WO2012070068A2 - Process for preparation of triclabendazole - Google Patents

Process for preparation of triclabendazole Download PDF

Info

Publication number
WO2012070068A2
WO2012070068A2 PCT/IN2011/000810 IN2011000810W WO2012070068A2 WO 2012070068 A2 WO2012070068 A2 WO 2012070068A2 IN 2011000810 W IN2011000810 W IN 2011000810W WO 2012070068 A2 WO2012070068 A2 WO 2012070068A2
Authority
WO
WIPO (PCT)
Prior art keywords
dichlorophenoxy
chloro
triclabendazole
obtain
preparation
Prior art date
Application number
PCT/IN2011/000810
Other languages
French (fr)
Other versions
WO2012070068A3 (en
Inventor
Ramkrishna Appaji Rane
Sudhakar Verma
Thangavel Arulmoli
Original Assignee
Sequent Scientific Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to IN3538CH2010 priority Critical
Priority to IN3538/CHE/2010 priority
Application filed by Sequent Scientific Limited filed Critical Sequent Scientific Limited
Publication of WO2012070068A2 publication Critical patent/WO2012070068A2/en
Publication of WO2012070068A3 publication Critical patent/WO2012070068A3/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28Sulfur atoms

Abstract

The present invention discloses a method for preparing Triclabendazole comprising condensing N-(4,5-dichloro-2-nitrophenyl)acetamide with 2,3-dichlorophenol to obtain 4-chloro-5(2,3-dichlorophenoxy)-2-nitrophenyl acetamide and it to obtain 4- chloro-5(2,3-dichlorophenoxy)-2-nitroaniline; reducing 4-chloro-5(2,3- dichlorophenoxy)-2-nitroaniline in presence of Raney nickel to obtain 4-chloro-5- (2,3-dichlorophenoxy)benzene-l,2-diamine of; cyclising 4-chloro-5-(2,3- dichlorophenoxy)benzene-l,2-diamine in presence of carbondisulfide to obtain 6- chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol; methylating 6-chloro-5- (2,3-dichlorophenoxy)-lH-benzimidazole-2 -thiol using a methylating agent to obtain triclabendazole methanesulfonate salt; converting triclabendazole methanesulfonate salt to hydrochloride salt of Triclabendazole and hydrolysing it to obtain Triclabendazole.

Description

Process for Preparation of Triclabendazole

Field of Invention

The present invention relates to a novel, cost-effective process for preparation of Triclabendazole.

Background of the Invention

Triclabendazole, chemically known as 5-chloro-6-(2,3-dichlorophenoxy)-2- (methylthio)-lH-benzimidazole represented by formula I,

Figure imgf000002_0001

is a halogenated benzimidazole compound that possesses high activity against immature and adult stages of the liver fluke, Faciola hepatica. The intensive use of Triclabendazole in endemic areas of facioliasis has resulted in the development of liver flukes resistant to this compound.

US 4, 197,307 discloses the process for the preparation of Triclabendazole, wherein 4- chloro-5-(2,3-dichlorophenoxy)-l,2-benzenediamine is reacted with carbondisulfide to give cyclic benzimidazole thione, which is further subjected to alkylation reaction with dimethyl sulfate to give Triclabendazole.

Chinese patent 10155523 ldescribes a process for the preparation of Triclabendazole by hydrolysing N-(4,5-dichloro-2-nitrophenyl)acetamide of formula VII to 4,5- dichloro-2-nitroaniline of formula VIII and condensing it with 2,3-dichlorophenol of formula VI in presence of a phase transfer catalyst to obtain 4-chloro-5(2,3- dichlorophenoxy)-2-nitroaniline of formula IV, which is further reduced in presence of Iron to obtain 4-chloro-5-(2,3-dichlorophenoxy)benzene-l ,2-diamine of formula III. The obtained diamine of formula III is cyclised in presence of carbondisulfide to obtain 6-chloro-5-(2,3-dichlorophenoxy)- lH-benzimidazole-2-thiol of formula II. The compound of formula II is methylated using dimethyl sulphate to obtain Triclabendazole of formula I. The process disclosed in this patent is illustrated in scheme 1 below:

Scheme 1

Figure imgf000003_0001

6-chloro-5-(2,3-dichlorophenoxy)-1H-benzimidazole-2-t ioi 4-chloro-5-(2,3-dichlorop enoxy)benzene-1 ,2-diamine

