CN104945316B - 一种微波法合成2-卤代烟酸酯及其中间体的方法 - Google Patents
一种微波法合成2-卤代烟酸酯及其中间体的方法 Download PDFInfo
- Publication number
- CN104945316B CN104945316B CN201510304831.2A CN201510304831A CN104945316B CN 104945316 B CN104945316 B CN 104945316B CN 201510304831 A CN201510304831 A CN 201510304831A CN 104945316 B CN104945316 B CN 104945316B
- Authority
- CN
- China
- Prior art keywords
- ester
- reaction
- methacrylaldehyde
- microwave
- cyanoacetic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 36
- 235000001968 nicotinic acid Nutrition 0.000 title claims abstract description 23
- 239000011664 nicotinic acid Substances 0.000 title claims abstract description 17
- 238000003786 synthesis reaction Methods 0.000 title claims description 27
- 230000015572 biosynthetic process Effects 0.000 title claims description 26
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 title claims description 19
- 125000001475 halogen functional group Chemical group 0.000 title claims description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 91
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 55
- -1 halo nicotinates Chemical class 0.000 claims abstract description 49
- 230000005855 radiation Effects 0.000 claims abstract description 43
- 239000012044 organic layer Substances 0.000 claims abstract description 28
- 239000010410 layer Substances 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910001868 water Inorganic materials 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 238000012544 monitoring process Methods 0.000 claims abstract description 3
- 238000013517 stratification Methods 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims description 42
- 229910052801 chlorine Inorganic materials 0.000 claims description 42
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 26
- STNJBCKSHOAVAJ-UHFFFAOYSA-N Methacrolein Chemical compound CC(=C)C=O STNJBCKSHOAVAJ-UHFFFAOYSA-N 0.000 claims description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 11
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 8
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 6
- 150000003053 piperidines Chemical class 0.000 claims description 6
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 6
- 239000011736 potassium bicarbonate Substances 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 claims description 5
- 150000004702 methyl esters Chemical class 0.000 claims description 5
- MMWNKXIFVYQOTK-UHFFFAOYSA-N 2-bromopyridine-3-carboxylic acid Chemical class OC(=O)C1=CC=CN=C1Br MMWNKXIFVYQOTK-UHFFFAOYSA-N 0.000 claims description 4
- 239000004472 Lysine Substances 0.000 claims description 4
- RCUIWQWWDLZNMS-UHFFFAOYSA-N benzyl 2-cyanoacetate Chemical compound N#CCC(=O)OCC1=CC=CC=C1 RCUIWQWWDLZNMS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- IGCSVRKAAHIVKV-UHFFFAOYSA-N CCCCCCN(C)C=C(C)C=O Chemical compound CCCCCCN(C)C=C(C)C=O IGCSVRKAAHIVKV-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 235000019766 L-Lysine Nutrition 0.000 claims description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- OCJMNSVWIYIHRK-UHFFFAOYSA-N pentyl 2-cyanoacetate Chemical compound CCCCCOC(=O)CC#N OCJMNSVWIYIHRK-UHFFFAOYSA-N 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- NLFIMXLLXGTDME-UHFFFAOYSA-N propyl 2-cyanoacetate Chemical compound CCCOC(=O)CC#N NLFIMXLLXGTDME-UHFFFAOYSA-N 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 150000001721 carbon Chemical class 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 abstract description 7
- 230000001681 protective effect Effects 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 2
- 238000007670 refining Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 239000007788 liquid Substances 0.000 description 53
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 32
