CN105017260B - Preparation method of sitagliptin intermediate triazolopyrazine derivative - Google Patents
Preparation method of sitagliptin intermediate triazolopyrazine derivative Download PDFInfo
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- CN105017260B CN105017260B CN201510458441.0A CN201510458441A CN105017260B CN 105017260 B CN105017260 B CN 105017260B CN 201510458441 A CN201510458441 A CN 201510458441A CN 105017260 B CN105017260 B CN 105017260B
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- -1 sitagliptin intermediate triazolopyrazine derivative Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 53
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 47
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 20
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims abstract description 14
- 150000007857 hydrazones Chemical class 0.000 claims abstract description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 57
- HYHBKLWDTGTBME-UHFFFAOYSA-N pyrazin-1-ium;chloride Chemical compound Cl.C1=CN=CC=N1 HYHBKLWDTGTBME-UHFFFAOYSA-N 0.000 claims description 43
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 29
- VKPPFDPXZWFDFA-UHFFFAOYSA-N 2-chloroethanamine Chemical compound NCCCl VKPPFDPXZWFDFA-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000004471 Glycine Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 12
- 150000007529 inorganic bases Chemical class 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- 239000012065 filter cake Substances 0.000 claims description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000010025 steaming Methods 0.000 claims description 3
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001099 ammonium carbonate Substances 0.000 claims description 2
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical class ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 2
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- VCYZVXRKYPKDQB-UHFFFAOYSA-N ethyl 2-fluoroacetate Chemical compound CCOC(=O)CF VCYZVXRKYPKDQB-UHFFFAOYSA-N 0.000 claims 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 14
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000009833 condensation Methods 0.000 abstract description 5
- 230000005494 condensation Effects 0.000 abstract description 5
- 230000018044 dehydration Effects 0.000 abstract description 5
- 238000006297 dehydration reaction Methods 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- WJPYOCIWVYDFDT-UHFFFAOYSA-N ethyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate Chemical compound CCOC(=O)CC(=O)CC1=CC(F)=C(F)C=C1F WJPYOCIWVYDFDT-UHFFFAOYSA-N 0.000 abstract description 2
- IVLXQGJVBGMLRR-UHFFFAOYSA-N 2-aminoacetic acid;hydron;chloride Chemical compound Cl.NCC(O)=O IVLXQGJVBGMLRR-UHFFFAOYSA-N 0.000 abstract 1
- SKOLWUPSYHWYAM-UHFFFAOYSA-N carbonodithioic O,S-acid Chemical compound SC(S)=O SKOLWUPSYHWYAM-UHFFFAOYSA-N 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 125000001425 triazolyl group Chemical group 0.000 abstract 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 12
- 229960004034 sitagliptin Drugs 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 206010012601 diabetes mellitus Diseases 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000002253 acid Chemical class 0.000 description 5
- OFUCCBIWEUKISP-UHFFFAOYSA-N 2,2,2-trifluoroacetohydrazide Chemical compound NNC(=O)C(F)(F)F OFUCCBIWEUKISP-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 235000011182 sodium carbonates Nutrition 0.000 description 4
- GELVZYOEQVJIRR-UHFFFAOYSA-N 2-chloropyrazine Chemical compound ClC1=CN=CC=N1 GELVZYOEQVJIRR-UHFFFAOYSA-N 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 230000036571 hydration Effects 0.000 description 3
- 238000006703 hydration reaction Methods 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical class O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- 206010054949 Metaplasia Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical group Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000015689 metaplastic ossification Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- MPNNOLHYOHFJKL-UHFFFAOYSA-N peroxyphosphoric acid Chemical compound OOP(O)(O)=O MPNNOLHYOHFJKL-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000005323 thioketone group Chemical group 0.000 description 2