Figure imgf000003_0002

6-chloro-5-(2,3-dichlorophenoxy)-2-(methylthio)-1H-benzimidazole

I

However, the above prior art process is not preferred at a commercial scale because the hydrolysis of N-(4,5-dichloro-2-nitrophenyl)acetamide of formula VII is carried out before condensation with 2,3-dichlorophenol of formula VI, which is labile to formation of impurities and moreover the condensation is carried out in the presence of a phase transfer catalyst. Further, Iron is used as a catalyst for reduction which is riot environment friendly and involves tedious work-up. The final compound Triclabendazole is directly obtained by the methylating the compound of formula II using dimethylsulfate. The purity of thus obtained Triclabendazole is not high. Thus it is highly desirable to develop a process which overcomes most of the prior art drawbacks. The present inventors have developed a process for the preparation of Thiabendazole, which is environment friendly, technologically safe, simple and cost effective

Summary of the Invention

The principal aspect of the present invention is to provide a process for the preparation of Triclabendazole comprising:

a) condensing N-(4,5-dichloro-2-nitrophenyl)acetamide of formula VII with 2,3- dichlorophenol of formula VI to obtain 4-chloro-5(2,3-dichlorophenoxy)-2- nitrophenyl acetamide of formula V;

b) hydrolysing 4-chloro-5(2,3-dichlorophenoxy)-2-nitrophenyl acetamide of formula V to obtain 4-chloro-5(2,3-dichlorophenoxy)-2-nitroaniline of formula IV;

c) reducing 4-chloro-5(2,3-dichlorophenoxy)-2-nitroaniline of formula IV in presence of Raney nickel to obtain 4-chloro-5-(2,3-dichlorophenoxy)benzene- 1 ,2-diamine of formula III;

d) cyclising 4-chloro-5-(2J3-dichlorophenoxy)benzene-l ,2-diamine of formula III in presence of carbondisulfide to obtain 6-chloro-5-(2,3-dichlorophenoxy)-lH- benzimidazole-2-thiol of formula II;

e) methylating '6-chloro-5-(2,3-diehlorophenoxy)^lH-benzimidazole-2-thiol of formula II using a methylating agent to obtain Triclabendazole methanesulfonate salt of formula IX;

f) converting Triclabendazole methanesulfonate salt of formula . IX to hydrochloride salt of Triclabendazole of formula X; and

g) hydrolysing Triclabendazole hydrochloride of formula X to obtain Triclabendazole of formula I.

The process of the present invention is illustrated in scheme 2 below:

Scheme 2

Figure imgf000005_0001

Figure imgf000005_0002

+ NH4CI + H20

Detail Description of the Invention

Accordingly in an embodiment of the invention, the condensation and hydrolysis in step a) and b) is carried out in-situ in presence of a polar aprotic solvent like dimethylformamide (DMF), DMSO, sulfolane^ N-methylpyrrolidinone and alcoholic solvent like methanol at a temperature 30 °C to 100 °C preferably at 50 °C to 90 °C. The base used for the condensation and hydrolysis are sodium carbonate, potassium carbonate, or sodium hydroxide or potassium hydroxide. The condensation is preferably carried out in presence of solvent dimethylformamide and base potassium carbonate whereas the hydrolysis is done in presence of sodium hydroxide. In further embodiment no phase transfer catalyst is required for the condensation of the present invention.

In another embodiment of the invention, the reduction in step c) is carried out in an alcoholic solvent like methanol, ethanol, isopropanol, preferably in presence of methanol and Raney nickel and sodium hydroxide. Preferably the reduction is carried out at H2 pressure of 6 kg and at temperature about 100 °C.

In another embodiment the obtained 4-chloro-5(2,3-dichlorophenoxy)-l,2- phenylenediamine in step c is directly cyclized with carbon disulfide in presence of strong base such as caustic lye without isolating followed by acidification with acetic acid.

In another embodiment of the invention, the cyclisation or ring closure in step d) is carried out at a temperature 50 °C to 140 °C in presence of carbondisulfide, a solvent selected from dimethylformamide, methanol, ethanol, or acetonitrile, preferably methanol and in presence of a base like sodium hydroxide.

