CN101743228B - Process for preparing telmisartan - Google Patents
Process for preparing telmisartan Download PDFInfo
- Publication number
- CN101743228B CN101743228B CN200880022887.7A CN200880022887A CN101743228B CN 101743228 B CN101743228 B CN 101743228B CN 200880022887 A CN200880022887 A CN 200880022887A CN 101743228 B CN101743228 B CN 101743228B
- Authority
- CN
- China
- Prior art keywords
- telmisartan
- compound
- methyl
- formula
- salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 0 *c1ccccc1-c1ccc(CBr)cc1 Chemical compound *c1ccccc1-c1ccc(CBr)cc1 0.000 description 3
Classifications
-
- 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
- C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Novel processes for preparing a telmisaitan nitrile intermediate (4'-[{2-n-propyl-4- methyI-6-f l-methyJbenzimidazol-2-yl}-benzimidazol- l -yl}-methyl}-biphenyl-2-nitrile} and further converting it to telmisaitan and/or salts thereof are disclosed.
Description
Technical field
The preparation method of telmisartan intermediate who the present invention relates to be substituted in 2 of the biphenyl groups of (4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl), the invention still further relates to the method that this intermediate is converted into telmisartan and/or its salt.The method according to this invention has cost and time benefit, and with high yield and high quality of production telmisartan.
Background technology
Chemistry 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-carboxylic acid by name of telmisartan, as shown in Equation 1, it is the non-peptide antagonist (AT of angiotensin-ii receptor hypotype 1 to its structure
1-antagonist), be used for the treatment of hypertension.It can use separately, or and other pharmaceutically active compound coupling, for example hydrochlorothiazide.
Telmisartan is disclosed in EP 0502314 and J.Med.Chem., and 36 (25), 4040-4051 (1993).Its polymorphic is from EP 1 144 386 and J.Pharm.Sci.89 (11), and 1465-1479 (2000) is known.
EP 0 502 314 and J.Med.Chem., 36 (25), 4040-4051 (1993) discloses the method (flow process 1) that intermediate that a kind of tertiary butyl with telmisartan replaces is prepared telmisartan.The final product of the method is difficult to filter, wash with separated.These characteristics become the obstacle of effective scale operation.
Flow process 1
From the chemistry that represented by formula 3 by name 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole]-2-yl)-benzoglyoxaline-1-yl)-methyl] the synthetic telmisartan of compound (being called again telmisartan nitrile) of-xenyl-2-nitrile is disclosed in EP 0 502 314A, WO 2004/087676, CN 1412183 and US 2006/264491.
In WO 2004/087676 and CN 1412183, telmisartan is prepared (flow process 2) by the compound of hydrolyzing type 3:
Flow process 2
Disclosed method can be for scale operation telmisartan, and its purifying is also relatively easy.
US 2006/0264491 discloses by hydrolysis 4 ' ((1; 4 "-dimethyl-2 '-propyl group (2,6 '-Lian-1H-benzoglyoxaline)-1 '-yl)-methyl)-(1,1 '-xenyl)-2-formamide becomes telmisartan, separated telmisartan crude product and alternatively by crystallization purifying telmisartan crude product.
Amorphous telmisartan is disclosed in US 200,6/1 11417 and WO 2006/050921, and the crystallized form of telmisartan is disclosed in WO 00/43370, IN 2005MU00164 and US 2006/0276525.
The multiple salt of telmisartan, for example, can know from CN 1548421, WO 03/037876, WO2006/044754, WO 2006/050509, WO 2006/050921, EP 1 719 766, WO2006/136916, WO 2007/010558 and WO 2007/147889.
Except the preparation method of telmisartan discussed above, still need a kind of further method of improved synthetic telmisartan.
Therefore, the object of this invention is to provide a kind of method of telmisartan intermediate that new production is substituted in 2 of the biphenyl groups of (4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl), the method is suitable for technical scale and economy, have cost and time benefit, the intermediate of producing can become with high quality telmisartan and/or its salt with high yield conversion.
Another object of the present invention is to provide novel telmisartan intermediate and derivative thereof, and the synthetic method of these compounds is new, has cost and time benefit.
Summary of the invention
On the one hand, the invention provides the method for the key intermediate of the synthetic telmisartan of preparation, this intermediate is substituted in the telmisartan intermediate of 2 of the biphenyl groups of 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl.
On the other hand, the invention provides novel intermediate, these intermediates are for the synthesis of being chosen as separation/or the telmisartan intermediate of 2 of the biphenyl groups that is substituted in 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl of purified form, and they in preparing telmisartan and/or its salt as the purposes of intermediate.
On the other hand, the invention provides the telmisartan intermediate of 2 of biphenyl groups that are substituted in 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl, it is prepared by method of the present invention, purity is greater than 98%, be preferably greater than 99%, wherein the content of single impurity is lower than 0.15%.
On the other hand, the invention provides a kind of pharmaceutical composition, it is for telmisartan or its salt prepared by method of the present invention that passes through with unit dosage form effective dosage, and described telmisartan or its salt are used separately or and other activeconstituents coupling.
Detailed Description Of The Invention
A kind of method that the object of this invention is to provide new intermediate of preparing telmisartan derivant with cost and time benefit, the intermediate of described telmisartan derivant is substituted in 2 of the biphenyl groups of 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl.These derivatives are by formula 3 " representative:
Wherein
R
1c
1-C
6alkyl,
R
2c
1-C
6alkyl,
R
3c
1-C
6alkyl,
Z is the group that can change into tetrazyl or carboxyl, and it can be selected from CN and COR
6, R wherein
6can be N (R)
2or OR
1, wherein R is H, C
1-C
6alkyl or benzyl.Preferably, Z is-CN ,-COOMe ,-COOEt ,-CONH
2or-CONMe
2.
First, this creationary method (method A) comprises the following steps:
A) with initial compounds 8 " diaminobenzene of acidylate N-alkyl-replacements is with formation compound 7 ",
B) condensation is to form compound 6 ",
C) reduction is to obtain compound 5 ",
D) aralkyl is to obtain compound 4 ", and
E) condensation is to prepare compound 3 "
Wherein
R
1c
1-C
6alkyl,
R
2c
1-C
6alkyl,
R
3c
1-C
6alkyl,
Z is the group that can change into tetrazyl or carboxyl, and it can be selected from CN and COR
6, R wherein
6can be N (R)
2or OR
1, wherein R is H, C
1-C
6alkyl or benzyl, and
X is Cl, Br or I.
More particularly, a kind of method (flow process 3, wherein Z is as definition above) that the object of this invention is to provide telmisartan intermediate of preparation formula 3 ' representative:
Flow process 3
More particularly, the object of this invention is to provide a kind of method (flow process 3, wherein Z is CN) of preparing telmisartan nitrile, comprise the following steps:
Step is a) under suitable solvent and suitable catalyzer exist, and with compound 8 acidylate N-methylbenzene-1,2-diamines, to form compound 7 (N-(2-aminophenyl)-4-(amide-based small)-N, 3-dimethyl-5-nitrobenzamide).
Available suitable catalyzer includes but not limited to: pyridine, triethylamine and analogue thereof.Available suitable solvent includes but not limited to: tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform, toluene, dimethyl formamide and analogue thereof, and any its mixture.
The temperature of carrying out acidylate can be in the scope of about 100 ℃ of about 0-, particularly approximately in the scope of about 60 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Above-mentioned preferred reaction conditions, catalysts and solvents are also to carry out according to the present invention the more preferred form of specializing of the acidylate step (a) of broad aspect.Following part herein also should be carried out identical necessary accommodation.
Step b) condensation compound 7 under suitable solvent and suitable catalyzer exist, to form compound 6 (N-(2-methyl-4-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl)-6-nitrophenyl) butyramide).
Available suitable catalyzer includes but not limited to: pyridine, tosic acid, acetic acid and the organic and mineral compound that similarly promotes intramolecular condensation.
Step b) suitable solvent available in includes but not limited to: tetrahydrofuran (THF), dioxane, pyridine, acetic acid, toluene and similar solvent thereof, and any its mixture.The temperature of carrying out condensation can be in the scope of about 130 ℃ of about 0-, particularly approximately in the scope of about 60 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Step c) hydro-reduction compound 6 under suitable solvent and suitable catalyzer exist, to obtain compound 5 (N-(2-amino-6-methyl-4-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl) phenyl) butyramide).
Step c) suitable catalyzer available in includes but not limited to: palladium charcoal, Raney-Ni and similar hydrogenation catalyst.
Available suitable solvent includes but not limited to: tetrahydrofuran (THF), methyl alcohol, ethanol, propyl alcohol and other have lower alcohol and the ether that is less than 6 carbon atoms; Water; And any its mixture.
The temperature of reducing can be in the scope of about 100 ℃ of about 0-, particularly approximately in the scope of about 50 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Steps d) be included under suitable solvent and suitable catalyzer exist, with 4 '-(brooethyl) xenyl-2-nitrile alkylated compound 5, to form compound 4 (N-((2-cyano group-xenyl-4 '-methyl) amino-6-methyl-4-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl) phenyl) butyramide).
Steps d) catalyzer suitable in can be inorganic base catalyst, includes but not limited to alkali-metal oxyhydroxide, for example lithium hydroxide, sodium hydroxide, potassium hydroxide and other alkaline hydrated oxide; Alkali-metal carbonate, for example sodium carbonate, salt of wormwood and other basic carbonate; Alkali-metal supercarbonate, for example sodium bicarbonate, saleratus and similar supercarbonate.Also can use mixture and the alkaline phosphate of these compounds, for example tertiary sodium phosphate.
