CN103319414A - Improved telmisartan preparation process - Google Patents

Improved telmisartan preparation process Download PDF

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Publication number
CN103319414A
CN103319414A CN 201310270872 CN201310270872A CN103319414A CN 103319414 A CN103319414 A CN 103319414A CN 201310270872 CN201310270872 CN 201310270872 CN 201310270872 A CN201310270872 A CN 201310270872A CN 103319414 A CN103319414 A CN 103319414A
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reaction
methyl
product
acid
cyclization
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CN 201310270872
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周智明
苏晓军
章军
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Beijing Institute of Technology BIT
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Beijing Institute of Technology BIT
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Abstract

The invention provides an improved process for preparing a telmisartan raw material medicament. The improved process comprises the following step: preparing an intermediate 2-n-propyl-4-methyl-benzimidazole-6-carboxylic acid by using methyl 4-butylacetamino-3-methylbenzoate as a raw material through four steps, namely nitration, reduction, cyclization and hydrolysis. According to the process, crude products in nitrification, reduction and cyclization reactions are not subjected to purification and separation, and a target product can be separated by regulating the pH of a reaction liquid obtained in a hydrolysis reaction to be between 6 and 7, so that the problems of complicated operation and yield loss caused by separation of nitrified and reduced products by recrystallization and chromatographic separation of a cyclized product by a column are solved. Therefore, the purity of the prepared telmisartan crude product is over 99 percent after recrystallization. The improved process is simple to operate, high in yield and low in cost, and is advantageous to industrial production.

