CN108727224B - Process for preparing intermediates for the synthesis of pharmaceuticals - Google Patents
Process for preparing intermediates for the synthesis of pharmaceuticals Download PDFInfo
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- CN108727224B CN108727224B CN201810359610.9A CN201810359610A CN108727224B CN 108727224 B CN108727224 B CN 108727224B CN 201810359610 A CN201810359610 A CN 201810359610A CN 108727224 B CN108727224 B CN 108727224B
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title abstract description 8
- 230000015572 biosynthetic process Effects 0.000 title abstract description 6
- 238000003786 synthesis reaction Methods 0.000 title abstract description 6
- 239000000543 intermediate Substances 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 142
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims abstract 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 33
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 14
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 11
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000006242 amine protecting group Chemical group 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- -1 t-butyloxycarbonyl Chemical group 0.000 claims description 5
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- VFPWGZNNRSQPBT-UHFFFAOYSA-N 2-bromobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1Br VFPWGZNNRSQPBT-UHFFFAOYSA-N 0.000 claims description 4
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 claims description 4
- 239000003377 acid catalyst Substances 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 229910052738 indium Inorganic materials 0.000 claims description 2
- 229910052748 manganese Inorganic materials 0.000 claims description 2
- MFIGJRRHGZYPDD-UHFFFAOYSA-N n,n'-di(propan-2-yl)ethane-1,2-diamine Chemical compound CC(C)NCCNC(C)C MFIGJRRHGZYPDD-UHFFFAOYSA-N 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- 150000002431 hydrogen Chemical group 0.000 claims 3
- 229910052802 copper Inorganic materials 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 12
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 6
- 229940124597 therapeutic agent Drugs 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract 1
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 13
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 13
- 239000000243 solution Substances 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- SFFUEHODRAXXIA-UHFFFAOYSA-N 2,2,2-trifluoroacetonitrile Chemical group FC(F)(F)C#N SFFUEHODRAXXIA-UHFFFAOYSA-N 0.000 description 3
- NITMACBPVVUGOJ-UHFFFAOYSA-N 2,2,2-trifluoroethanimidamide Chemical compound NC(=N)C(F)(F)F NITMACBPVVUGOJ-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KQQCTWHSWXCZHB-UHFFFAOYSA-N azane;propan-2-ol Chemical compound N.CC(C)O KQQCTWHSWXCZHB-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- FUHZEIWXMXDMSS-UHFFFAOYSA-N tert-butyl 3-oxo-4-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C(=O)C(F)(F)F)C(=O)C1 FUHZEIWXMXDMSS-UHFFFAOYSA-N 0.000 description 2
- JGTNAGYHADQMCM-UHFFFAOYSA-M 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F JGTNAGYHADQMCM-UHFFFAOYSA-M 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000000686 lactone group Chemical group 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- IMJVLGIFJUPNEJ-UHFFFAOYSA-N tert-butyl 2,4-bis(trifluoromethyl)-6,8-dihydro-5h-pyrido[3,4-d]pyrimidine-7-carboxylate Chemical compound N1=C(C(F)(F)F)N=C(C(F)(F)F)C2=C1CN(C(=O)OC(C)(C)C)CC2 IMJVLGIFJUPNEJ-UHFFFAOYSA-N 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/20—Preparation of carboxylic acid nitriles by dehydration of carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a preparation method of an intermediate for drug synthesis. Specifically, the present invention relates to a preparation method capable of preparing a compound of the following formula 2 under mild conditions, which is essentially used in the preparation of a compound of the following formula 1, the compound of the following formula 1 being an intermediate for synthesizing a DPP-IV inhibiting therapeutic agent for diabetes, and finally manufacturing the compound of the formula 1 in high yield and purity. Wherein R1, R2, R3, R4, R5 and P1 are defined in the specification.
Description
Technical Field
The present invention relates to a method for efficiently preparing amidine compounds, which are essentially used in the preparation of dihydropyridopyrimidine intermediates for synthesizing a diabetes therapeutic agent inhibiting dipeptidyl peptidase-IV (hereinafter referred to as "DPP-IV").
