A synthetic method of telmisartan

Technical Field

The invention belongs to the field of organic chemical synthesis, in particular relates to a synthesis method of telmisartan.

Background Art

Telmisartan, also known as the US card element, sha tingning, nation tanzania, sai equal, the chemical name 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} biphenyl -2 - carboxylic acid, in English Telmisartan, shown in the following formula.

The first telmisartan by the German BoehringerIngelheim pharmaceutical development, in 1999 for the first time in the United States listed, tradenames for Micardis. 2001 years in my import listed, is a new kind of blood pressure lowering medicines, is a specific angiotensin II receptor antagonists (AT1 type), which belongs to the chemical 2nd kind of new drug. Telmisartan alternative angiotensin II receptor with the AT1 receptor subtype (known angiotensin II site of action) high affinity binding. Telmisartan in AT1 receptor sites without any part of the agonist effect, the selectivity and the telmisartan AT1 receptor binding, the binding action of the lasting. Step-down stability does not cause cough. In many anti-hypertension drugs for treating angiotensin II receptor antagonists (ARB) is 20 century 90 emerging from a new generation of antihypertensive agent, the product as an angiotensin II receptor antagonist, has to maintain the normal regulating function of the cardiovascular system, the hypertension caused by the effective organ damage and the like, the efficacy is good and bad reaction is small, a once a day administration can stabilize the step-down, with the species than the early of the treatment on the characteristic of the further improved, is a relatively good antihypertensive drug.

The present domestic and foreign literature telmisartan more process route, the most commonly used method is the use of intermediate 2 - n-propyl -4 - methyl -6 - (1 - methyl - benzimidazole -2 - yl) - benzimidazole (compound 2) to synthesize telmisartan, compound 2 of the formula is shown as follows.

In order to compound 2 as raw material synthetic telmisartan has the following common method:

Wherein R=CN, or COOCH₃ , Or COOC (CH₃ )₃ .

A, cyano route (R=CN)

US20040236113 reported for compound 2 with 4' - bromomethyl biphenyl -2 - cyanoacetate reaction of the cyano derivatives of telmisartan, re-cyano hydrolysis telmisartan can be obtained. The method routes is comparatively simple, cyano hydrolysis is more fully, but intermediate 4' - bromomethyl biphenyl -2 - cyanoacetate is expensive, and synthetic process needs to be used in toxic sodium cyanide, more harmful to the human body, the environment also has a relatively large negative effects, thus limiting its use on a large scale.

Second, the route of the carboxylic acid methyl ester (R=COOCH₃ )

OrgProcResDev, 2007, 11 (1): 81 - 85 and US2007028784, US2006009488 literature reports such as the compound 2 with 4' - bromomethyl biphenyl -2 - methyl ester reaction, generating telmisartan carboxylic acid ester derivative, then hydrolyzed to obtain the telmisartan. The method synthesis route is relatively short, but hydrolysis reaction is not complete and easy, crude product purity is relatively low, the after-treatment is relatively complex, and the product needs to be refined.

Three, carboxylic acid tert-butyl route (R=COOC (CH₃ )₃ )

J.Med.Chem, 1993, 36 (25): 4040 - 4051 reported compound 2 with 4' - bromomethyl biphenyl -2 - tert-butyl reaction generating telmisartan carboxylic acid tert-butyl derivatives, then hydrolyzed to obtain the telmisartan, route similar with the carboxylic acid methyl ester, tert-butyl hydrolysis reaction is not complete and easy, and the reaction is not stable, tert-butyl easy to remove, the reaction is not easy to control, more impurities, the purity of the crude product is relatively low, the yield is relatively low, is not conducive to large-scale industrial production.

Four, to bromine bromine animal pen line

US20060264644 reported compound 2 with generated by the reaction to the bromine bromine animal pen, then palladium acetate as catalyst, tetrahydrofuran/potassium carbonate/triphenylphosphine common under the action of telmisartan, the reaction route is also relatively short, but the expensive bromine bromine animal pen, together with the water vapor and volatile, easy to sublimate, loss is large, often needs to add, so the raw materials and the cost is high.

Scheme 2 telmisartan synthesis route bromine bromine animal pen

The above method are to the same intermediate compound 2 as raw materials to synthesize telmisartan. Because of the 2 structure is also more complicated, it was not easy, the present its synthesis is by the simple structure of the 3 - methyl -4 - nitro benzoic acid (compound 5), through esterification, reduction, acylation, nitration, reduction, cyclization and condensation of the multi-step reaction.

