CN102145297A - Solid acid catalyst and method for catalytic synthesis of 5-substituted tetrazole by solid acid catalyst - Google Patents

Solid acid catalyst and method for catalytic synthesis of 5-substituted tetrazole by solid acid catalyst Download PDF

Info

Publication number
CN102145297A
CN102145297A CN 201110032549 CN201110032549A CN102145297A CN 102145297 A CN102145297 A CN 102145297A CN 201110032549 CN201110032549 CN 201110032549 CN 201110032549 A CN201110032549 A CN 201110032549A CN 102145297 A CN102145297 A CN 102145297A
Authority
CN
China
Prior art keywords
solid acid
ethyl acetate
acid catalyst
catalyst
substituted tetrazole
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
Application number
CN 201110032549
Other languages
Chinese (zh)
Inventor
范青明
赵海龙
方建兵
李细英
盛金火
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ZHEJIANG KINGLYUAN PHARMACEUTICAL Co Ltd
Original Assignee
ZHEJIANG KINGLYUAN PHARMACEUTICAL Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by ZHEJIANG KINGLYUAN PHARMACEUTICAL Co Ltd filed Critical ZHEJIANG KINGLYUAN PHARMACEUTICAL Co Ltd
Priority to CN 201110032549 priority Critical patent/CN102145297A/en
Publication of CN102145297A publication Critical patent/CN102145297A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention discloses a solid acid catalyst, which is characterized by taking bisulfate as an active ingredient and SiO2, ZnO, TiO2, ZrO2, Fe2O3, diatomite or active carbon as a carrier, wherein the loading amount of the active ingredients of the solid acid catalyst is 5 to 50wt%; and the bisulfate is ammonium bisulfate, sodium bisulfate or potassium bisulfate; the method of solid acid for the catalytic synthesis of 5-substituted tetrazole comprises the steps of: using nitrile compound and sodium azide as raw material and solid acid as catalyst, reacting for 8 to 72 hours in organic solvent at 120 to 160 DEG C, post-treating the reaction liquid to obtain the 5-substituted tetrazole; the solid acid catalyst of the invention has the advantages of moderate application conditions, high activity, simple preparation and no environmental pollution; and the process of the invention for synthesizing the 5-substituted tetrazole is simple and safe, easy in operation, high in yield, environmentally-friendly and suitable for industrial production.

