CN104478818A - Synthetic method of 2-(1-hydro-4-tetrazole)-4'-methyl diphenyl - Google Patents
Synthetic method of 2-(1-hydro-4-tetrazole)-4'-methyl diphenyl Download PDFInfo
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- CN104478818A CN104478818A CN201410749707.2A CN201410749707A CN104478818A CN 104478818 A CN104478818 A CN 104478818A CN 201410749707 A CN201410749707 A CN 201410749707A CN 104478818 A CN104478818 A CN 104478818A
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- methyl diphenyl
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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Abstract
The invention discloses a synthetic method of 2-(1-hydro-4-tetrazole)-4'-methyl diphenyl. The method comprises the following steps: by taking 2-carboxyl-4'-methyl diphenyl as a raw material, reacting with benzene sulfonamide under a high-temperature melting condition; subsequently adding ammonium acetate and reacting again at the high-temperature melting condition to prepare 2-amidino-4'-methyl diphenyl; afterwards allowing 2-amidino-4'-methyl diphenyl and hydrazine hydrate to have a substitution reaction to prepare 4'-methyl-[1,1'-diphenyl]-2-formamide hydrazide; finally allowing 4'-methyl-[1,1'-diphenyl]-2-formamide hydrazide and sodium nitrite to have a cyclization reaction to prepare 2-(1-hydro-4-tetrazole)-4'-methyl diphenyl. The synthetic method disclosed by the invention is mild in reaction condition, simple and convenient to operate and suitable for industrial production; carboxylic acid is creatively used for replacing nitrile as a raw material; the use of a highly-toxic and easily-explosive reagent is avoided, such as a reagent like sodium azide; the raw materials are easy to obtain and safe; convenience is provided for production management; the cost is relatively low; pollution of three wastes is reduced.
Description
Technical field
The present invention relates to the synthetic method of a kind of 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl.
Background technology
2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl (I) is the key intermediate of synthetic vessel Angiotensin Ⅱ antagonism class medicine, as losartan, telmisartan, valsartan, Irb etc.The features such as this type of medicine has efficiently, safety, better tolerance, target-organ protection, growth momentum is powerful, has a extensive future.Therefore, the improvement of 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl synthesis technique all has very important significance to the study on the synthesis of whole sartans and production.
For the synthesis of tetrazole, classical way is that nitrile is at Me
3snCl
3or (n-Bu)
3-SnCl
3naN is used under catalysis
3preparation, but NaN
3belong to poisonous reagent, and very easily explode.In addition, Me
3snCl
3or (n-Bu)
3-SnCl
3belong to poisonous reagent, in finished product, have heavy-metal residual, the application in drug manufacture is very prudent.Many scientific workers have paid unremitting effort for this reason, and in prior art, the chemosynthesis of tetrazole compound prepares in organic solvent with amine or amine salt catalysts.But cannot break away from all the time with nitrile is that tetrazole is prepared in raw material and sodium azide reaction, and raw material transport and keeping all exist potential safety hazard, and the application in drug manufacture is very inconvenient.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of safety, high yield, highly purified 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl.
Technical solution of the present invention is:
A kind of 2-(1-hydrogen-4-tetrazolium)-4 ' synthetic method of-methyl diphenyl, it is characterized in that: comprise the following steps: with 2-carboxyl-4 '-methyl diphenyl is raw material, react under high-temperature fusion condition with benzsulfamide, then add under ammonium acetate continues high-temperature fusion condition and react, obtained 2-amidino groups-4 '-methyl diphenyl; Then 2-amidino groups-4 '-methyl diphenyl and hydrazine hydrate generation substitution reaction, obtained 4'-methyl-[1,1'-biphenyl]-2-methane amide hydrazides; Last 4'-methyl-[1,1'-biphenyl]-2-methane amide hydrazides and Sodium Nitrite generation cyclization are obtained by reacting 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl.
2-carboxyl-4 ' temperature of reaction of-methyl diphenyl and benzsulfamide is 230 DEG C, adding the temperature of reaction after ammonium acetate is 180 DEG C.
2-amidino groups-4 ' solvent of-methyl diphenyl and hydrazine hydrate generation substitution reaction is methyl alcohol, ethanol or the trimethyl carbinol.
4'-methyl-[1,1'-biphenyl]-2-methane amide hydrazides and the acid used of Sodium Nitrite generation ring-closure reaction are acetic acid, hydrochloric acid or sulfuric acid, and solvent used is water, ethanol or acetic acid.
Reaction conditions of the present invention is gentle, easy and simple to handle, is applicable to suitability for industrialized production.
The present invention is also advantageous in that: avoid using nitrile to be raw material, but the carboxylic acid that employs of novelty is raw material; Avoid and use severe toxicity and the use of explosive reagent, as reagent such as sodium azides; Raw material is easy to get, safety, is convenient to production management; Cost is lower, reduces three-waste pollution.
Below in conjunction with embodiment, the invention will be further described.
Embodiment
2-amidino groups-4 ' preparation (III) of-methyl diphenyl
By 2-carboxyl-4 '-methyl diphenyl (106.12g, 0.50mol) and benzsulfamide (157.19g, 1.00mol) be placed in reaction flask, heating and melting, and start stirring, continue to be warming up to 230 DEG C, continue stirring reaction 1h.Then add 400g ammonium acetate, temperature is down to 180 DEG C and is continued reaction 4h, is poured into by reaction solution in large water gaging, filtration under diminished pressure removing insolubles, filtrate is adjusted pH to 8-10 with ammoniacal liquor, separates out white solid, filtration under diminished pressure, dry, obtain white solid (63.88g, productive rate 60.8%).
