CN102060798A - Method for synthesizing 2-(1-hydro-4-tetrazole)-4'-methylbiphenyl and derivatives thereof - Google Patents
Method for synthesizing 2-(1-hydro-4-tetrazole)-4'-methylbiphenyl and derivatives thereof Download PDFInfo
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- CN102060798A CN102060798A CN2011100005393A CN201110000539A CN102060798A CN 102060798 A CN102060798 A CN 102060798A CN 2011100005393 A CN2011100005393 A CN 2011100005393A CN 201110000539 A CN201110000539 A CN 201110000539A CN 102060798 A CN102060798 A CN 102060798A
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- tetrazole
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Abstract
The invention belongs to the technical field of medicinal chemistry, in particular to a method for synthesizing 2-(1-hydro-4-tetrazole)-4'-methylbiphenyl as key intermediates of Sartan medicament and derivatives thereof. According to the invention, commercially available o-halophenyl nitrile or o-biphenyl nitrile derivatives are used as raw materials and react with hydrazine hydrate in a protic solvent to obtain the 2-(1-hydro-4-tetrazole)-4'-methylbiphenyl and derivatives thereof through [3+2] cycloaddition reactions. The method provided by the invention has mild reaction conditions and low cost, is easy to operate, is green and friendly to the environment and is applicable to industrial production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, being specifically related to is synthetic method suc as formula the sartans key intermediate 2-shown in the I (1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl and derivative thereof.
Background technology
Sartans is to act on feritin--the Angiotensin of hypertensin system; have efficient, long-acting, safe, can be oral, characteristics such as better tolerance, target-organ protection; share of market improves constantly, and becomes on 21st century market one of the most potential antihypertensive drugs.And 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl (I) is the requisite key intermediates of medicine such as synthetic network sand is smooth, valsartan, irbesartan, Olmesartan, so 2-(1-hydrogen-4-tetrazolium)-4 '-methyl diphenyl and derivative thereof
IThe improvement of synthesis technique to the study on the synthesis of whole sartans and produce and all have very important significance.
R in the formula
1Be phenyl, 4 '-aminomethyl phenyl, 4 '-ethylphenyl, 4 '-the propyl group phenyl, 4 '-2-bromomethylphenyl, 4 '-chloromethyl phenyl, 4 '-hydroxymethyl phenyl, 4 '-bromophenyl, 4 '-chloro-phenyl-, halogen atoms such as fluorine, chlorine, bromine, iodine, C
3-C
6Cycloalkyl, C
2-C
6Thiazolinyl, aryl or optional position C
1-C
3Substituted aryl, halogenated aryl, hydroxyalkyl aryl.R
2Be C
1-C
6Alkyl, C
3-C
6Cycloalkyl, aryl.
For synthesizing of tetrazole, classical way is at Me
3Sn Cl
3Or (n-Bu)
3-Sn Cl
3Use NaN under the catalysis
3Preparation, but Me
3SnCl
3Or (n-Bu)
3-Sn Cl
3Belong to poisonous reagent, often have the heavy-metal residual of trace in finished product, the application in drug manufacture is inconvenience very; After scientist's unremitting effort, United States Patent (USP) (US5206474A) is used anhydrous ZnCl
2With LiCl be that catalyzer substitutes above-mentioned catalyzer; Your fortune of back Qi, Zhang Huibin or the like use NH instead
4Cl and triethylamine hydrochloride are catalyzer, have received comparatively satisfied yield; But can't break away from the use of sodium azide all the time, there are potential safety hazard in raw material transportation and keeping, and three wastes problem is outstanding, does not meet the cleaner production requirement.
Summary of the invention
It is not enough and the industrialized process for preparing of a kind of safe, high yield, highly purified 2-(1-hydrogen-4-tetrazole)-4 '-methyl diphenyl and derivative thereof is provided that the object of the invention is to overcome prior art.
