CN1189158A - Novel reagent for tetrazole synthesis and process for producing tetrazoles therewith - Google Patents

Novel reagent for tetrazole synthesis and process for producing tetrazoles therewith Download PDF

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Publication number
CN1189158A
CN1189158A CN96195084A CN96195084A CN1189158A CN 1189158 A CN1189158 A CN 1189158A CN 96195084 A CN96195084 A CN 96195084A CN 96195084 A CN96195084 A CN 96195084A CN 1189158 A CN1189158 A CN 1189158A
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straight
carbon atom
replaces
imposedly
branched alkyl
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德原吟朗
山口正
岩崎哲也
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Wakunaga Pharmaceutical Co Ltd
Chugoku Kayaku KK
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Wakunaga Pharmaceutical Co Ltd
Chugoku Kayaku KK
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Abstract

A process for producing 1H-tetrazoles represented by general formula (II) (wherein R represents an arbitrary substituent) from carbonitriles represented by the general formula (I)comprising an alkali metal azide and zinc chloride (wherein R is as defined above). The agent can be used in a variety of solvents and can fundamentally be applied to any carbonitriles. As zinc chloride is inexpensive, it contributes to cost reduction.

Description

Be used for the new reagent of synthetic tetrazolium and use this reagent to synthesize the method for tetrazolium
Technical field
The present invention relates to a kind of reagent of synthetic tetrazolium newly and use this reagent to synthesize the method for tetrazolium.
Background technology
Be the present known method that nitrile is changed into tetrazolium below.
(A) JACS (J.Ame.Chem.Soc., Vol.80,1958, pp.3908-3911) the middle method of describing.The document has been described the method for being reacted synthetic corresponding tetrazolium by alkyl nitrile or aryl nitrile and ammonium chloride/sodiumazide or alkylamine hydrochloride/sodiumazide in as dimethyl formamide (DMF) or diethyl sulfoxide.
(B) organic chemistry magazine (J.Org.Chem.), Vol.56,1991, the described method of pp.2395-2400.The document has been described the synthetic method with sterically hindered tetrazole compound.Simple speech, nitrile compounds reacts the synthetic sterically hindered tetrazole compound that has with trialkyl azide tin in solvent such as toluene or dimethylbenzene.
(C) the described method of the flat 6-73028 of Japanese patent application No..This application has been described cyano group benzene compound and formula (R) 3SnN 3The method of the synthetic tetrazolium benzene compound of (wherein R is the alkyl with 7-18 carbon atom) compound reaction.
(D) Chemische Berichte, Vol.89, No.11 (1956), the described method of pp.2648-2653.The document discloses nitrile compound and synthesized tetrazole compound with aluminum chloride/reaction of sodium azide in tetrahydrofuran (THF) (THF).
When radicals R volume in formula R-CN (wherein R the is any substituting group) nitrile compound greatly to can causing when sterically hindered, method (A) productive rate is very low or reach the gratifying very long reaction times of productive rate needs.
Known aforesaid method (B) and (C) can synthesize effectively and have sterically hindered tetrazole compound; But, the very expensive and vapour pressure that is used for the low alkyl group tin compound of method (B) such as azide tributyl tin of trialkyltin trinitride very your pupil with toxigenicity; Therefore, these methods all are not suitable for industrial manufacture process.
In addition, because the relation of its character, it is only compatible with limited solvent (typically being tetrahydrofuran (THF)) to produce the aluminum chloride that is used as reagent in the tetrazole compound by method (D), thereby does not have versatility.
Of the present invention open
The invention provides safety, cheap and be applicable to that industrial tetrazolium forms agent.The present invention also provides and has used these tetrazoliums to form the commercial run that tetrazole compound is produced in agent.
In order to solve the problem in the above-mentioned technology formerly, the inventor etc. are significant to industrial applicibility, and new tetrazolium forms agent and carried out careful research.Found that by using and an alkali metal azide such as NaN 3Bonded ZnCl 2Can produce required tetrazole compound safely industrial, this discovery has caused of the present invention finishing.
In brief, the present invention relates to be used for nitrile from formula (I):
R-CN (I) (wherein R is any substituting group) synthesis type (II) 1H-tetrazolium:
Figure A9619508400141
The new useful reagent of (wherein the R definition as above), being characterized as of this reagent comprises an alkali metal azide and zinc chloride.The present invention also relates to production formula (II) 1H-tetrazole compound:
Figure A9619508400142
The method of (wherein R is any substituting group) is characterized by and make formula (I) nitrile compound in the presence of the catalyzer zinc chloride:
R-CN (I) (wherein the R definition as above) and an alkali metal azide reaction.Carry out best mode of the present invention
The alkali metal azide that forms the agent component as tetrazolium of the present invention comprises Lithium Azide, sodiumazide, potassium azide, azide rubidium and cesium trinitride, wherein preferred especially sodiumazide.