Description

Telmisartan preparation technology's improvement
Technical field
The invention belongs to organic chemistry filed, thereby specifically be the production cost of simplifying the production operation reduction telmisartan of 2-n-propyl-4-methyl-benzoglyoxaline-6-carboxylic acid.
Background technology
2-n-propyl-4-methyl-benzoglyoxaline-6-carboxylic acid is a key intermediate of preparation antihypertensive drug telmisartan.And telmisartan can block renin-angiotensin system fully because having the effect of specificity inhibition AT II.Telmisartan is the longest AT II receptor antagonist class medicine of transformation period in addition, so it becomes one of hypertensive medicine for the treatment of commonly used clinically.
Synthesis technique for 2-n-propyl-4-methyl-benzoglyoxaline-6-carboxylic acid, have a lot of relevant patents and bibliographical information (as CN101838243A, CN101921235A, CN1412183A, US5591762, CN102267949A, WO200510837, J.Med.chem.1993,36 (25) 4040-4051) both at home and abroad.Bibliographical information 2-n-propyl-4-methyl-benzoglyoxaline-the most frequently used synthetic method of 6-carboxylic acid is to be made through nitrated, reduction, cyclization and hydrolysis by the positive amide-based small methyl benzoate 4 of 3-methyl-4-.Wherein the reaction formula of nitration reaction is as follows:
The nitration reaction products therefrom is outside the master divided by the positive amide-based small of 3-methyl-4--5-nitrobenzoic acid methyl esters 5, and also have following several: (1) nitro is in single nitration product (5a or 5b) of methyl ortho para; (2) all there is many nitrations product (5c) of nitro at methyl and n-Butyl Amine 99 acyl group ortho position.The pure system of nitrated crude product is the difficult problem that nitration reaction will solve.Because main by product 5a, 5b only are the position of functional group isomer of principal product 5, close structure extremely is unfavorable for the pure system of nitrated crude product.Wherein bibliographical information is to the separating of 5a, 5b and 5c, and the method that adopts is recrystallization or column chromatography usually.In addition, compound 5 crude product after reducing also needs recrystallization to purify; And the purification of cyclization product is used especially the column chromatography of complex operation.Adopt the pure system loss of recrystallization method bigger, each recrystallization loss will account for about 10% of product, and a recrystallization is difficult to obtain satisfied pure products; Adopt column chromatography for separation, cost is too high, is unfavorable for suitability for industrialized production.
Therefore, purpose of the present invention is for providing a kind of technology of improved preparation telmisartan, in the process of nitrated, reduction, cyclization, hydrolysis four steps preparation 2-n-propyl-4-methyl-benzoglyoxaline-6-carboxylic acid, the separation of not purifying of the crude product of nitrated, reduction and ring-closure reaction, separate out the purpose that target product reaches purification by pH to 6~7 of regulating hydrolysis reaction gained reaction solution, simplify the operation course, improve target product yield, be more suitable in suitability for industrialized production.
Summary of the invention
The objective of the invention is to solve that cost height in the existing telmisartan synthesis technique, environmental pollution are big, complex operation etc. is unfavorable for industrial difficult point problem, a kind of novel process for preparing telmisartan is provided, this technological operation is simple and easy, cost is low, environmental pollution is little, yield is higher, is fit to suitability for industrialized production.
The synthetic route that the present invention adopts is as follows:
The present invention includes the following step:
Compound 4 in-15~-12 ℃, reacted 3~5 hours under the effect of 95% nitrosonitric acid.After elutriation on the rocks went out yellow solid, filtration, filtration cakes torrefaction got compound 5 crude products.The crude product of compound 5 behind the hydrogenation reduction, filters filtering catalysis and adds under Raney Ni catalysis, pressurization steam desolventize compound 6 crude products.The crude product of compound 6 back flow reaction 1 hour under the Glacial acetic acid effect removes Glacial acetic acid under reduced pressure, hydrolysis in the methanol-water system, steam except conditioned reaction liquid pH behind the methyl alcohol be 6~7 get final product compound 7 elaboration.