The present invention is a raw material with adjacent cyano group substituted benzene (II), addition reaction (nucleophilic reaction) to aromatic ring cyano group takes place under protic solvent and acidic conditions, then under heating condition with the hydrazine hydrate effect, under Sodium Nitrite and acid participation, make aryl tetrazole and derivatives I thereof, yield>60% at last through [3+2] cycloaddition reaction (ring closure reaction).Its synthetic route is as follows:
R in the formula
1Be phenyl, 4 '-aminomethyl phenyl, 4 '-ethylphenyl, 4 '-the propyl group phenyl, 4 '-2-bromomethylphenyl, 4 '-chloromethyl phenyl, 4 '-hydroxymethyl phenyl, 4 '-bromophenyl, 4 '-chloro-phenyl-, halogen atoms such as fluorine, chlorine, bromine, iodine, C
3-C
6Cycloalkyl, C
2-C
6Thiazolinyl, aryl or optional position C
1-C
3Substituted aryl, halogenated aryl, hydroxyalkyl aryl.R
2Be C
1-C
6Alkyl, C
3-C
6Cycloalkyl, aryl.
Among the present invention, the solvent that uses is various nucleophilic protic solvents, as: methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, water, formic acid or acetate, or these nucleophilic protic solvents and various polar solvent: acetonitrile, methylene dichloride, tetrahydrofuran (THF), N, any mixing of dinethylformamide, N,N-dimethylacetamide.
Among the present invention, the used acid of nucleophilic reaction reaction is mineral acid, as HBr, HCl, HI or HF etc., or is Lewis acid, as AlCl
3, ZnCl
2Or FeCl
3Deng.
Among the present invention, the temperature of hydrazine hydrate substituted alcoxyl radical reaction is a reflux temperature.
Among the present invention, the salt that ring closure reaction uses is Sodium Nitrite, potassium nitrite or inferior ammonium nitrate.
Among the present invention, the acid that ring closure reaction uses is hydrochloric acid, acetic acid, Hydrogen bromide, hydroiodic acid HI, or perchloric acid etc.
Among the present invention, process ring closure reaction temperature is-10-50 ℃.
Reaction conditions gentleness of the present invention, easy and simple to handle, the total recovery height is fit to suitability for industrialized production.
Advantage of the present invention:
1, raw material be easy to get, safety, be easy to production management;
2, simple to operate, reduce impurity and generate, improve the purity and the yield of product;
3, reduce cost, reduce three-waste pollution.
Embodiment
Following embodiment illustrates content of the present invention better.But the invention is not restricted to following embodiment.
Embodiment 1:
With 2-(4'-tolyl) benzene nitrile (125.6g, 0.65 mol), saturated HCl methanol solution (31.6ml, 0.78mol) place reaction flask, stirred 1 hour in 5 ℃, after be warming up to 35 ℃ of stirrings, add the 30mol methylene dichloride after 3 hours, continue reaction 5 hours, pressure reducing and steaming residual salts acid gas, concentration of reaction solution adds ether 850ml in residuum, stirring at room 30 minutes has crystal to separate out.Filter, filter cake washs with ether, and vacuum-drying gets compound III 117g(80%).1H?NMR?(CDCl
3):?δ=?2.38?(?s, 3?H,?CH
3?),?3.38?(?s, 3?H,?CH
3),?7.02-7.37(m,?8H,?2Ar?),?8.05?(?s,?2H,?NH
2?)。
With compound III (11.5g, 0.052mol) acetonitrile (380ml) and hydrazine hydrate (5g, 1.85 equivalent) add reaction flask, stirring and refluxing 12 hours is cooled to room temperature, add 0.1mol/L NaOH solution and regulate pH value to neutral, tell organic layer, concentrating under reduced pressure, drying, get compound IV 10.1g(87%), 1H NMR (CDCl
3): δ=2.05 (s, H, NH), 2.15 (s, H, NH
2), 2.38 (s, 3 H, CH
3), 3.42 (s, 3 H, CH
3), 7.01-7.43 (m, 8H, 4Ar), 8.09 (s, 2H, NH
2).
