CN101717370A - New method for preparing 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole - Google Patents
New method for preparing 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole Download PDFInfo
- Publication number
- CN101717370A CN101717370A CN200910232720A CN200910232720A CN101717370A CN 101717370 A CN101717370 A CN 101717370A CN 200910232720 A CN200910232720 A CN 200910232720A CN 200910232720 A CN200910232720 A CN 200910232720A CN 101717370 A CN101717370 A CN 101717370A
- Authority
- CN
- China
- Prior art keywords
- methyl
- propyl
- benzoglyoxaline
- preferred
- tolimidazole
- 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.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a new method for preparing 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole for industrialized use.
Description
Technical field
But the present invention relates to the novel method of preparation 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline of industrialization use.
Background technology
2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline is the key intermediate of synthetic hypertension therapeutic medicine telmisartan (telmisartan).Telmisartan is the non-peptide class Angiotensin of an efficient highly selective || receptor antagonist also is to treat one of hypertensive common drug clinically.
2-n-propyl-4-methyl-6-(1-methyl
The benzoglyoxaline telmisartan (Telmisartan) of benzimidazolyl-2 radicals-yl)
The common method of Synthetic 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline is to be obtained by N-methyl-o-phenylenediamine hydrochloride (1) and 2-n-propyl-4-methyl isophthalic acid H-benzoglyoxaline-6-carboxylic acid (2) condensation, and synthetic route is as follows:
The condition of condensation reaction has following several: (1) Ries etc. has reported that compound 1 and 2 is in polyphosphoric acid, 150 ℃ are reacted after 20 hours down, carry out obtaining 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline (J.Med.Chem. after the aftertreatment with ethyl acetate and ether then, 1993,36,4040-4051); (2) disclose compound 1 and 2 in the U.S. Pat 2007037986 in polar solvent and 2-chloro-4, under the existence of 6-two replacement-1,3,5-triazines and tertiary amine, condensation obtains 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline; (3) Chinese patent CN1620437A discloses in the presence of methylsulfonic acid and Vanadium Pentoxide in FLAKES, compound 1 and 2 is at 125～145 ℃ of stoichiometric numbers hour, and carry out aftertreatment with activated carbon, obtain 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline; (4) and Chinese patent CN1454891A has reported and uses 1, alcohol reagents such as 2-propylene glycol are as reaction solvent and catalyzer, and compound 1 and 2 direct condensations obtain 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline under high temperature or the reflux conditions.All there is certain deficiency in above reaction conditions, 2-chloro-4, and the price of 6-two replacement-1,3,5-triazines and methylsulfonic acid is higher, and the molar weight of using in the reaction is big, and synthetic cost is higher.Adopting polyphosphoric acid is solvent and catalyzer, and the impurity that produces in the reaction is more, and aftertreatment is loaded down with trivial details, and quality product is difficult to control.With 1, the 2-propylene glycol is reaction solvent and catalyzer, and the yield of product is not high.
The invention provides the novel method of a kind of preparation 2-n-propyl capable of being industrialized-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline.This method raw material is easy to get and low price, the synthesis yield height, and good product quality is fit to large-scale industrial production.
Summary of the invention
The present invention adopts following condition and step to prepare 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline: in the mixed system of N-Methyl pyrrolidone and phosphorus oxychloride, under the heating condition, 2-n-propyl-7-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid and N-methyl-o-phenylenediamine or its salt carry out condensation reaction.Reaction adds water and organic solvent after finishing, and regulates the pH value with alkaline aqueous solution, add carbon sublimated again, filter the back and add elutriation and go out solid, filter or centrifugal after, washing, dry highly purified 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline that gets.
Wherein the salt of N-methyl-o-phenylenediamine can be selected the salt of mineral acids such as hydrochloride, vitriol, phosphoric acid salt, wherein preferably salt hydrochlorate.
Temperature of reaction can be selected 60～150 ℃, and preferred 80～120 ℃, preferred especially 100～110 ℃.
The mol ratio of 2-n-propyl-7-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid and phosphorus oxychloride can be selected 1: 2～1: 20, and preferred 1: 5～1: 15, preferred especially 1: 10～1: 12.
The mol ratio of 2-n-propyl-7-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid and N-Methyl pyrrolidone can be selected 1: 2～1: 6, and preferred 1: 3～1: 7, preferred especially 1: 4～1: 6.
