formula of being accredited as 9 compounds, and appraising datum is as follows:
1H-NMR(400MHz，CDCl
3)δ：7.626(d，J＝8.0Hz，1H，ArH)，7.538-7.463(m，3H，ArH)，7.405(s，2H，ArH)，7.405(s，2H，ArH)，7.302(s，2H，ArH)，4.491(s，2H，BrCH
2Ar)，1.242(s，9H，CH
3)。
13C-NMR(100MHz，CDCl
3)δ：156.616，153.234，143.879，141.054，138.809，137.840，131.911，130.116，129.564，129.031，127.755，123.401，87.299，60.352，32.842，27.328，14.242。
HRMS(TOF?MS，EI)Calcd?for?C
20H
19O
4Br430.0528(M
+)，Found430.0527。
Embodiment 6: preparation formula 11 compounds
The chemical name of formula 11 compounds: 2-oxyethyl group-1-[[2 '-(N-tertbutyloxycarbonyl-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester
21.5g (0.05mol) formula 9 compounds and 11.0g (0.05mol) 2-oxyethyl group-1H-benzoglyoxaline-7-carboxylate methyl ester (formula 10 compounds) are dissolved in the N of 100mL, dinethylformamide, add 20.7g (0.15mol) salt of wormwood, room temperature reaction 2 hours.Reaction solution is poured in 300mL water, adds 200mL methylene dichloride, stir, and layering, organic layer is after 2 × 100mL water washing, and solvent is sloughed in decompression, and the oily matter obtaining, through ethyl acetate crystallization, obtains light yellow solid 25.8g, yield 90.4%.
This light yellow solid is through the formula of being accredited as 11 compounds, and appraising datum is as follows:
Mp125-126℃
1H-NMR(400MHz，DMSO-d
6)δ：7.720(d，J＝7.6Hz，1H，ArH)，7.573(q，J＝7.6Hz，2H，ArH)，7.476(t，J＝7.2Hz，2H，ArH)，7.391(d，J＝8.0Hz，1H，ArH)，7.175(q，J＝8.4Hz，3H，ArH)，7.010(d，J＝7.6Hz，2H，ArH)，5.654(s，2H，NCH
2Ar)，4.663(q，J＝7.2Hz，2H，O
CH 2 CH
3)，3.753(s，3H，COOCH
3)，1.484(t，J＝7.2Hz，3H，OCH
2 CH 3 )，1.158(s，9H，CH
3)。
13C-NMR(100MHz，DMSO-d
6)δ：166.718，158.724，156.564，153.175，143.833，141.947，141.436，137.759，137.759，137.586，131.735，131.522，130.057，129.935，128.715，126.999，123.769，123.431，121.994，120.902，115.688，66.784，60.371，52.243，46.925，21.040，14.669，14.229。
MS(ESI
+)：m/z571.4(M+H)，1163.5(2M+Na)。
Embodiment 7: preparation formula 12 compounds
The chemical name of formula 12 compounds: 2-oxyethyl group-1-[[2 '-(N-tertbutyloxycarbonyl-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid
28.5g (0.05mol) formula 11 compounds add 2mol/L lithium hydroxide aqueous solution 50mL, 100mL ethanol, room temperature reaction 3 hours, is cooled to 0-5 DEG C, drips acetic acid to PH=4-5, separate out white solid, stir half an hour, filter, filter cake is through vacuum-drying, obtain white solid 26.2g, yield 94.1%.
This white solid is through the formula of being accredited as 12 compounds, and appraising datum is as follows:
Mp151-152℃
1H-NMR(400MHz，CDCl
3)δ：12.050(br?s，1H，COOH)，7.891(dd，J
1＝7.2Hz，J
2＝2.0Hz，1H，ArH)，7.587(dd，J
1＝8.8Hz，J
2＝1.6Hz，2H，ArH)，7.330(dd，J
1＝7.6Hz，J
2＝1.2Hz，1H，ArH)，7.211-7.189(m，1H，ArH)，6.980(d，J＝8.0Hz，2H，ArH)，6.773(q，J＝7.6Hz，3H，ArH)，6.490(d，J＝8.0Hz，1H，ArH)，5.671(s，2H，NCH
2Ar)，4.121(q，J＝7.2Hz，2H，O
CH 2 CH
3)，1.383(t，J＝7.2Hz，3H，OCH
2 CH 3 )，1.277(s，9H，CH
3)。
13C-NMR(100MHz，DMSO-d
6)δ：171.194，164.972，159.853，158.678，158.082，140.689，140.129，137.506，132.188，130.937，130.748，130.162，129.114，128.244，125.606，123.794，122.526，120.916，119.852，118.229，81.585，67.489，60.426，46.375，29.716，21.073，14.563。
MS(ESI
+)：m/z557.4(M+H)。
Embodiment 8: preparation formula 13 compounds
The chemical name of formula 13 compounds: 2-oxyethyl group-1-[[2 '-(N-tertbutyloxycarbonyl-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl ester
27.8g (0.05mol) formula 12 compounds add 200mL methylene dichloride, be cooled to below 10 DEG C, add 7.1g (0.07mol) triethylamine, after dissolution of solid, drip 8.9g (0.07mol) 4-chloromethyl-5-methyl-2-oxo-1,3-dioxole, dropwises, stirring at room temperature 1 hour, then rise to 35 DEG C of reactions 2 hours.Synthetic liquid is after using successively 5 × 100mL35 DEG C of warm water washing, and solvent is sloughed in organic layer decompression, and the oily matter obtaining, with ethyl acetate and normal hexane crystallization, obtains white solid 28.3g, yield 84.6%.
