WO2014067237A1

WO2014067237A1 - Telmisartan preparation method and intermediate thereof

Info

Publication number: WO2014067237A1
Application number: PCT/CN2013/001320
Authority: WO
Inventors: 吴明军; 李剑峰; 陈伟铭; 田广辉; 朱富强; 索瑾; 沈敬山
Original assignee: 上海特化医药科技有限公司; 中国科学院上海药物研究所; 山东特珐曼医药原料有限公司
Priority date: 2012-10-31
Filing date: 2013-10-31
Publication date: 2014-05-08
Also published as: CN103787982A; CN104768936A; CN104768936B

Abstract

Disclosed is a telmisartan preparation method, characterized in that: 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole (compound I) and 4'-halomethyl diphenyl-2-substituted compound (compound II) conduct a nucleophilic substitution reaction to obtain a compound III; when R is COOH, the compound III is telmisartan; and when R is COOR' or CN, the compound III can be hydrolyzed to obtain telmisartan.

Description

Method for preparing telmisartan and intermediate thereof

Technical field

The present invention relates to a process for the preparation of an antihypertensive drug, telmisartan, and a method thereof, and to a process for the preparation of these intermediates. Background technique

Telmisartan is a novel non-peptide angiotensin (Π Π ) receptor antagonist, clinically used for the treatment of hypertension, its chemical name is 4'-[(1,4'-dimethyl- 2'-propyl[2,6'-di-1Η-benzimidazole]-fluorenyl-methyl)biphenyl]-2-carboxylic acid, knot

Telmisartan

The synthetic route of telmisartan has been mainly obtained by N-acylation, nitration, reduction, cyclization, ester hydrolysis and condensation reaction using methyl 3-methyl-4-aminobenzoate as a starting material. 2-n-propyl-4-methyl- _6- ₍₁ -methylbenzimidazol-2-yl)benzimidazole α), anthracene and 4'-bromomethylbiphenyl-2-carboxylic acid tert-butyl ester (V) The nucleophilic substitution and hydrolysis of the two oxime reactions gave the final product telmisartan (Reaction formula 1) (J Med Chem, 1993, 36: 4040-4051).

Reaction formula 1

It has since been reported to prepare telmisartan using 4'-bromomethylbiphenyl-2-carboxylic acid methyl ester (or ethyl ester) (VI) or 4'-bromomethylbiphenyl-2-carbonitrile (VII) (CN01126367) .9 , CN01131915.1 ).

The above synthesis methods are both two, and there is still the possibility of simplifying the process and reducing the cost. Moreover, in the actual production process, it is necessary to find a more environmentally friendly, economical, and practical synthesis method that can reduce the formation of impurities, thereby improving process stability, reducing environmental pollution, reducing synthesis costs, and improving product quality. Summary of the invention

The object of the present invention is to find a new synthetic route for telmisartan which can improve the yield and product quality, reduce the cost, is simple to operate, is environmentally friendly, and is suitable for industrial production.

Another object of the invention is to provide an intermediate for the preparation of telmisartan. It is still another object of the present invention to provide a process for the preparation of an intermediate for the preparation of telmisartan.

In order to achieve the above object, the present invention provides a process for preparing telmisartan, which is carried out by the following reaction formula:

among them,

R is COOH, COOR, or CN;

R' is a linear or branched alkyl group of C1 to C12, a linear or branched alkenyl group of C2 to C12, an aryl group or a C1 to C5 alkyl group substituted by an aryl group, wherein the aryl group is a benzene group. Or a heteroaryl group, the heteroaryl group being a thiazolyl group, a pyrazolyl group, a pyridyl group or an imidazolyl group; When R is COOH, X is Cl, Br or I;

At this time, the compound of the formula I and the compound of the formula II are subjected to nucleophilic substitution reaction to obtain telmisartan;

When R is COOR' or CN, X is C1;

(1) a compound of formula I and a compound of formula II are subjected to nucleophilic substitution to give a compound of formula III;

(2) The compound of formula III is hydrolyzed to give telmisartan.

In a preferred embodiment of the invention:

R is COOH, COOR, or CN;

R is a linear or branched alkyl group of C1 to C5 or a phenyl group.

In a more preferred embodiment of the invention:

Wherein R is COOH; X is Cl, Br or I.

In another preferred embodiment of the invention: R is COOR', X is Cl, R' is a C3~C12 linear or branched alkyl group, a C2~C12 linear or branched alkenyl group, an aryl group or A C1 to C5 alkyl group substituted with an aryl group, wherein the aryl group is a phenyl group or a heteroaryl group, and the heteroaryl group is a thiazolyl group, a pyrazolyl group, a pyridyl group or an imidazolyl group.

The present invention is characterized in that: a compound of the formula I and a 4'-halomethylbiphenyl-2-substituted compound (compound of the formula II) are subjected to nucleophilic substitution reaction to give a compound of the formula: when R is COOH, the compound of the formula III is Telmisartan; when R is COOR' or CN, the compound of formula III is further hydrolyzed to give telmisartan.

Specifically, the method includes the following steps:

When R is COOH,

1) The compound of formula I and the compound of formula II are subjected to nucleophilic substitution reaction to obtain telmisartan;

Or, when R is COOR' or CN,

1) a compound of formula I and a compound of formula II are subjected to nucleophilic substitution to give a compound of formula III;

2) The compound of formula III is hydrolyzed to give telmisartan.

Wherein the compound of the formula II is prepared in the following manner, and the reaction formula is as follows:

IV

Where R and X are as defined above.