The mol ratio of 2-n-propyl-7-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid and N-methyl-o-phenylenediamine or its salt can be selected 1.0: 0.5～1.0: 2.5, and preferred 1.0: 0.6～1.0: 1.4, preferred especially 1.0: 0.9～1.0: 1.1.
Maximum 10 hours of condensation reaction time, preferred 1～5 hour.Subsequently, add a certain amount of water down at 20～30 ℃, the mol ratio of water and phosphorus oxychloride can be selected 1: 0.1～1: 20, and preferred 1: 10～1: 15, preferred especially 1: 12～1: 14.
After adding water and finishing, in reaction mixture, add organic solvent again, organic solvent can be selected propyl carbinol, the trimethyl carbinol, 2-methylpropanol, n-propyl alcohol, Virahol, ethanol, ethyl acetate, methylene dichloride, tetrahydrofuran (THF), toluene, preferred Virahol or ethanol, special preferred alcohol.
Regulate the pH value with alkaline aqueous solution subsequently, wherein alkali can be selected sodium hydroxide, yellow soda ash, triethylamine, ammonia, preferred especially sodium hydroxide or ammonia.PH value scope after the adjusting can select 7～11, preferred pH value 8～9.
Add carbon subsequently, preferred activated carbon.The carbon amount that adds may be selected to be 2-n-propyl-7-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid 5～30% of weight that feeds intake, preferred 10～25%, preferred especially 15%.The highest 90 ℃, preferred 60～80 ℃, under preferred especially 75～80 ℃, stirred 10～15 minutes, filter or centrifugal.Filtrate repeats to use carbon sublimated 2～5 times, preferred 3 times.
Add entry after the filtration, the water yield can be selected 50～200% (volume ratios) of organic solvent amount, preferred 100～150% (volume ratios), preferred especially 120% (volume ratio).
Filter, the products therefrom washing with alcohol, and the highest 120 ℃, preferably the highest 100 ℃, preferred especially 70～80 ℃ of dryings get 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline product.Yield 85～95%, the purity of product is greater than 95%.
Embodiment
Following type reaction is used for illustrating the present invention, within the technical scheme that those skilled in the art all belong to the present invention to simple replacement that the present invention did or improvement etc. and protected.
Embodiment 1:
After the N-Methyl pyrrolidone of 60L phosphorus oxychloride and 24Kg mixes, 2-n-propyl-7-methyl isophthalic acid H-benzoglyoxaline-5-the carboxylic acid that adds 10.9Kg, be heated to backflow, stirring reaction 3 hours, be cooled to 25～35 ℃, add the N-methyl-o-phenylenediamine hydrochloride of 9.8Kg, be warming up to backflow again, continue reaction and stirred 3 hours.Be cooled to 20～30 ℃, slowly add in the 150Kg water in the stirring downhill reaction liquid, add 5L ethanol subsequently.Under 60～70 ℃, regulate pH value to 8～9 with 50% aqueous sodium hydroxide solution.Subsequently, the 1Kg activated carbon is joined in the reaction soln, stirred at least under 75～80 ℃ 15 minutes, filter, filtrate repeats to use activated carbon treatment 3 times.After the filtration of active charcoal, in reaction solution, add about 240 liters water, have precipitation to separate out.Be cooled to room temperature, centrifugal, use 50L 90% ethanol, 50L water washing filter cake successively.70～80 ℃ of following forced air dryings get product.Productive rate 90.6%, HPLC testing product purity is 98.2%.
Claims (14)
1. novel method for preparing 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, it is characterized in that: in the mixed system of N-Methyl pyrrolidone and phosphorus oxychloride, under the heating condition, 2-n-propyl-7-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid and N-methyl-o-phenylenediamine or its salt carry out condensation reaction, after reaction finishes, add water and organic solvent, regulate the pH value with alkaline aqueous solution, add carbon sublimated again, filter back adding elutriation and go out solid, filter or centrifugal after, washing, dry highly purified 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline.
2. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, the salt that it is characterized in that the N-methyl-o-phenylenediamine can be selected the salt of mineral acids such as hydrochloride, vitriol, phosphoric acid salt, wherein preferably salt hydrochlorate.