2 - n-propyl -4 - methyl -6 - (1 - methyl - benzimidazole -2 - yl) - benzimidazole synthesis:

Line five: other synthetic routes

In addition, tang dynasty armed forces, such as CN101024631 chen weiren in reported of telmisartan in another synthesis method, the method to compound 11 as raw materials, chlorinated first acid radical, condensation, then with 4' - bromomethyl biphenyl -2 - tert-butyl (or methyl ester) reaction, finally through the two-step hydrolysis to obtain telmisartan, the despite the novel, but synthetic route is relatively long, the total yield is relatively low, so the material cost is very high, to the detriment of the industrial production.

The synthetic route above, have their own advantages, there are also some disadvantages, there is a need to develop a new synthetic method of telmisartan.

Content of the invention

The present invention provides a kind of route the novel, cheap, and less environmental pollution of the telmisartan synthetic method.

A synthetic method of telmisartan, characterized in that comprises the following steps:

(1) to 2 - n-propyl -4 - methyl -6 - (1 - methyl - benzimidazole -2 - yl) - benzimidazole as raw materials, in the presence of acid, in order to N, N - dimethyl formamide (DMF), N, N - dimethyl acetamide (DME), dioxane or dimethyl sulfoxide (DMSO) as the solvent, and to amino bromo substitution reaction to produce 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} aniline (compound 16);

(2) 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} aniline in the sodium nitrite, hydrochloric acid, - 15 - 5 °C under the condition of the diazotization reaction, to obtain 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} chlorobenzene (compound 17);

(3) to palladium acetate, palladium chloride or sulfuric acid palladium are the catalyst, in order to tetrahydrofuran or methyl tetrahydrofuran as solvent, in potassium carbonate, under the combined action of triphenyl phosphorus, 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} chlorobenzene with 2 - carboxylic acid sodium benzene boric generate condensation reaction to obtain the telmisartan.

The invention telmisartan method for synthesis of the specific synthetic route are as follows:

Further, steps (1) capture can be chosen from potassium carbonate, potassium bicarbonate, sodium carbonate and other inorganic alkali, can also adopt the triethylamine or three n-butylamine and the like organic base, preferably potassium carbonate;

Step (2) diazotization reaction temperature is controlled at 0 - 5 °C.

In order to save resources, step (3) reaction catalyst and 2 - n-propyl -4 - methyl -6 - (1 - methyl - benzimidazole -2 - yl) - benzimidazole in the weight ratio of 0.001 - 0.02: 1.

Step (3) the temperature of condensation reaction selected 50 - 100 °C, preferably 65 °C.

Compared with the prior art, this invention has the following advantages:

The invention has developed a synthesis method of telmisartan, is a brand new synthetic route, there is greater innovative, raw materials to amino bromo of simple structure, low cost, and is easy to obtain, abandons the cyano line show the use of the drug sodium cyanide; avoids the carboxylic acid methyl ester (tert-butyl) ester hydrolysis route not completely, impurity is relatively large, the defect of low product purity; it also avoids bromine bromine animal pen route and other routes the disadvantage of relatively high cost of the raw material; mild reaction conditions, easy operation and control, less environmental pollution, is suitable for industrial production.

Mode of execution

The combination of the following specific embodiment of the invention further described, but the scope of protection of the present invention is not limited to this:

Embodiment 1 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} aniline preparation

In the 500 ml bottle into four 2 - n-propyl -4 - methyl -6 - (1 - methyl - benzimidazole -2 - yl) - benzimidazole 30.4 g (0.1 µM), DMSO 150 ml, opening stirring, then sequentially adding potassium carbonate 13.8 g (0.1 µM), P-bromo 18.6 g (0.1 µM), room temperature reaction 10 h, adding 1200 ml toluene, 600 ml water, stirring a moment, layered, organic layer after drying with anhydrous sodium sulfate, filtered, concentrated to obtain oil objects, adding hexane 50 ml, stirring a moment, solids are separated out, filtering and collecting solid, directly used in the next step.

Embodiment 2 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} chlorobenzene preparation

The upper step instead should be solid, adding 120 ml water, 100 mL30% hydrochloric acid, stirring and cooling, in the 0 - 5 °C dropping sodium nitrite solution (6.9 gNaNO₂ Dissolved in 30 g water), after finishing dripping, continue to thermal insulation 2 h, then adding copper chloride salt acid solution, placed after adding 2 h above, filtering, washing, drying to obtain a dried product 39.5 g, two step yield [...] 92.1%.