Description

The method of a kind of solid acid catalyst and catalytic synthesis of 5-substituted tetrazole thereof
(1) technical field
The present invention relates to a kind of synthetic method of 5-substituted tetrazole, particularly a kind of method of solid acid catalyst catalytic synthesis of 5-substituted tetrazole.
(2) background technology
Tetrazole compound is the important intermediate of organic synthesis, can be used to synthetic medicine, agricultural chemicals, photosensitive material and industrial products such as blowing agent.The 5-substituted tetrazole has significant biologically active, be usually used in the modification transformation of cephalosporins, angiotensin receptor inhibitor and antineoplastic etc., tetrazole compound is more and more in the application of field of medicaments in recent years, and bright development prospect is arranged.
The synthetic method of 5-substituted tetrazole has a lot, to make under the condition of catalyst synthetic tetrazole compound be classic methods make solvent, acid (as glacial acetic acid) with alcohol (as n-butanol, isopropyl alcohol) to utilize nitrile compounds and sodium azide, but this method only is applicable to the simple tetrazole of composite structure.Solvent changed be non-proton type solvent (as DMF, DMAC), with inorganic salts or organic salt (as NH 4Cl, ZnCl 2, Et 3NHCl) make catalyst, nitrile compounds and reaction of sodium azide can be prepared the baroque tetrazole derivative that has aromatic radical, but same with above-mentioned reacting phase, this reaction speed is slower, the reaction time long (needing several days), and easily produce poisonous explosive HN 3, NH 4N 3Deng.Also have bibliographical information to adopt organotin catalysis, syntheticly in aromatic hydrocarbon solvent contain multi-functional tetranitroazole derivative, but accessory substance is many, target product is difficult to separate fully, productive rate is low, and post processing is loaded down with trivial details, and tin compound price height, toxicity are big.
(3) summary of the invention
The object of the invention provides the method for the synthetic 5-substituted tetrazole of a kind of solid acid catalysis, and the solid acid catalyst preparation is simple, active high, easily separated, and free from environmental pollution; Technology of the present invention is simple, easy operating, and the product yield height, production cost is low, and is environmentally friendly, suitability for industrialized production.
The technical solution used in the present invention is:
A kind of solid acid catalyst, described solid acid catalyst are to be active component with the disulfate, with SiO 2, ZnO, TiO 2, ZrO 2, Fe 2O 3, diatomite or active carbon be carrier; Described solid acid catalyst active component loading is 5～50wt%; Described disulfate is ammonium hydrogen sulfate, niter cake or potassium acid sulfate.
Described carrier is preferably SiO 2, ZnO or Fe 2O 3, ZnO more preferably.
Described active component loading is preferably 10～30%.
Described disulfate is preferably niter cake.
The preparation method of a kind of described solid acid catalyst of the present invention, described method is carried out as follows: (1) at 400～600 ℃ of roasting 3～6h, obtains the preliminary treatment carrier with carrier; (2) the preliminary treatment carrier is immersed in 3.5～60% the disulfate aqueous solution,, stirs 1～3h at 60～100 ℃ then, in 100～200 ℃ of down dry 12～24h, promptly get described solid acid catalyst again in 20～30 ℃ of dipping 3～8h down; Described solid acid catalyst active component loading is 5～50wt%; Described solid acid catalyst carrier is SiO 2, ZnO, TiO 2, ZrO 2, Fe 2O 3, diatomite or active carbon, described disulfate is ammonium hydrogen sulfate, niter cake or potassium acid sulfate.
In the described step (2), the volumetric usage of the described disulfate aqueous solution is counted 1.55～2.06mL/g with the quality of carrier.
The mass concentration of the described disulfate aqueous solution is preferably 3.5～48.5%, and more preferably 7.2～24.6%.
Further, a kind of method of utilizing the 5-substituted tetrazole shown in the described solid acid catalysis synthesis type (I) of the present invention, described method is: with nitrile compounds shown in the formula (II), sodium azide is raw material, with described solid acid catalyst is catalyst, in 120～160 ℃ of reaction 8～72h, reactant liquor makes the 5-substituted tetrazole through post processing in organic solvent; Organic solvent is the mixing of following one or more arbitrary proportions: dimethylbenzene, N, dinethylformamide, N, N-dimethylacetylamide or dimethyl sulfoxide (DMSO);
Figure BDA0000046043370000031
Figure BDA0000046043370000032
R is Br or N-valeryl-3-valine methyl ester in formula (I) and the formula (II).
The feed intake ratio of amount of substance of nitrile compounds described in the synthetic method of described 5-substituted tetrazole, sodium azide is 1: 1～2, and described nitrile compounds is 1: 0.05～0.3 with solid acid catalyst amount of substance ratio.
Described organic solvent volumetric usage is counted 5～10mL/g with the nitrile compounds quality.
Described nitrile compounds is 4 '-bromomethyl-2-cyanobiphenyl or (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester.
The synthetic method of described 5-substituted tetrazole, described post processing is: reactant liquor is cooled to room temperature, centrifugal or remove by filter insoluble matter, add ethyl acetate and hydrochloric acid vigorous stirring 20～60min in the filtrate, use ethyl acetate extraction again, organic facies is used saturated aqueous common salt and water washing successively, organic facies after washing drier drying, filter, filtrate decompression is steamed and is removed organic solvent, residue adds the recrystallization solvent recrystallization again, makes the 5-substituted tetrazole, and described recrystallization solvent is acetone or ethyl acetate.
Further, the synthetic method of 5-substituted tetrazole of the present invention, described method recommends to carry out according to following steps: with nitrile compounds, sodium azide is according to the ratio 1: 1.2～2.0 of amount of substance, nitrile compounds feeds intake with the ratio 1: 0.15～0.25 of solid acid catalyst amount of substance, add organic solvent again, at 120～160 ℃ of reaction 8～72h, thin-layer chromatography is followed the tracks of reaction, reaction finishes, reactant liquor is cooled off, centrifugal or remove by filter insoluble matter, add ethyl acetate and 4mol/mL hydrochloric acid vigorous stirring 20～60min in the filtrate, use ethyl acetate extraction again, organic facies is used saturated aqueous common salt and water washing successively, and the drier drying of the organic facies after the washing is filtered, filtrate decompression is steamed and is removed organic solvent, residue adds the recrystallization solvent recrystallization again, makes the 5-substituted tetrazole, and described recrystallization solvent is acetone or ethyl acetate.
