CN111471028A - 一种1,2,4-三氮唑-3-甲酸的合成方法 - Google Patents
一种1,2,4-三氮唑-3-甲酸的合成方法 Download PDFInfo
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- CN111471028A CN111471028A CN202010534184.5A CN202010534184A CN111471028A CN 111471028 A CN111471028 A CN 111471028A CN 202010534184 A CN202010534184 A CN 202010534184A CN 111471028 A CN111471028 A CN 111471028A
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- triazole
- formamidine
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- LJVQHXICFCZRJN-UHFFFAOYSA-N 1h-1,2,4-triazole-5-carboxylic acid Chemical compound OC(=O)C1=NC=NN1 LJVQHXICFCZRJN-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 31
- -1 oxalanilide hydrazine Chemical compound 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical class NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 150000001412 amines Chemical class 0.000 claims abstract description 6
- 239000012670 alkaline solution Substances 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 230000002194 synthesizing effect Effects 0.000 claims description 17
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 10
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 8
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 claims description 8
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical group [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 8
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 claims description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol Substances OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 7
- UMESNHVJZFCGBV-UHFFFAOYSA-N 2-methyl-4-[(2-methylphenyl)methylidene]-1,3-oxazol-5-one Chemical group O=C1OC(C)=NC1=CC1=CC=CC=C1C UMESNHVJZFCGBV-UHFFFAOYSA-N 0.000 claims description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- BRKFQVAOMSWFDU-UHFFFAOYSA-M tetraphenylphosphanium;bromide Chemical group [Br-].C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 BRKFQVAOMSWFDU-UHFFFAOYSA-M 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 5
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 5
- NRWLDEORXKOCEH-UHFFFAOYSA-N Cl.[Cs] Chemical compound Cl.[Cs] NRWLDEORXKOCEH-UHFFFAOYSA-N 0.000 claims description 4
- QWANGZFTSGZRPZ-UHFFFAOYSA-N aminomethylideneazanium;bromide Chemical compound Br.NC=N QWANGZFTSGZRPZ-UHFFFAOYSA-N 0.000 claims description 4
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 claims description 4