Steps d) suitable solvent available in includes but not limited to: tetrahydrofuran (THF), acetonitrile, toluene, DMF and analogue thereof; And any its mixture.Carrying out alkylating temperature can be in the scope of about 100 ℃ of about 0-, particularly approximately in the scope of about 50 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Step e) condensation compound 4 under suitable solvent and suitable catalyzer exist, to form compound 3 (4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-nitrile).
This step (comprise according to the present invention the more step e of broad aspect, as previously described) in available suitable catalyzer include but not limited to: pyridine, tosic acid, acetic acid and analogue thereof.Suitable solvent includes but not limited to: tetrahydrofuran (THF), dioxane, pyridine, acetic acid, toluene and analogue thereof, and any its mixture.
The temperature of carrying out condensation can be in the scope of about 130 ℃ of about 0-, particularly approximately in the scope of about 60 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Initial compounds 8 " or 8 (4-(amide-based small)-3-methyl-5-nitro phenylformic acid) can be according to J.Med.Chem.; 36 (25); the preparation of the disclosed method of 4040-4051 (1993); or prepare by acidylate 4-amino-5-methyl-3-nitro phenylformic acid, it is disclosed in US 3691166, US 7220862, WO 2005/065779 and WO 2007/056155.For acylation reaction method, can adopt the method for those acidylate amino groups known in the art, for example, with muriate, mixed acid anhydride and coupling reagent activation.
The present invention is method B on the other hand.The method also relates to the preparation of the intermediate of telmisartan derivant, the intermediate of described telmisartan derivant is substituted in 2 of the biphenyl groups of 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl, these derivatives are by formula 3 " representative, the method comprises the following steps:
A) esterification initial compounds 12 " to form compound 11 ",
B) alkylation is to form compound 10 ",
C) hydrolysis is to form compound 9 ", and
D) condensation is to form compound 3 "
Wherein
R
1c
1-C
6alkyl,
R
2c
1-C
6alkyl,
R
3c
1-C
6alkyl,
R
4cONR
5, R wherein
5h or C
1-C
3alkyl,
Z is the group that can change into tetrazyl or carboxyl, and it can be selected from CN and COR
6, R wherein
6can be N (R)
2or OR
1, wherein R is H, C
1-C
6alkyl or benzyl, and
X is Cl, Br or I.
The preferred aspect of the present invention is the method (flow process 4, wherein Z is as defined above) of shortening of the telmisartan intermediate of preparation formula 3 ':
Flow process 4
Another preferred aspect of this embodiment of the present invention is to prepare the method for telmisartan nitrile (flow process 4, wherein Z is CN), comprises the following steps:
A) carboxylic group of esterification compound 12 (7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid) to be to form compound 11 (7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid methyl esters),
B) with 4 '-(brooethyl) xenyl-2-nitrile alkylated compound 11 to form compound 10 (4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-methoxycarbonyl-3-yl)-methyl)-xenyl-2-nitrile),
C) hydrolysis compound 10 with form compound 9 (4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-carboxyl-3-yl)-methyl-xenyl-2-nitrile), and
D) condensation compound 9 and N-methylbenzene-1,2-diamines is to form compound 3 (4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-nitrile).
Step a) is included in suitable solvent and suitable catalyzer and exists the carboxylic group of lower esterification compound 12 to form compound 11 (7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid methyl esters).
Suitable catalyzer can be inorganic acid catalyst, includes but not limited to hydrochloric acid, sulfuric acid and similar inorganic acid.Available suitable solvent includes but not limited to, methyl alcohol, tetrahydrofuran (THF), acetonitrile, toluene and similar organic solvent, and any its mixture.
The temperature of carrying out esterification can be in the scope of about 100 ℃ of about 0-, particularly approximately in the scope of about 50 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Step b) be included in suitable solvent and suitable catalyzer exist lower with 4 '-(brooethyl) xenyl-2-nitrile alkylated compound 11 with formation compound 10 (4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-methoxycarbonyl-3-yl)-methyl)-xenyl-2-nitrile).
Suitable catalyzer can be inorganic base catalyst, includes but not limited to, alkali-metal oxyhydroxide, for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar alkaline hydrated oxide; Alkali-metal carbonate, for example sodium carbonate, salt of wormwood and similar carbonate, for example volatile salt; With alkali-metal supercarbonate, for example sodium bicarbonate, saleratus and similarly supercarbonate, for example bicarbonate of ammonia.
Available suitable solvent includes but not limited to: acetone, tetrahydrofuran (THF), acetonitrile, toluene, DMF and similar organic solvent; And any its mixture.
Carrying out alkylating temperature can be in the scope of about 100 ℃ of about 0-, particularly approximately in the scope of about 50 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Step c) being included in suitable solvent and suitable catalyzer exists lower hydrolysis compound 10 to form compound 9 (4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-carboxyl-3-yl)-methyl-xenyl-2-nitrile).
Suitable catalyzer can be inorganic base catalyst, includes but not limited to, alkali-metal oxyhydroxide, for example lithium hydroxide, sodium hydroxide, potassium hydroxide and analogue thereof; Alkali-metal carbonate, for example sodium carbonate, salt of wormwood and similar carbonate, for example volatile salt.
Available suitable solvent includes but not limited to, methyl alcohol, ethanol, propyl alcohol and analogue thereof, water; And any its mixture.
The temperature being hydrolyzed can be in the scope of about 80 ℃ of about 0-, particularly approximately in the scope of about 50 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Steps d) be included in suitable solvent and suitable catalyzer and have lower condensation compound 9 and N-methylbenzene-1,2-diamines is to form compound 3 (4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-nitrile).
Available suitable catalyzer includes but not limited to, SOCl
2and the similar compound that promotes moisture removal.
Available suitable solvent includes but not limited to, methylene dichloride, toluene, chlorobenzene and analogue thereof, and any its mixture.
The temperature of carrying out condensation can be in the scope of about 130 ℃ of about 0-, particularly approximately in the scope of about 100 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
As previously mentioned, these preferred conditions are general for method B, and are not limited to prepare by method B the embodiment of telmisartan nitrile.
Initial compounds 12 " or 12 (7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acids) can prepare by any method well known in the prior art; J.Med.Chem. for example; 36 (25); 4040-4051 (1993), WO 97/19911, CN 1623992, organic chemistry 26 (3), 318-323 (2006) and WO2006/044754.
Another preferred aspect of the present invention is the method for the following intermediate of preparing telmisartan derivant, the intermediate of described telmisartan derivant is substituted in 2 of the biphenyl groups of 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl, these derivatives are by formula 3 " representative, the method comprises the following steps:
A) alkylated compound 11 " to form compound 10 ", and
B) condensation is to form compound 3 "
10″or R9″(R
4＝H)
Wherein
R
1c
1-C
6alkyl,
R
2c
1-C
6alkyl,
R
3c
1-C
6alkyl,
R
4cONR
5, R wherein
5h or C
1-C
3alkyl,
Z is the group that can change into tetrazyl or carboxyl, and it can be selected from CN and COR
6, R wherein
6can be N (R)
2or OR
1, wherein R is H, C
1-C
6alkyl or benzyl, and
X is Cl, Br or I.
Step a) is included in suitable solvent and suitable catalyzer and has lower alkylated compound 11 " to form compound 10 ", and hydrolysis compound 10 under suitable solvent and suitable catalyzer exist alternatively " to form compound 9 ".
Suitable catalyzer can be inorganic base catalyst, includes but not limited to, alkali-metal oxyhydroxide, for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar basic oxide and oxyhydroxide; Alkali-metal carbonate, for example sodium carbonate, salt of wormwood and similar carbonate, for example volatile salt; With alkali-metal supercarbonate, for example sodium bicarbonate, saleratus and similarly supercarbonate, for example bicarbonate of ammonia.
Available suitable solvent includes but not limited to: tetrahydrofuran (THF), acetonitrile, toluene, DMF and analogue thereof; And any its mixture.
Carrying out alkylating temperature can be in the scope of about 100 ℃ of about 0-, particularly approximately in the scope of about 50 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Step b) be included in suitable solvent and suitable catalyzer and have lower condensation compound 9 " or compound 10 " and N-methylbenzene-1,2-diamines is to form compound 3 ".
More particularly, the object of this invention is to provide a kind of method (flow process 5, wherein Z is as defined) of telmisartan intermediate of preparation formula 3 ' above, comprising:
Flow process 5
Wherein
Z is the group that can change into tetrazyl or carboxyl, and it can be selected from CN and COR
6, R wherein
6can be N (R)
2or OR
1, wherein R is H, C
1-C
6alkyl or benzyl, and R
1c
1-C
6alkyl.
More particularly, the object of this invention is to provide a kind of method (flow process 5, wherein Z is CN) of preparing telmisartan nitrile, comprise the following steps:
A) with 4 '-(brooethyl) xenyl-2-nitrile alkylated compound 11 (7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid methyl esters), then be hydrolyzed ester group to form compound 9 (4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-methoxycarbonyl-3-yl)-methyl)-xenyl-2-nitrile)
B) condensation compound 9 and N-methylbenzene-1,2-diamines to be to form compound 9a (1-((2 '-cyanobiphenyl base-4-yl) methyl)-4-methyl-N-(2-(methylamino) phenyl)-2-propyl group-1H-benzo [d] imidazoles-6-methane amide), and
C) cyclization compound 9a is to form compound 3 (4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-nitrile).
Step a) is included in suitable solvent and suitable catalyzer and exists lower to 4 '-(brooethyl) xenyl-2-nitrile alkylated compound 11 (7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid methyl esters), to form compound 9 (4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-methoxycarbonyl-3-yl)-methyl)-xenyl-2-nitrile) after hydrolysis, and need not separated ester.
Suitable catalyzer can be inorganic base catalyst, includes but not limited to, alkali-metal oxyhydroxide, for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar basic oxide and oxyhydroxide; Alkali-metal carbonate, for example sodium carbonate, salt of wormwood, sodium phosphate, potassiumphosphate and similar highly basic salt; With alkali-metal supercarbonate, for example sodium bicarbonate, saleratus and similarly supercarbonate, for example bicarbonate of ammonia.