Background
It is well known that a compound disclosed in international publication WO2006/104356, which can be used as a diabetes therapeutic agent for inhibiting dipeptidyl peptidase-IV (DPP-IV) (see the compound of formula 1 in WO 2006/104356), shows excellent inhibitory activity against DPP-IV enzyme and thus can be effectively used for the treatment and prevention of diseases caused by enzymes such as diabetes, obesity, and the like. To prepare these DPP-IV inhibitor compounds, WO2006/104356 discloses a preparation method using the compound of formula 1 as a key intermediate (see reaction scheme 1 of WO 2006/104356). This method has a problem in that the substance of the following formula 2, which must be used in the preparation of the compound of the formula 1, is expensive. In addition, methods for converting amides to amidines are known in several prior art documents, and they can be broadly divided into two methods. One is a method of subjecting an amide to a condensation reaction with an amine in the presence of a dehydrating agent (phosphorus pentoxide or the like), and the other is a method of adding an amine to an activated amide using a strong electrophile such as trifluoromethanesulfonic anhydride (trifluoromethanesulfonic anhydride). However, a disadvantage is that these reactions take place predominantly under harsh conditions which are undesirable from a production standpoint.
Detailed Description
Technical problem
The present invention is intended to solve the above problems, and an object of the present invention is to provide a method for efficiently producing a compound of the following formula 2, which is essentially used in the preparation of a compound of the following formula 1, under mild conditions, which is an intermediate for synthesizing a DPP-IV inhibiting therapeutic agent for diabetes.
Technical scheme
In order to achieve the above object, the present invention provides a novel method for preparing a compound of the following formula 2, which is essentially used in the preparation of the compound of the following formula 1, the compound of the following formula 1 being a key intermediate of the compounds disclosed as DPP-IV inhibitors in international publication WO 2006/104356.
[ formula 1]
[ formula 2]
Wherein,
r1 is hydrogen or CF3；
R2 is selected from the group consisting of: hydrogen, substituted or unsubstituted C1～C10Alkyl, substituted or unsubstituted C3～C10A cycloalkyl group, a,Substituted or unsubstituted C4～C8Aryl and substituted and unsubstituted C3～C7A heteroaryl group;
r3, R4 and R5 are each independently hydrogen, substituted or unsubstituted C1～C4An alkyl group; and is
P1 represents an amine protecting group, preferably tert-butoxycarbonyl.
In the above definition, when C1～C10Alkyl radical, C3～C10Cycloalkyl and C3～C7When heteroaryl groups are substituted, they are preferably substituted with halogen groups or hydroxyl groups. When C is present4～C8When the aryl group is substituted, it is preferably substituted with a halogen group, a hydroxyl group or a substituted or unsubstituted C1～C4Alkyl (which may be substituted with a halogen group or hydroxy).
The heteroaryl group may include one or more heteroatoms selected from the group consisting of N, O and S, and preferred examples thereof include 2-furan, 3-furan, 2-thiophene, 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrrole, 3-pyrrole, and the like, which may be substituted forms as defined above.
The method of preparing the compound of formula 2 according to the present invention comprises converting the compound of formula 4 below into the compound of formula 3 below and then continuously manufacturing the compound of formula 2 under the condition of an ammonia solution.
Specifically, in the preparation method of the present invention, the step of converting the compound of formula 4 below into the compound of formula 3 below (step 1) can be performed by converting the compound of formula 4 into the compound of formula 3 in a solvent in the presence of pyridine and/or dichloromethane, methanesulfonyl chloride (MsCl), and trifluoroacetic anhydride (TFAA). Subsequently, the compound of formula 3 produced in a gaseous form can be continuously reacted with an ammonia solution to produce the compound of formula 2 (step 2). The reactions carried out in the production process in each of these stages are shown in the following reaction scheme 1.
[ reaction scheme 1]
Wherein,
r2 is selected from the group consisting of: hydrogen, substituted or unsubstituted C1～C10Alkyl, substituted or unsubstituted C3～C10Cycloalkyl, substituted or unsubstituted C4～C8Aryl and substituted and unsubstituted C3～C7A heteroaryl group.
Hereinafter, the preparation method of the present invention of reaction scheme 1 will be described in more detail.
