CN105622595A - Novel preparation method of azilsartan medoxomil sylvite and its intermediate - Google Patents

Abstract

The invention relates to a novel preparation method of azilsartan medoxomil sylvite and its intermediate. The method comprises the following steps: hydrolyzing a starting material VII to obtain an intermediate IX, then performing esterification with a side chain IV to obtain the intermediate X; reducing the other starting material VIII by hydroxylamine hydrochloride to obtain the intermediate XI, then performing esterification with ethyl chloroformate to obtain the intermediate XII, and closing ring to obtain the intermediate XIII; performing condensation of the intermediate X and the intermediate XIII to obtain the intermediate II, and finally performing reaction with potassium isooctanoate to obtain the azilsartan medoxomil sylvite. The method has the advantages of easy acquisition of raw materials, short synthesis route, less equipment investment, less by-product, low toxicity, little pollution, environment protection, and high product purity, and is suitable for industrial production.

Description

A kind of Azilsartan ester potassium salt and the new preparation method of intermediate thereof

Technical field

The preparation method that the present invention relates to a kind of medical compounds, is specifically related to preparation Azilsartan ester potassium salt intermediate and the new preparation method of Azilsartan ester potassium salt.

Background technology

Hypertension is a kind of to continue to raise the chronic disease into main manifestations with arteriotony, often causes the pathological changes of the vitals such as the heart, brain, kidney and corresponding consequence occurs. Being the topmost risk factor of cardiovascular and cerebrovascular disease, apoplexy, heart failure and chronic kidney disease are its major complications. Reduce the blood pressure level of hyperpietic, can obviously reduce apoplexy and the events of heart attack, significantly improve the life quality of patient, effectively reduce Disease Spectrum. Owing to part hyperpietic there is no obvious clinical symptoms, hypertension is otherwise known as " the invisible killer " of human health. Therefore improve the understanding to hypertension, early prevention, in time treatment are had extremely important meaning.

Azilsartan (Azilsartan) is the medicine of a kind of new and effective treatment hypertension, its chemistry is by name: 2-ethyoxyl-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazoles-3-base) biphenyl-4-base] methyl] benzimidazole-7-carboxylic acid, following formula be shown in its chemical structural formula:

Azilsartan is as new angiotensin II receptor inhibitor, and in April, 2012 lists in Japan, and commodity are called " Azilsartan ", and specification is 20mg and 40mg, and the curative effect of its treatment hypertension has caused the extensive concern of industry, and the market demand is wide.

Azilsartan potassium salt (Azilsartankamedoxomil) is as Azilsartan prodrug, its structure is to connect (5-methyl-2-oxo-1 in 7 carboxylic acid positions of Azilsartan benzimidazole structure, 3-dioxole-4-base) methyl ester, azoles ring is formed potassium salt, its chemistry is by name: (5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-diazole-3-base) biphenyl-4-base] methyl] benzimidazole-7-carboxylate potassium salt, following formula be shown in chemical structural formula:

This medicine is a kind of angiotensin ii receptor antagonist, and Takeda Pharmaceutical Company Limited of Japan completed this medicine phase iii clinical trial on April 28th, 2010, and before clinical, it has steadily lasting antihypertensive function with clinical research confirmation. And obtain food and drug administration (FDA) approval in February, 2011, it is used for treating hypertension, is considered the next-generation of candesartan Cilexetil.

Azilsartan potassium salt, in gastrointestinal absorption process, is hydrolyzed to activated product Azilsartan. In blood plasma, Azilsartan potassium is not detected after oral administration. After being administered with Azilsartan potassium, record the absolute bioavailability about 60% of Azilsartan. Azilsartan potassium is used for treating Adult Primary hypertension, it is recommended that dosage is that 80mg takes 1 time every day. Azilsartan potassium has steady blood pressure lowering, will not cause the advantage of dry cough, is reduced the risk of cardiovascular disease and diabetes by number of mechanisms, is an important new therapeutic choice for hyperpietic and health care professional thereof.