Can use additional catalyzer, for example iodide, comprise sodium iodide, potassiumiodide and lithium iodide.Preferably use potassiumiodide.
Available suitable solvent includes but not limited to: tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, 1,2-glycol dimethyl ether, acetonitrile, toluene, DMF, N,N-dimethylacetamide, DMSO, acetone, 2-butanone, propione and analogue thereof; And any its mixture.
Carrying out alkylating temperature can be in the scope of about 120 ℃ of about 0-, particularly approximately in the scope of about 60 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
After alkylation step, except desolventizing, carry out ester group hydrolysis and need not separated ester intermediate.To adding other solvent in residue.Available suitable solvent includes but not limited to: methyl alcohol, ethanol, propyl alcohol and similar alcohol; Water, and any its mixture.
Suitable catalyzer can be inorganic base catalyst, includes but not limited to, alkali-metal oxyhydroxide, for example lithium hydroxide, sodium hydroxide, potassium hydroxide and similar basic oxide and oxyhydroxide; With alkali-metal carbonate, for example sodium carbonate, salt of wormwood and similarly carbonate, for example volatile salt.
The temperature being hydrolyzed can be in the scope of about 80 ℃ of about 0-, particularly approximately in the scope of about 50 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
After reacting completely (after 1-10h), mixture is cooling, and adding acid to regulate the pH value of mixture is 2-7, preferred 5-6, for example ore deposit acid of described acid, for example HCl, H
2sO
4or H
3pO
4the aqueous solution, preferably add the HCl aqueous solution.
Step b) be included in suitable solvent and suitable reagent and have lower condensation compound 9 and N-methylbenzene-1,2-diamines is to form compound 9a (1-((2 '-cyanobiphenyl base-4-yl) methyl)-4-methyl-N-(2-(methylamino) phenyl)-2-propyl group-1H-benzo [d] imidazoles-6-methane amide).
N-methylbenzene-1, the form that 2-diamines can inorganic acid salt is used, for example HCl, H
3pO
4or H
2sO
4inorganic acid salt.
The reagent of available suitable formation amido linkage includes but not limited to, SOCl
2and analogue.The consumption of catalyzer is 1-7 equivalent, preferably 3-5 equivalent.
Available suitable solvent includes but not limited to, pyridine, N-Methyl pyrrolidone, toluene, methylene dichloride, chloroform, 1,2-glycol dimethyl ether, THF, 2-methyl-THF, Isosorbide-5-Nitrae-dioxane, pentane and similar polar non-proton organic solvent; With and composition thereof.
The temperature of carrying out condensation can be in the scope of about 130 ℃ of about 0-, particularly approximately in the scope of about 100 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.From residue, carry out after separating step (extraction), add organic solvent deposit product (compound 9a), described organic solvent is non-polar solvent for example, preferably hexane, heptane, sherwood oil, hexanaphthene, ether (diethyl ether, diisopropyl ether, t-butyl methyl ether), benzene,toluene,xylene and analogue thereof.
Step c) comprise that cyclization compound 9a is to form compound 3 (4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-nitrile).In compound 9a, add organic solvent.About organic solvent, can use following solvent: toluene, dimethylbenzene, benzene, hexanaphthene, Isosorbide-5-Nitrae-dioxane, THF, 2-methyl-THF, 1,2-glycol dimethyl ether, diisopropyl ether, t-butyl methyl ether and analogue thereof.To the acid catalyst that adds catalytic amount in this mixture.Use Lewis acid, preferably H
3bO
3.The amount that an acidic catalyst exists is 1-50mol%, preferably 1-10mol%.
The temperature of carrying out cyclization can be in the scope of about 140 ℃ of about 0-, particularly under the reflux temperature of solvent for use.The water forming between the reaction period can be separated and be removed.
After cyclization completely, reaction mixture is used activated carbon treatment alternatively.Finally, be cooled to-10-30 ℃ of product solution, preferably 15-25 ℃, then separation and desciccate.
Initial compounds 11 " or 11 (7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid methyl esters) can prepare by any method well known in the prior art; J.Med.Chem. for example; 36 (25); 4040-4051 (1993), WO 97/19911, CN 1623992, organic chemistry 26 (3), 318-323 (2006) and WO2006/044754.
Another aspect of the present invention is method C, the method is for the preparation of the intermediate of telmisartan derivant, the intermediate of described telmisartan derivant is substituted in 2 of the biphenyl groups of 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl, these derivatives are by formula 3 " representative, the method comprises the following steps:
A) acylated compounds 12 " alkyl diaminobenzene to form compound 15 ",
B) alkylation is to form compound 14 ",
C) reduction is to form compound 13 ", and
D) condensation is to form compound 3 "
Wherein
R
1c
1-C
6alkyl,
R
2c
1-C
6alkyl,
R
3c
1-C
6alkyl,
Z is the group that can change into tetrazyl or carboxyl, and it can be selected from CN and COR
6, R wherein
6can be N (R)
2or OR
1, wherein R is H, C
1-C
6alkyl or benzyl, and
X is Cl, Br or I.
The method that special aspect of the present invention is the telmisartan intermediate of preparation formula 3 ' (flow process 6, wherein Z is as defined above):
Flow process 6
Wherein
R
1c
1-C
6alkyl,
R
2c
1-C
6alkyl,
R
3c
1-C
6alkyl,
Z is the group that can change into tetrazyl or carboxyl, and it can be selected from CN and COR
6, R wherein
6can be N (R)
2or OR
1, wherein R is H, C
1-C
6alkyl or benzyl.
Preferred aspect of the present invention is to prepare the method for telmisartan nitrile (flow process 6, wherein Z is CN), comprises the following steps:
A) use compound 12 (7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid) acidylate N-methyl-2-N-methyl-p-nitroaniline to form compound 15 (N; 7-dimethyl-N-(2-nitrophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide)
B) with 4 '-(brooethyl) xenyl-2-nitrile alkylated compound 15 to form compound 14 (4 '-((N, 7-dimethyl-N-(2-nitrophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide-3-yl)-methyl)-xenyl-2-nitrile)
C) reducing compound 14 to be to form compound 13 (4 '-((N, 7-diformazan-N-(2-aminophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide-3-yl)-methyl)-xenyl-2-nitrile), and
D) condensation compound 13 is to form compound 3 (4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-nitrile).
Step a) comprises with thionyl chloride or oxalyl chloride and processes compound 12; then under suitable solvent and suitable catalyzer exist acidylate N-methyl-2-N-methyl-p-nitroaniline to form compound 15 (N, 7-dimethyl-N-(2-nitrophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide).
Available suitable catalyzer includes but not limited to, pyridine, triethylamine and similar alkaline catalysts.
Available suitable catalyzer includes but not limited to, tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform, toluene, dimethyl formamide and analogue thereof, and any its mixture.
The temperature of carrying out acidylate can be in the scope of about 100 ℃ of about 0-, particularly approximately in the scope of about 60 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Step b) be included in suitable solvent and suitable catalyzer exist lower with 4 '-(brooethyl) xenyl-2-nitrile alkylated compound 15 with formation compound 14 (4 '-((N, 7-dimethyl-N-(2-nitrophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide-3-yl)-methyl)-xenyl-2-nitrile).
Suitable catalyzer can be inorganic base catalyst, includes but not limited to, alkali-metal oxyhydroxide, for example lithium hydroxide, sodium hydroxide, potassium hydroxide and analogue thereof; Alkali-metal carbonate, for example sodium carbonate, salt of wormwood and analogue thereof; Alkali-metal supercarbonate, for example sodium bicarbonate, saleratus and analogue thereof.In context, statement " and analogue " can be particularly including corresponding ammonium hydroxide, volatile salt and bicarbonate of ammonia; This is all suitable in the application's full text.
Available suitable solvent includes but not limited to, tetrahydrofuran (THF), acetonitrile, toluene, DMF and similar polar aprotic solvent; With and composition thereof.
Carrying out alkylating temperature can be in the scope of about 100 ℃ of about 0-, particularly approximately in the scope of about 50 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Step c) being included in suitable solvent and suitable catalyzer exists lower reducing compound 14 to form compound 13 (4 '-((N, 7-diformazan-N-(2-aminophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide-3-yl)-methyl)-xenyl-2-nitrile).
Available suitable catalyzer includes but not limited to: palladium charcoal, Raney-Ni and similar hydrogenation catalyst.
Available suitable solvent includes but not limited to: tetrahydrofuran (THF), methyl alcohol, ethanol, propyl alcohol and similar protonic solvent; Water; And any its mixture.
The temperature of reducing can be in the scope of about 100 ℃ of about 0-, particularly approximately in the scope of about 50 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Steps d) being included in suitable solvent and suitable catalyzer exists lower condensation compound 13 to form compound 3 (4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-nitrile).
Available suitable catalyzer includes but not limited to: pyridine, tosic acid, acetic acid and similar compound thereof (seing above face).Suitable solvent includes but not limited to: tetrahydrofuran (THF), dioxane, pyridine, acetic acid, toluene and similar compound thereof (seing above face), and any its mixture.
The temperature of carrying out condensation can be in the scope of about 130 ℃ of about 0-, particularly approximately in the scope of about 60 ℃ of 20-, and more particularly, under the reflux temperature of solvent for use.
Initial compounds 12 " or 12 (7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acids) can prepare by any method well known in the prior art; J.Med.Chem. for example; 36 (25); 4040-4051 (1993), WO 97/19911, CN 1623992, organic chemistry 26 (3), 318-323 (2006) and WO2006/044754.