- 150000003852 triazoles Chemical group 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- DNTQTNXUBQIWFE-UHFFFAOYSA-N 1-sulfanylpiperazine Chemical compound SN1CCNCC1 DNTQTNXUBQIWFE-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- FMTDZGCPYKWMPT-UHFFFAOYSA-N FC(c1nnc2[n]1CCNC2)(F)F Chemical compound FC(c1nnc2[n]1CCNC2)(F)F FMTDZGCPYKWMPT-UHFFFAOYSA-N 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 101500016415 Lophius americanus Glucagon-like peptide 1 Proteins 0.000 description 1
- RXWOVONXAGAKIB-UHFFFAOYSA-N O=C(C(F)(F)F)N(CCNC1)C1=O Chemical compound O=C(C(F)(F)F)N(CCNC1)C1=O RXWOVONXAGAKIB-UHFFFAOYSA-N 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- YXVOGOMWPQXYGF-UHFFFAOYSA-N acetic acid;hydrazine;hydrate Chemical compound O.NN.CC(O)=O YXVOGOMWPQXYGF-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960004329 metformin hydrochloride Drugs 0.000 description 1
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 150000003216 pyrazines Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical group O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of a sitagliptin intermediate triazolopyrazine derivative. The method comprises the following steps: by using 2-chlorethamin hydrochloride as an initial raw material, reacting the 2-chlorethamin hydrochloride with trifluoroacetate and aminoacetate hydrochloride to generate 1-trifluoroacetyl-2-piperazino ketone (III), and carrying out condensation ring formation on the compound (III), hydrazine hydrate and hydrochloric acid to obtain the sitagliptin intermediate 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolyl[4,3-a]pyrazine hydrochloride (II). The high-activity triluoroacetyl carbonyl functional group and hydrazine hydrate are dehydrated into hydrazone, and the hydrochloric acid is directly added without separation, thereby performing intramolecular dehydration to generate the triazole ring. The method can avoid using thioketone, has the advantages of cheap and accessible raw materials, high reaction selectivity, short process, simple technical operation, high safety and environment friendliness.
Description
Technical field
The present invention relates to a kind of preparation method of sitagliptin intermediate, and in particular to a kind of Triazolopyridine oxazine derivatives
Preparation method, the intermediate is used to prepare diabetes B medicine sitagliptin, belongs to medicine bioengineering chemical field.
Background technology
Sitagliptin, chemical name be (3R) -3- amino -1- [3- (trifluoromethyl) -5,6,7,8- tetrahydrochysene -1,2,4- tri-
Azoles simultaneously [4,3-a] pyrazine -7- bases] -4- (2,4,5- trifluorophenyl) butyl- 1- ketone, No. CAS is 486460-32-6, and English is entitled
Sitagliptin, be MSD Corp. of the U.S. research and development dipeptidyl peptidase -1V (DPP-1V) inhibitor, the structural formula such as institute of formula I
Show.
In October, 2006, U.S. FDA approval sitagliptin listing.Sitagliptin is first two peptidyl enzyme -4 (DPP-4)
Inhibitor class diabetes B medicine, its mechanism of action is different from conventional oral hypoglycemic drug, and sitagliptin is by suppressing
DPP-4 reduces the degraded of glucagon-like peptide-I, improves the ability that diabetic itself beta Cell of islet produces insulin,
To control the blood sugar level of diabetic, hence it is evident that improve the hypoglycemic ability of patient itself.There is sitagliptin height to select
Property, its selectivity to DPP-4 is higher by 2500 times compared with DPP-8 and DPP-9, therefore causes pair without because DPP-8 and DPP-9 are suppressed
Effect.Sitagliptin opens a kind of new way for treating diabetes B, and daily oral once i.e. sustainable reduction DPP-4 lives
Property, it is oral safely and effectively, it is alone or can significantly reduce blood sugar with Metformin hydrochloride, Pioglitazone drug combination, using peace
It is complete effective, in 2009 in Discussion on Chinese Listed.
WO03004498, WO2004085378A, WO2005020920A, WO2005097733A, CN1832949 and
CN101863891 etc. describes sitagliptin and its salt or acid salt, the preparation technology of basic salt, wherein 3- trifluoromethyl -5,
6,7,8- tetrahydrochysene -1,2,4- triazoles [4,3-a] pyrazine hydrochloride (II) is wherein key intermediate, and its synthetic method is according to starting
Raw material difference is divided into following several:Glycine methyl ester route, 2- chloropyrazine routes, the thio piperazine routes of 1- benzyl -3-, hydration
Hydrazine-Trifluoroacetic Acid Ethyl Ester-chloracetyl chloride route.