- RUXXTRMIYSHYGJ-UHFFFAOYSA-N formic acid methanimidamide Chemical compound NC=N.OC=O RUXXTRMIYSHYGJ-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- SLZZQBVFSSKYSV-UHFFFAOYSA-N methanimidamide hydrofluoride Chemical compound C(=N)N.F SLZZQBVFSSKYSV-UHFFFAOYSA-N 0.000 claims description 4
- XZOMKPUMHJNJMH-UHFFFAOYSA-N methanimidamide;sulfuric acid Chemical compound NC=N.OS(O)(=O)=O XZOMKPUMHJNJMH-UHFFFAOYSA-N 0.000 claims description 4
- OXDRMTKMIYRQLY-UHFFFAOYSA-N octylazanium;hydroxide Chemical compound [OH-].CCCCCCCC[NH3+] OXDRMTKMIYRQLY-UHFFFAOYSA-N 0.000 claims description 4
- 150000004714 phosphonium salts Chemical group 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 229960004063 propylene glycol Drugs 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 4
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 claims description 4
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 claims description 4
- PZLXYMQOCNYUIO-UHFFFAOYSA-N lithium;hydrochloride Chemical compound [Li].Cl PZLXYMQOCNYUIO-UHFFFAOYSA-N 0.000 claims description 3
- WVULZDFWPQCPPJ-UHFFFAOYSA-N potassium;hydrochloride Chemical compound Cl.[K] WVULZDFWPQCPPJ-UHFFFAOYSA-N 0.000 claims description 3
- OTNVGWMVOULBFZ-UHFFFAOYSA-N sodium;hydrochloride Chemical compound [Na].Cl OTNVGWMVOULBFZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 150000002009 diols Chemical class 0.000 claims description 2
- 239000003444 phase transfer catalyst Substances 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229920005862 polyol Polymers 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 7
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- 239000002699 waste material Substances 0.000 abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 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 5
- 229960000329 ribavirin Drugs 0.000 description 5
- 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 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 210000001124 body fluid Anatomy 0.000 description 4
- 239000010839 body fluid Substances 0.000 description 4
- 239000012954 diazonium Substances 0.000 description 4
- 150000001989 diazonium salts Chemical class 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- FTWUXYZHDFCGSV-UHFFFAOYSA-N n,n'-diphenyloxamide Chemical compound C=1C=CC=CC=1NC(=O)C(=O)NC1=CC=CC=C1 FTWUXYZHDFCGSV-UHFFFAOYSA-N 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 3