With compound IV (14.6g, 0.065mol), 50ml 10N HCl, 100ml ethanol adds reaction flask, heated and stirred makes the III dissolving, and ice bath is cooled to 10 ℃, stirs fast down, in 30 minutes, sodium nitrite in aqueous solution (7g prepares) is added dropwise to reaction flask in 15mL water, continues temperature control and stirred 1 hour.Place 5 minutes after-filtration, filtrate is spin-dried for, and gets target compound I 15.3g(90%).1H?NMR?(CDCl
3):?δ=?2.37?(?s, 3?H,?CH
3),?7.02-7.37(m,?8H,?4Ar?),?8.05?(?s,?H,?NH)。
Embodiment 2:
With 2-(4'-tolyl) benzene nitrile (125.6g, 0.65 mol), saturated HBr methanol solution (31.6ml, 0.78mol) place reaction flask, stirred 1 hour in 0 ℃, after be warming up to 35 ℃ of stirrings, add the 30mol methylene dichloride after 3 hours, continue reaction 6 hours, pressure reducing and steaming residue HBr gas, concentration of reaction solution adds ether 850ml in residuum, stirring at room 30 minutes has crystal to separate out.Filter, filter cake washs with ether, and vacuum-drying gets compound III 112g(78%).1H NMR is the same.
With compound III (11.5g, 0.052mol) and hydrazine hydrate (10g, 2.7 equivalent) add reaction flask, stirring and refluxing 15 hours is cooled to room temperature, add 0.1mol/L NaOH solution and regulate pH value to neutral, tell organic layer, concentrating under reduced pressure, drying, get compound IV 9.1g(81%), 1H NMR is the same.
With compound IV (14.6g, 0.065mol), 50ml 10N HBr, 100ml methyl alcohol adds reaction flask, heated and stirred makes the III dissolving, and ice bath is cooled to 10 ℃, stirs fast down, in 30 minutes, the ammonium nitrite aqueous solution (7g prepares) is added dropwise to reaction flask in 15mL water, continues temperature control and stirred 1 hour.Place 5 minutes after-filtration, filtrate is spin-dried for, and gets target compound I 15.1g(89%).1H NMR is the same.
Embodiment 3:
With 2-chloro-benzene nitrile (89g, 0.65 mol), saturated HCl ethanol liquid (31.6ml, 0.78mol) place reaction flask, stirred 1 hour in 5 ℃, after be warming up to 35 ℃ of stirrings, add the 30mol acetonitrile after 3 hours, continue reaction 5 hours, pressure reducing and steaming residual salts acid gas, concentration of reaction solution adds ether 850ml in residuum, stirring at room 25 minutes has crystal to separate out.Filter, filter cake washs with ether, and vacuum-drying gets compound III 101g(85%).1H?NMR?(CDCl
3):?δ=?1.35?(?m, 3?H,?CH
3?),?3.58?(?m, 2?H,?CH
2),?7.01-7.38(m,?4H,?Ar?),?8.05?(?s,?H,?NH?)?。
With compound III (9.5g, 0.052mol) and hydrazine hydrate (5g, 1.85 equivalent) add reaction flask, stirring and refluxing 12 hours is cooled to room temperature, add 0.1mol/L NaOH solution and regulate pH value to neutral, tell organic layer, concentrating under reduced pressure, drying, get compound IV 7.8g(89%), 1H NMR (CDCl
3): δ=2.05 (s, H, NH), 2.15 (s, H, NH
2), 7.01-7.43 (m, 8H, 4Ar), 8.09 (s, H, NH).