Document Organic Process Research&Development 2005,9,634-639 using 2- chloropyrazines according to
Secondary and hydrazine hydrate, trifluoroacetic acid anhydride reactant generate N '-trifluoroacetyl group-N ' -2- pyrazinyl trifluoroacetyl hydrazines, then de- through phosphoric acid
Water cyclization, palladium carbon catalytic hydrogenating reduction, hydrochloric acid only has 25% into the compound of salt formula II, total recovery, its reaction method opinion
Learn reaction scheme 1.
The raw materials used 2- chloropyrazines of the method, 2 equivalent TFAAs, peroxophosphoric acid, 10% palladium-carbon catalyst price are higher,
It is unfavorable for cost control;Simultaneously a large amount of acid waste waters are produced using TFAA, peroxophosphoric acid, be unfavorable for environmental protection;Palladium carbon is hydrogenated with
Pressure is high, and operation hidden danger is big.
Chinese Journal of Pharmaceuticals, o. 11th in 2010,805-806. report using hydrazine hydrate and Trifluoroacetic Acid Ethyl Ester,
Chloracetyl chloride reaction generates N '-trifluoroacetyl group cianazide, then Jing POCl3s cyclic condensation prepares 2- chloromethyl -5- trifluoros
Methyl isophthalic acid, 3,4- oxadiazoles, then with ethylenediamine reset obtain N- [(2Z)-piperazine -2- subunits] trifluoroacetyl hydrazine, most after the dense salt of Jing
Acid-cyclic the compound of formula II of chloroform backflow, total recovery is 54%, and its reaction method is shown in chemical reaction route 2:
When the method Trifluoroacetic Acid Ethyl Ester and hydration hydrazine reaction, the easy and active stronger trifluoro of two amino of hydrazine hydrate
Acetic acid ethyl reaction, reaction selectivity is poor, produces a large amount of N, N '-two (trifluoroacetyl) hydrazine;Produced using POCl3 and contained in a large number
Phosphorus waste water, the feature of environmental protection is poor.
Chemical reagent, the 3rd phase in 2015,270-272. is reported with ethylenediamine, ethyl chloroacetate as raw material, be substituted,
Condensation prepares 2- piperazinones, and 2- piperazinones are carried out after amido protecting using Boc acid anhydrides, and Jing phosphorus pentasulfides thio reaction prepares 4-
(N- tertbutyloxycarbonyls) -2- piperazine thioketones, the latter is substituted again reaction, ring-closure reaction, de- tertbutyloxycarbonyl with trifluoroacetyl hydrazine
Into the compound of salt formula II, total recovery is 54%, and its reaction method is shown in chemical reaction route 3:
The drawbacks of there is reaction selectivity difference simultaneously in the method, while producing the stronger sulphur of activity using phosphorus pentasulfide
Ketone, then at trifluoroacetyl hydrazine reaction, produces hypertoxic hydrogen sulphide by-product, and smell is big, and potential safety hazard is high.
Above method is unfavorable for that II cost is reduced and green safety industrialized production.And at present China is that diabetes are big
One of state, estimates patient up to 60,000,000 people, wherein about 95% is diabetes B patient.Therefore in order to optimize the life of sitagliptin
Route is produced, production cost is reduced, the synthetic method of the intermediate of sitagliptin is developed, with important productive value and society's meaning
Justice.
The content of the invention
For the deficiencies in the prior art, the present invention provides a kind of preparation of sitagliptin intermediate Triazolopyridine oxazine derivatives
Method, the Triazolopyridine oxazine derivatives are Formula II compound 3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1,2,4- triazoles [4,3-
A] pyrazine hydrochloride.That is, a kind of green safety of present invention offer, 3- trifluoromethyl -5 of low cost, 6,7,8- tetrahydrochysene -1,2,
The preparation method of 4- triazoles [4,3-a] pyrazine hydrochloride (II).
Formula II compound and 3- trifluoromethyl -5 clear in order to be concise in expression, mentioned by the present invention, 6,7,8- tetrahydrochysene -1,
2,4- triazols [4,3-a] pyrazine hydrochloride (II) is synonymous, each means 3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1,2,4- triazoles
And [4,3-a] pyrazine hydrochloride, it is the target compound of the present invention.