More specifically, the present invention includes the following steps:

(1) Preparation of a compound of formula II

The compound of formula II is prepared by reacting a 2'-substituted methylbiphenyl compound (compound of formula IV) with a halogenating reagent. Wherein, when X is chlorine, the chlorinating agent may be chlorine gas, sulfuryl chloride/tert-butoxy hydrogen peroxide, N-chlorosuccinimide (NCS), dichlorohydantoin, chlorosulfonic acid/chlorination Sulfoxide, trichloroisocyanuric acid, CuCl ₂ /Pb(OAc) ₂ , NaOCl, and the like. When X is bromine, the bromination reagent may be liquid bromine, N-bromosuccinimide (NBS), dibromohydantoin or the like. An initiator such as azobisisobutyronitrile, benzoyl peroxide or the like may be added during the halogenation reaction, or the reaction may be carried out under light. The halogenation reaction solvent may be chlorobenzene, dichloromethane, chloroform, dichloroethane, carbon tetrachloride, acetonitrile, benzene, acetic acid or the like. When X is iodine, it can be prepared by iodo reaction of a compound of formula II wherein X is bromine, said iodide reagent being Nal or prepared by the addition of I ₂ /NaOBu-t, said solvent being the same as above.

(2) Preparation of a compound of formula III

III

2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole (compound of formula I) and 4'-halomethylbiphenyl-2-substituted compound ( The compound of formula II) is subjected to a nucleophilic substitution reaction to form a compound of formula III. More specifically, the nucleophilic substitution reaction is carried out in the presence of a base, wherein the base may be an organic base or an inorganic base, wherein the organic base may be sodium alkoxide (for example, sodium methoxide, sodium ethoxide, sodium propoxide, Sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, etc.), potassium alkoxide (eg potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, Potassium n-butoxide, potassium t-butoxide, etc.), butyl lithium, metal hydrides (eg NaH, KH, CaH _{2 ,} etc.), 1,8-diazabicyclo [5.4.0] ^-carbon-7-ene (DBU), pyridine, 4-dimethylaminopyridine (DMAP), organic amine (such as triethylamine, tri-n-butylamine, tripropylamine, diisopropylethylamine, etc.); the inorganic base may be NaOH , KOH, LiOH, CsOH, Ba(OH) ₂ , Mg(OH) ₂ , Ca(OH) ₂ , Sr(OH) ₂ , KHC0 ₃ , K ₂ C0 ₃ , Na ₂ C0 ₃ , Cs ₂ C0 _{3 ,} etc.; More preferably, sodium alkoxide, potassium alkoxide, metal hydride, NaOH, KOH or potassium carbonate is preferred. The reaction solvent may be selected from an aromatic hydrocarbon solvent, an ether solvent, a 3⁄4 hydrocarbon solvent or other solvent. Wherein the aromatic hydrocarbon solvent such as benzene, toluene, chlorobenzene, nitrobenzene, etc.; the ether solvent such as tetrahydrofuran (THF), diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene Alcohol monomethyl ether, dioxane, etc.; the halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, etc.; the other solvent such as dimethylformamide (DMF), Ν, Ν dimethyl acetamide, dimethyl sulfoxide (DMSO), pyrrolidone solvent, hexamethylphosphoramide, acetone, acetonitrile, etc., may also be a mixed solvent of the above solvents, but the present invention is not limited to the above solvents . The reaction temperature is not limited, and a temperature range of -78 to 120 ° C is preferable, and -30 to 120 ° C is more preferable. The reaction time is not limited, and it is preferably 1 to 10 hours.

When R is COOH, the compound of formula III is telmisartan; when R is COOR' or CN, the compound of formula III is hydrolyzed by the following step (3) to give telmisartan.

(3) Preparation of telmisartan

Telmisartan

1) When R is COOH, the compound of formula III is telmisartan.

2) When R is COOR', the ester group of the compound of formula III is hydrolyzed and deprotected to give 4'-[(1,4'-dimethyl-2'-propyl[2,6'-di-1H-benzene And imidazo]-l'-yl)methyl]biphenyl]-2-carboxylic acid, ie telmisartan. formula

The compound III can be hydrolyzed under acidic conditions, and the acid can be an organic acid or an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, acetic acid, trifluoroacetic acid, etc., but is not limited to the above acid. The solvent may be water, glacial acetic acid or the like, but is not limited to the above solvents. The reaction temperature can be controlled at -20 ° C to Within the range of the reflux state, but not limited to this temperature range. The compound of formula III can also be hydrolyzed under basic conditions, more specifically in inorganic bases (e.g., NaOH, KOH, CsOH, LiOH, Ba(OH) ₂ , Mg(OH) ₂ , Ca(OH) ₂ , Sr (OH) ₂ , KHC0 ₃ , K ₂ C0 ₃ , Na ₂ C0 ₃ , Cs ₂ C0 ₃ ) or an organic base (for example, sodium alkoxide, potassium alkoxide, butyl lithium, NaH, DBU, pyridine or DMAP, organic amine, etc. Among them, sodium alcohol such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, etc.; potassium alkoxide such as potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, n-butyl potassium alkoxide, potassium tert-butoxide and the like, wherein the organic amine such as triethylamine, tributylamine, tripropylamine, diisopropylethylamine and the like) in the presence of water, ₅ ^ ~ lower alcohols (e.g. methanol, a mixed solvent of any ratio of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isoamyl alcohol, ethylene glycol, propylene glycol, glycerol) and water, or Other solvents (eg DMF, DMSO, THF, dioxane, pyrrolidone solvents, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol A mixed solvent of any ratio of monomethyl ether or the like with water is a solvent, and is reacted at a temperature of 0 to 200 ° C (preferably 60 to 100 ° C) for 1 to 20 hours to be hydrolyzed to the target telmisartan.