In the preparation of the compound of formula 3 as step 1 of reaction scheme 1, the compound of formula 4 used may be, for example, trifluoroacetamide. A compound of formula 4, such as trifluoroacetamide, may be reacted with a mixed solution of one or more selected from the group consisting of: methanesulfonyl chloride (MsCl), trifluoromethanesulfonyl chloride (TfCl), toluenesulfonyl chloride (TsCl) and bromobenzenesulfonyl chloride (BsCl), preferably methanesulfonyl chloride, wherein trifluoroacetamide is replaced with trifluoroacetonitrile (CF)3CN) to produce a nitrile from the amide group of formula 4.
In the preparation of the compound of formula 2 as step 2 of reaction scheme 1, the compound of formula 3 produced in step 1 is reacted with an ammonia solution, preferably an ammonia isopropanol solution in which ammonia is contained in isopropanol, to produce the compound of formula 2, in which ammonia is contained in a solvent selected from the group consisting of isopropanol, ethanol, and methanol. In a preferred embodiment, in step 2, the compound of formula 3 produced in step 1 may be in gaseous form. Reacting a gaseous compound of formula 3 (e.g., trifluoroacetonitrile gas (CF)3CN gas)) was bubbled through the ammonia solution and allowed to react to give the compound of formula 2. In the case of using an ammonia solution, particularly an ammonia isopropanol solution, the compound of formula 2 can be continuously reacted with the compound of formula 5 without a subsequent purification step to produce the compound of formula 1 below. In this case, the problem of lowering the reaction yield does not occur, and the compound of formula 1 can be produced with an excellent reaction yield.
In another aspect, the present invention relates to a method of preparing a compound of formula 1, comprising the steps of:
(a) converting the compound of formula 4 to a compound of formula 3;
(b) reacting the compound of formula 3 prepared in step (a) with an ammonia solution to prepare a compound of formula 2; and
(c) cyclizing the compound of formula 2 prepared in step (b) with the compound of formula (5) to prepare the compound of formula 1.
Steps (a) and (b) are shown in reaction scheme 1 above, and step (c) is shown in reaction scheme 2 below.
[ reaction scheme 2]
Wherein,
r1 is hydrogen or CF3；
R2 is selected from the group consisting of: hydrogen, substituted or unsubstituted C1～C10Alkyl, substituted or unsubstituted C3～C10Cycloalkyl, substituted or unsubstituted C4～C8Aryl and substituted and unsubstituted C3～C7A heteroaryl group;
r3, R4 and R5 are each independently hydrogen, substituted or unsubstituted C1～C4An alkyl group; and is
P1 represents an amine protecting group, preferably tert-butoxycarbonyl.
The respective steps will be described in detail below.
Steps (a) and (b) are all steps of preparing the compound of formula 2, which can be carried out in the same manner as described in the method of preparing the compound of formula 2.
Further, the step (c) is a step of reacting the compound of formula 5 with the compound of formula 2 to obtain the compound of formula 1, and specifically, is characterized in that the compound of formula 2 and the compound of formula 5 are cyclized to obtain the compound of formula 1 by using a substance selected from the group consisting of a base, an acid, a metal catalyst and an organic catalyst, alone or in combination, or under a condition that all of the above substances are not contained.Here, as the base, a substance selected from the group consisting of: c1～C4Trialkylamine, diisopropylethylenediamine (DIPEA, Hunig's base), pyridine, K2CO3、KOH、NaOH、NaOMe、NaOEt、Cs2CO3And LiOH. As the acid catalyst, a substance selected from the group consisting of: TsOH and AcOH. As the metal catalyst, a substance selected from the group consisting of: cu, In, Mn, Zn and Al. As the organic catalyst, a substance selected from the group consisting of: NaOAc and BF3OEt2And pyridine is preferably used.
As the reaction solvent, isopropyl alcohol (IPA), ethanol, methanol, n-butanol, t-butanol, sec-butanol, toluene, ethyl acetate, and the like can be used as a single solvent or a mixed solvent, and preferably, isopropyl alcohol can be used. The reaction can be carried out at any temperature ranging from room temperature to reflux temperature, and is preferably carried out at 70 ℃ to 90 ℃.
The process for producing the compound of formula 2 according to the present invention has an advantage in that the compound of formula 2 can be easily produced under mild reaction conditions, unlike the case where harsh conditions, which are not desirable in terms of production, have been used in the past in converting an amide into an amidine. Further, the compound of formula 2 dissolved in the solution is suitable for producing the compound of formula 1 in high yield and high purity by continuously reacting with the compound of formula 5 without additional purification steps.