1H NMR (400 MHz, DMSO, ppm) δ: 7.31-7.44 (m, 6H), 7.20 (d, 2H), 6.06(s,3H), 2.33（s，3H）。
The preparation of 4'-methyl-[1,1'-biphenyl]-2-methane amide hydrazides (IV)
Compound III (42.02g, 0.20mol) is placed in reaction flask, adds 200mL dehydrated alcohol, stirring and dissolving, then add 16.7mL concentrated hydrochloric acid, add 80% hydrazine hydrate (25.00g, 0.40mol), heating reflux reaction 4h.Revolve and steam except desolventizing, add methylene dichloride and dissolve, then instill in a large amount of ethyl acetate, separate out white solid, filtration under diminished pressure, dry, obtain white solid (43.22g, productive rate 96.1%).
1H NMR (400 MHz, DMSO, ppm) δ: 7.30-7.42 (m, 6H), 7.18 (d, 2H), 5.31(s,2H)，4.63(s，2H)，2.33(s，2H)。
The preparation of 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl (I)
Compounds Ⅳ (22.51g, 0.10mol) is placed in reaction flask, adds 200mL acetic acid, stirring and dissolving, be added dropwise to Sodium Nitrite (10.35g, 0.15mol) aqueous solution 50mL, drip and continue reaction 1h.Reaction solution is poured in large water gaging, separate out solid particulate, filtration under diminished pressure, dry, obtain white solid (23.14g, 98.1%).
1H NMR (400 MHz, DMSO, ppm) δ: 10.96(s, 1H), 9.31 (d, 1H), 7.57(m,2H)，7.41(d，1H)，7.30(d，2H)，7.18(d,2H)，2.45(s,3H)。
Claims (4)
1. a 2-(1-hydrogen-4-tetrazolium)-4 ' synthetic method of-methyl diphenyl, it is characterized in that: comprise the following steps: with 2-carboxyl-4 '-methyl diphenyl is raw material, react under high-temperature fusion condition with benzsulfamide, then add under ammonium acetate continues high-temperature fusion condition and react, obtained 2-amidino groups-4 '-methyl diphenyl; Then 2-amidino groups-4 '-methyl diphenyl and hydrazine hydrate generation substitution reaction, obtained 4'-methyl-[1,1'-biphenyl]-2-methane amide hydrazides; Last 4'-methyl-[1,1'-biphenyl]-2-methane amide hydrazides and Sodium Nitrite generation cyclization are obtained by reacting 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl.
2. the synthetic method of 2-according to claim 1 (1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl, is characterized in that: 2-carboxyl-4 ' temperature of reaction of-methyl diphenyl and benzsulfamide is 230 DEG C, adding the temperature of reaction after ammonium acetate is 180 DEG C.
3. the synthetic method of 2-according to claim 1 and 2 (1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl, is characterized in that: 2-amidino groups-4 ' solvent of-methyl diphenyl and hydrazine hydrate generation substitution reaction is methyl alcohol, ethanol or the trimethyl carbinol.
4. the synthetic method of 2-according to claim 1 and 2 (1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl, it is characterized in that: 4'-methyl-[1,1'-biphenyl]-2-methane amide hydrazides and the acid used of Sodium Nitrite generation ring-closure reaction is acetic acid, hydrochloric acid or sulfuric acid, solvent used is water, ethanol or acetic acid.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892535A (en) * | 2015-06-03 | 2015-09-09 | 启东东岳药业有限公司 | Synthesis method of 5-(4'-methyl-[1,1'-biphenyl]-2-yl)-1-hydro-tetrazole |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0711762A1 (en) * | 1994-05-16 | 1996-05-15 | Sumitomo Chemical Company Limited | Process for producing tetrazole compound and intermediate therefor |
| CN102060798A (en) * | 2011-01-04 | 2011-05-18 | 复旦大学 | Method for synthesizing 2-(1-hydro-4-tetrazole)-4'-methylbiphenyl and derivatives thereof |
| CN102911129A (en) * | 2012-11-15 | 2013-02-06 | 江苏阿尔法药业有限公司 | Method for preparing substituted tetrazole compound |
| CN104892535A (en) * | 2015-06-03 | 2015-09-09 | 启东东岳药业有限公司 | Synthesis method of 5-(4'-methyl-[1,1'-biphenyl]-2-yl)-1-hydro-tetrazole |
-
2014
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0711762A1 (en) * | 1994-05-16 | 1996-05-15 | Sumitomo Chemical Company Limited | Process for producing tetrazole compound and intermediate therefor |
| CN102060798A (en) * | 2011-01-04 | 2011-05-18 | 复旦大学 | Method for synthesizing 2-(1-hydro-4-tetrazole)-4'-methylbiphenyl and derivatives thereof |
| CN102911129A (en) * | 2012-11-15 | 2013-02-06 | 江苏阿尔法药业有限公司 | Method for preparing substituted tetrazole compound |
| CN104892535A (en) * | 2015-06-03 | 2015-09-09 | 启东东岳药业有限公司 | Synthesis method of 5-(4'-methyl-[1,1'-biphenyl]-2-yl)-1-hydro-tetrazole |
Non-Patent Citations (1)
| Title |
|---|
| JEAN BOIVIN ET AL.: "A Practical Synthesis of 5-Substituted Tetrazoles", 《TETRAHEDRON》, vol. 51, no. 43, 31 December 1995 (1995-12-31), pages 11737 - 11742, XP005254758, DOI: doi:10.1016/0040-4020(95)00725-N * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892535A (en) * | 2015-06-03 | 2015-09-09 | 启东东岳药业有限公司 | Synthesis method of 5-(4'-methyl-[1,1'-biphenyl]-2-yl)-1-hydro-tetrazole |
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| CN104478818B (en) | 2016-04-13 |
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