3) When R is CN, the cyano group of the compound of formula III is hydrolyzed to give telmisartan. The compound of formula III can be hydrolyzed under acidic conditions, and the acid can be an organic acid or an inorganic acid, such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, acetic acid, trifluoroacetic acid, etc., but is not limited thereto. The above acid; the solvent may be water, glacial acetic acid or the like, but is not limited to the above solvent. The reaction temperature can be controlled in the range of room temperature to 200 °C. The compound of formula III can also be hydrolyzed under basic conditions, more specifically by hydrolysis in an aqueous solvent in the presence of an inorganic or organic base to give telmisartan. Wherein the inorganic base such as NaOH, KOH, CsOH, LiOH, Ba(OH) ₂ , Mg(OH) ₂ , Ca(OH) ₂ , Sr(OH) ₂ , KHC0 ₃ , K ₂ C0 ₃ , Na ₂ C0 ₃ , Cs ₂ C0 ₃ ; the organic base such as sodium alkoxide, potassium alkoxide, butyl lithium, NaH, etc., the sodium alkoxide such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium n-butoxide, Sodium tert-butoxide or the like, potassium alkoxide such as potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium n-butoxide, potassium t-butoxide, etc.; the aqueous solvent such as water, d-C ₅ lower alcohol (for example Mixture of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, n-pentanol, isoamyl alcohol, ethylene glycol, propylene glycol, glycerol) with water in any ratio Any ratio of solvent or other solvent (such as DMF, DMSO, THF, dioxane, pyrrolidone solvent, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, etc.) to water Mixed solvent. The reaction temperature may be in the range of 30 to 250 ° C, and the reaction time is 10 to 20 hours, and the hydrolysis is the target telmisartan.

The present invention can also be carried out by a one-pot method, § Ρ, when R is COOR' or CN, the compound of the formula I and the compound of the formula II are subjected to nucleophilic substitution reaction to obtain the compound of the formula III, without post-treatment or purification, directly A protic solvent is added to the reaction system and hydrolyzed under alkaline conditions to obtain telmisartan.

details as follows:

' When the reaction is as follows:

The compound of the formula I and the compound of the formula lib are subjected to nucleophilic substitution reaction to obtain a compound of the formula nib, and a protic solvent such as water, an alcohol-water mixed solvent or a mixed solvent of other solvent and water is directly added to the reaction system without post-treatment. Continue the hydrolysis reaction and synthesize telmisartan in one pot. The reaction conditions are the same

, / - 刖.

More specifically, after the compound of the formula I and the compound of the formula lib are prepared to obtain the compound of the formula nib, water, C^Cs lower alcohol (for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, or the like) is directly added to the reaction system. a mixed solvent of isobutanol, tert-butanol, n-pentanol, isoamyl alcohol, ethylene glycol, propylene glycol, glycerol) and water in any ratio, or other solvent (eg DMF, DMSO, THF, dioxane) And a mixed solvent of pyrrolidone solvent, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, etc. in any ratio with water, hydrolyzing the ester group to obtain telmisartan. The temperature range may be a temperature range of 0 to 200 ° C, and the reaction time may be 1 to 20 hours, but the reaction temperature and reaction time are not limited thereto.

(2) When R is CN, the reaction formula is as follows:

The compound of the formula I and the compound of the formula lie are subjected to nucleophilic substitution reaction to obtain a compound of the formula IIIc. Without post-treatment, a protic solvent such as water, an alcohol-water mixed solvent, a mixed solvent of other solvent and water, etc., is added to the reaction system. The hydrolysis reaction was carried out to synthesize telmisartan in one pot. The reaction conditions are the same as before.

More specifically, after the compound of the formula I and the compound of the formula lie are prepared to obtain the compound of the formula IIIc, water, C^Cs lower alcohol (for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, or the like) is directly added to the reaction system. a mixed solvent of isobutanol, tert-butanol, n-pentanol, isoamyl alcohol, ethylene glycol, propylene glycol, glycerol) and water in any ratio, or other solvent (eg DMF, DMSO, THF, dioxane) And a mixed solvent of pyrrolidone solvent, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, etc. in any ratio with water, hydrolyzing the cyano group to obtain telmisartan. The reaction temperature range can be

The reaction time may be 10 to 20 hours in the temperature range of 30 to 250 ° C, but the temperature and reaction time are not limited thereto.

More preferably, telmisartan is prepared as follows:

Telmisartan

2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole (compound of formula I) with 4'-chloromethylbiphenyl-2-carboxylic acid or 4 '-Bromomethylbiphenyl-2-carboxylic acid (compound of formula II) is nucleophilic substituted to form telmisartan. More specifically, the nucleophilic substitution reaction is carried out in the presence of a base, wherein the base may be an organic base or an inorganic base, wherein the organic base may be sodium alkoxide (for example, sodium methoxide, sodium ethoxide, sodium propoxide, different Sodium propoxide, sodium n-butoxide, sodium t-butoxide, etc.), potassium alkoxide (eg potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium n-butoxide, potassium t-butoxide, etc.), butyl lithium , metal hydride (eg NaH, KH, Ca3⁄4, etc.), 1,8-diazabicyclo [5.4.0] ^-carbon-7-ene (DBU), pyridine, 4-dimethylaminopyridine (DMAP) , organic amines (such as triethylamine, tri-n-butylamine, tripropylamine, diisopropylethylamine, etc.); inorganic bases can be NaOH, KOH, LiOH, CsOH, Ba(OH) ₂ , Mg(OH ₂ , Ca(OH) ₂ , Sr(OH) ₂ , KHC0 ₃ , K ₂ C0 ₃ , Na ₂ C0 ₃ , Cs ₂ C0 _{3 ,} etc.; among the bases, more preferred are sodium alkoxide, potassium alkoxide, metal hydride , NaOH, KOH or K ₂ C0 ₃ .

The solvent for the nucleophilic substitution reaction may be selected from an aromatic hydrocarbon solvent, an ether solvent, a halogenated hydrocarbon solvent or other solvent. Wherein the aromatic hydrocarbon solvent such as benzene, toluene, chlorobenzene, nitrobenzene, etc.; the ether solvent such as tetrahydrofuran (THF), diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene Alcohol monomethyl ether, dioxane, etc.; the halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, etc.; the other solvent such as dimethylformamide (DMF), Ν, Ν-dimethylacetamide, dimethyl sulfoxide (DMSO), pyrrolidone solvent, hexamethylphosphoramide, acetone, acetonitrile, etc., may also be a mixed solvent of the above solvents, but the present invention is not limited to the above Solvent.

