CN101172968B - 2-propyl-4 methyl-6-(tolimidazole-2group) benzoglioxaline salt and method for producing the same - Google Patents
2-propyl-4 methyl-6-(tolimidazole-2group) benzoglioxaline salt and method for producing the same Download PDFInfo
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- CN101172968B CN101172968B CN200610117824A CN200610117824A CN101172968B CN 101172968 B CN101172968 B CN 101172968B CN 200610117824 A CN200610117824 A CN 200610117824A CN 200610117824 A CN200610117824 A CN 200610117824A CN 101172968 B CN101172968 B CN 101172968B
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Abstract
The invention relates to an intermediate 2-n-propyl-4 methyl-6-(methyl benzimidazole-2- radical) benzimidazole salt for high blood pressure resistance medicine that is telmisartan and the preparation method thereof. The intermediate has no any reports in the literature. The invention has the advantages of easy control of the preparation reaction condition, easy getting of raw material, and being suitable for mass production. The intermediate can be used for preparing the telmisartan.
Description
Technical field
The present invention relates to field of medicine preparing technology, be specifically related to prepare intermediate 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt of telmisartan and preparation method thereof.
Background technology:
Along with the research of medical sci-tech antagonism hypertension, antihypertensive drug of new generation comes out gradually, and is widely used in clinical.Non-peptide class vasotonia II acceptor inhibitor, promptly sartans has become antihypertensive generation new drug, and such medicine has remarkable curative effect and good tolerability, and to treatment primary and secondary hypertension, and congestive heart failure has effect preferably.Preparation for sartans has also become the problem of paying close attention to.Telmisartan is a kind of of sartans, and this medical instrument has advantages such as bioavailability height, long half time.About the existing various kinds of document report of the preparation method of telmisartan.J.Med.Chem. (1993), 36 (25), 4040-51 and International Patent Application WO 0063158, CN1412183A, CN1344712A, CN1768044A have announced the synthetic method J.Med.Chem. (1993) of telmisartan, 36 (25), 4040-51 and International Patent Application WO 0063158, US6770762 discloses preparation of 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline and process for purification.Wherein 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline is the intermediate of preparation telmisartan, (but some defectives are arranged with this synthesis technique of making intermediate, yield and purity were not ideal enough when two imidazoles were synthetic in the former technology, next step N alkylated reaction is complete inadequately simultaneously, cause purifying telmisartan difficulty), it is synthetic that the alternative former 2-n-propyl of 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline carries out telmisartan, also help next step N alkylated reaction simultaneously, and do not influence the synthetic and quality of telmisartan.The telmisartan yield that obtains is higher, easier purifying.
Summary of the invention:
Inventor's technical problem to be solved is to overcome above-mentioned weak point, the intermediate of the preparation telmisartan that research and design is new.
The invention provides a kind of preparation telmisartan intermediate 2-n-propyl-4 methyl-6-(tolimidazole 2-yl) benzoglioxaline salt, its structural formula is as follows:
(be dissolved in alcohol (as methyl alcohol. ethanol etc.), water insoluble.
Be hydrolyzed to 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline under the non-alkaline condition.2-n-propyl-4 methyl-6-(methylbenzene, and imidazoles-2-yl) benzoglioxaline salt need could be stablized with highly basic (as: NaOH, KOH etc.) symbiosis.2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt can be applicable to the synthetic of telmisartan.
2-n-propyl of the present invention-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt (mp:198-201 ℃ .) makes by following method:
R is Na, metal ions such as K, or ROH is sodium methylate, sodium ethylate, potassium tert.-butoxide etc.
Temperature of reaction is 20 ℃-100 ℃
The inventive method comprises the following steps:
1,2-n-propyl-4 methyl-6-carboxy benzimidazole and N-methyl-o-phenylenediamine (or its hydrochloride) are that solvent was 100 ℃-160 ℃ reactions 8～20 hours with PPA (polyphosphoric acid) or PPA and methylsulfonic acid or methylsulfonic acid and P2O5, wherein 2-n-propyl-4 methyl-6-carboxy benzimidazole and N-methyl-o-phenylenediamine (or its hydrochloride) are 1: 1.0～1.3: 3～8 with the mol ratio of solvent, generate 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline.Add an amount of distilled water then, add hydrochloric acid to PH=1～2, activated carbon decolorizing is 12～14 regulating PH with mineral alkali ROH or organic bases repeatedly.React 1～5 hour after-filtration under the room temperature, get product 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt.