Using tetrazolium of the present invention to form agent (being zinc chloride/an alkali metal azide) can be from the synthetic 1H-tetrazole compound of formula (I) nitrile compound, its Chinese style (I) nitrile compound is not limited to any specific compound, and tetrazolium of the present invention forms agent can use any type of nitrile in principle.In other words, R represents any substituting group in the formula (I).The example of R comprises: the alkyl that replaces (for example, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl non-imposedly, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, undecyl, pentadecyl and heptadecyl); The alkenyl that replaces (for example, vinyl, 1-propenyl, allyl group, 1-butylene base, crotyl and 3-butenyl) non-imposedly; The alkynyl that replaces (for example, ethynyl and propargyl) non-imposedly; The alkoxyl group that replaces (for example, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and tert.-butoxy) non-imposedly; The alkylthio that replaces (for example, methylthio group and ethylmercapto group) non-imposedly; The alkyl sulphonyl that replaces (for example, methylsulfonyl) non-imposedly; The alkyl sulphinyl that replaces (for example, methylsulfinyl) non-imposedly; The alkylamino that replaces (for example, methylamino-and ethylamino) non-imposedly; The alkenyloxy that replaces (for example, vinyloxy group, 1-propenyloxy group and allyloxy) non-imposedly; Substituted non-imposedly alkenyl thio (for example, ethene sulfenyl, 1-propylene sulfenyl and allyl sulfenyl); The carbalkoxy that replaces (for example, methoxycarbonyl, ethoxycarbonyl, the positive third oxygen carbonyl, the different third oxygen carbonyl, positive butoxy carbonyl and tertbutyloxycarbonyl) non-imposedly; The aryl that replaces (for example, phenyl, o-tolyl, a tolyl, p-methylphenyl, adjacent xenyl, an xenyl, to xenyl, Alpha-Naphthyl and betanaphthyl) non-imposedly; The aryloxy that replaces (phenoxy group for example, oxy-o-cresyl, a tolyloxy, to tolyloxy, adjacent biphenylyloxy, a biphenylyloxy, to biphenylyloxy, alpha-naphthoxy base and β-naphthyloxy) non-imposedly; The aralkyl that replaces (for example, benzyl and styroyl) non-imposedly; The aromatic yl alkenyl that replaces (for example, styryl and cinnamyl) non-imposedly; And non-imposed the heterocyclic radical (for example, 2-pyridyl, 3-pyridyl and 4-pyridyl) that replaces.
Comprise the low alkyl group (for example, methyl and ethyl) with 1-4 carbon atom as the example that can be replaced in the group on the above-mentioned substituting group, the lower alkoxy with 1-4 carbon atom (for example, methoxyl group and oxyethyl group), halogen atom (for example, F, Cl, Br and I), hydroxyl, amino, nitro, cyano group, trifluoromethyl and carboxyl.Above-mentioned substituting group can be replaced by one or more groups.
More particularly, R is selected from hydrogen; Straight or branched has the alkyl that replaces of 1-4 carbon atom non-imposedly; Straight or branched has the alkoxyl group that replaces of 1-4 carbon atom non-imposedly; Straight or branched has the alkyl sulphonyl that replaces of 1-4 carbon atom non-imposedly; Phenyl; Mono-substituted phenyl shown in the following formula:
Figure A9619508400161
(R wherein 1Be selected from and can be F, Cl, the halogen atom of any one among Br and the I has the straight or branched alkyl of 1-4 carbon atom, has the straight or branched alkyl sulphonyl of 1-4 carbon atom, nitro, amino and carboxyl); Di-substituted-phenyl shown in the following formula:
Figure A9619508400162
(R wherein 2And R 3Be independently selected from and can be F, Cl, the halogen atom of any one among Br and the I, straight or branched alkyl with 1-4 carbon atom has the straight or branched alkoxyl group of 1-4 carbon atom, has the straight or branched alkyl sulphonyl of 1-4 carbon atom, nitro, amino and carboxyl); 4 '-methyl diphenyl-2-base; Group shown in the following formula: (wherein A can be O, NH or CH 2In any one; Z has to be selected from down any one divalent group of array structure:
Figure A9619508400171
R 4, R 5And R 6Be independently selected from and can be F, Cl, the halogen atom of any one among Br and the I, straight or branched alkyl with 1-4 carbon atom has the straight or branched alkoxyl group of 1-4 carbon atom, has the straight or branched alkyl sulphonyl of 1-4 carbon atom, nitro, amino and carboxyl); Group shown in the following formula: (wherein X and Y are independently selected from CH and N, and R 4, R 5And R 6Be independently selected from halogen atom, can be F, Cl, any one has the straight or branched alkyl of 1-4 carbon atom among Br and the I, has the straight or branched alkoxyl group of 1-4 carbon atom, straight or branched alkyl sulphonyl with 1-4 carbon atom, nitro, amino and carboxyl); Any one group of representing by following formula A: formula A:
Figure A9619508400191
(R wherein 7, R 8, R 9And R 10Be independently selected from hydrogen, straight or branched alkyl (for example, methyl, ethyl with 1-4 carbon atom, n-propyl, sec.-propyl, the normal-butyl or the tertiary butyl), hydroxyl, phenyl, can be F, Cl, the halogen atom of any one among Br and the I, trifluoroacetyl group, five fluorine propionyls, straight or branched carbalkoxy (for example, methoxycarbonyl or ethoxycarbonyl), the straight or branched alkyl with 1-4 carbon atom that phenyl replaces (for example, benzyl or styroyl), and the straight or branched alkyl (for example, methylol or 2-hydroxyethyl) of hydroxyl replacement); Any one group of representing by following formula B: formula (B):
Figure A9619508400201
(R wherein 11, R 12, R 13And R 14Be independently selected from hydrogen, straight or branched alkyl with 1-4 carbon atom (for example, methyl, ethyl, n-propyl, sec.-propyl, the normal-butyl or the tertiary butyl), hydroxyl, phenyl, can be F, Cl, the halogen atom of any one among Br and the I, trifluoroacetyl group, five fluorine propionyls, straight or branched carbalkoxy (for example methoxycarbonyl or ethoxycarbonyl) with 1-4 carbon atom, the straight or branched alkyl with 1-4 carbon atom (for example, benzyl or styroyl) that phenyl replaces, and the straight or branched alkyl with 1-4 carbon atom (for example, methylol or 2-hydroxyethyl) of hydroxyl replacement); And by any one group of following formula (C) expression: formula (C):
Figure A9619508400211
(R wherein 15, R 15, R 17And R 18Be independently selected from hydrogen; straight or branched alkyl (for example, methyl, ethyl with 1-4 carbon atom; n-propyl; sec.-propyl, the normal-butyl or the tertiary butyl), hydroxyl; phenyl; halogen atom can be F, Cl; among Br and the I any one; trifluoroacetyl group, five fluorine propionyls have the straight or branched carbalkoxy (for example methoxycarbonyl or ethoxycarbonyl) of 1-4 carbon atom; the straight or branched alkyl with 1-4 carbon atom that phenyl replaces (for example; benzyl or styroyl), and the straight or branched alkyl with 1-4 carbon atom (for example, methylol or 2-hydroxyethyl) of hydroxyl replacement).