Technical scheme is as follows:
A kind of preparation method of Formula II compound, including step is as follows:
(1) in the presence of solvent and inorganic base, 2-chloroethyl amine hydrochloride successively with trifluoro-acetate, glycine ester hydrochloride
Reaction generates 1- trifluoroacetyl groups -2- piperazinones (III), is completed using " one kettle way ";
(2) reactant of step (1) is cooled to into 20-25 DEG C, is filtered, with toluene filter cake is washed;Merging filtrate, goes to band
In having the reactor of water knockout drum, hydrazine hydrate, the carbonyl and hydrazine hydrate for making trifluoroacetyl group is added to be dehydrated into hydrazone, be subsequently adding salt
Acid, is heated to reflux azeotropic water removing, until point water is thoroughly, after recovered under reduced pressure toluene 3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1,2,
4- triazols [4,3-a] pyrazine hydrochloride (II);
Reaction scheme is as follows:
Wherein, R is methyl, ethyl or carbon four and other carbon alkyl below four.
Above method gained 3- trifluoromethyls -5,6,7,8- tetrahydrochysenes -1,2,4- triazols [4,3-a] pyrazine hydrochloride (II)
Jing ethanol-activated carbon recrystallization decolourizes, and obtains white solid 3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1,2,4- triazols [4,3-a]
Pyrazine hydrochloride (II).
In above step (1), 2-chloroethyl amine hydrochloride and trifluoroacetic acid amidation generate N-TFA base -2- chloroethenes
Amine, N-TFA base -2-chloroethyl amine and glycine ester hydrochloride carry out SN under inorganic base effect2Substitution reaction, dechlorination
Hydrogen condensation generates 2 '-trifluoroacetyl amido ethyl glycine ester;Then 2 '-trifluoroacetyl amido ethyl glycine ester is in 80-110
DEG C there is intramolecular dealcoholysis, amidatioon generates 1- trifluoroacetyl group -2- piperazinones, and the above respectively reacts " one kettle way " and complete.
According to a kind of currently preferred, 3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1,2,4- triazols [4,3-a] pyrazine
The preparation method of hydrochloride (II), step is as follows:
(1) solvent, inorganic base, 2-chloroethyl amine hydrochloride, trifluoro-acetate are sequentially added in four-hole boiling flask, in 20-40
After DEG C stirring reaction 1-3 hour, product is N-TFA base -2-chloroethyl amine;Glycine ester hydrochloride is subsequently adding, in
40-60 DEG C of reaction 1-3 hour, generates 2 '-trifluoroacetyl amido ethyl glycine ester, little then at 80-110 DEG C of stirring reaction 2-5
When dealcoholysis, 1- trifluoroacetyl groups -2- piperazinones (III) is generated, while reclaiming the ethanol that steams;
(2) 20-25 DEG C is cooled to, is filtered, filter cake is washed 1-3 time with toluene, and the filtrate of merging is transferred to water knockout drum
Four-hole boiling flask in, hydrazine hydrate is added dropwise between 20-25 DEG C, completion of dropping after 40-60 DEG C of temperature stirring reaction 1-3 hour,
The carbonyl for making 1- trifluoroacetyl group -2- piperazinones is dehydrated into hydrazone;Hydrochloric acid is added, flow back azeotropic water removing, until point water is thoroughly, subtracts
Receipts toluene is pushed back, 3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1,2,4- triazoles [4,3-a] pyrazine hydrochloride is obtained.
Reaction equation is as follows in more detailed above-mentioned steps (1):
3- trifluoromethyl -5 obtained as above, 6,7,8- tetrahydrochysene -1,2,4- triazols [4,3-a] pyrazine hydrochloride is crude product,
Proceeding post processing can be by prior art.Present invention preferably provides the post-processing approach of following steps (3):
(3) it is thick to 3- trifluoromethyls -5,6,7,8- tetrahydrochysenes -1,2,4- triazols [4,3-a] pyrazine hydrochloride obtained as above
Activated carbon and ethanol are added in product, is stirred at a temperature of 50-65 DEG C, then filtered while hot;Filtrate is cooled to 0-5 DEG C, filters, and does
It is dry, obtain white solid 3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1,2,4- triazols [4,3-a] pyrazine hydrochloride (II).