Another embodiment of the invention is telmisartan intermediate and the formula 3 ' and 3 of 2 of the biphenyl groups that is substituted in 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl of the formula 3 prepared by the inventive method " its derivative of representative; the purity of these materials is greater than 98%; be preferably greater than 99%, and wherein the content of single impurity is lower than 0.15%.
We are surprised to find that formula 3 or 3 ' or 3 " the chemical purity of compound in the method for producing telmisartan or telmisartan derivant and/or its salt, play crucial effect.If for example the chemical purity of the compound of formula 3 is lower than 98%, the telmisartan material of being prepared by formula 3 compounds will not meet pharmacopeia requirement.
The formula 3 ' of preparing by the inventive method and 3 " the telmisartan intermediate of 2 of biphenyl groups that is substituted in 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl and the intermediate of telmisartan derivant by method for hydrolysis (flow process 7a and flow process 7b), transform respectively an accepted way of doing sth 1 and 1 " telmisartan and telmisartan derivant.Suitable method for hydrolysis is well known in the prior art, for example, be disclosed in EP 0 502 314, CN 1412183, WO 2004/087676 and ongoing application WO 2007/147889.
Flow process 7a
Flow process 7b
Wherein
R
1c
1-C
6alkyl,
R
2c
1-C
6alkyl,
R
3c
1-C
6alkyl,
Z is the group that can change into tetrazyl or carboxyl, and it can be selected from CN and COR
6, R wherein
6can be N (R)
2or OR
1, wherein R is H, C
1-C
6alkyl or benzyl.
Gained telmisartan preferably changes into its pharmacy acceptable salt, and for example sodium, potassium, meglumine, tert-butyl amine salt, or from any other salt known in the art, for example, from other salt known to ongoing application WO2007/147889.
On the other hand, the invention provides the synthetic novel intermediate of telmisartan nitrile, it is the form of separation and/or purifying alternatively, and these intermediates are selected from:
Compound 4, chemical name
N-((2-cyano group-xenyl-4 '-methyl) amino-6-methyl-4-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl) phenyl) butyramide
Compound 5, chemical name
N-(2-amino-6-methyl-4-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl) phenyl) butyramide
Compound 6, chemical name
N-(2-methyl-4-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl)-6-nitrophenyl) butyramide
Compound 9, chemical name
4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-carboxyl-3-yl)-methyl)-xenyl-2-nitrile
Compound 9a, chemical name
1-((2 '-cyanobiphenyl base-4-yl) methyl)-4-methyl-N-(2-(methylamino) phenyl)-2-propyl group-1H-benzo [d] imidazoles-6-methane amide
Compound 10, chemical name
4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-methoxycarbonyl-3-yl)-methyl)-xenyl-2-nitrile
Compound 13, chemical name
4 '-((N, 7-dimethyl-N-(2-aminophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide-3-yl)-methyl)-xenyl-2-nitrile
Compound 14, chemical name
4 '-((N, 7-dimethyl-N-(2-nitrophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide-3-yl)-methyl)-xenyl-2-nitrile
Compound 15, chemical name
N, 7-dimethyl-N-(2-nitrophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide
On the other hand, the invention provides the purposes of described novel intermediate in preparing telmisartan and/or its salt.
The method according to this invention has avoided 1,7 '-dimethyl-2 '-propyl group-1H, 3 ' H-2,5 '-biphenyl is the use of [d] imidazoles also, it is the key intermediate (referring to flow process 1) of synthetic telmisartan known in the art, and it is difficult to preparation (in prior art, disclosed method is used polyphosphoric acid to reach 20 hours at 150 ℃).
Another aspect of the present invention is a kind of pharmaceutical composition, it is for telmisartan or its salt prepared by a kind of method of the present invention that passes through of effective dosage, described telmisartan or its salt use separately or and other activeconstituents and at least one pharmaceutically acceptable vehicle coupling, described vehicle is selected from but is not limited to alkaline agent, thinner, tackiness agent, disintegrating agent, tensio-active agent, crystallization retarding agent, lubricant and glidant.Term " pharmaceutically acceptable vehicle " refers to for pharmaceutically active compounds being changed into the additive of the pharmaceutical dosage form that is applicable to delivering medicine to patient.
Solid composite medicament of the present invention is preferably made unit dosage form, and every dosage is containing having an appointment 10-160mg, preferred about 20-80mg telmisartan and/or its salt.When the stable solid composite medicament of the present invention contains one or more other activeconstituentss, the content of described other activeconstituents is 6.25-50mg, preferably 12.5-25mg.Term " unit dosage form " refers to be suitable for to deliver medicine to telmisartan and/or its salt and the suitable pharmaceutically acceptable vehicle that the ，Mei unit, physically separated unit of the mankind or other mammiferous single dose contains the predetermined amount that can produce desirable result for the treatment of calculating.
Term alkaline agent refers to that the pH value that maintains pharmaceutical composition is at least 7, is preferably at least these reagent of 8.The pH of pharmaceutical composition is by being dissolved in the pharmaceutical composition of appropriate amount in neutral water and preparation 20%[w/w] measured in solution.Can use any standard pH meter for detection of pH.Alkaline agent for pharmaceutical composition of the present invention can be selected from, but is not limited to ammoniacal liquor, choline, tert-butylamine, thanomin, NaOH, KOH, Ca (OH)
2, Na and K carbonate, supercarbonate and phosphoric acid salt, meglumine, piperazine, diethylamine, L-arginine and any its mixture.Preferred ammoniacal liquor, NaOH, KOH and meglumine.
Thinner used in pharmaceutical composition of the present invention can be selected from but be not limited to, Microcrystalline Cellulose, Solka-floc, lactose (anhydrous and monohydrate), sompressible sugar, fructose, dextran, sugar alcohol (as N.F,USP MANNITOL, sorbyl alcohol, maltose alcohol, Xylitol, Saccharum lactis) or other sugar (as sucrose, raffinose, trehalose, fructose or its mixture), silicified microcrystalline cellulose, secondary calcium phosphate, calcium carbonate, calcium lactate and any its mixture.Preferred water miscible weighting agent is other sugar of N.F,USP MANNITOL, sorbyl alcohol, Xylitol and lactose for example.
Tackiness agent used in pharmaceutical composition of the present invention can be selected from but be not limited to, polyvinylpyrrolidone, Microcrystalline Cellulose, Natvosol, hydroxypropylcellulose, HPMC or other cellulose ethers, starch, pregelatinized Starch or polymethacrylate and any its mixture.
Disintegrating agent used in pharmaceutical composition of the present invention can be selected from but be not limited to, polyvinylpolypyrrolidone, starch, pregelatinized Starch, sodium starch glycollate, Microcrystalline Cellulose, Xylo-Mucine (CMC-Na) or calcium (CMC-Ca), crosslinked CMC-Na, Polacrilin potassium, low-substituted hydroxypropyl cellulose and any its mixture.Preferably, at least one disintegrating agent is selected from crosslinked CMC-Na, starch and low-substituted hydroxypropyl cellulose.
Tensio-active agent used in pharmaceutical composition of the present invention can be selected from but be not limited to, negatively charged ion, positively charged ion, both sexes and nonionogenic tenside.Anion surfactant, its hydrophilic radical is with negative charge, for example carbonyl (RCOO
-), sulfonic group (RSO
3 -) or sulfate (ROSO
3 -), example comprises potassium laurate (CH
3(CH
2)
10cOO
-k
+), sodium lauryl sulphate (CH
3(CH
2)
11sO
4 -na
+).Cats product, its hydrophilic radical with positive charge (as quaternary ammonium halide, R
4n
+cl
-), example comprises Cetrimonium Bromide, the mixture mainly being formed by tetradecyl (approximately 68%), dodecyl (approximately 22%) and cetyl trimethylammonium bromide (approximately 7%) and Benzalkonii Chloridum, and general formula is [C
6h
5cH
2n
+(CH
3)
2r] Cl
-alkyl benzyl dimethyl ammonium chloride mixture, wherein R represents C
8h
17to C
18h
37alkyl mixture.Amphoterics (also referred to as zwitterionics), its molecule contains or can contain potentially simultaneously negative charge and positive charge (as sulfuration trimethyl-glycine (sulfobetaines), RN
+(CH
3)
2cH
2cH
2sO
3 -), example comprises N-dodecyl-N, N-dimethyl betaine (C
12h
25n
+(CH
3)
2cH
2cOO
-).Nonionic surface active agent, its hydrophilic group neutral, its water-soluble sources is from high polar group, for example hydroxyl or polyethylene group ((OCH
2cH
2o-)
n), example comprises polyoxyethylene glycol monoether (as cetomacrogol), sorb sugar ester
and polysorbate
polyethylene glycol-propylene glycol copolymers, and any its mixture.Preferred nonionic surfactants.
Crystallization retarding agent used in pharmaceutical composition of the present invention can be selected from but be not limited to, polyvidone, copolyvidone, polyvinylpolypyrrolidone, Xylo-Mucine, hydroxypropylcellulose, HPMC and any its mixture.Preferred polyvidone and copolyvidone.
Lubricant and glidant used in pharmaceutical composition of the present invention can be selected from but be not limited to, stearic acid or stearate (as Magnesium Stearate), magnesium palmitate, magnesium oleate, hydrogenated vegetable oil, hydrogenated castor oil, talcum powder, sodium stearyl fumarate, polyethylene glycols, silicon-dioxide and any its mixture.Preferably, at least one lubricant is selected from stearic acid, Magnesium Stearate, hydrogenated vegetable oil.
One preferred embodiment in, pharmaceutical composition of the present invention contains one or more vehicle, is selected from meglumine, Poloxamer 188, PVP K30, KOH, NaOH, sorbyl alcohol, Microcrystalline Cellulose, lactose, N.F,USP MANNITOL, maltose and Magnesium Stearate.
