CN105669495A - Novel preparation method for azilsartan and intermediate thereof - Google Patents
Novel preparation method for azilsartan and intermediate thereof Download PDFInfo
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Abstract
The invention relates to an intermediate for preparing azilsartan and a novel preparation method for the azilsartan. The method includes the following steps: 1) reducing 2-cyano-4'-bromomethylbiphenyl with hydroxylamine hydrochloride to generate (Z)-4'-bromomethyl-(N')-hydroxy-[1,1'-biphenyl]-2-amidine; 2) performing esterification with ethyl chloroformate to generate (Z)-4'-bromomethyl-(N')-((ethoxycarbonyl)oxyl)-[1,1'-biphenyl]-2-amidine; 3) performing ring closing to prepare 3-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1,2,4-oxadiazole-5-(4H)-one; 4) performing a condensation reaction to 2-ethoxy-1H-benzimidazole-7-methyl carboxylate and the 3-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1,2,4-oxadiazole-5-(4H)-one to prepare 2-ethoxy-1-((2'-(2,5-dihydro-5-oxy-1,2,4-oxadiazole-3-yl)biphenyl-4-yl)methyl)benzimidazole-7-methyl carboxylate; and 5) finally performing hydrolysis to prepare the azilsartan. The method employs the raw material being easy to obtain, is short in synthetic route, is low in device cost, is less in side products, is low in toxicity and pollution, is environment-friendly, is high in product purity and is suitable for industrial production.
Description
Technical field
The preparation method that the present invention relates to a kind of medical compounds, is specifically related to preparation Azilsartan intermediate and the new preparation method of Azilsartan.
Background technology
In recent years, along with people's living standard improve constantly, the growth of aging population, hypertension is just becoming the commonly encountered diseases that a kind of prevalence is high. There is no effective means both at home and abroad can effect a radical cure hypertension at present, and therefore, hypertension is once suffer from adjoint lifelong, and causes a lot of other relevant disease. According to the World Health Organization's necrology to global various diseases, account for the ratio of total death toll will be risen to 36.0% in 2002 by 28.8% in 1997 with the cardiovascular and cerebrovascular disease death toll that hypertension etc. is representative, the positive serious harm human health of hypertension. Therefore the feature " once fallen ill, lifelong medication " and huge patient population provide huge market potential for antihypertensive drugs. Hypertension is the cardiovascular disease that a class is common, and whole world hypertensive patient is more than 1,000,000,000, and China hyperpietic estimates have 200,000,000, and patient is also in continuous growth, and therefore hypertension brings up a huge medical market. And along with society people's rhythm of life accelerate rapidly, physical work reduces day by day, dietary structure tends to high heat further, high esterified, the trend that hyperpietic's number substantially rises will continue within a very long time.
The drug main being currently used for blood pressure lowering to have following 5 classes, namely diuretic, beta-blocker, calcium antagonist, angiotensin converting enzyme inhibitor, Angiotensin Ⅱ receptor antagonist. Wherein angiotensin ii receptor antagonist is clinical practice condition of medicine treatment for hypertension one quantum jump in recent years, and Losartan, valsartan, irbesartan, Candesartan, telmisartan and Candesartan are widely used to clinic. These resisting hypertension first-line treatment medications, have brand-new Hypotensive Mechanism, and its blood pressure lowering is steady, curative effect strong, long action time, the features such as patient tolerability is good.
Azilsartan (Azilsartan), chemistry 2-ethyoxyl-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-bases) biphenyl-4-base] methyl] benzimidazole-7-carboxylic acid by name, following formula be shown in its chemical structural formula:
Wu Tian company is former grinds for Japan for Azilsartan, and in April, 2012 lists in Japan, and commodity are called " Azilsartan ", and specification is 20mg and 40mg.List currently without in other countries. Azilsartan is the prodrug of Azilsartan, currently also lists America and Europe, and commodity are called Azilsartan.
Azilsartan is closely similar with the chemical constitution of Candesartan, and the tetrazole ring that the difference of Azilsartan is only Candesartan 5 is replaced by oxo-oxadiazoles ring. This chemical modification makes the acidity of Azilsartan more weak than Candesartan, and lipotropy is higher.