Pass through literature search, existing published patent and documents and materials, it it is all the key intermediate using Azilsartan ester as synthesis Azilsartan ester potassium salt, Azilsartan esterification formal name used at school is: (5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-diazole-3-base) biphenyl-4-base] methyl] benzimidazole-7-carboxylate, following formula be shown in its chemical structural formula:

Its chemical constitution is 7 carboxylic acids of Azilsartan benzimidazole structure and side chain 4-methylol-5-methyl isophthalic acid, 3-dioxole-2-ketone (IV) or side chain 4-chloromethyl-5-methyl isophthalic acid, and 3-dioxole-2-ketone (V) carries out esterification and obtains. The chemical structural formula of side chain IV and V is as follows:

Intermediate II and organic sylvite are obtained by reacting Azilsartan potassium salt, and its reaction equation is shown in following formula:

Therefore the emphasis studied just concentrates in the synthetic method of Azilsartan ester, and by literature search, the preparation method of current Azilsartan mainly has following two lines:

Route one: by first synthesizing Azilsartan, then prepare Azilsartan ester.

The document of this route report is relatively more; patent WO2013186792A(is hereinafter referred to as WO ' 792) report from fairly simple organic molecule material 3-nitrophthalic acid be starting material; through over-churning, acidylate, Azide, rearrangement, alkylation, deprotection, reduction nitro, cyclization imidazole ring; restore cyano group; it is esterified with ethyl chloroformate; close azoles ring again; hydrolysis obtains Azilsartan; last with side chain IV or side chain V, totally ten three-step reactions occurring to be esterified and obtain Azilsartan ester (II), synthetic route is as follows:

This route steps is many, 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.

Certainly some document prepares Azilsartan ester with certain intermediate of above-mentioned route for starting material, route such as patent CN1946717A report, this route is with Azilsartan (III) for starting material, occurring esterification to obtain Azilsartan ester (II) through side chain IV or side chain V, synthetic route is as follows:

This route initiation material is difficult to obtain, and the price of Azilsartan is higher, therefore this route cost is higher.

Additionally patent WO2012107814, is an intermediate 1-[(2'-cyanobiphenyl-4-base) the methyl]-2-ethyoxyl-1 with WO ' 792 routeH-benzimidazole-7-methyl formate (VI) is starting material, and its chemical structural formula is as follows:

Intermediate VI through cyano reduction, withN,N-carbonyl dimidazoles is esterified, and closes azoles ring, then hydrolysis obtains Azilsartan, and last and side chain IV or side chain V occur esterification four-step reaction altogether to obtain Azilsartan ester, and synthetic route is as follows:

Although the method has cut the step before intermediate VI, but needs to useN,N-carbonyl dimidazoles and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU) close azoles ring, andN,N-carbonyl dimidazoles and DBU price are all higher, and the amount adding DBU is also relatively larger, and therefore cost is higher, is not suitable for industrialized production.

Route two: being exchange the esterification of Azilsartan ester and azoles ring cyclization order, namely first allow the carboxylic acid on Azilsartan benzimidazole structure 7, with side chain IV or side chain V, esterification occurs, the then azoles ring on 1 biphenyl of cyclization, thus obtaining Azilsartan ester.

Such as patent WO2013114305A, with intermediate VI for starting material, through cyano reduction, hydrolysis, one-tenth sodium salt, the six-step processes such as 7 are esterified with side chain IV, the hydroxy esterification on amidino groups, azoles ring cyclization obtain Azilsartan ester (II), and synthetic route is as follows:

Owing to reaction temperature is higher when this route subject matter is the cyano reduction of VI, causing 2 easy scission of links of ethyoxyl, fall down ethyl, impurity increases; Hydroxyl on 7 carboxyls and amidino groups all easily reacts with side chain IV, thus introducing impurity, reduces yield (yield 71.%, purity 96.78%); Azoles ring cyclization one step adopts 110 ~ 115 DEG C of high temperature cyclizations, and yield is also very low (40.9%), is primarily due to lower 7 ester bonds of high temperature and is easy to caused by fracture. So yield is low in route, relatively costly, be not suitable for industrialized production.

Additionally patent CN103588764A, CN103588765A and WO ' 792 also discusses above-mentioned route, with intermediate (VI) for starting material, through cyano reduction, hydrolysis, the steps such as 7 are esterified with side chain IV or V, azoles ring cyclization. Equally existing problems with: temperature higher (115 ~ 120 DEG C) during (1) cyano group hydroxylamine reduction, during reaction, 2 easy scission of links of ethyoxyl, fall down ethyl, cause that impurity increases; Hydroxyl on (2) 7 carboxyls and amidino groups all easily reacts with side chain (IV), thus introducing impurity, yield reduces; (3) temperature significantly high (110 DEG C or 140 DEG C) during the cyclization of azoles ring, 7 established ester bonds are easy to fracture, cause that yield is low; (4) price comparison has been used during cyclization highN,N-carbonyl dimidazoles reagent, causes that cost of material is higher, is not suitable for industrialized production.

Additionally the amino also discussed above-mentioned route amidino groups in WO ' 792 is first protected, 7 with side chain V esterification after, then deprotection, finally cyclization again, synthetic route is as follows:

This method adds two steps on the basis of patent WO2013114305A route, adds raw materials consumption and production operation, and during deprotection, yield is not high (71.1%), reduces total recovery, causes that cost is significantly increased yet. The amino of amidino groups need not be protected by its tangible this, because the amino on amidino groups is also little with the probability that side chain IV or side chain V react.

In a word, route two is the route that an industrial practical significance is little, Azilsartan is first esterified closes azoles ring afterwards and there will be the side reaction that comparison is many in real reaction, the hydroxyl on amidino groups after exposing carboxylic acid and cyano reduction after being because the methyl ester hydrolysis of intermediate VI 7 has very strong activity, no matter it is all easily corresponding side reaction occurs simultaneously when esterification or cyclization, causing that impurity is more, yield is relatively low, and cost increases.

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. Process route of the present invention is as follows:

The preparation method that the invention provides a kind of Azilsartan ester potassium salt, further, the preparation method additionally providing each step intermediate. The present invention with the place that route one is identical with two is, first synthesis Azilsartan ester (II), then obtains Azilsartan ester potassium salt (I) with isooctyl acid nak response.

Process route of the present invention is as follows:

The present invention is with 2-ethyoxyl-1H'-bromomethylbiphenyl (VIII) is two crucial starting materials for-benzimidazole-7-carboxylate methyl ester (VII) and 2-cyano group-4, starting material VII is hydrolyzed in sodium hydroxide solution and obtains 2-ethyoxyl-3H-benzimidazole-7-carboxylic acid (��), then (5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1 is obtained with side chain IV esterificationH-benzo [d] imidazoles-7-carboxylate (��).

2-cyano group-4 '-bromomethylbiphenyl (VIII) by oxammonium hydrochloride. reduction generate (Z)-4'-(bromomethyl)-N��-hydroxyl-[1,1'-biphenyl]-2-amidine (��), then obtain with ethyl chloroformate esterification (Z)-4'-(bromomethyl)-N��-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine (��), then cyclization obtains 3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one (XIII).

Latter two important intermediate (5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1H-benzo [d] imidazoles-7-carboxylate (��) and 3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one (XIII) condensation obtains (5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-diazole-3-base) biphenyl-4-base] methyl] benzimidazole-7-carboxylate (II), then obtain Azilsartan ester potassium salt (I) with isooctyl acid nak response.

The present invention compares with route one, reactions steps length directly decreases six 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. Compared with route two, reactions steps is identical, but raw material is domestic all easily purchases, and price is cheaper, useless to pyroreaction, more energy efficient, it does not have the so many side reactions of route two, product quality is more excellent, total recovery is higher, lower in cost, is more conducive to industrialization large-scale production.

Preparation method of the present invention comprises the following steps:

(1) starting material VII is hydrolyzed in alkaline aqueous solution and obtains intermediate ��;

(2) intermediate �� obtains intermediate �� with side chain IV esterification;

(3) starting material VIII oxammonium hydrochloride. reduction obtains intermediate ��

(4) intermediate �� obtains intermediate �� with ethyl chloroformate esterification;

(5) intermediate �� cyclization obtains intermediate X III;

(6) intermediate �� and intermediate X III condensation obtain intermediate;

(7) intermediate II becomes potassium salt to obtain Azilsartan ester potassium salt I.

Further, wherein alkaline solution described in step (1) includes the solution such as Lithium hydrate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, it is preferable that Lithium hydrate, alkaline solution of sodium hydroxide.

Esterification described in step (2) is under acting at acid binding agent and catalyst, with side chain IV or side chain V, esterification occurs, catalyst select paratoluensulfonyl chloride, thionyl chloride, 2,4,6-trichloro-benzoyl chlorides etc., it is preferable that paratoluensulfonyl chloride and 2,4,6-trichloro-benzoyl chlorides; Acid binding agent comprises, pyridine,N,N-diisopropylethylamine, methylamine, dimethylamine, ethamine, diethylamine, sodium carbonate, potassium carbonate etc., it is preferable that triethylamine, sodium carbonate and potassium carbonate etc. Reaction dissolvent comprise ethyl acetate, dichloromethane, oxolane, acetonitrile,N,N-dimethylformamide,N,N-dimethyl acetylamide, methyl iso-butyl ketone (MIBK) etc., it is preferable that dichloromethane and oxolane etc. Reaction temperature 0 ~ 60 DEG C, it is preferable that 30 ~ 40 DEG C.

2-cyano group-4 described in step (3) '-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 (4), 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 (5) 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 (6), reaction is under the effect of acid binding agent, there is condensation reaction in intermediate �� and intermediate X III, 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 ~ 80 DEG C, it is preferable that 20 ~ 50 DEG C.

Described in step (7), reaction is to become potassium salt in organic solvent with isooctyl acid potassium, isooctyl acid potassium and Azilsartan ester (II) mole ratio are 1:1 ~ 2, preferred 1:1.2 ~ 1.5, organic solvent includes acetone, ethyl acetate, oxolane and acetonitrile etc., it is preferable that acetoneand ethyl acetate etc.

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 critical materialses of-bromomethylbiphenyl is arrived, and price is relatively low;

2, route is shorter, shortens seven step reactions than route one;

3, do not use severe toxicity and be not suitable for the raw material of industrialized great production, as thionyl chloride, sodium azide etc.;

4, not using the reaction such as high-pressure hydrogenation, high temperature, equipment investment is few, reduces energy consumption, has saved the energy, more environmental protection,

5, product quality is better, and purity is higher;

6, 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 12-ethyoxyl-3HPrepared by-benzimidazole-7-carboxylic acid

By 44g intermediate 2-ethyoxyl-1H-benzimidazole-7-carboxylate methyl ester and 300ml methanol add in reaction bulb, open stirring, add 120g10% sodium hydroxide solution, rise to backflow insulation reaction, control with in HPLC. 15-25 DEG C it is cooled to after reacting completely, the dilute hydrochloric acid of dropping 10%, to adjust pH to 1 ~ 2, adjust and finish stirring 1h, sucking filtration, wash by 30ml purified water, sucking filtration, to dry, in 55 ~ 65 DEG C of drying under reduced pressure to dry, obtains 2-ethyoxyl-3H-benzimidazole-7-carboxylic acid 37.9g, yield 92.0%, purity 98.3%.

Example 22-ethyoxyl-3HPrepared by-benzimidazole-7-carboxylic acid

By 55.1g intermediate 2-ethyoxyl-1H-benzimidazole-7-carboxylate methyl ester and 350ml methanol add in reaction bulb, open stirring, add 90g10% lithium hydroxide solution, rise to backflow insulation reaction, control with in HPLC. 15-25 DEG C it is cooled to after reacting completely, the dilute hydrochloric acid of dropping 10%, to adjust pH to 1 ~ 2, adjust and finish stirring 1h, sucking filtration, wash by 50ml purified water, sucking filtration, to dry, in 55 ~ 65 DEG C of drying under reduced pressure to dry, obtains 2-ethyoxyl-3H-benzimidazole-7-carboxylic acid 46.2g, yield 89.5%, purity 98.9%.