In another embodiment of the invention, methylation 6-chloro-5-(2,3- dichlorophenoxy)-lH-benzimidazole-2 -thiol of formula II in step e) is carried out using a methylating agent like dimethylsulfate in temperature range of 20 to 80 °C preferably 40 to 65 °C. and in presence of an alcoholic solvent preferably methanol to obtain Triclabendazole methanesulfonate salt.

In another embodiment the obtained 4-chloro-5(2,3-dichlorophenoxy)-l ,2- phenylenediamine in step c is directly cyclized with carbon disulfide in presence of strong base such as caustic lye without isolating followed by acidification with acetic acid.

In yet another embodiment of the invention, Triclabendazole methanesulfonate salt is dissolved in an alcoholic solvent preferably methanol, charcolated and added concentrated hydrochloric acid and cooled to isolate hydrochloride salt of Triclabendazole. Which is further treated with water and ammonia to obtain Triclabendazole. In yet another embodiment of the invention, 6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2 -thiol of formula II is methylated using a methylating agent like dimethylsulfate in presence of an alcoholic solvent preferably methanol and a base preferably sodium carbonate in temperature range of 40 to 90 °C preferably 60 to 90 °C. to obtain Triclabendazole directly.

In still further embodiment of the invention the obtained triclabendazole is optionally purified by dissolving in toluene at 90 -100 °C, removing water azeotropically, cooling & charcolyzing, and again adding isopropanol at 90 -100 °C.

The preferred embodiment of the invention can be illustrated by the below given examples, however it should not be construed to limit the scope of the invention.

Example 1: Preparation of 5-chIoro-6-(2,3-dichlorophenoxy)-2-(methylthio)-lH- benzimidazole (I)

(a) Preparation of 4-chloro-5(2,3-dichlorophenoxy)-2-nitroaniline;

2, 3-dichIorophenol (1 kg) in DMF (1.5 L), 2-nitro 4,5-dichloroacetanilide (1.52 kg), and potassium carbonate were heated into the flask for 12 hrs while maintaining the temperature at 90°C under vacuum and after that cooled to room temperature. Methanol (2 L), 48% caustic lye (0.3 kg) in 300 mL water were added to it and heated to 50°C for 4 hrs. Further water (4 L) was added, stirred, filtered and washed with water and with methanol.

Weight= 2 kg.

(b) Preparation of 4-chloro-5(2,3-dichlorophenoxy)-l,2-phenylenediamine;

Raney nickel (10.8 g) was added into a reaction mixture containing 4-chIoro- 5(2,3-dichlorophenoxy)-2-nitroaniline (900 g), methanol (3.4 L) at RT, caustic lye (2.72 g). Nitrogen was flushed into and charged with hydrogen. The reaction mixture was heated slowly to 100°C for 12 hrs, cooled to RT and filtered.

Weight: 819 g (c) Preparation of 6-chloro-5(2,,3-dichlorophenoxy)-lH- benzimidazole-2- thiol:

In the mixture of 4-chloro-5(2,3-dichlorophenoxy)-l ,2-phenylenediamine in methanol (800 g) and caustic lye (245 mL), carbondisulfide (259 g) was added slowly and the reaction mass was refluxed' for 6 hrs. After completion of the reaction water (2.5 L) and acetic acid was added over a period of 2hrs at 60°C. Water was added (2.5 litre) again and heated to 90°C for 2hrs, filtered and washed with hot water to obtain the title compound.

Weight: 863 g.

(d) Preparation of 6-chloro-5(2.3-dichlorophenoxy)-2-(metylthio)-lH- benzimidazole:

6-chloro-5(2,3-dichlorophenoxy)-l H- benzimidazole-2-thiol(400kg) was added to methanol (700 L) and heated to 40°C. Dimethyl sulphate was added slowly at 40°C to it. The reaction mass was heated to 60-65°C and maintain for 6hrs. After completion of the reaction the reaction mass was cooled to 15°C, centrifuged the material and washed with 75 L of methanol to obtain wet cake of Triclabendazole methanesulfonate (520-560 kg).

Triclabendazole methanesulfonate (200 g) and methanol (1.2 L) was refluxed, cooled and charcoal was added and refluxed again for 1 hr. The reaction mass was filtered and concentrated hydrochloric acid was added. The precipitate was' cooled to RT, stirred for 1 hr, filtered and Triclabendazole hydrochloride was isolated (250 g wet) .