2, with gained intermediate 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt dissolving crude product in alcohol (methyl alcohol, ethanol, Virahol etc.) reflux 5-10 minute, filtered while hot adds an amount of ROH solution, cooling, crystallization.Both can obtain 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt.ROH is NaOH, inorganic strong alkali or sodium methylates such as KOH, sodium ethylate, organic alkalis such as potassium tert.-butoxide.
The present invention with the reaction of 2-n-propyl-4 methyl-6-carboxy benzimidazole and N-methyl-o-phenylenediamine (or its hydrochloride) after, in treating processes, add excessive alkali (as organic alkalis such as inorganic strong alkali such as NaOH, KOH or sodium methylate, sodium ethylate, potassium tert.-butoxides) and obtain this compound.This compound must with the ROH symbiosis, could keep the stability of this compound, and the ROH needed acid binding agent of next step N alkylated reaction just.
Use intermediate 2-n-propyl of the present invention-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt and 4-brooethyl-2-carboxyl ester biphenyl) the prepared in reaction telmisartan, have following advantage:
1, same raw material, the yield that the inventive method obtains new intermediate is high by 5～10%.
2, easier purifying after processing obtains new intermediate.
3, this intermediate is used for the synthetic of telmisartan, can also reduce next step reaction base consumption.
4, simple to operate, be fit to scale operation.
Embodiment:
Below each example further specify the present invention, but do not impose any restrictions.
Example 1
1, with 100gPPA; 21.8g (0.1mol) 2-n-propyl-4-methyl-6-carboxy benzimidazole and 21.5gN-methyl-o-phenylenediamine add in the reaction flask; under the N2 protection, feed intake; be heated to 100 ℃-160 ℃; reacted 8-20 hour; reduce to 70-80 ℃ and will react adding 200ml water; regulate PH=1～2 with hydrochloric acid, drop into gac 5-8%; 80 ℃ of filtrations in left and right sides 5-10 minute; reaction repeatedly, will regulate PH with NaOH is 12-14, stoichiometric number hour; filter, get intermediate crude product 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline sodium salt.
2, put into 200 milliliters of ethanol with previous step product 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline sodium salt crude product is molten, heating for dissolving, be cooled to room temperature, add 400 milliliters of 1N NaOH, separate out compound 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline sodium salt.50-80 ℃ of vacuum-drying.
3, previous step product 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline sodium salt is dropped into 200 milliliters of dimethyl sulfoxide (DMSO), stir, at room temperature add 4-brooethyl-diphenyl-2-carboxylic acid methyl esters 33.55 grams, stirred 14 hours, with dichloromethane extraction (200,100,100), evaporated under reduced pressure adds 300 ml methanol and 10% potassium hydroxide (240 milliliters 0.6mol) mix backflow 6 hours, cooling, with 80 milliliters of washed with dichloromethane, transfer to PH=6 with glacial acetic acid, separate out a large amount of white wadding precipitations, filter, whitely dry for rice crude product 49.6 grams, in crude product, add 100 milliliters of reflux of chloroform, decolorizing with activated carbon, crystallization, filter, 80 ℃ of vacuum-dryings get white pure product telmisartan (HLPC＞99.0%) 41 grams, refining yield 82%.mp?261～263℃；
1H-NMR(d
6-DMSO)δ1.05t，3H)，1.83(m，2H)，2.71(s，3H)，2.94(t，2H)，3.81(s，3H)，5.57(s，2H)，7.16-7.83(m，14H).C
33H
33N
4O
2
Example 2 preparation telmisartans
1, with 100gPPA; 21.8g (0.1) 2-n-propyl-4 methyl-6-carboxy benzimidazole and 21.5gN-methyl-o-phenylenediamine add in the reaction flask; under the N2 protection, feed intake; be heated to 100 ℃-160 ℃; reacted 8-20 hour; reduce to 70-80 ℃ and will react adding 200ml water; regulate PH=1～2 with hydrochloric acid, drop into gac 5-8%; 80 ℃ of filtrations in left and right sides 5-10 minute; reaction repeatedly, will regulate PH with KOH is 12-14, stoichiometric number hour; filter, get intermediate crude product 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline sylvite.
2, previous step product 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline sylvite crude product is put into 200 milliliters of ethanol, heating for dissolving, be cooled to room temperature, add 400 milliliters of 1N KOH, separate out compound 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline sylvite.50-80 ℃ of vacuum-drying.
3,2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline sylvite and 27.2 gram 4-brooethyl-2-cyanobiphenyls with the previous step preparation, 10.4 gram triethylamine and DMF (DMA, methylene dichloride, ethylene dichloride) mixes, 35-40 degree reaction 5-10 hour, TLC pours reaction solution in frozen water 600 grams into after detecting no raw material, ethyl acetate extraction (300ml*3) merges organic phase, washing (300ml*2), dry, precipitation adds petroleum ether and stirring to solid again and separates out, and gets crude product 45.6 grams.
