CN112724101B - Synthetic method of 4-methylthiazole-5-formaldehyde - Google Patents
Synthetic method of 4-methylthiazole-5-formaldehyde Download PDFInfo
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- CN112724101B CN112724101B CN202110123150.1A CN202110123150A CN112724101B CN 112724101 B CN112724101 B CN 112724101B CN 202110123150 A CN202110123150 A CN 202110123150A CN 112724101 B CN112724101 B CN 112724101B
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- methylthiazole
- formaldehyde
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- JJVIEMFQPALZOZ-UHFFFAOYSA-N 4-methyl-1,3-thiazole-5-carbaldehyde Chemical compound CC=1N=CSC=1C=O JJVIEMFQPALZOZ-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- BKAWJIRCKVUVED-UHFFFAOYSA-N 5-(2-hydroxyethyl)-4-methylthiazole Chemical compound CC=1N=CSC=1CCO BKAWJIRCKVUVED-UHFFFAOYSA-N 0.000 claims abstract description 14
- BHYWREOEQYCKSC-UHFFFAOYSA-N 4-methylthiazole-5-acetic-acid Chemical compound CC=1N=CSC=1CC(O)=O BHYWREOEQYCKSC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical class [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052751 metal Chemical class 0.000 claims abstract description 7
- 239000002184 metal Chemical class 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- 239000001301 oxygen Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical group CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical group [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 4
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical group Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 3
- 229960002218 sodium chlorite Drugs 0.000 claims description 3
- 229950009390 symclosene Drugs 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 claims description 2
- 229910001488 sodium perchlorate Inorganic materials 0.000 claims description 2
- IAHFWCOBPZCAEA-UHFFFAOYSA-N succinonitrile Chemical compound N#CCCC#N IAHFWCOBPZCAEA-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- -1 lithium aluminum hydride Chemical compound 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052707 ruthenium Inorganic materials 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical group [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- ZSPCITYHOYJDBW-UHFFFAOYSA-N (4-methyl-1,3-thiazol-5-yl)methanol Chemical compound CC=1N=CSC=1CO ZSPCITYHOYJDBW-UHFFFAOYSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- UWDMKTDPDJCJOP-UHFFFAOYSA-N 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-ium-4-carboxylate Chemical compound CC1(C)CC(O)(C(O)=O)CC(C)(C)N1 UWDMKTDPDJCJOP-UHFFFAOYSA-N 0.000 description 1
- OUQMXTJYCAJLGO-UHFFFAOYSA-N 4-methyl-1,3-thiazol-2-amine Chemical compound CC1=CSC(N)=N1 OUQMXTJYCAJLGO-UHFFFAOYSA-N 0.000 description 1
- ZGWGSEUMABQEMD-UHFFFAOYSA-N 4-methyl-1,3-thiazole-5-carboxylic acid Chemical compound CC=1N=CSC=1C(O)=O ZGWGSEUMABQEMD-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- WIBDVAQUHGQUSI-UHFFFAOYSA-L Cl[Ru](Cl)C1=CC=CC=C1 Chemical class Cl[Ru](Cl)C1=CC=CC=C1 WIBDVAQUHGQUSI-UHFFFAOYSA-L 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910021603 Ruthenium iodide Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 238000005902 aminomethylation reaction Methods 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001649 bromium compounds Chemical group 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- AFZFFLVORLEPPO-UVYJNCLZSA-N cefditoren pivoxil Chemical compound S([C@@H]1[C@@H](C(N1C=1C(=O)OCOC(=O)C(C)(C)C)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C AFZFFLVORLEPPO-UVYJNCLZSA-N 0.000 description 1
- 229960002142 cefditoren pivoxil Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- JIDMEYQIXXJQCC-UHFFFAOYSA-L copper;2,2,2-trifluoroacetate Chemical compound [Cu+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F JIDMEYQIXXJQCC-UHFFFAOYSA-L 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- WIWBLJMBLGWSIN-UHFFFAOYSA-L dichlorotris(triphenylphosphine)ruthenium(ii) Chemical compound [Cl-].[Cl-].[Ru+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 WIWBLJMBLGWSIN-UHFFFAOYSA-L 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- 229910000358 iron sulfate Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- MVFCKEFYUDZOCX-UHFFFAOYSA-N iron(2+);dinitrate Chemical compound [Fe+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MVFCKEFYUDZOCX-UHFFFAOYSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
- OJLCQGGSMYKWEK-UHFFFAOYSA-K ruthenium(3+);triacetate Chemical compound [Ru+3].CC([O-])=O.CC([O-])=O.CC([O-])=O OJLCQGGSMYKWEK-UHFFFAOYSA-K 0.000 description 1
- LJZVDOUZSMHXJH-UHFFFAOYSA-K ruthenium(3+);triiodide Chemical compound [Ru+3].[I-].[I-].[I-] LJZVDOUZSMHXJH-UHFFFAOYSA-K 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a synthesis method of 4-methylthiazole-5-formaldehyde, which comprises the following steps: 1) Dissolving 4-methylthiazole-5-ethanol in a solvent, and carrying out oxidation reaction under the condition of a catalyst to obtain 4-methylthiazole-5-acetic acid; 2) Heating the 4-methylthiazole-5-acetic acid obtained in the step 1) to react under the conditions of oxygen and a metal salt catalyst to obtain 4-methylthiazole-5-formaldehyde. The method takes the 4-methylthiazole-5-ethanol as a raw material, the raw material is green, cheap and easily available, the reaction process conditions are mild, the environment is friendly, the result selectivity is good, the yield is high, and the method has good economic benefits and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, in particular to a synthesis method of 4-methylthiazole-5-formaldehyde.