- 229940035437 1,3-propanediol Drugs 0.000 description 3
- VPIXQGUBUKFLRF-UHFFFAOYSA-N 3-(2-chloro-5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N-methyl-1-propanamine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCNC)C2=CC=CC=C21 VPIXQGUBUKFLRF-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 3
- 235000013772 propylene glycol Nutrition 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- MYFXBBAEXORJNB-UHFFFAOYSA-N calcium cyanamide Chemical compound [Ca+2].[N-]=C=[N-] MYFXBBAEXORJNB-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000006698 hydrazinolysis reaction Methods 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- WPRKVIPHGOHZAL-UHFFFAOYSA-N n'-methyloxamide Chemical compound CNC(=O)C(N)=O WPRKVIPHGOHZAL-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 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 description 1
- GUQHFZFTGHNVDG-UHFFFAOYSA-N 1h-1,2,4-triazole-5-carbonitrile Chemical compound N#CC1=NC=NN1 GUQHFZFTGHNVDG-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 208000032982 Hemorrhagic Fever with Renal Syndrome Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 206010019785 Hepatitis neonatal Diseases 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
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- 238000011010 flushing procedure Methods 0.000 description 1
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
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- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000004072 triols Chemical class 0.000 description 1
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供一种1,2,4‑三氮唑‑3‑甲酸的合成方法,包括将草酰苯胺肼和甲脒盐于有机溶剂中进行反应得到1,2,4‑三氮唑‑3‑甲酰‑(N‑苯基)胺;然后在碱性溶液中,并在催化剂下加热水解后用调酸调pH,得到1,2,4‑三氮唑‑3‑甲酸;该方法原材料易得,反应条件温和,后处理简单,收率升高,避免了传统工艺的致爆危险性及使用污染环境的恶臭物,三废也明显减少,具有产业化前景。
Description
技术领域
本发明属于医药化工领域,尤其涉及一种1,2,4-三氮唑-3-甲酸的合成方法。
背景技术
利巴韦林(Ribavirin,也称病毒唑,三氮唑核苷),能渗入DNA,RNA,抑制核酸的合成,干扰细胞的正常代谢,使细胞增殖受抑制死亡。国内批准用于治疗肺炎,流行性出血热、角膜炎、流感等;国外用于治疗艾滋病、丙肝及新生儿鲁斯肉瘤毒感染等。1,2,4-三氮唑-3-甲酸是合成抗病毒药利巴韦林关键性中间体,同时1、2、4-三氮唑基团在药理上也是一种活性官能团,可用来制备一些其它的具生物活性的药物,如3-氰基-1,2,4-三氮唑,1,2,4-三氮唑、甲酰胺等化合物,已被用于抗肿瘤临床(CN2004100649333)。随着1、2、4-三氮唑基团在药理上的开发应用,1,2,4-三氮唑-3-甲酸的需求量在急剧地增加。
传统合成1,2,4-三氮唑-3-甲酸的方法主要有下面几种:
(1)重氮法:以石灰氮为起始原料,经肼解、环合、酯化、重氮化、脱氮等七步反应制得(参考中国医药工业杂志,1982,13,111;1993,24,4)。其步骤为:先用石灰氮,水合肼及碳酸氢铵制得氨基胍碳酸盐,氨基胍碳酸盐经草酸酰化后,在强碱条件下环合得到氨基三氮唑甲酸,后者在大量硫酸存在下与甲醇酯化,得到了3-氨基-1,2,4-三氮唑-5-甲酸甲酯,再与亚硝酸发生重氮化反应后离心得到重氮盐,该重氮盐经次磷酸还原脱氮或于甲醇中脱氮得到1,2,4-三氮唑-3-甲酸粗品,后者水解得到1,2,4-三氮唑-3-甲酸。反应式为:
该方法原料易得,反应条件温和,是目前厂家生产的主要方法,但其弊端显而易见,在用硫酸甲酯化时需用大大过量的硫酸催化,使之产生的废酸或废盐较多,另外在重氮盐分离时,由于重氮盐不稳定有致爆的危险性。
(2)氨基硫脲法:以氨基硫脲为原料,经乙酰化、环合、脱硫、氧化制得(参考J.A.C.S.,1995,77-81;1538-1540.),其步骤为氨基硫脲与乙酰氯在吡啶中反应生产乙酰氨基硫脲,然后在甲醇钠中成得到5-硫基-3-甲基-1,2,4-三氮唑-3-甲酸,后者分别经硝酸氧化、高猛酸钾氧化而得1,2,4-三氮唑-3-甲酸。反应式为:
该方法要用到恶臭的试剂氨基硫脲和吡啶,在生产过程中会产生剧毒且恶臭的硫化氢产生。另外,浓硝酸和高猛酸钾的使用量较大,成本较高,且二者均易导致反应冲料和爆炸。
3)亚硫化二磷法:日本专利JP85-206367记载以苯酸二甲酯为原料。经氨解、硫化、肼解,环合制得。其步骤为:向草酸二甲酯中通入氨气得到草酰胺单甲酯,后者与五硫化二磷反应得到硫化草酰胺甲酯,硫化草酰胺单甲酯再和甲酰肼反应成环而得。反应式为:
该方法反应条件温和,但五硫化二磷,价格高且臭味大。其处理液中含大量的磷、硫,成份复杂,味道大,难以处理,环保压力大。
发明内容
针对传统合成1,2,4-三氮唑-3-甲酸的方法中存在副产物多,试剂臭味大,易引发爆炸等的技术缺陷,本发明提供一种更安全、更环保的合成方法,该方法能避免传统方法在生产过程中的致爆危险性,及恶臭引起的环保性。
为实现发明目的,本发明采用如下的技术方案:
一种1,2,4-三氮唑-3-甲酸的合成方法,包括如下步骤:
(1)将草酰苯胺肼和甲脒盐于有机溶剂中加热反应,冷却,过滤得到1,2,4-三氮唑-3-甲酰-(N-苯基)胺;
(2)将1,2,4-三氮唑-3-甲酰-(N-苯基)胺溶于碱性溶液中,并在催化剂下加热水解后用调酸调pH,得到1,2,4-三氮唑-3-甲酸;
反应式为:
具体的,步骤(1)中的草酰苯胺肼为市售易得的化工原料。
作为优选,所述步骤(1)中的甲脒盐选自甲脒乙酸盐,甲脒盐酸盐,甲脒甲酸盐,甲脒氢溴酸盐、甲脒氢氟酸盐,甲脒氢碳碘酸盐或甲脒硫酸盐。
作为优选,所述步骤(1)中的有机溶剂为是醇类溶剂,选自10碳以下直链或支链醇,包括甲醇、乙醇、丙醇、丁醇或戊醇;或选自6碳以下的二醇、三醇等多元醇,包括二乙醇、1,2-丙二醇、1,3-丙二醇、1,2,3-丙三醇。
作为优选,所述步骤(1)中的反应温度应保持在100℃-200℃之间。如低沸点的醇类溶剂常温下难以达到该反应温度可以在加压下达到这一反应温度,温度低于100℃反应特别慢。
作为优选,所述步骤(2)中所述的碱性溶液选自氢氯化钠、氢氯化钾,氢氯化锂或氢氯化铯水溶液;或者四烃基氢氧化铵水溶液,选自四丁基氢氧化铵、四甲基氢氧化铵、四乙基氢氧化铵,正辛基氢氧化铵或金刚烷三甲基氢氧化铵水溶液。
作为优选,所述步骤(2)中所述的催化剂为相转移催化剂,选自季铵盐,季磷盐,三乙基苄基氯化铵、四丁基溴化铵,正辛基三甲基氯化铵、四苯基溴化磷等;或聚乙二醇非离子型的催化剂。
具体的,所述步骤(2)中1,2,4-三氮唑-3-甲酰-(N-苯基)胺的水解的做法是边回流加热边蒸出反应体系中生产的苯胺,以此来促进该平衡反应。这样反应时间一般可由30小时缩短为8-9小时,同时,随水蒸汽蒸出的的苯胺经回收可套用。
步骤(2)的反应完成后,减压蒸去水,再用酸中和至pH=2-3,产品析出后过滤,烘干得到产品。
本发明关于1,2,4-三氮唑-3-甲酸的合成方法的有益效果体现在:原材料易得,反应条件温和,后处理简单,收率升高,避免了传统工艺的致爆危险性及使用污染环境的恶臭物,三废也明显减少,具有产业化前景。
具体实施方式
根据下述实施例,可以更好地理解本发明。实施例所描述的具体的物料比,工艺条件及结果仅用于本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
实施例1:1,2,4-三氮唑-3-甲酸的合成方法
步骤(1):在装有搅拌器、温度计、回流冷凝管的三口瓶中,加入35.8g(0.198mol)草酰苯胺肼,25g(0.24mol)甲脒乙酸盐,及700ml正丁醇,反应混合物搅拌下升温至145℃回流3-4小时。直至分析显示原料草酰苯胺肼消耗完毕。冷却至10℃,过滤,再以少量正丁醇洗一次,烘干得34.4g 1,2,4-三氮唑-3-甲酰-N-苯基胺,收率92.4%,熔点:229-231℃。
步骤(2):在装有搅拌器,温度计、苯回流冷凝的三口瓶中加入30g(0.1595mol)1,2,4-三氮唑-3-甲酰-N-苯基胺,500ml水、24g NaOH及2g三乙基苄基氯化铵,反应混合物升温回流2小时后,改回流为蒸馏,即边反应边常压蒸出反应体液中的低沸物,直至釜底取样原料全转化完成。反应毕,水泵减压下蒸出大部分水后,降温至50-60℃,以盐酸调PH=1-2,冷却至10℃,过滤冷水洗一次后,烘干得14.5g 1,2,4-三氮唑-3-甲酸。MP:134-137℃,收率:81%。
实施例1中,步骤(1)中的正丁醇可用甲醇、乙醇、丙醇、或戊醇代替;甲脒乙酸盐可用甲脒盐酸盐,甲脒甲酸盐,甲脒氢溴酸盐、甲脒氢氟酸盐,甲脒氢碳碘酸盐或甲脒硫酸盐代替;步骤(2)中三乙基苄基氯化铵可用四丁基溴化铵,正辛基三甲基氯化铵或四苯基溴化磷代替。
实施例2:1,2,4-三氮唑-3-甲酸的合成方法
步骤(1):在装有搅拌器、温度计、回流冷凝管的三口瓶中,加入35.8g(0.198mol)草酰苯胺肼,25g(0.24mol)甲脒乙酸盐,及700ml乙二醇,反应混合物搅拌下升温至180℃回流3-4小时。直至分析显示原料草酰苯胺肼消耗完毕。冷却至10℃,过滤,再以少量乙二醇洗一次,烘干得33.6g 1,2,4-三氮唑-3-甲酰-N-苯基胺,收率90.2%,熔点:229-231℃。