Accordingly, in another aspect, the present invention provides a method for preparing a compound of the following formula 8 showing inhibitory activity against dipeptidyl peptidase IV (hereinafter referred to as "DPP-IV"), the method comprising the steps of:
(a) converting the compound of formula 4 to a compound of formula 3;
(b) reacting the compound of formula 3 prepared in step (a) with an ammonia solution to prepare a compound of formula 2;
(c) cyclizing the compound of formula 2 prepared in step (b) with a compound of formula 5 to prepare a compound of formula 1;
(d) deprotecting the compound of formula 1 and introducing it into the compound of formula 6 below to prepare a compound of formula 7 below; and
(e) deprotecting the compound of formula 7 to produce a compound of formula 8 below.
Steps (a) to (c) are shown in the above reaction schemes 1 and 2, and steps (d) and (e) are shown in the following reaction scheme 3.
[ reaction scheme 3]
Wherein,
a is
B is
P2 represents an amine protecting group, preferably Boc (tert-butyloxycarbonyl), Fmoc (fluorenylmethyloxycarbonyl) or Cbz (benzyloxycarbonyl),
r1 to R5 are as defined above, and
r6, R7, R8 and R9 are each independently hydrogen, halogen, or substituted or unsubstituted C1～C4An alkyl group.
Specifically, in reaction scheme 3, the compound of formula 8 having DPP-IV inhibitory effect can be obtained by adding the compound of formula 1 and introducing it into formula 6 via a coupling reaction to produce the compound of formula 7 as an amide having a as an amine group, and then removing the amine protecting group P2.
As a specific example, the coupling reaction of the compound of formula 6 with the compound of formula 1 can be performed by adding EDC and HOBT. In the deprotection of the amine protecting group P2, by using a strong acid comprising TFA or HCl when P2 is Boc, and H in the case of Cbz2/Pd/C or TMSI, and Et in the case of Fmoc2This reaction can be carried out by removing NH.
Further, the compound of formula 6 can be prepared by the following reaction scheme 4.
[ reaction scheme 4]
Wherein,
p2 is an amine protecting group as defined above, and
p3 and P4 are independently benzyl, methyl, ethyl, isopropyl or tert-butyl, and
g1 is a good leaving group leaving with oxygen. G1O is trifluoromethanesulfonate (trifluoromethanesulfonate), methanesulfonate, toluenesulfonate, benzenesulfonate or nonafluorosulfonate (nonafluorobutanesulfonate), preferably trifluoromethanesulfonate or nonafluorosulfonate.
Specifically, the reaction scheme 4 may include the following steps:
(i) performing a coupling reaction by adding a base to the compound of formula 9 and the compound of formula 10;
(ii) (ii) cyclizing the product of step (i) by adding an acid to obtain a compound of formula 11; and
(iii) removing the carboxylic acid protecting group by hydrolyzing the prepared compound of formula 11 to obtain the compound of formula 6.
In scheme 4, a) is a base such as Et3N, Hunig's base, etc.;
b) comprises the following steps: acids such as AcOH and the like; and organic solvents such as CH2Cl2Etc.;
c) varies with the protecting group and is typically selected from the following conditions when P2 is Boc and P3 is tert-butyl: (1) strong acids such as H2SO4Etc. and CH2Cl2NaOH aqueous solution and Boc2O; and (2) NaOH, EtOH, H2O and reflux or hydrolysis conditions using the base specified in the above condition (2) when P1 is Boc and P2 is benzyl, methyl, ethyl and isopropyl. R6, R7, R8, R9, P2, P3, P4 and G1 are as defined above.
Specifically, in step (a), the unprotected compound of formula 9Is coupled to a carbon atom having a leaving group in the compound of formula 10 under basic conditions, and-OG 1 is removed. The reaction uses C1～C4Trialkylamines, preferably triethylamine or diisopropylethylamine, are used as bases. As reaction solvent, it is possible to use the customary organic solvents such as dichloroethane or dichloromethane, or cyclic ethers, for example Tetrahydrofuran (THF) or bis
An alkane). To facilitate the reaction, the base used instead acts as a solvent. The reaction can be carried out at any temperature between 0 ℃ and the reflux temperature.