The reaction temperature of the nucleophilic substitution reaction is not limited, and is preferably in the range of -78 to 120 °C, more preferably in the range of -30 to 120 °C. The reaction time is not limited, and it is preferably 1 to 10 hours.

In particular, when R is COOH and X is bromine, §Ρ, telmisartan is prepared as follows

Ding elmjsartan inventors have found through a large number of experiments that the choice of reaction temperature and base is the key to this reaction. The inventors compared in detail the reaction temperature and the effect of the base on the reaction, as follows: (1) Selection of base: The inventors have found through a large number of experiments that the reaction is more easily achieved by using a metal hydride or potassium alkoxide as a base under the same reaction conditions, and the reaction rate can be significantly accelerated and the product yield can be improved. However, when other bases are used, the reaction proceeds slowly or has many side reactions, and more impurities are generated and the proportion of impurities is large. Therefore, the metal hydride and potassium alkoxide are most preferable in the present reaction. The metal hydride may be NaH, KH, CaH ₂ or the like, and the potassium alkoxide may be potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium n-butoxide, potassium t-butoxide or the like.

(2) Reaction temperature: In the present reaction, if the other reaction conditions are the same, the reaction temperature is too high, and impurity 1 and impurity 2 (structure is shown below) are easily generated, and impurity 1 is an isomer of telmisartan. Impurity 2 is an impurity formed by the continued esterification of the carboxyl group of telmisartan; however, the reaction temperature is too low, the reaction proceeds for a long time, and the reaction proceeds incompletely, and the yield of telmisartan decreases significantly. To better balance yield and purity, we conducted extensive experiments to find the right temperature range. It has been found that when the reaction is not heated or carried out at a low temperature, the impurities generated in the reaction solution are significantly reduced as the temperature is lowered, the main product content is significantly increased, and accordingly, the purification is also easier, and the yield is improved (Table 1). . A suitable temperature range is -50 ° C, more preferably -30 to 30 ° C.

Impurity 1 (isomer) Impurity 2 (esterification impurity) In order to compare the effects of different temperatures on the reaction, the present invention uses NaH as a base, and fixes other reaction conditions and uses the same post-treatment operation, and only changes the reaction temperature to carry out the reaction. At the same time, the impurities of the reaction solution and the product (the crude product of telmisartan, without recrystallization) were compared by HPLC, and the test results are shown in Table 1.

Table 1 Comparison of reaction conditions Reaction temperature Reaction liquid detection Crude product (telmisartan)

Target pure impurity 1 impurity 2 purity impurity 1 impurity 2 crude yield O

Degree (%) (%) (%) (%) (%) (%) (%)

50 °C 43.49 7.39 9.20 61.93 10.43 10.92 72%

20-30 °C 56.73 8.67 10.58 65.26 8.85 13.42 81%

0~10°C 76.01 7.16 5.92 96.97 0.65 0.88 92%

86.83 6.71 0.85 94.10 3.57 0.12 100%

-40-30 °C 84.37 6.12 0.11 93.21 4.93 No 100% test found that after the reaction temperature is lower than -30 °C, the reaction rate becomes slower with the decrease of temperature, and the reaction liquid becomes viscous, which is not conducive to the reaction, lower than After -50 ° C, the phenomenon is more obvious, the reaction solution is thick and difficult to stir, and the practical application value of the scale-up production is not large. When the reaction temperature is 50 ° C, another large impurity is formed in the reaction, and when the reaction temperature is above 50 ° C, the number of impurities is larger and the proportion of impurities is larger. Therefore, considering the factors such as yield, purity, reaction time and the like, the reaction temperature is suitably -50 to 50 ° C, more preferably -30 to 30 ° C. In the temperature range of -30~30 °C, the product impurity content is small, followed by pure

Ding elmjsartan

The base in the reaction is most preferably a metal hydride or potassium alkoxide. The metal hydride may be NaH, KH, CaH ₂ or the like, and the potassium alkoxide may be potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium n-butoxide, potassium t-butoxide or the like.

The most preferred temperature range for this reaction is from 20 to 120 °C.

The present invention also relates to intermediates for the preparation of telmisartan.

A compound of the following formula II:

Wherein, when R is COOH, X is I; when R is COOR, X is Cl, R' is a linear or branched alkyl group of C3~C12, and a linear or branched alkenyl group of C2~C12 And an aryl group or a C1 to C5 alkyl group substituted by an aryl group, wherein the aryl group is a phenyl group or a heteroaryl group, and the heteroaryl group is a thiazolyl group, a pyrazolyl group, a pyridyl group or an imidazolyl group.

One of the following formula III

III

Wherein R is COOR', R' is a linear or branched alkyl group of C3 to C12, a linear or branched alkenyl group of C2 to C12, an aryl group or a C1 to C5 alkyl group substituted by an aryl group, wherein , the aryl group is a phenyl group or a heteroaryl group, and the heteroaryl group is a thiazolyl group, a pyrazolyl group, a pyridyl group or an imidazolyl group;

The invention has the following advantages:

(1) When R is COOH, X is Cl, Br or I. This method has the following advantages:

1) The method is simple and convenient to operate, and the compound of the formula I is reacted with the compound of the formula II to obtain the final product telmisartan, which reduces the reaction and saves the synthesis cost and shortens the production cycle.

2) In this method, the purity of the compound of formula II is not high. For example, when X is bromine, the purity of the compound of formula II is 85% or more, and the compound of formula II can be obtained by the reaction and can be directly used without further purification. The material is fed in the lower jaw, which greatly saves the synthesis cost and simplifies the operation.

3) The method is suitable for mass production.

