CN102731407A - Method for preparing telmisartan - Google Patents
Method for preparing telmisartan Download PDFInfo
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- 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
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- telmisartan
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- binding agent
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- preparing telmisartan
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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
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.
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 |
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| CN102731407A true CN102731407A (en) | 2012-10-17 |
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| CN2012102318965A Pending CN102731407A (en) | 2012-07-04 | 2012-07-04 | Method for preparing telmisartan |
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Cited By (3)
| 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 |
| CN109748912A (en) * | 2017-11-03 | 2019-05-14 | 武汉朗来科技发展有限公司 | The preparation method of low impurity content benzimidizole derivatives |
Citations (1)
| 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 |
-
2012
- 2012-07-04 CN CN2012102318965A patent/CN102731407A/en active Pending
Patent Citations (1)
| 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 (9)
| 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 |
| CN109305965B (en) * | 2017-07-28 | 2021-03-16 | 武汉朗来科技发展有限公司 | Benzimidazole derivative preparation and analysis method |
| CN109748912A (en) * | 2017-11-03 | 2019-05-14 | 武汉朗来科技发展有限公司 | The preparation method of low impurity content benzimidizole derivatives |
| CN109748912B (en) * | 2017-11-03 | 2023-08-22 | 武汉朗来科技发展有限公司 | Process for preparing benzimidazole derivatives with low impurity content |
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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 |
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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. |
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Application publication date: 20121017 |