Thin-layer chromatography of the present invention is a solvent with the mixed solution of 1: 5 ethyl acetate of volume ratio and n-hexane, the colour developing of 254nm ultraviolet, and nitrile compounds raw material point disappears and is reaction end.
Compared with prior art, beneficial effect of the present invention is mainly reflected in: solid acid catalyst used in the present invention, service condition are gentle and active higher, and this Preparation of Catalyst is simple, free from environmental pollution; The synthesis technique of 5-substituted tetrazole of the present invention is simple and safe, easy operating, yield height, environmental friendliness, suitability for industrialized production.
(4) specific embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Thin-layer chromatography of the present invention is a solvent with the mixed solution of 1: 5 ethyl acetate of volume ratio and n-hexane, the colour developing of 254nm ultraviolet, and nitrile compounds raw material point disappears and is reaction end.
Embodiment 1
With 10g SiO 2Carrier obtains the preliminary treatment carrier at 500 ℃ of roasting 4h, and the preliminary treatment carrier is added in the 15.6mL 6.89% ammonium hydrogen sulfate aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains silica supported ammonium hydrogen sulfate catalyst 10.88g (NH again 4HSO 4/ SiO 2) (ammonium hydrogen sulfate weight is 10wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 2.63g (0.015mol) NH 4HSO 4/ SiO 2Catalyst, in 120 ℃ of reaction 15h, thin-layer chromatography (TLC) is followed the tracks of reaction, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, use the 150mL ethyl acetate extraction again 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 26.2g, yield 83.1% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 2
With 10g SiO 2Carrier obtains the preliminary treatment carrier at 500 ℃ of roasting 4h, and the preliminary treatment carrier is added in the 15.5mL 6.89% niter cake aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains silica supported sodium bisulfate catalysis agent 10.90g (NaHSO again 4/ SiO 2) (niter cake weight is 10wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 2.70g (0.015mol) NaHSO 4/ SiO 2Catalyst, in 120 ℃ of reaction 15h, thin-layer chromatography (TLC) is followed the tracks of reaction, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, use the 150mL ethyl acetate extraction again 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 27.6g, yield 87.7% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 3
With 10g SiO 2Carrier obtains the preliminary treatment carrier at 500 ℃ of roasting 4h, and the preliminary treatment carrier is added in 15.5mL 6.89% aqueous potassium hydrogen sulfate, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains silica supported Catalyzed by Potassium Bisulfate agent 10.90g (KHSO again 4/ SiO 2) (potassium acid sulfate weight is 10wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 2.94g (0.015mol) KHSO 4/ SiO 2Catalyst, in 120 ℃ of reaction 15h, thin-layer chromatography (TLC) is followed the tracks of reaction, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, use the 150mL ethyl acetate extraction again 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 27.5g, yield 87.4% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 4
With 10g SiO 2Carrier obtains the preliminary treatment carrier at 500 ℃ of roasting 4h, and the preliminary treatment carrier is added in the 16.0mL 14.29% niter cake aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains silica supported sodium bisulfate catalysis agent 12.28g (NaHSO again 4/ SiO 2) (niter cake weight is 20wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 2.70g (0.015mol) NaHSO 4/ SiO 2Catalyst, in 120 ℃ of reaction 15h, thin-layer chromatography (TLC) is followed the tracks of reaction, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, use the 150mL ethyl acetate extraction again 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 28.5g, yield 90.5% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 5
With 10g SiO 2Carrier obtains the preliminary treatment carrier at 500 ℃ of roasting 4h, and the preliminary treatment carrier is added in the 16.8mL 22.22% niter cake aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains silica supported sodium bisulfate catalysis agent 13.99g (NaHSO again 4/ SiO 2) (niter cake weight is 30wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 2.70g (0.015mol) NaHSO 4/ SiO 2Catalyst, in 120 ℃ of reaction 15h, thin-layer chromatography (TLC) is followed the tracks of reaction, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, use the 150mL ethyl acetate extraction again 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 23.6g, yield 75.0% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 6
With 10g Fe 2O 3Carrier obtains the preliminary treatment carrier at 500 ℃ of roasting 4h, and the preliminary treatment carrier is added in the 15.6mL 6.89% ammonium hydrogen sulfate aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains the ammonium hydrogen sulfate catalyst 10.89g (NH that di-iron trioxide supports again 4HSO 4/ Fe 2O 3) (ammonium hydrogen sulfate weight is 10wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 4.12g (0.015mol) NH 4HSO 4/ Fe 2O 3Catalyst, in 120 ℃ of reaction 15h, thin-layer chromatography (TLC) is followed the tracks of reaction, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, use the 150mL ethyl acetate extraction again 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 25.6g, yield 81.4% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 7
With 10g Fe 2O 3Carrier obtains the preliminary treatment carrier at 500 ℃ of roasting 4h, and the preliminary treatment carrier is added in the 15.5mL 6.89% niter cake aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains the sodium bisulfate catalysis agent 10.91g (NaHSO that di-iron trioxide supports again 4/ Fe 2O 3) (niter cake weight is 10wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 4.20g (0.015mol) NaHSO 4/ Fe 2O 3Catalyst, in 120 ℃ of reaction 15h, thin-layer chromatography (TLC) is followed the tracks of reaction, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, use the 150mL ethyl acetate extraction again 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 27.3g, yield 86.7% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 8
