CN108863965A - The method that one kettle way prepares 1,2,4- triazole -3- formamide - Google Patents
The method that one kettle way prepares 1,2,4- triazole -3- formamide Download PDFInfo
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- hydrazine
- triazole
- alcohol
- formamide
- organic solvent
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- 238000000034 method Methods 0.000 title claims abstract description 33
- ZEWJFUNFEABPGL-UHFFFAOYSA-N 1,2,4-triazole-3-carboxamide Chemical compound NC(=O)C=1N=CNN=1 ZEWJFUNFEABPGL-UHFFFAOYSA-N 0.000 title claims abstract description 19
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical class NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims abstract description 11
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 238000006482 condensation reaction Methods 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 9
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 9
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003495 polar organic solvent Substances 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- FUSNOPLQVRUIIM-UHFFFAOYSA-N 4-amino-2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-n-[3-(trifluoromethyl)phenyl]pyrimidine-5-carboxamide Chemical compound O=C1NC(C)(C)CN1C(N=C1N)=NC=C1C(=O)NC1=CC=CC(C(F)(F)F)=C1 FUSNOPLQVRUIIM-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- SHOTZAAGWLBZQV-UHFFFAOYSA-N aminoazanium;carbonate Chemical compound NN.NN.OC(O)=O SHOTZAAGWLBZQV-UHFFFAOYSA-N 0.000 claims description 3
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical group Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 239000012493 hydrazine sulfate Substances 0.000 claims description 3
- 229910000377 hydrazine sulfate Inorganic materials 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229940113088 dimethylacetamide Drugs 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims 1
- 235000011054 acetic acid Nutrition 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 150000004040 pyrrolidinones Chemical class 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 12
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000003443 antiviral agent Substances 0.000 abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000010792 warming Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- LJVQHXICFCZRJN-UHFFFAOYSA-N 1h-1,2,4-triazole-5-carboxylic acid Chemical compound OC(=O)C1=NC=NN1 LJVQHXICFCZRJN-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 4
- 238000005915 ammonolysis reaction Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 229960000329 ribavirin Drugs 0.000 description 3
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 3
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N anhydrous methyl formate Natural products COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 241000709721 Hepatovirus A Species 0.000 description 1
- 241000725303 Human immunodeficiency virus Species 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical class [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to synthesize the preparation field of the key intermediate of antiviral drug, the method that one kettle way prepares 1,2,4- triazole -3- formamides is disclosed.This method is oxamides and N, and condensation reaction occurs for N- dimethylacetal, and the product of condensation reaction synthesizes 1,2,4- triazole -3- formamides with hydrazine or hydrazonium salt cyclization under the action of catalyst.This method raw material is easy to get, and synthetic route is short, and convenient post-treatment is simple, and reaction will not generate pollution, and quantity of three wastes is few, is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation of the key intermediate of synthesis antiviral drug more particularly to one kettle way preparations
The method of 1,2,4- triazole -3- formamide.
Background technique
Ribavirin is the antiviral drugs of broad spectrum high-effect, belongs to the synthesis of nucleoside medicine, to Respiratory Syncytial Virus(RSV), parainfluenza
Virus, hepatitis A virus and AIDS virus etc. have inhibiting effect, and 1,2,4- triazole -3- formamide is synthesis Ribavirin
Key intermediate, Witkowski etc. synthesize Ribavirin with ribose -1- phosphoric acid with enzymatic triazole formamide, are detailed in the U.S.
Patent US3976545.
Currently, the first is with 1,2,4- tri- there are mainly three types of the synthetic routes of 1,2,4- triazole -3- formamides of preparation
Nitrogen azoles -3- formic acid is raw material through esterification or ethyl esterified generation 1,2,4- triazole -3- methyl formate or 1,2,4- triazole -
3- Ethyl formate, then 1,2,4- triazole -3- formamides are prepared through ammonolysis.To the methanol of 1,2,4- triazole -3- methyl formate
It is passed through ammonia in solution to being saturated, reacts 48 hours ammonolysis at room temperature and prepares target product, reaction equation is as follows：
Above-mentioned raw materials used 1,2,4- triazole -3- carboxylate synthetic route of first method is long, and cost of material is high, the three wastes
Amount is big.