Show that domestic " husky smooth class " pharmaceutical market in 2011 has reached the market scale of 4,500,000,000 yuan according to SFDA south institute data, account for resisting hypertension market 33.17%. Wherein: 22 city sample hospital sartans sales volumes have exceeded 1,000,000,000 yuan, and the increasing degree going up a year on year-on-year basis has exceeded 17%. " husky smooth class " class medicine that Yao Shen center accepts is up to kind more than 1100, Azilsartan is as new angiotensin II receptor inhibitor, its curative effect has caused the extensive concern of industry, it may be said that the market demand of Azilsartan is very wide, exploitation this product will produce good Social and economic benef@, it is therefore necessary to the synthesis of Azilsartan is studied.
By literature search, now published patent and documents and materials, be all with 1-[(2'-cyanobiphenyl-4-base) methyl]-2-ethyoxyl-1H-benzimidazole-7-methyl formate (its structural formula is shown in II) is the key intermediate of synthesis Azilsartan, and this intermediate is by by hydroxylamine reduction, then with ethyl chloroformate condensation, then cyclization, final hydrolysis obtains Azilsartan.
According to synthesis 1-[(2'-cyanobiphenyl-4-base) methyl]-2-ethyoxyl-1HThe difference of-benzimidazole-7-methyl formate (II) starting material, synthesis Azilsartan mainly has following two lines:
Route one: Azilsartan basic patent route, the route of patent CN1040755 report, this route 2-(((the double; two phenyl-4-base of 2 '-cyano group) methyl) amino)-3-nitrobenzene methyl is starting material, through reduction nitro, cyclization imidazole ring, restore cyano group, it is esterified with ethyl chloroformate, closing azoles ring again, be finally hydrolyzed totally six steps and obtain Azilsartan, synthetic route is as follows:
This route initiation material is not easy to obtain, and total recovery (9.6%) is relatively low. And used corrosivity and all very strong hydrazine hydrate of toxicity, it is unfavorable for environmental conservation; Cyclization temperature higher (140 DEG C), energy consumption is higher, and due to dimethylbenzene, to do its boiling point height post processing of solvent also highly difficult, is unfavorable for saving energy and reduce the cost, and pyroreaction to generate impurity relatively more, affect product purity and yield, be therefore not suitable for industrial mass production.
The route of route two: patent WO2013186792 report; this route is with 3-nitrophthalic acid for starting material; through over-churning, acidylate, Azide, rearrangement, alkylation, deprotection, reduction nitro, cyclization imidazole ring; restore cyano group; it is esterified with ethyl chloroformate; closing azoles ring again, be finally hydrolyzed totally ten two steps and obtain Azilsartan, synthetic route is as follows:
This route steps is up to 12 steps, and the production cycle is longer, has used the relatively hazardous industrial chemicals of industrial ratio such as thionyl chloride, sodium azide, has also used high-pressure hydrogenation reduction reaction, production operates ratio relatively hazardous, and safety is not high, is unfavorable for industrial mass production. Owing to route is very long, the raw material types used is relatively more, complicated operation, and equipment investment is very big, and yield is relatively low, therefore relatively costly.
Two lines are from key intermediate 1-[(2'-cyanobiphenyl-4-base) methyl]-2-ethyoxyl-1HAfter-benzimidazole-7-methyl formate (II), until the route of Azilsartan finished product is basically identical.In different documents different from the hydroxy esterification amidino groups to closing esterifying reagent used in azoles ring two step, esterifying reagent mainly have ethyl chloroformate, chloro-carbonic acid-2-Octyl Nitrite, chloro-carbonic acid 4-nitro phenyl ester,N,N-carbonyl dimidazoles etc.
JournalofMedicinalChemistry1996,39,5228-5235 chloro-carbonic acid-2-Octyl Nitrite substitutes ethyl chloroformate and closes azoles ring, owing to azoles ring cyclization one step yield is still relatively low (23%), and chloro-carbonic acid-2-Octyl Nitrite is than ethyl chloroformate unit price more expensive, therefore cost is still higher. CN102731491, WO2012107814, CN103588764A, CN103588765A and WO2013186792 useN,N-carbonyl dimidazoles substitutes and closes azoles ring after ethyl chloroformate is esterified, but the amount relatively larger (mol ratio 1:1) of 1, the 8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU) to add, andN,N-carbonyl dimidazoles and DBU price are all higher, and two step yields do not improve, therefore cyclization azoles ring does not have cost advantage in this way. Substituting after ethyl chloroformate is esterified with chloro-carbonic acid 4-nitro phenyl ester in WO2013114305A and close azoles ring, remain because chloro-carbonic acid 4-nitro phenyl ester unit price is higher than ethyl chloroformate, cost is higher without advantage. Therefore closing azoles ring with ethyl chloroformate after being esterified is a kind of both economical cyclization mode.
Key intermediate 1-[(2'-cyanobiphenyl-4-base) the methyl]-2-ethyoxyl-1 of above two linesH2 ethyoxyl instability on the benzimidazole of-benzimidazole-7-methyl formate (II), four-step reaction below easily falls ethyl, and becomes carbonyl, thus generating again other impurity a series of in follow-up reaction, thus reducing yield, bring very big difficulty to the purification of product.
Summary of the invention
Deficiency for above-mentioned technique, we have redesigned a new process route, and explore through lot of experiments, perfect process conditions, have found that a kind of cost of material is lower, process route is shorter, more environmentally-friendly, be more suitable for the synthetic method of industrialized production.
The preparation method that the invention provides a kind of Azilsartan, further, the preparation method additionally providing each step intermediate.
Process route of the present invention is as follows:
The present invention is with 2-ethyoxyl-1H-benzimidazole-7-carboxylate methyl ester (III) and 2-cyano group-4 '-bromomethylbiphenyl (IV) is two crucial starting materials. 2-cyano group-4 '-bromomethylbiphenyl (IV) by oxammonium hydrochloride. reduction generate (Z)-4'-(bromomethyl)-N’-hydroxyl-[1,1'-biphenyl]-2-amidine (V), then obtain with ethyl chloroformate esterification (Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine (VI), then cyclization obtains 3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one (VII). Last raw material 2-ethyoxyl-1H-benzimidazole-7-carboxylate methyl ester (III) and intermediate 3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one (VII) condensation obtains 2-ethyoxyl-1-((2 '-(2,5-dihydro-5-oxygen-1,2,4-diazole-3-bases) double; two phenyl-4-bases) methyl) benzimidazole-7-carboxylate methyl ester (VIII), then hydrolysis obtains Azilsartan (I).
The present invention compares with route one, decreases single step reaction, and route shortens, and raw material is domestic all easily to be purchased, and price is relatively low, it does not have use corrosivity and all very strong hydrazine hydrate of toxicity, more environmental protection, also useless to pyroreaction, more energy efficient, it is more conducive to industrialization large-scale production.Compared with route two, reactions steps length directly decreases seven steps, production cycle is greatly shortened, do not use the relatively hazardous industrial chemicals of industrial ratio such as thionyl chloride, sodium azide, also useless decrease equipment investment to high-pressure hydrogenation reduction reaction, reduce operational hazards, safety is greatly improved, and is more conducive to industrial mass production.
Preparation method of the present invention comprises the following steps:
(1) starting material 2-cyano group-4 '-bromomethylbiphenyl (IV) by oxammonium hydrochloride. reduction generate intermediate V;
(2) intermediate V obtains intermediate VI with ethyl chloroformate esterification;
(3) intermediate VI cyclization obtains intermediate VII;
(4) intermediate VII and raw material III condensation obtain intermediate VIII;
(5) intermediate VIII hydrolysis obtains Azilsartan (I)
Further, wherein 2-cyano group-4 described in step (1) '-bromomethylbiphenyl and oxammonium hydrochloride. mole ratio be 1:2 ~ 20, preferred 1:5 ~ 12, free hydrochloric acid azanol agents useful for same comprises sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium bicarbonate, triethylamine, pyridine, methylamine, dimethylamine, Feldalat NM and Sodium ethylate etc., it is preferable that sodium carbonate, Feldalat NM and triethylamine. Reaction dissolvent comprises acetonitrile, acetone, dimethyl sulfoxide, oxolane and ethanol etc., it is preferable that dimethyl sulfoxide, oxolane and ethanol etc.