The present invention has following advantage:
1. simplified control is compared other technology, preparation midbody compound 5,6 and the cyclization product all do not relate to and separate the purification problem, therefore can shorten the production cycle, reduce production costs, improve productive rate.
2. environmental pollution is little, replaces nitric-sulfuric acid as nitrating agent with nitrosonitric acid, reduces the difficulty of wastewater treatment, thereby saves production cost.
Embodiment:
The invention will be further described below in conjunction with embodiment, but and can't help these examples and limit the scope of the invention.
Embodiment 1
The preparation of 3-methyl-4-nitrobenzoic acid methyl esters (2)
In the 3L there-necked flask that reflux condensing tube and thermometer are housed of drying, add 300g3-methyl-4-nitrobenzoic acid 1(1.66mol) and 1000mL methyl alcohol, on reflux condensing tube, make a simple and easy device for absorbing tail gas, absorption liquid is the NaOH aqueous solution.Dropwise add 100g thionyl chloride (0.85mol) with constant pressure funnel under the induction stirring, the temperature of reaction solution is between 30-40 ℃ in the control dropping process, and this moment, reaction solution was milky white solution.About 45min dropwises, heat temperature raising to 60 ℃, and this moment, reactant was yellow clear solution.Stirring and refluxing reaction 2h stops heating under this temperature, and reaction solution slowly cools off, and separates out a large amount of solids during to 50 ℃.Continue cooling and be down to 30 ℃, 1000mL water is added in the reaction solution, stir about is emitted to no longer including gas half an hour, filtering reaction thing, gained filter cake be with 100mL * 3 water washings, in 40 ℃ dry 314g yellow powder shape solid, productive rate 97.2%, m.p.80~82 ℃.
Embodiment 2
The preparation of 3-methyl-4-Methyl anthranilate (3)
In 2L hydrogenation still, add the 1.2mL dehydrated alcohol, 6.5g Raney Ni catalyzer and 130g compound 2 pump air with oil pump, logical N 2Gas is drained air in the still for three times, leads to H in still 2Gas is to 1.2MPa.Adjust the reactor controller, be warming up to 80 ℃ after observing response still internal pressure, when hydrogen pressure no longer reduces, react 2h with this understanding.Reactant is cooled to room temperature, discharges remaining hydrogen in the still, emits reaction solution.Filter filtration catalizer removes alcohol solvent under reduced pressure, obtains the 105.5g white solid, yield 96.2%.
Embodiment 3
The preparation of the positive amide-based small methyl benzoate of 3-methyl-4-(4)
In the 3L there-necked flask that reflux condensing tube, thermometer are housed, add 182g(1.1mol) compound 3, add 1.6L acetonitrile and 350mL triethylamine successively under stirring.Under the ice-water bath condition, drip 160.5g n-butyryl chloride (1.5mol) in the there-necked flask by constant pressure funnel, the temperature in the control dropping process is no more than 20 ℃, this moment the reaction solution liquid that is creamy white.Drip and finish, slowly be warming up to backflow, the solution clear.Stirring reaction 2h naturally cools to room temperature, the white solid that filtering is separated out.Remove acetonitrile solution under reduced pressure, solid residue is used saturated Na respectively 2CO 3Solution and water washing are neutral until washings for several times.Filtration cakes torrefaction, behind the ethyl alcohol recrystallization white solid, the 229g that weighs, yield 88.5%, m.p.118~120 ℃.
Embodiment 4
The preparation of 4-methyl-2-n-propyl-1H-benzoglyoxaline-6-formic acid (7)
In having the 3L there-necked flask of thermometer, mechanical stirrer, add the positive amide-based small methyl benzoate of 300g3-methyl-4-4(1.275mol), place the cold cycle pump, setting medium temperature is-15 ℃, slowly drip the 900mL nitrosonitric acid with constant pressure funnel, the control rate of addition maintains between-15~-10 ℃ reacting liquid temperature.Dropwise the back in stirring reaction 3h, stopped reaction.Reaction solution is poured in the frozen water, separates out a large amount of yellow solids, suction filtration, and the filter cake washing obtains yellow solid 312.8g after the drying.
In 2L hydrogenation still, add the 1.2mL dehydrated alcohol, 6.25g Raney Ni catalyzer and 125g gained yellow solid pump air with oil pump, logical N 2Gas is drained air in the still for three times, leads to H in still 2Gas is to 2.2MPa.Adjust the reactor controller, be warming up to 80 ℃ after observing response still internal pressure, when hydrogen pressure no longer reduces, react 2h with this understanding.Reactant is cooled to room temperature, discharges remaining hydrogen in the still, emits reaction solution.Filter filtration catalizer removes alcohol solvent under reduced pressure, obtains faint yellow solid 100.5g.