Second is 1,2,4- triazole -3- formamides to be prepared with Formamidine acetate cyclization, using careless amine hydrazides as raw material with grass
Amide hydrazine is raw material, and ethyl alcohol is solvent, and temperature rising reflux cyclisation prepares 1,2,4- triazole of target compound-after Formamidine acetate is added
3- formamide.Reaction equation is as follows：
The raw acetic acid carbonamidine that above-mentioned second method uses is prepared by hydrogen cyanide, and raw material is difficult to obtain, and price is higher to be made
Product cost is higher.
The third method is with 1,2,4- triazole -3- carboxylic acid dimer for starting material, such as German patent DE 1979-
2940654 with 1,2,4- triazole -3- carboxylic acid dimer be raw material, ammonolysis is heated in ammonium hydroxide, is evaporated after the reaction was completed more
Remaining ammonia, generates 1,2,4- triazole -3- formamide, and reaction equation is as shown in Equation 3：
1,2,4- triazole -3- carboxylic acid dimer in the third above-mentioned method is still needed to by 1,2,4- triazole -3- carboxylic acid
It is dehydrated and prepares through thionyl chloride, generation sulfur dioxide gas is seriously polluted, and quantity of three wastes is big, and production cost is higher.
In view of this, providing, a kind of reaction raw materials are cheap and easy to get, reduce production cost, synthesis technology simply prepares 1,2,
The method of 4- triazole -3- formamide, is of great significance.
Summary of the invention
In order to solve preparation method cost of material height, the synthesis road of 1,2,4- triazole -3- formamide in the prior art
The problem that line is cumbersome and quantity of three wastes is big, the present invention provides the methods that one kettle way prepares 1,2,4- triazole -3- formamides.
In order to solve the above-mentioned technical problem, the present invention uses following technical scheme：
The method that one kettle way prepares 1,2,4- triazole -3- formamides, oxamides and N, N- dimethylacetal are condensed
Reaction, the product of condensation reaction synthesize 1,2,4- triazole -3- formamides with hydrazine or hydrazonium salt cyclization under the action of catalyst,
Reaction is shown below：
Wherein, alkyl R is selected from methyl, ethyl, propyl, isopropyl or normal-butyl in N, N- dimethylacetal.
Reaction raw materials provided by the invention are compared in the prior art, oxamides, N, N- dimethylacetal and hydrazine or
Hydrazonium salt is cheap, and raw material is easy to get, and reaction is completed in one pot, and reaction route is brief, simple process.
The raw material oxamides can be through commercially available purchase, can also be by diethy-aceto oxalate or dimethyl oxalate through routine
Ammonolysis is prepared.
The hydrazine is pure hydrazine, hydrazine hydrate or hydrazonium salt, it is preferable that the hydrazonium salt is hydrazine sulfate, hydrazine hydrochloride or carbonic acid hydrazine.
The organic solvent of condensation reaction provided by the invention is polar organic solvent；The polar organic solvent is selected from N, N-
Dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide, formamide, N-Methyl pyrrolidone or alcohol organic solvent；
Preferably, the alcohol organic solvent is one kind of methanol, ethyl alcohol, isopropanol, butanol, n-amyl alcohol, isoamyl alcohol or ethylene glycol
Or it is several, it is further preferable that alcohol organic solvent is isoamyl alcohol.
The pressure of entire reaction system is 0.1-5Mpa, and the heating method of reaction is direct conventional heating or microwave heating side
Formula.
The present invention also provides the 1,2,4- triazole -3- formamides prepared by the above method.
The present invention provides the methods that one kettle way prepares 1,2,4- triazole -3- formamide.The oxamides, N of this method, N-
Dimethylacetal and hydrazine or hydrazonium salt are cheap, and raw material is easy to get, and reaction is completed in one pot, and synthetic route is short；It is anti-simultaneously
Answer product that can obtain product through cooling, filtering, washing and drying, convenient post-treatment is simple；Reaction will not generate pollution, quantity of three wastes
It is few, it is suitable for industrialized production.