The special case of formula (A) expression is as follows:
Figure A9619508400221
Compound N o. ?????R 7 ????R 8 ????R 9 ????R 10
????1 ????n-Bu ????Cl ????H ????Me ????Et ????n-Pr ????n-Bu ????OH
????H ????Me ????Et ????n-Pr ????n-Bu ????CH 2OH
????H ????Me ????Et ????n-Pr ????n-Bu ????CH 2CH 2OH
????2 ????-Me ????H ????Me ????Et ????n-Pr ????n-Bu
????-Et ????H ????Me ????Et ????n-Pr ????n-Bu
????-CH 2CH 2-Ph ????H ????Me ????Et ????n-Pr ????n-Bu
????-CH 2-Ph ????H ????Me ????Et ????n-Pr ????n-Bu
????3 ????-COOMe ????H ????Me ????Et ????n-Pr ????n-Bu
????-COOEt ????H ????Me ????Et ????n-Pr ????n-Bu
????4 ????H ????Me ????Et ????n-Pr ????n-Bu ????Cl ????-COOMe ????H
Compound N o. ????R 7 ????R 8 ????R 9 ????R 10
????4 ????H ????Me ????Et ????n-Pr ????n-Bu ????Cl ????-COOEt ????H
????H ????Me ????Et ????n-Pr ????n-Bu ????Cl ????-COOMe ????Me
????H ????Me ????Et ????n-Pr ????n-Bu ????Cl ????-COOEt
????H ????Me ????Et ????n-Pr ????n-Bu ????H ????Cl ????-COOEt ????Et
????Me ????Et ????n-Pr ????n-Bu ????Cl ????-COOEt
????5 ????H ????H ????Me ????Et ????n-Pr ????n-Bu
????Me ????H ????Me ????Et ????n-Pr ????n-Bu
????n-Pr ????H ????Me ????Et ????n-Pr ????n-Bu
????n-Bu ????H ????Me ????Et ????n-Pr ????n-Bu
????6 ????H ????Me ????Et ????n-Pr ????n-Bu
Compound N o. ????R 7 ????R 8 ????R 9 ????R 10
????7 ????Me ????H ????Me ????Et ????n-Pr ????n-Bu
????Et ????H ????Me ????Et ????n-Pr ????n-Bu
????n-pr ????H ????Me ????Et ????n-Pr ????n-Bu
????n-Bu ????H ????Me ????Et ????n-Pr ????n-Bu
????8 ????Me ????H ????Me ????Et ????n-Pr ????n-Bu
????Et ????H ????Me ????Et ????n-Pr ????n-Bu
????n-Pr ????H ????Me ????Et ????n-Pr ????n-Bu
????n-Bu ????H ????Me ????Et ????n-Pr ????n-Bu
????9 ????Me ????H ????Me ????Et ????n-Pr ????n-Bu
????Et ????H ????Me ????Et ????n-Pr ????n-Bu
Compound N o. ????R 7 ????R 8 ????R 9 ????R 10
????9 ????n-Pr ????H ????Me ????Et ????n-Pr ????n-Bu
????n-Bu ????H ????Me ????Et ????n-Pr ????n-Bu
????10 ????-CO-CF 3 ????H ????Me ????Et ????n-Pr ????n-Bu
????-CO-CH 3 ????H ????Me ????Et ????n-Pr ????n-Bu
????11 ????H ????Me ????Et ????n-Pr ????n-Bu ????Me
????H ????Me ????Et ????n-Pr ????n-Bu ????Et
????H ????Me ????Et ????n-Pr ????n-Bu ????-ph
????H ????Me ????Et ????n-Pr ????n-Bu ????-CH 2-Ph
The special case of the group of formula (B) expression comprises:
Compound N o. ????R 11 ????R 12 ????R 13
????12 ????Me ????Et ????n-Pr ????n-Bu ????H ????H
????Me ????Et ????n-Pr ????n-Bu ????Me
????Me ????Et ????n-Pr ????n-Bu ????Et
????Me ????Et ????n-Pr ????n-Bu ????H ????-OH
????Me ????Et ????n-Pr ????n-Bu ????Me
????Me ????Et ????n-Pr ????n-Bu ????Et
????13 ????H ????Me ????Et ????n-Pr ????n-Bu
????14 ????H ????Me ????Et ????n-Pr ????n-Bu ????-NH-CO-NH-R 9 ????H
????H ????Me ????Et ????n-Pr ????n-Bu ?????-NH-CO-NH-R 9 ????Me
Compound N o. ????R 11 ????R 12 ????R 13
????14 ????H ????Me ????Et ????n-Pr ????n-Bu ????-NH-CO-NH-R 9 ????Et
????15 ????H ????Me ????Et ????n-Pr ????n-Bu
????16 ????H ????Me ????Et ????n-Pr ????n-Bu ????-NH-R 9 ????H
????H ????Me ????Et ????n-Pr ????n-Bu ????-NH-R 9 ????Me
????H ????Me ????Et ????n-Pr ????n-Bu ????-NH-R 9 ????Et