With 10g Fe 2O 3Carrier obtains the preliminary treatment carrier at 500 ℃ of roasting 4h, and the preliminary treatment carrier is added in the 16.0mL 14.29% niter cake aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃,, obtain supporting the sodium bisulfate catalysis agent 12.30g (NaHSO of silica again in 120 ℃ of following dry 24h 4/ Fe 2O 3) (niter cake weight is 20wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 4.20g (0.015mol) NaHSO 4/ Fe 2O 3Catalyst, in 120 ℃ of reaction 15h, thin-layer chromatography (TLC) is followed the tracks of reaction, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, use the 150mL ethyl acetate extraction again 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 28.2g, yield 89.6% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 9
With 10g Fe 2O 3Carrier obtains the preliminary treatment carrier at 500 ℃ of roasting 4h, and the preliminary treatment carrier is added in 16.1mL 14.29% aqueous potassium hydrogen sulfate, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains the Catalyzed by Potassium Bisulfate agent 12.29g (KHSO that di-iron trioxide supports again 4/ Fe 2O 3) (potassium acid sulfate weight is 20wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 4.20g (0.015mol) KHSO 4/ Fe 2O 3Catalyst, in 120 ℃ of reaction 15h, thin-layer chromatography (TLC) is followed the tracks of reaction, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, use the 150mL ethyl acetate extraction again 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 28.0g, yield 89.1% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 10
10g ZnO carrier at 500 ℃ of roasting 4h, is obtained the preliminary treatment carrier, the preliminary treatment carrier is added in the 15.5mL 6.89% niter cake aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains the sodium bisulfate catalysis agent 10.92g (NaHSO that zinc oxide supports again 4/ ZnO) (niter cake weight is 10wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 3.02g (0.015mol) NaHSO 4/ ZnO catalyst, in 120 ℃ of reaction 15h, thin-layer chromatography (TLC) is followed the tracks of reaction, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, use the 150mL ethyl acetate extraction again 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 27.8g, yield 88.3% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 11
10g ZnO carrier at 500 ℃ of roasting 4h, is obtained the preliminary treatment carrier, the preliminary treatment carrier is added in the 15.7mL 11.76% niter cake aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains the sodium bisulfate catalysis agent 11.57g (NaHSO that zinc oxide supports again 4/ ZnO) (niter cake weight is 15wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 3.02g (0.015mol) NaHSO 4/ ZnO catalyst, in 120 ℃ of reaction 12h, TLC follows the tracks of, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, with 150mL ethyl acetate extraction 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 27.9g, yield 88.6% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 12
10g ZnO carrier at 500 ℃ of roasting 4h, is obtained the preliminary treatment carrier, the preliminary treatment carrier is added in the 16.0mL 14.29% niter cake aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains the sodium bisulfate catalysis agent 12.29g (NaHSO that zinc oxide supports again 4/ ZnO) (niter cake weight is 20wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 3.02g (0.015mol) NaHSO 4/ ZnO catalyst, in 120 ℃ of reaction 10h, TLC follows the tracks of, reaction finishes afterreaction liquid and is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, with 150mL ethyl acetate extraction 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization again, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 28.6g, yield 90.8% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 13
10g ZnO carrier at 500 ℃ of roasting 4h, is obtained the preliminary treatment carrier, the preliminary treatment carrier is added in the 16.4mL 18.18% niter cake aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains the sodium bisulfate catalysis agent 13.11g (NaHSO that zinc oxide supports again 4/ ZnO) (niter cake weight is 25wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 3.02g (0.015mol) NaHSO 4/ ZnO catalyst, in 120 ℃ of reaction 10h, TLC follows the tracks of, the afterreaction liquid that reacts completely is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, with 150mL ethyl acetate extraction 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization again, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 27.6g, yield 87.6% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 14
10g ZnO carrier at 500 ℃ of roasting 4h, is obtained the preliminary treatment carrier, the preliminary treatment carrier is added in the 16.8mL 22.22% niter cake aqueous solution, flood 6h down in 20 ℃, stir 2h at 80 ℃, dry 24h under 120 ℃ obtains the sodium bisulfate catalysis agent 14.01g (NaHSO that zinc oxide supports again 4/ ZnO) (niter cake weight is 30wt.%).
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 3.02g (0.015mol) NaHSO 4/ ZnO catalyst, in 120 ℃ of reaction 12h, TLC follows the tracks of, reactant liquor is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, with 150mL ethyl acetate extraction 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization again, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 23.7g, yield 75.2% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 15
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 9.8g (0.15mol) sodium azide, 3.02g (0.015mol) NaHSO 4/ ZnO catalyst, in 120 ℃ of reaction 10h, TLC follows the tracks of, reaction finishes afterreaction liquid and is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, with 150mL ethyl acetate extraction 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization again, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 28.8g, yield 91.4% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 16
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 11.7g (0.18mol) sodium azide, 3.02g (0.015mol) NaHSO 4/ ZnO catalyst, in 120 ℃ of reaction 10h, TLC follows the tracks of, reaction finishes afterreaction liquid and is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, with 150mL ethyl acetate extraction 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization again, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 29.1g, yield 92.4% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 17