With compound IV (11g, 0.065mol), 50ml 10N HCl, 100ml ethanol adds reaction flask, heated and stirred makes the IV dissolving, and ice bath is cooled to 10 ℃, stirs fast down, in 30 minutes, the ammonium nitrite aqueous solution (7g prepares) is added dropwise to reaction flask in 15mL water, continues temperature control and stirred 1 hour.Place 5 minutes after-filtration, filtrate is spin-dried for, and gets target compound I 10.8g(92%).1H?NMR?(CDCl
3):?δ=?7.05-7.36(m,?4H,?Ar?),?8.01?(?s,?H,?NH)。
Claims (4)
1. the synthetic method of a 2-(1-hydrogen-4-tetrazole)-4 '-methyl diphenyl and derivative I thereof,
R in the formula
1Be phenyl, 4 '-aminomethyl phenyl, 4 '-ethylphenyl, 4 '-the propyl group phenyl, 4 '-2-bromomethylphenyl, 4 '-chloromethyl phenyl, 4 '-hydroxymethyl phenyl, 4 '-bromophenyl, 4 '-chloro-phenyl-, fluorine, chlorine, bromine, iodine halogen atom, C
3-C
6Cycloalkyl, C
2-C
6Thiazolinyl, aryl or optional position C
1-C
3Substituted aryl, halogenated aryl, hydroxyalkyl aryl; R
2Be C
1-C
6Alkyl, C
3-C
6Cycloalkyl, aryl;
It is characterized in that concrete steps are:
With adjacent cyano group substituted benzene is raw material, nucleophilic reaction to aromatic ring cyano group takes place under protic solvent and acidic conditions, then under heating condition with the hydrazine hydrate effect, at last under salt and acid participate in through [3+2] ring ring closure reaction, make aryl tetrazole and derivatives I thereof, yield>60%;
Wherein, the solvent that nucleophilic reaction is used is the nucleophilic protic solvent: methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, water, formic acid or acetate, or nucleophilic protic solvent and following polar solvent: acetonitrile, methylene dichloride, tetrahydrofuran (THF), N, any mixing of dinethylformamide, N,N-dimethylacetamide;
The temperature of hydrazine hydrate substituted alcoxyl radical reaction is a reflux temperature; The ring closure reaction temperature is-10-50 ℃.
2. synthetic method according to claim 1 is characterized in that the used acid of nucleophilic reaction is mineral acid: HBr, HCl, HI or HF, perhaps is Lewis acid: AlCl
3, ZnCl
2Or FeCl
3
3. synthetic method as claimed in claim 1 or 2, its feature exists
InThe salt that ring closure reaction uses is Sodium Nitrite, potassium nitrite or inferior ammonium nitrate.
4. as synthetic method as described in the claim 3, it is characterized in that the acid that ring closure reaction uses is hydrochloric acid, acetic acid, Hydrogen bromide, hydroiodic acid HI or perchloric acid.
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
CN103351352A (en) * | 2013-07-15 | 2013-10-16 | 南通市华峰化工有限责任公司 | Novel synthetic method for 5-phenyl tetrazole |
CN103804354A (en) * | 2012-11-08 | 2014-05-21 | 天津药物研究院 | Dabigatran preparation method |
CN104478818A (en) * | 2014-12-10 | 2015-04-01 | 启东东岳药业有限公司 | Synthetic method of 2-(1-hydro-4-tetrazole)-4'-methyl diphenyl |
Citations (2)
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 |
US6255327B1 (en) * | 1998-02-01 | 2001-07-03 | Boehringer Ingelheim Pharma Kg | Diphenyl-substituted heterocycles, processes for preparing them and their use as pharmaceutical compositions |
-
2011
- 2011-01-04 CN CN2011100005393A patent/CN102060798A/en active Pending
Patent Citations (2)
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 |
US6255327B1 (en) * | 1998-02-01 | 2001-07-03 | Boehringer Ingelheim Pharma Kg | Diphenyl-substituted heterocycles, processes for preparing them and their use as pharmaceutical compositions |
Non-Patent Citations (1)
Title |
---|
JEAN BOIVIN ET AL.: "A Practical Synthesis of 5-substituted Tetrazoles.", 《TETRAHEDRON》 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103804354A (en) * | 2012-11-08 | 2014-05-21 | 天津药物研究院 | Dabigatran preparation method |
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 |
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 |
CN103351352A (en) * | 2013-07-15 | 2013-10-16 | 南通市华峰化工有限责任公司 | Novel synthetic method for 5-phenyl tetrazole |
CN103351352B (en) * | 2013-07-15 | 2015-10-21 | 南通市华峰化工有限责任公司 | A kind of 5-phenyl tetrazole novel synthesis |
CN104478818A (en) * | 2014-12-10 | 2015-04-01 | 启东东岳药业有限公司 | Synthetic method of 2-(1-hydro-4-tetrazole)-4'-methyl diphenyl |
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Application publication date: 20110518 |