In the 3L there-necked flask of thermometer, magnetic stirrer, reflux condensing tube and alkaline drying tube is housed, add the above-mentioned gained faint yellow solid of 200g (compound 6 crude products) and 1.2L Glacial acetic acid, after being heated to back flow reaction 1h, remove solvent acetic acid under reduced pressure, get the sticky thing of reddish-brown, extract with ethyl acetate (500mL * 3), the ester layer washes with water for several times to neutral, water layer extracts with ethyl acetate (100mL * 3), merge organic phase, after removing ethyl acetate under reduced pressure, add 800mL methyl alcohol and 400mL6molL -1The NaOH aqueous solution, heating, the reaction solution color is by the orange burgundy that gradually becomes, and refluxes and is down to room temperature behind the reaction 3h down.Steam except the methyl alcohol in the reaction solution, the dilute hydrochloric acid with 5% is regulated residuum pH to 6~7, leaves standstill the several seconds, separates out a large amount of solids.Suction filtration, filter cake wash with water for several times the back dry white solid 114.5g, calculating four step overall yields by raw material 4 is 57%, m.p.180~182 ℃.
Embodiment 5
(the preparation of 1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-1H-benzoglyoxaline (9) of 4-methyl-2-n-propyl-6-
Thermometer is being housed; add 114g (467.4mmol) N-methyl-o-phenylenediamine hydrochloride and 129g (467.4mmol) compound 7 in the 3L there-necked flask of mechanical stirrer and reflux condensing tube; add 1; 2-propylene glycol 1.8L; under nitrogen protection, begin heating; react 20h under the reflux conditions; this moment, reaction solution was blackish green; having reacted afterreaction liquid pours in the 2L frozen water; regulate pH to 9~10 with concentrated ammonia solution; separate out a large amount of green solid, filter, solid dissolves with the mixing solutions of 500mL ethyl acetate-methyl alcohol (30:5); the filtering insolubles; add activated carbon and boil the 30min decolouring, remove mixed solvent under reduced pressure, obtain white solid 134.5g; productive rate 71.5%, m.p.133~135 ℃.
Embodiment 6
4'-{[4-methyl-6-(1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)-2-n-propyl-1H-benzoglyoxaline-1-yl] methyl } preparation of biphenyl-2-methyl-formiate (11)
In the 3L there-necked flask of thermometer is housed, add 134.5g(442.5mmol) compound 9 and 1200mL N, dinethylformamide, place ice-water bath, add 59.2g potassium tert.-butoxide (527.2mmol) under the induction stirring, after the control temperature is-5~0 ℃ of stirring reaction 1h, add 161.0g compound 4'-bromomethylbiphenyl-2-methyl-formiate 10(527mmol in batches), rise to room temperature (about 30 ℃) naturally, about 8h afterreaction finishes.Pour in the 1000mL frozen water, fully stir the back with dichloromethane extraction (300mL * 3), merge organic phase, wash organic phase with water for several times, anhydrous MgSO 4Dry 4h, methylene dichloride is removed in decompression, gets white solid 191.5g, productive rate 82%, m.p.181~183 ℃.
Embodiment 7
The preparation of telmisartan (12)
In the 3L there-necked flask of reflux condensing tube is housed, add 190g(359.5mmol successively) compound 11, the NaOH aqueous solution of 1500mL methyl alcohol and 500mL10% fully mixes under the induction stirring, temperature rising reflux reaction 3h, reaction solution is cooled to room temperature, filter the filtering solid, remove solvent methanol under reduced pressure, the dilute hydrochloric acid with 10% is regulated pH and is about 5, separate out a large amount of faint yellow precipitations, filter the back dry cake, obtain the thick product 167.2g of telmisartan, productive rate 90.5%.
In having the 3000mL single port bottle of reflux condensing tube, add 167.2g telmisartan crude product, 5g gac and 835mL dimethyl formamide (DMF) respectively, be heated to 100 ℃ under the induction stirring.Filtered while hot filtering gac after stirring 30min under this temperature, filtrate naturally cools to the room temperature after-filtration, filter cake is used a small amount of dimethyl formamide (DMF) and water wash successively, the dry telmisartan highly finished product 151.3g that gets, the recrystallization yield is 90.5%, m.p.270~271 ℃, HPLC purity 〉=99.2.