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 13.0g (0.20mol) sodium azide, 3.02g (0.015mol) NaHSO 4/ ZnO catalyst, in 120 ℃ of reaction 9h, TLC follows the tracks of, reaction finishes afterreaction liquid and is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, with 150mL ethyl acetate extraction 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization again, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 28.9g, yield 91.7% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 18
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 11.7g (0.18mol) sodium azide, 4.02g (0.020mol) NaHSO 4/ ZnO catalyst, in 120 ℃ of reaction 8h, TLC follows the tracks of, reaction finishes afterreaction liquid and is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, with 150mL ethyl acetate extraction 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization again, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 29.4g, yield 93.3% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 19
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With 4 '-bromomethyl-2-cyanobiphenyl 27.2g (0.10mol), be dissolved in 150mL N, in the dinethylformamide, add 11.7g (0.18mol) sodium azide, 5.04g (0.025mol) NaHSO 4/ ZnO catalyst, in 120 ℃ of reaction 8h, TLC follows the tracks of, reaction finishes afterreaction liquid and is cooled to room temperature, remove by filter insoluble matter, filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 100mL and 4mol/L, with 150mL ethyl acetate extraction 3 times, organic facies is used the saturated common salt water washing 2 times successively, anhydrous sodium sulfate drying is used in running water washing 1 time, filters, remove organic solvent under reduced pressure, residue adds the 100mL acetone recrystallization again, obtains 5-[4 '-(bromomethyl)-biphenyl-2-yl]-1H-tetrazole 29.2g, yield 92.7% (in 4 '-amount of substance of bromomethyl-2-cyanobiphenyl).
Embodiment 20
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester 40.7g (0.10mol), be dissolved in 250mL N, in the dinethylformamide, add 7.8g (0.12mol) sodium azide, 3.02g (0.015mol) NaHSO 4/ ZnO catalyst; in 120 ℃ of reaction 70h; TLC follows the tracks of; the afterreaction liquid that reacts completely is cooled to room temperature; remove by filter insoluble matter; filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 200mL and 4mol/L; with 300mL ethyl acetate extraction 3 times; organic facies is used the saturated common salt water washing 2 times successively; running water washing 1 time; use anhydrous sodium sulfate drying; filter; remove organic solvent under reduced pressure, residue adds the 100mL re-crystallizing in ethyl acetate again, obtains (S)-N-valeryl-N-[[2 '-(1H-5-tetrazole-yl) [1; 1 '-biphenyl]-the 4-yl] methyl]-valine methyl ester 18.4g, yield 40.9% (in (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } amount of substance of valine methyl ester).
Embodiment 21
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester 40.7g (0.10mol), be dissolved in 250mL N, in the dinethylformamide, add 9.8g (0.15mol) sodium azide, 3.02g (0.015mol) NaHSO 4/ ZnO catalyst; in 120 ℃ of reaction 58h; TLC follows the tracks of; the afterreaction liquid that reacts completely is cooled to room temperature; remove by filter insoluble matter; filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 200mL and 4mol/L; with 300mL ethyl acetate extraction 3 times; organic facies is used the saturated common salt water washing 2 times successively; running water washing 1 time; use anhydrous sodium sulfate drying; filter; remove organic solvent under reduced pressure, residue adds the 100mL re-crystallizing in ethyl acetate again, obtains (S)-N-valeryl-N-[[2 '-(1H-5-tetrazole-yl) [1; 1 '-biphenyl]-the 4-yl] methyl]-valine methyl ester 27.8g, yield 61.8% (in (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } amount of substance of valine methyl ester).
Embodiment 22
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester 40.7g (0.10mol), be dissolved in 250mL N, in the dinethylformamide, add 9.8g (0.15mol) sodium azide, 4.02g (0.020mol) NaHSO 4/ ZnO catalyst; in 120 ℃ of reaction 48h; TLC follows the tracks of; the afterreaction liquid that reacts completely is cooled to room temperature; remove by filter insoluble matter; filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 200mL and 4mol/L; with 300mL ethyl acetate extraction 3 times; organic facies is used the saturated common salt water washing 2 times successively; running water washing 1 time; use anhydrous sodium sulfate drying; filter; remove organic solvent under reduced pressure, residue adds the 100mL re-crystallizing in ethyl acetate again, obtains (S)-N-valeryl-N-[[2 '-(1H-5-tetrazole-yl) [1; 1 '-biphenyl]-the 4-yl] methyl]-valine methyl ester 32.7g, yield 72.7% (in (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } amount of substance of valine methyl ester).
Embodiment 23
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester 40.7g (0.10mol), be dissolved in 250mL N, in the dinethylformamide, add 11.7g (0.18mol) sodium azide, 4.02g (0.020mol) NaHSO 4/ ZnO catalyst; in 120 ℃ of reaction 42h; TLC follows the tracks of; the afterreaction liquid that reacts completely is cooled to room temperature; remove by filter insoluble matter; filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 200mL and 4mol/L; with 300mL ethyl acetate extraction 3 times; organic facies is used the saturated common salt water washing 2 times successively; running water washing 1 time; use anhydrous sodium sulfate drying; filter; remove organic solvent under reduced pressure, residue adds the 100mL re-crystallizing in ethyl acetate again, obtains (S)-N-valeryl-N-[[2 '-(1H-5-tetrazole-yl) [1; 1 '-biphenyl]-the 4-yl] methyl]-valine methyl ester 36.8g, yield 81.9% (in (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } amount of substance of valine methyl ester).
Embodiment 24
