CN102731407A - Method for preparing telmisartan - Google Patents

Method for preparing telmisartan Download PDF

Info

Publication number
CN102731407A
CN102731407A CN2012102318965A CN201210231896A CN102731407A CN 102731407 A CN102731407 A CN 102731407A CN 2012102318965 A CN2012102318965 A CN 2012102318965A CN 201210231896 A CN201210231896 A CN 201210231896A CN 102731407 A CN102731407 A CN 102731407A
Authority
CN
China
Prior art keywords
telmisartan
reaction
preparing telmisartan
binding agent
acid binding
Prior art date
Application number
CN2012102318965A
Other languages
Chinese (zh)
Inventor
吴绍伟
陶伟坚
沈磊
张达
Original Assignee
宁波九胜创新医药科技有限公司
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
Application filed by 宁波九胜创新医药科技有限公司 filed Critical 宁波九胜创新医药科技有限公司
Priority to CN2012102318965A priority Critical patent/CN102731407A/en
Publication of CN102731407A publication Critical patent/CN102731407A/en

Links

Abstract

The invention discloses a method for preparing telmisartan, which can be used for directly producing telmisartan by carrying out nucleophilic substitution reaction on 2-n-propyl-4-methyl-6-(1'-methyl benzimidazole-2-yl) benzimidazole and 4-brooethyl diphenyl-2-carboxylic acid under the action of acid-binding agent. The method is simple in operation, thus improving the yield of the final product and being suitable for the synthetic route of telmisartan in industrial production.

Description

A kind of method for preparing telmisartan

Technical field

The present invention relates to the preparation method of antihypertensive drug, particularly, the present invention relates to the preparation method of telmisartan (Telmisartan).

Background technology

Telmisartan is a kind of novel non-peptide class II Angiotensin II (AT), and its structure is following:

The synthetic route of existing telmisartan mainly is, and to be starting raw material with 3-methyl-4-Methyl anthranilate get midbody 2-n-propyl-4-methyl-6-(1'-tolimidazole-2-yl) benzoglyoxaline through N-acidylate, nitrated, reduction, cyclization, ester hydrolysis, condensation reaction, with 4-bromomethylbiphenyl carboxylicesters (R=CH 3, C 2H 5, t-Bu) nucleophilic substitution gets compound IV, is hydrolyzed to final telmisartan (Chinese patent CN 1344712A) again.Among this preparation method, be with the carboxyl of methyl or ethyl or tertiary butyl protection 4-bromomethylbiphenyl carboxylic acid again with the chemical compounds I reaction, obtain final telmisartan through hydrolysis again.But this route reaction step number is many, protection in the elder generation, back deprotection.Overall yield is not high, and complex operation is unfavorable for suitability for industrialized production.Reaction formula is following:

Summary of the invention

Technical problem to be solved by this invention provides a kind of method for preparing telmisartan, and method of the present invention has been simplified operation, has improved the yield of the finished product, is the synthetic route that is fit to the telmisartan of suitability for industrialized production.

The present invention solves the problems of the technologies described above the technical scheme that is adopted: a kind of method for preparing telmisartan; In reaction solvent; Compound ii 4-bromomethylbiphenyl-2-carboxylic acid shown in chemical compounds I 2-n-propyl-4-methyl-6-shown in the adding formula I (1'-tolimidazole-2-yl) benzoglyoxaline and the formula II; Heat temperature raising, under the effect of acid binding agent, the 2-n-propyl-4-methyl-6-shown in nucleophilic reaction to the formula I (1'-tolimidazole-2-yl) benzoglyoxaline reacts completely; Reaction solution obtains the telmisartan shown in the formula III through separation and purification;

Wherein, the 4-bromomethylbiphenyl-2-carboxylic acid shown in the n-propyl of the 2-shown in the formula I-4-methyl-6-(1'-tolimidazole-2-yl) benzoglyoxaline, the formula II and the amount of substance ratio of acid binding agent are: 1:1.1 ~ 2.0:1.0 ~ 2.0.