????H ????Me ????Et ????n-Pr ????n-Bu ????-NH-R 9 ????n-Bu
????H ????Me ????Et ????n-Pr ????n-Bu ????-NH-R 9 ????n-C 5H 11
????17 ????H ????Me ????Et ????n-Pr ????n-Bu
Compound N o. ????R 11 ????R 12 ????R 13
????18 ????H ????H ????Me ????Et ????n-Pr ????n-Bu ????H
????-CHO ????H ????Me ????Et ????n-Pr ????n-Bu
????19 ????H ????Me ????Et ????n-Pr ????n-Bu ????H ????H ????H
????Me ????Et ????n-Pr ????n-Bu ????Me
????H ????Me ????Et ????n-Pr ????n-Bu ????H ????Me
????H ????Me ????Et ????n-Pr ????n-Bu ????Me
????20 ????-COOMe ????H ????Me ????Et ????n-Pr ????n-Bu
????-COOEt ????H ????Me ????Et ????n-Pr ????n-Bu
????21 ????H ????Me ????Et ????n-Pr ????n-Bu ????-COOH
Compound N o. ????R 11 ????R 12 ???R 13
????21 ????H ????Me ????Et ????n-Pr ????n-Bu ????-COOMe
????H ????Me ????Et ????n-Pr ????n-Bu ????-COOEt
????22 ????H ????Me ????Et ????n-Pr ????n-Bu ????H
????H ????Me ????Et ????n-Pr ????n-Bu ????Me
????H ????Me ????Et ????n-Pr ????n-Bu ????Et
????H ????Me ????Et ????n-Pr ????n-Bu ????n-Bu
The special case of the group of formula (C) expression comprises:
Figure A9619508400321
Compound N o. ????R 15 ????R 16 ????R 17 ????R 18
????23 ????H ????H ????Me ????Et ????n-Pr ????n-Bu ????Et
????H ????Me ????Et ????n-Pr ????n-Bu ????n-Bu
????H ????Me ????Et ????n-Pr ????n-Bu ????-COOMe
????H ????Me ????Et ????n-Pr ????n-Bu ????-COOEt
????Me ????H ????Me ????Et ????n-Pr ????n-Bu ????Et
????H ????Me ????Et ????n-Pr ????n-Bu ????n-Bu
????H ????Me ????Et ????n-Pr ????n-Bu ????-COOMe
????H ????Me ????Et ????n-Pr ????n-Bu ????-COOEt
????24 ????H ????Me ????Et ????n-Pr ????n-Bu
Compound N o. ????R 15 ????R 16 ????R 17 ????R 18
????25 ????H ????Me ????Et ????n-Pr ????n-Bu
????26 ????H ????Me ????Et ????n-Pr ????n-Bu
????27 ????H ????Me ????Et ????n-Pr ????n-Bu ????H ????H ????H
????H ????Me ????Et ????n-Pr ????n-Bu ????Me ????H
????H ????Me ????Et ????n-Pr ????n-Bu ????H ????-COOMe
????H ????Me ????Et ????n-Pr ????n-Bu ????H ????-COOEt
????28 ????H ????Me ????Et ????n-Pr ????n-Bu ????H ????H
????H ????Me ????Et ????n-Pr ????n-Bu ????-COOMe
????H ????Me ????Et ????n-Pr ????n-Bu ????-COOEt
Compound N o. ????R 15 ????R 16 ????R 17 ????R 18
????28 ????H ????Me ????Et ????n-Pr ????n-Bu ????Me ????H
????H ????Me ????Et ????n-Pr ????n-Bu ????-COOMe
????H ????Me ????Et ????n-Pr ????n-Bu ????-COOEt
????29 ????H ????Me ????Et ????n-Pr ????n-Bu ????H
????H ????Me ????Et ????n-Pr ????n-Bu ????Me
????H ????Me ????Et ????n-Pr ????n-Bu ????Et
????30 ????H ????Me ????Et ????n-Pr ????n-Bu
Use synthetic agent of the present invention to prepare synthesizing typically under atmospheric pressure of 1H-tetrazole compound, and carried out 30 minutes to 24 hours 50-150 ℃ condition.If desired, among the present invention, tetrazole compound can prepare in reaction solvent, and the example of these solvents has methylethylketone, DMF, propyl carbinol, amylalcohol, n-hexyl alcohol, ethanol, Virahol, enanthol, DMSO, chloroform, ethylene dichloride, THF ， diox, N-Methyl pyrrolidone, 1, and 3-methylimidazole alkane diketone (1,3-diethylimidazolidinone) and t-butyl methyl ether.