Example 3(5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1H-benzo [d] prepared by imidazoles-7-carboxylate

By 45g2-ethyoxyl-1H-benzimidazole-7-carboxylic acid and 500ml add dichloromethane in adding in reaction bulb, stirring is cooled to less than 20 DEG C, it is added dropwise to 50.7g triethylamine, drip and finish, be added dropwise to 54.0g paratoluensulfonyl chloride and 100ml dichloromethane mixed liquor, drip and finish in 10 ~ 20 DEG C of stirring reaction 3h, 39.7g4-methylol-5-methyl isophthalic acid is added in 10 ~ 20 DEG C, 3-dioxole-2-ketone, adds and is warming up to 30 ~ 40 DEG C of stirring reactions, controls with in HPLC. It is cooled to 15-25 DEG C after reacting completely, adds the stirring of 400ml purified water, layering, dry with 30g anhydrous sodium sulfate. Evaporated under reduced pressure dichloromethane, add 300ml methyl tertiary butyl ether(MTBE) to refine, it is cooled to 0 ~ 5 DEG C of stirring and crystallizing 3h, filter, the methyl tertiary butyl ether(MTBE) washing of 0 ~ 5 DEG C it is cooled to 20ml, (5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1 is obtained to dry in 40 ~ 50 DEG C of drying under reduced pressureH-benzo [d] imidazoles-7-carboxylate 63.6g. Yield 91.6%, purity 98.1%

Example 4(5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1H-benzo [d] prepared by imidazoles-7-carboxylate

By 60g2-ethyoxyl-1H-benzimidazole-7-carboxylic acid and 700ml add oxolane in adding in reaction bulb, stirring is cooled to less than 20 DEG C, adds 61.7g sodium carbonate, stirs 10 minutes, it is added dropwise to 92.3g2,4,6-trichloro-benzoyl chlorides and 150ml oxolane mixed liquor, drip and finish in 10 ~ 20 DEG C of stirring reaction 4h, 56.9g4-methylol-5-methyl isophthalic acid is added in 10 ~ 20 DEG C, 3-dioxole-2-ketone, adds and is warming up to 30 ~ 40 DEG C of stirring reactions, controls with in HPLC. 15-25 DEG C it is cooled to after reacting completely, filter, evaporated under reduced pressure oxolane, add 400ml methyl tertiary butyl ether(MTBE) to refine, it is cooled to 0 ~ 5 DEG C of stirring and crystallizing 3h, filters, be cooled to the methyl tertiary butyl ether(MTBE) washing of 0 ~ 5 DEG C with 40ml, (5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1 is obtained to dry in 40 ~ 50 DEG C of drying under reduced pressureH-benzo [d] imidazoles-7-carboxylate 82.8g. Yield 89.4%, purity 97.8%.

Example 5 (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 6 (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 7 (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 8 (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 9 (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 10 (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 113-(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 123-(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 133-(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 97.2%.

Prepared by example 14 Azilsartan ester

By 79.5g(5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1H-benzo [d] imidazoles-7-carboxylate and 300ml methanol adds clean reaction bulb, it is stirred at room temperature 10 minutes, adds 68.8g potassium carbonate and 78.0g3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one. Stir 24h in 20 ~ 30 DEG C, be cooled to 5 ~ 10 DEG C, filter, 20ml methanol washs, evaporated under reduced pressure methanol, adds the frozen water stirring of 400ml0 ~ 5 DEG C, adjust pH value to neutral, stir half an hour, filter, 50ml water washing, sucking filtration is to dry, solid 2500ml acetone temperature rising reflux molten clear after, be cooled to 0 ~ 5 DEG C, insulation crystallize 2 hours. Sucking filtration, uses 20ml washing with acetone, and sucking filtration, to dry, in 40 ~ 50 DEG C of drying under reduced pressure to dry, obtains Azilsartan ester 98.0g, yield 73.2%, purity 99.2%.