, according to the invention it is preferred to, the solvent is 10 with the mass ratio of 2-chloroethyl amine hydrochloride:1 to 20:1;It is described molten
Agent is C1-C4 low-carbon alcohols and toluene mixture;It is preferred that C1-C4 low-carbon alcohols are 1 with the mass ratio of toluene:(1-3);Further preferably
C1-C4 low-carbon alcohols are methyl alcohol or ethanol.
, according to the invention it is preferred to, the inorganic base is (1.5-2.5) with the mol ratio of 2-chloroethyl amine hydrochloride:1;Institute
It is sodium carbonate, potassium carbonate, calcium carbonate, brium carbonate or ammonium carbonate to state inorganic base, and further preferred inorganic base is sodium carbonate or carbonic acid
Potassium.
, according to the invention it is preferred to, the trifluoro-acetate is trifluoro-acetate or Trifluoroacetic Acid Ethyl Ester;The sweet ammonia
Acid esters hydrochloride is glycine methyl ester hydrochloride or glycine ethyl ester hydrochloride;I.e. in reaction equation, R is methyl or ethyl.
, according to the invention it is preferred to, the 2-chloroethyl amine hydrochloride and trifluoro-acetate, glycine ester hydrochloride rub
You are than being 1:(1.0-1.2):(1.0-1.2);
, according to the invention it is preferred to, 2-chloroethyl amine hydrochloride and trifluoro-acetate reaction temperature are 20-40 DEG C;Further
Preferable reaction temperature is 30-35 DEG C, and the reaction time is 1.5-2 hours;
, according to the invention it is preferred to, the product N-TFA base -2- of 2-chloroethyl amine hydrochloride and trifluoro-acetate
The reaction temperature of chlorethamin and glycine ester hydrochloride is 50-55 DEG C, and the reaction time is 1.5-2 hours;
, according to the invention it is preferred to, product 2- tri- of N-TFA base -2-chloroethyl amine and glycine ester hydrochloride
It is 90-95 DEG C that the dealcoholysis of acetyl fluoride amido ethyl glycine ester generates the reaction temperature of 1- trifluoroacetyl group -2- piperazinones, and stirring is anti-
Answer 3-4 hours;
, according to the invention it is preferred to, the mol ratio of hydrazine hydrate and 2-chloroethyl amine hydrochloride is (1.0-1.5);1- trifluoro second
It is 50-55 DEG C that mixing filtrate and the hydrazine hydrate of acyl group -2- piperazinones and toluene is dehydrated into the reaction temperature of hydrazone, and the reaction time is
1.5-2 hour.
, according to the invention it is preferred to, 1- trifluoroacetyl group -2- piperazinones and hydrazine hydrate dehydration generate hydrazone without isolation,
Hydrochloric acid is directly added into, dehydration generates triazole ring, i.e. 3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1,2,4- triazoles [4,3-a] pyrazine salt
Hydrochlorate (II).The hydrochloric acid, converts into hydrogen chloride meter, is (1.2-2.0) with the mol ratio of 2-chloroethyl amine hydrochloride:1, back flow reaction
Temperature is toluene-water azeotropic temperature, and the reaction time is 2-5 hours;
According to currently preferred, the mass concentration of hydrochloric acid used is 30-35%;The concentration of hydrazine hydrate used is 75-
80% hydrazine hydrate.
Beneficial effects of the present invention:
The present invention with 2-chloroethyl amine hydrochloride as initial feed, using 2-chloroethyl amine hydrochloride and trifluoro-acetate, sweet ammonia
Acid esters hydrochloric acid reactant salt generate 1- trifluoroacetyl groups -2- piperazinones (III), the compound III again with hydrazine hydrate, hydrochloric acid cyclic condensation
3- trifluoromethyls -5,6,7,8- tetrahydrochysenes -1,2,4- triazoles [4,3-a] pyrazine hydrochloride (II).The present inventor's research finds, active
Stronger trifluoroacetyl group is dehydrated into hydrazone with hydrazine hydrate, without isolation, is directly added into hydrochloric acid, and intramolecular dehydration generates triazole ring,
Can avoid using thioketones.