Embodiment
The following examples are used to further specify the present invention and do not limit the present invention in any way.The preparation of embodiment 1:5-ethoxycarbonyl-1H-tetrazolium
Figure A9619508400361
On the glass reactor of a 200mL, equip thermometer, dropping funnel and reflux exchanger, 14.4g (105.6mmol) zinc chloride of packing into therein, 13.7g (211.2mmol) sodiumazide and 70mL methylethylketone stir it then in water-bath.In the gained mixture, in about 30 minutes time, drip 10.15g (102.5mmol) ethyl cyanoformate by dropping funnel; Then, elevated temperature makes and carried out under the internal temperature that is reflected at 60-70 ℃ 1 hour.
After reaction finishes, cool off and add excessive dilute hydrochloric acid, stir about is 1 hour then.Vacuum is steamed and is removed methylethylketone and extract (continuous extraction) residual water layer with t-butyl methyl ether; Use MgSO 4After the drying, steaming desolventizes and obtains the 12.8g white crystals.Use the benzene recrystallization, obtain high purity terazole derivatives 11.68g (productive rate behind the recrystallization: 80.2%).m.p.：90.4-91.6℃。The preparation of embodiment 2:5-methyl isophthalic acid H-tetrazolium
Figure A9619508400362
With acetonitrile (50mL), 13g (95.4mmol) zinc chloride and 12.4g (190.7mmol) sodiumazide are packed in the 100mL glass reactor with thermometer and reflux exchanger.When stirring,, reaction was carried out about 10 hours with the reaction mixture reflux.
Add rare HCl in reaction mixture, behind the formation individual layer, vacuum is removed unreacted acetonitrile.Behind extraction (continuous extraction) residue (water layer), ethyl acetate layer MgSO 4Drying, vacuum boils off solvent, obtains 5-methyl isophthalic acid H-tetrazolium white crystals.Crude product, 7.4g (productive rate, 92.5%).m.p.：146.2-147.0℃。The preparation of embodiment 3:5-(4 '-methyl biphenyl-2-yl)-1H-tetrazolium
Make 5g (25.9mmol) 4 '-methyl biphenyl-2-nitrile, 7.06g (51.8mmol) zinc chloride, 6.73g (103.6mmol) in the 50mL glass reactor of the mixture of sodiumazide and 15mL DMF in thermometer and reflux exchanger are housed, 110-120 ℃ of reaction 15 hours.
After confirming that by TLC raw material has not existed, cooling and internal temperature reduce to 100 ℃ or lower after, slowly add rare HCl.Filter the white crystals that collecting precipitation goes out, wash with water and vacuum-drying, obtain highly purified terazole derivatives 5.74g (productive rate, 94.0%).m.p.：147.5-148.5℃。The preparation of embodiment 4:5-phenyl-1H-tetrazolium
Figure A9619508400372
With 10g (97.0mmol) cyanobenzene, 14.5g (106.7mmol) zinc chloride, 13.9g (213.3mmol) mixture of sodiumazide and 20mL DMF is packed in the 100mL glass reactor that has thermometer and reflux exchanger, stir down, this mixture was reacted 30 minutes under 100-110 ℃ internal temperature.
After determining that by FLC raw material has not existed, cool off and add excessive rare HCl acidifying mixture, then with this mixture stirred for several hour under acid state.Filter the crystallization that collecting precipitation goes out, wash with water, vacuum-drying obtains highly purified 5-phenyl-1H-tetrazolium 13.7g (productive rate: 96.6%).m.p.：215.5-217.0℃。The preparation of embodiment 5:5-(2-bromophenyl)-1H-tetrazolium
Figure A9619508400381
With 8.83g (48.5mmol) 2-bromobenzylcyanide, 7.27g (53.4mmol) zinc chloride, 6.94g (106.8mmol) mixture of sodiumazide and 10mL DMF is packed in the 50mL glass reactor that has thermometer and reflux exchanger, when stirring, this mixture was reacted 2 hours under 100-110 ℃ internal temperature.
After determining that by TLC raw material has not existed, carry out aftertreatment by embodiment 4.Obtain highly purified 5-(2-bromophenyl)-1H-tetrazolium 9.44g (productive rate, 86.5%).m.p.：181.5-182.5℃。Embodiment 6:5-ethyl-2 imido grpups-3-(2 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl)-methyl isophthalic acid, 3, the preparation of 4-Thiadiazoline
Figure A9619508400391
Final product follows these steps to (1)-(4) preparation.(1) 2-trifluoroacetamido-5-ethyl-1,3, the preparation of 4-thiadiazoles
At room temperature, the 260mL triethylamine is added 200g 2-amino-5-ethyl-1,3, in the suspension of 4-thiadiazoles in 3L toluene; In this mixture, drip the 265mL trifluoroacetic anhydride down ice-cooled, and this mixture was at room temperature stirred 1 hour.In reaction mixture, add entry, filter the crystallization that collecting precipitation goes out.Add ethyl acetate in addition in filtrate, organic layer is told and used anhydrous magnesium sulfate drying, vacuum is steamed and is desolventized then, obtains title compound 237.5g (60%).(2) preparation of 4-brooethyl-2 '-cyanobiphenyl
In the 110mg tetracol phenixin, add 4-methyl-2 '-cyanobiphenyl (10.5g), N-bromosuccinimide (9.79g) and 2,2 '-Diisopropyl azodicarboxylate (120mg), and with this mixture heating up backflow 2 hours.The filtering insolubles cools off filtrate while hot; Then, filter the crystallization that collecting precipitation goes out, obtain title compound 6.6g (44%).(3) 5-ethyl-2-trifluoroacetyl imino--3-(2 '-cyanobiphenyl-4-yl) methyl isophthalic acid, 3, the preparation of 4-Thiadiazoline