- 238000000926 separation method Methods 0.000 description 31
- 239000011734 sodium Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 238000001514 detection method Methods 0.000 description 18
- 229910052740 iodine Inorganic materials 0.000 description 18
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 17
- 239000007789 gas Substances 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000011630 iodine Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 15
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 description 14
- 229960004194 lidocaine Drugs 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 239000002808 molecular sieve Substances 0.000 description 11
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 11
- 230000006837 decompression Effects 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 238000004064 recycling Methods 0.000 description 6
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 description 5
- RKSONJBMHDMLNW-UHFFFAOYSA-N CCCCCCCCN(C)C=C(C)C=O Chemical compound CCCCCCCCN(C)C=C(C)C=O RKSONJBMHDMLNW-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229960003512 nicotinic acid Drugs 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- RKVUCIFREKHYTL-UHFFFAOYSA-N 2-chloro-3-methylpyridine Chemical class CC1=CC=CN=C1Cl RKVUCIFREKHYTL-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HBSKIEXRPKUHIG-UHFFFAOYSA-N C(CCC)N(CCCC)C=C(C=O)C Chemical compound C(CCC)N(CCCC)C=C(C=O)C HBSKIEXRPKUHIG-UHFFFAOYSA-N 0.000 description 3
- BPJXURWPWDJPFZ-UHFFFAOYSA-N CCCCCCCCCCCCCCCCCCNC=C(C)C=O Chemical compound CCCCCCCCCCCCCCCCCCNC=C(C)C=O BPJXURWPWDJPFZ-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- WSMYVTOQOOLQHP-UHFFFAOYSA-N Malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- 229910019213 POCl3 Inorganic materials 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- KVYGGMBOZFWZBQ-UHFFFAOYSA-N benzyl nicotinate Chemical compound C=1C=CN=CC=1C(=O)OCC1=CC=CC=C1 KVYGGMBOZFWZBQ-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 235000019504 cigarettes Nutrition 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- QOFKYVXBHUEWBX-UHFFFAOYSA-N ethyl 2-bromopyridine-3-carboxylate Chemical class CCOC(=O)C1=CC=CN=C1Br QOFKYVXBHUEWBX-UHFFFAOYSA-N 0.000 description 2
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- RAFFKXWNTXTTFO-UHFFFAOYSA-N methyl 2-bromopyridine-3-carboxylate Chemical class COC(=O)C1=CC=CN=C1Br RAFFKXWNTXTTFO-UHFFFAOYSA-N 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- DLJMSHXCPBXOKX-UHFFFAOYSA-N n,n-dibutylprop-2-enamide Chemical compound CCCCN(C(=O)C=C)CCCC DLJMSHXCPBXOKX-UHFFFAOYSA-N 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000006053 organic reaction Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- ALOAITLALXBYNM-UHFFFAOYSA-N pentyl 2-bromopyridine-3-carboxylate Chemical class C(CCCC)OC(C1=C(N=CC=C1)Br)=O ALOAITLALXBYNM-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 229910001950 potassium oxide Inorganic materials 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- RRLMPLDPCKRASL-ONEGZZNKSA-N (e)-3-(dimethylamino)prop-2-enal Chemical compound CN(C)\C=C\C=O RRLMPLDPCKRASL-ONEGZZNKSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- JAUPUQRPBNDMDT-UHFFFAOYSA-N 2-chloropyridine-3-carbonitrile Chemical compound ClC1=NC=CC=C1C#N JAUPUQRPBNDMDT-UHFFFAOYSA-N 0.000 description 1
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- FJKWKEZAHVWIOR-UHFFFAOYSA-N Dihydroachillin Natural products C1CC(C)C2C(=O)C=C(C)C2C2OC(=O)C(C)C21 FJKWKEZAHVWIOR-UHFFFAOYSA-N 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000005586 Nicosulfuron Substances 0.000 description 1
- JZFPYUNJRRFVQU-UHFFFAOYSA-N Niflumic acid Chemical compound OC(=O)C1=CC=CN=C1NC1=CC=CC(C(F)(F)F)=C1 JZFPYUNJRRFVQU-UHFFFAOYSA-N 0.000 description 1