Background
4-methylthiazole-5-formaldehyde is an important intermediate for synthesizing cefditoren pivoxil tablets serving as third-generation cephalosporin antibacterial drugs. The structural formula is
The compound has been studied more.
JP 45036908 proposes a method for reducing 4-methyl-5-thiazolecarboxylate and then reoxidizing it to aldehyde using lithium aluminum hydride, which is flammable, dangerous and not easy to control, and thus not suitable for industrial production.
Patent CN 1628108A reports reduction of 4-methyl-5-thiazole formate with sodium tetrahydroborate and aluminum trichloride in glyme to give 4-methyl-5-hydroxymethyl-thiazole, followed by oxidation with sodium hypochlorite or pyridinium chlorochromate to give 4-methylthiazole-5-carbaldehyde. The first step of the reaction requires low temperature and no water in the system, the conditions are harsh, the post-treatment is relatively troublesome, and the solvent recovery cost is relatively high.
In patent CN 109053623A, 2-amino-4-methylthiazole is used as a raw material, aminomethylation is carried out firstly, then vilsmeier reaction is carried out to obtain aldehyde, and finally, aminomethyl is removed by hydrogenation to obtain 4-methylthiazole-5-formaldehyde. The reaction needs a large amount of caustic soda flakes and phosphorus oxychloride in production, has high danger and corrosivity, and does not accord with the green chemical concept.
Therefore, the research and development of the synthesis process of the 4-methylthiazole-5-formaldehyde which is environment-friendly and has good economic benefit has very important significance.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a method for synthesizing 4-methylthiazole-5-formaldehyde, which takes 4-methylthiazole-5-ethanol as a raw material and generates the 4-methylthiazole-5-formaldehyde through two-step reaction. The whole reaction condition is mild, the method is environment-friendly, the result selectivity is good, the yield is high, the reaction raw materials are green, cheap and easy to obtain, and the method has good economic benefit and is suitable for industrial production.
The invention is realized by the following technical scheme:
a method for synthesizing 4-methylthiazole-5-formaldehyde comprises the following steps: 1) Dissolving 4-methylthiazole-5-ethanol in a solvent, and carrying out oxidation reaction under the condition of a catalyst to obtain 4-methylthiazole-5-acetic acid; 2) Dissolving the 4-methylthiazole-5-acetic acid obtained in the step 1) in a solvent, and heating and reacting under the conditions of oxygen and a metal salt catalyst to obtain the 4-methylthiazole-5-formaldehyde.
Wherein, in the step 1), the catalyst is piperidine nitroxide free radical or a compound containing transition metal ruthenium.
Preferably, the piperidine nitroxide radical is one or more of the following structural compounds
Preferably, the transition metal ruthenium-containing compound is one or a combination of more of ruthenium trichloride, ruthenium acetate, ruthenium iodide, potassium chlororuthenate, ruthenium hexacarbonyl chloride, ammonium chlororuthenate, dichloro (p-methylisoprophenyl) ruthenium dimer, tris (triphenylphosphine) ruthenium dichloride, and dichlorophenyl ruthenium dimer.
Wherein, the dosage of the catalyst in the step 1) is 1-10% of the molar weight of the 4-methylthiazole-5-ethanol when the catalyst is piperidine nitroxide radical; when the catalyst is a compound containing transition metal ruthenium, the dosage of the compound is 0.1 to 10 percent of the molar weight of the 4-methylthiazole-5-ethanol.
Wherein, the oxidant of the oxidation reaction in the step 1) is one or a combination of more of sodium hypochlorite, sodium chlorite, sodium perchlorate, sodium periodate and trichloroisocyanuric acid; the dosage of the oxidant is 100-400% of the molar weight of the 4-methylthiazole-5-ethanol.
In the step 1), the solvent is one or more of acetone, acetonitrile, propionitrile, benzonitrile, succinonitrile, dichloromethane, chloroform, 1, 2-dichloroethane, methyl cyclopentyl ether, acetic acid, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and N, N-dimethylformamide.