In step (b), the compound of formula 11 is synthesized by cyclizing the secondary amine group of the compound resulting from said step (a) with a lactone group under acidic conditions. In this reaction, as the acid, there can be used: inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as formic acid, acetic acid, tartaric acid, etc., with acetic acid being particularly preferred. The solvents and temperature conditions described in step (a) above can be used in this step. Said steps (a) and (b) are carried out in a continuous manner.
In step (c), the compound of formula 11 from step (b) is hydrolyzed to give the compound of formula 6. Specifically, in the case of the compound of formula 11 in which P2 is Boc and P3 is t-butyl, first a strong acid such as sulfuric acid, hydrochloric acid, phosphoric acid, TFA (trifluoroacetic acid), etc. can be used to remove both protecting groups, and then the Boc protecting group can be attached to the amine group again under basic conditions to give the desired compound of formula 6. Alternatively, hydrolysis under basic conditions, rather than acidic conditions, can result in the selective removal of only P3 in protecting groups P2 and P3 to provide compounds of formula 6, and the process in this manner is more efficient. Preferably, sodium hydroxide solution is used as the base. Upon completion of the reaction, the compound of formula 6 can be obtained as a solid product by acidification using an acid.
In the case of compounds in which P2 is Boc and P3 is benzyl, methyl, ethyl or isopropyl, hydrolysis can be carried out with a base. H is used when P2 is Cbz2Pd-C to carry out the deprotection reactionAlternatively, Bu is used when P2 is Fmoc4N+F-To carry out the deprotection reaction.
Preferably, when P3 is tert-butyl or isopropyl, more preferably tert-butyl and P4 is methyl or ethyl, the compound of formula 6 can be obtained in high yield.
In addition to the above-mentioned methods, methods for preparing the DPP-IV inhibitor compound of formula 8 are described in detail in International publication WO2006/104356 and Korean patent No. 10-1378984. Therefore, the method disclosed in this patent publication can be used without limitation. The entire contents of the above-mentioned patent publications are incorporated herein by reference.
Advantageous effects
According to the present invention, it is possible to efficiently produce a compound of formula 2 such as 2,2, 2-trifluoro-1-imino-1-ethylamine, which is required in the production of a compound of formula 1, which is an intermediate necessarily used in the synthesis of a therapeutic agent for diabetes that inhibits DPP-IV, under mild conditions, thereby finally enabling the production of the compound of formula 1 in high yield and high purity, and thus it is very useful.
Detailed Description
Hereinafter, the configuration and effect of the present invention will be described in more detail by way of examples. These examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention thereto.
Example 1: synthesis of 2,2, 2-trifluoro-1-imino-1-ethylamine
2,2, 2-trifluoroacetamide (200.1g) was added to a mixed solution of dichloromethane (1325.8g) and pyridine (420.1g) and stirred at 20 ℃. A mixed solution of methanesulfonyl chloride (243.4g) and trifluoroacetic anhydride (37.2g) was slowly added dropwise thereto. And bubbling the generated trifluoroacetonitrile gas into an ammonia isopropanol solution with the molar concentration of 1.7-1.9. When the reaction was completed, about 10% to 20% of the reaction mixture solution was distilled under reduced pressure to obtain 158.7g of the objective compound in a state of being dissolved in an isopropanol solution.
1H NMR(500MHz,CDCl3)δ8.51(s,2H)
Example 2: synthesis of tert-butyl 2, 4-bis (trifluoromethyl) -5,6,7, 8-tetrahydropyrido [3,4-d ] pyrimidine-7-carboxylate
To tert-butyl 3-oxo-4- (2,2, 2-trifluoroacetyl) -1-piperidinecarboxylate (8.4g) was added dropwise a solution of 2,2, 2-trifluoro-1-imino-1-ethylamine (4.7g) in isopropanol (60ml), and the mixture was stirred at room temperature for 1 hour. When the starting material, tert-butyl 3-oxo-4- (2,2, 2-trifluoroacetyl) -1-piperidinecarboxylate, had disappeared, pyridine (6.8g) was added dropwise thereto. After the temperature was increased, the reaction mixture was stirred under reflux for more than 6 hours. When the reaction was complete, purified water (40g) was added and slowly cooled to make a solid. The resulting mixture is aged at about 5 ℃ to 10 ℃ for more than 1 hour and filtered. The obtained solid compound was washed with a mixture of ethanol and purified water and dried under nitrogen to obtain 8.6g of the objective compound in a yield of 81%.