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KXIRHWPVRUKGFS-UHFFFAOYSA-N [N].C(C1=CN=CC=C1)(=O)O Chemical compound [N].C(C1=CN=CC=C1)(=O)O KXIRHWPVRUKGFS-UHFFFAOYSA-N 0.000 description 1
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- GNHQSAUHXKRQMC-UHFFFAOYSA-N benzene;chlorine Chemical compound [Cl].C1=CC=CC=C1 GNHQSAUHXKRQMC-UHFFFAOYSA-N 0.000 description 1
- ZXQYQSQVLUABEK-UHFFFAOYSA-N benzyl 2-bromopyridine-3-carboxylate Chemical class BrC1=NC=CC=C1C(=O)OCC1=CC=CC=C1 ZXQYQSQVLUABEK-UHFFFAOYSA-N 0.000 description 1
- 229950004580 benzyl nicotinate Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 235000015177 dried meat Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- RTCOGUMHFFWOJV-UHFFFAOYSA-N nicosulfuron Chemical compound COC1=CC(OC)=NC(NC(=O)NS(=O)(=O)C=2C(=CC=CN=2)C(=O)N(C)C)=N1 RTCOGUMHFFWOJV-UHFFFAOYSA-N 0.000 description 1
- 229960000916 niflumic acid Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960003101 pranoprofen Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- NBBJYMSMWIIQGU-UHFFFAOYSA-N propionic aldehyde Natural products CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 1
- XQMLQABLAGEWFZ-UHFFFAOYSA-M sodium;ethenolate Chemical compound [Na+].[O-]C=C XQMLQABLAGEWFZ-UHFFFAOYSA-M 0.000 description 1
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一种微波法合成2‑卤代烟酸酯及其中间体的方法,反应器中加入取代氨基丙烯醛、催化剂和氰基乙酸酯,在微波辐射下反应,跟踪反应至取代氨基丙烯醛消失,制得2‑卤代烟酸酯的中间体的反应液;然后向反应液中加入卤化氢继续反应,跟踪监测至反应完全;反应液中加入碱液调节pH值至5‑6,静置分层得到水层和有机层,水层用有机溶剂萃取,然后合并有机层,再经过精制,制得2‑卤烟酸酯。本发明所述的2‑卤烟酸酯的合成方法具有绿色环保、反应时间且操作简单和产品收率高、质量好的优点。
Description
技术领域
本发明涉及有机化学技术领域,具体涉及一种微波法合成2-卤代烟酸酯及其中间体的方法。
背景技术
许多传统的有机反应是在有机溶剂中进行的,而大多数溶剂都易燃、易爆、有毒,对环境不友好,微波辐射条件下进行的有机反应,因其合成能耗低、时间短、副反应少、易纯化、产率高等特点,已成为20世纪80年代后期兴起的一项有机合成新技术,目前已得到了迅速的发展。
2-氯烟酸天名精内酯醇酯对番茄灰霉病有药效(刘永.天名精内醋醇醋类衍生合成及其抑菌活性研究[D].西北农林科技大学,2011,12-22.),2-卤代烟酸酯经水解可以制备2-卤代烟酸,其中,2-氯烟酸是一种重要的药物和农药中间体,主要用于制备高效消炎镇痛药尼氟灭酸、普拉洛芬、HIV逆转录酶抑制剂奈韦拉平和高效除草剂烟嘧磺隆等。现有技术中2-氯烟酸的主要制备方法有:
(1)氰基乙酸乙酯氯化法(Tony Y Z,Eric F V,Scriven.Processes forProducing 2-Halonicotonic Acid Derivatives and Precursors Thereto:US,5493028[P].1994;Mayer J.Process of Preparing 2-Halogenonicotinic acids:US,4081451[P].1977),氰乙酸乙酯与丙烯醛为起始原料,经闭环、水解合成制得2-氯烟酸。该方法需加热回流且溶剂消耗量大,工艺路线复杂等缺点。
(2)丙二醛与氰基乙酸乙酯成环法(Yoshitomi Pharmaceutical IndustriesLtd.Japan.2-Chloronicotinic acid:JP,55076863[P].1980;徐效华,吕培,谢龙观,等.2-氯烟酸的合成方法[P].CN 101367760,2009;一种2-氯烟酸及其衍生物的合成方法[P].CN 103193705 A,2013;陆孙彬,季红楼,高小山.一种2-氯烟酸的合成方法[P].CN102993092 A,2013),将氰乙酸乙酯与丙二醛为起始原料,经闭环、水解合成制得2-氯烟酸。该合成路线丙二醛不稳定且原料不易得,故该合成路线也不适合工业化生产。
(3)以乙醛、甲醇钠、甲酸甲酯作为原料,生成醛基乙烯醇钠,再与甲醇反应生成1,1-二甲氧基丙醛,再与丙二腈反应生成环合的前体,再经环合、氯化、氰基水解生成2-氯烟酸(高倩,钱勇,薛谊,等.一种制备2-氯烟酸的方法[P].CN 104592104 A,2015),该法的缺点是废液多且难处理。
(4)烟酸氮氧化-氯化-水解法(Gedeon R,Vegyeszeti G R T.2-Chloronicotinic acid:HU,22161[P].1982;Ference N,Bela S,Teljes H.2-Chloronicotinic acid:HU,33464[P].1984;Adel S,Wallis B.Process for Pure White2-Chloronicotinic Acid:DE,2713316[P].1977),以烟酸作为起始原料,经H2O2将环上氮原子氧化,生成N-氧化物,再使用POCl3作为氯化试剂,进行亲核取代反应。此合成路线中原料烟酸价格昂贵,所制得的产品成本较高,产品分离困难、纯度也较低,不符合药物和农药的要求。
(5)2-氯-3-甲基吡啶氧化法(王文奎,等.一种2-氯烟酸的合成方法[P].CN201410703012,2014;杨寿海,等.一种一步氧化合成2-氯烟酸的方法[P].CN201410015351,2014),将2-氯-3-甲基吡啶用高锰酸钾氧化,吡啶环侧链的烷基被氧化成羧酸钾,用浓盐酸酸化2-氯烟酸析出。该法的缺点是原料2-氯-3-甲基吡啶不易得,环境污染大,故也不适合大规模的工业化生产。
(6)3-氰基吡啶-氯化-水解法(Fumiya H.Preparation of 2-Chloro-3-cyanopyridine and 2-Chloronicotinic Acid:JP,56-169672[P].1981;直井嘉诚.2-氯烟酸的制备:JP,59-144759[P].1984)该路线将3-氰基吡啶经H2O2氧化,生成N-氧化物,再使用POCl3作为氯化试剂,进行亲核取代反应,再经水解、中和制得产品,但该法的缺点是废液多且处理困难。
由此可见,现有的2-卤代烟酸制备方法普遍存在“三废”多而且难于处理,因此,开发2-卤代烟酸酯和2-卤代烟酸的绿色环保合成方法是非常有必要的。
发明内容
本发明的目的是为克服现有技术的问题,提供一种微波法合成2-卤代烟酸酯及其中间体的方法,该方法绿色环保、操作简单、产品收率高。
为实现上述目的,本发明采用的技术方案如下:
一种微波法合成2-卤代烟酸酯中间体的方法,反应器中加入取代氨基丙烯醛、催化剂和氰基乙酸酯,在微波辐射下反应,跟踪反应至取代氨基丙烯醛消失,经分离可制得2-卤代烟酸酯中间体,5-(N,N-二烃基)氨基-2-氰基-2,4-戊二烯酸酯,结构如式(Ⅱ)化合物。