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester 40.7g (0.10mol), be dissolved in 250mL N, in the dinethylformamide, add 11.7g (0.18mol) sodium azide, 5.04g (0.025mol) NaHSO 4/ ZnO catalyst; in 120 ℃ of reaction 40h; TLC follows the tracks of; the afterreaction liquid that reacts completely is cooled to room temperature; remove by filter insoluble matter; filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 200mL and 4mol/L; with 300mL ethyl acetate extraction 3 times; organic facies is used the saturated common salt water washing 2 times successively; running water washing 1 time; use anhydrous sodium sulfate drying; filter; remove organic solvent under reduced pressure, residue adds the 100mL re-crystallizing in ethyl acetate again, obtains (S)-N-valeryl-N-[[2 '-(1H-5-tetrazole-yl) [1; 1 '-biphenyl]-the 4-yl] methyl]-valine methyl ester 36.4g, yield 81.0% (in (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } amount of substance of valine methyl ester).
Embodiment 25
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester 40.7g (0.10mol), be dissolved in 250mL N, in the dinethylformamide, add 13.0g (0.20mol) sodium azide, 4.02g (0.020mol) NaHSO 4/ ZnO catalyst; in 120 ℃ of reaction 40h; TLC follows the tracks of; the afterreaction liquid that reacts completely is cooled to room temperature; filter; filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 200mL and 4mol/L; with 300mL ethyl acetate extraction 3 times; organic facies is used the saturated common salt water washing 2 times successively; running water washing 1 time; use anhydrous sodium sulfate drying; filter; remove organic solvent under reduced pressure, residue adds the 100mL re-crystallizing in ethyl acetate again, obtains (S)-N-valeryl-N-[[2 '-(1H-5-tetrazole-yl) [1; 1 '-biphenyl]-the 4-yl] methyl]-valine methyl ester 36.7g, yield 81.6% (in (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } amount of substance of valine methyl ester).
Embodiment 26
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester 40.7g (0.10mol), be dissolved in 250mL N, in the dinethylformamide, add 13.0g (0.20mol) sodium azide, 5.04g (0.025mol) NaHSO 4/ ZnO catalyst; in 120 ℃ of reaction 40h; TLC follows the tracks of; the afterreaction liquid that reacts completely is cooled to room temperature; filter; filtrate adds the hydrochloric acid 20mL vigorous stirring 30min of ethyl acetate 200mL and 4mol/L; with 300mL ethyl acetate extraction 3 times; organic facies is used the saturated common salt water washing 2 times successively; running water washing 1 time; use anhydrous sodium sulfate drying; filter; remove organic solvent under reduced pressure, residue adds the 100mL re-crystallizing in ethyl acetate again, obtains (S)-N-valeryl-N-[[2 '-(1H-5-tetrazole-yl) [1; 1 '-biphenyl]-the 4-yl] methyl]-valine methyl ester 36.5g, yield 81.2% (in (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } amount of substance of valine methyl ester).。
Embodiment 27
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester 40.7g (0.10mol), be dissolved in 250mL N, in the N-dimethylacetylamide, add 11.7g (0.18mol) sodium azide, 4.02g (0.020mol) NaHSO 4/ ZnO catalyst; in 120 ℃ of reaction 40h; TLC follows the tracks of; reactant liquor filters out catalyst after being cooled to room temperature; the hydrochloric acid 20mL that adds ethyl acetate 200mL and 4mol/L in filtrate stirs 30min; with 300mL ethyl acetate extraction 3 times; organic facies is used the saturated common salt water washing 2 times successively; running water washing 1 time; use anhydrous sodium sulfate drying; filter; remove organic solvent under reduced pressure; residue adds the 100mL re-crystallizing in ethyl acetate again; obtain (S)-N-valeryl-N-[[2 '-([1,1 '-biphenyl]-4-yl of 1H-5-tetrazole-yl)] methyl]-valine methyl ester 35.9g, yield 80.8% (in (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } amount of substance of valine methyl ester).
Embodiment 28
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester 40.7g (0.10mol), be dissolved in the 250mL dimethyl sulfoxide (DMSO), add 11.7g (0.18mol) sodium azide, 4.02g (0.020mol) NaHSO 4/ ZnO catalyst; in 120 ℃ of reaction 40h; TLC follows the tracks of; reactant liquor filters out catalyst after being cooled to room temperature; the hydrochloric acid 20mL that adds ethyl acetate 200mL and 4mol/L in filtrate stirs 30min; with 300mL ethyl acetate extraction 3 times; organic facies is used the saturated common salt water washing 2 times successively; running water washing 1 time; use anhydrous sodium sulfate drying; filter; remove organic solvent under reduced pressure; residue adds the 100mL re-crystallizing in ethyl acetate again; obtain (S)-N-valeryl-N-[[2 '-([1,1 '-biphenyl]-4-yl of 1H-5-tetrazole-yl)] methyl]-valine methyl ester 35.5g, yield 79.9% (in (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } amount of substance of valine methyl ester).
Embodiment 29
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester 40.7g (0.10mol), be dissolved in the mixed solvent of 250mL dimethylbenzene, add 11.7g (0.18mol) sodium azide, 4.02g (0.020mol) NaHSO 4/ ZnO catalyst; in 120 ℃ of reaction 40h; TLC follows the tracks of; reactant liquor filters out catalyst after being cooled to room temperature; the hydrochloric acid 20mL that adds ethyl acetate 200mL and 4mol/L in filtrate stirs 30min; with 300mL ethyl acetate extraction 3 times; organic facies is used the saturated common salt water washing 2 times successively; running water washing 1 time; use anhydrous sodium sulfate drying; filter; remove organic solvent under reduced pressure; residue adds the 100mL re-crystallizing in ethyl acetate again; obtain (S)-N-valeryl-N-[[2 '-([1,1 '-biphenyl]-4-yl of 1H-5-tetrazole-yl)] methyl]-valine methyl ester 36.6g, yield 81.5% (in (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } amount of substance of valine methyl ester).
Embodiment 30
NaHSO 4The preparation of/ZnO catalyst is with embodiment 12.
With (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } valine methyl ester 40.7g (0.10mol); be dissolved in 150mL N; in the mixed solvent of dinethylformamide and 100mL dimethylbenzene, add 11.7g (0.18mol) sodium azide, 4.02g (0.020mol) NaHSO 4/ ZnO catalyst; in 120 ℃ of reaction 40h; TLC follows the tracks of; reactant liquor filters out catalyst after being cooled to room temperature; the hydrochloric acid 20mL that adds ethyl acetate 200mL and 4mol/L in filtrate stirs 30min; with 300mL ethyl acetate extraction 3 times; organic facies is used the saturated common salt water washing 2 times successively; running water washing 1 time; use anhydrous sodium sulfate drying; filter; remove organic solvent under reduced pressure; residue adds the 100mL re-crystallizing in ethyl acetate again; obtain (S)-N-valeryl-N-[[2 '-([1,1 '-biphenyl]-4-yl of 1H-5-tetrazole-yl)] methyl]-valine methyl ester 36.7g, yield 81.7% (in (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl } amount of substance of valine methyl ester).