步骤(2):在装有搅拌器,温度计、苯回流冷凝的三口瓶中加入30g(0.1595mol)1,2,4-三氮唑-3-甲酰-N-苯基胺,500ml水、24g氢氯化铯及2g聚乙二醇非离子型的催化剂,反应混合物升温回流2小时后,改回流为蒸馏。即边反应边常压蒸出反应体液中的低沸物,直至釜底取样原料全转化完成。反应毕,水泵减压下蒸出大部分水后,降温至50-60℃,以盐酸调PH=1-2,冷却至10℃,过滤冷水洗一次后,烘干得14.5g 1,2,4-三氮唑-3-甲酸。MP:134-137℃,收率:81%。
实施例2中二乙醇可用1,2-丙二醇、1,3-丙二醇或1,2,3-丙三醇代替;聚乙二醇非离子型的催化剂可用季铵盐、季磷盐,三乙基苄基氯化铵、四丁基溴化铵,正辛基三甲基氯化铵或四苯基溴化磷代替;氢氯化铯可用氢氯化钠、氢氯化钾,氢氯化锂、四丁基氢氧化铵、四甲基氢氧化铵、四乙基氢氧化铵,正辛基氢氧化铵或金刚烷三甲基氢氧化铵代替。
实施例3:1,2,4-三氮唑-3-甲酸的合成方法
步骤(1):在装有搅拌器、温度计、回流冷凝管的三口瓶中,加入35.8g(0.198mol)草酰苯胺肼,35g(0.346mol)甲脒乙酸盐,及500ml正丁醇,反应混合物搅拌下升温至145℃回流3-4小时。直至分析显示原料草酰苯胺肼消耗完毕。冷却至10℃,过滤,再以少量正丁醇洗一次,烘干得34.7g 1,2,4-三氮唑-3-甲酰-N-苯基胺,收率93.2%,熔点:229-231℃。
步骤(2):在装有搅拌器,温度计、苯回流冷凝的三口瓶中,加入30g(0.1595mol)1,2,4-三氮唑-3-甲酰-N-苯基胺,500ml水、24g KOH及2g三乙基苄基氯化铵,反应混合物升温回流2小时后,改回流为蒸馏,即边反应边常压蒸出反应体液中的低沸物,直至釜底取样原料全转化完成。反应毕,水泵减压下蒸出大部分水后,降温至50-60℃,以盐酸调PH=1-2,冷却至10℃,过滤冷水洗一次后,烘干得14.5g 1,2,4-三氮唑-3-甲酸。MP:134-137℃,收率:81%。
实施例1中,步骤(1)中的正丁醇可用甲醇、乙醇、丙醇、或戊醇代替;甲脒乙酸盐可用甲脒盐酸盐,甲脒甲酸盐,甲脒氢溴酸盐、甲脒氢氟酸盐,甲脒氢碳碘酸盐或甲脒硫酸盐代替;步骤(2)中三乙基苄基氯化铵可用四丁基溴化铵,正辛基三甲基氯化铵或四苯基溴化磷代替。
实施例4:1,2,4-三氮唑-3-甲酸的合成方法
步骤(1):在装有搅拌器、温度计、回流冷凝管的三口瓶中,加入35.8g(0.198mol)草酰苯胺肼,25g(0.24mol)甲脒乙酸盐,及700ml乙二醇,反应混合物搅拌下升温至180℃回流3-4小时。直至分析显示原料草酰苯胺肼消耗完毕。冷却至10℃,过滤,再以少量乙二醇洗一次,烘干得33.6g 1,2,4-三氮唑-3-甲酰-N-苯基胺,收率90.2%,熔点:229-231℃。
步骤(2):在装有搅拌器,温度计、苯回流冷凝的三口瓶中,加入30g(0.1595mol)1,2,4-三氮唑-3-甲酰-N-苯基胺,500ml水、28g四丁基氢氧化铵及2g聚乙二醇非离子型的催化剂,反应混合物升温回流2小时后,改回流为蒸馏。即边反应边常压蒸出反应体液中的低沸物,直至釜底取样原料全转化完成。反应毕,水泵减压下蒸出大部分水后,降温至50-60℃,以盐酸调PH=1-2,冷却至10℃,过滤冷水洗一次后,烘干得14.8g 1,2,4-三氮唑-3-甲酸。MP:134-137℃,收率:83%。
实施例4中二乙醇可用1,2-丙二醇、1,3-丙二醇或1,2,3-丙三醇代替;聚乙二醇非离子型的催化剂可用季铵盐、季磷盐,三乙基苄基氯化铵、四丁基溴化铵,正辛基三甲基氯化铵或四苯基溴化磷代替;四丁基氢氧化铵可用四甲基氢氧化铵、四乙基氢氧化铵,正辛基氢氧化铵或金刚烷三甲基氢氧化铵代替。
Claims (8)
2.根据权利要求1所述的1,2,4-三氮唑-3-甲酸的合成方法,其特征在于所述步骤(1)中的甲脒盐选自甲脒乙酸盐,甲脒盐酸盐,甲脒甲酸盐,甲脒氢溴酸盐、甲脒氢氟酸盐,甲脒氢碳碘酸盐或甲脒硫酸盐。
3.根据权利要求1所述的1,2,4-三氮唑-3-甲酸的合成方法,其特征在于所述步骤(1)中的有机溶剂为醇类溶剂,选自10碳以下直链或支链醇,包括甲醇、乙醇、丙醇、丁醇或戊醇;或选自6碳以下的二醇、三醇多元醇,包括二乙醇、1,2-丙二醇、1,3-丙二醇、1,2,3-丙三醇。
4.根据权利要求1所述的1,2,4-三氮唑-3-甲酸的合成方法,其特征在于所述步骤(1)的反应温度保持在100℃-200℃之间。
5.根据权利要求1所述的1,2,4-三氮唑-3-甲酸的合成方法,其特征在于所述步骤(2)中所述的碱性溶液选自氢氯化钠、氢氯化钾,氢氯化锂或氢氯化铯水溶液;或者四烃基氢氧化铵水溶液,选自四丁基氢氧化铵、四甲基氢氧化铵、四乙基氢氧化铵,正辛基氢氧化铵或金刚烷三甲基氢氧化铵水溶液。
6.根据权利要求1所述的1,2,4-三氮唑-3-甲酸的合成方法,其特征在于所述步骤(2)中所述的催化剂为相转移催化剂,选自季铵盐、季磷盐,三乙基苄基氯化铵、四丁基溴化铵,正辛基三甲基氯化铵、四苯基溴化磷;或聚乙二醇非离子型的催化剂。
7.根据权利要求1所述的1,2,4-三氮唑-3-甲酸的合成方法,其特征在于所述步骤(2)采用边回流加热边蒸出反应体系中生产的苯胺,以此来促进该平衡反应。
8.根据权利要求1所述的1,2,4-三氮唑-3-甲酸的合成方法,其特征在于所述步骤(2)中调酸调至pH=1-2。
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