一种微波法合成2-卤代烟酸酯的方法,反应器中加入取代氨基丙烯醛、催化剂和氰基乙酸酯,在微波辐射下反应,跟踪反应至取代氨基丙烯醛消失,然后加入卤化氢继续反应,跟踪监测至反应完全。反应液中加入碱液调节pH值至5-6,静置分层得到水层和有机层,水层用有机溶剂萃取,然后合并有机层,再经过精制,制得如式(Ⅰ)所示的2-卤烟酸酯产品。其中,水相中可以回收卤化胺盐,有机相可以回收用作有机溶剂。
式(Ⅰ)中,X表示F或Cl或Br或I,优选为Cl或Br。式(Ⅰ)和式(Ⅱ)中R3表示C1-C18的烃基或苄基,优选为乙基或正丙基或正丁基。式(Ⅱ)中,R1和R2各自独立为H或C1-C18的烃基或苯基或苄基,优选R1和R2均为甲基或乙基。
本发明涉及的化学反应如反应式(Ⅰ)和反应式(Ⅱ)所示:
所述取代氨基丙烯醛与氰基乙酸酯的物质的量比为1:(0.5-1.5)。
所述分离的方法为水洗、干燥或重结晶。
优选的,3-二甲氨基丙烯醛或3-二乙氨基丙烯醛或N,N-二丁胺基丙烯醛或N-甲基-(N–苄基)胺基丙烯醛或N-甲基-N-己基-3-氨基丙烯醛或N-甲基-N–异辛基-3-氨基丙烯醛或N-甲基-N–正辛基-3-氨基丙烯醛或N-甲基-N-十二烷基-3-氨基丙烯醛或N-十二烷基-3-氨基丙烯醛或N-十八烷基-3-氨基丙烯醛。
优选的,所述氰基乙酸酯为氰基乙酸甲酯或氰基乙酸乙酯或氰基乙酸正丙酯或氰基乙酸正丁酯或氰基乙酸正戊酯或氰基乙酸正辛酯或氰基乙酸异辛酯或氰基乙酸十二碳酯或氰基乙酸十八碳酯或氰基乙酸苄酯。
本发明所述的反应温度为0-200℃,优选温度为50-100℃。所述反应温度为整个反应过程的温度。
本发明中微波辐射的功率为10-1000W,优选功率为50-200W。
本发明中微波辐射的频率为915MHz或2450MHz,优选频率为2450MHz。
本发明所用催化剂为碱性化合物,这类碱性化合物有利于提高反应速度,主要为叔丁醇钠或丙醇钠或乙醇钠或甲醇钠或三乙胺或二乙胺或哌啶或吡啶或L-赖氨酸或L-脯氨酸或L-色氨酸或四丁基溴化铵或四丁基氯化铵或乙醇胺或二乙醇胺或三乙醇胺或尿素或KOH或NaOH或K2CO3或Na2CO3或KHCO3或NaHCO3或CH3CO2K或CH3CO2Na,优选催化剂为三乙胺或二乙胺或哌啶或吡啶,进一步优选为哌啶或吡啶。
本发明所用催化剂的物质的量为取代氨基丙烯醛物质的量的0.01-10倍,优选催化剂的用量为0.2-1倍。
本发明所用碱液为氢氧化钠溶液或或氢氧化钾溶液或碳酸钾溶液或或碳酸钠溶液或碳酸氢钾溶液或碳酸氢钠溶液或氨水,优选碱液为质量分数为10%-30%氢氧化钠溶液。
所述的有机溶剂为二氯甲烷或1,2-二氯乙烷或氯仿或四氯化碳或苯或甲苯或氯苯或乙酸甲酯或乙酸乙酯或乙酸丙酯或乙酸丁酯或***或石油醚。
所述精制的方法为:将有机层经过精馏收集适当馏分制得产品或经过干燥、过滤、蒸馏制得产品。同时,有机溶剂可回收重复使用。
本发明所述的合成方法的优点为:(1)在微波辐射下反应,绿色环保,不用有机溶剂进行反应,避免了有机溶剂易燃、易爆、有毒,对环境不友好的缺点;(2)反应时间短且操作简单,通常30分钟内即可完成整个反应,合成能耗低、时间短、副反应少,而且易于分离;(3)产品收率高、质量好,收率可达到90%以上,高于传统的溶剂法加热回流法的收率(85%)。
具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此。
实施例1 2-氯烟酸甲酯的合成
在装有温度计的500mL三口烧瓶中,先加入N,N-二丁胺基丙烯醛69mL(0.5mol)和KHCO35.0g,再加入氰基乙酸甲酯65mL(0.6mol),将准备好的装置放入微波仪中。设置微波辐射条件,在温度为60℃、微波功率为100W和频率为915MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)N,N-二丁胺基丙烯醛反应完全。之后,再通入HCl气体,微波辐射条件同上,反应约30min,HPLC跟踪反应直到反应结束。然后反应结束后,加入碳酸钠溶液调节pH=5-6,分液,水层用乙酸乙酯20mL×3次萃取,合并有机层,分子筛干燥过夜,过滤,减压脱去溶剂,残余物减压精馏,收集110-115℃/1mmHg馏分,制得2-氯烟酸甲酯,无色液体78.5g,收率为91.5%。产物的HRMS和NMR表征如下:
ESI-MS:m/z Calcd for C7H6NClO2172.5887[M+H]+,found 172.5881[M+H]+。
1HNMR(300MHz,CDCl3)δ(ppm):3.19(s,CH3),7.33(t,J=6Hz,1H,CH),8.15(d,J=6Hz,1H.CH),8.49(d,J=6Hz,1H,CH).
13CNMR(75MHz,CDCl3)δ(ppm):61.07(OCH3),122.09(CH=*CH-CH),127.27(*C-COOCH3),140.16(*CH=C),149.98(Cl-*C=N),151.39(N-*CH=CH),164.55(C=O)。
对比例1 2-氯烟酸甲酯的合成
在装有温度计的500mL三口烧瓶中,先加入N,N-二丁胺基丙烯醛69mL(0.5mol)、质量分数为95%乙醇100mL和KHCO35.0g,再加入氰基乙酸甲酯65mL(0.6mol),将准备好的装置放入微波仪中。设置微波辐射条件,在温度为60℃、微波功率为100W和频率为915MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)N,N-二丁胺基丙烯醛反应完全。之后,再通入HCl气体,微波辐射条件同上,反应约30min,HPLC跟踪反应直到反应结束。然后反应结束后,加入碳酸钠溶液调节pH=5-6,分液,水层用乙酸乙酯20mL×3次萃取,合并有机层,分子筛干燥过夜,过滤,蒸去溶剂,残余物减压精馏,收集110-115℃/1mmHg馏分,制得2-氯烟酸甲酯,无色液体78.2g,收率为91.2%。产物的HRMS和NMR表征如下:
ESI-MS:m/z Calcd for C7H6NClO2172.5887[M+H]+,found 172.5880[M+H]+。
1HNMR(300MHz,CDCl3)δ(ppm):3.21(s,CH3),7.35(t,J=6Hz,1H,CH),8.17(d,J=6Hz,1H.CH),8.51(d,J=6Hz,1H,CH)。
由实施例1和对比例1可得,在不使用有机溶剂溶解反应原料时,产品收率与使用有机溶剂溶解反应原料时的产品收率相当,收率甚至更高,因为对比例1去除这一部分的有机溶剂时会损耗产物的收率使产品收率降低,所以在微波辐射的条件下,没有必要使用有机溶剂溶解反应原料。
实施例2 2-溴烟酸甲酯的合成
在装有温度计的500mL三口烧瓶中,先加入3-二乙氨基丙烯醛61mL(0.5mol)、二乙醇胺20mL,再加入氰基乙酸甲酯65mL(0.6mol),将准备好的装置放入微波仪中。设置好微波辐射条件,在温度为60℃、微波功率为200W和频率为915MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)3-二乙氨基丙烯醛反应完全。之后,通入HBr气体,微波辐射条件同上,反应约35min,HPLC跟踪反应直到反应结束。然后反应结束后,加入质量分数为10%氢氧化钾溶液调节pH=5-6,分液,水层用乙酸乙酯20mL×3次萃取,合并有机层,水洗后分液,有机层分子筛干燥过夜,过滤,减压脱去溶剂,制得2-溴烟酸甲酯,淡棕色液体97.5g,收率为91.7%。产物的HRMS如下:
ESI-MS:m/z Calcd for C7H6NBrO2217.0400[M+H]+,found 217.0395[M+H]+。
实施例3 2-氯烟酸乙酯的合成
在装有温度计的500mL三口烧瓶中,先加入3-二甲氨基丙烯醛62mL(0.5mol)和哌啶10mL,再加入氰基乙酸乙酯65mL(0.6mol),将准备好的装置放入微波仪中。设置微波辐射条件,在温度为120℃、微波功率为350W和频率为2450MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)3-二甲氨基丙烯醛反应完全。之后,再通入HCl气体,微波辐射条件如上,HPLC跟踪反应直到反应结束。然后反应结束后,加入碳酸钾溶液调节pH=5-6,分液,水层用二氯甲烷20mL×3次萃取,合并有机层,加无水Na2SO4干燥,过滤,蒸去溶剂,残余物减压精馏,收集110-115℃/1mmHg馏分,制得2-氯烟酸乙酯,无色液体86.6g,收率为93.3%。产物的HRMS和NMR表征如下:
ESI-MS:m/z Calcd for C8H8NClO2186.0316[M+H]+,found 186.0311[M+H]+。
1HNMR(300MHz,CDCl3)δ(ppm):1.41(t,J=6Hz,CH3),4.41(q,J=6Hz,CH2),7.33(t,J=6Hz,1H,CH),8.14(d,J=6Hz,1H.CH),8.49(d,J=6Hz,1H,CH).