Wherein, the step 1) also comprises a cocatalyst and/or a basic additive; the dosage of the cocatalyst is 1-20% of the molar weight of 4-methylthiazole-5-ethanol.
Preferably, the cocatalyst is bromide; preferably, the cocatalyst is potassium bromide, sodium bromide, hydrogen bromide or sodium hypobromite.
Preferably, the basic additive is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium monohydrogen phosphate, and potassium monohydrogen phosphate.
Preferably, in step 1), the reaction temperature is 0 to 50 ℃.
Wherein, in the step 2), the dosage of the metal salt catalyst is 1-10% of the molar weight of the 4-methylthiazole-5-acetic acid.
Wherein, in the step 2), the metal salt catalyst is copper salt or iron salt; more preferably copper chloride, copper bromide, copper acetate, copper nitrate, copper sulfate, copper trifluoromethanesulfonate, copper trifluoroacetate, iron trichloride, iron nitrate or iron sulfate.
In the step 2), the reaction solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide and 1, 3-dimethyl-2-imidazolidinone.
Wherein in the step 2), the temperature of the heating reaction is 50-200 ℃.
The starting materials and reagents of the invention are commercially available.
The invention has the beneficial effects that:
compared with the reported method, the synthesis method has the advantages of cheap and easily obtained reaction raw materials, mild whole reaction conditions, environmental friendliness, good result selectivity, high yield, green and easily obtained reaction raw materials, good economic benefit and suitability for industrial production.
Drawings
FIG. 1 is a synthetic route of 4-methylthiazole-5-carbaldehyde proposed by the present invention
FIG. 2 gas chromatogram of 4-methylthiazole-5-carbaldehyde prepared by the present invention
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the technical solutions of the present invention are further described in detail with reference to specific examples below.
Example 1
71.6g (0.5 mol) of 4-methylthiazole-5-ethanol, 3.12g (0.02 mol) of 2, 6-tetramethylpiperidine oxide and 200mL of acetonitrile are added into a three-neck flask, the mixture is fully stirred, the temperature is raised to 35 ℃, 113.05g (1.0 mol) of 80wt% sodium chlorite aqueous solution and 6.7g (0.01 mol) of 10wt% sodium hypochlorite aqueous solution are slowly added, the mixture is continuously stirred and reacted for 4 hours at the temperature of 35 ℃, and the reaction is detected by gas chromatography.
After the reaction is finished, quenching the reaction by using a sodium sulfite solution, adjusting the pH value of the system to 2-3 by using hydrochloric acid, concentrating under negative pressure to evaporate acetonitrile, adding 300mL of ethyl acetate, washing for 2 times by using 50mL of water, washing for one time by using a saturated sodium chloride solution, standing for layering, recovering ethyl acetate by organic phase vacuum distillation, and remaining 4-methylthiazole-5-acetic acid for later use;
putting the 4-methylthiazole-5-acetic acid obtained in the last step, 9g (0.05 mol) of copper acetate and 10mL of 2-methyltetrahydrofuran into a high-pressure reaction kettle, introducing oxygen into the reaction kettle to maintain the pressure in the kettle to be 0.5MPa, heating to 120 ℃, stirring for reacting for 10 hours, and monitoring the reaction by using gas chromatography.
After the reaction, insoluble matter was removed by filtration, 300mL of ethyl acetate was added, washing was performed with 50mL of water for 2 times, washing was performed with saturated sodium chloride solution once, the aqueous layer was extracted with 20mL of ethyl acetate twice, the organic phases were combined, dried overnight with anhydrous sodium sulfate, the solvent was recovered by distillation under reduced pressure to obtain a pale yellow solid, which was recrystallized from n-heptane to obtain pale yellow crystalline 4-methylthiazole-5-carbaldehyde with a content of 99% in a yield of 82%.
Example 2
71.6g (0.5 mol) of 4-methylthiazole-5-ethanol, 0.9g (0.005 mol) of 4-hydroxy-2, 6-tetramethylpiperidine oxide, 1.03g (0.01 mol) of sodium bromide, 200mL of acetone and 20mL of 5% sodium carbonate solution are added into a three-neck flask, the mixture is fully stirred, the temperature is reduced to 0 ℃, 116.2g (0.5 mol) of trichloroisocyanuric acid is added in a small amount for a plurality of times, the temperature is controlled not to exceed 20 ℃, and the stirring reaction is continued for 2 hours after the addition.