Claims (10)

1. solid acid catalyst, described solid acid catalyst are to be active component with the disulfate, with SiO 2, ZnO, TiO 2, ZrO 2, Fe 2O 3, diatomite or active carbon be carrier; Described solid acid catalyst active component loading is 5～50wt%; Described disulfate is ammonium hydrogen sulfate, niter cake or potassium acid sulfate.
2. solid acid catalyst as claimed in claim 1 is characterized in that described carrier is SiO 2, ZnO or Fe 2O 3
3. the preparation method of a solid acid catalyst as claimed in claim 1, it is characterized in that described method carries out as follows: (1) at 400～600 ℃ of roasting 3～6h, obtains the preliminary treatment carrier with carrier; (2) the preliminary treatment carrier is immersed in the disulfate aqueous solution of mass concentration 3.5～60%, dipping 3～8h under 20～30 ℃ stirs 1～3h at 60～100 ℃ then, in 100～200 ℃ of down dry 12～24h, promptly gets described solid acid catalyst again; Described solid acid catalyst active component loading is 5～50wt%; Described solid acid catalyst carrier is SiO 2, ZnO, TiO 2, ZrO 2, Fe 2O 3, diatomite or active carbon, described disulfate is ammonium hydrogen sulfate, niter cake or potassium acid sulfate.
4. as claim 1 or 3 described solid acid catalysts, it is characterized in that the volumetric usage of the described disulfate aqueous solution is counted 1.55～2.06mL/g with the quality of carrier in the described step (2).
5. method of utilizing the 5-substituted tetrazole shown in the solid acid catalysis synthesis type as claimed in claim 1 (I), it is characterized in that described method is: with nitrile compounds shown in the formula (II), sodium azide is raw material, with described solid acid catalyst is catalyst, in 120～160 ℃ of reaction 8～72h, reactant liquor makes the 5-substituted tetrazole through post processing in organic solvent; Organic solvent is the mixing of following one or more arbitrary proportions: dimethylbenzene, N, dinethylformamide, N, N-dimethylacetylamide or dimethyl sulfoxide (DMSO);
Figure FDA0000046043360000021
Figure FDA0000046043360000022
R is Br or N-valeryl-3-valine methyl ester in formula (I) and the formula (II).
6. the synthetic method of 5-substituted tetrazole as claimed in claim 5, it is characterized in that the feed intake ratio of amount of substance of described nitrile compounds, sodium azide is 1: 1～2, described nitrile compounds is 1: 0.05～0.3 with solid acid catalyst amount of substance ratio.
7. the synthetic method of 5-substituted tetrazole as claimed in claim 5 is characterized in that described organic solvent volumetric usage counts 5～10mL/g with the nitrile compounds quality.
8. the synthetic method of 5-substituted tetrazole as claimed in claim 5, it is characterized in that described nitrile compounds be 4 '-bromomethyl-2-cyanobiphenyl or (S)-N-valeryl-3-{[2-cyanobiphenyl-4-yl] methyl valine methyl ester.
9. the synthetic method of 5-substituted tetrazole as claimed in claim 5, it is characterized in that described post processing is: reactant liquor is cooled to room temperature, centrifugal or remove by filter insoluble matter, add ethyl acetate and hydrochloric acid vigorous stirring 20～60min in the filtrate, use ethyl acetate extraction again, organic facies is used saturated aqueous common salt and water washing successively, organic facies after washing drier drying, filter, filtrate decompression is steamed and is removed organic solvent, residue adds the recrystallization solvent recrystallization again, makes the 5-substituted tetrazole, and described recrystallization solvent is acetone or ethyl acetate.
10. the synthetic method of 5-substituted tetrazole as claimed in claim 5, it is characterized in that described method carries out according to following steps: with nitrile compounds, sodium azide is according to the ratio 1: 1.2～2.0 of amount of substance, nitrile compounds feeds intake with the ratio 1: 0.15～0.25 of solid acid catalyst amount of substance, add organic solvent again, at 120～160 ℃ of reaction 8～72h, thin-layer chromatography is followed the tracks of reaction, reaction finishes, reactant liquor is cooled off, centrifugal or remove by filter insoluble matter, add ethyl acetate and 4mol/mL hydrochloric acid vigorous stirring 20～60min in the filtrate, use ethyl acetate extraction again, organic facies is used saturated aqueous common salt and water washing successively, organic facies after washing drier drying, filter, filtrate decompression is steamed and is removed organic solvent, and residue adds the recrystallization solvent recrystallization again, make the 5-substituted tetrazole, described recrystallization solvent is acetone or ethyl acetate.
CN 201110032549 2011-01-29 2011-01-29 Solid acid catalyst and method for catalytic synthesis of 5-substituted tetrazole by solid acid catalyst Pending CN102145297A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 201110032549 CN102145297A (en) 2011-01-29 2011-01-29 Solid acid catalyst and method for catalytic synthesis of 5-substituted tetrazole by solid acid catalyst