13CNMR(75MHz,CDCl3)δ(ppm):14.11(*CH3),62.09(*CH2CH3),122.05(CH=*CH-CH),127.24(*C-COOCH2CH3),140.13(*CH=C-COO),149.94(Cl--C=N),151.35(N-*CH=CH),164.53(C=O).。
实施例4 2-溴烟酸乙酯的合成
在装有温度计的500mL三口烧瓶中,先加入3-二甲氨基丙烯醛62mL(0.5mol)和吡啶20mL,再加入氰基乙酸乙酯65mL(0.6mol),将准备好的装置放入微波仪中。设置微波辐射条件,在温度为40℃、微波功率为150W和频率为2450MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)3-二甲氨基丙烯醛反应完全。之后,通入HBr气体,微波辐射条件如上,HPLC跟踪反应直到反应结束。然后反应结束后,加入30%氢氧化钠溶液调节pH=5-6,分液,水层用二氯甲烷20mL×3次萃取,合并有机层,水洗后分液,有机层加无水Na2SO4干燥,过滤,液相减压脱去溶剂,制得2-溴烟酸乙酯,淡棕色液体106.3g,收率为92.4%。产物的HRMS和NMR表征如下:
ESI-MS:m/z Calcd for C8H8NBrO2231.0666[M+H]+,found 231.0661[M+H]+。
1HNMR(300MHz,CDCl3)δ(ppm):1.39(t,J=6Hz,CH3),4.38(q,J=6Hz,CH2),7.31(t,J=6Hz,1H,CH),8.13(d,J=6Hz,1H.CH),8.48(d,J=6Hz,1H,CH)。
实施例5 2-碘烟酸乙酯的合成
在装有温度计的500mL三口烧瓶中,先加入3-二乙氨基丙烯醛61mL(0.5mol)和三乙胺10mL,再加入氰基乙酸乙酯65mL(0.6mol),将准备好的装置放入微波仪中。设置微波辐射条件,在温度为30℃、微波功率为50W和频率为2450MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)3-二乙氨基丙烯醛反应完全。之后,再通入HI气体,微波辐射条件如上,HPLC跟踪反应直到反应结束。然后反应结束后,加入氨水溶液调节pH=5-6,分液,水层用二氯甲烷20mL×3次萃取,合并有机层,水洗后分液,有机层水洗后分液,有机层分子筛干燥过夜,过滤,有机相减压脱去溶剂,制得2-碘烟酸乙酯,淡棕色液体126.5g,收率为91.3%。产物的HRMS和NMR表征如下:
ESI-MS:m/z Calcd for C8H8NIO2278.0671[M+H]+,found 278.0664[M+H]+。
1HNMR(300MHz,CDCl3)δ(ppm):1.37(t,J=6Hz,CH3),4.37(q,J=6Hz,CH2),7.31(t,J=6Hz,1H,CH),8.10(d,J=6Hz,1H.CH),8.46(d,J=6Hz,1H,CH)。
实施例6 2-氟烟酸乙酯的合成
在装有温度计的500mL三口烧瓶中,先加入3-二乙氨基丙烯醛61mL(0.5mol)和二乙胺20mL,再加入氰基乙酸乙酯65mL(0.6mol),将准备好的装置放入微波仪中。设置微波辐射条件,在温度为0℃、微波功率为50W和频率为915MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)3-二乙氨基丙烯醛反应完全。之后,再通入HF气体,微波辐射条件为温度为0℃、微波功率为20W和频率为16KHz的条件下反应约10min,HPLC跟踪反应直到反应结束。然后反应结束后,加入氨水溶液调节pH=5-6,分液,水层用乙酸乙酯20mL×3次萃取,合并有机层,分子筛干燥过夜,过滤,减压脱去溶剂,制得2-氟烟酸乙酯,淡棕色液体75.9g,收率为89.7%。产物的HRMS表征如下:
ESI-MS:m/z Calcd for C8H8NFO2170.1610[M+H]+,found 170.1614[M+H]+。
实施例7 2-氯烟酸丙酯的合成
在装有温度计的500mL三口烧瓶中,先加入3-二甲氨基丙烯醛62mL(0.5mol)和叔丁醇钠2.0g,再加入氰基乙酸丙酯66.5mL(0.6mol),将准备好的装置放入微波仪器中。设置微波辐射条件,在温度为80℃、微波功率为200W和频率为915MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)3-二甲氨基丙烯醛反应完全。之后,再通入HCl气体,微波辐射条件如上,HPLC法跟踪反应直到反应结束。然后反应结束后,加入10%氢氧化钾溶液调节pH=5-6,分液,水层用二氯甲烷20mL×3次萃取,合并有机层,加无水Na2SO4干燥,过滤,蒸去溶剂,残余物减压精馏,收集110-117℃/1mmHg馏分,制得2-氯烟酸丙酯,无色液体96.7g,收率为90.5%。产物的HRMS表征如下:
ESI-MS:m/z Calcd for C9H10NClO2200.6419[M+H]+,found 200.6411[M+H]+。
实施例8 2-溴烟酸正戊酯的合成
在装有温度计的500mL三口烧瓶反应器中,加入氰基乙酸正戊酯62mL(0.5mol)、三乙胺20mL、N-甲基-N-辛基-3-氨基丙烯醛46mL(0.4mol),将准备好的装置放入微波仪中。设置微波辐射条件,110℃温度、微波功率为1000W和频率为2450MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)N-甲基-N-辛基-3-氨基丙烯醛反应完全,降温至室温,通入HBr气体,继续在微波辐射条件下反应,HPLC跟踪反应直到反应结束。加入5%氢氧化钾溶液调节pH=5-6,分液,水层用乙酸乙酯20mL×3次萃取,合并有机层,水洗后分液,分子筛干燥,过滤,蒸出溶剂乙酸乙酯回收后,制得2-溴烟酸正戊酯,无色液体102.5g,收率为94.2%。产物的HRMS表征如下:
ESI-MS:m/z Calcd for C11H14O2NBr 295.1282[M+Na]+,found 295.1270[M+Na]+。
实施例9 2-氯烟酸正己酯的合成
在装有温度计的500mL三口烧瓶反应器中,加入氰基乙酸正己酯63mL(0.5mol)、二乙胺20mL、N-甲基-N-己基-3-氨基丙烯醛35mL(0.3mol),将准备好的装置放入微波仪中。设置微波辐射条件,100℃温度、微波功率为2000W和频率为2450MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)N-甲基-N-己基-3-氨基丙烯醛反应完全,降温至室温,通入HCl气体,继续在微波辐射条件下反应,HPLC跟踪反应直到反应结束。加入5%氢氧化钾溶液调节pH=5-6,分液,水层用乙酸乙酯20mL×3次萃取,合并有机层,水洗后分液,分子筛干燥,过滤,蒸出溶剂乙酸乙酯回收后,制得2-溴烟酸正己酯,无色液体69.3g,收率为95.5%。产物的HRMS表征如下:
ESI-MS:m/z Calcd for C12H16O2NCl 264.7034[M+Na]+,found 264.7013[M+Na]+。
实施例10 2-溴烟酸正庚酯的合成
在装有温度计的500mL三口烧瓶反应器中,加入氰基乙酸正庚酯64mL(0.5mol)、L-色氨酸50mL、N-甲基-N-辛基-3-氨基丙烯醛45mL(0.4mol),将准备好的装置放入微波仪中。设置微波辐射条件,50℃温度、微波功率为500W和频率为915MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)N-甲基-N-辛基-3-氨基丙烯醛反应完全,降温至室温,通入HBr气体,继续在微波辐射条件下反应,HPLC跟踪反应直到反应结束。加入5%氢氧化钾溶液调节pH=5-6,分液,水层用乙酸乙酯20mL×3次萃取,合并有机层,水洗后分液,无水硫酸钠干燥,过滤,蒸出溶剂乙酸乙酯回收后,制得2-溴烟酸正庚酯,无色液体109.3g,收率为91.2%。产物的HRMS表征如下:
ESI-MS:m/z Calcd for C13H18O2NBr 323.1813[M+Na]+,found 323.1797[M+Na]+。
实施例11 2-氯烟酸正辛酯的合成
在装有温度计的500mL三口烧瓶反应器中,加入氰基乙酸正辛酯32mL(0.25mol)、四丁基溴化铵10mL、3-二乙氨基丙烯醛62mL(0.5mol),将准备好的装置放入微波仪中。设置微波辐射条件,40℃温度、微波功率为100W和频率为2450MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)3-二乙氨基丙烯醛反应完全,降温至室温,通入HCl气体,继续在微波辐射条件下反应,HPLC跟踪反应直到反应结束。加入5%氢氧化钾溶液调节pH=5-6,分液,水层用乙酸丁酯20mL×3次萃取,合并有机层,水洗后分液,分子筛干燥,过滤,蒸出溶剂乙酸丁酯回收后,制得2-氯烟酸正辛酯,无色液体61.3g,收率为92.4%。产物的HRMS表征如下:
ESI-MS:m/z Calcd for C14H20O2NCl 292.7566[M+Na]+,found 292.7553[M+Na]+。
实施例12 2-氯烟酸2-乙基己酯的合成
在装有温度计的500mL三口烧瓶反应器中,加入氰基乙酸2-乙基己酯40mL(0.3mol)、哌啶5mL、3-二乙氨基丙烯醛62mL(0.5mol),将准备好的装置放入微波仪中。设置微波辐射条件,30℃温度、微波功率为80W和频率为915MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)3-二乙氨基丙烯醛反应完全,降温至室温,通入HCl气体,继续在微波辐射条件下反应,HPLC跟踪反应直到反应结束。加入5%氢氧化钾溶液调节pH=5-6,分液,水层用二氯甲烷20mL×3次萃取,合并有机层,水洗后分液,分子筛干燥,过滤,蒸出溶剂二氯甲烷回收后,制得2-氯烟酸2-乙基己酯,无色液体73.3g,收率为90.5%。产物的HRMS表征如下:
ESI-MS:m/z Calcd for C14H20O2NCl 292.7566[M+Na]+,found 292.7554[M+Na]+。
实施例13 2-氯烟酸苄酯的合成
在装有温度计的500mL三口烧瓶反应器中,加入氰基乙酸苄酯63mL(0.5mol)、吡啶10mL、N-十八烷基-3-氨基丙烯醛42mL(0.25mol),将准备好的装置放入微波仪中。设置微波辐射条件,35℃温度、微波功率为20W和频率为2450MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)N-十八烷基-3-氨基丙烯醛反应完全,降温至室温,通入HCl气体,继续在微波辐射条件下反应,HPLC跟踪反应直到反应结束。加入浓氨水调节pH=5-6,分液,水层用1,2-二氯乙烷20mL×3次萃取,合并有机层,水洗后分液,减压蒸出溶剂1,2-二氯乙烷回收,制得2-氯烟酸苄酯,淡黄色液体59.1g,收率为95.4%。产物的HRMS表征如下:
ESI-MS:m/z Calcd for C13H10O2NCl 270.6665[M+Na]+,found 270.6652[M+Na]+。
实施例14 2-溴烟酸苄酯的合成
在装有温度计的500mL三口烧瓶反应器中,加入氰基乙酸苄酯63mL(0.5mol)、哌啶5mL、3-二甲氨基丙烯醛62mL(0.5mol),将准备好的装置放入微波仪中。设置微波辐射条件,40℃温度、微波功率为60W和频率为915MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)3-二甲氨基丙烯醛反应完全,降温至室温,通入HBr气体,继续在微波辐射条件下反应,HPLC跟踪反应直到反应结束。加入浓氨水调节pH=5-6,分液,水层用1,2-二氯乙烷20mL×3次萃取,合并有机层,水洗后分液,减压蒸出溶剂1,2-二氯乙烷回收,制得2-溴烟酸苄酯,淡棕色液体138.3g,收率为94.7%。产物的HRMS表征如下:
ESI-MS:m/z Calcd for C13H10O2NBr 315.1178[M+Na]+,found 315.1161[M+Na]+。
实施例15 2-氯烟酸正十二碳酯的合成
在装有温度计的500mL三口烧瓶中,先加入3-二乙氨基丙烯醛61mL(0.5mol)和L-赖氨酸6.0g,再加入氰基乙酸正十二碳酯73mL(0.6mol),将准备好的装置放入微波仪中。设置好微波辐射条件,在温度为70℃、微波功率为100W和频率为915MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)二乙氨基丙烯醛反应完全。之后,通入HCl气体,微波辐射条件同上,反应约50min,HPLC跟踪反应直到反应结束。然后反应结束后,加入氢氧化钠溶液调节pH=5-6,分液,水层用乙酸乙酯20mL×3次萃取,合并有机层,水洗后分液,有机层经分子筛干燥过夜,过滤,减压脱去溶剂,制得2-氯烟酸正十二碳酯无色液体149.1g,收率为91.5%。产物的HRMS表征如下:
ESI-MS:m/z Calcd for C18H28NClO2326.8811[M+H]+,found 326.8807[M+H]+。
对比例15 2-氯烟酸正十二碳酯的合成