3. the novel method of preparation according to claim 1 2-n-propyl-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline is characterized in that temperature of reaction can select 60～150 ℃, preferred 80～120 ℃, and preferred especially 100～110 ℃.
4. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, the mol ratio that it is characterized in that 2-n-propyl-7-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid and phosphorus oxychloride can be selected 1: 2～1: 20, preferred 1: 5～1: 15, preferred especially 1: 10～1: 12.
5. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, the mol ratio that it is characterized in that 2-n-propyl-7-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid and N-Methyl pyrrolidone can be selected 1: 2～1: 6, preferred 1: 3～1: 7, preferred especially 1: 4～1: 6.
6. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, the mol ratio that it is characterized in that 2-n-propyl-7-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid and N-methyl-o-phenylenediamine or its salt can be selected 1.0: 0.5～1.0: 2.5, preferred 1.0: 0.6～1.0: 1.4, preferred especially 1.0: 0.9～1.0: 1.1.
7. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline is characterized in that condensation reaction time maximum 10 hours, preferred 1～5 hour.
8. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, it is characterized in that reaction finishes the back and adds a certain amount of water down at 20～30 ℃, the mol ratio of water and phosphorus oxychloride can be selected 1: 0.1～1: 20, preferred 1: 10～1: 15, preferred especially 1: 12～1: 14.
9. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, it is characterized in that adding entry after reaction finishes, in reaction mixture, add organic solvent again, organic solvent can be selected propyl carbinol, the trimethyl carbinol, 2-methyl-propyl alcohol, n-propyl alcohol, Virahol, ethanol, ethyl acetate, methylene dichloride, tetrahydrofuran (THF), toluene, preferred Virahol or ethanol, special preferred alcohol.
10. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, it is characterized in that regulating the pH value with alkaline aqueous solution, wherein alkali can be selected sodium hydroxide, yellow soda ash, triethylamine, ammonia, preferred sodium hydroxide or ammonia, pH value scope after the adjusting can select 7～11, preferred pH value 8～9.
11. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, it is characterized in that using carbon sublimated, preferred activated carbon, the carbon amount that adds may be selected to be 2-n-propyl-7-methyl isophthalic acid H-benzoglyoxaline-5-carboxylic acid 5～30% of weight that feeds intake, preferred 10～25%, preferred especially 15%.
12. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline is characterized in that repeating purifying 2～5 times, preferred 3 times with carbon.
13. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline, add entry after it is characterized in that filtering carbon, the water yield can be selected 50～200% (volume ratios) of organic solvent amount, preferred 100～150% (volume ratios), preferred especially 120% (volume ratio).
14. the novel method of preparation 2-n-propyl according to claim 1-4-methyl-6-(1-tolimidazole-2-yl) benzoglyoxaline is characterized in that the temperature of product drying is up to 120 ℃, preferably the highest 100 ℃, and preferred especially 70～80 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910232720A CN101717370A (en) | 2009-11-30 | 2009-11-30 | New method for preparing 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910232720A CN101717370A (en) | 2009-11-30 | 2009-11-30 | New method for preparing 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101717370A true CN101717370A (en) | 2010-06-02 |
Family
ID=42432014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910232720A Pending CN101717370A (en) | 2009-11-30 | 2009-11-30 | New method for preparing 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101717370A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295604A (en) * | 2011-07-13 | 2011-12-28 | 四川科伦药物研究有限公司 | Preparation method of telmisartan intermediate |
| CN110698410A (en) * | 2019-10-25 | 2020-01-17 | 合肥立方制药股份有限公司 | Preparation method of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole |
| CN115466222A (en) * | 2022-07-28 | 2022-12-13 | 江苏中邦制药有限公司 | Preparation method of telmisartan intermediate |
| CN115466222B (en) * | 2022-07-28 | 2024-06-04 | 江苏中邦制药有限公司 | Preparation method of telmisartan intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1620437A (en) * | 2002-01-18 | 2005-05-25 | 贝林格尔英格海姆法玛两合公司 | Method for the production and purification of 1,7'-dimethyl-2'-propyl-2,5'-bi-1h-benzimidazole |
| WO2007010558A1 (en) * | 2005-07-19 | 2007-01-25 | Matrix Laboratories Limited | A process for the preparation of telmisartan |
-
2009
- 2009-11-30 CN CN200910232720A patent/CN101717370A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1620437A (en) * | 2002-01-18 | 2005-05-25 | 贝林格尔英格海姆法玛两合公司 | Method for the production and purification of 1,7'-dimethyl-2'-propyl-2,5'-bi-1h-benzimidazole |
| WO2007010558A1 (en) * | 2005-07-19 | 2007-01-25 | Matrix Laboratories Limited | A process for the preparation of telmisartan |
Non-Patent Citations (2)
| Title |
|---|
| UWE J.RIES ET AL.: "6-substituted benzimidazoles as new nonpeptide angiotensin II teceptor antagonists:synthesis,biological activity,and structure-activity relationships", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 石卫兵等: "血管紧张素受体拮抗剂替米沙坦的合成研究", 《中国药物化学杂志》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295604A (en) * | 2011-07-13 | 2011-12-28 | 四川科伦药物研究有限公司 | Preparation method of telmisartan intermediate |
| CN102295604B (en) * | 2011-07-13 | 2013-05-15 | 四川科伦药物研究有限公司 | Preparation method of telmisartan intermediate |
| CN110698410A (en) * | 2019-10-25 | 2020-01-17 | 合肥立方制药股份有限公司 | Preparation method of 2-n-propyl-4-methyl-6- (1' -methylbenzimidazole-2-yl) benzimidazole |
| CN115466222A (en) * | 2022-07-28 | 2022-12-13 | 江苏中邦制药有限公司 | Preparation method of telmisartan intermediate |
| CN115466222B (en) * | 2022-07-28 | 2024-06-04 | 江苏中邦制药有限公司 | Preparation method of telmisartan intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103665032B (en) | A kind of preparation method of careless ammonium phosphine | |
| JP6114881B2 (en) | Compound of “3- (5-substitutedoxy-2,4-dinitro-phenyl) -2-oxo-propionic ester”, process and use thereof | |
| CN102557977A (en) | Synthesis intermediate of erlotinib and preparation method thereof | |
| CN102584795A (en) | Preparing method of crizotinib | |
| CN104945332B (en) | The preparation method of Erlotinib | |
| CN102367260A (en) | Synthesis method of 2-aminopyrimidine-5-boric acid | |
| CN103087059B (en) | Preparation method for high-purity olprinone hydrochloride | |
| CN102498102A (en) | Novel method for synthesizing ivabradine and the addition salts thereof with a pharmaceutically acceptable acid | |
| CN106674084B (en) | A kind of preparation method of 2- isopropyl oxygroup -5- methyl -4- (piperidin-4-yl) aniline dihydrochloride | |
| CN101717370A (en) | New method for preparing 2-n-propyl-4-methyl-6-(1-methyl benzimidazole-2-yl) benzimidazole | |
| CN1301963C (en) | Process for producing N-(4-fluobenzene radical)-N-(2-hydroxy-4-chlorobenzene group) glycocoll | |
| CN102321086B (en) | Synthesizing method of adenine | |
| CN112062726B (en) | Preparation method of 2-amino-4, 6-dichloro-5-formamido pyrimidine | |
| CN103058936B (en) | The preparation method of 4-[(the chloro-2-pyrimidyl of 4-) is amino] cyanophenyl | |
| CN103373995A (en) | Method for preparing pyronaridine | |
| CN103168037A (en) | Synthesis and use of kinase inhibitors | |
| CN102731407A (en) | Method for preparing telmisartan | |
| CN101220016A (en) | Method for synthesizing 4-hydroxyl coumarin and derivant thereof | |
| CN107522742A (en) | A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediates | |
| CN102718720B (en) | Method for preparing 4-[(4,6-dichloro-2-pyrimidyl) amino] cyanophenyl | |
| CN103224476A (en) | New process for preparing 1-[2-(2-hydroxyethoxy)ethyl]piperazine through diethanolamine method | |
| CN106883185B (en) | Preparation method of 4-chloro-2-trifluoromethylpyrimidine | |
| CN102712602A (en) | Process for preparing 2-methyl-4-amino-5-cyanopyrimidine | |
| CN102459243A (en) | Process for the preparation of olmesartan medoxomil | |
| CN105348285A (en) | Low-cost and high-yield adenine preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20100602 |