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 201110032549 CN102145297A (en) 2011-01-29 2011-01-29 Solid acid catalyst and method for catalytic synthesis of 5-substituted tetrazole by solid acid catalyst

Publications (1)

Publication Number Publication Date
CN102145297A true CN102145297A (en) 2011-08-10

Family

ID=44419890

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 201110032549 Pending CN102145297A (en) 2011-01-29 2011-01-29 Solid acid catalyst and method for catalytic synthesis of 5-substituted tetrazole by solid acid catalyst

Country Status (1)

Country Link
CN (1) CN102145297A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106179511A (en) * 2016-07-08 2016-12-07 盐城工学院 A kind of support type NaHSO of oleophylic4catalyst and its preparation method and application
CN111892053A (en) * 2020-07-08 2020-11-06 桂林理工大学 Zirconium-loaded activated carbon high-activity material and preparation method and application thereof
CN117969500A (en) * 2024-03-27 2024-05-03 山东新蓝环保科技有限公司 Method for detecting aldehydes in urea aqueous solution of nitrogen oxide reducing agent

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1709877A (en) * 2005-05-24 2005-12-21 南通市华峰化工有限责任公司 5-substituted aromatic laydrocarbon tetrazole production method
CN101230046A (en) * 2008-02-21 2008-07-30 南京大学 Method for catalytic synthesis of 5-substituted tetrazole by tungstate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1709877A (en) * 2005-05-24 2005-12-21 南通市华峰化工有限责任公司 5-substituted aromatic laydrocarbon tetrazole production method
CN101230046A (en) * 2008-02-21 2008-07-30 南京大学 Method for catalytic synthesis of 5-substituted tetrazole by tungstate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
《Synlett》 20101222 Biswanath Das et al., A Simple，Advantageous Synthesis of 5-Substituted 1H-Tetrazoles 391-394 1-10 , 第3期 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106179511A (en) * 2016-07-08 2016-12-07 盐城工学院 A kind of support type NaHSO of oleophylic4catalyst and its preparation method and application
CN111892053A (en) * 2020-07-08 2020-11-06 桂林理工大学 Zirconium-loaded activated carbon high-activity material and preparation method and application thereof
CN117969500A (en) * 2024-03-27 2024-05-03 山东新蓝环保科技有限公司 Method for detecting aldehydes in urea aqueous solution of nitrogen oxide reducing agent
CN117969500B (en) * 2024-03-27 2024-06-07 山东新蓝环保科技有限公司 Method for detecting aldehydes in urea aqueous solution of nitrogen oxide reducing agent

Similar Documents

Publication Publication Date Title
CN101723852B (en) Novel method for condensing aromatic aldehydes and active methylene compounds through catalysis of functional ionic liquid
CN102442930A (en) Preparation method of DL-p-methylsulfonylphenyl serine ethyl ester
CN101817795A (en) Improved method for synthesizing valsartan
CN102627594A (en) Preparation method of waterless aziridine compound
CN101781235A (en) Method for preparing 2-cyanophenol
CN102145297A (en) Solid acid catalyst and method for catalytic synthesis of 5-substituted tetrazole by solid acid catalyst
CN102002066A (en) Synthesis method of 4-acetoxyl-2-azetidinone
CN101973943B (en) Preparation method of (E)-2-[2-(6-pyrimidine-4-yloxy) phenyl]-3-methoxyacrylate
CN113061111A (en) Method for preparing amino acid compound with photocrosslinking activity
CN102675267B (en) Preparation method of dronedarone hydrochloride and intermediate of dronedarone hydrochloride
CN101773846A (en) Loaded solid alkali zeolite catalyst for synthesizing long-chain alkyl carbonate
CN102617395B (en) Preparation method of glycylcycline antibiotic
CN113024364B (en) Efficient green synthesis method of hydroxycitronellal
CN100348588C (en) Chemical synthesis method of pyrimidine thioketone
CN105272911B (en) A kind of preparation method of Sorafenib Tosylate
CN101318885B (en) Preparation method for converting organic carboxylic acid into organic aldehyde
CN103214400A (en) Preparation method of hexaflumuron
CN103709116B (en) A kind of preparation method of 4-(4-alkoxycarbonylamino) phenyl-3-morpholone mai
CN108976130B (en) A method of preparing treatment ovarian cancer intermediate
CN101654426B (en) Method for preparing ilomastat
CN101906058A (en) Method for preparing dithiocyano-methane
CN102491910B (en) Method for synthesizing 2,6-dibromo-4-(trifluoromethoxy) aniline by water-phase method
CN101418033A (en) Method for synthesizing finasteride
CN101100444A (en) Method for synthesizing diphenyldiazomethane
CN100560558C (en) A kind of 2,3,5, the preparation method of 6-tetrafluorobenzoic aid

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: 20110810