在装有温度计的500mL三口烧瓶中,先加入3-二乙氨基丙烯醛61mL(0.5mol)、1,2-二氯乙烷20mL和L-赖氨酸6.0g,再加入氰基乙酸正十二碳酯73mL(0.6mol),将准备好的装置放入微波仪中。设置好微波辐射条件,在温度为70℃、微波功率为100W和频率为915MHz的条件下反应,TLC检测(石油醚:二氯甲烷1:2展开,升华碘显色)二乙氨基丙烯醛反应完全。之后,通入HCl气体,微波辐射条件同上,反应约50min,HPLC跟踪反应直到反应结束。然后反应结束后,加入氢氧化钠溶液调节pH=5-6,分液,水层用乙酸乙酯20mL×3次萃取,合并有机层,水洗后分液,有机层经分子筛干燥过夜,过滤,减压脱去溶剂,制得2-氯烟酸正十二碳酯无色液体148.8g,收率为91.0%。产物的HRMS表征如下:
ESI-MS:m/z Calcd for C18H28NClO2326.8811[M+H]+,found 326.8801[M+H]+。
实施例16 5-(N,N-二甲基)氨基-2-氰基-2,4-戊二烯酸乙酯
在500mL的三口圆底烧瓶中,加入62mL(0.5mol)的3-二甲氨基丙烯醛、三乙胺10mL和氰基乙酸乙酯65mL(0.6mol),将准备好的装置放入微波仪中。设置微波辐射条件,在温度为50℃、微波功率为200W和频率为2450MHz的条件反应,高效液相跟踪检测反应进程直到反应结束,加去离子水10mL除杂质,过滤,得粗产品,再用无水乙醇重结晶,过滤干燥,制得白色粉末88.3g,熔点为134-135℃,产品收率为90.9%。产品经过HRMS、1H NMR、13C NMR波谱表征,即5-(N,N-二甲基)氨基-2-氰基-2,4-戊二烯酸乙酯。
ESI-MS:m/z Calcd for C10H14N2O2217.0947[M+Na]+,found 217.0952[M+Na]+;
1HNMR(300MHz,CDCl3)δ(ppm):1.31(t,J=9Hz,3H,CH3),2.98(s,3H,NCH3),3.17(s,3H,NCH3),4.24(q,J=6Hz.2H,OCH2),5.56(t,J=12Hz,1H,CH),7.07(d,J=12Hz,1H,CH),7.78(d,J=12Hz,1H,CH);
13CNMR(75MHz,CDCl3)δ(ppm):14.39(*CH3),37.49(N*CH3),45.32(N*CH3),60.65(*CH2CH3),86.68(CH=*CH-CH),96.83(*CH=C-CN),117.94(*C-CN),156.87(CN),157.29(*CHN(CH3)2),165.30(C=O)。
实施例17 5-(N,N-二乙基)氨基-2-氰基-2,4-戊二烯酸丁酯
在500mL的三口圆底烧瓶中,加入61mL(0.5mol)的3-二乙氨基丙烯醛、乙醇钠10mL和氰基乙酸丁酯67mL(0.6mol),将准备好的装置放入微波仪中。设置微波辐射条件,在温度为100℃、微波功率为300W和频率为2450MHz的条件下反应,高效液相跟踪检测反应进程直到反应结束,加去离子水10mL除杂质,分液,蒸馏后制得淡棕色油状物115.4g,收率为92.2%。产品经过HRMS表征,即5-(N,N-二乙基)氨基-2-氰基-2,4-戊二烯酸丁酯。
ESI-MS:m/z Calcd for C14H22N2O2273.3265[M+Na]+,found 273.3269[M+Na]+。
Claims (4)
1.一种微波法合成2-卤代烟酸酯的方法,其特征是:反应器中加入取代氨基丙烯醛、催化剂和氰基乙酸酯,在微波辐射下反应,跟踪反应至取代氨基丙烯醛消失,制得2-卤代烟酸酯的中间体的反应液;
然后向反应液中加入卤化氢继续反应,跟踪监测至反应完全;反应液中加入碱液调节pH值至5-6,静置分层得到水层和有机层,水层用有机溶剂萃取,然后合并有机层,再经过精制,制得2-卤烟酸酯;
所述取代氨基丙烯醛为N,N-二丁胺基丙烯醛、3-二乙氨基丙烯醛、3-二甲氨基丙烯醛、N-甲基-N -辛基-3-氨基丙烯醛、N-甲基-N -己基-3-氨基丙烯醛或N -十八烷基-3-氨基丙烯醛;
所述氰基乙酸酯为氰基乙酸甲酯、氰基乙酸丙酯、氰基乙酸正戊酯、氰基乙酸正庚酯、氰基乙酸正辛酯、氰基乙酸2-乙基己酯、氰基乙酸苄酯或氰基乙酸正十二碳酯;
所述2-卤烟酸酯为2-氯烟酸甲酯、2-溴烟酸甲酯、2-溴烟酸乙酯、2-碘烟酸乙酯、2-氟烟酸乙酯、2-氯烟酸丙酯、2-溴烟酸正戊酯、2-氯烟酸正己酯、氰基乙酸正己酯、2-溴烟酸正庚酯、2-氯烟酸正辛酯、2-氯烟酸2-乙基己酯、2-氯烟酸苄酯、2-溴烟酸苄酯或2-氯烟酸正十二碳酯;
所述催化剂为三乙胺或二乙胺或哌啶或吡啶或乙醇钠或KHCO3或叔丁醇钠或L-色氨酸或L-赖氨酸或四丁基溴化铵或乙醇胺,所述催化剂的物质的量为取代氨基丙烯醛物质的量的0.2-1倍;
其中,所述微波辐射的功率为10-1000W,微波辐射的频率为2450 MHz。
2.如权利要求1所述的方法,其特征是:所述取代氨基丙烯醛与氰基乙酸酯的物质的量比为1:(0.5-1.5)。
3.如权利要求1所述的方法,其特征是:所述的反应温度为0-200℃,所述反应温度为整个反应过程的温度。
4.如权利要求1所述的方法,其特征是:所述碱液为氢氧化钠溶液或氢氧化钾溶液或碳酸钾溶液或碳酸钠溶液或碳酸氢钾溶液或碳酸氢钠溶液或氨水。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510304831.2A CN104945316B (zh) | 2015-06-04 | 2015-06-04 | 一种微波法合成2-卤代烟酸酯及其中间体的方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510304831.2A CN104945316B (zh) | 2015-06-04 | 2015-06-04 | 一种微波法合成2-卤代烟酸酯及其中间体的方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104945316A CN104945316A (zh) | 2015-09-30 |
CN104945316B true CN104945316B (zh) | 2018-05-04 |
Family
ID=54160450
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510304831.2A Expired - Fee Related CN104945316B (zh) | 2015-06-04 | 2015-06-04 | 一种微波法合成2-卤代烟酸酯及其中间体的方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104945316B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106349157B (zh) * | 2016-08-26 | 2019-02-01 | 山东华阳农药化工集团有限公司 | 一种水热法合成2-卤代烟酸酯和2-卤代烟酸的方法 |