This white solid is through the formula of being accredited as 13 compounds, and appraising datum is as follows:
Mp123-125℃
1H-NMR(400MHz，CDCl
3)δ：7.768(d，J＝8.0Hz，1H，ArH)，7.649-7.601(m，2H，ArH)，7.486-7.471(m，2H，ArH),7.436(d，J＝7.6Hz，1H，ArH)，7.192(t，J＝7.6Hz，3H，ArH)，6.974(d，J＝7.2Hz，2H，ArH)，5.681(s，2H，NCH
2Ar)，4.931(s，2H，COOCH
2)，4.667(q，J＝7.2Hz，2H，O
CH 2 CH
3)，2.176(s，3H，CH
3)，1.486(t，J＝7.2Hz，3H，OCH
2 CH 3 )，1.156(s，9H，CH
3)。
13C-NMR(100MHz，DMSO-d
6)δ：165.308，158.836，156.536，153.288，152.084，143.770，142.103，141.320，140.275，137.774，137.640，133.463，132.036，131.862，130.076，129.869，128.782，127.514，126.702，124.400，123.437，122.943，121.060，114.236，87.241，66.942，54.313，47.140，27.224，14.669。
MS(ESI
+)：m/z669.4(M+H)，691.2(M+Na)。
Embodiment 10: preparation formula 1 compound (Azilsartan)
The chemical name of formula 1 compound (Azilsartan): 2-oxyethyl group-1-[[2 '-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylic acid (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl ester
33.4g (0.05mol) formula 11 compounds add 160mL acetone, and 5.7g (0.05mol) trifluoroacetic acid, stirs under room temperature 2 hours.Separate out white solid, be cooled to 0 DEG C and stir 1 hour, filter, filter cake, through vacuum-drying, obtains white solid 26.2g, yield 92.2%, HPLC purity 99.2%.
This white solid is through the formula of being accredited as 1 compound (Azilsartan), and appraising datum is as follows:
Mp166.0℃
1H-NMR(400MHz，DMSO-d
6)δ：12.381(s，1H，NH)，7.735(d，J＝8.0Hz，1H，ArH)，7.663(t，J＝8.4Hz，2H，ArH)，7.545(t，J＝8.8Hz，2H，ArH)，7.478(d，J＝7.6Hz，1H，ArH)，7.219(t，J＝7.6Hz，3H，ArH)，7.007(d，J＝7.2Hz，2H，ArH)，5.562(s，2H，NCH
2Ar)，5.123(s，2H，COOCH
2)，4.604(q，J＝6.8Hz，2H，O
CH 2 CH
3)，2.167(s，3H，CH
3)，1.390(t，J＝6.8Hz，3H，OCH
2 CH 3 )。
13C-NMR(100MHz，DMSO-d
6)δ：170.294，165.041，159.445，158.218，151.773，141.701，140.728，140.348，137.815，136.666，131.832，131.181，130.600，130.113，128.823，127.820，126.358，123.422，122.157，120.868，114.484，66.674，59.727，54.671，46.435，20.729，14.329。
MS(ESI
+)：m/z569.2(M+H)，591.1(M+Na)。
Above specific embodiments of the invention be have been described in detail, but it is just as example, the present invention is not restricted to specific embodiment described above.To those skilled in the art, any equivalent modifications that the present invention is carried out and alternative also all among category of the present invention.Therefore, equalization conversion and the amendment done without departing from the spirit and scope of the invention, all should contain within the scope of the invention.
Claims (11)
1. the synthetic method of an Azilsartan intermediate, it is characterized in that, described Azilsartan intermediate is 2-oxyethyl group-1-[[2 '-(N-tertbutyloxycarbonyl-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester, as shown in structural formula (11), be prepared from according to following proposal:
wherein,
Formula (7) compound reacts the formula of obtaining (8) compound under the catalysis of alkali with tert-Butyl dicarbonate,
Formula (8) compound reacts the formula of obtaining (9) compound under Diisopropyl azodicarboxylate catalysis with N-bromo-succinimide,
The condensation under alkali exists of formula (9) compound and formula (10) compound obtains formula (11) compound.