The water was added to the above Triclabendazole hydrochloride and ammonia was charged and stired for 2-3 hrs. The reaction mass was filtered, washed with water and dried to obtain Triclabendazole.

Weight: 156 g.

Example 2:Preparation of 6-chloro-5(2,3-dichlorophenoxy)-2-(metylthio)-lH- benzimidazole In a RBF methanol (200 mL), 6-chloro-5(2,3-dichlorophenoxy)-lH- benzimidazole-2-thiol ((200 g) and dimethylsulfate (40 g) were heated to 60 ± 2°C and water (100 mL) was added and stirred for half an hr. Sodium carbonate solution (25 g Na2CC>3 in 200 mL water) was added slowly and temperature was raised to 60 °C and stirred for VA hr. After completion of reaction, the reaction mixture was cooled to 60°C, filtered, washed with water further washed with toluene and dried.

To the above wet crude 6-chloro-5(2,3-dichlorophenoxy)-2-(metylthio)-lH- benzimidazole, toluene (500 mL) was charged and water was removed azeotropically using Dean Stark apparatus. The mixture was heated to 100-1 12°C and 5 g charcoal was added, stirred for half an hr at 100-105°C. The reaction mixture was filtered through hyflow bed and washed with fresh toluene. The mother liquor was cooled to 70°C and isopropanol (7 mL) was added, cooled to room temperature to precipitate, filtered and washed with fresh toluene, dried at 75°C for 4 hrs to obtain pure Triclabendazole.

Yield of Triclabendazole is 85 gm. (81.7%).

Example 3: Purification of Triclabendazole:

The wet cake of Triclabendazole was heated to 90-100°C in toluene (1.92 litre). Water was removed azeotropically. The solution/mixture was cooled charcoal was added, refluxed and filtered. Again the obtained material was heated to 90-100°C, 180 ml of IPA was added, cooled to RT, filtered and dried for 24 hrs at 90-100°C.

Wt: 132 g (1st crop) and \2±\ g (2nd crop)

Claims

We claim:
1. A process for the preparation of Triclabendazole comprising:
a) condensing N-(4,5-dichloro-2-nitrophenyl)acetamide with 2,3-dichlorophenol to obtain 4-chloro-5(2,3-dichlorophenoxy)-2-nitrophenyl acetamide;
b) hydrolysing 4-chloro-5(2,3-dichlorophenoxy)-2-nitrophenyl acetamide to obtain 4-chloro-5(2,3-dichlorophenoxy)-2-nitroaniline of;
c) reducing 4-chloro-5(2,3-dichlorophenoxy)-2-nitroaniline in presence of Raney nickel to obtain 4-chloro-5-(2,3-dichlorophenoxy)benzene-l ,2-diamine;
d) cyclising 4-chloro-5-(2,3-dichlorophenoxy)benzene-l ,2-diamine in presence of carbondisulfide to obtain 6-chloro-5-(2,3-dichlorophenoxy)-lH- benzimidazole-2-thiol; and
e) methylating 6-chloro-5 -(2,3 -dichlorophenoxy)- 1 H-benzim idazole-2 -thiol using a methylating agent to obtain Triclabendazole.
2. A process for the preparation of Triclabendazole according to claim 1, wherein the condensation and hydrolysis in step a) and b) is carried out in-situ in presence of solvent selected from dimethylformamide (DMF), DMSO, sulfolane, N- methylpyrrolidinone and methanol at a temperature 30 °C to 100°C.
3. A process for the preparation of Triclabendazole according to claim 1, wherein the condensation and hydrolysis in step a) and b) is carried out in-situ in presence of a base sodium carbonate, potassium carbonate, or sodium hydroxide or potassium hydroxide.
4. A process for the preparation of Triclabendazole according to claim 1, wherein the condensation in step a) is carried out in absence of a phase transfer catalyst.
5. A process for the preparation of Triclabendazole according to claim 1, wherein the reduction in step c) is carried out in presence of an alcoholic solvent like methanol and a base sodium hydroxide.
6. A process for the preparation of Triclabendazole according to claim 1, wherein cyclisation in step d) is carried out in a solvent selected from dimethylformamide, methanol, ethanol, acetonitrile or mixture thereof and a base like sodium hydroxide.
7. A process for the preparation of Triciabendazole according to claim 1, where in methylation of 6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol to obtain Triciabendazole comprises:
a) methylating 6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol using a methylating agent to obtain Triciabendazole methanesulfonate salt; b) converting Triciabendazole methanesulfonate salt to a hydrochloride salt of Triciabendazole; and
c) hydrolysing Triciabendazole hydrochloride to obtain Triciabendazole.
8. A process for the preparation of Triciabendazole according to claim 1 , where in 6- chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol is methylated using a methylating agent in presence of an alcoholic solvent like methanol and a base like sodium carbonate, potassium carbonate in temperature range of 40 to 90 °C to obtain Triciabendazole directly.
9. A process for the preparation of Triciabendazole according to any of the previous claim, wherein the methylating agent used is dimethylsulfate.
10. A process for the preparation of Triciabendazole according to claim 1, wherein the obtained Triciabendazole is crystallised using toluene and isopropanol.
PCT/IN2011/000810 2010-11-24 2011-11-23 Process for preparation of triclabendazole WO2012070068A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
IN3538CH2010 2010-11-24
IN3538/CHE/2010 2010-11-24