(2) When R is COOR' or CN, X is Cl. This method has the following advantages:

1) The present invention employs a chloromethylbiphenyl derivative (a compound of formula II, X is C1) in place of a bromomethyl group. The preparation of telmisartan as a key intermediate in benzene derivatives avoids the use of bromomethylbiphenyl derivatives. The bromomethylbiphenyl derivative (V, VI, VII) is obtained by bromination of a methylbiphenyl derivative. In large production, the bromination reagent and the bromination reaction are on the skin relative to the chlorination reaction. It is highly irritating, polluting people and the environment, and the bromination reaction is also corrosive to the equipment in the workshop. After the invention is changed to chloride, it is more environmentally friendly, the atom is more economical, and the corrosion of the equipment is also reduced.

2) The bromomethylbiphenyl derivative (V, VI, VII) is more reactive than the chloromethylbiphenyl derivative (the compound of formula II, R is COOR' or CN, X is C1), and the compound of formula I and bromine Methyl biphenyl derivative

The nucleophilic substitution reaction of (V, VI, VII) easily forms a disubstituted product on the N of the benzimidazole ring, that is, a quaternary ammonium salt is formed, thereby producing impurities, especially in a large amount of preparation, the impurity content is up to 3- 5%, poor control or even up to 10%, resulting in uncontrollable reaction and increased purification costs; and the use of chloromethylbiphenyl derivatives (compounds of formula II, X is C1) avoids the above-mentioned side reactions and therefore reduces during the reaction The formation of impurities, for this yield and product quality, also reduces the cost of synthesis.

3) Telmisartan can be obtained by one-pot method, which reduces the operation steps.

4) The method is suitable for mass production. Example

The invention is illustrated by the following examples without any limitation.

Example 1: Preparation of 4'-chloromethylbiphenyl-2 acid (II, R=COOH, X=C1)

Add 4'-methylbiphenyl 2-carboxylic acid (IV) (10 g, 0.047 mol), azobisisobutyronitrile (AIBN) (0.11 g, 1.5 mol%) to chlorobenzene (35 mL), Stir, heat to 90 ° C, slowly add S0 ₂ C1 ₂ (3.8 mL, 0.047 mol) of chlorobenzene solution (15 mL), stir for 1 hour after the completion of the addition, TLC detection reaction is completed; the reaction solution is naturally cooled To the room temperature, a solid was precipitated, and the mixture was cooled in an ice bath for 1 hour, and filtered, and the obtained filtrate was washed with toluene (10 mL x 2) and dried to give white granule solid II (9.5 g, yield 82%). NMR (300 MHz, DMSO-d6): 12.79 (s, 1H, OH), 7.21-7.75 (m, 8H, EtOAc), 4.81 (s, 2H, CH2), MS: 246.1.

Example 2: Preparation of 4'-chloromethylbiphenyl-2 acid (II, R=COOH, X=C1) Add 4'-methylbiphenyl 2-carboxylic acid (IV) (10 g, 0.047 mol), azobisisobutyronitrile (AIBN) (0.11 g, 1.5 mol%) to chlorobenzene (70 mL), Stirring, heating to 80 ° C, adding trichloroisocyanuric acid (10.9 g, 0.047 mol), stirring the reaction for 12 hours, hot filtered out insoluble matter; the reaction solution was naturally cooled to room temperature, a solid precipitated, the resulting filtrate used The toluene was washed (10 mL x 2) and dried to give a white solid (yel.

Example 3: Preparation of 4'-chloromethylbiphenyl-2 acid (II, R=COOH, X=C1)

4'-Methylbiphenyl 2-carboxylic acid (IV) (10 g, 0.047 mol) was dissolved in dichloromethane (150 mL), benzoyl peroxide (0.23 g, 2 mol%) was added, and 1.1 equivalents were added. The chlorine gas was stirred for 12 hours; a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the organic layer was evaporated. The solvent was evaporated to dryness to give a white solid (yield: 52 g).

Example 4: Preparation of telmisartan (III, R=COOH)

60% NaH (1.0 g, 0.025 mol) was added to DMF (10 mL), and the mixture was stirred well in ice-water bath, and the compound of formula I (3.05 g, 0.01 mol) was added and stirred at room temperature for 30 minutes; (II) (2.46 g, 0.01 mol) After dissolving in DMF (10 mL), slowly added to the above reaction solution, and stirred at room temperature for 1 hour; then heated to 50 ° C for 4 hours, and the reaction was terminated by TLC. The reaction solution was poured into ice water (100 mL), stirred, and the pH was adjusted to a solid with concentrated hydrochloric acid. After suction filtration, the filtrate was washed once with water and dried to give a white solid telmisartan (4.3 g, yield 84) %). It can be recrystallized as needed.

Example 5: Preparation of telmisartan (III, R=COOH)

Potassium tert-butoxide (2.8 g, 0.025 mol) was added to DMF (25 mL), and the mixture was stirred well in ice-water bath, and the compound of formula I (3.05 g, 0.01 mol) was added and stirred at room temperature for 30 minutes; The compound (II) (2.46 g, 0.01 mol) was added to the above reaction solution, and stirred at room temperature for 1 hour; then heated to 80 ° C for 12 hours, and the reaction was terminated by TLC. The reaction solution was poured into ice water (120 mL), stirred, and the pH was adjusted to a solid with concentrated hydrochloric acid. After suction filtration, the filtrate was washed once with water and dried to give a white solid telmisartan (4.0 g, yield 78) %). It can be recrystallized as needed. Example 6: Preparation of 4'-bromomethylbiphenyl-2 acid (II, R=COOH, X=Br)

4'-Methylbiphenyl 2-carboxylic acid (21.2 g, leq) and dibromohydantoin (15 g, 0.53 eq) were added to dichloromethane (210 ml) at room temperature to maintain the temperature at 0-10 ° C. The reaction was carried out under light for about 5-10 hours. After the basic reaction of the starting material was completed by TLC, the organic phase was washed twice with water (120 ml). The organic phase was concentrated to a small volume (ca. 30 mL). EtOAc (EtOAc m. HPLC) can be used directly in the sputum reaction without further purification.