Described in step (2), reaction is under acid binding agent effect, and ethyl chloroformate generation esterification, (Z)-4'-(bromomethyl)-N’The mol ratio of-hydroxyl-[1,1'-biphenyl]-2-amidine and ethyl chloroformate is 1:1 ~ 3. Acid binding agent includes triethylamine, methylamine, dimethylamine, Feldalat NM and Sodium ethylate etc., wherein preferred triethylamine. Reaction dissolvent is dichloromethane, oxolane and acetonitrile etc., it is preferable that dichloromethane and oxolane.
Reaction described in step (3) is to carry out under reflux state in organic solvent, and temperature range is at 60 ~ 110 DEG C, it is preferable that 70 ~ 80 DEG C;
Described in step (4), reaction is under the effect of acid binding agent, there is condensation reaction in raw material III and intermediate VII, acid binding agent includes sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium bicarbonate, triethylamine, pyridine, methylamine, dimethylamine, Feldalat NM and Sodium ethylate etc., it is preferable that potassium carbonate and sodium carbonate. Reaction dissolvent comprises acetonitrile, methanol, ethanol, toluene etc., it is preferable that methanol and ethanol. Range of reaction temperature 10 ~ 90 DEG C, it is preferable that 60 ~ 80 DEG C.
Described in step (5), reaction is the reaction that is hydrolyzed in the basic conditions, and alkaline reagent includes sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and Lithium hydrate etc., it is preferable that sodium hydroxide, potassium hydroxide and Lithium hydrate.
This invention has the advantage that
1, raw material is easy to get, 2-ethyoxyl-1H-benzimidazole-7-carboxylate methyl ester and 2-cyano group-4 ' the domestic all easily buying of two kinds of crucial starting materials of-bromomethylbiphenyl is arrived, and price is relatively low;
2, route is shorter, shortens single step reaction than route one, shortens seven step reactions than route two;
3, do not use severe toxicity and be not suitable for the raw material of industrialized great production, as thionyl chloride, sodium azide, hydrazine hydrate etc.;
4, product quality is better, and purity is higher;
5, total recovery is high, the cost of raw material is low
Detailed description of the invention
Following embodiment is only used for further illustrating the present invention, is not limiting as the present invention. All changes within the scope of the present invention or in the equivalent scope of the invention are all included in the invention.
Example 1 (Z)-4'-(bromomethyl)-N’Prepared by-hydroxyl-[1,1'-biphenyl]-2-amidine
100ml dimethyl sulfoxide is added in dry reaction bulb, add 182g oxammonium hydrochloride., stir molten clear after, add raw material 2-cyano group-4 '-bromomethylbiphenyl 60g, temperature 25-30 DEG C in controlling, adds 302g natrium carbonicum calcinatum, is warming up to 75-80 DEG C, insulation reaction, controls (until 2-cyano group-4 '-bromomethylbiphenyl≤0.5% till) with in HPLC.It is cooled to 20-30 DEG C, is slowly added to 3L water, finishes, continue stirring 1 hour. Sucking filtration, filter cake about 200ml water washing, sucking filtration is to dry, in 50 ± 5 DEG C of drying under reduced pressure, (Z)-4'-(bromomethyl)-N’-hydroxyl-[1,1'-biphenyl]-2-amidine dry product 57g. Yield 85.4%, purity 96.7%.