With sodium hydride (124.1g; Be dispersed in 55% oil) be suspended in 1.5L N, ice-cooled following in the dinethylformamide, with the 2-trifluoroacetamido-5-ethyl-1,3 of preparation among the 533.7g (1), the 4-thiadiazoles adds in the ice-cooled suspension.After treating that release hydrogen stops, at 3LN, the solution in the dinethylformamide splashes in this mixture with above-mentioned (2) middle 4-brooethyl-2 '-cyanobiphenyl (643.6g) for preparing.This mixture was at room temperature stirred 1 hour, stirred 5 hours at 80 ℃ then.With the reaction mixture vacuum concentration; After adding entry and ethyl acetate, organic layer is washed with water, use anhydrous magnesium sulfate drying, vacuum is steamed and is desolventized.Residue is carried out silica gel column chromatography, with the mixture wash-out of 3: 1 hexanes and ethyl acetate.The coarse crystallization ethyl alcohol recrystallization obtains title compound 490.8g (50%).(4) 5-ethyl-2-imino--3-(2 '-(1H-tetrazolium-5-yl) biphenyl-4-yl) methyl isophthalic acid, 3, the preparation of 4-Thiadiazoline
Thermometer is being housed, and reflux exchanger adds 30mL n-BuOH in the 100mL glass reactor of calcium chloride tube and agitator, 6.0g (44mmol) zinc chloride and 7.4g (113.8mmol) sodiumazide, and with its stirring 30 minutes.5-ethyl-2-trifluoroacetyl imino--3-(2 '-cyanobiphenyl-4-yl) methyl isophthalic acid that in this mixture, adds preparation among the 9.5g (22.8mmol) above-mentioned (3), 3, the 4-Thiadiazoline rises to 105-115 ℃ with the internal temperature of this mixture.Under this temperature, reaction was carried out 24 hours.
After determining that by TLC raw material has reacted completely, add an amount of chloroform and water; Then use 10%H 2SO 4Handle, and tell organic layer.In organic layer, add the 5%NaOH aqueous solution, and with this compound stirred for several hour; After determining that by TLC hydrolysis fully, divide water-yielding stratum.With the 3NHCl aqueous solution pH value of the buck layer that reclaims is adjusted to 5.5-6.0, at this moment white crystals occurs in the solution; This crystallization is told in filtration, and drying obtains required compound 6.5g (thick productive rate, 78.5%).Embodiment 7:5-ethyl-2-imino--3-(2 '-(1H-tetrazolium-5-yl)-biphenyl-4-yl) methyl isophthalic acid, 3, the preparation of 4-Thiadiazoline
Figure A9619508400401
Thermometer is being housed, is adding 300mL n-BuOH in the 1000mL glass reactor of reflux exchanger and agitator, 73.9g (0.54mmol) zinc chloride and 71.0g (1.1mol) sodiumazide also stir this mixture 30 minutes.In mixture, add in addition 90.0g (0.28mol) 5-ethyl-2-imino--3-(2 '-cyanobiphenyl-4-yl) methyl isophthalic acid, 3, the 4-Thiadiazoline, and the internal temperature of this mixture is heated to 105-115 ℃, reaction was carried out 24 hours.
After determining that by TLC raw material has reacted completely, add an amount of chloroform and water; Then use 10%H 2SO 4Handle, and tell organic layer.In organic layer, add 5% aqueous sodium hydroxide solution, and with reaction mixture stirred for several hour; Divide water-yielding stratum then.With the 3N HCl aqueous solution pH value of the alkali aqueous solution that reclaims is adjusted to 5.5-6.0, at this moment produces white crystals in the solution.This crystallization is told in filtration, and drying obtains required compound 76.5g (thick productive rate, 75%).
Industrial applicibility
The application of the invention tetrazolium reagent, expection will have following advantages, and therefore, as the commercial run of producing 1H-tetrazole compound, the present invention is exceedingly useful. (1) replacement method (B) or (C) in the trialkyltin azide of the costliness used, the present invention uses cheap zinc chloride, thereby has reduced cost of material. In addition, can avoid the tin compound (causing the skin dermexanthesis) that uses toxicity very high. (2) compare with method (D), method of the present invention can allow to use multi-solvents, and the inventive method in use has the flexibility of height. In addition, zinc chloride is than aluminium chloride cheap (the former price of per minute jin be the latter about 60%); Aluminium chloride needs alkali metal azide of three molar equivalents in addition, and zinc chloride only needs two molar equivalents, and this also makes expense reduce. The restriction that is not had the form of sterically hindered nitrile when (3) using for zinc chloride of the present invention/alkali metal azide, they can be used for any type of nitrile in principle.

Claims (8)

1. nitrile by formula (I):
R-CN (I) wherein R is any substituting group, the reagent of synthesis type (II) 1H-tetrazolium,
Figure A9619508400021
R defines as above in the formula (II), and it is characterized in that: it comprises an alkali metal azide and zinc chloride.
2. according to the synthetic agent of claim 1, wherein an alkali metal azide is a sodiumazide.
3. according to the synthetic agent of claim 1 or 2; wherein R is selected from hydrogen; the alkyl that replaces non-imposedly; the alkenyl that replaces non-imposedly; the alkynyl that replaces non-imposedly; the alkoxyl group that replaces non-imposedly; the alkylthio that replaces non-imposedly; the alkyl sulphonyl that replaces non-imposedly; the alkyl sulphinyl that replaces non-imposedly, the alkylamino that replaces, the alkenyloxy that replaces non-imposedly non-imposedly; the carbalkoxy that replaces non-imposedly; the aryl that replaces non-imposedly, the aryloxy that replaces, the artyl sulfo that replaces non-imposedly non-imposedly; the aralkyl that replaces, the aromatic yl alkenyl that replaces and non-imposed the heterocyclic radical that replaces non-imposedly non-imposedly.