In the technique scheme, removed the tertiary butyl of the prior art, methyl, ethyl protection, directly by 4-bromomethylbiphenyl-2-carboxylic acid, it and chemical compounds I nucleo philic substitution reaction directly generate purpose product III.Promptly; 2-n-propyl-4-methyl-6-(1'-tolimidazole-2-yl) benzoglyoxaline and 4-bromomethylbiphenyl-2-carboxylic acid nucleo philic substitution reaction directly generate telmisartan 4'-[(1; 4'-dimethyl--2'-propyl group [2; 6'-two-1H-benzoglyoxaline]-the 1' yl) methyl]-[1,1'-biphenyl]-2-carboxylic acid.

Said acid binding agent is an organic bases, and said organic bases is selected from any one in sodium alkoxide, triethylamine, tri-n-butylamine and the tripropylamine.

Said acid binding agent is a mineral alkali, and said mineral alkali is selected from NaOH, KOH, CsOH, Ba (OH) 2, Mg (OH) 2, Ca (OH) 2, KHCO 3, K 2CO 3, Na 2CO 3And Cs 2CO 3In any one.

The temperature of said nucleophilic reaction is 50-120 ℃, reaction times 8-16 hour.

Said reaction solvent is selected from any one in DMF, DMSO, dioxane, pyrrolidinone compounds, butanone, 2-MIBK and the glycol dimethyl ether.

The step of said reaction solution separation and purification is: reaction solution is added to the water, regulates the pH value to 2-3, separate out solid, filtering drying obtains bullion, and the gained bullion with the ETHYLE ACETATE making beating once obtains the Mi Sha that replaces shown in the formula III with the DMF recrystallization after the oven dry again.

The present invention compared with prior art has following advantage:

(1) the present invention has searched out a kind of new chemical synthesis process in order to production medicine telmisartan.Under the effect of acid binding agent, nucleo philic substitution reaction directly generates telmisartan to the inventive method through 2-n-propyl-4-methyl-6-(1'-tolimidazole-2-yl) benzoglyoxaline and 4-bromomethylbiphenyl-2-carboxylic acid.The route of this chemical synthesis process is more reasonable, and its reaction conditions is gentle more.

(2) synthetic route of the present invention shortens with respect to the prior art step, has therefore simplified production operation, and other production costs comprise that the cost of time, equipment, auxiliary material also reduces greatly, therefore more are applicable to suitability for industrialized production.

(3) preparation method of the present invention has improved the yield of the finished product telmisartans, has remarkable economic efficiency.

Specific embodiment:

In order to understand content of the present invention better, be described further below in conjunction with specific embodiment.Should be understood that these embodiment only are used for the present invention is further specified, and be not used in restriction scope of the present invention.Should be understood that in addition that after having read content of the present invention the technician in this field makes some nonessential change or adjustment to the present invention, still belongs to protection scope of the present invention.

Embodiment 1 preparation telmisartan

With the 2-n-propyl-4-methyl-6-shown in the formula I (1'-tolimidazole-2-yl) benzoglyoxaline (30.4g; 0.10mol), 4-bromomethylbiphenyl-2-carboxylic acid (43.6g, 0.15mol), (30g 0.2mol) mixes with DMSO 500ml the salt of wormwood fine powder; 100 ℃ were reacted 10 hours down; Reaction solution is poured in the frozen water, slowly be adjusted to pH2-3, separate out solid with Hydrogen chloride.Filter, 70 ℃ dry bullion, the gained bullion adds hot breakdown once with ETHYLE ACETATE 300ml.Filter 70 ℃ of oven dry.Get the telmisartan 44.2g shown in the formula III, yield: 86.5% with the DMF recrystallization.

Wherein, said DMSO can use any one replacement in DMF, dioxane, pyrrolidinone compounds, butanone, 2-MIBK and the glycol dimethyl ether.