After the reaction is finished, quenching the reaction by using a sodium sulfite solution, adjusting the pH of the system to 2-3 by using hydrochloric acid, concentrating under negative pressure to evaporate the solvent, adding 300mL of ethyl acetate, washing with 50mL of water for 2 times, washing with a saturated sodium chloride solution for one time, standing for layering, recovering ethyl acetate by organic phase vacuum distillation, and keeping the rest of 4-methylthiazole-5-acetic acid for later use;
putting the 4-methylthiazole-5-acetic acid obtained in the last step, 0.81g (0.005 mol) of ferric trichloride solution and 10mL of dimethyl sulfoxide into a high-pressure reaction kettle, introducing oxygen into the reaction kettle to maintain the pressure in the kettle to be 0.5MPa, heating to 150 ℃, and stirring for reacting for 5 hours.
After the reaction is finished, insoluble substances are removed by filtration, 300mL of ethyl acetate is added, the mixture is stirred for 30 minutes and then is kept stand for layering, a water layer is extracted twice by 20mL of ethyl acetate, organic phases are combined and washed by 50mL of water for 2 times, the mixture is dried overnight by anhydrous sodium sulfate, the solvent is recovered by reduced pressure distillation to obtain a light yellow solid, and the light yellow solid is recrystallized by n-heptane to obtain light yellow crystal-shaped 4-methylthiazole-5-formaldehyde with the content of 99 percent and the yield of 77 percent.
Example 3
71.6g (0.5 mol) of 4-methylthiazole-5-ethanol, 50mL of acetonitrile, 50mL of ethyl acetate and 20mL of water were put in a three-necked flask, and after sufficiently stirring at room temperature, 1.04g (0.005 mol) of ruthenium trichloride was added, 213.9g (1 mol) of sodium periodate was added in portions, and after completion of the addition, the reaction was continued to stir at room temperature for 2 hours.
After the reaction is finished, quenching the reaction by using a saturated sodium sulfite solution, filtering to remove insoluble substances, adjusting the pH of the system to 2-3 by using hydrochloric acid, concentrating under negative pressure to evaporate the solvent, adding 300mL of ethyl acetate, washing with 50mL of water for 2 times, washing with a saturated sodium chloride solution once, standing for layering, performing organic phase reduced pressure distillation to recover ethyl acetate, and recovering 4-methylthiazole-5-acetic acid for later use;
putting the 4-methylthiazole-5-acetic acid obtained in the last step, 1.34g (0.01 mol) of copper chloride and 10mL of 2-methyltetrahydrofuran into a high-pressure reaction kettle, introducing oxygen into the reaction kettle to maintain the pressure in the kettle to be 0.5MPa, heating to 60 ℃, and stirring for reacting for 15 hours.
After the reaction is finished, filtering to remove insoluble substances, adding 300mL of ethyl acetate, stirring for 30 minutes, standing for layering, extracting a water layer twice with 20mL of ethyl acetate, combining organic phases, washing with 50mL of water for 2 times, drying overnight with anhydrous sodium sulfate, distilling under reduced pressure to recover the solvent to obtain a light yellow solid, and recrystallizing with n-heptane to obtain light yellow crystalline 4-methylthiazole-5-formaldehyde with the content of 99% and the yield of 87%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (4)
1. A method for synthesizing 4-methylthiazole-5-formaldehyde, which is characterized by comprising the following steps: 1) Dissolving 4-methylthiazole-5-ethanol in a solvent, and carrying out oxidation reaction under the condition of a catalyst to obtain 4-methylthiazole-5-acetic acid; 2) Dissolving the 4-methylthiazole-5-acetic acid obtained in the step 1) in a solvent, introducing oxygen into a reaction kettle to maintain the pressure in the kettle to be 0.5MPa, and heating and reacting under the conditions of oxygen and a metal salt catalyst to obtain 4-methylthiazole-5-formaldehyde;
in the step 1), the catalyst is ruthenium trichloride; the oxidant is one or more of sodium hypochlorite, sodium chlorite, sodium perchlorate, sodium periodate and trichloroisocyanuric acid;
in the step 2), the dosage of the metal salt catalyst is 2% of the molar weight of 4-methylthiazole-5-ethanol; the metal salt catalyst is copper chloride; the reaction solvent is 2-methyltetrahydrofuran; the temperature of the heating reaction was 60 ℃.
2. The method for synthesizing 4-methylthiazole-5-formaldehyde according to claim 1, wherein in the step 1), the amount of the catalyst ruthenium trichloride is 0.1 to 10 percent of the molar amount of the 4-methylthiazole-5-ethanol.
3. The method for synthesizing 4-methylthiazole-5-carbaldehyde according to claim 1, wherein the amount of the oxidant used in the step 1) is 100 to 400 percent of the molar amount of 4-methylthiazole-5-carbaldehyde.
4. The method for synthesizing 4-methylthiazole-5-carbaldehyde according to claim 1, wherein in the step 1), the solvent is one or more of acetone, acetonitrile, propionitrile, benzonitrile, succinonitrile, dichloromethane, chloroform, 1, 2-dichloroethane, methyl cyclopentyl ether, acetic acid, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and N, N-dimethylformamide.
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