Example 7: Preparation of 4'-bromomethylbiphenyl-2 acid (II, R=COOH, X=Br)

Add 4'-methylbiphenyl 2-carboxylic acid (21.2g, leq) and NBS (l.leq) to chloroform (210ml) at room temperature, add benzoyl peroxide, heat reflux, TLC detection of raw materials After the basic reaction was completed, the organic phase was washed twice with water (120 ml). The organic phase is concentrated to a small volume (about 30 ml), and then added with petroleum ether (50 ml), and the mixture is heated to reflux, and then slowly cooled to about 0 ° C. The obtained solid is filtered to give the title compound II, yield 75%, which can be used without further purification. In the sputum reaction.

Example 8: Preparation of telmisartan (III, R=COOH)

Add compound of formula I (10g, leq) to DMF (50ml), stir to dissolve, then cool to 0-5

V, 55% NaH (3.4 g, 2.5 eq) was slowly added in portions, and after stirring, the mixture was stirred at the same temperature for about 1 hour, and the temperature of the reaction liquid was controlled to 10 ° or less, and the title compound of Example 6 (9.5) was further added. g) Dissolve in DMF (10ml), slowly instill, continue to stir at this temperature for 1-2 hours, after TLC or HPLC to detect the basic reaction of the raw materials, keep the temperature below 10 degrees, add dilute hydrochloric acid to adjust the pH value. The solid was precipitated, stirred, and the obtained solid was filtered, washed with water, and dried to give telmisartan (15.2 g) in a yield of 95%.

Example 9: Preparation of telmisartan (III, R=COOH)

The compound of the formula I (10 g, leq) was added to acetonitrile (50 ml) at rt. After the basic reaction of the starting material was completed by TLC or HPLC, concentrated to a small volume, water (150 ml) was added, and dilute hydrochloric acid (1.5 eq) was added dropwise to adjust the pH to solid precipitation. The obtained solid was filtered, washed with water and dried to give telmisartan. , yield 80%. Example 10: Preparation of 4'-chloromethylbiphenyl-2 acid methyl ester (11, R=COOCH ₃ , X=C1) In a 250 ml three-necked flask with a drying tube, 4'-methylbiphenyl 2 was added. Methyl carboxylate (IV) (22.6 g, 0.1 mol), dichloromethane (44 mL). The temperature of the water bath was controlled at 20-30 °C, while 65% t-butoxy hydrogen peroxide (4.7 g, 0.5 eq) and sulfonyl chloride (19 g, 1.4 eq) were slowly added dropwise. The exotherm was released and a large amount of acid gas was released for about 30 minutes. After the completion of the addition, sample 1 hour later, HPLC detection of less than 5% of the raw materials, dilute with dichloromethane (10ml), add saturated sodium sulfite, adjust the pH of the sodium carbonate solution to 6-7, wash 3 times, dry, filter, minus concentrated to remove dichloromethane pressure to give a yellow oil 24g, add ethanol (30ml) was stirred in an ice bath to cool, the precipitated white solid was large, suction filtration to give a white solid _{(11, R = COOCH 3)} 23.4g, HPLC purity 95 detected %, ethanol (40 mL) was recrystallized to give 21 g of product, and the liquid phase purity was 98.2%.

Example 11: 4'-[(1,4'-Dimethyl-2'-propyl[2,6'-di-1H-benzimidazole]-1'-yl)methyl]-[1, Preparation of 1'-biphenyl]-2 acid methyl ester (III, R=COOCH ₃ )

The compound of the formula I (0.62 g, leq) was added to acetonitrile (7 ml). After stirring well, KOH (0.14 g, l. leq) was slowly added. After the addition was completed, the title compound of Example 10 was stirred for about 10 minutes. (11, R=COOCH ₃ ) (0.5g, leq) Add slowly, stir for 3-4 hours, after TLC detects the reaction, reduce the temperature to -5~5 °C, stir for 4-5 hours, filter the solid The filter cake was rinsed with a small amount of acetonitrile, washed with water, and dried (50-60 ° C) to obtain compound (III, R = COOCH ₃ ) (0.93 g, yield 92%), and the liquid phase purity was more than 98%.

Example 12: Preparation of telmisartan

The title compound of Example 11 (III, R = COOCH ₃ ) (52.8 g, 0.1 mol) and glacial acetic acid

(200 ml) was mixed with concentrated hydrochloric acid (250 ml) and reacted at 100 ° C for 5-6 hours. Concentrate under reduced pressure to remove most of the mixed acid. The residue is slowly poured into crushed ice. The pH is adjusted to neutral with saturated K ₂ CO^ solution under ice cooling. Solids are precipitated, filtered, and the filtrate is washed with water. Tantan, recrystallized to telmisartan (40.1g), liquid phase purity greater than 99%.

Example 13: Preparation of telmisartan The compound of the formula I (0.62 g, leq) was added to acetonitrile (10 ml). After stirring well, KOH (0.14 g, 1. leq) was slowly added. After the addition was completed, the title compound of Example 10 was stirred for about 10 minutes. (11, R=COOCH ₃ ) (0.5 g, leq) was slowly added. After stirring for 3-4 hours, after the TLC reaction was completed, 50% ethanol (30 mL) was directly added, and the reaction was refluxed for 6 hours. After the TLC reaction was completed, the organic solvent was recovered under reduced pressure, and the remaining solution was added dropwise hydrochloric acid (1:1) to pH neutral. Solid precipitated, filtered, washed with water, crude telmisartan, recrystallized to telmisartan (yield 75.1%), liquid phase purity greater than 98%.

Example 14: Preparation of 4'-chloromethylbiphenyl-2-carbonitrile (II, R=CN)

The preparation was carried out in the same manner as in the examples 1 to 3.