CN106518757B (zh) * | 2017-01-25 | 2019-03-19 | 山东师范大学 | 一种微波法合成2-卤代-3-取代烃基磺酰基吡啶及其中间体的方法 |
CN106748988B (zh) * | 2017-02-10 | 2019-05-28 | 山东师范大学 | 一种超声波法合成2-卤代-3-取代烃基磺酰基吡啶及其中间体的方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101367760A (zh) * | 2008-10-08 | 2009-02-18 | 南开大学 | 2-氯烟酸的合成方法 |
CN102933195A (zh) * | 2010-03-15 | 2013-02-13 | 莱雅公司 | 包含二苯甲酰基甲烷掩蔽剂和部花青二氰基或氰基乙酸酯衍生物的组合物;用于二苯甲酰基甲烷掩蔽剂的光稳定化的方法 |
CN103193705A (zh) * | 2013-03-22 | 2013-07-10 | 浙江工业大学 | 一种2-氯烟酸及其衍生物的合成方法 |
-
2015
- 2015-06-04 CN CN201510304831.2A patent/CN104945316B/zh not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101367760A (zh) * | 2008-10-08 | 2009-02-18 | 南开大学 | 2-氯烟酸的合成方法 |
CN102933195A (zh) * | 2010-03-15 | 2013-02-13 | 莱雅公司 | 包含二苯甲酰基甲烷掩蔽剂和部花青二氰基或氰基乙酸酯衍生物的组合物;用于二苯甲酰基甲烷掩蔽剂的光稳定化的方法 |
CN103193705A (zh) * | 2013-03-22 | 2013-07-10 | 浙江工业大学 | 一种2-氯烟酸及其衍生物的合成方法 |
Non-Patent Citations (1)
Title |
---|
The cyclization of 2-chloro nicotinic acid;ZhangQi wei等;《Advanced Materials Research》;20110531;第233-235卷;第289页图2和倒数第6-20行,第290页表1,第291页结论部分 * |
Also Published As
Publication number | Publication date |
---|---|
CN104945316A (zh) | 2015-09-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104945316B (zh) | 一种微波法合成2-卤代烟酸酯及其中间体的方法 | |
CN105001154B (zh) | 一种离子液法合成2-卤代烟酸酯及其中间体的方法 | |
IL212991A (en) | Process for the production of 5-methoxymethylpyridine-3,2-dicarboxylic acid | |
CN114605308B (zh) | 一种帕罗韦德的氮杂双环医药中间体的制备方法及中间体 | |
CN104945317B (zh) | 一种超声波法合成2-卤代烟酸酯及其中间体的方法 | |
CN103896855A (zh) | 一种4-(1-溴代乙基)-5-氟-6-氯嘧啶的合成方法 | |
Naeimi et al. | Preparation and characterization of functionalized graphene oxide Cu (I) complex: A facile and reusable nanocatalyst for microwave assisted heterocyclization of alkyl halides with alkynes and sodium azide | |
US6635767B2 (en) | Synthesis of heteroarylamine intermediate compounds | |
CN102675196B (zh) | 一种利用dctc短蒸残渣制备5,6-二氯烟酸的方法 | |
CN104311485A (zh) | 一种治疗白血病的药物博舒替尼的制备方法 | |
CN111777564A (zh) | 一种在水相中光催化醇氧化合成喹唑啉酮化合物的方法 | |
CN105968109B (zh) | 一种制备帕博西尼中间体的方法 | |
CN107353245A (zh) | 一种喹啉类化合物的合成方法 | |
CN106518757B (zh) | 一种微波法合成2-卤代-3-取代烃基磺酰基吡啶及其中间体的方法 | |
CN104447539B (zh) | 一种二级、三级芳香酰胺化合物的合成方法 | |
WO2006048172A1 (en) | Process for preparation of isonicotinic acid derivatives | |
JP3046136B2 (ja) | 2−クロルピリジンの製法 | |
JP4239038B1 (ja) | ジアルコキシチオフェンおよびアルキレンジオキシチオフェンの製造方法 | |
CN106831551B (zh) | 一种离子液法合成2-卤代-3-取代烃基磺酰基吡啶及其中间体的方法 | |
CN106748988B (zh) | 一种超声波法合成2-卤代-3-取代烃基磺酰基吡啶及其中间体的方法 | |
CN105732375B (zh) | 一种没食子酸合成3,4,5—三甲氧基苯甲酸甲酯的方法 | |
CN109836375A (zh) | 一种4-甲氧基-2,3,5-三甲基吡啶的制备方法 | |
CN114181142B (zh) | 一种6-(4-甲基哌嗪-1-基)-4-邻甲苯基烟酰胺的合成方法 | |
CN107721917A (zh) | 一种多取代烟酸酯类化合物的绿色合成方法 | |
US20030135046A1 (en) | Synthesis of heteroarylamine intermediate compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180504 |
|
CF01 | Termination of patent right due to non-payment of annual fee |