Example 3 preparation of telmisartan

2 - carboxylic acid sodium benzene boric 27.8 g (0.12 µM) dissolved in 40 ml water, 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} chlorobenzene 34.3 g (0.08 µM), methyl tetrahydrofuran 200 ml, potassium carbonate 16.6 g (0.12 µM), triphenylphosphine 31.5 g (0.12 µM), palladium acetate 0.5 g, nitrogen protection, raising the temperature to 65 °C, thermal insulation 20 h, then decompressing and steams methyl tetrahydrofuran, residue by adding 150 ml of water, adjusting pH with acetic acid to 5, separating solid, filtering, then using ethanol to recrystallize the, drying to obtain telmisartan 36.2 g, molar yield 88.0%.

Product of¹ H - NMR (DMSO - d₆ , 400 MHz); δ 7.66 - 7.69 (m, 3 H), 7.41 - 7.53 (m, 4 H), 7.15 - 7.30 (m, 7 H), 5.60 (s, 2 H), 3.80 (s, 3 H), 2.91 (m, 2 H), 2.60 (s, 3 H), 1.80 (m, 2 H), 0.98 (m, 2 H), shows that the product is telmisartan.

Embodiment 4 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} aniline preparation

In the 500 ml bottle into four 2 - n-propyl -4 - methyl -6 - (1 - methyl - benzimidazole -2 - yl) - benzimidazole 30.4 g (0.1 µM), DMF150mL, opening stirring, then sequentially adding potassium carbonate 13.8 g (0.1 µM), P-bromo 18.6 g (0.1 µM), room temperature reaction 12 h, adding 1200 ml toluene, 600 ml water, stirring a moment, layered, organic layer after drying with anhydrous sodium sulfate, filtered, concentrated to obtain oil objects, adding hexane, stirring a moment, solids are separated out, filtering and collecting solid, directly used in the next step.

Embodiment 5 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} chlorobenzene preparation

The embodiment 4 solid, adding 120 ml water, 100 mL30% hydrochloric acid, stirring and cooling, in the 0 - 5 °C dropping sodium nitrite solution (6.9 gNaNO₂ Dissolved in 30 g water), after finishing dripping, continue to thermal insulation 2 h, then adding copper chloride salt acid solution, placed after adding 2 h above, filtering, washing, drying to obtain a dried product 38.9 g, two step yield [...] 90.6%.

Example 6 preparation of telmisartan

2 - carboxylic acid sodium benzene boric 28.1 g (0.12 µM) dissolved in 40 ml water, 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} chlorobenzene 34.3 g (0.08 µM), methyl tetrahydrofuran 200 ml, potassium carbonate 16.6 g (0.12 µM), triphenylphosphine 31.5 g (0.12 µM), palladium acetate 0.5 g, nitrogen protection, raising the temperature to 65 °C, thermal insulation 20 h, then decompressing and steams methyl tetrahydrofuran, residue by adding 150 ml of water, adjusting pH with acetic acid to 5, separating solid, filtering, then using ethanol to recrystallize the, drying to obtain telmisartan 35.8 g, molar yield 87.0%.

Product of¹ H - NMR (DMSO - d₆ , 400 MHz); δ 7.66 - 7.69 (m, 3 H), 7.41 - 7.53 (m, 4 H), 7.15 - 7.30 (m, 7 H), 5.60 (s, 2 H), 3.80 (s, 3 H), 2.91 (m, 2 H), 2.60 (s, 3 H), 1.80 (m, 2 H), 0.98 (m, 2 H), shows that the product is telmisartan.

Example 7 preparation of telmisartan

2 - carboxylic acid sodium benzene boric 28.1 g (0.12 µM) dissolved in 40 ml water, 4 - {[2 - n-propyl -4 - methyl -6 - (1 - methylbenzimidazole -2 - yl) benzimidazole -1 - yl] methyl} chlorobenzene 34.3 g (0.08 µM), tetrahydrofuran 200 ml, potassium carbonate 16.6 g (0.12 µM), triphenylphosphine 31.5 g (0.12 µM), palladium acetate 0.5 g, nitrogen protection, raising the temperature to 65 °C, thermal insulation 20 h, then decompressing and steams tetrahydrofuran, residue by adding 150 ml of water, adjusting pH with acetic acid to 5, separating solid, filtering, then using ethanol to recrystallize the, drying to obtain telmisartan 35.3 g, molar yield 85.8%.

Product of¹ H - NMR (DMSO - d₆ , 400 MHz); δ 7.66 - 7.69 (m, 3 H), 7.41 - 7.53 (m, 4 H), 7.15 - 7.30 (m, 7 H), 5.60 (s, 2 H), 3.80 (s, 3 H), 2.91 (m, 2 H), 2.60 (s, 3 H), 1.80 (m, 2 H), 0.98 (m, 2 H), shows that the product is telmisartan.