In the presence of solvent and inorganic base, " one kettle way " carries out successively following reaction:2-chloroethyl amine hydrochloride and trifluoro second
Ester amides metaplasia is into N-TFA base -2-chloroethyl amine, N-TFA base -2-chloroethyl amine and glycine ester hydrochloride Jing
SN2Substitution reaction generates 2 '-trifluoroacetyl amido ethyl glycine ester, 2 '-trifluoroacetyl amido ethyl glycine ester in high temperature
Lower intramolecular amide metaplasia is into 1- trifluoroacetyl group -2- piperazinones.Replace 1,2- second used by document using 2-chloroethyl amine hydrochloride
Diamines and trifluoro-acetate react, and are related to functional group reactionses single;And the amidatioon is carried out successively by controlling reaction temperature
Reaction, SN2Substitution reaction and intramolecular amideization are reacted, selective good, high income.The present invention does not use thioketones described in document,
But acted on using the activation of trifluoromethyl, make in 1- trifluoroacetyl group -2- piperazinones and trifluoromethyl is connected carbonyl and hydration
Hydrazine is dehydrated into hydrazone, is then heated to reflux azeotropic with hydrochloric acid, promotes intramolecular dehydration to form 1,2,4- triazole rings, i.e. 3- fluoroforms
Base -5,6,7,8- tetrahydrochysene -1,2,4- triazols [4,3-a] pyrazine hydrochloride (II) is not related to the emission problem of hypertoxic hydrogen sulfide.
The present invention is cheap and easy to get using raw material, and reaction selectivity is high, and flow process is short, and technological operation is easy, production process green
Safety and environmental protection, is conducive to industrialized production.
Specific embodiment
The present invention is described in detail with reference to embodiments, but the present invention is not only limited to this.
, by gas chromatographic detection, gas chromatograph is island for the monitoring of the stage of reaction and the purity of each intermediate in embodiment
Tianjin GC-2010PLUS.Concentration % in embodiment is mass percent.
Embodiment 1:The system of 3- trifluoromethyls -5,6,7,8- tetrahydrochysenes -1,2,4- triazols [4,3-a] pyrazine hydrochloride (II)
It is standby
Sequentially add 50 grams of ethanol in 250 milliliters of four-hole boiling flasks, 100 grams of toluene, 17 grams of powdered sodium carbonates, 11.6 grams
(0.1 mole) 2-chloroethyl amine hydrochloride, 14.5 grams of (0.10 mole) Trifluoroacetic Acid Ethyl Esters, stirring reaction 2 hours between 30-35 DEG C
Afterwards, 14.5 grams of (0.10 mole) glycine ethyl ester hydrochlorides are added, is reacted 2 hours between 50-55 DEG C, stirred between 90-95 DEG C
Reaction 3 hours, while reclaiming the ethanol for steaming.20-25 DEG C is cooled to, is filtered, filter cake is washed with 30 grams of toluene;The filter that will merge
Liquid is transferred in water knockout drum 250 milliliters of four-hole boiling flasks, 6.5 gram of 80% hydrazine hydrate of dropwise addition between 20-25 DEG C, about 1 hour
Drop finishes, hereafter stirring reaction 2 hours between 50-55 DEG C, and 15 grams of concentration of addition are 35% hydrochloric acid, and flow back azeotropic water removing, until
Divide water thoroughly, about 3 hours, recovered under reduced pressure toluene, 0.5 gram of activated carbon of addition in gained faint yellow solid, 25 grams of ethanol, 60 DEG C
Lower stirring reaction 1 hour, filters while hot, and filtrate is cooled to 0-5 DEG C, filters, dry white solid 3- trifluoromethyl -5, and 6,7,
8- tetrahydrochysene -1, (II) 19.7 gram of 2,4- triazols [4,3-a] pyrazine hydrochloride, yield 86.2%, fusing point:264℃.
Product analysis data are as follows:
Infrared V (cm-1):3014,2975,1499,1267,1165。
Nuclear-magnetism1HNMR (deuterated DMSO, 400MHz) δ (ppm):3.51 (triplet, 2H), 4.43 (triplet, 2H), 4.71
(unimodal, 2H), 9.82 (broad peak, 2H).
Liquid chromatography mass spectrometric result LC-MS cation is scanned:[M+1]229.
