WO2014067237A1 - Procédé de préparation de telmisartan et son intermédiaire - Google Patents

Procédé de préparation de telmisartan et son intermédiaire Download PDF

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WO2014067237A1
WO2014067237A1 PCT/CN2013/001320 CN2013001320W WO2014067237A1 WO 2014067237 A1 WO2014067237 A1 WO 2014067237A1 CN 2013001320 W CN2013001320 W CN 2013001320W WO 2014067237 A1 WO2014067237 A1 WO 2014067237A1
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compound
group
potassium
formula
reaction
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PCT/CN2013/001320
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English (en)
Chinese (zh)
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吴明军
李剑峰
陈伟铭
田广辉
朱富强
索瑾
沈敬山
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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
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Priority to CN201380053511.3A priority Critical patent/CN104768936B/zh
Publication of WO2014067237A1 publication Critical patent/WO2014067237A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
    • C07C63/72—Polycyclic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/65—Halogen-containing esters of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring

Definitions

  • 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.
  • Telmisartan is a novel non-peptide angiotensin ( ⁇ ⁇ ) receptor antagonist, clinically used for the treatment of hypertension, its chemical name is 4'-[(1,4'-dimethyl- 2'-propyl[2,6'-di-1 ⁇ -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.
  • 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.
  • 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;
  • R is COOH, X is Cl, Br or I;
  • R is COOH, COOR, or CN
  • R is a linear or branched alkyl group of C1 to C5 or a phenyl group.
  • R is COOH; X is Cl, Br or I.
  • 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.
  • the method includes the following steps:
  • R is COOR' or CN
  • the present invention includes the following steps:
  • the compound of formula II is prepared by reacting a 2'-substituted methylbiphenyl compound (compound of formula IV) with a halogenating reagent.
  • 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.
  • the bromination reagent may be liquid bromine, N-bromosuccinimide (NBS), dibromohydantoin or the like.
  • NBS N-bromosuccinimide
  • 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.
  • X 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.
  • 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, diisopropyleth
  • the reaction solvent may be selected from an aromatic hydrocarbon solvent, an ether solvent, a 3 ⁇ 4 hydrocarbon solvent or other solvent.
  • 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), ⁇ , ⁇ dimethyl acetamide, dimethyl sulfoxide (DMSO), pyrrolidone solvent, hexamethylphosphoramide, acetone, acetonitrile, etc.
  • DMF dimethylformamide
  • DMSO dimethyl acetamide
  • the compound of formula III 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.
  • 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.
  • 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
  • organic base for example, sodium alkoxide, potassium alkoxide, butyl lithium, NaH, DBU
  • 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.
  • 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.
  • 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-
  • the present invention can also be carried out by a one-pot method, ⁇ ⁇ , 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.
  • 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
  • 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.
  • 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.
  • a protic solvent such as water, an alcohol-water mixed solvent, a mixed solvent of other solvent and water, etc.
  • 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.
  • telmisartan is prepared as follows:
  • 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.
  • 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, diisopropyleth
  • 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.
  • 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), ⁇ , ⁇ -dimethylacetamide, dimethyl sulfoxide (DMSO), pyrrolidone solvent, hexamethylphosphoramide, acetone, acetonitrile, etc.
  • DMF dimethylformamide
  • 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.
  • 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.
  • 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
  • the potassium alkoxide may be potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium n-butoxide, potassium t-butoxide or the like.
  • 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.
  • a suitable temperature range is -50 ° C, more preferably -30 to 30 ° C.
  • Impurity 1 (isomer) Impurity 2 (esterification impurity)
  • 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.
  • the impurities of the reaction solution and the product were compared by HPLC, and the test results are shown in Table 1.
  • 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
  • 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
  • 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.
  • R 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.
  • 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 purity of the compound of formula II is not high.
  • 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.
  • the present invention employs a chloromethylbiphenyl derivative (a compound of formula II, X is C1) in place of a bromomethyl group.
  • 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.
  • 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.
  • 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.
  • Telmisartan can be obtained by one-pot method, which reduces the operation steps.
  • 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%.
  • 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.
  • 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.

Abstract

L'invention concerne un procédé de préparation de telmisartan, caractérisé en ce que : du 2-n-propyl-4-méthyl-6-(1-méthylbenzimidazole-2-yl)benzimidazole (composé I) et un composé substitué par 4'-halogénométhyldiphényle en 2ème position (composé II) réagissent par une réaction de substitution nucléophile pour obtenir un composé III; lorsque R représente COOH, le composé III est le telmisartan; et lorsque R représente COOR' ou CN, le composé III peut être hydrolysé pour obtenir du telmisartan.
PCT/CN2013/001320 2012-10-31 2013-10-31 Procédé de préparation de telmisartan et son intermédiaire WO2014067237A1 (fr)

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CN114436833A (zh) * 2021-12-27 2022-05-06 南京红太阳医药研究院有限公司 一种替米沙坦关键中间体4′-甲基联苯-2-羧酸酯的制备方法

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CN104086480A (zh) * 2014-06-20 2014-10-08 沈阳化工研究院有限公司 一种制备2-氯-5-氯甲基吡啶的方法
CN111454148A (zh) * 2020-04-23 2020-07-28 东南大学 一种替米沙坦杂质化合物及其制备方法

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