2. synthetic method according to claim 1, is characterized in that, in the process by formula (7) compound preparation formula (8) compound,
Alkali used is selected from the one in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, sodium methylate, potassium tert.-butoxide;
The molar ratio of tert-Butyl dicarbonate and formula (7) compound is 1.0-3.0; The molar ratio of alkali and formula (7) compound is 1.0-3.0;
Reaction solvent is the one in methylene dichloride or tetrahydrofuran (THF), and temperature of reaction is 0-40 DEG C, and the reaction times is 1-5h.
3. synthetic method according to claim 1, is characterized in that, in the process by formula (8) compound preparation formula (9) compound,
The molar ratio of N-bromo-succinimide and formula (8) compound is 1.0-1.2, and the molar ratio of Diisopropyl azodicarboxylate and formula (8) compound is 0.01-0.1;
Reaction solvent is the one in methylene dichloride or trichloromethane; Temperature of reaction is 0-40 DEG C, and the reaction times is 1-5 hour.
4. synthetic method according to claim 1, is characterized in that, in the process by formula (9) compound preparation formula (11) compound,
Alkali used is selected from the one in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, sodium methylate, potassium tert.-butoxide;
The molar ratio of formula (10) compound and formula (9) compound is 0.9-1.1; The molar ratio of alkali and formula (9) compound is 0.5-2.0;
Reaction solvent is the one in dimethyl formamide, N,N-DIMETHYLACETAMIDE, toluene; Temperature of reaction is 20-80 DEG C, and the reaction times is 2-10 hour.
5. a synthetic method for Azilsartan, is characterized in that, Azilsartan is as shown in structural formula (1), synthetic according to following proposal:
Wherein, formula (11) compound is prepared from according to the synthetic method described in any one in claim 1-3, and the hydrolysis under alkali exists of formula (11) compound obtains formula (12) compound,
Formula (12) compound and 4-chloromethyl-5-methyl isophthalic acid, 3-dioxole-2-ketone in the time that alkali exists under DMAP catalysis condensation obtain formula (13) compound;
The de-Boc protection under acidic conditions of formula (13) compound obtains Azilsartan.
6. synthetic method according to claim 5, is characterized in that, in the process of formula (12) compound preparation formula (13) compound,
Alkali used is selected from the one in triethylamine, diisopropylethylamine, sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide;
4-chloromethyl-5-methyl isophthalic acid, the molar ratio of 3-dioxole-2-ketone and formula 12 compounds is 1.0-2.0;
The molar ratio of alkali and formula 12 compounds is 1.0-3.0; The molar ratio of DMAP and formula 12 compounds is≤0.1;
Reaction solvent is selected from the one in methylene dichloride, tetrahydrofuran (THF), dimethyl formamide, N,N-DIMETHYLACETAMIDE; Temperature of reaction is 0-40 DEG C, and the reaction times is 1-10 hour.
7. an Azilsartan intermediate, it is characterized in that, described Azilsartan intermediate is 2-oxyethyl group-1-[[2 '-(N-tertbutyloxycarbonyl-5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl]-1H-benzoglyoxaline-7-carboxylate methyl ester, as shown in structural formula (11):
8. an Azilsartan intermediate, is characterized in that, described Azilsartan intermediate is N-tertbutyloxycarbonyl-3-(4 '-bromomethylbiphenyl-2-yl)-5-oxo-4,5-dihydro-1, and 2,4-oxadiazole, as shown in structural formula (9):
9. a synthetic method for Azilsartan intermediate claimed in claim 8, is characterized in that, is prepared from according to following proposal:
10. an Azilsartan intermediate, is characterized in that, described Azilsartan intermediate is N-tertbutyloxycarbonyl-3-(4 '-methyl diphenyl-2-yl)-5-oxo-4,5-dihydro-1, and 2,4-oxadiazole, as shown in structural formula (8):
The synthetic method of 11. 1 kinds of Azilsartan intermediates claimed in claim 10, is characterized in that, is prepared from according to following proposal:
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| CN105399738A (en) * | 2014-09-12 | 2016-03-16 | 方晏燕 | Azilsartan medoxomil preparation method |
| CN108358907A (en) * | 2018-04-03 | 2018-08-03 | 山东科兴生物制品有限公司 | A kind of preparation method of Azilsartan sylvite hydrate |
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| CN105399738A (en) * | 2014-09-12 | 2016-03-16 | 方晏燕 | Azilsartan medoxomil preparation method |
| CN108358907A (en) * | 2018-04-03 | 2018-08-03 | 山东科兴生物制品有限公司 | A kind of preparation method of Azilsartan sylvite hydrate |
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