In a preferred embodiment, pharmaceutical composition of the present invention contains meglumine, PVP K30, NaOH, sorbyl alcohol, lactose and the Magnesium Stearate as vehicle.
In a particularly preferred embodiment, pharmaceutical composition of the present invention is characterised in that it is comprised of telmisartan or its pharmacy acceptable salt, meglumine, PVP K30, NaOH, sorbyl alcohol, lactose, Magnesium Stearate.
In pharmaceutical composition of the present invention, the amount that meglumine exists can be 1-30mg, the amount that PVP K30 exists can be 5-30mg, and the amount that NaOH and Magnesium Stearate exist separately can be 2-10mg, and the amount that sorbyl alcohol and lactose exist separately can be 50-300mg.
Pharmaceutical composition of the present invention can be prepared by any means known in the art, and for example spraying is dry, fluidized bed granulation and freeze-drying.If pharmaceutical composition is prepared by spray drying process, telmisartan and/or its salt are dissolved in suitable solvent together with optional alkaline agent and/or optional crystallization retarding agent, and for example, in water or organic solvent, then spraying is dry.Spray dried particle further with other pharmaceutically acceptable mixed with excipients to form final composition.If with fluidized bed granulation method, telmisartan and/or its salt are dissolved in suitable solvent together with optional alkaline agent and/or crystallization retarding agent, for example, in water or organic solvent, to form granulation liquid.Other pharmaceutically acceptable vehicle is placed in fluidised bed granulator and then by granulation liquid, sprays.After pelletization completes, gained particle drying, and alternatively with other pharmaceutically acceptable mixed with excipients to form final composition.
Pharmaceutical composition of the present invention can further contain at least one other active pharmaceutical ingredient.The arbitrary combination of the therapeutic dose of telmisartan and/or its salt and at least one other active pharmaceutical ingredient all can be used in pharmaceutical composition of the present invention.Described other active pharmaceutical ingredient can be selected from but be not limited to, hydragog(ue), for example hydrochlorothiazide or indapamide; Antihypertensive drug, for example angiotensin-converting enzyme (ACE) inhibitor, for example captopril, enalapril, lisinopril, Trolapril, Yipingshu, Ramipril, fosinopril, Perindopril or any its pharmacy acceptable salt; Angiotensin receptor blocker (ARB); AT
1-receptor antagonist, for example Candesartan, irbesartan, iosartan, Olmesartan, valsartan or any its pharmacy acceptable salt; Calcium channel blocker (CCB), for example amlodipine, Odizem, felodipine, Nifedipine, nitrendipine and verapamil or any its pharmacy acceptable salt; Beta-adrenaline blocker, for example acebutolol, atenolol USP 23, betaxolol, bisoprolol, metoprolol or any its pharmacy acceptable salt; α-and beta-adrenaline mixing blocker Kredex is also includable; Regulation of fat agent, for example 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitor, for example lovastatin, Simvastatin, Pravastatin, atorvastatin, fluvastatin, western rivastatin, superstatin or any its pharmacy acceptable salt; And antidiabetic drug, for example sulphonyl urine, meglitinides (for example nateglinide and repaglinide) or any its pharmacy acceptable salt, thiazolidinedione (for example pioglitazone or rosiglitazone) or any its pharmacy acceptable salt, alpha-glucosidase inhibitor, incretin mimetic or biguanides, for example metformin or analogue with and pharmacy acceptable salt.
Hydragog(ue), for example hydrochlorothiazide or indapamide, can all be present in particle, or they can all be added in particle foreign minister after granulation, or they can be distributed in particle and particle foreign minister.In each dose unit, the amount of hydragog(ue) can be at 5-50mg, preferred 10-30mg.Any combination of the hydragog(ue) of telmisartan and/or its salt and any this tittle is all possible, and for example the ratio of telmisartan and/or its salt and hydrochlorothiazide [mg: mg] can be 40: 12.5,80: 12.5 and 80: 25.If use indapamide as hydragog(ue), 0.5-3mg, preferably 1.25mg indapamide and 20,40 or 80mg telmisartan (free acid) combination.
The pharmaceutical composition that contains telmisartan and/or its salt and at least one other active pharmaceutical ingredient (for example hydrochlorothiazide) according to the present invention can be prepared by any means known in the art.For example, telmisartan and/or its salt can be dried by spraying or bed process granulates to form the particle that contains telmisartan.Then this particle and at least one other active pharmaceutical ingredient mix and are pressed into tablet.Another kind of possibility is that telmisartan and/or its salt can be granulated, and other active pharmaceutical ingredient also can be granulated.Right latter two independently particle mixes to form final composition.Another kind of possibility is that at least one other active pharmaceutical ingredient can be granulated, and then the particle of gained and telmisartan and/or its salt mix, and then form final composition.Another possibility is that telmisartan and/or its salt are granulated, then any particle-separation reagent dressing for gained particle.Then the particle of dressing and other active medicine mix, and then form final composition.Also having a kind of possibility is that other active pharmaceutical ingredient can be granulated, then with any particle-separation reagent dressing.Then the particle of this dressing mixes with the particle that contains telmisartan and/or its salt, then forms final composition.In another kind of possibility, can prepare double-deck tablet.The particle that one deck contains telmisartan and/or its salt, another layer contains at least one other active pharmaceutical ingredient.In another kind of possibility, bilayer tablet can be prepared by method above, and wherein this bilayer separates by the 3rd layer again, to guarantee the separation of particle.In another kind of possibility, can prepare and a kind ofly there is middle label and around the outer field bilayer tablet of this label.Alternatively, this bilayer can be separated by particle separate layer again.Telmisartan and/or its salt may reside in label, and other active pharmaceutical ingredient is present in skin, or vice versa.
Pharmaceutical composition of the present invention can any formulation deliver medicine to patient, such as tablet, pill, lozenge, lozenge, capsule, powder, liquid, suppository, sachet, elixir, solution, syrup, suspensoid etc., preferred tablet or capsule form.Formulation can be according to patient's route of administration adjustment, for example oral, cheek, parenteral, eye, rectum and transdermal route, preferred oral approach.
Tilmisartan salt prepared in accordance with the present invention can be included in pharmaceutical composition, or it also can form on the spot in the process of preparation pharmaceutical composition of the present invention.Under latter event, then telmisartan is placed in solvent together with corresponding alkaline reagents mixes.Thereby obtain the salt form of the dissolving of telmisartan.This Tilmisartan salt can directly be used in spray dry or bed process.
Finally, the invention provides a kind of method for the treatment of morbid state, this morbid state needs patient's prepared according to the methods of the invention telmisartan and/or its salt of this treatment prevent, alleviate or eliminate by delivering medicine to.
The present invention also provides prepared according to the methods of the invention telmisartan and/or the application of its salt in preparing medicine, the pharmaceutical composition that described medicine contains previously described treatment morbid state, described morbid state is prevented, alleviates or eliminated by administration telmisartan and/or its salt.
The present invention also provides prepared according to the methods of the invention telmisartan and/or the purposes of its salt in treatment morbid state, and described morbid state is prevented, alleviates or eliminated by administration telmisartan and/or its salt.
Provide following examples to illustrate in greater detail particular aspects of the present invention, but should be understood that, these embodiment do not limit the present invention in any way.
Embodiment
Embodiment 1
N-(2-aminophenyl)-4-(amide-based small)-N, the preparation of 3-dimethyl-5-nitrobenzamide (compound 7):
Toward 3.9g (20mmol) N-methylbenzene-1,2-diamines dihydrochloride and 10ml CH
2cl
2mixture in add 1.6ml pyridine (20mmol), under room temperature, stir to obtain free N-methylbenzene-1,2-bis-amine aqueous solutions.Gained solution joins in the mixture of 2.66g (10mmol) compound 8,3.24g (20mmol) CDI and 60mlTHF, stirs 3h and filters.Wet filter cake is dry in baking oven, obtains 2.26g solid chemical compound 7 (productive rates: 61%).
1H NMR(300MHz，DMSO-d
6)：δ8.33(s，1H)，8.19(s，1H)，7.11(d，2H，J＝6.9Hz)，6.63(d，2H，J＝7.8Hz)，2.70(s，3H)，2.30～2.36(m，5H)，1.60(m，2H)，0.93(t，3H，J＝7.5Hz)；ESI-MS：369[M-1]
-
Embodiment 2
The preparation of N-(2-methyl-4-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl)-6-nitrophenyl) butyramide (compound 6):
The mixture of 370mg (1mmol) compound 7 and 5ml pyridine is heated to reflux, and stirs 5h.Mixture with ethyl acetate dilute, wash with water, Na
2sO
4be dried and filter, under vacuum, except desolventizing, obtain 0.3g compound 6 (productive rates: 85%).
ESI-MS：353[M+1]
+
Embodiment 3
The preparation of N-(2-amino-6-methyl-4-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl) phenyl) butyramide (compound 5):
The mixture of 0.21g (0.6mmol) compound 6,8ml methyl alcohol and 3.5mg (0.06mmol) Raney-Ni is at room temperature in H
2middle stirring 2h.White solid forms, and adds methyl alcohol to dissolve this white solid.Gained mixture filters, and filtrate is concentrated under vacuum, obtains 0.183g white solid (productive rate: 94.8%).
1H NMR(300MHz，DMSO-d
6)：δ7.61(d，1H，J＝4.5Hz)，7.57(d，1H，J＝7.2Hz)，7.24(m，2H)，7.05(s，1H)，6.90(s，1H)，3.86(s，3H)，2.34(t，2H，J＝7.2Hz)，1.65(m，2H)，0.97(t，3H，J＝4.5Hz)；ESI-MS：323[M+1]
+
Embodiment 4
The preparation of N-((2-cyano group-xenyl-4 '-methyl) amino-6-methyl-4-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl) phenyl) butyramide (compound 4):
Toward 0.13g (0.4mmol) compound 5,0.11g K
2cO
3(0.8mmol) and in the mixture of 5ml DMF add 0.115g (0.42mmol) 4 '-brooethyl-xenyl-2-nitrile, under room temperature, stir 22h.Ethyl acetate dilution for mixture, water and saturated brine washing, Na
2sO
4be dried and filter, decompression is lower to desolventizing, obtains solid.With this solid of methanol wash, obtain 81mg compound 4 (productive rates: 40%).