1H NMR(500MHz,CDCl3)δ1.50(s,9H),3.12(bt,2H),3.78(t,2H,J＝5.8Hz),4.85(s,2H)。
Claims (18)
1. A process for preparing a compound of the following formula 2, characterized by comprising: converting the compound of the following formula 4 into the compound of the following formula 3 and then continuously producing the compound of the following formula 2 under the condition of an ammonia solution,
[ formula 2]
[ formula 3]
[ formula 4]
Wherein,
r2 is selected from the group consisting of: hydrogen; unsubstituted C1～C10Alkyl or C substituted by halogen radicals or hydroxy groups1～C10An alkyl group; unsubstituted C3～C10Cycloalkyl or C substituted by halogen radicals or hydroxy groups3～C10A cycloalkyl group; unsubstituted C4～C8Aryl or by halogen radicals, hydroxy radicals, unsubstituted C1～C4Alkyl or C substituted by halogen radicals or hydroxy groups1～C4Alkyl substituted C4～C8An aryl group; and unsubstituted C3～C7Heteroaryl or C substituted by halogen radicals or hydroxy groups3～C7A heteroaryl group; and is
The conversion of the compound of formula 4 to the compound of formula 3 is carried out in the presence of pyridine, dichloromethane, methanesulfonyl chloride (MsCl) and trifluoroacetic anhydride (TFAA).
2. The method of claim 1, wherein R2 is CF3。
3. The process of claim 1, wherein a mixture of trifluoroacetamide and one or more selected from the group consisting of trifluoroacetic anhydride (TFAA) is reacted in the presence of pyridine and dichloromethane to produce the compound of formula 3 in gaseous form: methanesulfonyl chloride (MsCl), trifluoromethanesulfonyl chloride (TfCl), toluenesulfonyl chloride (TsCl) and bromobenzenesulfonyl chloride (BsCl).
4. The method according to claim 1, characterized in that, when converting the compound of formula 3 into the compound of formula 2, the gaseous compound of formula (3) is bubbled through an ammonia solution in which ammonia is dissolved in a solvent selected from the group consisting of isopropanol, ethanol and methanol and thereby converted into the compound of formula 2.
5. A process for preparing a compound of formula 1, comprising the steps of:
(a) converting the compound of formula 4 below into the compound of formula 3 below;
(b) reacting the compound of formula 3 prepared in the step (a) with an ammonia solution to prepare a compound of the following formula 2; and
(c) cyclizing the compound of formula 2 prepared in the step (b) with a compound of the following formula (5) to prepare the compound of formula 1,
[ formula 1]
[ formula 2]
[ formula 3]
[ formula 4]
[ formula 5]
Wherein,
r1 is hydrogen or CF3；
R2 is selected from the group consisting ofThe group consisting of: hydrogen; unsubstituted C1～C10Alkyl or C substituted by halogen radicals or hydroxy groups1～C10An alkyl group; unsubstituted C3～C10Cycloalkyl or C substituted by halogen radicals or hydroxy groups3～C10A cycloalkyl group; unsubstituted C4～C8Aryl or by halogen radicals, hydroxy radicals, unsubstituted C1～C4Alkyl or C substituted by halogen radicals or hydroxy groups1～C4Alkyl substituted C4～C8An aryl group; and unsubstituted C3～C7Heteroaryl or C substituted by halogen radicals or hydroxy groups3～C7A heteroaryl group;
r3, R4 and R5 are each independently hydrogen, unsubstituted C1～C4Alkyl or C substituted by halogen radicals or hydroxy groups1～C4An alkyl group; and is
P1 represents a tert-butoxycarbonyl group as an amine protecting group; and is
The conversion of the compound of formula 4 to the compound of formula 3 is carried out in the presence of pyridine, dichloromethane, methanesulfonyl chloride (MsCl) and trifluoroacetic anhydride (TFAA).