Embodiment 2 preparation telmisartans

With the 2-n-propyl-4-methyl-6-shown in the formula I (1'-tolimidazole-2-yl) benzoglyoxaline (30.4g; 0.10mol), 4-bromomethylbiphenyl-2-carboxylic acid (37.83g, 0.13mol), (5.6g 0.10mol) mixes with 2-MIBK 500ml Pottasium Hydroxide; 80 ℃ were reacted 16 hours down; Reaction solution is poured in the frozen water, slowly transferred pH2-3, separate out solid with Hydrogen chloride.Filter, 70 ℃ dry bullion, the gained bullion adds hot breakdown once with ETHYLE ACETATE 300ml.Filter 70 ℃ of oven dry.Get the telmisartan 38.8g shown in the formula III, yield: 76% with the DMF recrystallization.

Wherein, said 2-MIBK can be used any one replacement in DMF, DMSO, dioxane, pyrrolidinone compounds, butanone and the glycol dimethyl ether.

Embodiment 3 preparation telmisartans

With (1'-tolimidazole-2-yl) benzoglyoxaline of the 2-n-propyl-4-methyl-6-shown in the formula I (30.4g 0.10mol), 4-bromomethylbiphenyl-2-carboxylic acid (43.6g; 0.15mol), sodium ethylate (13.6g; 0.2mol) mix with N-Methyl pyrrolidone 500ml, 50 degrees centigrade were reacted 10 hours down, reaction solution are poured in the frozen water; Slowly transfer pH2-3 with Hydrogen chloride, separate out solid.Filter, 70 ℃ dry bullion, the gained bullion adds hot breakdown once with ETHYLE ACETATE 300ml.Filter 70 ℃ of oven dry.Get the telmisartan 27.7g shown in the formula III, yield: 54% with the DMF recrystallization.

Wherein, said N-Methyl pyrrolidone can be used any one replacement in DMF, DMSO, dioxane, other pyrrolidinone compounds, 2-MIBK, butanone and the glycol dimethyl ether.

Embodiment 4 preparation telmisartans

With the 2-n-propyl-4-methyl-6-shown in the formula I (1'-tolimidazole-2-yl) benzoglyoxaline (30.4g; 0.10mol), 4-bromomethylbiphenyl-2-carboxylic acid (43.6g, 0.15mol), (12.1g 0.15mol) mixes with glycol dimethyl ether 500ml triethylamine; 100 degree reacted 6 hours down; Reaction solution is poured in the frozen water, slowly transferred pH2-3, separate out solid with Hydrogen chloride.Filter, 70 ℃ dry bullion, the gained bullion adds hot breakdown once with ETHYLE ACETATE 300ml.Filter 70 ℃ of oven dry.Get the telmisartan 25.7g shown in the formula III, yield: 50% with the DMF recrystallization.

Wherein, said glycol dimethyl ether can be used any one replacement in DMF, DMSO, dioxane, pyrrolidinone compounds, 2-MIBK and the butanone.

As stated, just can realize the present invention preferably.

Claims (7)