1H NMR(300MHz，DMSO-d
6)：δ7.93(d，1H，J＝8.1Hz)，7.79(m，1H)，7.45～7.62(m，8H，J＝7.2Hz)，7.21(m，2H)，6.90(s，1H)，6.62(s，1H)，4.52(s，2H)，3.49(s，3H)，2.42(t，2H，J＝7.2Hz)，1.69(m，2H)，0.96(t，3H，J＝4.5Hz)；ESI-MS：514[M+1]
+
Embodiment 5
Preparation 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-nitrile (compound 3) from compound 4:
In the mixture of 45mg (0.08mmol) compound 4 and 5ml toluene, add 15mg (0.42mmol) p-TsOH, be heated to reflux, stir 5h.Ethyl acetate dilution for mixture, water and saturated brine washing, Na
2sO
4be dried and filter, under vacuum, except desolventizing, obtain 37mg compound 3 (productive rates: 86%).
1H NMR(300MHz，CDCl
3)：δ7.75(m，2H)，7.62(m，1H)，7.16～7.51(m，11H)，5.48(s，2H)，3.80(s，3H)，2.94(t，2H，J＝7.2Hz)，2.77(s，3H)，1.85(m，2H)，1.06(t，3H，J＝4.5Hz)；EI-MS：495[M]
+
Embodiment 6
The preparation of 7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid methyl esters (compound 11):
5g (23mmol) 7-methyl-2-propyl-3H-benzo [d] imidazole-5-carboxylic acid joins in 100ml methyl alcohol, stirs, and adds 3ml concentrated hydrochloric acid (37%), then in 70 ℃ of heating 20h.Add again 3ml concentrated hydrochloric acid, then reflux 4h.Add again 4ml concentrated hydrochloric acid, then reflux 3h.Under vacuum, except desolventizing, obtain the crude product of 6.6g compound 11.
Embodiment 7
The preparation of 4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-methoxycarbonyl-3-yl)-methyl)-xenyl-2-nitrile (compound 10):
The crude product of 6.6g compound 11 and 5.48g (20mmol) 4 '-brooethyl-xenyl-2-nitrile is dissolved in 100ml DMF, then adds 13.8g (100mmol) K
2cO
3, under room temperature, stir 18h.In mixture, add 150ml water, white solid forms.Filter and obtain filter cake, dry rear two batches of compound 10 crude products that obtain, altogether 8g (productive rate: 82.5%).
1H NMR(300MHz，DMSO-d
6)：δ7.97(m，2H)，7.74(t，1H，J＝6.3Hz)，7.53～7.67(m，5H)，7.19(d，2H，J＝8.1Hz)，5.68(s，2H)，3.83(s，3H)，2.88(t，2H，J＝7.2Hz)，2.58(s，3H)，1.76(m，2H)，0.94(t，3H，J＝4.5Hz).
Embodiment 8
The preparation of 4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-carboxyl-3-yl)-methyl)-xenyl-2-nitrile (compound 9):
In the mixture of 7.2g compound 10 and 180ml methyl alcohol, add 30ml 10%NaOH, reflux 5h.Under vacuum, remove desolventizing.In mixture, add 50ml water, with 1M HCl, regulate pH value to 5-6.Filtering mixt, obtains wet filter cake, washing and the dry rear 4.5g compound 9 (productive rates: 65%) that obtain.
1H NMR(300MHz，DMSO-d
6)：δ7.94(m，2H)，7.75(t，1H，J＝6.3Hz)，7.54～7.65(m，5H)，7.20(d，2H，J＝8.1Hz)，5.68(s，2H)，2.88(t，2H，J＝7.5Hz)，2.58(s，3H)，1.77(m，2H)，0.96(t，3H，J＝4.5Hz).
Embodiment 9
The preparation of 4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-carboxyl-3-yl)-methyl)-xenyl-2-nitrile (compound 9):
98.9%), 480g K 400g compound 11 (1.72mol, HPLC purity:
2cO
3join in 2.0L acetone with 1.7g KI.Then add 440g (1.72mol) 4 '-brooethyl-xenyl-2-nitrile, mixture stirs 18h under reflux temperature.Under decompression, boil off solvent, then add 2L methyl alcohol and 1.72L 2MNaOH, mixture stirs 4h under reflux temperature.Cooling mixture regulates pH value to 5-6 with 720ml 12MHCl at 30-40 ℃.Filter the solid precipitation forming, washing, the dry rear 600g compound 9 (productive rates: 85%, HPLC purity: 97.5%) that obtain.
Embodiment 10
From compound 9, prepare 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzimidazole-1-yl)-methyl]-xenyl-2-nitriles (compound 3):
200mg compound 9 joins 1ml SOCl
2in.Mixture is heated to reflux.After 2 hours, in decompression and 45 ℃ at boil off SOCl
2, obtain light yellow spumescence residue.Residue is dissolved in 2ml dry pyridine, adds 100mg N-methylbenzene-1,2-diamines.Mixture reflux 24h.
Vacuum boils off pyridine.Residue extracts by ethyl acetate, uses NaHCO
3with salt water washing, anhydrous Na
2sO
4after dry, filter, concentrate to obtain 188mg compound 3 crude products (productive rate: 78%).
EI-MS：496[M+1]
+
Embodiment 11
From compound 9, prepare 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-nitriles (compound 3):
445g (1.09mol) compound 9 joins 1.5L CH
2cl
2in, then add 513g (4.35mol) SOCl
2.Mixture heats 5h under reflux temperature, and the lower enriched mixture of decompression, obtains light yellow spumescence residue.Residue is dissolved in 5.5L CH
2cl
2in, in 10-15 ℃, be added drop-wise to methylbenzene-1 by 425g (2.18mol) N-, 2-diamines dihydrochloride, 916g NaHCO
3, 3L water and 2L CH
2cl
2in the mixture forming, time for adding 10h.Mixture stirs 1h at this temperature.Then stop stirring layering.Organic layer washing (2 * 5L), under decompression, being concentrated into residue volume is about 3-4L.At 30 ℃, in this residue, drip 3L sherwood oil, time for adding 1h.Leach the solid of formation, after dry, obtain 560g 1-((2 '-cyanobiphenyl base-4-yl) methyl)-4-methyl-N-(2-(methylamino) phenyl)-2-propyl group-1H-benzo [d] imidazoles-6-methane amide (productive rate: 90%, HPLC purity: 90%).
In this product (560g, 0.98mol), add 5L toluene and 3g (0.048mol) H
3bO
3.Mixture is heated to reflux, the water forming during separating reaction.After reacting completely (about 2h), 50g charcoal joins in reaction mixture, this mixture backflow 0.5h.After heat filter, filtrate is cooled to 15-25 ℃, then at this temperature, stirs 5h.
Leach the precipitation of formation, dry rear 303g compound 3 (the HPLC purity: 99.9%) that obtain.
Filtrate is concentrated into about 2L volume, and concentrated solution stirs 5h in 15-25 ℃.Leach the solid of formation, and dry rear acquisition 150g compound 3 (HPLC purity: 98.4%, overall yield: 90%).
Embodiment 12
N, the preparation of 7-dimethyl-N-(2-nitrophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide (compound 15):
Toward 1.09g (5mmol) 2-propyl group-3H-benzo [d] imidazole-5-carboxylic acid and 50ml CH
2cl
2mixture in add 7.26mJ (100mmol) SOCl
2.Mixture stirs 18h, concentrating under reduced pressure.
Residue is dissolved in 30ml DMF, adds 1.6g (10.5mmol) N-methyl-2-N-methyl-p-nitroaniline.Under mixture room temperature, stir 48h.Add saturated NaHCO
3regulate pH value to 8.Gained mixture extracts twice by ethyl acetate.Organic layer water after merging and salt water washing, anhydrous Na
2sO
4dry, filter and concentrate, obtain residue, after silica gel column chromatography purifying, obtain 0.69g compound 15 (productive rate: 39%).
1H NMR(300MHz，DMSO-d
6)：δ7.70～7.83(m，3H)，7.44(m，1H)，6.84～7.07(m，2H)，3.47(s，3H)，3.37(s，3H)，2.29(m，2H)，1.775(m，2H)，0.93(t，3H，J＝4.5Hz)；ESI-MS：353[M+1]
+；351[M-1]
-.
Embodiment 13
The preparation of 4 '-((N, 7-dimethyl-N-(2-nitrophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide-3-yl)-methyl)-xenyl-2-nitrile (compound 14):
0.7g compound 15 (2mmol) and 0.82g (3mmol) 4 '-brooethyl-xenyl-2-nitrile are dissolved in 30ml acetonitrile.Then add 0.55g (4mmol) K
2cO
3, under room temperature, stir 22h.Add methyl alcohol diluted reaction mixture.Then filter, vacuum concentrated filtrate, obtains residue.Use acetic acid ethyl dissolution residue.Then washing, anhydrous Na
2sO
4dry, filter and concentrate, obtain the crude product (productive rate: 77%) of 0.84g compound 14.
1H NMR(300MHz，DMSO-d
6)：δ7.95(d，1H，J＝4.8Hz)，7.52～7.81(m，8H)，7.32(m，1H)，6.88～6.99(m，4H)，5.38(s，3H)，3.37(s，3H)，2.71(m，2H)，2.39(s，3H)，1.66(m，2H)，0.91(t，3H，J＝4.5Hz)；EI-MS：543[M]
+.