4. according to the synthetic agent of claim 1 or 2, wherein R is selected from hydrogen; Straight or branched has the alkyl that replaces of 1-4 carbon atom non-imposedly; Straight or branched has the alkoxyl group that replaces of 1-4 carbon atom non-imposedly; Straight or branched has the alkyl sulphonyl that replaces of 1-4 carbon atom non-imposedly; Phenyl; Mono-substituted phenyl shown in the following formula:
Figure A9619508400022
R wherein 1Be selected from and can be F, Cl, the halogen atom of any one among Br and the I has the straight or branched alkyl of 1-4 carbon atom, has the straight or branched alkoxyl group of 1-4 carbon atom, has the straight or branched alkyl sulphonyl of 1-4 carbon atom, nitro, amino and carboxyl; Di-substituted-phenyl shown in the following formula: R wherein 2And R 3Be independently selected from and can be F, Cl, the halogen atom of any one among Br and the I, straight or branched alkyl with 1-4 carbon atom has the straight or branched alkoxyl group of 1-4 carbon atom, has the straight or branched alkyl sulphonyl of 1-4 carbon atom, nitro, amino and carboxyl; 4 '-methyl diphenyl-2-base; Group shown in the following formula:
Figure A9619508400032
Wherein A can be O, NH or CH 2In any one, Z has to be selected from down any one divalent group of array structure:
R 4, R 5And R 6Be independently selected from and can be F, Cl, the halogen atom of any one among Br and the I, straight or branched alkyl with 1-4 carbon atom has the straight or branched alkoxyl group of 1-4 carbon atom, has the straight or branched alkyl sulphonyl of 1-4 carbon atom, nitro, amino and carboxyl; Group shown in the following formula: Wherein X and Y are independently selected from CH and N, and R 4, R 5And R 6Be independently selected from and can be F, Cl, the halogen atom of any one among Br and the I, straight or branched alkyl with 1-4 carbon atom has the straight or branched alkoxyl group of 1-4 carbon atom, has the straight or branched alkyl sulphonyl of 1-4 carbon atom, nitro, amino and carboxyl; Any one group that is expressed from the next:
Figure A9619508400051
R wherein 7, R 8, R 9And R 10Be independently selected from hydrogen, straight or branched alkyl with 1-4 carbon atom, hydroxyl, phenyl, can be F, Cl, the halogen atom of any one among Br and the I, trifluoroacetyl group, five fluorine propionyls, the straight or branched carbalkoxy, the straight or branched alkyl that phenyl replaces, and the straight or branched alkyl of hydroxyl replacement with 1-4 carbon atom; Any one group that is expressed from the next:
Figure A9619508400061
R wherein 11, R 12, R 13And R 14Be independently selected from hydrogen, straight or branched alkyl with 1-4 carbon atom, hydroxyl, phenyl, can be F, Cl, the halogen atom of any one among Br and the I, trifluoroacetyl group, five fluorine propionyls, straight or branched carbalkoxy with 1-4 carbon atom, the straight or branched alkyl that phenyl replaces, and the straight or branched alkyl with 1-4 carbon atom of hydroxyl replacement with 1-4 carbon atom; And any one group that is expressed from the next:
Figure A9619508400062
R wherein 15, R 16, R 17And R 18Be independently selected from hydrogen; straight or branched alkyl with 1-4 carbon atom, hydroxyl, phenyl; can be F; Cl, the halogen atom of any one among Br and the I, trifluoroacetyl group; five fluorine propionyls; straight or branched carbalkoxy with 1-4 carbon atom, the straight or branched alkyl that phenyl replaces, and the straight or branched alkyl with 1-4 carbon atom of hydroxyl replacement with 1-4 carbon atom.
5. the method for a synthesis type (II) 1H-tetrazolium:
Figure A9619508400072
Wherein R is any substituting group, it is characterized in that making the nitrile of formula (I):
R-CN (I) wherein R definition as above reacts with an alkali metal azide in the presence of the catalyzer zinc chloride.
6. according to the method for claim 5, wherein an alkali metal azide is a sodiumazide.
7. according to the method for claim 5 or 6; wherein R is selected from hydrogen; the alkyl that replaces non-imposedly; the alkenyl that replaces non-imposedly; the alkynyl that replaces non-imposedly; the alkoxyl group that replaces non-imposedly; the alkylthio that replaces non-imposedly; the alkyl sulphonyl that replaces non-imposedly; the alkyl sulphinyl that replaces non-imposedly, the alkylamino that replaces, the alkenyloxy that replaces non-imposedly non-imposedly; the carbalkoxy that replaces non-imposedly; the aryl that replaces non-imposedly, the aryloxy that replaces, the artyl sulfo that replaces non-imposedly non-imposedly; the aralkyl that replaces, the aromatic yl alkenyl that replaces and non-imposed the heterocyclic radical that replaces non-imposedly non-imposedly.