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13/989,147 US20130303781A1 (en) 2010-11-24 2011-11-23 Process for preparation of triclabendazole
EP11843342.4A EP2642995A2 (en) 2010-11-24 2011-11-23 Process for preparation of triclabendazole

Publications (2)

Publication Number Publication Date
WO2012070068A2 true WO2012070068A2 (en) 2012-05-31
WO2012070068A3 WO2012070068A3 (en) 2012-07-19

Family

ID=46146225

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2011/000810 WO2012070068A2 (en) 2010-11-24 2011-11-23 Process for preparation of triclabendazole

Country Status (3)

Country Link
US (1) US20130303781A1 (en)
EP (1) EP2642995A2 (en)
WO (1) WO2012070068A2 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103319416A (en) * 2013-06-24 2013-09-25 常州佳灵药业有限公司 Novel veterinary drug triclabendazole sulfoxide and preparation method thereof
CN103319417A (en) * 2013-06-24 2013-09-25 常州佳灵药业有限公司 Method for preparing triclabendazole sulfoxide
CN103360323A (en) * 2013-06-24 2013-10-23 常州佳灵药业有限公司 Preparation method of triclabendazole
CN104230815A (en) * 2013-06-07 2014-12-24 连云港市亚晖医药化工有限公司 Preparation method of triclabendazole

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105218375A (en) * 2015-10-31 2016-01-06 丁玉琴 Synthesis method of 2-methyl-4-nitrobenzoic acid

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2529887A (en) * 1949-05-19 1950-11-14 Du Pont Process for the preparation of anisole
US3538108A (en) * 1967-08-17 1970-11-03 Merck & Co Inc Water - soluble 2 - substituted benzimidazole methanesulfonic acid salts
US4197307A (en) * 1977-04-12 1980-04-08 Ciba-Geigy Corporation 2-Alkylthio-, 2-alkylsulphinyl- and 2-alkylsulfonyl-6-phenylbenzimidazoles as anthelmintic agents

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4492708A (en) * 1982-09-27 1985-01-08 Eli Lilly And Company Antiviral benzimidazoles
CN101555231B (en) * 2009-05-04 2011-03-23 扬州天和药业有限公司 Method for preparing triclabendazole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2529887A (en) * 1949-05-19 1950-11-14 Du Pont Process for the preparation of anisole
US3538108A (en) * 1967-08-17 1970-11-03 Merck & Co Inc Water - soluble 2 - substituted benzimidazole methanesulfonic acid salts
US4197307A (en) * 1977-04-12 1980-04-08 Ciba-Geigy Corporation 2-Alkylthio-, 2-alkylsulphinyl- and 2-alkylsulfonyl-6-phenylbenzimidazoles as anthelmintic agents