4, solid 45.6 grams with previous step add 200ml ethylene glycol, 150ml water, 12 gram sodium hydroxide, back flow reaction 10 hours, after TLC detects no raw material, be cooled to room temperature, transferring PH with hydrochloric acid is 5～6, has solid to separate out, filter, washing, the telmisartan crude product, the DMF recrystallization gets the 44.5 gram pure product of telmisartan (HLPC＞99.0%) mp261～263 ℃.
1H-NMR(d
6-DMSO)δ1.05t，3H)，1.83(m，2H)，2.71(s，3H)，2.94(t，2H)，3.81(s，3H)，5.57(s，2H)，7.16-7.83(m，14H).C
33H
33N
4O
2
Example 3
1; with 100gPPA; 21.8g (0.1) 2-n-propyl-4 methyl-6-carboxy benzimidazole and 21.5gN-methyl-o-phenylenediamine add in the reaction flask; under the N2 protection, feed intake; be heated to 100 ℃-160 ℃; reacted 8-20 hour, and reduced to 70-80 ℃ and will react adding 200ml water, regulate pH=1～2 with hydrochloric acid; drop into gac 5-8%;, 80 ℃ of filtrations in left and right sides 5-10 minute, reactions repeatedly; to regulate PH with NaOH is 12～14; stoichiometric number hour filters, intermediate crude product 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline sodium salt.
2, previous step product 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline sodium salt crude product is put into 200 milliliters of Virahols, heating for dissolving, add activated carbon 2 grams, filtered while hot, add 200 ml waters in the filtrate, be cooled to room temperature, separate out compound 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline, filter, 80 degree vacuum-dryings get pure product 26 gram (HLPC＞99.5%) .mp:193-195 ℃ of 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline.
Claims (3)
1. 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt is characterized in that it has following array structure:
R is N
a +Or K
+Metal ion; Be dissolved in alcohol, water insoluble; Under non-alkaline condition, be hydrolyzed to 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline.
2. the preparation method of the described 2-n-propyl of claim 1-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt is characterized in that this method comprises the following steps:
1) 2-n-propyl-4 methyl-6-carboxy benzimidazole and N-methyl-o-phenylenediamine or its hydrochloride are with polyphosphoric acid or polyphosphoric acid and methylsulfonic acid or methylsulfonic acid and P
2O
5Be solvent, wherein the mol ratio of 2-n-propyl-4 methyl-6-carboxy benzimidazole and N-methyl-o-phenylenediamine or its hydrochloride and solvent is 1: 1.0～1.3: 3～8; 100 ℃-160 ℃ reactions 8-20 hour, generate 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglyoxaline, add an amount of distilled water then, add hydrochloric acid to pH be 1～2, activated carbon decolorizing repeatedly, regulating pH with alkali again is 12～14, reacts 1～5 hour after-filtration, gets product 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt;
2) with gained intermediate 2-n-propyl 4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt dissolving crude product in methyl alcohol, ethanol or Virahol, reflux 5-10 minute, filtered while hot, add NaOH or KOH, cooling, crystallization is filtered, and obtains 2-n-propyl-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt; The add-on of described NaOH or KOH and 2-n-propyl 4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt is 1-10: 1 mol ratio.
3. according to the preparation method of the described 2-n-propyl of claim 2-4 methyl-6-(tolimidazole-2-yl) benzoglioxaline salt, it is characterized in that this method steps 1) described alkali is NaOH, KOH, sodium methylate, sodium ethylate or potassium tert.-butoxide.
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| JP6210599B2 (en) * | 2014-02-26 | 2017-10-11 | 株式会社トクヤマ | Process for producing 4-methyl-6 (1-methylbenzimidazol-2-yl) -2-n-propyl-1H-benzimidazole |
| CN104974096B (en) * | 2015-07-07 | 2019-02-01 | 威海迪素制药有限公司 | A kind of 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 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| WO2005108375A1 (en) * | 2004-05-11 | 2005-11-17 | Cipla Limited | Process for the preparation of telmisartan |
| 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 |
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2006
- 2006-11-01 CN CN200610117824A patent/CN101172968B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
| WO2005108375A1 (en) * | 2004-05-11 | 2005-11-17 | Cipla Limited | Process for the preparation of telmisartan |
Non-Patent Citations (2)
| Title |
|---|
| 常选妞等.替米沙坦的合成工艺改进.精细化工23 7.2006,23(7),661-663. |
| 常选妞等.替米沙坦的合成工艺改进.精细化工23 7.2006,23(7),661-663. * |
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