Prepared by example 15 Azilsartan ester

By 72.2g(5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1H-benzo [d] imidazoles-7-carboxylate and 300ml methanol adds clean reaction bulb, it is stirred at room temperature 10 minutes, adds 34g potassium carbonate and 62.0g3-(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, is cooled to 5 ~ 10 DEG C, filters, 20ml methanol washs, evaporated under reduced pressure methanol, adds the frozen water stirring of 300ml0 ~ 5 DEG C, adjust pH value to neutral, stir half an hour, filter, 50ml water washing, sucking filtration is to dry, solid 2100ml acetone temperature rising reflux molten clear after, be cooled to 0 ~ 5 DEG C, insulation crystallize 2 hours. Sucking filtration, uses 20ml washing with acetone, and sucking filtration, to dry, in 40 ~ 50 DEG C of drying under reduced pressure to dry, obtains Azilsartan ester 74.3g, yield 69.8%, purity 98.7%.

Prepared by example 16 Azilsartan ester

By 86.9g(5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1H-benzo [d] imidazoles-7-carboxylate and 500ml ethanol adds clean reaction bulb, it is stirred at room temperature 10 minutes, add 75.5g potassium carbonate and 60.0g3-(4 '-(bromomethyl)-[1, 1'-biphenyl]-2-base)-1, 2, 4-diazole-5(4H)-one and tetrabutyl ammonium bromide 4.8g, it is warming up to 40 ~ 50 DEG C, stirring reaction 10h, evaporated under reduced pressure ethanol, it is cooled to 5 ~ 10 DEG C, filter, 20ml washing with alcohol, evaporated under reduced pressure ethanol, add the frozen water stirring of 300ml0 ~ 5 DEG C, adjust pH value to neutral, stir half an hour, filter, 50ml water washing, sucking filtration is to dry, solid 2200ml acetone temperature rising reflux molten clear after, it is cooled to 0 ~ 5 DEG C, insulation crystallize 2 hours. sucking filtration, uses 20ml washing with acetone, and sucking filtration, to dry, in 40 ~ 50 DEG C of drying under reduced pressure to dry, obtains Azilsartan ester 80.3g, yield 77.9%, purity 99.1%.

Prepared by example 17 Azilsartan ester potassium salt

16g Azilsartan ester and 200ml acetone are added in reaction bulb, stirs half an hour, cool to the mixed liquor of 10 ~ 20 DEG C of dropping 6.2g isooctyl acid potassium and 80ml acetone, in 10 ~ 20 DEG C of stirring reactions, controlling with in HPLC, reaction cools to 0 ~ 5 DEG C after terminating, filter, the washing with acetone of 20ml cooling, sucking filtration, to dry, obtains Azilsartan ester potassium salt 14.9g in 40 ~ 50 DEG C of drying under reduced pressure, yield 87.8%, purity 99.7%.

Prepared by example 18 Azilsartan ester potassium salt

20g Azilsartan ester and 200ml ethyl acetate are added in reaction bulb, stirs half an hour, cool to the mixed liquor of 10 ~ 20 DEG C of dropping 9.6g isooctyl acid potassium and 80ml ethyl acetate, in 10 ~ 20 DEG C of stirring reactions, controlling with in HPLC, reaction cools to 0 ~ 5 DEG C after terminating, filter, the ethyl acetate washing of 20ml cooling, sucking filtration, to dry, obtains Azilsartan ester potassium salt 17.8g in 40 ~ 50 DEG C of drying under reduced pressure, yield 83.9%, purity 99.6%.