8. according to the method for claim 5 or 6, wherein R is selected from hydrogen; Straight or branched has the alkyl that replaces of 1-4 carbon atom non-imposedly; Straight or branched has the alkoxyl group that replaces of 1-4 carbon atom non-imposedly; Straight or branched has the alkyl sulphonyl that replaces of 1-4 carbon atom non-imposedly; Phenyl; Mono-substituted phenyl shown in the following formula: R wherein 1Be selected from and can be F, Cl, the halogen atom of any one among Br and the I has the straight or branched alkyl of 1-4 carbon atom, has the straight or branched alkoxyl group of 1-4 carbon atom, has the straight or branched alkyl sulphonyl of 1-4 carbon atom, nitro, amino and carboxyl; Di-substituted-phenyl shown in the following formula: R wherein 2And R 3Be independently selected from and can be F, Cl, the halogen atom of any one among Br and the I, straight or branched alkyl with 1-4 carbon atom has the straight or branched alkoxyl group of 1-4 carbon atom, has the straight or branched alkyl sulphonyl of 1-4 carbon atom, nitro, amino and carboxyl; 4 '-methyl diphenyl-2-base; Group shown in the following formula: Wherein A can be O, NH or CH 2In any one; Z has to be selected from down any one divalent group of array structure:
Figure A9619508400091
R 4, R 5And R 6Be independently selected from and can be F, Cl, the halogen atom of any one among Br and the I, straight or branched alkyl with 1-4 carbon atom has the straight or branched alkoxyl group of 1-4 carbon atom, has the straight or branched alkyl sulphonyl of 1-4 carbon atom, nitro, amino and carboxyl; Group shown in the following formula: Wherein X and Y are independently selected from CH and N, and R 4, R 5And R 6Be independently selected from and can be F, Cl, the halogen atom of any one among Br and the I, straight or branched alkyl with 1-4 carbon atom has the straight or branched alkoxyl group of 1-4 carbon atom, has the straight or branched alkyl sulphonyl of 1-4 carbon atom, nitro, amino and carboxyl; Any one group that is expressed from the next:
Figure A9619508400102
R wherein 7, R 8, R 9And R 10Be independently selected from hydrogen, straight or branched alkyl with 1-4 carbon atom, hydroxyl, phenyl, can be F, Cl, the halogen atom of any one among Br and the I, trifluoroacetyl group, five fluorine propionyls, the straight or branched carbalkoxy, the straight or branched alkyl that phenyl replaces, and the straight or branched alkyl of hydroxyl replacement with 1-4 carbon atom; Any one group that is expressed from the next:
Figure A9619508400112
R wherein 11, R 12, R 13And R 14Be independently selected from hydrogen, straight or branched alkyl with 1-4 carbon atom, hydroxyl, phenyl, can be F, Cl, the halogen atom of any one among Br and the I, trifluoroacetyl group, five fluorine propionyls, straight or branched carbalkoxy with 1-4 carbon atom, the straight or branched alkyl that phenyl replaces, and the straight or branched alkyl with 1-4 carbon atom of hydroxyl replacement with 1-4 carbon atom; And any one group that is expressed from the next: R wherein 15, R 16, R 17And R 18Be independently selected from hydrogen; straight or branched alkyl with 1-4 carbon atom, hydroxyl, phenyl; can be F; Cl, the halogen atom of any one among Br and the I, trifluoroacetyl group; five fluorine propionyls; straight or branched carbalkoxy with 1-4 carbon atom, the straight or branched alkyl that phenyl replaces, and the straight or branched alkyl with 1-4 carbon atom of hydroxyl replacement with 1-4 carbon atom.
CN96195084A 1995-05-26 1996-05-27 Novel reagent for tetrazole synthesis and process for producing tetrazoles therewith Pending CN1189158A (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1304381C (en) * 2004-07-09 2007-03-14 浙江工业大学 Chemical synthesis method of 1,2,3,4-tetra nitroazole kind compound
CN103360334A (en) * 2013-07-11 2013-10-23 浙江海蓝化工有限公司 Aqueous-phase synthesis method of 5-phenyl-1H-tetrazole
CN107556256A (en) * 2016-06-30 2018-01-09 东友精细化工有限公司 The synthetic method of 5 (C1 ~ C4 alkyl) tetrazoliums
CN110117791A (en) * 2019-05-23 2019-08-13 电子科技大学 A kind of binding force promotor for holes on high density interconnected printed circuit board brownification liquid
CN111943899A (en) * 2020-09-08 2020-11-17 河北凯力昂生物科技有限公司 Synthesis method of 5-ethyl formate tetrazole

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1304381C (en) * 2004-07-09 2007-03-14 浙江工业大学 Chemical synthesis method of 1,2,3,4-tetra nitroazole kind compound
CN103360334A (en) * 2013-07-11 2013-10-23 浙江海蓝化工有限公司 Aqueous-phase synthesis method of 5-phenyl-1H-tetrazole
CN107556256A (en) * 2016-06-30 2018-01-09 东友精细化工有限公司 The synthetic method of 5 (C1 ~ C4 alkyl) tetrazoliums
CN110117791A (en) * 2019-05-23 2019-08-13 电子科技大学 A kind of binding force promotor for holes on high density interconnected printed circuit board brownification liquid
CN110117791B (en) * 2019-05-23 2023-11-10 电子科技大学 Binding force promoter for brown oxide liquid of high-density interconnection printed circuit board
CN111943899A (en) * 2020-09-08 2020-11-17 河北凯力昂生物科技有限公司 Synthesis method of 5-ethyl formate tetrazole
CN111943899B (en) * 2020-09-08 2023-04-21 河北凯诺中星科技有限公司 Synthesis method of 5-ethyl formate tetrazole

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