Specific embodiment
The invention discloses the method that one kettle way prepares 1,2,4- triazole -3- formamides, those skilled in the art can be with
Present disclosure is used for reference, realization of process parameters is suitably modified.In particular, it should be pointed out that all similar substitutions and modifications are to ability
It is it will be apparent that they are considered as including in the present invention for field technique personnel.Method and application of the invention is
Through being described by preferred embodiment, related personnel obviously can not depart from the content of present invention, in spirit and scope to this
Methods and applications described in text are modified or appropriate changes and combinations, carry out implementation and application the technology of the present invention.
In preparation method provided by the invention, further include the steps that purifying product.Specifically, including to product into
Row cooling, filtering, washing and drying and other steps.
Below with reference to embodiment, the present invention is further explained：
Embodiment 1
Oxamides (15.0g, 0.17mol) is added in the there-necked flask of 250mL, 100mL n-butanol is added, drips at room temperature
Add N, N- dimethyl-acetal (25.0g, 0.17mol) is warming up to 60 DEG C and reacts 8 hours, and TLC detects N, N- dimethyl-acetal
Then hydrazine hydrate (0.17mol) and formic acid (7.82g, 0.17mol) are added into reaction mixture, is warming up to 120 for conversion completely
DEG C back flow reaction 10 hours, fully reacting was detected through TLC.Room temperature is cooled the temperature to, solid will be precipitated and filter and suspend in water,
It is neutrality that sodium hydroxide, which is added, and adjusts aqueous pH values, and obtained solid filtered, be washed with water, and dry white solid 12.4g is received
Rate 65%, 316 DEG C -317 DEG C of fusing point.
1H NMR(DMSO-d6,500MHz),δ:7.68,7.92(bs,1H+1H,NH),8.39(s,1H,CH)；HRMS
calcd for:C3H5N4O[M+H+]113.0463,found:113.0468。
Embodiment 2
Oxamides (15.0g, 0.17mol) is added in the there-necked flask of 250mL, 100mL isoamyl alcohol is added, drips at room temperature
Add N, N- dimethyl methyl acetal (20.2g, 0.17mol) is warming up to 80 DEG C and reacts 8 hours, and TLC detects N, N- dimethyl methyl acetal
Conversion completely.Hydrazine hydrochloride (17.5g, 0.17mol) and acetic acid (20.4g, 0.340mol) are added into reaction mixture, is warming up to
130 DEG C back flow reaction 10 hours.Fully reacting is detected through TLC.Room temperature is cooled the temperature to, solid will be precipitated and filter and be suspended in water
In, it is neutrality that sodium hydroxide, which is added, and adjusts aqueous pH values.Obtained solid is filtered, and is washed with water, dry white solid
13.3g, yield 70%, 316 DEG C -317 DEG C of fusing point.
1H NMR(DMSO-d6,500MHz),δ:7.68,7.92(bs,1H+1H,NH),8.39(s,1H,CH)；HRMS
calcd for:C3H5N4O[M+H+]113.0463,found:113.0468。
Embodiment 3
Oxamides (15.0g, 0.17mol) is added in the there-necked flask of 250mL, 100mL N, N- dimethylacetamide is added
N is added dropwise in amine at room temperature, and N- dimethyl methyl acetal (20.2g, 0.17mol) is warming up to 50 DEG C and reacts 8 hours, and TLC detects N, N-
Dimethyl methyl acetal converts completely.Into reaction mixture be added carbonic acid hydrazine (47.9g, 0.51mol) propionic acid (25.2g,
0.34mol), 80 DEG C of back flow reactions are warming up to 10 hours.Fully reacting is detected through TLC.Room temperature is cooled the temperature to, solid will be precipitated
It filters and suspends in water, it is neutrality that sodium hydroxide, which is added, and adjusts aqueous pH values.Obtained solid is filtered, and is washed with water, dry
White solid 11.0g, yield 58%, 316 DEG C -317 DEG C of fusing point.