Example 15: 4'-[(1,4'-Dimethyl-2'-propyl[2,6'-di-1H-benzimidazole]-1'-yl)methyl]-[1, Preparation of 1'_biphenyl]-2-carbonitrile (III, =CN)

I (30.4 g, 0.1 mol), the title compound of Example 14 4'-chloromethylbiphenyl-2-carbonitrile (0.1 mol), K ₂ C0 ₃ (or other inorganic base as described above) (0.3 mol) was mixed with DMF (or other solvent as described above) (300 ml) and reacted at 70 ° C for about 5 to 6 hours. After the TLC was used to detect the absence of the starting material, the reaction solution was poured into ice water, and extracted with dichloromethane for 3 times. The organic phase was combined and washed once with saturated brine, dried over anhydrous sodium sulfate and concentrated to a small volume under reduced pressure. Ether, solid precipitated and filtered to give the title compound. .

Example 16: Preparation of telmisartan

The title compound of Example 15 (III, R = CN) (24.8 g, 0.05 mol) was added to propylene glycol (100 ml) and water (100 ml) (or other aqueous mixed solvent as described above:), potassium hydroxide (or as The other inorganic base (0.2 mol) described above was refluxed for 10 hours. After TLC was tested, the raw material was cooled to room temperature, concentrated under reduced pressure to a small volume, and adjusted to pH 5-6 with hydrochloric acid dropwise. Solid precipitated, filtered, and washed with water to obtain telmisartan.

Example 17: Preparation of telmisartan

I (30.4 g, 0.10 moi>, the title compound 4'-chloromethylbiphenyl-2-carbonitrile (0.12 mol) of Example 14, sodium ethoxide (or other organic base as described above) (0.3 mol) DMF (or other The solvent (200 ml) was mixed and reacted at 65 ° C for about 5 hours. After TLC detects no raw materials, add ethylene glycol (100ml and water (50ml) (or other aqueous solvent), and heat to 160 ° C. After TLC detects no raw materials, adjust the pH to 5~6 with concentrated hydrochloric acid under ice cooling. The solid was precipitated, and the obtained solid was filtered, washed with water, and the crude product of telmisartane was obtained by recrystallization to give telmisartan.

Examples 18~24: Preparation of telmisartan

Referring to the method of Example 8, the compound of the formula I (10 g, leq) and the title compound of Example 6 were used as a reactant, and NaH was used as a base to carry out a reaction under different reaction conditions, and the reaction liquid was subjected to liquid phase detection. Conventional work-up gave telmisartan (crude), yield was calculated, and the purity of telmisartan was determined by liquid phase. The test results are shown in Table 2.

Table 2 Comparison of reaction conditions

Claims

Rights request

A method of preparing a compound of formula III, which is carried out by the following reaction formula:

The compound of formula I and the compound of formula II are subjected to nucleophilic substitution to give a compound of formula III;

among them,

R is COOH, COOR, or CN;

R' is a linear or branched alkyl group of C1 to C12, a linear or branched alkenyl group of C2 to C12, an aryl group or a C1 to C5 alkyl group substituted by an aryl group, wherein the aryl group is a phenyl or heteroaryl group, the heteroaryl group being a thiazolyl, pyrazolyl, pyridyl or imidazolyl group;

When R is COOH, X is Cl, Br or I;

When R is COOR' or CN, X is Cl.

2. The method according to claim 1, wherein

R is COOH, COOR, or CN;

R is a linear or branched alkyl group of C1 to C5 or a phenyl group.

3. The method according to claim 2, wherein R is COOH and X is Cl, Br or I.

The method according to claim 1, wherein the compound of the formula I is subjected to nucleophilic substitution reaction with a compound of the formula II under basic conditions to form a compound of the formula III; wherein the base is an organic base or an inorganic base.

5. The method according to claim 4, wherein the organic base is selected from the group consisting of sodium alkoxide, potassium alkoxide, butyl lithium, metal hydride, 1,8-diazabicyclo[5.4.0]undecene- 7-ene, pyridine, 4-dimethylaminopyridine, triethylamine, tri-n-butylamine, tripropylamine and diisopropylethylamine; the inorganic base is selected from the group consisting of NaOH, KOH, CsOH, LiOH, Ba (OH) ₂ , Mg(OH) ₂ , Ca(OH) ₂ , Sr(OH) ₂ , KHC0 ₃ , K ₂ C0 ₃ , Na ₂ C0 ₃ And Cs ₂ C0 _{3 ;} the base is preferably sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, Potassium n-butoxide, potassium t-butoxide, butyl lithium, NaH, KH, CaH ₂ , NaOH, KOH or K ₂ C0 ₃ .

6. The method according to claim 1, wherein the solvent for the nucleophilic substitution reaction is an aromatic hydrocarbon solvent, an ether solvent, a 3⁄4 hydrocarbon solvent or other solvent, preferably selected from the group consisting of benzene, toluene, chlorobenzene, and nitrate. Benzobenzene, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, dioxane, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, Dimethylformamide, hydrazine, hydrazine dimethylacetamide, dimethyl sulfoxide, pyrrolidone solvent, hexamethylphosphoramide, acetone and acetonitrile, or a mixed solvent of the above solvents.

7. The method of claim 1 further comprising: hydrolyzing the compound of formula III to give telmisartan:

Ding slmissrtsn where R is COOR' or CN;

R' is defined in the same way as claim 1.

8. The method according to claim 7, wherein the hydrolysis reaction is carried out under acidic or basic conditions, wherein the acidic condition is an organic acid or an inorganic acid, preferably sulfuric acid, hydrochloric acid, hydrobromic acid, hydrogen iodine Acid, phosphoric acid, nitric acid, acetic acid or trifluoroacetic acid; the basic condition is an organic base or an inorganic base, preferably NaOH, KOH, CsOH, LiOH, Ba(OH) ₂ , Mg(OH) ₂ , Ca(OH) ₂ , Sr(OH) ₂ , KHC0 ₃ , K ₂ C0 ₃ , Na ₂ C0 ₃ , Cs ₂ C0 ₃ , sodium alkoxide, potassium alkoxide, butyl lithium, NaH, DBU, pyridine, DMAP, triethylamine, tri-n-butyl Amine, tripropylamine or diisopropylethylamine.