Example 2 (Z)-4'-(bromomethyl)-N’Prepared by-hydroxyl-[1,1'-biphenyl]-2-amidine
Join 69.5g oxammonium hydrochloride. in 400ml oxolane to stir and molten be added dropwise to the methanol solution 210g of the Feldalat NM of 27% under room temperature clearly, stir 10 minutes, add 54.2g2-cyano group-4 '-bromomethylbiphenyl, in 90 ~ 95 DEG C of stirring reactions, control (until 2-cyano group-4 '-bromomethylbiphenyl≤0.5% till) with in HPLC, be cooled to 20-30 DEG C, 1.2L water it is added dropwise under room temperature, stir 30 minutes, filter, use 100 water washings, in 50 ~ 60 drying under reduced pressure, (Z)-4'-(bromomethyl)-N’-hydroxyl-[1,1'-biphenyl]-2-amidine dry product 54.6g, yield 89.9%, purity 95.8%
Example 3 (Z)-4'-(bromomethyl)-N’Prepared by-hydroxyl-[1,1'-biphenyl]-2-amidine
Join 139g oxammonium hydrochloride. in 750ml ethanol to stir and molten be added dropwise to 220g triethylamine under room temperature clearly, stir 60 minutes 35 ~ 40, add 66g2-cyano group-4 '-bromomethylbiphenyl, in 65 ~ 70 stirring reactions, control (until 2-cyano group-4 '-bromomethylbiphenyl≤0.5% till) with in HPLC, be cooled to room temperature, 2L water it is added dropwise under room temperature, stirring 1h, filters, uses 150ml water washing, in 50 ~ 60 drying under reduced pressure, (Z)-4'-(bromomethyl)-N’-hydroxyl-[1,1'-biphenyl]-2-amidine dry product 59.2g, yield 79.8%, purity 96.4%
Example 4 (Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl] is prepared by-2-amidine
Add in dry reaction bulb 1000ml dichloromethane and 56g (Z)-4'-(bromomethyl)-N’-hydroxyl-[1,1'-biphenyl]-2-amidine, stir molten clearly, be cooled to 10-15 DEG C add 28g triethylamine, dropping 24g ethyl chloroformate is to reaction bulb, drip and finish, be warming up to 30-40 DEG C of reaction 3h, after reacting completely, be cooled to 0-5 DEG C, 370ml water is added to reaction bulb, stirring, is layered after standing, and organic layer is again with 100ml × 2 water washing twice. Organic layer decompression is distilled to disconnected evaporating, obtain intermediate (Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine 64.2g, yield 92.7%, purity 97.3%.
Example 5 (Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl] is prepared by-2-amidine
By 80g (Z)-4'-(bromomethyl)-N’-hydroxyl-[1,1'-biphenyl]-2-amidine and 300ml oxolane add dry reaction bulb, stir molten clear after, be cooled to 10-15 DEG C, add 53g triethylamine, under cooling, be added dropwise to ethyl chloroformate 56.8g, 4h is stirred at room temperature, filter, oxolane washs. Filtrate be concentrated into dry (Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine 95.9g, yield 97.0%, purity 94.2%.
Example 6 (Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl] is prepared by-2-amidine
By 80g (Z)-4'-(bromomethyl)-N’-hydroxyl-[1,1'-biphenyl]-2-amidine and 300ml oxolane add dry reaction bulb, stir molten clear after, be cooled to 0 ~ 5 DEG C, add 53g triethylamine. Being cooled to 0 ~ 5 DEG C, drip ethyl chloroformate 85.3g, react 6h in 0 ~ 5 DEG C, filter, oxolane washs, and is evaporated to dry, adds 200ml ethanol, stirs 2h, adds 30ml washing with alcohol, in 50 ~ 60 drying under reduced pressure, (Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine 87.9g, yield 88.9% purity 99.1%.
Example 73-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H) prepared by-one
Will (Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine 50g and 250ml toluene add in clean reaction bulb, and stirring is warming up to back flow reaction. Control with in HPLC, after reacting completely, be cooled to 0-5 DEG C, insulation crystallize 2 hours. Sucking filtration, washs with 10ml toluene, and sucking filtration, to dry, in 50 ~ 60 drying under reduced pressure, obtains 3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one 38.2g, yield 86.7%, purity 98.0%.
Example 83-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H) prepared by-one
Will (Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine 50g and 200ml ethanol add in clean reaction bulb, and stirring is warming up to back flow reaction. Control with in HPLC, after reacting completely, be cooled to 0-5 DEG C, insulation crystallize 2 hours. Sucking filtration, uses 10ml washing with alcohol, and sucking filtration, to dry, in 50 ~ 60 drying under reduced pressure, obtains 3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one 37.1g, yield 84.2%, purity 98.8%.