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HERNANDEZ-LUIS ET AL.: 'Synthesis and biological activity of 2-trifluoromethyl)-1 H-benzimidazole derivatives against some protozoa and Trichinella spiralis' EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY vol. 45, 07 April 2010, pages 3135 - 3141, XP027050440 *
SORIA-ARTECHE ET AL.: 'Studies on the Selective S-oxidation of Albendazole, Fenbendazole, Triclabendazole, and Other Benzimidazole Sulfides' J.MED.CHEM.SOC. vol. 49, no. 4, 2005, pages 353 - 358, XP055116213 *
TOWNSEND ET AL.: 'The Synthesis and Chemistry of Certain Anthelmintic Benzimidazoles' PARASITOLOGY TODAY vol. 6, no. 4, 1990, pages 107 - 112, XP055116216 *
ZHOU ET AL.: 'Separation and characterization of synthetic impurites of triclabendazole by reversed -phase high performance liquid chromatography/electrospray ionization mass spectrometry' JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS vol. 37, 2005, pages 97 - 107, XP027718678 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104230815A (en) * 2013-06-07 2014-12-24 连云港市亚晖医药化工有限公司 Preparation method of triclabendazole
CN103319416A (en) * 2013-06-24 2013-09-25 常州佳灵药业有限公司 Novel veterinary drug triclabendazole sulfoxide and preparation method thereof
CN103319417A (en) * 2013-06-24 2013-09-25 常州佳灵药业有限公司 Method for preparing triclabendazole sulfoxide
CN103360323A (en) * 2013-06-24 2013-10-23 常州佳灵药业有限公司 Preparation method of triclabendazole
CN103319417B (en) 2013-06-24 2014-07-09 常州佳灵药业有限公司 Method for preparing triclabendazole sulfoxide
CN103360323B (en) 2013-06-24 2014-07-09 常州佳灵药业有限公司 Preparation method of triclabendazole
CN103319416B (en) * 2013-06-24 2015-02-25 常州佳灵药业有限公司 Novel veterinary drug triclabendazole sulfoxide and preparation method thereof

Also Published As

Publication number Publication date
EP2642995A2 (en) 2013-10-02
US20130303781A1 (en) 2013-11-14
WO2012070068A3 (en) 2012-07-19

Similar Documents

Publication Publication Date Title
FI108434B (en) Menetelmõ the preparation of the benzimidazole derivatives of the pharmacologically active
Rinehart Jr et al. Eudistomins AQ,. beta.-carbolines from the antiviral Caribbean tunicate Eudistoma olivaceum
US5614519A (en) (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists
US5602127A (en) (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists
Little et al. A simple and practical synthesis of 2-aminoimidazoles
US3954791A (en) Anthelmintically active 2-carbalkoxy-amino-benzimidazole-5(6)-phenyl ethers
PT93689B (en) Process for the preparation of benzimidazoles and pharmaceutical compositions containing them
KR101411961B1 (en) Improved process for the preparation of the salts of 4-(benzimidazolylmethylamino)-benzamides
US7067513B1 (en) Phenylpiperazines
CN100418953C (en) Process for manufacture of telmisartan
CZ288624B6 (en) Process for preparing a form of A 2-n-butyl-3-[[2 -(tetrazol-5-yl)biphenyl-4-yl] methyl]-1,3-diazaspiro[4.4]non-1-en-4-one
FI60010B (en) Foerfarande Foer framstaellning of nya terapeutiskt anvaendbara 4- (2-imidazol-2-ylamino) -2,1,3-bensotiadiazoler
CA2040235A1 (en) Benzimidazolinone derivatives
GB1562812A (en) 1-sulphonyl-2-(amino or acylamino)-benzimidazoles
US20050267099A1 (en) Synthesis of olanzapine and intermediates thereof
Temple Jr et al. Pyrimido [5, 4-e]-as-triazines. I. The Preparation and Properties of 5-Chloro-1, 2-dihydropyrimido [5, 4-e]-as-triazine and Some of Its Methyl Derivatives1
CA1326035C (en) Process for the preparation of substituted quinolines
CA2297486C (en) 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1h-indole derivatives interacting with the dopamine d4 receptor
OA4289A (en) Derivatives pyrimidone- (4) substituted by a base and preparation of such derivatives processes.
EP0477819A2 (en) Benzimidazole derivatives, their preparation and use
CA2707334C (en) A process for the preparation or purification of olmesartan medoxomil
FI87210C (en) Foerfarande Foer framstaellning of terapeutiskt anvaendbara bensimidazolderivat
KR101677915B1 (en) Method for producing an intermediate product of dabigatran etexilate
CA2808230C (en) Process for producing 1-triazole-2-butanol derivatives
US20080221338A1 (en) Processes for preparing darifenacin hydrobromide

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11843342

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 2011843342

Country of ref document: EP

NENP Non-entry into the national phase in:

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 13989147

Country of ref document: US