9. The method according to claim 7, wherein the hydrolysis reaction is carried out in the following reaction solvent: the acid hydrolysis solvent is water or glacial acetic acid; or the alkali hydrolysis solvent is water; <^~(^ lower alcohol and water Any combination of solvents; or DMF, DMSO, THF, dioxane, pyrrolidone solvents, A mixed solvent of ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether and water in any ratio.

10. The method according to claim 7, wherein when R is COOR', the reaction temperature of the hydrolysis reaction is 0 to 200 ° C; when R is CN, the reaction temperature of the hydrolysis reaction is 30 to 250 ° C.

11. The method of claim 1 wherein the compound of formula II is prepared as follows: a compound of formula IV is reacted with a reagent of formula 4 to provide a compound of formula II,

Wherein R and X are as defined in claim 1.

12. The method according to claim 10, wherein when X is chlorine, the chlorinating agent is chlorine gas, sulfuryl chloride/tert-butoxy hydrogen peroxide, chlorosuccinimide, dichlorohydantoin, chlorine Sulfonic acid / thionyl chloride, trichloroisocyanuric acid, CuCl ₂ /Pb(OAc) ₂ or NaOCl, if necessary, the initiator azobisisobutyronitrile, benzoyl peroxide; or the reaction under light When X is bromine, the bromination reagent is liquid bromine, N-bromosuccinimide or dibromohydantoin, if necessary, the initiator azobisisobutyronitrile or benzoyl peroxide; or in the light The reaction is carried out under conditions; when X is iodine, the compound of formula II wherein X is bromine is prepared by iodo reaction, and the iodo reagent is Nal or I ₂ /NaOBu-t.

The method according to claim 11, wherein the halogenated reaction solvent is chlorobenzene, methylene chloride, chloroform, dichloroethane, carbon tetrachloride, acetonitrile, benzene or acetic acid.

14. The method according to claim 1 or 7, wherein the one-pot method is used to prepare the temisa

Wherein R is COOR' or CN; X is C1;

R' is defined in the same manner as in claim 1; The compound of the formula I and the compound of the formula II are subjected to nucleophilic substitution reaction to obtain a compound of the formula III. The post-treatment is carried out, and a protic solvent is directly added to the reaction system to continue the hydrolysis reaction, and the telmisartan is synthesized in one pot.

The method for synthesizing telmisartan according to claim 14, wherein: the solvent is water; d~C ₅ lower alcohol (for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, iso a mixed solvent of any ratio of butanol, tert-butanol, n-pentanol, isoamyl alcohol, ethylene glycol, propylene glycol, glycerol) and water; or DMF, DMSO, THF, dioxane, pyrrolidone solvent, A mixed solvent of ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether, or the like in any ratio with water.

16. The method according to claim 3, wherein R is COOH and X is Cl,

Ding elmjsartan

The method according to claim 16, wherein the compound of the formula I and the compound of the formula II are subjected to nucleophilic substitution reaction under basic conditions to form telmisartan; wherein the base is an organic base or an inorganic base.

18. The method according to claim 17, wherein the organic base is selected from the group consisting of sodium alkoxide, potassium alkoxide, butyl lithium, metal hydride, 1,8-diazabicyclo[5.4.0]undecene- 7-ene, pyridine, 4-dimethylaminopyridine, triethylamine, tri-n-butylamine, tripropylamine and diisopropylethylamine; the inorganic base is selected from the group consisting of NaOH, KOH, CsOH, LiOH, Ba (OH) ₂ , Mg(OH) ₂ , Ca(OH) ₂ , Sr(OH) ₂ , KHC0 ₃ , K ₂ C0 ₃ , Na ₂ C0 ₃ and Cs ₂ C0 ₃ .

19. The method according to claim 17, wherein the base is sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium n-butoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, propanol Potassium, potassium isopropoxide, potassium n-butoxide, potassium t-butoxide, butyl lithium, NaH, KH, CaH ₂ , NaOH, KOH or K ₂ C0 ₃ .

20. The method according to claim 16, wherein the reaction temperature is 20 to 120 °C.

21. The method of claim 3, wherein R is COOH and X is Br,

The method according to claim 21, wherein the compound of the formula I and the compound of the formula II are subjected to nucleophilic substitution reaction under basic conditions to form telmisartan; wherein the base is an organic base or an inorganic base.

The method according to claim 22, wherein the organic base is selected from the group consisting of metal hydrides and potassium alkoxides; the inorganic base is selected from the group consisting of LiOH, Sr(OH) ₂ , and the base is preferably NaH, KH, CaH ₂ , potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium n-butoxide or potassium t-butoxide.

The method according to claim 21, wherein the reaction temperature is -50 to 50 ° C, preferably -30 to 30 ° C.

25, a method shown in the following formula II

Wherein, when R is COOH, X is I; when R is COOR', X is Cl, R' is a linear or branched alkyl group of C3~C12, and a linear or branched alkenyl group of C2~C12 An aryl group or a C1 to C5 alkyl group substituted by an aryl group, wherein the aryl group is a phenyl group or an aromatic heterocyclic group, and the aromatic heterocyclic group is a thiazolyl group, a pyrazolyl group, a pyridyl group or an imidazolyl group.

26, one of the following formula III

Wherein R is COOR', R' is a C3 to C12 linear or branched alkyl group, a C2 to C12 alkenyl group, an aryl group or a C1 to C5 alkyl group substituted with an aryl group, wherein the aryl group The phenyl or aromatic heterocyclic group is a thiazolyl, pyrazolyl, pyridyl or imidazolyl group.