1. a method for preparing telmisartan is characterized in that, said method is: in reaction solvent; Compound ii shown in chemical compounds I shown in the adding formula I and the formula II; Heat temperature raising, under the effect of acid binding agent, nucleophilic reaction to said chemical compounds I reacts completely; Reaction solution obtains the telmisartan shown in the formula III through separation and purification;
2. the method for preparing telmisartan as claimed in claim 1 is characterized in that: the amount of substance ratio of the chemical compounds I of adding, compound ii and acid binding agent is: 1:1.1 ~ 2.0:1.0 ~ 2.0.
3. the method for preparing telmisartan as claimed in claim 2 is characterized in that: said acid binding agent is an organic bases, and said organic bases is selected from any one in sodium alkoxide, triethylamine, tri-n-butylamine and the tripropylamine.
4. the method for preparing telmisartan as claimed in claim 2 is characterized in that: said acid binding agent is a mineral alkali, and said mineral alkali is selected from NaOH, KOH, CsOH, Ba (OH) 2, Mg (OH) 2, Ca (OH) 2, KHCO 3, K 2CO 3, Na 2CO 3And Cs 2CO 3In any one.
5. the method for preparing telmisartan as claimed in claim 2 is characterized in that, the temperature of said nucleophilic reaction is 50-120 ℃, reaction times 8-16 hour.
6. the method for preparing telmisartan as claimed in claim 5 is characterized in that, said reaction solvent is selected from any one in DMF, DMSO, dioxane, pyrrolidinone compounds, butanone, 2-MIBK and the glycol dimethyl ether.
7. like any described method for preparing telmisartan of claim 1-5; It is characterized in that the step of said reaction solution separation and purification is: reaction solution is added to the water, regulates the pH value to 2-3; Separate out solid; Filtering drying obtains bullion, and the gained bullion with the ETHYLE ACETATE making beating once obtains the telmisartan shown in the formula III with the DMF recrystallization after the oven dry again.
CN2012102318965A 2012-07-04 2012-07-04 Method for preparing telmisartan CN102731407A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2012102318965A CN102731407A (en) 2012-07-04 2012-07-04 Method for preparing telmisartan

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2012102318965A CN102731407A (en) 2012-07-04 2012-07-04 Method for preparing telmisartan

Publications (1)

Publication Number Publication Date
CN102731407A true CN102731407A (en) 2012-10-17

Family

ID=46987792

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2012102318965A CN102731407A (en) 2012-07-04 2012-07-04 Method for preparing telmisartan

Country Status (1)

Country Link
CN (1) CN102731407A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014067237A1 (en) * 2012-10-31 2014-05-08 上海特化医药科技有限公司 Telmisartan preparation method and intermediate thereof
WO2019020104A1 (en) * 2017-07-28 2019-01-31 武汉朗来科技发展有限公司 Preparation and analysis methods for benzimidazole derivative

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1344712A (en) * 2001-07-30 2002-04-17 中国科学院上海药物研究所 Synthesis path of Timisatem

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1344712A (en) * 2001-07-30 2002-04-17 中国科学院上海药物研究所 Synthesis path of Timisatem

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014067237A1 (en) * 2012-10-31 2014-05-08 上海特化医药科技有限公司 Telmisartan preparation method and intermediate thereof
CN103787982A (en) * 2012-10-31 2014-05-14 上海特化医药科技有限公司 Telmisartan preparation method and intermediate of telmisartan
CN104768936A (en) * 2012-10-31 2015-07-08 上海特化医药科技有限公司 Enzalutamide polymorphic forms and its preparation
CN104768936B (en) * 2012-10-31 2017-07-28 上海特化医药科技有限公司 Prepare the method and its intermediate of Telmisartan
WO2019020104A1 (en) * 2017-07-28 2019-01-31 武汉朗来科技发展有限公司 Preparation and analysis methods for benzimidazole derivative
CN109305965A (en) * 2017-07-28 2019-02-05 武汉朗来科技发展有限公司 Benzimidizole derivatives preparation and analysis method