Example 93-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H) prepared by-one
Will (Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine 50g and 200ml methanol add in clean reaction bulb, and stirring is warming up to back flow reaction. Control with in HPLC, after reacting completely, be cooled to 0-5 DEG C, insulation crystallize 3 hours. Sucking filtration, washs with 8ml methanol, and sucking filtration, to dry, in 50 ~ 60 drying under reduced pressure, obtains 3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one 35.4g, yield 80.5%, purity 99.2%.
Example 102-ethyoxyl-1-((2 '-(2,5-dihydro-5-oxygen-1,2,4-diazole-3-base) double; two phenyl-4-bases) methyl) prepared by benzimidazole-7-carboxylate methyl ester
By 55g2-ethyoxyl-1H-benzimidazole-7-carboxylate methyl ester and 300ml methanol add clean reaction bulb, are stirred at room temperature 10 minutes, add 68.8g potassium carbonate and 78.3g3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one. Stir 24h, evaporated under reduced pressure methanol in 20 ~ 30 DEG C, add 1600ml water stirring half an hour, filter, 100ml water washing, sucking filtration to dry, solid 200ml methanol temperature rising reflux molten clear after, be cooled to 0-5 DEG C, insulation crystallize 2 hours. Sucking filtration, washs with 20ml methanol, and sucking filtration is to dry, in 50 ~ 60 drying under reduced pressure, 2-ethyoxyl-1-((2 '-(2,5-dihydro-5-oxygen-1,2,4-diazole-3-base) double; two phenyl-4-bases) methyl) benzimidazole-7-carboxylate methyl ester 76.7g, yield 68.9%, purity 99.4%.
Example 112-ethyoxyl-1-((2 '-(2,5-dihydro-5-oxygen-1,2,4-diazole-3-base) double; two phenyl-4-bases) methyl) prepared by benzimidazole-7-carboxylate methyl ester
By 50g2-ethyoxyl-1H-benzimidazole-7-carboxylate methyl ester and 300ml methanol add clean reaction bulb, are stirred at room temperature 10 minutes, add 34g potassium carbonate, 62.6g3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one and tetrabutyl ammonium bromide 4.2g. Intensification is stirred at reflux 14h, evaporated under reduced pressure methanol, adds 1500ml water stirring half an hour, filters, 80ml water washing, sucking filtration to dry, solid 180ml methanol temperature rising reflux molten clear after, be cooled to 0-5 DEG C, insulation crystallize 2 hours.Sucking filtration, washs with 20ml methanol, and sucking filtration is to dry, in 50 ~ 60 drying under reduced pressure, 2-ethyoxyl-1-((2 '-(2,5-dihydro-5-oxygen-1,2,4-diazole-3-base) double; two phenyl-4-bases) methyl) benzimidazole-7-carboxylate methyl ester 66.7g, yield 75.0%, purity 99.2%.
Example 122-ethyoxyl-1-((2 '-(2,5-dihydro-5-oxygen-1,2,4-diazole-3-base) double; two phenyl-4-bases) methyl) prepared by benzimidazole-7-carboxylate methyl ester
By 60g2-ethyoxyl-1H-benzimidazole-7-carboxylate methyl ester and 500ml ethanol add clean reaction bulb, are stirred at room temperature 10 minutes, add 75.5g potassium carbonate, 60.3g3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one and tetrabutyl ammonium bromide 4.8g, heat up and be stirred at reflux 10h, evaporated under reduced pressure ethanol, add 1800ml water stirring half an hour, filter, 120ml water washing, sucking filtration to dry, solid 400ml ethanol temperature rising reflux molten clear after, be cooled to 0-5 DEG C, insulation crystallize 2 hours. Sucking filtration, uses 20ml washing with alcohol, and sucking filtration is to dry, in 50 ~ 60 drying under reduced pressure, 2-ethyoxyl-1-((2 '-(2,5-dihydro-5-oxygen-1,2,4-diazole-3-base) double; two phenyl-4-bases) methyl) benzimidazole-7-carboxylate methyl ester 66.8g, yield 78.0%, purity 98.9%.