Claims (14)

1.(5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1H-benzo [d] imidazoles-7-carboxylate (��)

(Z)-4'-(bromomethyl)-N��-hydroxyl-[1,1'-biphenyl]-2-amidine (��)

(Z)-4'-(bromomethyl)-N��-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine (��)

3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one (XIII)

A kind of new method preparing Azilsartan, its synthetic route is as follows:

Comprise the following steps:

(1) starting material 2-ethyoxyl-1H-benzimidazole-7-carboxylate methyl ester (VII) is hydrolyzed in alkaline solution and obtains intermediate 2-ethyoxyl-3H-benzimidazole-7-carboxylic acid (��);

(2) intermediate �� and side chain 4-methylol-5-methyl isophthalic acid, 3-dioxole-2-ketone ester obtains intermediate (5-methyl-2-oxo-1,3-dioxole-4-base) methyl 2-ethyoxyl-1H-benzo [d] imidazoles-7-carboxylate (��)

(2) another starting material 2-cyano group-4 '-bromomethylbiphenyl (VIII) by oxammonium hydrochloride. reduction generate intermediate (Z)-4'-(bromomethyl)-N��-hydroxyl-[1,1'-biphenyl]-2-amidine (��);

(3) intermediate �� and ethyl chloroformate esterification obtain intermediate (Z)-4'-(bromomethyl)-N��-((carbethoxyl group) oxygen base)-[1,1'-biphenyl]-2-amidine (��);

(4) intermediate �� cyclization obtains intermediate 3-(4 '-(bromomethyl)-[1,1'-biphenyl]-2-base)-1,2,4-diazole-5(4H)-one (XIII);

(5) intermediate �� and intermediate X III condensation obtain intermediate Azilsartan (II);

(6) intermediate II and isooctyl acid nak response obtain Azilsartan ester potassium salt (I).

2. in claim 5, alkaline solution described in step (1) includes the solution such as Lithium hydrate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, it is preferable that Lithium hydrate, alkaline solution of sodium hydroxide.

3. in claim 5, esterification described in step (2) is under acting at acid binding agent and catalyst, with side chain 4-methylol-5-methyl isophthalic acid, 3-dioxole-2-ketone generation esterification, catalyst select paratoluensulfonyl chloride, thionyl chloride, 2,4,6-trichloro-benzoyl chlorides etc., it is preferable that paratoluensulfonyl chloride and 2,4,6-trichloro-benzoyl chlorides; Acid binding agent comprises, pyridine,N,N-diisopropylethylamine, methylamine, dimethylamine, ethamine, diethylamine, sodium carbonate, potassium carbonate etc., it is preferable that triethylamine, sodium carbonate and potassium carbonate etc.

4. reaction dissolvent comprise ethyl acetate, dichloromethane, oxolane, acetonitrile,N,N-dimethylformamide,N,N-dimethyl acetylamide, methyl iso-butyl ketone (MIBK) etc., it is preferable that dichloromethane and oxolane etc.

5. reaction temperature 0 ~ 60 DEG C, it is preferable that 30 ~ 40 DEG C.

6. 2-cyano group-4 described in step (3) in claim 5 '-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.

7. reaction dissolvent comprises acetonitrile, acetone, dimethyl sulfoxide, oxolane and ethanol etc., it is preferable that dimethyl sulfoxide, oxolane and ethanol etc.

8. in claim 5, described in step (4), 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.

9. acid binding agent includes triethylamine, methylamine, dimethylamine, Feldalat NM and Sodium ethylate etc., wherein preferred triethylamine.

10. reaction dissolvent is dichloromethane, oxolane and acetonitrile etc., it is preferable that dichloromethane and oxolane.

11. reaction described in step (5) is to carry out under reflux state in organic solvent in claim 5, temperature range is at 60 ~ 110 DEG C, it is preferable that 70 ~ 80 DEG C;

In claim 5, described in step (6), reaction is under the effect of acid binding agent, there is condensation reaction in intermediate �� and intermediate X III, 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.

12. reaction dissolvent comprises acetonitrile, methanol, ethanol, toluene etc., it is preferable that methanol and ethanol.

13. range of reaction temperature 10 ~ 80 DEG C, it is preferable that 20 ~ 50 DEG C.

14. described in step (7), reaction is to become potassium salt in organic solvent with isooctyl acid potassium in claim 5, isooctyl acid potassium and Azilsartan ester (II) mole ratio are 1:1 ~ 2, preferred 1:1.2 ~ 1.5, organic solvent includes acetone, ethyl acetate, oxolane and acetonitrile etc., it is preferable that acetoneand ethyl acetate etc.