6. The process of claim 5, wherein the compound of formula 2 prepared in step (b) is continuously cyclized with the compound of formula 5 prepared in step (c) without isolation and purification steps.
7. The method of claim 5, wherein R1 and R2 are each independently CF3。
8. The method of claim 5, wherein R3, R4, and R5 are each independently hydrogen.
9. The method according to claim 5, wherein the cyclization reaction of step (c) is performed by adding one or more substances selected from the group consisting of a base, an acid, a metal catalyst and an organic catalyst to the compound of formula 5 and the compound of formula 2.
10. The method according to claim 9, wherein the base is one or more selected from the group consisting of: c1～C4Trialkylamine, diisopropylethylenediamine (Hunig's base), pyridine, K2CO3、KOH、NaOH、NaOMe、NaOEt、Cs2CO3And LiOH.
11. The method of claim 9, wherein the acid catalyst is one or more selected from the group consisting of TsOH and AcOH.
12. The method of claim 9, wherein the metal catalyst is one or more selected from the group consisting of Cu, In, Mn, Zn, and Al.
13. The method of claim 9, wherein the organic catalyst is selected from the group consisting of NaOAc and BF3OEt2One or more of the group consisting of.
14. The process according to claim 9, wherein the cyclization reaction of step (c) is carried out in the presence of pyridine.
15. The process of claim 5, wherein said cyclization reaction of step (c) is carried out without using all of said base, said acid catalyst, and said metal catalyst.
16. The process according to claim 5, characterized in that the reaction solvent used in the cyclization reaction of step (c) is one or more solvents selected from the group consisting of: isopropanol, ethanol, methanol, n-butanol, t-butanol, sec-butanol, toluene and ethyl acetate.
17. The process according to claim 5, characterized in that the cyclization reaction of step (c) is carried out at a temperature of 70 ℃ to 90 ℃.
18. A method of making a DPP-IV inhibitor compound of the following formula (8), said method comprising the steps of:
(a) converting the compound of formula 4 below into the compound of formula 3 below;
(b) reacting the compound of formula 3 prepared in the step (a) with an ammonia solution to prepare a compound of the following formula 2;
(c) cyclizing the compound of formula 2 prepared in the step (b) with a compound of formula 5 below to prepare a compound of formula 1 below;
(d) deprotecting the compound of formula 1 and introducing it into the compound of formula 6 below to prepare a compound of formula 7 below; and
(e) deprotecting the compound of formula 7 to produce a compound of the following formula 8,
[ formula 1]
[ formula 2]
[ formula 3]
[ formula 4]
[ formula 5]
[ formula 6]
[ formula 7]
[ formula 8]
Wherein,
a is
B is
P1 is Boc (tert-butyloxycarbonyl) as an amine protecting group;
p2 represents Boc (t-butyloxycarbonyl), Fmoc (fluorenylmethyloxycarbonyl) or Cbz (benzyloxycarbonyl) as an amine protecting group;
r1 is hydrogen or CF3；
R2 is selected from the group consisting of: hydrogen; unsubstituted C1～C10Alkyl or C substituted by halogen radicals or hydroxy groups1～C10An alkyl group; unsubstituted C3～C10Cycloalkyl or C substituted by halogen radicals or hydroxy groups3～C10A cycloalkyl group; unsubstituted C4～C8Aryl or by halogen radicals, hydroxy radicals, unsubstituted C1～C4Alkyl or C substituted by halogen radicals or hydroxy groups1～C4Alkyl substituted C4～C8An aryl group; and unsubstituted C3～C7Heteroaryl or C substituted by halogen radicals or hydroxy groups3～C7A heteroaryl group;
r3, R4 and R5 are each independently hydrogen, unsubstituted C1～C4Alkyl or C substituted by halogen radicals or hydroxy groups1～C4An alkyl group;
r6, R7, R8 and R9 are each independently hydrogen, halogen, unsubstituted C1～C4Alkyl or C substituted by halogen radicals or hydroxy groups1～C4An alkyl group; and is
Wherein the conversion of the compound of formula 4 to the compound of formula 3 is carried out in the presence of pyridine, dichloromethane, methanesulfonyl chloride (MsCl) and trifluoroacetic anhydride (TFAA).
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