Similar Documents

Publication Publication Date Title
CN104892509B (en) Nuo get Si Ta preparation method
CN101967145B (en) Method for preparing antithrombotic medicament apixaban
JP5269798B2 (en) Trityl olmesartan medoxomil and method for producing olmesartan medoxomil
JP5202635B2 (en) Processes and intermediates for the preparation of integrase inhibitors
DE19901921C2 (en) Polymorphs of telmisartan, process for their preparation and their use in the manufacture of a medicament
CN1182122C (en) Synthesis path of Timisatem
KR101565169B1 (en) Process and intermediates for preparing integrase inhibitors
EP1874762B1 (en) Method for the production of 5-(4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide
CA2520714C (en) Process for manufacture of telmisartan
CN104130261A (en) Idelalisib synthetic method
WO2016145990A1 (en) Method of preparation for ledipasvir and derivative thereof, and intermediate compound for preparation of ledipasvir
CN105473562A (en) Process for manufacturing 4-propargylated amino-benzoxazinones
CN102639486B (en) Process for manufacture of N-acylbphenyl alanine
CN101456856B (en) Method for preparing 1-propone-1,3-sultone
CN102311392A (en) Synthetic method of azoxystrobin and special intermediate for synthesis
CN103108869A (en) Process for preparing aminobenzoylbenzofuran derivatives
CN1984898A (en) Process for production of azulene derivatives and intermediates for the synthesis of the same
CN103665032B (en) A kind of preparation method of careless ammonium phosphine
CN105294699B (en) Ba Rui replaces the preparation method of Buddhist nun
CN103554201B (en) Gamithromycin preparation method
CN100548968C (en) A kind of method for preparing 2-to octyl group styroyl-2-amino-propanediol hydrochloride
CN103724329A (en) Preparation method of 4-[5-(pyridyl-4-yl)-1H-[1,2,4]triazolyl-3-yl]pyridyl-2-formonitrile
JP4544432B2 (en) Method for producing diamine compound having cinnamoyl group
CN100391945C (en) S-(-)-indolyl-2-carboxylic acid synthesizing method
CN103601645B (en) The preparation method of 1-(phenethyl amino) propane-2-alcohol compound or its salt

Legal Events

Date Code Title Description
PB01 Publication
C06 Publication
SE01 Entry into force of request for substantive examination
TA01 Transfer of patent application right

Effective date of registration: 20121112

Address after: 315000 Zhejiang city of Ningbo province Beilun xinqie Mingzhou Road No. 503 -2315800

Applicant after: Ningbo Chemgoo Pharmaceutical Technology Innovation Limited

Applicant after: Haimen City Chemgoo Pharma Co., Ltd.

Address before: 315000 Zhejiang city of Ningbo province Beilun xinqie Mingzhou Road No. 503 -2315800

Applicant before: Ningbo Chemgoo Pharmaceutical Technology Innovation Limited

C10 Entry into substantive examination
C41 Transfer of patent application or patent right or utility model
ASS Succession or assignment of patent right

Owner name: HAIMEN XIN GANG PHARMACEUTICAL TECHNOLOGY CO., LTD

Effective date: 20121112

C41 Transfer of patent application or patent right or utility model
TA01 Transfer of patent application right

Effective date of registration: 20130311

Address after: 226100 Jiangsu Province, Linjiang New District, Linjiang Industrial Area, Wangjiang Road, Thousand Island intersection

Applicant after: Haimen City Chemgoo Pharma Co., Ltd.

Applicant after: Ningbo Chemgoo Pharmaceutical Technology Innovation Limited

Address before: Ningbo city Beilun xinqie Mingzhou Road No. 503 -2315800

Applicant before: Ningbo Chemgoo Pharmaceutical Technology Innovation Limited

Applicant before: Haimen City Chemgoo Pharma Co., Ltd.

COR Change of bibliographic data

Free format text: CORRECT: ADDRESS; FROM: NINGBO, ZHEJIANG PROVINCE TO: 226100 NANTONG, JIANGSU PROVINCE

ASS Succession or assignment of patent right

Owner name: HAIMEN XIN GANG PHARMACEUTICAL TECHNOLOGY CO., LTD

Free format text: FORMER OWNER: NINGBO CHEMGOO PHARMACEUTICAL TECHNOLOGY INNOVATION LIMITED

Effective date: 20130311

Owner name: NINGBO CHEMGOO PHARMACEUTICAL TECHNOLOGY INNOVATIO

Free format text: FORMER OWNER: HAIMEN XIN GANG PHARMACEUTICAL TECHNOLOGY CO., LTD.

Effective date: 20130311

RJ01 Rejection of invention patent application after publication

Application publication date: 20121017