Embodiment 2:The system of 3- trifluoromethyls -5,6,7,8- tetrahydrochysenes -1,2,4- triazols [4,3-a] pyrazine hydrochloride (II)
It is standby
Sequentially add 50 grams of methyl alcohol in 250 milliliters of four-hole boiling flasks, 100 grams of toluene, 17 grams of powdered sodium carbonates, 11.6 grams
(0.1 mole) 2-chloroethyl amine hydrochloride, 13.0 grams of (0.1 mole) trifluoro-acetates, stirring reaction 2 hours between 30-35 DEG C
Afterwards, 13.1 grams of (0.10 mole) glycine methyl ester hydrochlorides are added, is reacted 2 hours between 50-55 DEG C, stirred between 90-95 DEG C
Reaction 3 hours, while reclaiming the methyl alcohol for steaming.20-25 DEG C is cooled to, is filtered, filter cake is washed with 30 grams of toluene;The filter that will merge
Liquid is transferred in water knockout drum 250 milliliters of four-hole boiling flasks, and 6.5 gram 80% of hydrazine hydrate is added dropwise between 20-25 DEG C, and about 1 is little
When drop finish, hereafter stirring reaction 2 hours between 50-55 DEG C add 15 gram of 35% hydrochloric acid, and flow back azeotropic water removing, until point water is thorough
Bottom, about 3 hours, recovered under reduced pressure toluene added 0.5 gram of activated carbon, 25 grams of ethanol to stir at 60 DEG C in gained faint yellow solid
Reaction 1 hour, filters while hot, and filtrate is cooled to 0-5 DEG C, filters, dry white solid 3- trifluoromethyl -5, and 6,7,8- tetra-
Hydrogen -1, (II) 18.7 gram of 2,4- triazols [4,3-a] pyrazine hydrochloride, yield 81.5%.
Embodiment 3:The system of 3- trifluoromethyls -5,6,7,8- tetrahydrochysenes -1,2,4- triazols [4,3-a] pyrazine hydrochloride (II)
It is standby
Replace 17 grams of powdered sodium carbonates of embodiment 1 with 22 grams of potassium carbonate powders, remaining obtains white solid with embodiment 1
3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1, (II) 19.1 gram of 2,4- triazols [4,3-a] pyrazine hydrochloride, yield 83.6%.
Embodiment 4:The system of 3- trifluoromethyls -5,6,7,8- tetrahydrochysenes -1,2,4- triazols [4,3-a] pyrazine hydrochloride (II)
It is standby
Replace 17 grams of powdered sodium carbonates of embodiment 2 with 22 grams of potassium carbonate powders, remaining obtains white solid with embodiment 2
3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1, (II) 19.0 gram of 2,4- triazols [4,3-a] pyrazine hydrochloride, yield 83.2%.
Claims (12)
1. a kind of preparation method of Formula II compound, it is characterised in that as follows including step:
(1) in the presence of solvent and inorganic base, 2-chloroethyl amine hydrochloride reacts successively with trifluoro-acetate, glycine ester hydrochloride
1- trifluoroacetyl groups -2- piperazinones (III) is generated, is completed using " one kettle way ";
(2) reactant of step (1) is cooled to into 20-25 DEG C, is filtered, with toluene filter cake is washed;Merging filtrate, goes to carry and divides
In the reactor of hydrophone, hydrazine hydrate, the carbonyl and hydrazine hydrate for making trifluoroacetyl group is added to be dehydrated into hydrazone, be subsequently adding hydrochloric acid, plus
Heat backflow azeotropic water removing, until point water is thoroughly, after recovered under reduced pressure toluene 3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1,2,4- tri-
Azoles simultaneously [4,3-a] pyrazine hydrochloride (II);
Reaction scheme is as follows:
Wherein, R be methyl, ethyl or carbon atom be 4 or other carbon atoms less than 4 alkyl.