1H NMR(DMSO-d6,500MHz),δ:7.68,7.92(bs,1H+1H,NH),8.39(s,1H,CH)；HRMS
calcd for:C3H5N4O[M+H+]113.0463,found:113.0468。
Embodiment 4
Oxamides (15.0g, 0.17mol) is added in the there-necked flask of 250mL, 100mL dimethyl sulfoxide, room temperature is added
Lower dropwise addition N, N- dimethyl n butyral (34.5g, 0.17mol) is warming up to 80 DEG C and reacts 8 hours, and TLC detects N, N- dimethyl
Positive butyral converts completely.Be added into reaction mixture hydrazine sulfate (22.1g, 0.17mol) and p-methyl benzenesulfonic acid (29.2g,
0.17mol), 140 DEG C are warming up to react 5 hours.Fully reacting is detected through TLC.Room temperature is cooled the temperature to, solid will be precipitated and filter
And suspend in water, it is neutrality that sodium hydroxide, which is added, and adjusts aqueous pH values.Obtained solid is filtered, and is washed with water, whitely dry
Color solid 12.2g, yield 64%, 316 DEG C -317 DEG C of fusing point.
1H NMR(DMSO-d6,500MHz),δ:7.68,7.92(bs,1H+1H,NH),8.39(s,1H,CH)；HRMS
calcd for:C3H5N4O[M+H+]113.0463,found:113.0468。
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (9)
1. the method that one kettle way prepares 1,2,4- triazole -3- formamides, which is characterized in that oxamides and N, N- dimethylacetal
Condensation reaction occurs, the product of condensation reaction synthesizes 1,2,4- triazoles-with hydrazine or hydrazonium salt cyclization under the action of catalyst
3- formamide, reaction are shown below：
Wherein, alkyl R is selected from methyl, ethyl, propyl, isopropyl or normal-butyl in N, N- dimethylacetal.
2. the method as described in claim 1, which is characterized in that the hydrazine is pure hydrazine or hydrazine hydrate.
3. method according to claim 2, which is characterized in that the hydrazonium salt is hydrazine hydrochloride, hydrazine sulfate and carbonic acid hydrazine.
4. the method as described in claim 1, which is characterized in that the organic solvent of the condensation reaction is polar organic solvent；
The polar organic solvent is selected from N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide, formamide, N- first
Base pyrrolidones or alcohol organic solvent.
5. method as claimed in claim 4, which is characterized in that the alcohol organic solvent is methanol, ethyl alcohol, isopropanol, fourth
The one or more of alcohol, n-amyl alcohol, isoamyl alcohol or ethylene glycol.
6. the method as described in claim 1, which is characterized in that the temperature of the condensation reaction is 50-130 DEG C；The cyclisation
The temperature of reaction is 80-160 DEG C.
7. the method as described in claim 1, which is characterized in that the oxamides and N, N- dimethylacetal, hydrazine or hydrazonium salt are urged
Agent molar ratio is 1.0:1.0-3.0:1.0-3.0:1.0-3.0.
8. method as claimed in claim 1 or 7, which is characterized in that the catalyst is formic acid, acetic acid, propionic acid or to toluene
Sulfonic acid.
9. the 1,2,4- triazole -3- formamide of the method as described in claim 1 preparation.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1760186A (en) * | 2004-10-13 | 2006-04-19 | 唐保清 | Preparation method of 3-cyano-1, 2, 4-triazole |
| CN1788002A (en) * | 2003-03-18 | 2006-06-14 | 麦克公司 | Biaryl substituted triazoles as sodium channnel blockers |
-
2018
- 2018-06-25 CN CN201810661846.8A patent/CN108863965A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1788002A (en) * | 2003-03-18 | 2006-06-14 | 麦克公司 | Biaryl substituted triazoles as sodium channnel blockers |
| CN1760186A (en) * | 2004-10-13 | 2006-04-19 | 唐保清 | Preparation method of 3-cyano-1, 2, 4-triazole |
Non-Patent Citations (1)
| Title |
|---|
| YINGJU XU,ET AL.: ""Practical Synthesis of Functionalized 1,5-Disubstituted 1,2,4-Triazole Derivatives"", 《J. ORG. CHEM.》 * |
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