Embodiment 14
The preparation of 4 '-((N, 7-dimethyl-N-(2-aminophenyl)-2-propyl group-3H-benzo [d] imidazoles-5-methane amide-3-yl)-methyl)-xenyl-2-nitrile (compound 13):
100mg (0.2mmol) compound 14 is dissolved in 35ml methyl alcohol, then adds 40mg Pd/C (10%), under room temperature at H
2middle stirring 2h.Reaction mixture removes by filter Pd/C, and filtrate vacuum concentration obtains 63mg compound 13, the solid that is white in color (productive rate: 67%).
ESI-MS：514[M+1]
+.
Embodiment 15
From compound 13, prepare 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-nitriles (compound 3):
100mg (0.2mmol) compound 13 and 5ml pyridine reflux 22h (TLC monitors reaction), cool to room temperature.Add ethyl acetate diluted reaction mixture.Organic phase is water, saturated NH successively
4cl solution and salt water washing, Na
2sO
4dry, filter and concentrate, obtain 74mg residue.Residue obtains 45mg compound 3 (productive rate: 47%) after silica gel column chromatography purifying.
1H NMR(300MHz，CDCl
3)：δ7.77(m，2H)，7.59(m，1H)，7.51～7.26(m，9H)，5.47(s，3H)，3.78(s，3H)，2.94(t，2H，J＝7.8Hz)，2.77(s，3H)，1.88(m，2H)，1.06(t，3H，J＝4.5Hz)；EI-MS：495[M]
+
Embodiment 16
The preparation of 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-carboxylic acid (compound 1):
The mixture backflow 8h of 2.5g compound 3 (5mmol), 1.0g sodium hydroxide (25mmol), 0.18g water (10mmol) and 30ml ethylene glycol.After reacting completely, reaction mixture is cooled to room temperature, adds H
2o (250ml).After pH value to 4 with HOAc (12ml) regulator solution, product precipitation, then uses CH
2cl
2extract 3 times.The salt water washing of organic phase after merging, Na
2sO
4dry, filter and concentrated filtrate, obtain the crude product (productive rate: 98%) of 2.55g compound 1.
Embodiment 17
The preparation of 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-carboxylic acid (compound 1):
The mixture backflow 19h of 15g compound 3 (30mmol), 6.0g potassium hydroxide (91mmol), 1.6g water and 54ml propylene glycol.After reacting completely, reaction mixture is cooled to room temperature, adds H
2o (120ml).After pH value to 4.9 with 6M HCl (17ml) regulator solution, product CH
2cl
2extract 3 times.Organic phase after merging washes with water, Na
2sO
4dry, filter and concentrated filtrate.In residue, add acetone.Filtering suspension liquid, the crude product of acquisition 12.55g compound 1.
Embodiment 18
The crystallization of 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-carboxylic acid (compound 1):
The mixture of 3g telmisartan and 20ml DMF is heated to about 100 ℃, until telmisartan dissolves.Filter this solution, be cooled to room temperature.Solution stirs 3h at this temperature, then at 0 ℃, stirs 2h.Leach product, with DMF washing, drying under reduced pressure at 70-90 ℃, obtain 2.7g telmisartan (HPLC purity: 99.5%).
Embodiment 19
The crystallization of 4 '-[(2-n-propyl group-4-methyl-6-(1-tolimidazole-2-yl)-benzoglyoxaline-1-yl)-methyl]-xenyl-2-carboxylic acid (compound 1):
The mixture of 21.4g telmisartan, 107ml ethanol and 1.1g charcoal stirs 15min under room temperature.Then add 4.7ml 25%NH
3, mixture stirs 1.5h again.Then filtering mixt, filtrate is heated to 80 ℃.
At this temperature, slowly add 4.76ml acetic acid, mixture is cooled to room temperature.Mixture stirs 1h at this temperature, then leaches product, after water and washing with alcohol at 70-90 ℃ drying under reduced pressure, obtain 19.7g telmisartan (HPLC purity: 99.6%).
Embodiment 20
The preparation of telmisartan and/or its pharmacy acceptable salt:
The mixture of 1.0g (2.0mmol) compound 3,5ml Virahol, 5ml water and 1.03g (18.4mmol) KOH is in 120 ℃ of about 48h of heating.Then this solution is cooled to room temperature, adds 10ml water.Mixture adds 3M HCl neutralization, until pH value reaches about 7.Filtration, washing and desciccate (telmisartan).
Gained telmisartan is by adding corresponding acid or alkali to change into its salt through follow-up separation again.
Embodiment 21
Contain telmisartan prepared by the method according to this invention or any currently known methods or the pharmaceutical composition of its salt
| mg | mg | mg | mg | mg | mg | |
| Telmisartan meglumine salt | 54 | 54 | 54 | 54 | 54 | 54 |
| Meglumine | 10 | 10 | ||||
| KOH | 4 | 4 | ||||
| NaOH | 3 | 3 | ||||
| PLURONICS F87 | 8 | 8 | 8 | |||
| Sorbyl alcohol | 120 | 120 | 120 | 120 | 120 | 120 |
| Microcrystalline Cellulose | 53.6 | 45.6 | 59.6 | 51.6 | 60.6 | 52.6 |
| Magnesium Stearate | 2.4 | 2.4 | 2.4 | 2.4 | 2.4 | 2.4 |
| mg | mg | mg | mg | mg | mg | |
| Telmisartan | 40 | 40 | 40 | 40 | 40 | 40 |
| Meglumine | 20 | 20 | 20 | 20 | 2 | 20 |
| PVP K30 | 12 | 12 | 12 | 12 | 12 | 12 |
| Sorbyl alcohol | 225 | 168.75 | 112.5 | |||
| Agglomerating lactose | 225 | 56.25 | 112.5 | |||
| N.F,USP MANNITOL | 225 | |||||
| Maltose | 225 | |||||
| Magnesium Stearate | 3 | 3 | 3 | 3 | 3 | 3 |
| mg | mg | mg | mg | mg | mg | |
| Telmisartan | 40 | 40 | 40 | 40 | 40 | 40 |
| Meglumine | 12 | 12 | 12 | 12 | 12 | 12 |
| PVP K30 | 12 | 12 | 12 | 12 | 12 | 12 |
| KOH | 4.7 | 4.7 | 4.7 | |||
| NaOH | 3.36 | 3.36 | 3.36 | |||
| Sorbyl alcohol | 148.3 | 149.64 | ||||
| Agglomerating lactose | 60 | 60 | 80 | 80 | 100 | 100 |
| N.F,USP MANNITOL | 128.3 | 129.64 |
| Maltose | 108.3 | 109.64 | ||||
| Magnesium Stearate | 3 | 3 | 3 | 3 | 3 | 3 |
The aforementioned composition that contains telmisartan can be prepared by several different methods.Two kinds of suitable methods are that spraying is dried and fluidized bed granulation.If telmisartan and/or its salt are prepared by spray drying process, telmisartan and/or its salt are dissolved in suitable solvent (water or organic solvent) together with alkaline agent and/or optional crystallization retarding agent, and then spraying is dry.The final composition that the dried particle of spraying is further used to form compressing tablet with other mixed with excipients.If with fluidized bed granulation method, telmisartan and/or its salt are dissolved in suitable solvent (water or organic solvent), to form granulation liquid together with alkaline agent and/or optional crystallization retarding agent.Other vehicle is placed in fluidised bed granulator and then by granulation liquid, sprays.After pelletization completes, particle is dried, and the final composition of using to form compressing tablet with other mixed with excipients alternatively, and described other vehicle is flow control reagent and/or lubricant for example.
Embodiment 22
The pharmaceutical composition of the coupling product that contains telmisartan prepared by the method according to this invention or any currently known methods and/or its salt and hydrochlorothiazide
The particle that contains telmisartan is passable, for example, according to embodiment 21 preparations.The particle that contains hydrochlorothiazide can be prepared by any currently known methods, dry etc. such as wet method or dry granulation, spraying.Then by two kinds of particles being mixed to the final composition of preparation.Another kind of possibility is that telmisartan and/or its salt are granulated, then any particle-separation reagent dressing for gained particle.Then the particle of dressing mixes with the particle that contains hydrochlorothiazide, to prepare final composition.Another kind of possibility is any particle-separation reagent dressing for particle that contains hydrochlorothiazide.Then the particle of this dressing mixes with the particle that contains telmisartan and/or its salt, and then forms final composition.In another kind of possibility, can prepare double-deck tablet.The particle that one deck contains telmisartan and/or its salt, the particle that another layer contains hydrochlorothiazide.In another kind of possibility, bilayer tablet can be prepared by method above, and wherein bilayer separates by the 3rd layer again, to guarantee the separation of particle.In another kind of possibility, can prepare and a kind ofly there is middle label and around the outer field bilayer tablet of this label.Alternatively, this bilayer can be separated by particle separate layer again.Telmisartan and/or its salt may reside in label, and hydrochlorothiazide is present in skin, or vice versa.
Claims (12)
1. the method for the intermediate of the telmisartan derivant of preparation formula 3 ',
The method comprises the following steps:
A) then N-alkylated compound 11 is hydrolyzed to form compound 9 ',
B) condensation compound 9 ' and N-methylbenzene-1,2-diamines to be to form compound 9 ' a, and
C) cyclization to be to form compound 3 ',
Wherein
Z is the group that can change into tetrazyl or carboxyl, and it is selected from CN and COR
6, R wherein
6can be N (R)
2or O-C
1-C
6alkyl, wherein R is H, C
1-C
6alkyl or benzyl.
2. the method for the telmisartan that preparation formula 1 represents,
Comprise claim 1 preparation formula 3 ' compound method and also comprise the step that the group Z in the compound of formula 3 ' is changed into carboxyl:
3. according to the method for claim 2, wherein Z is undertaken by hydrolysis to the conversion of carboxyl.