2. the preparation method of Formula II compound as claimed in claim 1, it is characterised in that as follows including step:
(1) solvent, inorganic base, 2-chloroethyl amine hydrochloride, trifluoro-acetate are sequentially added in four-hole boiling flask, is stirred in 20-40 DEG C
After mixing reaction 1-3 hours, product is N-TFA base -2-chloroethyl amine;Glycine ester hydrochloride is subsequently adding, in 40-
60 DEG C of reaction 1-3 hours, generate 2 '-trifluoroacetyl amido ethyl glycine ester, de- then at 80-110 DEG C of stirring reaction 2-5 hour
Alcohol, generates 1- trifluoroacetyl groups -2- piperazinones (III), while reclaiming the ROH for steaming;
(2) 20-25 DEG C is cooled to, is filtered, filter cake is washed 1-3 time with toluene, and the filtrate of merging is transferred to water knockout drum four
In mouth flask, hydrazine hydrate is added dropwise between 20-25 DEG C, completion of dropping makes 1- after 40-70 DEG C of temperature stirring reaction 1-3 hour
The carbonyl of trifluoroacetyl group -2- piperazinones is dehydrated into hydrazone;Hydrochloric acid is added, flow back azeotropic water removing, until point water is thoroughly, reduces pressure back
Toluene is received, 3- trifluoromethyl -5,6,7,8- tetrahydrochysene -1,2,4- triazols [4,3-a] pyrazine hydrochloride is obtained.
3. the preparation method of Formula II compound as claimed in claim 1 or 2, it is characterised in that to the 3- tri- obtained by step (2)
Methyl fluoride -5,6,7,8- tetrahydrochysene -1 add activated carbon and ethanol, 50-65 DEG C of temperature in 2,4- triazols [4,3-a] pyrazine hydrochloride
The lower stirring of degree, then filters while hot;Filtrate is cooled to 0-5 DEG C, filters, and is dried, and obtains white solid 3- trifluoromethyl -5, and 6,7,8-
Tetrahydrochysene -1,2,4- triazols [4,3-a] pyrazine hydrochloride (II).
4. the preparation method of Formula II compound as claimed in claim 1 or 2, it is characterised in that the solvent and 2-chloroethyl amine salt
The mass ratio of hydrochlorate is 10:1 to 20:1;The solvent is C1-C4 low-carbon alcohols and toluene mixture, C1-C4 low-carbon alcohols and toluene
Mass ratio be 1:(1-3).
5. the preparation method of Formula II compound as claimed in claim 4, it is characterised in that the C1-C4 low-carbon alcohols be methyl alcohol or
Ethanol.
6. the preparation method of Formula II compound as claimed in claim 1 or 2, it is characterised in that the inorganic base and 2- chloroethenes
The mol ratio of amine hydrochlorate is (1.5-2.5):1.
7. the preparation method of Formula II compound as claimed in claim 6, it is characterised in that the inorganic base is sodium carbonate, carbon
Sour potassium, calcium carbonate, brium carbonate or ammonium carbonate.
8. the preparation method of Formula II compound as claimed in claim 1 or 2, it is characterised in that the 2-chloroethyl amine hydrochloride
It is 1 with the mol ratio of trifluoro-acetate, glycine ester hydrochloride:(1.0-1.2):(1.0-1.2).
9. the preparation method of Formula II compound as claimed in claim 1 or 2, it is characterised in that 2-chloroethyl amine hydrochloride and three
Ethyl fluoroacetate reaction temperature is 25-35 DEG C;Reaction time is 1-2 hours;The reaction of 2-chloroethyl amine hydrochloride and trifluoro-acetate
The reaction temperature of product N-TFA base -2-chloroethyl amine and glycine ester hydrochloride is 50-55 DEG C, and the reaction time is that 1-3 is little
When.
10. the preparation method of Formula II compound as claimed in claim 1 or 2, it is characterised in that 2 '-trifluoro second in step (1)
Amido-ethyl glycinate dealcoholization temperature is 80-110 DEG C, stirring reaction 2-4 hour.
The preparation method of 11. Formula II compounds as claimed in claim 1 or 2, it is characterised in that the hydrazine hydrate and 2- chloroethenes
The mol ratio of amine hydrochlorate is (1.0-1.5):1;It is 40-60 DEG C that step (2) is dehydrated into the reaction temperature of hydrazone, and the reaction time is 1-
3 hours.
The preparation method of 12. Formula II compounds as claimed in claim 1 or 2, it is characterised in that the hydrochloric acid, converts into chlorination
Hydrogen meter, is (1.2-2.0) with the mol ratio of 2-chloroethyl amine hydrochloride:1.
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