Prepared by example 13 Azilsartan
By 65g intermediate 2-ethyoxyl-1-((2 '-(2,5-dihydro-5-oxygen-1,2,4-diazole-3-base) double; two phenyl-4-bases) methyl) benzimidazole-7-carboxylate methyl ester and 620ml methanol adds in reaction bulb, open stirring, add 160g10% sodium hydroxide solution, rise to backflow insulation reaction, control with in HPLC. Being cooled to 15-25 DEG C after reacting completely, add 18g activated carbon, stirring is decoloured half an hour. Sucking filtration, with the washing of 30ml purified water, sucking filtration, to dry, drips hydrochloric acid, adjusts pH to 2 ~ 3, tune to finish stirring 1h, sucking filtration, washs by 30ml purified water, and sucking filtration is to doing to obtain crude product.
Being added by crude product in 200ml methanol, open stirring, temperature rising reflux 1h, be cooled to 0 ~ 5 DEG C, stir 1h, sucking filtration, wash with 20ml methanol, sucking filtration, to dry, is dried to dry Azilsartan finished product 56.1g, yield 89.1%, purity 99.6% in 60 ~ 70 DEG C.
Prepared by example 14 Azilsartan
By 55g intermediate 2-ethyoxyl-1-((2 '-(2,5-dihydro-5-oxygen-1,2,4-diazole-3-base) double; two phenyl-4-bases) methyl) benzimidazole-7-carboxylate methyl ester and 400ml methanol adds in reaction bulb, open stirring, add 160g10% potassium hydroxide solution, rise to backflow insulation reaction, control with in HPLC. Being cooled to 15-25 DEG C after reacting completely, add 15g activated carbon, stirring is decoloured half an hour. Sucking filtration, with the washing of 40ml purified water, sucking filtration, to dry, drips hydrochloric acid, adjusts pH to 2 ~ 3, tune to finish stirring 1h, sucking filtration, washs by 40ml purified water, and sucking filtration is to doing to obtain crude product.
Crude product adding recrystallization in 400ml1,4-dioxane, is cooled to 0 ~ 5 DEG C, stir 1h, sucking filtration, wash with 30ml1,4-dioxane, sucking filtration, to dry, is dried to dry Azilsartan finished product 44.8g, yield 84.1%, purity 99.9% in 80 ~ 90 DEG C.
Prepared by example 15 Azilsartan
By 60g intermediate 2-ethyoxyl-1-((2 '-(2,5-dihydro-5-oxygen-1,2,4-diazole-3-base) double; two phenyl-4-bases) methyl) benzimidazole-7-carboxylate methyl ester and 600ml ethanol adds in reaction bulb, open stirring, add 150g10% lithium hydroxide solution, rise to backflow insulation reaction. Control with in HPLC.Being cooled to 15-25 DEG C after reacting completely, add 15g activated carbon, stirring is decoloured half an hour. Sucking filtration, with the washing of 50ml purified water, sucking filtration, to dry, drips hydrochloric acid, adjusts pH to 2 ~ 3, tune to finish stirring 1h, sucking filtration, washs by 40ml purified water, and sucking filtration is to doing to obtain crude product.
Being added by crude product in 200ml ethanol, open stirring, temperature rising reflux 1h, be cooled to 0 ~ 5 DEG C, stir 1h, sucking filtration, use 20ml washing with alcohol, sucking filtration, to dry, is dried to dry Azilsartan finished product 53.3g, yield 88.2%, purity 99.7% in 60 ~ 70 DEG C.
Claims (12)
1.(Z)-4'-(bromomethyl)-N’-hydroxyl-[1,1'-biphenyl]-2-amidine (VI)
(Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine (VII)
3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one (VIII)
A kind of new method preparing Azilsartan, its synthetic route is as follows:
Comprise the following steps:
(1) beginning material 2-cyano group-4 '-bromomethylbiphenyl (IV) by oxammonium hydrochloride. reduction generate intermediate (Z)-4'-(bromomethyl)-N’-hydroxyl-[1,1'-biphenyl]-2-amidine (V);
(2) intermediate V and ethyl chloroformate esterification obtain intermediate (Z)-4'-(bromomethyl)-N’-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine (VI);
(3) intermediate VI cyclization obtains intermediate 3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one (VII);
(4) raw material III and intermediate VII condensation obtain intermediate 2-ethyoxyl-1-((2 '-(2,5-dihydro-5-oxygen-1,2,4-diazole-3-base) V pair phenyl-4-base) methyl) benzimidazole-7-carboxylate methyl ester (VIII);
(5) intermediate VIII hydrolysis obtains Azilsartan (I).