4. the method for the pharmacy acceptable salt of the telmisartan of preparation formula 1,
Comprise the method for the telmisartan that preparation formula 1 claimed in claim 2 represents and also comprise the step that the telmisartan of formula 1 is changed into its pharmacy acceptable salt.
5. a method of preparing medicine, comprises the step of preparing the telmisartan being represented by formula 1 according to the method for claim 2, or according to the step of the pharmacy acceptable salt of the telmisartan of the method preparation formula 1 of claim 4;
And also comprise and prepare to provide the step of medicine by telmisartan or its pharmacy acceptable salt of formula 1 representative together with pharmaceutically acceptable vehicle.
6. according to the method for claim 5, wherein said medicine is for orally using.
7. according to the method for claim 5, wherein said medicine supplies to orally use with tablet or capsule form.
8. compound, is selected from
(iv) 4 '-((7-methyl-2-propyl-3H-benzo [d] imidazoles-5-carboxyl-3-yl)-methyl)-xenyl-2-nitrile of formula 9 representatives
(v) 1-((2 '-cyanobiphenyl base-4-yl) methyl)-4-methyl-N-(2-(methylamino) phenyl)-2-propyl group-1H-benzo [d] imidazoles-6-methane amide of formula 9a representative
And salt.
9. compound is according to Claim 8 as the telmisartan with formula 1 of intermediate definition in preparation claim 2, or the purposes in its pharmacy acceptable salt.
10. the telmisartan with formula 1 that compound according to Claim 8 contains definition in claim 2 as intermediate in preparation, or the purposes in the medicine of its pharmacy acceptable salt.
11. methods according to claim 1, the purity of the intermediate of the telmisartan derivant of the formula 3 ' of wherein being prepared by the method be greater than 98% and the content of single impurity lower than 0.15%.
12. methods according to claim 1, the purity of the intermediate of the telmisartan derivant of the formula 3 ' of wherein being prepared by the method is greater than 99%.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SI200700161A SI22585A (en) | 2007-07-03 | 2007-07-03 | Procedure for preparation of telmisartan |
| SIP-200700161 | 2007-07-03 | ||
| SI200700322A SI22674A (en) | 2007-12-10 | 2007-12-10 | Procedure for preparation of telmisartan |
| SIP200700322 | 2007-12-10 | ||
| PCT/EP2008/058616 WO2009004064A1 (en) | 2007-07-03 | 2008-07-03 | Process for preparing telmisartan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101743228A CN101743228A (en) | 2010-06-16 |
| CN101743228B true CN101743228B (en) | 2014-01-29 |
Family
ID=39744880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200880022887.7A Expired - Fee Related CN101743228B (en) | 2007-07-03 | 2008-07-03 | Process for preparing telmisartan |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2170835A1 (en) |
| CN (1) | CN101743228B (en) |
| EA (1) | EA200901619A1 (en) |
| WO (1) | WO2009004064A1 (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009116089A2 (en) * | 2008-03-14 | 2009-09-24 | Ipca Laboratories Limited | Novel intermediates and method for synthesis of 4'-[(1,4'-dimethyl-2'-propyl-[2,6'- bi-1hbenzimidazol]-l-yl)methyl]-1,1-biphenyl]-2-carboxylic acid. |
| WO2010146187A2 (en) | 2009-06-19 | 2010-12-23 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of telmisartan |
| EP2277866A1 (en) * | 2009-06-22 | 2011-01-26 | Inke, S.A. | Process for preparing telmisartan |
| CN101798287A (en) * | 2010-03-18 | 2010-08-11 | 北京理工大学 | [(4-methyl-2-propyl-N-methoxyl-substituted benzene alkyl-1H-benzimidazole-6-formamide)-1-yl] methyldiphenyl compound and preparation method thereof |
| CN102219744B (en) * | 2010-04-13 | 2013-01-16 | 上海联化生物医药技术有限公司 | Preparation method of telmisartan intermediate and intermediate compound |
| CN101921235A (en) * | 2010-09-06 | 2010-12-22 | 宜昌长江药业有限公司 | Preparation method of telmisartan |
| WO2012055941A1 (en) | 2010-10-27 | 2012-05-03 | Krka,Tovarna Zdravil, D. D., Novo Mesto | Multilayer pharmaceutical composition comprising telmisartan and amlodipine |
| CN102219746B (en) * | 2011-04-07 | 2014-02-26 | 威海迪素制药有限公司 | Preparation method of telmisartan impurity B |
| CN102212034B (en) * | 2011-04-14 | 2014-02-26 | 威海迪素制药有限公司 | Method for preparing telmisartan impurity B |
| CN102229570B (en) * | 2011-04-22 | 2013-10-16 | 浙江海正药业股份有限公司 | New method for synthesizing telmisartan intermediates |
| CN105130905B (en) * | 2015-09-17 | 2017-09-08 | 浙江金立源药业有限公司 | A kind of synthetic method of Telmisartan |
| WO2021037127A1 (en) * | 2019-08-29 | 2021-03-04 | 上海特化医药科技有限公司 | Benzimidazole substitution-based phenyl n-butyramide compound and preparation method therefor |
| CN111689903A (en) * | 2020-07-17 | 2020-09-22 | 浙江金立源药业有限公司 | Synthesis method of 2-n-propyl-4-methyl-6- (1-methylbenzimidazole-2-yl) benzimidazole |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0502314A1 (en) * | 1991-02-06 | 1992-09-09 | Dr. Karl Thomae GmbH | Benzimidazol, medicaments containing them and process for their preparation |
| CN1344712A (en) * | 2001-07-30 | 2002-04-17 | 中国科学院上海药物研究所 | Synthesis path of Timisatem |
| CN1412183A (en) * | 2001-10-15 | 2003-04-23 | 中国科学院上海药物研究所 | New preparation method of timixatan |
| CN1768044A (en) * | 2003-03-31 | 2006-05-03 | 贝林格尔·英格海姆国际有限公司 | Process for manufacture of telmisartan |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100460396C (en) * | 2007-03-08 | 2009-02-11 | 杭州盛美医药科技开发有限公司 | Intermediate of telmisartan, its preparation and use |
-
2008
- 2008-07-03 EP EP20080774728 patent/EP2170835A1/en not_active Withdrawn
- 2008-07-03 EA EA200901619A patent/EA200901619A1/en unknown
- 2008-07-03 CN CN200880022887.7A patent/CN101743228B/en not_active Expired - Fee Related
- 2008-07-03 WO PCT/EP2008/058616 patent/WO2009004064A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0502314A1 (en) * | 1991-02-06 | 1992-09-09 | Dr. Karl Thomae GmbH | Benzimidazol, medicaments containing them and process for their preparation |
| CN1344712A (en) * | 2001-07-30 | 2002-04-17 | 中国科学院上海药物研究所 | Synthesis path of Timisatem |
| CN1412183A (en) * | 2001-10-15 | 2003-04-23 | 中国科学院上海药物研究所 | New preparation method of timixatan |
| CN1768044A (en) * | 2003-03-31 | 2006-05-03 | 贝林格尔·英格海姆国际有限公司 | Process for manufacture of telmisartan |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009004064A1 (en) | 2009-01-08 |
| CN101743228A (en) | 2010-06-16 |
| EP2170835A1 (en) | 2010-04-07 |
| EA200901619A1 (en) | 2010-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101743228B (en) | Process for preparing telmisartan | |
| US9682987B2 (en) | Solid forms of an antiviral compound | |
| JP6367187B2 (en) | Of N-[(R) -1-[(S) -1- (4-aminomethyl-benzylcarbamoyl) -2-phenylethylcarbamoyl] -2- (4-ethoxy-phenyl) -ethyl] -benzamide hydrochloride Polymorph | |
| EP1678139B1 (en) | Solid-state montelukast | |
| US20060223794A1 (en) | Novel olanzapine forms and related methods of treatment | |
| US7692023B2 (en) | Candesartan cilexetil polymorphs | |
| AU2016344627B2 (en) | Pyrimidine compositions, ultra-pure compositions and salts thereof, methods of making the same, and methods of using the same for treating histamine H4 receptor (H4) mediated diseases and conditions | |
| US20090123538A1 (en) | Angiotensin II Receptor Antagonists | |
| WO2013028495A1 (en) | Dihydropyridophthalazinone inhibitors of poly (adp-ribose) polymerase (parp) for the treatment of multiple myeloma | |
| KR20090083918A (en) | Crystalline forms of aliskiren hemifumarate | |
| EP2210888B1 (en) | Stable micronized candesartan cilexetil and methods for preparing thereof | |
| CN114805478A (en) | Deuterated peptidomimetic compound and application thereof | |
| EP2019668B1 (en) | Pharmaceutical composition comprising candesartan cilexetil | |
| AU2005280419B2 (en) | Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid | |
| CN102452986B (en) | N-formyl hydroxylamine compounds, preparation method thereof, and purposes thereof | |
| TW202214555A (en) | Indene compounds, pharmaceutical compositions thereof, and their therapeutic applications | |
| ES2415357T3 (en) | Procedure for the preparation of telmisartan | |
| WO2022159507A1 (en) | Combination of cannabinoids with additional therapeutic agents for treating diseases or disorders | |
| EP2194050A1 (en) | A new process for the preparation of irbesartan | |
| EP2909169B1 (en) | Crystalline phase of (3s,3s') 4,4'-disulfanediylbis(3-aminobutane 1-sulfonic acid) with l-lysine | |
| CA3196482A1 (en) | Jak inhibitors having a specific particle size distribution | |
| WO2005077359A1 (en) | Stabilized pharmaceutical composition containing indoline compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140129 Termination date: 20140703 |
|
| EXPY | Termination of patent right or utility model |