Claims (5)

1. process modification for preparing telmisartan, it is characterized in that: when the positive amide-based small methyl benzoate of intermediate 3-methyl-4-prepares intermediate 2-n-propyl-4-methyl-benzoglyoxaline-6-carboxylic acid through nitrated, reduction, cyclization, hydrolysis four-step reaction, crude product to nitrated, reduction and ring-closure reaction is not purified, and is 6~7 to reach the purification purpose by the pH that regulates hydrolysis reaction gained reaction solution.
2. by the described method for preparing 2-n-propyl-4-methyl-benzoglyoxaline-6-carboxylic acid of claim 1, it comprises following step:
(a) be that raw material carries out nitration reaction with the positive amide-based small methyl benzoate of 3-methyl-4-.Add elutriation after reaction finishes and go out solid, filter and wash with water filter cake, the dry nitration product that gets.
(b) nitration product of step (a) gained carries out hydrogenation reduction.Reaction finishes the after-filtration filtration catalizer, removes solvent under reduced pressure and gets reduzate.
(c) reduzate cyclization in Glacial acetic acid of step (b) gained.Reaction removes the cyclization product that Glacial acetic acid gets thickness under reduced pressure after finishing.
(d) the thick product of step (c) gained steams except ethyl acetate after with ethyl acetate extraction, in the mixed solvent of methanol-water, adds the mineral alkali reaction that is hydrolyzed.Reaction removes methyl alcohol under reduced pressure after finishing, and pH is 6~7 with dilute hydrochloric acid conditioned reaction liquid, leaves standstill and separates out solid, filtration, washing, the dry 2-n-propyl-4-methyl-benzoglyoxaline-6-carboxylic acid that gets.
3. by claim 1 and 2 described methods, wherein the used nitrating agent of nitration reaction is nitrosonitric acid, the volume of nitrosonitric acid is 3~5 times of the positive amide-based small methyl benzoate of 3-methyl-4-quality, and temperature of reaction is-15~-12 ℃, and the reaction times is 3~5 hours.
4. by claim 1 and 2 described methods, wherein the ring-closure reaction condition is: the volumetric usage of Glacial acetic acid is 5~10 times of reduzate quality, and the reaction times is 50~80min, and temperature of reaction is 120~150 ℃.
5. by claim 1 and 2 described methods, wherein the used raw materials quality ratio of the used mixed solvent volume of hydrolysis reaction and ring-closure reaction is: 5:1~8:1, mixed solvent consist of methyl alcohol: 6molL -1The NaOH aqueous solution=1.8:1~2.2:1,80~120 ℃ of temperature of reaction, 3 hours reaction times.
CN 201310270872 2013-07-01 2013-07-01 Improved telmisartan preparation process Pending CN103319414A (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104610161A (en) * 2015-01-05 2015-05-13 河南师范大学 Preparation method for telmisartan
JP2015160810A (en) * 2014-02-26 2015-09-07 株式会社トクヤマ METHOD OF PRODUCING 4-METHYL-6(1-METHYLBENZIMIDAZOL-2-YL)-2-n-PROPYL-1H-BENZIMIDAZOLE
CN106008356A (en) * 2016-06-07 2016-10-12 浙江华海药业股份有限公司 Preparation method for telmisartan
CN107118161A (en) * 2017-05-05 2017-09-01 湖北工业大学 The synthetic method of the carboxylic acid of 2 n-propyl, 4 tolimidazole 6
CN110836943A (en) * 2019-11-29 2020-02-25 江西杏林白马药业有限公司 Analysis method for impurity detection of telmisartan tablets and telmisartan capsules
CN111423382A (en) * 2020-04-03 2020-07-17 南京国星生物技术研究院有限公司 Preparation method of telmisartan key intermediate
CN111925299A (en) * 2020-08-13 2020-11-13 浙江金立源药业有限公司 Continuous flow method for synthesizing 3-methyl-4-butyryl-5-nitrobenzoic acid methyl ester and reaction device thereof

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015160810A (en) * 2014-02-26 2015-09-07 株式会社トクヤマ METHOD OF PRODUCING 4-METHYL-6(1-METHYLBENZIMIDAZOL-2-YL)-2-n-PROPYL-1H-BENZIMIDAZOLE
CN104610161A (en) * 2015-01-05 2015-05-13 河南师范大学 Preparation method for telmisartan
CN106008356A (en) * 2016-06-07 2016-10-12 浙江华海药业股份有限公司 Preparation method for telmisartan
CN107118161A (en) * 2017-05-05 2017-09-01 湖北工业大学 The synthetic method of the carboxylic acid of 2 n-propyl, 4 tolimidazole 6
CN107118161B (en) * 2017-05-05 2019-12-31 湖北工业大学 Synthesis method of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid
CN110836943A (en) * 2019-11-29 2020-02-25 江西杏林白马药业有限公司 Analysis method for impurity detection of telmisartan tablets and telmisartan capsules
CN111423382A (en) * 2020-04-03 2020-07-17 南京国星生物技术研究院有限公司 Preparation method of telmisartan key intermediate
CN111423382B (en) * 2020-04-03 2022-03-15 南京国星生物技术研究院有限公司 Preparation method of telmisartan key intermediate
CN111925299A (en) * 2020-08-13 2020-11-13 浙江金立源药业有限公司 Continuous flow method for synthesizing 3-methyl-4-butyryl-5-nitrobenzoic acid methyl ester and reaction device thereof

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Application publication date: 20130925