2. 2-cyano group-4 described in step (2) in claim 4 '-bromomethylbiphenyl and oxammonium hydrochloride. mole ratio be 1:2 ~ 20, it is preferable that 1:5 ~ 12.
3. free hydrochloric acid azanol agents useful for same is sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium bicarbonate, triethylamine, pyridine, methylamine, dimethylamine, Feldalat NM and Sodium ethylate etc., it is preferable that sodium carbonate, Feldalat NM, triethylamine.
4. reaction dissolvent comprises acetonitrile, acetone, dimethyl sulfoxide, oxolane and ethanol etc., it is preferable that dimethyl sulfoxide, oxolane, ethanol.
5. in claim 4, described in step (3), reaction is under acid binding agent effect, and chloro-carbonic acid triethyl generation esterification, (Z)-4'-(bromomethyl)-N’The mol ratio of-hydroxyl-[1,1'-biphenyl]-2-amidine and ethyl chloroformate is 1:1 ~ 3.
6. acid binding agent includes triethylamine, methylamine, dimethylamine, Feldalat NM and Sodium ethylate etc., wherein preferred triethylamine.
7. reaction dissolvent is dichloromethane, oxolane and acetonitrile etc., it is preferable that dichloromethane and oxolane.
8. in claim 4, reaction described in step (4) is to carry out under reflux state in organic solvent, and temperature range is at 60 ~ 110 DEG C, it is preferable that 70 ~ 80 DEG C.
9. in claim 4, described in step (5), reaction is under the effect of acid binding agent, there is condensation reaction in raw material III and intermediate VII, acid binding agent includes sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium bicarbonate, triethylamine, pyridine, methylamine, dimethylamine, Feldalat NM and Sodium ethylate etc., it is preferable that potassium carbonate, sodium carbonate.
10. reaction dissolvent comprises acetonitrile, methanol, ethanol and toluene etc., it is preferable that methanol and ethanol.
11. range of reaction temperature 10 ~ 90 DEG C, it is preferable that 60 ~ 80 DEG C.
12. described in step (6), reaction is the reaction that is hydrolyzed in the basic conditions in claim 4, alkaline reagent includes sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and Lithium hydrate etc., it is preferable that sodium hydroxide, potassium hydroxide and Lithium hydrate.
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| WO2017131218A1 (en) * | 2016-01-28 | 2017-08-03 | 株式会社トクヤマ | Azilsartan and method for producing same |
| CN107325092A (en) * | 2017-08-07 | 2017-11-07 | 山东鲁宁药业有限公司 | A kind of new preparation process of Azilsartan |
| JP2018087178A (en) * | 2016-11-30 | 2018-06-07 | 株式会社トクヤマ | Method for producing azilsartan |
| CN108640911A (en) * | 2018-04-03 | 2018-10-12 | 山东科兴生物制品有限公司 | A kind of novel processing step of Azilsartan |
| JP2021059607A (en) * | 2021-01-21 | 2021-04-15 | 株式会社トクヤマ | Azilsartan alkyl ester, method for producing azilsartan methyl ester, and method for producing azilsartan |
| CN112898287A (en) * | 2020-12-31 | 2021-06-04 | 南京国星生物技术研究院有限公司 | Preparation method of azilsartan |
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| CN112898287A (en) * | 2020-12-31 | 2021-06-04 | 南京国星生物技术研究院有限公司 | Preparation method of azilsartan |
| JP2021059607A (en) * | 2021-01-21 | 2021-04-15 | 株式会社トクヤマ | Azilsartan alkyl ester, method for producing azilsartan methyl ester, and method for producing azilsartan |
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