CN104478818B - The synthetic method of 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl - Google Patents
The synthetic method of 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl Download PDFInfo
- Publication number
- CN104478818B CN104478818B CN201410749707.2A CN201410749707A CN104478818B CN 104478818 B CN104478818 B CN 104478818B CN 201410749707 A CN201410749707 A CN 201410749707A CN 104478818 B CN104478818 B CN 104478818B
- Authority
- CN
- China
- Prior art keywords
- methyl
- methyl diphenyl
- tetrazolium
- hydrogen
- diphenyl
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
Abstract
The invention discloses the synthetic method of a kind of 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl, 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 ˊ-methyl-[1,1 ˊ-biphenyl]-2-imines is for formyl hydrazine; Last 4 ˊ-methyl-[1,1 ˊ-biphenyl]-2-imines is obtained by reacting 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl for formyl hydrazine and Sodium Nitrite generation cyclization.Reaction conditions of the present invention is gentle, easy and simple to handle, is applicable to suitability for industrialized production; 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.
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-imines is for formyl hydrazine; Last 4'-methyl-[1,1'-biphenyl]-2-imines is obtained by reacting 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl for formyl hydrazine and Sodium Nitrite generation cyclization.
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-imines is acetic acid, hydrochloric acid or sulfuric acid for formyl hydrazine and the acid used of Sodium Nitrite generation ring-closure reaction, 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%).
1HNMR(400MHz,DMSO,ppm)δ:7.31-7.44(m,6H),7.20(d,2H),6.06(s,3H),2.33(s，3H)。
4'-methyl-[1,1'-biphenyl]-2-imines is for the preparation of formyl hydrazine (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%).
1HNMR(400MHz,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%).
1HNMR(400MHz,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-imines is for formyl hydrazine; Last 4'-methyl-[1,1'-biphenyl]-2-imines is obtained by reacting 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl for formyl hydrazine and Sodium Nitrite generation cyclization.
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-imines is acetic acid, hydrochloric acid or sulfuric acid for formyl hydrazine and the acid used of Sodium Nitrite generation ring-closure reaction, solvent used is water, ethanol or acetic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410749707.2A CN104478818B (en) | 2014-12-10 | 2014-12-10 | The synthetic method of 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410749707.2A CN104478818B (en) | 2014-12-10 | 2014-12-10 | The synthetic method of 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104478818A CN104478818A (en) | 2015-04-01 |
| CN104478818B true CN104478818B (en) | 2016-04-13 |
Family
ID=52753449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410749707.2A Active CN104478818B (en) | 2014-12-10 | 2014-12-10 | The synthetic method of 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104478818B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892535B (en) * | 2015-06-03 | 2017-03-22 | 启东东岳药业有限公司 | Synthesis method of 5-(4'-methyl-[1,1'-biphenyl]-2-yl)-1-hydro-tetrazole |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2167384A1 (en) * | 1994-05-16 | 1995-11-23 | Hideki Ushio | 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 |
| CN102911129B (en) * | 2012-11-15 | 2015-02-18 | 江苏阿尔法药业有限公司 | Method for preparing substituted tetrazole compound |
| CN104892535B (en) * | 2015-06-03 | 2017-03-22 | 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
- 2014-12-10 CN CN201410749707.2A patent/CN104478818B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104478818A (en) | 2015-04-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zlotin et al. | Recent advances in synthesis of organic nitrogen–oxygen systems for medicine and materials science | |
| Chen et al. | The palladium-catalyzed desulfitative cyanation of arenesulfonyl chlorides and sodium sulfinates | |
| Galenko et al. | Fe (II)/Au (I) relay catalyzed propargylisoxazole to pyridine isomerization: Access to 6-halonicotinates | |
| KR20210099079A (en) | Method for preparing N-phenylpyrazole-1-carboxamide | |
| Jing et al. | Lanthanide-catalyzed cyclocarbonylation and cyclothiocarbonylation: a facile synthesis of benzannulated 1, 3-diheteroatom five-and six-membered heterocycles | |
| Muñoz et al. | Application of flow chemistry to the reduction of nitriles to aldehydes | |
| Brahim et al. | Conditions for palladium-catalyzed direct arylations of 4-bromo and 4-iodo N-substituted pyrazoles without C–Br or C–I bond cleavage | |
| CN104478818B (en) | The synthetic method of 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl | |
| Bollikolla et al. | Advances in synthesis and biological activities of benzotriazole analogues: A micro review | |
| Saha et al. | Practical application of PhI (OAc) 2/I2 combination to synthesize benzimidazoles from 2-aminobenzylamine through ring distortion strategy | |
| CN102060798A (en) | Method for synthesizing 2-(1-hydro-4-tetrazole)-4'-methylbiphenyl and derivatives thereof | |
| CN104086456B (en) | A kind of synthetic method of sartanbiphenyl | |
| CN103992302A (en) | Synthesis process of 2-thiopheneacetic acid | |
| JP5881837B2 (en) | Method for deprotecting tetrazole compounds | |
| Myznikov et al. | Tetrazoles: LVI. Synthesis of 5-substituted tetrazoles under microwave activation in the presence of heterogeneous catalyst (zinc oxide). | |
| CN103450084B (en) | Preparation method of fluazolate as herbicide | |
| Vedpathak et al. | An improved and convenient route for the synthesis of 5-methyl-1H-tetrazol-1-yl substituted benzenamines | |
| CN102690207B (en) | Gabapentin synthesizing method | |
| CN104003903B (en) | The synthetic method of sartanbiphenyl | |
| CN102977027B (en) | Preparation method of 5-aryl-3-trifluoromethyl-1H-pyrazole compound | |
| CN106243010A (en) | A kind of preparation method of 4 nitroindolines | |
| CN108299303B (en) | Novel synthesis method of tetraarylpyrazole compound | |
| CN102911129B (en) | Method for preparing substituted tetrazole compound | |
| CN104557725A (en) | One-pot synthesis method of 1,2-diarylbenzimidazole and derivatives thereof | |
| Shuangxia et al. | An efficient and green synthetic route to losartan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |