WO2012072036A1 - 西他列汀的中间体及其制备方法 - Google Patents
西他列汀的中间体及其制备方法 Download PDFInfo
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- WO2012072036A1 WO2012072036A1 PCT/CN2011/083315 CN2011083315W WO2012072036A1 WO 2012072036 A1 WO2012072036 A1 WO 2012072036A1 CN 2011083315 W CN2011083315 W CN 2011083315W WO 2012072036 A1 WO2012072036 A1 WO 2012072036A1
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- Prior art keywords
- group
- tert
- reaction
- benzyl
- compound
- Prior art date
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- 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 title claims abstract description 24
- 229960004034 sitagliptin Drugs 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000000543 intermediate Substances 0.000 title abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 33
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims description 179
- -1 acridine compound Chemical class 0.000 claims description 176
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 58
- 150000001875 compounds Chemical class 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- DZBUGLKDJFMEHC-UHFFFAOYSA-N benzoquinolinylidene Natural products C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 239000003153 chemical reaction reagent Substances 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical group OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 20
- 125000002252 acyl group Chemical group 0.000 claims description 20
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 19
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 18
- 229960004115 sitagliptin phosphate Drugs 0.000 claims description 18
- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 claims description 18
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 16
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 16
- 239000012312 sodium hydride Substances 0.000 claims description 16
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 15
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 13
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 12
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 10
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 10
- 229910052751 metal Inorganic materials 0.000 claims description 10
- 239000002184 metal Substances 0.000 claims description 10
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 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 9
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 9
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- FNZIWSISDJDZFU-UHFFFAOYSA-N tert-butyl-methoxy-phenylsilicon Chemical compound CO[Si](C(C)(C)C)C1=CC=CC=C1 FNZIWSISDJDZFU-UHFFFAOYSA-N 0.000 claims description 7
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 7
- PEBWOGPSYUIOBP-UHFFFAOYSA-N 1,2,4-trifluorobenzene Chemical compound FC1=CC=C(F)C(F)=C1 PEBWOGPSYUIOBP-UHFFFAOYSA-N 0.000 claims description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical class C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 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 5
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 125000006242 amine protecting group Chemical group 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 3
- 239000000920 calcium hydroxide Substances 0.000 claims description 3
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- OPHUWKNKFYBPDR-UHFFFAOYSA-N copper lithium Chemical compound [Li].[Cu] OPHUWKNKFYBPDR-UHFFFAOYSA-N 0.000 claims description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 3
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 3
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 3
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 3
- 238000007142 ring opening reaction Methods 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- JIWRAHHCDZUHKY-UHFFFAOYSA-M [Br-].FC1=CC(F)=C([Mg+])C=C1F Chemical group [Br-].FC1=CC(F)=C([Mg+])C=C1F JIWRAHHCDZUHKY-UHFFFAOYSA-M 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 150000002191 fatty alcohols Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims 9
- 125000004797 2,2,2-trichloroethoxy group Chemical group ClC(CO*)(Cl)Cl 0.000 claims 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 4
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims 3
- 229910052703 rhodium Inorganic materials 0.000 claims 2
- 239000010948 rhodium Substances 0.000 claims 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 125000004492 methyl ester group Chemical group 0.000 claims 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 17
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 182
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 181
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 165
- 235000019439 ethyl acetate Nutrition 0.000 description 71
- 239000000243 solution Substances 0.000 description 70
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 53
- 239000012074 organic phase Substances 0.000 description 48
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 46
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 44
- 239000012043 crude product Substances 0.000 description 40
- 239000012267 brine Substances 0.000 description 36
- 239000008346 aqueous phase Substances 0.000 description 35
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- 229920006395 saturated elastomer Polymers 0.000 description 24
- 229910052757 nitrogen Inorganic materials 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 235000019270 ammonium chloride Nutrition 0.000 description 11
- 239000012299 nitrogen atmosphere Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 10
- 238000007039 two-step reaction Methods 0.000 description 10
- DVTULTINXNWGJY-UHFFFAOYSA-N 1-Bromo-2,4,5-trifluorobenzene Chemical compound FC1=CC(F)=C(Br)C=C1F DVTULTINXNWGJY-UHFFFAOYSA-N 0.000 description 9
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000011777 magnesium Substances 0.000 description 9
- 229910052749 magnesium Inorganic materials 0.000 description 9
- WZZMHOBVLAEJOD-UHFFFAOYSA-N methylsulfanylmethane;hydrobromide Chemical compound [Br-].C[SH+]C WZZMHOBVLAEJOD-UHFFFAOYSA-N 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- 239000012279 sodium borohydride Substances 0.000 description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 0 *N[C@@](CC(O)=O)Cc(cc(c(F)c1)F)c1F Chemical compound *N[C@@](CC(O)=O)Cc(cc(c(F)c1)F)c1F 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 8
- 239000011449 brick Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 6
- 239000010779 crude oil Substances 0.000 description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- OFJWFSNDPCAWDK-UHFFFAOYSA-N 2-phenylbutyric acid Chemical class CCC(C(O)=O)C1=CC=CC=C1 OFJWFSNDPCAWDK-UHFFFAOYSA-N 0.000 description 5
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 229960004452 methionine Drugs 0.000 description 5
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
- AJKNNUJQFALRIK-UHFFFAOYSA-N 1,2,3-trifluorobenzene Chemical compound FC1=CC=CC(F)=C1F AJKNNUJQFALRIK-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- ODCCJTMPMUFERV-UHFFFAOYSA-N ditert-butyl carbonate Chemical compound CC(C)(C)OC(=O)OC(C)(C)C ODCCJTMPMUFERV-UHFFFAOYSA-N 0.000 description 4
- 229930182817 methionine Natural products 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005935 nucleophilic addition reaction Methods 0.000 description 3
- 229910000077 silane Inorganic materials 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 239000011345 viscous material Substances 0.000 description 3
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- FMTDZGCPYKWMPT-UHFFFAOYSA-N FC(c1nnc2[n]1CCNC2)(F)F Chemical compound FC(c1nnc2[n]1CCNC2)(F)F FMTDZGCPYKWMPT-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DETXZQGDWUJKMO-UHFFFAOYSA-N alpha-hydroxymethanesulfonic acid Natural products OCS(O)(=O)=O DETXZQGDWUJKMO-UHFFFAOYSA-N 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 2
- 150000001804 chlorine Chemical class 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- DETXZQGDWUJKMO-UHFFFAOYSA-M hydroxymethanesulfonate Chemical compound OCS([O-])(=O)=O DETXZQGDWUJKMO-UHFFFAOYSA-M 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000012071 phase Substances 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
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 150000003333 secondary alcohols Chemical class 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- TUUMZEPFCCXCEJ-UHFFFAOYSA-N 1,1,3,3-tetra(propan-2-yl)urea Chemical compound CC(C)N(C(C)C)C(=O)N(C(C)C)C(C)C TUUMZEPFCCXCEJ-UHFFFAOYSA-N 0.000 description 1
- IXADHCVQNVXURI-UHFFFAOYSA-N 1,1-dichlorodecane Chemical compound CCCCCCCCCC(Cl)Cl IXADHCVQNVXURI-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- AQCSCRYRCRORET-UHFFFAOYSA-N 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine;hydrochloride Chemical class Cl.C1NCCN2C(C(F)(F)F)=NN=C21 AQCSCRYRCRORET-UHFFFAOYSA-N 0.000 description 1
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- ABJLXXRNUCWTAN-UHFFFAOYSA-N CC(C)(C)OC(N1C(CCSC)C1)=O Chemical compound CC(C)(C)OC(N1C(CCSC)C1)=O ABJLXXRNUCWTAN-UHFFFAOYSA-N 0.000 description 1
- IPIBDQMAIDPJBU-QMMMGPOBSA-N CC(C)(C)OC(N[C@@H](CCSC)CO)=O Chemical compound CC(C)(C)OC(N[C@@H](CCSC)CO)=O IPIBDQMAIDPJBU-QMMMGPOBSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-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
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 1
- 229930195722 L-methionine Natural products 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- JLCHNBRGUPQWKF-UHFFFAOYSA-J [OH-].[C+4].[OH-].[OH-].[OH-] Chemical compound [OH-].[C+4].[OH-].[OH-].[OH-] JLCHNBRGUPQWKF-UHFFFAOYSA-J 0.000 description 1
- 150000001251 acridines Chemical class 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 150000001576 beta-amino acids Chemical class 0.000 description 1
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 1
- XKLVLDXNZDIDKQ-UHFFFAOYSA-N butylhydrazine Chemical compound CCCCNN XKLVLDXNZDIDKQ-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000010493 gram-scale synthesis Methods 0.000 description 1
- NEXSMEBSBIABKL-UHFFFAOYSA-N hexamethyldisilane Chemical compound C[Si](C)(C)[Si](C)(C)C NEXSMEBSBIABKL-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 229940090473 januvia Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
- C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
- C07D203/10—Radicals substituted by singly bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/22—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
- C07D203/24—Sulfur atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
Definitions
- the present invention relates to the field of pharmaceutical synthesis, in particular, to an intermediate of sitagliptin and a process for the preparation thereof, and a process for synthesizing sitagliptin using these intermediates.
- BACKGROUND OF THE INVENTION The selective construction of chiral amino groups has been the goal of organic synthetic chemists. In 1979, Professor Kozikowski of the University of Pittsburgh studied the organometallic reagents to selectively ring-open the synthesis of amino compounds to acridine compounds (J. Org. Chem., 1979, 44, 788-2790); in recent years, chiral ⁇ The selective ring-opening synthesis of chiral amino compounds of pyridine compounds has also been vigorously developed (Org. Lett., 2001, 3, 2349-2351). Compared with chiral induction and chiral resolution, the use of natural chiral sources to synthesize chiral amino compounds has considerable advantages due to its simple and intuitive method and customizable chiral structure.
- Sitagliptin phosphate (Sitagliptin phosphate) was first approved by the FDA in 2006 a dipeptidyl peptidase listed -IV (DPP-4) inhibitors, for the treatment of type II diabetes, which alone or with metformin, The combination of pioglitazone has obvious hypoglycemic effect, and it is safe to take, well tolerated, and has few adverse reactions.
- Sitagliptin phosphate was developed by Merck and was approved by the Mexican Ministry of Health on August 8, 2006 for the treatment of type 2 diabetes once a day. The market name is Januvia. In the United States, sitagliptin sulphate was approved by the FDA on October 16, 2006. Sitagliptin phosphate has been approved for use in 60 countries around the world.
- 6,699,871 discloses a synthetic route to sitagliptin, which is a gram-scale synthesis method of the research department, which uses a chiral source to induce chiral alpha-amino acids, and then The nitridation reaction produces a beta-amino acid to construct the desired chiral center.
- the raw material cost required for the synthetic route is relatively high, and the reaction operation is troublesome, and
- the present invention provides a novel intermediate for the synthesis of sitagliptin, namely an acridine compound I having an absolute configuration of R, which has the following structural formula:
- R 1 is -CH 2 SR 3 , R 3 is selected from the alkyl group of dC 4 ; or R 1 is -CH 2 OR 4 , and R 4 is selected from the group consisting of hydrogen, methyl, substituted methyl, tetrahydropyranyl, a methoxyphenyl group, an ethyl group, a benzyl group, a substituted benzyl group or a silane group;
- the substituted methyl group is selected from the group consisting of methoxymethyl, methylthiomethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, 2-methoxyethoxymethyl or 2-trimethylsilyl Ethoxymethyl;
- the substituted benzyl group is selected from p-methoxybenzyl, 3,4-dimethoxybenzyl or p-nitrobenzyl;
- the silane group is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl Or tert-butylmethoxyphenyl silicon;
- R 2 is selected from the group consisting of hydrogen, a formate group, an acyl group, a sulfonyl group, a benzyl group or a 4-methoxybenzyl group; wherein the formate group is selected from the group consisting of methyl formate, ethyl formate, 9-fluorenyl Methoxylated, 2-chloro-3-indolylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, Benzyloxycarbonyl or allyloxycarbonyl;
- the acyl group is selected from formyl, acetyl, trifluoroacetyl or benzoyl;
- the sulfonyl group is selected from a benzenesulfonyl group or a trifluoromethanesulfonyl group
- R 1 is -CH 2 SR 3 and R 3 is a methyl group; or R 1 is -CH 2 OR 4 , and R 4 is selected from hydrogen and methoxy groups.
- R 2 is selected from the group consisting of a formate group, an acyl group, a sulfonyl group, a benzyl group or a 4-methoxybenzyl group; wherein the formate group is selected from the group consisting of methyl formate, t-butoxy, benzyloxy Or an allyloxy group; the acyl group is a benzoyl group; and the sulfonyl group is selected from the group consisting of a benzenesulfonyl group and a trifluoromethanesulfonyl group.
- R 1 is -CH 2 SR 3 , R 3 is methyl; or R 1 is -CH 2 OR 4 , R 4 is selected from hydrogen, benzyl, tert-butyldimethylsilyl; R 2 is selected from Tert-butoxycarbonyl, benzyl, benzenesulfonyl.
- the present invention also provides a method for synthesizing the above acridine compound I having an absolute configuration of R, comprising the steps of: treating an amino compound II having an absolute configuration of R and having the following structure in a base and a phase transfer catalyst; The intramolecular cyclization reaction occurs, that is, the acridine compound I having an absolute configuration of R;
- R 1 is -CH 2 SR 3
- R 3 is selected from the alkyl group of dC 4
- R 1 is -CH 2 OR 4
- R 4 is selected from the group consisting of hydrogen, methyl, substituted methyl, tetrahydropyranyl , methoxyphenyl, ethyl, benzyl, substituted benzyl or silane;
- substituted methyl group is selected from the group consisting of methoxymethyl, methylthiomethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, 2-methoxyethoxymethyl or 2-trimethylsilyl Ethoxymethyl;
- the substituted benzyl group is selected from p-methoxybenzyl, 3,4-dimethoxybenzyl or p-nitrobenzyl;
- the silane group is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl Or tert-butylmethoxyphenyl silicon;
- R 2 is selected from the group consisting of hydrogen, a formate group, an acyl group, a sulfonyl group, a benzyl group or a 4-methoxybenzyl group; wherein the formate group is selected from the group consisting of methyl formate, ethyl formate, 9-fluorenyl Methoxylated, 2-chloro-3-indolylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, Benzyloxycarbonyl or allyloxycarbonyl;
- the acyl group is selected from formyl, acetyl, trifluoroacetyl or benzoyl;
- the sulfonyl group is selected from the group consisting of benzenesulfonyl or trifluoromethanesulfon
- R 5 is selected from the group consisting of a hydroxyl group, a sulfonate, and a halogen
- sulfonate is selected from the group consisting of mesylate, p-toluenesulfonate or triflate; 3 ⁇ 4 is selected from chlorine, bromine or hydrazine.
- R 1 is -CH 2 SR 3 , R 3 is methyl; or R 1 is -CH 2 OR 4 , R 4 is selected from hydrogen, benzyl, tert-butyldimethylsilyl; R 2 is selected from Tert-butoxy-reactive, benzyl, benzenesulfonyl; R 5 is selected from mesylate, p-toluenesulfonate.
- the base is an organic base or an inorganic base
- the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium hydride, calcium hydroxide, sodium carbonate, potassium phosphate, potassium carbonate;
- Said organic base is selected from pyridine, substituted pyridine, piperidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 4 dC fatty amines, fatty alcohols 4 sodium dC, dC fat 4 Potassium ketone, butyl 4, two One or more of isopropylamino, hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide.
- the base is sodium hydride, sodium methoxide or a mixture of the two.
- the solvent in the reaction is selected from anhydrous solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, dimethylformamide, dimethylacetamide and dimethyl sulfoxide. .
- the invention also provides a chiral amino compound IV of R, which has the following structural formula:
- R 1 is -CH 2 SR 3 , R 3 is selected from the alkyl group of dC 4 ; or R 1 is -CH 2 OR 4 , and R 4 is selected from the group consisting of hydrogen, methyl, substituted methyl, tetrahydropyranyl , methoxyphenyl, ethyl, benzyl, substituted benzyl or silane;
- substituted methyl group is selected from the group consisting of methoxymethyl, methylthiomethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, 2-methoxyethoxymethyl or 2-trimethylsilyl Ethoxymethyl;
- the substituted benzyl group is selected from p-methoxybenzyl, 3,4-dimethoxybenzyl or p-nitrobenzyl;
- the silane group is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl Or tert-butylmethoxyphenyl silicon;
- R 2 is selected from the group consisting of hydrogen, a formate group, an acyl group, a sulfonyl group, a benzyl group or a 4-methoxybenzyl group; wherein the formate group is selected from the group consisting of methyl formate, ethyl formate, 9-fluorenyl Methoxylated, 2-chloro-3-indolylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, Benzyloxycarbonyl or allyloxycarbonyl;
- the acyl group is selected from formyl, acetyl, trifluoroacetyl or benzoyl;
- the sulfonyl group is selected from a benzenesulfonyl group or a trifluoromethanesulfonyl group
- R 1 is -CH 2 SR 3 and R 3 is methyl; or R 1 is -CH 2 OR 4 , R 4 is selected from hydrogen, substituted methyl, benzyl, substituted benzyl a silane group, wherein the substituted The methyl group is a methoxymethyl group, the substituted benzyl group is a p-nitrobenzyl group, the silane group is selected from the group consisting of tert-butyldimethylsilyl and tert-butyldiphenylsilyl; and R 2 is selected from a formate group, an acyl group, a sulfonyl group, a benzyl group or a 4-methoxybenzyl group, wherein the formate group is selected from the group consisting of methyl formate, tert-butoxy, benzyloxycarbonyl, allyloxycarbonyl, The acyl group is a benzoyl group, and the sulf
- R 1 is -CH 2 SR 3 , R 3 is methyl; or R 1 is -CH 2 OR 4 , and R 4 is selected from hydrogen, benzyl, tert-butyldimethylsilyl; R 2 is selected from the group consisting of t-butoxycarbonyl, benzyl, and benzenesulfonyl.
- the present invention also provides a method of synthesizing the chiral amino compound IV of the above configuration R, comprising the steps of:
- I 1 and R 2 are as defined above, and M is selected from the group consisting of lithium, copper lithium, magnesium bromide, and magnesium chloride.
- the preferred compound of the metal reagent III of 2,4,5-trifluorobenzene as described above is 2,4,5-trifluorophenylmagnesium bromide.
- the solvent is selected from the group consisting of anhydrous solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether and methyl tert-butyl ether;
- the acridine compound I having an absolute configuration of R is used in the process for preparing sitagliptin phosphate X, firstly, the action of an amino compound II having an absolute configuration of R in the base Intramolecular cyclization reaction occurs to obtain compound I;
- the base as described above is an organic base or an inorganic base; wherein the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium hydride, calcium hydroxide, sodium carbonate, phosphoric acid clock, potassium carbonate.
- One or more of the organic bases selected from the group consisting of pyridine, substituted pyridine, piperidine, 1,8-diazabicyclo [5.4.0]undec-7-ene, C r C 4 fatty amine , C r C 4 fatty acid sodium, dC 4 fatty acid potassium, butyl lithium, diisopropylamino ketone, hexamethyldisilazide, hexamethyldisilazide sodium, hexamethyldisilane One or more of the amine potassium.
- the base is preferably sodium hydride and sodium methoxide.
- the reaction solvent in the above reaction step is selected from the group consisting of anhydrous solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, dimethylformamide, dimethylacetamide and dimethyl sulfoxide;
- anhydrous solvents such as tetrahydrofuran, methyltetrahydrofuran, diethyl ether, methyl tert-butyl ether, dimethylformamide, dimethylacetamide and dimethyl sulfoxide
- step (2) of the above process for preparing sitagliptin phosphate X from an acridine compound I having an absolute configuration of R when R 1 in the chiral amino compound IV is -CH 2 OH, a chiral amino group Compound IV is a ⁇ -amino alcohol compound, the compound is first subjected to oxidation reaction to obtain a ⁇ -amino acid compound VI;
- the ⁇ -amino acid compound VI obtained by the oxidation reaction of the ⁇ -amino alcohol compound V can be realized by a conventionally known technique.
- R 1 in the chiral amino compound IV is -CH 2 SR 3
- R 3 is selected from an alkyl group of dC 4
- R 1 is -CH 2 OR 4
- R 4 is selected from a methyl group, a substituted methyl group, and four Hydropyranyl, methoxyphenyl, Ethyl, benzyl, substituted benzyl, silane, wherein the substituted methyl group is selected from the group consisting of methoxymethyl, methoxymethyl, methoxymethyl, p-methoxyoxymethyl, 2- Methoxyethoxymethyl, 2-trimethylsilylethoxymethyl, the substituted benzyl group is selected from p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl
- the silane group is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, ter
- a chiral ⁇ -amino alcohol compound having a configuration of R after removal of a sulfanyl group or a hydroxy protecting group by a chiral amino compound IV having a configuration of R can be carried out by a conventionally known technique.
- the present invention provides a method for synthesizing the methylthio group of the compound IV-1, that is, The reactant V is carried out by using the compound IV-1 and methyl iodide in an alcohol solvent such as methanol or ethanol at room temperature or at a low temperature.
- the compound (IV) when R 1 is -CH 2 OR 4 (wherein R 4 is hydrogen, benzyl, tert-butyldimethylsilyl), the compound (IV) is characterized by the following structure IV-2
- the present invention provides a method for synthesizing the hydroxy protecting group of the compound (IV-2), and using the corresponding protecting group on the hydroxyl group of the compound (IV-2), selecting a suitable de-clearing method, for example, when R 4 is a benzyl group, the present invention utilizes pd/C as a catalyst to carry out catalytic hydrogenation in an alcohol solvent such as methanol to remove a benzyl group; for example, when R 4 is a tert-butyldimethylsilyl group, The invention utilizes a special reagent fluoride for removing a silicon-based protecting group, such as tetrabutylammonium fluoride, etc., in a solvent such as tetrahydrofuran, at room temperature
- the ⁇ -amino alcohol compound V is subjected to an oxidation reaction to obtain a ⁇ -amino acid compound VI;
- R 2 in the above reaction formula is as defined above.
- the present invention provides a method for oxidizing a compound V to a ⁇ -amino acid compound VI under certain conditions.
- the compound V is catalyzed by TEMPO, and the primary alcohol is oxidized by sodium hypochlorite to obtain a ⁇ -amino acid compound VI;
- a ⁇ -amino acid compound VI is condensed with a triazosin compound W to give an amine group.
- R 2 in the above reaction formula is as defined above.
- the present invention also provides a method for peptide-binding a ⁇ -amino acid compound VI and a triazosin compound W, such as a ⁇ -amino acid compound VI and a triazosin compound W in a solvent such as acetonitrile or dichloromethane, as in Under the action of a condensation reagent such as DCC or EDCI and an organic base such as triethylamine, the reaction is carried out at room temperature to obtain an amine-protected sitagliptin derivative ring in a higher yield; in the above-mentioned absolute configuration R
- the amine-protected sitagliptin derivative ring is obtained by removing the amine protecting group R 2
- R 2 in the above reaction formula is as defined above.
- the invention provides a method for synthesizing a ring-removing amine protecting group of the compound, and using the corresponding protecting group on the amine group of the compound, that is, when R 2 is a tert-butoxy group, a benzyl group and a benzenesulfonyl group, respectively.
- the present invention provides the use of a strong acid such as hydrochloric acid to carry out a normal temperature or heating reaction in an alcohol solvent to remove the t-butoxy group;
- a strong acid such as hydrochloric acid
- R 4 is a benzyl group
- the present invention removes a benzyl group by catalytic hydrogenation in an alcohol solvent such as methanol using pd/C as a catalyst.
- sitagliptin IX is reacted with phosphoric acid to obtain sitagliptin phosphate X;
- the invention utilizes a chiral amine-based compound which is cheap and easy to obtain as a starting material, and obtains a chiral acridine compound I after a cyclization reaction, and then obtains a nucleophilic addition reaction with a trifluorobenzene metal reagent to prepare a preparation.
- the precursor compound of sitagliptin is a chiral amino alcohol compound, which is then subjected to an oxidation reaction, a condensation reaction and a deprotection reaction to obtain sitagliptin.
- the chiral acridine compound I provided by the present invention is used for synthesizing sitagliptin phosphate.
- the synthetic route can introduce chirality using chiral raw materials. Center, avoiding the use of complex chiral reagents to construct amine-based chirality, and avoiding asymmetric asymmetric catalytic hydrogenation; it has the advantages of simple synthetic route, economical atomicity, environmental friendliness and low raw material cost. . detailed description
- the crude product obtained in the previous step was dissolved in a mixed solvent of 50 mL of water and 50 mL of acetonitrile, and NaOH (2 g, 0.05 mol) was added thereto, and 10.9 g of di-tert-butyl carbonate (0.05 mol) was added thereto after cooling to 0 °C.
- the organic phase was extracted twice with 50 mL of dichloromethane, washed with 50 mL of brine, dried over anhydrous sodium sulfate and concentrated to give 11.3 g of viscous material, yield 81%.
- EtOAc methanol
- Example 11 In a 500 mL three-necked flask, the above compound (144.5 g, 0.5 mol) and 250 mL of tetrahydrofuran were added, and the temperature of the reaction system was adjusted to about 0-5 °C with stirring, and slowly added to the reaction system.
- Example 12 In a 500 mL three-necked flask, the above compound (126.5 g, 0.5 mol) and 250 mL of tetrahydrofuran were added, and the temperature of the reaction system was adjusted to about 0-5 °C with stirring, and slowly added to the reaction system.
- Sodium borohydride (19 g, 0.5 mol) add 50 mL of methanol, add, add ⁇ (127 g, 0.5 mol) in 100 mL of tetrahydrofuran solution, drop the temperature, raise the temperature of the reaction system to reflux, and continue The reaction was stirred for 2 hours.
- H0 2 C OTBS 2.NaBH 4 , THF OTBS In a 100 mL three-necked flask, add 8.5 g of the above compound (0.025 mol), 50 mL of ethyl acetate, and cool to 0 °C, add 3.14 g of HOSu (0.027 mol), DCC (5.27 g, 0.026 mol) dissolved in 20 mL of acetic acid. Ethyl acetate was slowly added dropwise to the above system. After the dropwise addition was completed, the mixture was naturally allowed to react to room temperature for 8 hours.
- the temperature of the reaction system was adjusted with a water-bath, and the reaction was quenched with a saturated aqueous solution of ammonium chloride, and then evaporated to dryness EtOAc (100 mL THF)
- EtOAc 100 mL THF
- the organic phase was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and brine, dried and concentrated to yield 150 g of crude oil. After column chromatography, the product was obtained.
- Example 16 In a 500 mL three-necked flask, the above compound (149.5 g, 0.5 mol) and 250 mL of tetrahydrofuran were added, and the temperature of the reaction system was adjusted to about 0-5 °C with stirring, and slowly added to the reaction system.
- Sodium borohydride (19 g, 0.5 mol) add 50 mL of methanol, add, add ⁇ (127 g, 0.5 mol) in 100 mL of tetrahydrofuran solution, drop, and set the temperature of the reaction system. The temperature was raised to reflux, and the reaction was further stirred for 2 hours.
- the intermediate in the previous step was dissolved in 50 mL of anhydrous tetrahydrofuran, protected with nitrogen, and 60% sodium hydride (0.8 g, 0.02 mol) was added in portions at 0 ° C. After stirring for 15 minutes, 50 mL of saturated chlorination was added. The ammonium solution was quenched, the aqueous phase was extracted with 50 mL of ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The yield of the step reaction was 86%.
- the intermediate in the previous step was dissolved in 50 mL of anhydrous tetrahydrofuran, protected with nitrogen, and 2.5 M butyl hydrazine (10 mL, 0.025 mol) was added dropwise at -10 °C. After stirring for 30 minutes, 50 mL of saturated chlorine was added. The ammonium salt solution was quenched, the aqueous phase was extracted with 50 mL of ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The yield of the two-step reaction was 90%.
- the intermediate of the previous reaction was dissolved in 50 mL of anhydrous tetrahydrofuran, protected with nitrogen, and 60% sodium hydride (0.8 g, 0.02 mol) was added in portions at 0 ° C, and the reaction was stirred for 15 minutes.
- the reaction was quenched by the addition of 50 mL of a saturated aqueous solution of ammonium chloride.
- the aqueous phase was extracted with 50 mL of ethyl acetate.
- the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.
- the thick liquid was 4.3 g, and the yield of the two-step reaction was 80%.
- the intermediate of the previous reaction was dissolved in 50 mL of anhydrous tetrahydrofuran, protected with nitrogen, and 60% sodium hydride (0.8 g, 0.02 mol) was added in portions at 0 ° C. After stirring for 15 minutes, 50 mL of saturated chlorination was added. The ammonium solution was quenched, the aqueous phase was extracted with 50 mL of ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was obtained by column chromatography to yield 3.9 g of viscous liquid. The yield of the step reaction was 76%.
- the intermediate in the previous step was dissolved in 50 mL of anhydrous tetrahydrofuran, protected with nitrogen, and 60% sodium hydride (0.8 g, 0.02 mol) was added in portions at 0 ° C. After stirring for 15 minutes, 50 mL of saturated chlorination was added. The ammonium solution was quenched, the aqueous phase was extracted with 50 mL of ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was obtained by column chromatography to give the product as a viscous liquid 2.5 g, The yield of the step reaction was 57%.
- OTBS DCM " ma ⁇ OTBS ⁇ OTBS
- the crude product obtained above was dissolved in 50 mL of anhydrous tetrahydrofuran, protected with nitrogen, and 60% sodium hydride (0.8 g, 0.02 mol) was added in portions at 0 ° C. After stirring for 15 minutes, 50 mL of saturated ammonium chloride was added. The solution was quenched, the aqueous phase was extracted with 50 mL of ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to give product as a viscous liquid 4.3 g. The yield of the reaction was 73%.
- OTBS OTBS OTBS In a 250 mL three-necked flask, add the above compound (6.38 g, 0.02 mol), dichloromethane 60 mL, and slowly add triphenyl brick (7.86 g, 0.03 mol), NBS (5.34 g, 0.03 mol) at 0 °C. After the addition is completed, the mixture is stirred at room temperature for 4 hours, quenched by adding 60 mL of 1 N water, and the mixture is allowed to stand for separation. The organic phase is washed with 50 mL of saturated brine, dried, filtered and concentrated, and the crude product is not refined. , used directly in the next step.
- the crude product obtained by the above reaction was dissolved in 50 mL of anhydrous tetrahydrofuran, and protected with nitrogen.
- 60% sodium hydride (0.8 g, 0.02 mol) was added in portions at 0 ° C, and the reaction was stirred for 15 minutes, then 50 mL of saturated chlorine was added.
- the ammonium salt solution was quenched, the aqueous phase was extracted with 50 mL of ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was obtained by column chromatography to give the product as a viscous liquid 3.83 g.
- the yield of the two-step reaction was 65%.
- the intermediate of the previous reaction was dissolved in 50 mL of anhydrous tetrahydrofuran, protected with nitrogen, and 60% sodium hydride (0.8 g, 0.02 mol) was added in portions at 0 ° C. After stirring for 15 minutes, 50 mL of saturated chlorination was added. The ammonium solution was quenched, the aqueous phase was extracted with 50 mL of ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography to give the product as a viscous liquid 3.5 g, The yield of the step reaction was 76%.
- the intermediate in the previous step was dissolved in 50 mL of anhydrous tetrahydrofuran, protected with nitrogen, and 60% sodium hydride (0.8 g, 0.02 mol) was added in portions at 0 ° C. After stirring for 15 minutes, 50 mL of saturated chlorination was added. The ammonium solution was quenched, the aqueous phase was extracted with 50 mL of ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was obtained by column chromatography to give viscous liquid 4.4 g, The yield of the step reaction was 80%.
- the intermediate in the previous step was dissolved in 50 mL of anhydrous tetrahydrofuran, protected with nitrogen, and 60% sodium hydride (0.8 g, 0.02 mol) was added in portions at 0 ° C. After stirring for 15 minutes, 50 mL of saturated chlorination was added. The ammonium solution was quenched, the aqueous phase was extracted with 50 mL of ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was obtained by column chromatography to give viscous liquid 4.4 g, The yield of the step reaction was 83%.
- Cuprous bromide-dimethyl sulfide (0.41 g, 0.002 mol) was suspended in 5 mL of anhydrous tetrahydrofuran, cooled to -5 ° C, and the above-mentioned format reagent was slowly added dropwise under nitrogen atmosphere. After 15 minutes, a solution of the acridine compound (3.26 g, 0.015 mol) in 30 mL of tetrahydrofuran was slowly added dropwise. After 5 minutes, the reaction was quenched by the addition of 50 mL of saturated ammonium chloride solution. Then 50 mL of ethyl acetate was added and the solution was separated. The aqueous phase was extracted with 50 mL of ethyl acetate. EtOAc was evaporated.
- Cuprous bromide-dimethyl sulfide (0.41 g, 0.002 mol) was suspended in 5 mL of anhydrous tetrahydrofuran, cooled to -5 °C, and the above-mentioned format reagent was slowly added dropwise under nitrogen atmosphere. After 15 minutes, a solution of the acridine compound (4.1 g, 0.015 mol) in 30 mL of tetrahydrofuran was slowly added dropwise. After 5 minutes, the reaction was quenched by the addition of 50 mL of saturated ammonium chloride solution. Then 50 mL of ethyl acetate was added and the solution was separated. The aqueous phase was extracted with 50 mL of ethyl acetate. EtOAc was evaporated, evaporated, evaporated, evaporated.
- Cuprous bromide-dimethyl sulfide (0.41 g, 0.002 mol) was suspended in 5 mL of anhydrous tetrahydrofuran, cooled to -5 °C, and the above-mentioned format reagent was slowly added dropwise under nitrogen atmosphere. After 15 minutes, a solution of the acridine compound (4.16 g, 0.015 mol) in 30 mL of tetrahydrofuran was slowly added dropwise. After 5 minutes, the reaction was quenched by the addition of 50 mL of saturated ammonium chloride solution. Then 50 mL of ethyl acetate was added and the solution was separated.
- aqueous phase was extracted with 50 mL of ethyl acetate. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
- Cuprous bromide-dimethyl sulfide (0.41 g, 0.002 mol) was suspended in 5 mL of anhydrous tetrahydrofuran, cooled to -5 °C, and the above-mentioned format reagent was slowly added dropwise under nitrogen atmosphere. After 15 minutes, a solution of the acridine compound (4.16 g, 0.015 mol) in 30 mL of tetrahydrofuran was slowly added dropwise. After 5 minutes, the reaction was quenched by the addition of 50 mL of saturated aqueous ammonium chloride. Then 50 mL of ethyl acetate was added and the solution was separated. The aqueous phase was extracted with 50 mL of EtOAc. EtOAc (EtOAc m. The yield is 85%.
- Cuprous bromide-dimethyl sulfide (0.41 g, 0.002 mol) was suspended in 5 mL of anhydrous tetrahydrofuran, cooled to -5 °C, and the above-mentioned format reagent was slowly added dropwise under nitrogen atmosphere. After 15 minutes, a solution of the acridine compound (4.54 g, 0.015 mol) in 30 mL of tetrahydrofuran was slowly added dropwise. After 5 minutes, the reaction was quenched by the addition of 50 mL of saturated ammonium chloride solution. Then 50 mL of ethyl acetate was added and the solution was separated.
- aqueous phase was extracted with 50 mL of ethyl acetate. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
- Cuprous bromide-dimethyl sulfide (0.41 g, 0.002 mol) was suspended in 5 mL of anhydrous tetrahydrofuran, cooled to -5 °C, and the above-mentioned format reagent was slowly added dropwise under nitrogen atmosphere. After 15 minutes, a solution of the acridine compound (3.46 g, 0.015 mol) in 30 mL of tetrahydrofuran was slowly added dropwise. After 5 minutes, the reaction was quenched by the addition of 50 mL of saturated ammonium chloride solution. Then 50 mL of ethyl acetate was added and the solution was separated. The aqueous phase was extracted with 50 mL of ethyl acetate. EtOAc (EtOAc m.)
- Cuprous bromide-dimethyl sulfide (0.41 g, 0.002 mol) was suspended in 5 mL of anhydrous tetrahydrofuran, cooled to -5 °C, and the above-mentioned format reagent was slowly added dropwise under nitrogen atmosphere. After 15 minutes, a solution of the acridine compound (4.16 g, 0.015 mol) in 30 mL of tetrahydrofuran was slowly added dropwise. After 5 minutes, the reaction was quenched by the addition of 50 mL of saturated aqueous ammonium chloride. Then 50 mL of ethyl acetate was added and the solution was separated. The aqueous phase was extracted with 50 mL of EtOAc. EtOAc (EtOAc m.)
- Cuprous bromide-dimethyl sulfide (0.41 g, 0.002 mol) was suspended in 5 mL of anhydrous tetrahydrofuran, cooled to -5 °C, and the above-mentioned format reagent was slowly added dropwise under nitrogen atmosphere. After 15 minutes, a solution of the acridine compound (4.16 g, 0.015 mol) in 30 mL of tetrahydrofuran was slowly added dropwise. After 5 minutes, the reaction was quenched by the addition of 50 mL of saturated ammonium chloride solution. Then 50 mL of ethyl acetate was added and the solution was separated.
- aqueous phase was extracted with 50 mL of ethyl acetate. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
- Cuprous bromide-dimethyl sulfide (0.41 g, 0.002 mol) was suspended in 5 mL of anhydrous tetrahydrofuran, cooled to -5 °C, and the above-mentioned format reagent was slowly added dropwise under nitrogen atmosphere. After 15 minutes, a solution of the acridine compound (2.81 g, 0.015 mol) in 30 mL of tetrahydrofuran was slowly added dropwise. After 5 minutes, the reaction was quenched by the addition of 50 mL of saturated ammonium chloride solution. Then 50 mL of ethyl acetate was added and the solution was separated.
- aqueous phase was extracted with 50 mL of ethyl acetate. EtOAc was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
- the obtained crude solid product was added to a double-necked round bottom flask, dissolved in 20 mL of water, and a solution of 1.909 g (0.0227 mol) of sodium hydrogencarbonate in 10 mL of a solution was slowly added dropwise to the above reaction liquid in a constant pressure dropping funnel. Keep the pH of the reaction system between 3 and 6. The oil bath is heated slowly to reflux. TLC is followed. The pH of the reaction is close to 7. The solvent is distilled off to obtain a viscous yellowish gum. Methylene chloride (50) The crude product (2.83 g, 72%) was obtained by washing with EtOAc EtOAc EtOAc.
- the obtained crude solid product was added to a double-necked round bottom flask, dissolved in 20 mL of water, and a solution of 1.91 g (0.027 mol) of sodium hydrogencarbonate in 10 mL of a solution was slowly added dropwise to the above reaction liquid in a constant pressure dropping funnel. In the middle, keep the pH of the reaction system between 3 and 6. The oil bath is heated slowly to reflux, TLC is followed, the pH of the reaction is close to 7, and the solvent is distilled off to obtain a viscous yellowish gum. (50 mL), water (50 mL), EtOAc (EtOAc) m.
- the obtained crude solid product was added to a double-necked round bottom flask, dissolved in 20 mL of water, and a solution of 1.91 g (0.0227 mol) of sodium hydrogencarbonate in 10 mL of a solution was slowly added dropwise to the above reaction liquid in a constant pressure dropping funnel. Keep the pH of the reaction system between 3 and 6. The oil bath is heated slowly to reflux. TLC is followed. The pH of the reaction is close to 7. The solvent is distilled off to obtain a viscous yellowish gum.
- the aqueous phase was extracted with 3 ⁇ 100 mL of ethyl acetate, and the organic phase was combined and washed with 200 mL of brine. It was dried over anhydrous magnesium sulfate for 1 hr, filtered and evaporated.
- the raw material (5.61 g, 10 mmol), 50 mL of acetic acid and 25 mL of concentrated hydrochloric acid were dissolved in a 250 mL round bottom flask, and gradually heated to reflux for 3 hours.
- the TCL was monitored until the reaction was complete, and the reaction system was cooled. After room temperature, the reaction system was poured into 200 g of crushed water, and the pH of the reaction system was adjusted by dissolving with 6 N sodium hydroxide.
- the aqueous phase was extracted with 3 ⁇ 100 mL of ethyl acetate, and the organic phases were combined and saturated with 200 mL. The mixture was washed with brine, dried over anhydrous magnesium sulfate
- the raw material (5.11 g, 10 mmol) was added to a 100 mL round bottom flask, dissolved in 50 mL of ethanol, and sodium ethoxide (3.4 g, 50 mmol) was added to a round bottom flask. After stirring at room temperature for 7.5 hours, TCL was monitored until The reaction was completed, and the solvent in a round-bottomed flask was evaporated to dryness, and water (100 mL) was added, and the aqueous phase was extracted with 3 ⁇ 10 mL of dichloromethane. The organic phase was combined and washed with 200 mL of brine and dried over anhydrous magnesium sulfate Filtered and concentrated to give an oil.
- the raw material (5.47 g, 10 mmol), 50 mL of acetic acid and 25 mL of concentrated hydrochloric acid were dissolved in a 250 mL round bottom flask, and gradually heated to reflux for 3 hours.
- the TCL was monitored until the reaction was complete, and the reaction system was cooled. After room temperature, the reaction system was poured into 200 g of crushed water, and the pH of the reaction system was adjusted by dissolving with 6 N sodium hydroxide.
- the aqueous phase was extracted with 3 ⁇ 100 mL of ethyl acetate, and the organic phases were combined and saturated with 200 mL. The mixture was washed with brine, dried over anhydrous magnesium sulfate
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Description
西他列汀的中间体及其制备方法 技术领域
本发明涉及药物合成领域, 具体说, 涉及西他列汀的中间体及其制 备方法, 以及利用这些中间体合成西他列汀的方法。 背景技术 选择性的构建手性氨基一直是有机合成化学家们不懈努力的目标。 1979 年, 匹兹堡大学的 Kozikowski教授研究了有机金属试剂可以选择性地对 吖啶化合物进行开环合成氨基化合物 ( J. Org. Chem., 1979, 44, 788-2790 ); 近年来, 手性吖啶化合物的选择性开环合成手性氨基化合物 也得到了大力的发展( Org. Lett., 2001, 3, 2349-2351 )。相对于手性诱导以 及手性拆分, 利用天然手性源来合成手性氨基化合物由于方法简洁直观、 手性结构定制等特点, 有着相当的优势。
西他列汀磷酸盐 (Sitagliptin phosphate)是 2006年 FDA批准上市的第 一个二肽基肽酶 -IV ( DPP-4 )抑制剂, 用于治疗 II型糖尿病, 其单用或 与二甲双胍、 吡格列酮合用都有明显的降血糖作用, 且服用安全, 耐受 性好, 不良反应少。 西他列汀磷酸盐是由默克公司研发, 于 2006年 8月 8 日被墨西哥卫生部批准一日一次用药治疗 II型糖尿 病, 上市的商品名为 Januvia。 在美国, 西他列汀磚酸盐于 2006年 10月 16日通过 FDA批准。西他列汀磷酸盐已经在全世界 60个国家批准使用, 仅 2007年第三季度收益为 1.85亿美元, 预计到 2009年的销售额可以达 到 10亿美元, 顺利上市后的峰值销售额有望达到 14亿美元。 因此, 降 血糖药物-西他列汀磷酸盐是属于国际最新且附加值极高的 "重磅炸弹"产 品。 该品种的开发可谓意义重大, 因其技术难度高, 到目前为止, 国内 目前尚未有产业化的企业, 而已公布的西他列汀磷酸盐的合成路线都是 默克公司研发的, 其合成方法简介如下:
( 1 ) 美国专利 US 6699871公开报道了一条西他列汀的合成路线, 该路线是研究部门的克量级合成方法, 该合成路线采用手性源来诱导出 手性的 α-氨基酸, 而后经重氮化反应产生 β-氨基酸, 来构建所需的手性 中心。 该合成路线所需的原料成本相对较高, 反应的操作较为麻烦, 且
( 2 ) 国际专利 WO 2004087650公开报道了默克公司的第二代西他 列汀的合成路线, 利用手性磷钌催化剂对酮进行不对称催化氢化, 构建 手性二级醇, 然后将手性二级醇转化为手性的二级胺以达到构建手性胺 的目的; 该合成路线中, 关键步骤中需要用到铑催化的不对称催化氢化, 该步反应不仅催化剂的价格比较昂贵, 而且在后期产业化时, 工艺的放 大过程中放大效应比较明显, 产品的质量难以控制。
( 3 ) 国际专利 WO 2005003135公开艮道了默克公司开发的第三代 合成方法, 以 S-苯甘氨酰胺作为手性助剂来诱导催化氢化而合成手性胺。 该合成路线相对较合适, 但是也存在较大的问题是, 就是需要两次催化 加氢, 用到比较昂贵的铂催化剂, 且在最后一步脱除保护基时需要用到 大量的 Pd(OH)2/C, 成本很高。
( 4 ) 国际专利 WO 2007050485公开报道了默克公司的最新一代合 成方法, 采用了手性铑催化剂对烯胺的不对称催化氢化来构建手性中心, 该合成路线简洁, 步骤较短, 但该方法需要用到昂贵的催化剂和手性辅 剂, 且该方法在产业化也存在放大效应, 导致产品的质量不稳定。 其合 成 如下:
针对目前西他列汀合成方法中存在的收率低、 成本高、 环保压力大 等缺陷, 进一步研究收率高、 成本低、 绿色环保的西他列汀合成方法具 有广阔的市场前景, 这就需要研发新的西他列汀中间体, 为改善西他列 汀的合成方法提供新的路径。 发明内容
I
其中 R1为 -CH2SR3, R3选自 d-C4的烷基; 或 R1为 -CH2OR4, R4选 自氢、 甲基、 取代的甲基、 四氢吡喃基、 甲氧基苯基、 乙基、 苄基、 取 代的苄基或硅烷基;
其中所述取代的甲基选自甲氧基甲基、 甲硫基甲基、 苄氧甲基、 对 甲氧苄氧甲基、 2-甲氧基乙氧基甲基或 2-三甲硅基乙氧甲基;
所述取代的苄基选自对甲氧基苄基、 3,4-二甲氧基苄基或对硝基苄 基;
所述硅烷基选自三甲基硅基、 三乙基硅基、 三异丙基硅基、 叔丁基 二甲基硅基、 叔丁基二苯基硅基、 二苯基甲基硅基或叔丁基甲氧基苯基 硅基;
R2选自氢、 甲酸酯基、 酰基、 磺酰基、 苄基或 4-甲氧基苄基; 其中所述甲酸酯基选自甲酸甲酯基、 甲酸乙酯基、 9-芴基甲氧叛基、 2-氯 -3-茚基甲氧羰基、 2,2,2-三氯乙氧羰基、 2-三甲基硅基乙氧羰基、 高 苄氧羰基、 叔丁氧羰基、 苄氧羰基或烯丙氧羰基;
所述酰基选自甲酰基、 乙酰基、 三氟乙酰基或苯甲酰基;
所述磺酰基选自苯磺酰基或三氟甲磺酰基。
上述绝对构型为 R的吖啶类化合物 I中, 进一步优选 R1为 -CH2SR3, R3为甲基; 或 R1为 -CH2OR4, R4选自氢、 甲氧基甲基、 苄基、 对硝基苄 基、 叔丁基二甲基硅基或叔丁基二苯基硅基;
优选 R2选自甲酸酯基、 酰基、 磺酰基、 苄基或 4-甲氧基苄基; 其中 所述甲酸酯基选自甲酸甲酯基、 叔丁氧叛基、 苄氧叛基或烯丙氧叛基; 所述酰基为苯甲酰基; 所述磺酰基选自苯磺酰基、 三氟甲磺酰基。
更进一步优选 R1为 -CH2SR3, R3为甲基; 或 R1为 -CH2OR4, R4选自 氢、 苄基、 叔丁基二甲基硅基; R2选自叔丁氧羰基、 苄基、 苯磺酰基。
本发明还提供了一种合成上述绝对构型为 R的吖啶类化合物 I的方 法, 包括步骤: 将一种绝对构型为 R、 结构如下的氨基类化合物 II在碱 和相转移催化剂的作用下发生分子内环合反应, 即得绝对构型为 R的吖 啶类化合物 I;
其中, R1为 -CH2SR3, R3选自 d-C4的烷基; 或 R1为 -CH2OR4, R4 选自氢、 甲基、 取代的甲基、 四氢吡喃基、 甲氧基苯基、 乙基、 苄基、 取代的苄基或硅烷基;
其中所述取代的甲基选自甲氧基甲基、 甲硫基甲基、 苄氧甲基、 对 甲氧苄氧甲基、 2-甲氧基乙氧基甲基或 2-三甲硅基乙氧甲基;
所述取代的苄基选自对甲氧基苄基、 3,4-二甲氧基苄基或对硝基苄 基;
所述硅烷基选自三甲基硅基、 三乙基硅基、 三异丙基硅基、 叔丁基 二甲基硅基、 叔丁基二苯基硅基、 二苯基甲基硅基或叔丁基甲氧基苯基 硅基;
R2选自氢、 甲酸酯基、 酰基、 磺酰基、 苄基或 4-甲氧基苄基; 其中所述甲酸酯基选自甲酸甲酯基、 甲酸乙酯基、 9-芴基甲氧叛基、 2-氯 -3-茚基甲氧羰基、 2,2,2-三氯乙氧羰基、 2-三甲基硅基乙氧羰基、 高 苄氧羰基、 叔丁氧羰基、 苄氧羰基或烯丙氧羰基;
所述酰基选自甲酰基、 乙酰基、 三氟乙酰基或苯甲酰基;
所述磺酰基选自苯磺酰基或三氟甲磺酰基;
R5选自羟基、 磺酸酯、 鹵素;
其中所述的磺酸酯选自甲磺酸酯、 对甲苯磺酸酯或三氟甲磺酸酯; 所述! ¾素选自氯、 溴或捵。
优选地, R1为 -CH2SR3, R3为甲基; 或 R1为 -CH2OR4, R4选自氢、 苄基、 叔丁基二甲基硅基; R2选自叔丁氧叛基、 苄基、 苯磺酰基; R5选 自甲磺酸酯、 对甲苯磺酸酯。
所述的碱为有机碱或无机碱;
其中所述的无机碱选自氢氧化钠、 氢氧化钾、 氢化锂、 氢化钠、 氢 化钾、 氢氧化钙、 碳酸钠、 磷酸钾、 碳酸钾中的一种或多种;
所述的有机碱选自吡啶、 取代吡啶、 哌啶、 1,8-二氮杂双环 [5.4.0]十 一碳 -7-烯、 d-C4脂肪胺、 d-C4脂肪醇钠、 d-C4脂肪醇钾、 丁基 4里、 二
异丙基胺基里、 六甲基二硅烷胺基里、 六甲基二硅烷胺基钠、 六甲基二 硅烷胺基钾中的一种或多种。
优选地, 所述的碱为氢化钠、 甲醇钠或两者的混合物。
如上所述的制备方法中, 反应中溶剂选自四氢呋喃、 甲基四氢呋喃、 乙醚、 甲基叔丁基醚、 二甲基甲酰胺、 二甲基乙酰胺和二甲基亚砜等无 水溶剂中。
本发明还提供了一种构 R的手性氨基化合物 IV,其结构式如下:
其中, R1为 -CH2SR3, R3选自 d-C4的烷基; 或 R1为 -CH2OR4, R4 选自氢、 甲基、 取代的甲基、 四氢吡喃基、 甲氧基苯基、 乙基、 苄基、 取代的苄基或硅烷基;
其中所述取代的甲基选自甲氧基甲基、 甲硫基甲基、 苄氧甲基、 对 甲氧苄氧甲基、 2-甲氧基乙氧基甲基或 2-三甲硅基乙氧甲基;
所述取代的苄基选自对甲氧基苄基、 3,4-二甲氧基苄基或对硝基苄 基;
所述硅烷基选自三甲基硅基、 三乙基硅基、 三异丙基硅基、 叔丁基 二甲基硅基、 叔丁基二苯基硅基、 二苯基甲基硅基或叔丁基甲氧基苯基 硅基;
R2选自氢、 甲酸酯基、 酰基、 磺酰基、 苄基或 4-甲氧基苄基; 其中所述甲酸酯基选自甲酸甲酯基、 甲酸乙酯基、 9-芴基甲氧叛基、 2-氯 -3-茚基甲氧羰基、 2,2,2-三氯乙氧羰基、 2-三甲基硅基乙氧羰基、 高 苄氧羰基、 叔丁氧羰基、 苄氧羰基或烯丙氧羰基;
所述酰基选自甲酰基、 乙酰基、 三氟乙酰基或苯甲酰基;
所述磺酰基选自苯磺酰基或三氟甲磺酰基。
其中,优选的化合物 IV是, R1为 -CH2SR3, R3为甲基;或 R1为 -CH2OR4, R4选自氢、 取代的甲基、 苄基、 取代的苄基、 硅烷基, 其中所述取代的
甲基为甲氧基甲基, 所述取代的苄基为对硝基苄基, 所述硅烷基选自叔 丁基二甲基硅基、 叔丁基二苯基硅基; R2选自甲酸酯基、 酰基、 磺酰基、 苄基或 4-甲氧基苄基, 其中所述甲酸酯基选自甲酸甲酯基、 叔丁氧叛基、 苄氧羰基、 烯丙氧羰基, 所述酰基为苯甲酰基, 所述磺酰基选自苯磺酰 基、 三氟甲磺酰基;
其更优选的化合物是, R1为 -CH2SR3, R3为甲基; 或 R1为 -CH2OR4, R4选自氢、 苄基、 叔丁基二甲基硅基; R2选自叔丁氧羰基、 苄基、 苯磺 酰基。
本发明还提供了一种合成上述构型为 R的手性氨基化合物 IV的方 法, 包括步骤:
( 1 ) 由 2,4,5-三氟苯的金属试剂 III与吖啶类化合物 I发生开环反应 后得到构 R的手性氨基化合物 IV:
( 2 ) 由手性氨基化合物 IV制备得到西他列汀磷酸盐:
如上所述的 2,4,5-三氟苯的金属试剂 III优选的化合物是 2,4,5-三氟 苯溴化镁。 溶剂选自四氢呋喃、 甲基四氢呋喃、 乙醚、 甲基叔丁基醚等 无水溶剂;
II I 其中上述反应式中的 R R2、 R5如前所述。
如上所述的碱为有机碱或无机碱; 其中, 所述的无机碱选自氢氧化 钠、 氢氧化钾、 氢化锂、 氢化钠、 氢化钾、 氢氧化钙、 碳酸钠、 磷酸钟、 碳酸钾中的一种或多种; 所述的有机碱选自吡啶、 取代吡啶、 哌啶、 1,8- 二氮杂双环 [5.4.0]十一碳 -7-烯、 CrC4脂肪胺、 CrC4脂肪醇钠、 d-C4脂 肪醇钾、 丁基锂、 二异丙基胺基里、 六甲基二硅烷胺基里、 六甲基二硅 烷胺基钠、 六甲基二硅烷胺基钾中的一种或多种。 碱优选为氢化钠和甲 醇钠。
上述反应步骤中的反应溶剂选自四氢呋喃、 甲基四氢呋喃、 乙醚、 甲基叔丁基醚、 二甲基甲酰胺、 二甲基乙酰胺和二甲基亚砜等的无水溶 剂;
上述由绝对构型为 R的吖啶类化合物 I制备西他列汀磷酸盐 X的方 法的步骤( 2 ) 中, 当手性氨基化合物 IV中的 R1为 -CH2OH时, 手性氨基 化合物 IV就是 β-氨基醇类化合物 , 该化合物先经过氧化反应得到 β-氨 基酸类化合物 VI;
当手性氨基化合物 IV中的 R1为 -CH2SR3, R3选自 d-C4的烷基; 或 R1为 -CH2OR4, R4选自甲基、 取代的甲基、 四氢吡喃基、 甲氧基苯基、
乙基、 苄基、 取代的苄基、 硅烷基, 其中所述取代的甲基选自甲氧基甲 基、 甲石克基甲基、 千氧甲基、 对甲氧千氧甲基、 2-甲氧基乙氧基甲基、 2- 三甲硅基乙氧甲基, 所述取代的苄基选自对甲氧基苄基、 3,4-二甲氧基苄 基、 对硝基苄基, 所述硅烷基选自三甲基硅基、 三乙基硅基、 三异丙基 硅基、 叔丁基二甲基硅基、 叔丁基二苯基硅基、 二苯基甲基硅基、 叔丁 基甲氧基苯基硅基时, 构型为 R的手性氨基化合物 IV先经过脱除硫烷基 或羟基保护基后得到构型为 R的手性 β-氨基醇类化合物 V, 然后 β-氨基 醇类 -氨基酸类化合物 VI;
IV V VI 由构型为 R的手性氨基化合物 IV经过脱除硫烷基或羟基保护基后得 到构型为 R的手性 β-氨基醇类化合物 , 可以通过常规的公知技术来实 现。 例如:
在上述反应式中, 当 R1为 -CH2SC¾时, 即化合物 IV特征化为下述结 构式 IV-1 时, 本发明提供了该类化合物 IV-1脱除甲硫基的合成方法, 即 利用该类化合物 IV-1 和碘甲烷在甲醇或乙醇等醇类溶剂中, 在室温或低 温下进行反应 物 V。
在上述反应式中, 当 R1为 -CH2OR4 (其中 R4为氢、 苄基、 叔丁基二 甲基硅基)时, 即化合物 (IV)特征化为下述结构 IV-2时, 本发明提供了该 类化合物 (IV -2)脱除羟基保护基的合成方法, 利用该类化合物 (IV -2)羟基 上相应的保护基团, 选择合适的脱去方法, 例如, 当 R4为苄基时, 本发 明利用 pd/C为催化剂, 在甲醇等醇类溶剂中进行催化氢化的方法脱去苄 基; 还例如, 当 R4为叔丁基二甲基硅基时, 本发明利用脱除硅基类保护 基的专用试剂氟化物, 如四丁基氟化铵等, 在四氢呋喃等溶剂, 常温或
加热反应的方
IV- 2 V
在上述的由绝对构型为 R的吖啶类化合物 I制备西他列汀磷酸盐 X 的方法中, β-氨基醇类化合物 V经过氧化反应得到 β-氨基酸类化合物 VI;
本发明提供了在一定条件下, 将化合物 V氧化为 β-氨基酸类化合物 VI的方法, 例如化合物 V在 TEMPO 的催化下, 利用次氯酸钠氧化伯醇 为酸反应制得 β-氨基酸类化合物 VI;
在上述由绝对构型为 R的吖啶类化合物 I制备西他列汀磷酸盐 X的 方法中, β-氨基酸类化合物 VI与三唑嗪类化合物 W进行缩合反应得到胺基
其中上述反应式中的 R2如前所述。
本发明还提供了 β-氨基酸类化合物 VI与三唑嗪类化合物 W进行接肽 的方法, 如 β-氨基酸类化合物 VI与三唑嗪类化合物 W在乙腈、 二氯甲烷 等溶剂中, 如在 DCC、 EDCI等缩合试剂和三乙胺等有机碱作用下, 在 室温下进行反应, 以较高的产率得到胺基保护的西他列汀衍生物環; 在上述由绝对构型为 R的吖啶类化合物 I制备西他列汀磷酸盐 X的 方法中, 胺基保护的西他列汀衍生物環经过脱除胺基保护基 R2后得到西
其中上述反应式中的 R2如前所述。
本发明提供了该类化合物環脱除胺基保护基的合成方法, 利用该类 化合物胺基上相应的保护基团, 即当 R2分别为叔丁氧叛基、 苄基和苯磺 酰基时选择合适的脱去方法, 例如, 当 R2分别为叔丁氧叛基, 本发明提 供了利用强酸, 如盐酸, 在醇类溶剂中进行常温或加热反应, 脱除叔丁 氧叛基; 当 R4为苄基时, 本发明利用 pd/C为催化剂, 在甲醇等醇类溶剂 中进行催化氢化的方法脱去苄基。
在上述由绝对构型为 R的吖啶类化合物 I制备西他列汀磷酸盐 X的 方法中, 西他列汀 IX与磷酸反应后得到西他列汀磷酸盐 X;
通过实施本发明, 可获得如下有益效果:
本发明利用价廉易得的手性胺基类化合物作为起始原料, 经过环合 反应后得到手性的吖啶类化合物 I, 再与三氟苯金属试剂进行亲核加成 反应后得到制备西他列汀的前体化合物 手性的胺基醇类化合物 , 再经过氧化反应、 缩合反应和脱保护基反应后得到西他列汀。
本发明在合成手性的吖啶类化合物 I时, 发现当手性的吖啶类化合 物 I中,当 R1为酯类(-C02R )或为羟基甲基磺酸酯(-CH2OMs或 -CH2OTs )
或为鹵代羟甲基 (-CH2X)时, 吖啶类化合物与三氟苯金属试剂进行亲核加 成反应时, 三氟苯金属试剂不仅能与吖啶进行开环反应, 而且同时还能 与酯类 (-C02R )或羟基甲基磺酸酯( -CH2OMs或 -CH2OTs )或鹵代羟甲 基 (-CH2X)等发生反应, 因此反应的选择性较差, 反应体系比较复杂, 因 此, 本发明提供了文中所述的手性的吖啶类化合物 I, 其与三氟苯金属 试剂进行亲核加成反应时, 反应的位点只有一个, 反应的选择性较好。
进而, 本发明提供的手性的吖啶类化合物 I用于合成西他列汀磷酸 盐的工艺与目前报道的、 或产业化的合成工艺相比, 该合成路线可以利 用手性原料引入手性中心, 避免利用各种复杂的手性试剂构建胺基的手 性, 也避免了手性的不对称催化氢化反应; 具有合成路线简洁、 原子的 经济性、 环境的友好性和原料成本低等优点。 具体实施方式
通过下述实施例将有助于进一步理解本发明, 但是并不用来限制本 发明的内容。
NHo NHBoc
' 2 Boc20, DCM, Et3N V 将蛋氨酸 7.2 g溶解在 50 mL水和 50 mL乙腈的混合溶剂中, 加入 2 g NaOH ( 0.05 mol ), 冷却至 0 °C下加入 10.9 g碳酸二叔丁酯( Boc20 ) ( 0.05 mol ), 升至室温(24〜25 °C )反应 12小时。 蒸除乙腈, 残余物加 入碳酸钾调节 pH = 12, 用 50 mL二氯甲烷萃取两次, 舍弃有机相, 水相 用 1N稀盐酸调节 pH = 6, 再用 50 mL二氯甲烷萃取两次, 合并有机相, 用 50 mL饱和食盐水洗涤, 无水硫酸钠干燥、 浓缩, 得到粘稠物 11.4 g, 产率 95 %。
!H NMR (500 MHz, CDC13) δ 11.62 (br, 1 Η), 6.91 (br, 1 Η), 4.40 (m. 1Η), 2.52 (t, J = 4.8 Hz, 2 H), 2.05 (s, 3H), 1.92-2.15 (m. 2 H), 1.42 (s, 9 H). Ms (M++1): 250. 实施例 2
将 7.5 g蛋氨酸 (0.05 mol)溶解在 100 mL二氯甲烷的中, 加入三乙胺 ( 10.5 mL, 0.075 mol ),将反应体系的温度冷却至 0 °C下滴加对甲苯磺酰 氯 (11.5 g, 0.06 mol ), 升至室温反应 12小时, 加入 20 mL的水淬灭反应, 再加入碳酸 4甲调节 pH = 12, 用 50 mL二氯甲烷萃取两次, 舍弃有机相, 水相用 1N稀盐酸调节 pH = 6, 再用 50 mL二氯甲烷萃取两次, 合并有 机相, 用 50 mL饱和食盐水洗涤, 无水硫酸钠干燥、 浓缩, 得到粘稠物 13.2 g, 产率 91 %。
!H NMR (400 MHz, CDC13)6 8.06-7.76 (m, 2H), 7.59 (t, J = 6.6 Hz, 3H), 6.35 (s, 1H), 3.86 (t, J = 6.6 Hz, 1H), 2.70 (s, 2H),2.35 (s, 3 H), 2.21 (s, 1H), 2.15 (s, 3H), 2.12 (s, 1H). Ms (M++l): 304.
将 7.5 g蛋氨酸 (0.05 mol)溶解在 100 mL二氯甲烷的中, 加入三乙胺 ( 10.5 mL, 0.075 mol ), 将反应体系的温度冷却至 0 下滴加苯甲酰氯 (8.4g, 0.06 mol ), 升至室温反应 12小时, 加入 20 mL的水淬灭反应, 再 加入碳酸 4甲调节 pH = 12, 用 50 mL二氯甲烷萃取两次, 舍弃有机相, 水 相用 1N稀盐酸调节 pH = 6, 再用 50 mL二氯甲烷萃取两次, 合并有机 相, 用 50 mL饱和食盐水洗涤, 无水硫酸钠干燥、 浓缩, 得到粘稠物 9.9 g, 产率 78 %。
!H NMR (400 MHz, CDC13) δ 8.41 (s, 1Η), 7.98-7.67 (m, 2H), 7.58 (s, 1H), 7.54〜 7.33 (m, 2H), 4.53 (s, 1H), 2.72 (s, 2H), 2.36 (s, 3H), 2.22 (d, J = 27.6 Hz, 2H). Ms (M++1): 254.
将 7.5 g蛋氨酸 (0.05 mol)溶解在 100 mL二氯甲烷的中, 加入三乙胺 ( 10.5 mL, 0.075 mol ), 将反应体系的温度冷却至 0 下滴加苯磺酰氯 (10.6 g, 0.06 mol ), 升至室温反应 12小时, 加入 20 mL的水淬灭反应, 再加入碳酸 4甲调节 pH = 12, 用 50 mL二氯甲烷萃取两次, 舍弃有机相, 水相用 1N稀盐酸调节 pH = 6, 再用 50 mL二氯甲烷萃取两次, 合并有 机相, 用 50 mL饱和食盐水洗涤, 无水硫酸钠干燥、 浓缩, 得到粘稠物 12.9 g, 产率 89 %。
!H NMR (400 MHz, CDC13)6 8.06-7.76 (m, 2H), 7.59 (t, J = 6.6 Hz, 3H), 6.35 (s, 1H), 3.86 (t, J = 6.6 Hz, 1H), 2.70 (s, 2H), 2.21 (s, 1H), 2.15 (s, 3H), 2.12 (s, 1H). Ms (M++l): 290.
实施例 5
在 500 mL三口烧瓶中, 加入 15 g L-蛋氨酸 (0.1 mol), 300 mL水中, 室温下滴加 38.4g碘甲烷(0.3 mol ), 氮气球保护下反应 24小时。 减压下 浓缩至 200 mL, 过量的碘甲烷减压即可除去。 将上述体系加热回流, 10 g KHCO3(0.1 mol)溶解于 50 mL水里面,通过滴液漏斗慢慢滴加至上述体系 中, 控制滴加速度, 使体系 pH值维持在 3-6之间。 滴加完毕继续回流 10 h, 溶剂减压抽干, 加入 200 mL甲醇: 水 =100: 1的溶液, 滴加浓盐酸调 pH = 5-6,趁热过滤出盐, 浓缩至 50 mL, 冷冻结晶,抽滤, 干燥, 即得 8.8 g 的 L-高丝氨酸的白色固体, 产率 74%。
!H NMR (500 MHz, D20) δ 3.71 (dd, Ji = 7.5 Hz, J2 = 4.8 Hz, 1 H), 3.67〜3.61 (m, 2 H), 2.01-2.06 (m, 1 H), 1.86〜1.92 (m, 1 H). Ms (M++l): 120.
1 . TBSCI, Imidazole NHBoc
100 mL三口瓶中, 加入 5 g高丝氨酸( 0.042 mol ), 50 mL DMF, 冷 却至(TC, 加入 3.4 g咪唑( 0.05 mol ), 氮气保护下分批加入 TBSC1 ( 6.6 g, 0.044 mol ), 加完后升至室温搅拌 16小时。 加入 10 mL水淬灭反应, 减压浓缩溶剂, 加入 50 mL水以及 50 mL二氯甲烷, 分液, 水相再用 50 mL二氯甲烷提取, 合并有机相, 再用 50 mL饱和食盐水洗涤, 无水硫酸 钠干燥、 浓缩, 得到粘稠物。
将上一步得到的粗产品溶解于 50 mL水和 50 mL乙腈的混合溶剂中, 加入 NaOH ( 2 g, 0.05 mol ),冷却至 0 °C下加入 10.9g碳酸二叔丁酯(0.05 mol ),升至室温反应 12小时,蒸除乙腈,残余物加入碳酸 4甲调节 pH = 12, 用 50 mL二氯甲烷萃取两次, 舍弃有机相, 水相用 1 N稀盐酸调节 pH =
6, 再用 50 mL二氯曱烷萃取两次, 合并有机相, 用 50 mL饱和食盐水洗 涤, 无水硫酸钠干燥、 浓缩, 得到粘稠物 11.3 g, 产率 81 % 。
!H NMR (500 MHz, CDC13) δ 8.04(br, IH), 5.86 (d, J = 6.7 Hz, IH), 4.61-4.13 (m, IH), 3.94-3.62 (m, 2H), 2.19-2.04 (m, IH), 2.04-1.91 (m, IH) 1.44 (s, 9H), 0.90 (s, 9H), 0.08 (d, J = 12.9 Hz, 6H). Ms (M++l): 334.
100 mL三口瓶中, 力口入 5 g高丝氨酸(0.042 mol ), 50 mL DMF, 冷 却至 0 °C , 加入 3.4 g咪唑(0.05 mol ), 氮气保护下分批加入 TBDPSCl ( 12.1 g, 0.044 mol ), 加完后升至室温搅拌 16小时。 加入 10 mL水淬灭 反应, 减压浓缩溶剂, 加入 50 mL水以及 50 mL二氯甲烷, 分液, 水相 再用 50 mL二氯甲烷提取, 合并有机相, 再用 50 mL饱和食盐水洗涤, 无水硫酸钠干燥、 浓缩, 得到粘稠物。
将上一步得到的粗产品溶解于 50 mL水和 50 mL乙腈的混合溶剂中, 加入 2g NaOH ( 0.05 mol ),冷却至 0 °C下加入 10.9g碳酸二叔丁酯( 0.05 mol ),升至室温反应 12小时。蒸除乙腈, 残余物加入碳酸甲调节 pH=12, 用 50 mL二氯甲烷萃取两次,舍弃有机相, 7 相用 1N稀盐酸调节 pH = 6, 再用 50 mL二氯甲烷萃取两次,合并有机相, 用 50 mL饱和食盐水洗涤, 无水硫酸钠干燥、 浓缩, 得到粘稠物 14.4g, 产率 75 %。
】H NMR (500 MHz, CDC13) δ 8.04(br, IH), 7.35-7.62 (m, 10 H), 5.86 (d, J = 6.7 Hz, IH), 4.61-4.13 (m, IH), 3.94〜3.62 (m, 2H), 2.19-2.04 (m, IH), 2.04〜1.91 (m, IH), 1.44 (s, 9H), 0.90 (s, 9H). Ms (M++1): 459.
議
100 mL三口瓶中, 加入 5 g高丝氨酸(0.042 mol ), 50 mL DCM, 冷 却至(TC,加入 3.4 g咪唑( 0.05 mol ),氮气保护下分批加入 MOMCK 3.52 g, 0.044 mol ), 加完后升至室温搅拌 8小时。 加入 10 mL水淬灭反应, 减压浓缩溶剂, 加入 50 mL水以及 50 mL二氯甲烷, 分液, 水相再用 50 mL二氯甲烷提取, 合并有机相, 再用 50 mL饱和食盐水洗涤, 无水硫酸 钠干燥、 浓缩, 得到粘稠物。
将上一步得到的粗产品溶解于 50 mL水和 50 mL乙腈的混合溶剂中, 加入 2g NaOH ( 0.05 mol ),冷却至 0 °C下加入 10.9 g碳酸二叔丁酯( 0.05 mol ),升至室温反应 12小时。蒸除乙腈,残余物加入碳酸 4甲调节 pH = 12, 用 50 mL二氯甲烷萃取两次,舍弃有机相,水相用 1N稀盐酸调节 pH = 6, 再用 50mL二氯甲烷萃取两次, 合并有机相, 用 50 mL饱和食盐水洗涤, 无水硫酸钠干燥、 浓缩, 得到粘稠物 7.8 g, 产率 71 %。
!H NMR (500 MHz, CDC13) δ 8.04(br, 1Η), 5.86 (d, J = 6.7 Hz, 1H), 4.61-4.13 (m, 1H), 4.60 (s, 3 H), 3.94-3.62 (m, 2H), 3.52 (s, 3H), 2.19-2.04 (m, 1H), 2.04-1.91 (m, 1H), 1.44 (s, 9H). Ms (M++1): 264.
0C
在 500 mL的三口瓶中, 加入上述化合物 (49.8 g, 0.5 mol)和 250 mL 的四氢呋喃,搅拌下将反应体系的温度用水盐浴调节到 0-5 °C左右,慢慢 向反应体系中加入硼氢化钠 (19 g, 0.5 mol), 再加入甲醇 50 mL, 加毕, 滴加捵 (127 g, 0.5 mol)的 100 mL四氢呋喃溶液, 滴毕, 将反应体系的温 度升到回流, 并继续搅拌反应 2小时, TLC检测原料反应完毕后, 用水 水浴调节反应体系的温度, 用饱和氯化铵水溶液淬灭反应, 减压旋蒸出 lOO mL THF后, 残留物用乙酸乙酯 (300 mLx2)萃取, 有机相依次用稀盐 酸、 饱和碳酸氢钠水溶液和盐水洗, 干燥后浓缩, 得油状物粗品 120 g, 柱层析后, 得纯品 97.5g, 收率 85%。
Ή NMR (400 MHz, CDC13) δ 11.64(br, IH), 6.85 (br, IH), 4.55-4.48 (m, IH), 2.53 (t, J = 4.9 Hz, 2H), 3.44 (s, 3H), 2.05 (s, 3H), 2.02-1.87 (m, 2H), 1.48 (s, 9H). Ms (M++l): 236. 实施例 10
在 2 L的三口瓶中, 加入上述化合物(151.5 g, 0.5 mol)和 1000 mL的 四氢呋喃,搅拌下将反应体系的温度用水盐浴调节到 0-5 °C左右,慢慢向 反应体系中加入硼氢化钠 (19 g, 0.5 mol), 再加入甲醇 150 mL, 加毕, 滴 加碘 (127 g, 0.5 mol)的 500 mL四氢呋喃溶液, 滴毕, 将反应体系的温度 升到回流, 并继续搅拌反应 2小时, TLC检测原料反应完毕后, 用水水 浴调节反应体系的温度,用饱和氯化铵水溶液淬灭反应,减压旋蒸出 1200 mL THF后, 残留物用乙酸乙酯 (500 mLx2)萃取, 有机相依次用稀盐酸、 饱和碳酸氢钠水溶液和盐水洗, 干燥后浓缩, 得油状物粗品 120 g, 柱层 析后, 得纯品 108 g, 收率 75%。
!H NMR (400 MHz, CDC13) δ 7.91〜 7.76 (m, 2Η), 7.58 (t, J = 8.1 Hz, 3H), 5.47 (s, IH), 3.90 (s, IH), 3.55 (s, IH), 3.20 (s, IH), 2.58 (s, 2H), 2.36 (s 3H), 2.32 (s, 3H), 1.85 (s, 2H), 1.44 (s, 1 H). Ms (M++l): 290. 实施例 11
在 500 mL的三口瓶中, 加入上述化合物(144.5 g, 0.5 mol)和 250 mL 的四氢呋喃,搅拌下将反应体系的温度用水盐浴调节到 0-5 °C左右,慢慢 向反应体系中加入硼氢化钠 (19 g, 0.5 mol), 再加入甲醇 50 mL, 加毕, 滴加捵 (127 g, 0.5 mol)的 100 mL四氢呋喃溶液, 滴毕, 将反应体系的温 度升到回流, 并继续搅拌反应 2小时, TLC检测原料反应完毕后, 用水
水浴调节反应体系的温度, 用饱和氯化铵水溶液淬灭反应, 减压旋蒸出 lOO mL THF后, 残留物用乙酸乙酯 (300 mLx2)萃取, 有机相依次用稀盐 酸、 饱和碳酸氢钠水溶液和盐水洗, 干燥后浓缩, 得油状物粗品 130.5 g, 柱层析后, 得纯品 114.1 g, 收率 83%。
!H NMR (400 MHz, CDC13) δ 7.91〜7.76 (m, 2Η), 7.58 (t, J = 8.1 Hz, 3H), 5.47 (s, IH), 3.90 (s, IH), 3.55 (s, IH), 3.20 (s, IH), 2.58 (s, 2H), 2.32 (s, 3H) 1.85 (s, 2H), 1.44 (s, IH). Ms (M++l): 276. 实施例 12
在 500 mL的三口瓶中, 加入上述化合物(126.5 g, 0.5 mol)和 250 mL 的四氢呋喃,搅拌下将反应体系的温度用水盐浴调节到 0-5 °C左右,慢慢 向反应体系中加入硼氢化钠 (19 g, 0.5 mol), 再加入甲醇 50 mL, 加毕, 滴加捵 (127 g, 0.5 mol)的 100 mL四氢呋喃溶液, 滴毕, 将反应体系的温 度升到回流, 并继续搅拌反应 2小时, TLC检测原料反应完毕后, 用水 水浴调节反应体系的温度, 用饱和氯化铵水溶液淬灭反应, 减压旋蒸出 lOO mL THF后, 残留物用乙酸乙酯 (300 mLx2)萃取, 有机相依次用稀盐 酸、 饱和碳酸氢钠水溶液和盐水洗, 干燥后浓缩, 得油状物粗品 85 g, 柱层析后, 得纯品 72.9 g, 收率 61%。
!H NMR (400 MHz, CDC13) δ 7.84-7.69 (m, 2H), 7.64-7.38 (m, 3H), 6.69 (s, IH), 4.01 (br, IH), 3.87 - 3.75 (m, IH), 3.63 (s, IH), 2.52 (s, 2H), 2.38 (s, 3H), 2.08 (s, IH), 1.89-1.82 (m, IH), 1.44-1.38 (m, IH). Ms (M++l): 240. 实施例 13
NHBoc HOSu, DCC, EtOAc NHBoc
HO、
H02C OTBS 2.NaBH4, THF OTBS
100 mL三口瓶中, 加入 8.5 g上述化合物( 0.025 mol ), 50 mL乙酸 乙酯, 冷却至 0 °C下加入 3.14 g HOSu ( 0.027 mol ), DCC ( 5.27 g, 0.026 mol )溶解在 20 mL乙酸乙酯中, 慢慢滴加至上述体系中, 滴加完毕, 自 然升至室温反应 8 小时, 过滤掉体系中生成的大量不溶物, 滤液依次用 100 mL饱和碳酸氢钠、 食盐水洗涤, 无水硫酸钠干燥, 过滤、 浓缩得到 乳白色油状物。 0 °C下, 硼氢化钠(0.95 g, 0.025 mol )溶解于水(5 mL ) 和四氢呋喃( 40 mL )的混合液中, 上述乳白色油状物溶解于 10 mL乙酸 乙酯中迅速加入至硼氢化钠溶液中。 5分钟后, 加入 50 mL饱和氯化铵 溶液淬灭反应。 水相用 50 mL乙酸乙酯萃取, 有机相用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱层析得到粘稠物 5.2 g, 产 率 65 %。
!H NMR (400 MHz, CDC13) δ 5.74-5.26 (m, 1Η), 3.74 (t, J = 5.3 Hz, 3H): 3.72-3.58 (m, 2H), 3.51 (s, 1H), 1.83 (s, 1H), 1.73 (d, J = 6.1 Hz, 1H), 1.45 (s 9H), 0.90 (s, 9H), 0.07 (d, J = 12.4 Hz, 6H). Ms (M++l): 320. 实施例 14
NHBoc LHOSu, DCC, EtOAc NHBoc
H02C^^^OMOM 2.NaBH4, MeOH HO\^\^^0MOM
100 mL三口瓶中, 加入 13.2 g上述化合物( 0.025 mol ), 50 mL乙酸 乙酯,冷却至 0 °C下加入 3.14 g HOSu ( 0.027 mol ), DCC ( 5.27 g, 0.026 mol )溶解在 20 mL乙酸乙酯中, 慢慢滴加至上述体系中。 滴加完毕, 自 然升至室温反应 8 小时。 过滤掉体系中生成的大量不溶物, 滤液依次用 100 mL饱和碳酸氢钠、 食盐水洗涤, 无水硫酸钠干燥, 过滤、 浓缩得到 乳白色油状物。 0 °C下, 硼氢化钠( 0.95 g, 0.025 mol )溶解于水( 5 mL ) 和四氢呋喃( 40 mL )的混合液中。 上述乳白色油状物溶解于 10 mL乙酸 乙酯中迅速加入至硼氢化钠溶液中。 5分钟后, 加入 50 mL饱和氯化铵 溶液淬灭反应。 水相用 50 mL乙酸乙酯萃取, 有机相用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱层析得到粘稠物 3.9 g, 产
率 62 %。
!H NMR (400 MHz, CDC13) δ 6.09 (s, 1H), 4.50 (s, 2H), 4.21-4.18 (m 1H), 3.78 (s, 1H), 3.59 (s, 1H), 3.40 (s, 3H), 3.33-3.19 (m, 2H), 1.90 (s, 1H): 1.71 (s, 1H), 1.49 (s, 9H), 1.44 (s, 1H). Ms (M++l): 320. Ms (M++l): 250. 实施例 15
NHBoc NaBH4
H02C v 、oBn THF
在 500 mL的三口瓶中, 加入上述化合物(154.5 g, 0.5 mol)和 250 mL 的四氢呋喃,搅拌下将反应体系的温度用水盐浴调节到 0-5 °C左右,慢慢 向反应体系中加入硼氢化钠 (19 g, 0.5 mol), 再加入甲醇 50 mL, 加毕, 滴加捵 (127 g, 0.5 mol)的 100 mL四氢呋喃溶液, 滴毕, 将反应体系的温 度升到回流, 并继续搅拌反应 2小时, TLC检测原料反应完毕后, 用水 水浴调节反应体系的温度, 用饱和氯化铵水溶液淬灭反应, 减压旋蒸出 lOO mL THF后, 残留物用乙酸乙酯 (300 mLx2)萃取, 有机相依次用稀盐 酸、 饱和碳酸氢钠水溶液和盐水洗, 干燥后浓缩, 得油状物粗品 150 g, 柱层析后, 得纯品 126.8 g, 收率 86%。
!H NMR (400 MHz, CDC13) δ 7.53〜7.22 (m, 5H), 5.74〜5.26 (m, 1H), 3.74 (t, J = 5.3 Hz, 3H), 3.72〜3.58 (m, 2H), 3.51 (s, 2H), 3.11 (br, 1H), 1.83 (s, 1H), 1.73 (d, J = 6.1 Hz, 1H), 1.45 (s, 9H). Ms (M++l): 296. 实施例 16
在 500 mL的三口瓶中, 加入上述化合物(149.5 g, 0.5 mol)和 250 mL 的四氢呋喃,搅拌下将反应体系的温度用水盐浴调节到 0-5 °C左右,慢慢 向反应体系中加入硼氢化钠 (19 g, 0.5 mol), 再加入甲醇 50 mL, 加毕, 滴加捵 (127 g, 0.5 mol)的 100 mL四氢呋喃溶液, 滴毕, 将反应体系的温
度升到回流, 并继续搅拌反应 2小时, TLC检测原料反应完毕后, 用水 水浴调节反应体系的温度, 用饱和氯化铵水溶液淬灭反应, 减压旋蒸出 lOO mL THF后, 残留物用乙酸乙酯 (300 mLx2)萃取, 有机相依次用稀盐 酸、 饱和碳酸氢钠水溶液和盐水洗, 干燥后浓缩, 得油状物粗品 145 g, 柱层析后, 得纯品 129.7 g, 收率 91%。
!H NMR (400 MHz, CDC13) δ 7.33-7.18 (m, 10Η), 4.77 (s, 2H), 4.05 (d, J = 6.3 Hz, 2H), 3.75 (s, 1H), 3.62 (s, 1H), 3.53 (s, 2H), 3.43 (s, 1H), 3.27 (s, 1H), 1.66 (s, 1H), 1.56 (s, 1H), 1.45 (s, 1H). Ms (M++l): 286. 实施例 17
250 mL三口瓶中, 加入上述化合物(4.7 g, 0.02 mol ), 二氯甲烷 60 mL,三乙胺(3.03 g, 0.03mol ), 0 。C下慢慢滴加 MsCl ( 3.15 g, 0.03 mol ), 滴加完毕升至室温搅拌 4小时,加入 60 mL 1 N稀盐酸淬灭反应,静置分 液, 有机相再用 50 mL饱和食盐水洗涤, 干燥、 过滤、 浓缩, 得到的粗 产品不经过精制, 直接用于下一步反应。
上一步反应的中间体溶解于 50 mL的无水四氢呋喃中,氮气保护, 0°C 下分批加入 60% 氢化钠 (0.8 g, 0.02 mol ), 搅拌反应 15分钟后, 加入 50 mL饱和氯化铵溶液淬灭反应, 水相用 50 mL乙酸乙酯萃取, 有机相用饱 和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱层析得到 产物为粘稠液体 3.7 g, 两步反应的收率为 86 %。
!H NMR (400 MHz, CDC13) δ 2.80 (d, J = 5.4 Hz, 2H), 2.49 (s, 1H), 2.38 (s, 3H), 2.16 (s, 1H), 2.04 (s, 2H), 1.51 (d, J = 4.9 Hz, 10H). 13C NMR (400 MHz, CDC13) δ 162.31, 80.95, 36.99, 32.02, 31.59, 31.43, 27.84, 15.50. Ms (M++l): 218.
实施例 18
¥HB0C MsCI, Et3N VHB0C BuLi, THF
250 mL三口瓶中, 加入上述化合物(4.7 g, 0.02 mol ), 二氯甲烷 60 mL,三乙胺(3.03 g, 0.03mol ), 0 。C下慢慢滴加 MsCl ( 3.15 g, 0.03 mol ), 滴加完毕升至室温搅拌 4小时,加入 60 mL 1 N稀盐酸淬灭反应,静置分 液, 有机相再用 50 mL饱和食盐水洗涤, 干燥、 过滤、 浓缩, 得到的粗 产品不经过精制, 直接用于下一步反应。
上一步反应的中间体溶解于 50 mL的无水四氢呋喃中, 氮气保护, -10 °C滴加 2.5 M的丁基娌( 10 mL, 0.025 mol ), 搅拌反应 30分钟后, 加 入 50 mL饱和氯化铵溶液淬灭反应, 水相用 50 mL乙酸乙酯萃取, 有机相 用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱层析 得到产物为粘稠液体 3.9 g, 两步反应的收率为 90 %。
!H NMR (400 MHz, CDC13) δ 2.80 (d, J = 5.4 Hz, 2H), 2.49 (s, 1H), 2.38 (s, 3H), 2.16 (s, 1H), 2.04 (s, 2H), 1.51 (d, J = 4.9 Hz, 10H). 13C NMR (400 MHz, CDC13) δ 162.31, 80.95, 36.99, 32.02, 31.59, 31.43, 27.84, 15.50. Ms (M++l): 218. 实施例 19
250 mL三口瓶中, 加入上述化合物(5.8 g, 0.02 mol ), 二氯甲烷 60 mL,三乙胺(3.03 g, 0.03mol ), 0 。C下慢慢滴加 MsCl ( 3.15 g, 0.03 mol ), 滴加完毕升至室温搅拌 4小时,加入 60 mL 1 N稀盐酸淬灭反应,静置分 液, 有机相再用 50 mL饱和食盐水洗涤, 干燥、 过滤、 浓缩, 得到的粗 产品不经过精制, 直接用于下一步反应。
上一步反应的中间体溶解于 50 mL的无水四氢呋喃中, 氮气保护, 0 °C下分批加入 60% 氢化钠 (0.8 g, 0.02 mol ), 搅拌反应 15分钟后,
加入 50 mL饱和氯化铵溶液淬灭反应, 水相用 50 mL乙酸乙酯萃取, 有 机相用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱 层析得到产物为粘稠液体 4.3 g, 两步反应的收率为 80 %。
!H NMR (400 MHz, CDC13) δ 8.10-7.35 (m, 5Η), 2.80 (d, J = 5.4 Hz, 2H), 2.49 (s, IH), 2.38 (s, 3H), 2.35 (s, 3H), 2.16 (s, IH), 2.04 (s, 2H), 1.51 (s IH). Ms (M++1): 272. 实施例 20
NHS02Ph MsCI, Et3N ¾IHS02Ph NaH, THF
MsO、
S
250 mL三口瓶中, 加入上述化合物(5.5 g, 0.02 mol ), 二氯甲烷 60 mL,三乙胺(3.03 g, 0.03mol ), 0 。C下慢慢滴加 MsCl ( 3.15 g, 0.03 mol ), 滴加完毕升至室温搅拌 4小时,加入 60 mL 1 N稀盐酸淬灭反应,静置分 液, 有机相再用 50 mL饱和食盐水洗涤, 干燥、 过滤、 浓缩, 得到的粗 产品不经过精制, 直接用于下一步反应。
上一步反应的中间体溶解于 50 mL的无水四氢呋喃中, 氮气保护, 0 °C下分批加入 60% 氢化钠 (0.8 g, 0.02 mol ), 搅拌反应 15分钟后, 加入 50 mL饱和氯化铵溶液淬灭反应, 水相用 50 mL乙酸乙酯萃取, 有 机相用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱 层析得到产物为粘稠液体 3.9 g, 两步反应的收率为 76 %。
!H NMR (400 MHz, CDC13) δ 8.10-7.35 (m, 5H), 2.80 (d, J = 5.4 Hz, 2H), 2.49 (s, IH), 2.38 (s, 3H), 2.16 (s, IH), 2.04 (s, 2H), 1.51 (s, IH). Ms (M++l): 258. 实施例 21
250 mL三口瓶中, 加入上述化合物( 4.78 g, 0.02 mol ), 二氯甲烷 60
mL, 三乙胺 ( 3.03 g, 0.03mol ), 0 °C下慢慢滴加 MsCl ( 3.15 g, 0.03 mol ), 滴加完毕升至室温搅拌 4小时,加入 60 mL 1 N稀盐酸淬灭反应,静置分 液, 有机相再用 50 mL饱和食盐水洗涤, 干燥、 过滤、 浓缩, 得到的粗 产品不经过精制, 直接用于下一步反应。
上一步反应的中间体溶解于 50 mL的无水四氢呋喃中,氮气保护, 0°C 下分批加入 60% 氢化钠 (0.8 g, 0.02 mol ), 搅拌反应 15分钟后, 加入 50 mL饱和氯化铵溶液淬灭反应, 水相用 50 mL乙酸乙酯萃取, 有机相 用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱层析 得到产物为粘稠液体 2.5 g, 两步反应的收率为 57 %。
!H NMR (400 MHz, CDC13) δ 7.80-7.25 (m, 5Η), 2.80 (d, J = 5.4 Hz, 2H), 2.49 (s, IH), 2.38 (s, 3H), 2.16 (s, IH), 2.04 (s, 2H), 1.51 (d, J = 4.9 Hz, IH). Ms (M++l): 222. 实施例 22
NHBoc MsCl, Et3N NHBoc H, THF
MsO、 . BN
、OTBS DCM " ma ^^^OTBS ^ OTBS
250 mL三口瓶中, 加入上述化合物( 6.38 g, 0.02 mol ), 二氯甲烷 60 mL, 三乙胺(3.03 g, 0.03mol ), 0。C下慢慢滴加 MsCl ( 3.15 g, 0.03 mol ), 滴加完毕升至室温搅拌 4小时,加入 60 mL 1 N稀盐酸淬灭反应,静置分 液, 有机相再用 50 mL饱和食盐水洗涤, 干燥、 过滤、 浓缩, 得到的粗 产品不经过精制, 直接用于下一步反应。
将上述得到的粗品溶解于 50 mL的无水四氢呋喃中,氮气保护, 0 °C 下分批加入 60% 氢化钠 (0.8 g, 0.02 mol ), 搅拌反应 15分钟后, 加入 50 mL饱和氯化铵溶液淬灭反应, 水相用 50 mL乙酸乙酯萃取, 有机相 用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱层析 得到产物为粘稠液体 4.3 g, 两步反应的收率为 73 %。
!H NMR (500 MHz, CDC13) δ 3.95〜3.63 (m, 2H), 2.61-2.43 (m, IH), 2.28 (d,
J = 6.1 Hz, IH), 1.96 (d, J = 3.8 Hz, IH), 1.86〜1.72 (m, IH), 1.72〜 1.55 (m,
1H), 1.46 (s, 6H), 0.93 (s, 9H), 0.07 (d, J = 1.8 Hz, 6H). Ms (M++1): 302. "C NMR (CDC13) δ 162.47, 80.84, 60.12, 35.52, 35.41, 31.40, 28.30, 27.86, 27.81, 22.75, -0.58. Ms (M++1): 302.
实施例 23
NHBoc TsCI, Et3N NHBoc
HO、 TsO、 NaH, THF
OTBS DCM OTBS OTBS
250 mL三口瓶中, 加入上述化合物( 6.38 g, 0.02 mol ), 二氯甲烷 60 mL, 三乙胺 (3.03 g, 0.03mol ), 0 °C下慢慢滴加 TsCI ( 5.7 g, 0.03 mol ), 滴加完毕升至室温搅拌 4小时,加入 60 mL 1 N稀盐酸淬灭反应,静置分 液, 有机相再用 50 mL饱和食盐水洗涤, 干燥、 过滤、 浓缩, 得到的粗 产品不经过精制, 直接用于下一步反应。
将上述反应所得的粗产物溶解于 50 mL的无水四氢 BN呋 BN o , o , c喃中, 氮气保 c
护, 0 °C下分批加入 60% 氢化钠(0.8 g, 0.02 mol ),搅拌反应 15分钟后, 加入 50 mL饱和氯化铵溶液淬灭反应, 水相用 50 mL乙酸乙酯萃取, 有 机相用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱 层析得到产物为粘稠液体 4.6 g, 两步反应的收率为 78 %。
!H NMR (500 MHz, CDC13) δ 3.95-3.63 (m, 2Η), 2.61-2.43 (m, 1H), 2.28 (d, J = 6.1 Hz, 1H), 1.96 (d, J = 3.8 Hz, 1H), 1.86〜1.72 (m, 1H), 1.72〜 1.55 (m, 1H), 1.46 (s, 6H), 0.93 (s, 9H), 0.07 (d, J = 1.8 Hz, 6H). 13C NMR (CDCI3) δ 162.47, 80.84, 60.12, 35.52, 35.41, 31.40, 28.30, 27.86, 27.81, 22.75, -0.58. Ms (M++1): 302. 实施例 24
NHBoc Ph3P, NBS NHBoc
NaH, THF
HO、
OTBS OTBS OTBS
250 mL三口瓶中, 加入上述化合物( 6.38 g, 0.02 mol ), 二氯甲烷 60 mL, 0 °C下慢慢滴加三苯基磚( 7.86 g, 0.03mol ), NBS ( 5.34 g, 0.03 mol ), 加完毕升至室温搅拌 4小时, 加入 60 mL 1 N水淬灭反应, 静置分液, 有 机相再用 50 mL饱和食盐水洗涤, 干燥、 过滤、 浓缩, 得到的粗产品不 经过精制, 直接用于下一步反应。
将上述反应所得的粗产物溶解于 50 mL的无水四氢呋喃中, 氮气保 护, 0 °C下分批加入 60% 氢化钠(0.8 g, 0.02 mol ),搅拌反应 15分钟后, 加入 50 mL饱和氯化铵溶液淬灭反应, 水相用 50 mL乙酸乙酯萃取, 有 机相用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱 层析得到产物为粘稠液体 3.83 g, 两步反应的收率为 65 %。
!H NMR (500 MHz, CDC13) δ 3.95〜3.63 (m, 2Η), 2.61〜2.43 (m, 1Η), 2.28 (d, J = 6.1 Hz, 1H), 1.96 (d, J = 3.8 Hz, 1H), 1.86〜1.72 (m, 1H), 1.72〜 1.55 (m, 1H), 1.46 (s, 6H), 0.93 (s, 9H), 0.07 (d, J = 1.8 Hz, 6H). 13C NMR (CDC13) δ 162.47, 80.84, 60.12, 35.52, 35.41, 31.40, 28.30, 27.86, 27.81, 22.75, -0.58. Ms (M++1): 302. 实施例 25
NHBoc Ph3P,DEAD N°°
OTBS DCM OTBS 在氮气氛中, 250 mL三口瓶中,加入上述化合物( 6.38 g, 0.02 mol ), 干燥的四氢呋喃 60 mL, 0 °C下慢慢滴加三苯基磚(7.86 g, 0.03mol ), 在 慢慢滴加偶氮二碳酸二乙酯 DEAD (5.22 g, 0.03mol), 常温下搅拌反应 10 小时后, 减压下浓缩反应体系后, 得到的残留物中加入 10 mL的四氢呋 喃, 加热搅拌溶解后, 向反应体系中滴加正己烷, 到反应体系中析出白 色的固体, 冷却, 过滤, 滤液浓缩后, 通过柱层析得到产物为粘稠液体 3.65 g, 两步反应的收率为 61 %。
!H NMR (500 MHz, CDC13) δ 3.95-3.63 (m, 2Η), 2.61-2.43 (m, 1H), 2.28 (d, J = 6.1 Hz, 1H), 1.96 (d, J = 3.8 Hz, 1H), 1.86〜1.72 (m, 1H), 1.72-
1.55 (m, IH), 1.46 (s, 6H), 0.93 (s, 9H), 0.07 (d, J = 1.8 Hz, 6H). "C NMR (CDC13) δ 162.47, 80.84, 60.12, 35.52, 35.41, 31.40, 28.30, 27.86, 27.81, 22.75, -0.58. Ms (M++1): 302. 实施例 26
MOM
250 mL三口瓶中, 加入上述化合物( 4.98 g, 0.02 mol ), 二氯甲烷 60 mL,三乙胺 ( 3.03 g, 0.03mol ), 0 °C下慢慢滴加 MsCl ( 3.15 g, 0.03 mol ), 滴加完毕升至室温搅拌 4小时,加入 60 mL 1 N稀盐酸淬灭反应,静置分 液, 有机相再用 50 mL饱和食盐水洗涤, 干燥、 过滤、 浓缩, 得到的粗 产品不经过精制, 直接用于下一步反应。
上一步反应的中间体溶解于 50 mL的无水四氢呋喃中,氮气保护, 0°C 下分批加入 60% 氢化钠( 0.8 g, 0.02 mol ),搅拌反应 15分钟后,加入 50 mL 饱和氯化铵溶液淬灭反应, 水相用 50 mL乙酸乙酯萃取, 有机相用饱和食 盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱层析得到产物 为粘稠液体 3.5 g, 两步反应的收率为 76 %。
!H NMR (400 MHz, CDC13) δ 4.50-4.47 (m, 2Η), 3.60 (s, 2H), 3.41 (s, 3H), 2.49 (br, IH), 2.12 (s, IH), 1.84 (s, 2H), 1.51-1.47 (m, 10H). Ms (M++l): 232. 实施例 27
NHBoc MsCl, Et3N
、OBn MsO
250 mL三口瓶中, 加入上述化合物(5.9 g, 0.02 mol ), 二氯甲烷 60 mL,三乙胺 ( 3.03 g, 0.03mol ), 0 °C下慢慢滴加 MsCl ( 3.15 g, 0.03 mol ), 滴加完毕升至室温搅拌 4小时,加入 60 mL 1 N稀盐酸淬灭反应,静置分 液, 有机相再用 50 mL饱和食盐水洗涤, 干燥、 过滤、 浓缩, 得到的粗
产品不经过精制, 直接用于下一步反应。
上一步反应的中间体溶解于 50 mL的无水四氢呋喃中,氮气保护, 0°C 下分批加入 60% 氢化钠 (0.8 g, 0.02 mol ), 搅拌反应 15分钟后, 加入 50 mL饱和氯化铵溶液淬灭反应, 水相用 50 mL乙酸乙酯萃取, 有机相 用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱层析 得到产物为粘稠液体 4.4 g, 两步反应的收率为 80 %。
!H NMR (400 MHz, CDC13) δ 7.30 (dt, J = 1.3, 0.6 Hz, 5H), 4.79 (s, 2H), 3.56 (s, 2H), 2.52 (s, 1H), 2.16 (s, 1H), 1.84 (s, 2H), 1.51 (d, J = 2.1 Hz, 10H). Ms (M++1): 278.
NHBn Λ Λ k , NHBn k, ■■ ■>■■■「
― MsCI, Et3N I NaH, THF
MsO '
ΌΒη v v 、0Bn z v 、0Bn
250 mL三口瓶中, 加入上述化合物(5.7 g, 0.02 mol ), 二氯甲烷 60 mL, 三乙胺(3.03 g, 0.03mol ), 0。C下慢慢滴加 MsCI ( 3.15 g, 0.03 mol ), 滴加完毕升至室温搅拌 4小时,加入 60 mL 1 N稀盐酸淬灭反应,静置分 液, 有机相再用 50 mL饱和食盐水洗涤, 干燥、 过滤、 浓缩, 得到的粗 产品不经过精制, 直接用于下一步反应。
上一步反应的中间体溶解于 50 mL的无水四氢呋喃中,氮气保护, 0°C 下分批加入 60% 氢化钠 (0.8 g, 0.02 mol ), 搅拌反应 15分钟后, 加入 50 mL饱和氯化铵溶液淬灭反应, 水相用 50 mL乙酸乙酯萃取, 有机相 用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过柱层析 得到产物为粘稠液体 4.4 g, 两步反应的收率为 83 %。
!H NMR (400 MHz, CDC13) δ 7.30-7.22 (m, 10H), 4.79 (s, 4H), 3.56 (s, 4H), 2.52 (s, 1H), 2.16 (s, 1H), 1.84 (s, 2H), 1.51 (s, 1H). Ms (M++l): 268. 实施例 29
OH
将上述化合物( 6 g ,0.02 mol )溶于 40 mLTHF,加入溶于 40 mL THF 的 TBAF ( 7.3 g, 0.027 mol ), 常温下反应于 2小时, 加入 5 mL饱和氯化 铵溶液淬灭反应, 浓缩回收四氢呋喃, 残留物用 50 mL乙酸乙酯萃取, 有机相用饱和食盐水洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 粗产品通过 柱层析得到产物为粘稠液体 3.4 g, 反应的收率为 92 %。
!H NMR (500 MHz, CDC13) δ 3.74 (s, 2Η), 3.15 (s, 1H), 2.41 (d, J = 5.9 Hz,
1H), 2.26 (d, J = 6.1 Hz, 1H), 1.93 (d, J = 3.4 Hz, 1H), 1.90 -1.78 (m, 1H),
1.54〜1.42 (m, 1H), 1.38 (s, 9H). 13C NMR (CDC13) δ 162.55, 81.55, 60.54,
35.96, 34.35, 31.06, 28.31, 28.27, 27.85. Ms (M++1): 188. 施例 30
lOO mL三口瓶中, 加入 4.62 g 2,4,5-三氟溴苯(0.022 mol ), 无水四 氢呋喃(50 mL ), 冷却至 -20 V, 氮气保护下慢慢滴加异丙基溴化镁( 22 mmol ) 的四氢呋喃溶液(22 mL, 1M的 THF溶液), 滴加完毕后 -20 V 保温备用。
溴化亚铜-二甲硫醚( 0.41 g, 0.002mol )悬浮于 5 mL无水四氢呋喃, 冷却至 -5°C, 氮气保护下慢慢滴加上述格式试剂。 15 分钟后, 慢慢滴加 吖啶化合物(3.26 g, 0.015 mol ) 的 30 mL四氢呋喃溶液。 5分钟后, 加 入 50 mL饱和氯化铵溶液淬灭反应。 随后加入 50 mL乙酸乙酯, 分液。 水相用 50 mL乙酸乙酯提取, 合并有机相, 饱和食盐水洗涤, 无水硫酸 钠干燥、 过滤、 浓缩, 粗产品通过柱层析得到化合物 4.29 g, 收率 82 %。
!H NMR (400 MHz, CDC13) δ 7.15-6.94 (m, 1H), 6.88 (d, J = 6.8 Hz, 1H), 4.47 (d, J = 8.9 Hz, 1H), 4.00-3.80 (m, 1H), 2.92-2.76 (m, 1H), 2.76-2.64 (m, 1H), 2.64-2.44 (m, 2H), 2.06 (d, J = 14.6 Hz, 3H), 1.84 (s, 1H)
1.66 (qd, J = 14.0, 8.0 Hz, IH), 1.47-1.31 (m, 9H). Ms (M +1): 350. 实施例 31
lOO mL三口瓶中, 加入 4.62 g 2,4,5-三氟溴苯(0.022 mol ), 无水四 氢呋喃(50 mL ), 冷却至 -20 V, 氮气保护下慢慢滴加异丙基溴化镁( 22 mmol ) 的四氢呋喃溶液(22 mL, 1M的 THF溶液), 滴加完毕后 -20 V 保温备用。
溴化亚铜-二甲硫醚( 0.41 g, 0.002mol )悬浮于 5 mL无水四氢呋喃, 冷却至 -5 °C, 氮气保护下慢慢滴加上述格式试剂。 15分钟后, 慢慢滴加 吖啶化合物(4.1 g, 0.015 mol ) 的 30 mL四氢呋喃溶液。 5分钟后, 加 入 50 mL饱和氯化铵溶液淬灭反应。 随后加入 50 mL乙酸乙酯, 分液。 水相用 50 mL乙酸乙酯提取, 合并有机相, 饱和食盐水洗涤, 无水硫酸 钠干燥、 过滤、 浓缩, 粗产品通过柱层析得到化合物 5.26 g, 收率 87 %。
!H NMR (400 MHz, CDC13) δ 7.87-7.61 (m, 5Η), 7.15〜6.94 (m, IH), 6.88 (d, J = 6.8 Hz, IH), 5.02 (d, J = 8.9 Hz, IH), 4.00-3.80 (m, IH), 2.92-2.76 (m, IH), 2.76-2.64 (m, IH), 2.64-2.44 (m, 2H), 2.06 (d, J = 14.6 Hz, 3H), 1.84 (s, IH), 1.62 (s, IH). Ms (M++l): 404. 实施例 32
lOO mL三口瓶中, 加入 4.62 g 2,4,5-三氟溴苯(0.022 mol ), 无水四 氢呋喃(50 mL ), 冷却至 -20 V, 氮气保护下慢慢滴加异丙基溴化镁( 22 mmol ) 的四氢呋喃溶液(22 mL, 1M的 THF溶液), 滴加完毕后 -20 V
保温备用。
溴化亚铜-二甲硫醚( 0.41 g, 0.002mol )悬浮于 5 mL无水四氢呋喃, 冷却至 -5 °C, 氮气保护下慢慢滴加上述格式试剂。 15分钟后, 慢慢滴加 吖啶化合物(4.16 g, 0.015 mol ) 的 30 mL四氢呋喃溶液。 5分钟后, 加 入 50 mL饱和氯化铵溶液淬灭反应。 随后加入 50 mL乙酸乙酯, 分液。 水相用 50 mL乙酸乙酯提取, 合并有机相, 饱和食盐水洗涤, 无水硫酸 钠干燥、过滤、浓缩,粗产品通过柱层析得到化合物(4.08 g, 0.0116 mol ), 收率 77 % 。
!H NMR (400 MHz, CDC13) δ 8.10 (d, J = 5.4 Hz, 2H), 7.72-7.66 (m, 3H), 7.15〜6.94 (m, 1H), 6.88 (d, J = 6.8 Hz, 1H), 4.47 (d, J = 8.9 Hz, 1H), 4.00-3.80 (m, 1H), 2.92- 2.76 (m, 1H), 2.76-2.64 (m, 1H), 2.64- 2.44 (m, 2H), 2.06 (d, J = 14.6 Hz, 3H), 1.84 (s, 1H), 1.66 (qd, J = 14.0, 8.0 Hz, 1H). Ms (M++1): 354. 实施 33
lOO mL三口瓶中, 加入 4.62 g 2,4,5-三氟溴苯(0.022 mol ), 无水四 氢呋喃(50 mL ), 冷却至 -20 V, 氮气保护下慢慢滴加异丙基溴化镁( 22 mmol ) 的四氢呋喃溶液(22 mL, 1M的 THF溶液), 滴加完毕后 -20 V 保温备用。
溴化亚铜-二甲硫醚( 0.41 g, 0.002mol )悬浮于 5 mL无水四氢呋喃, 冷却至 -5 °C, 氮气保护下慢慢滴加上述格式试剂。 15分钟后, 慢慢滴加 吖啶化合物(4.16 g, 0.015 mol ) 的 30 mL四氢呋喃溶液。 5分钟后, 加 入 50 mL饱和氯化铵溶液淬灭反应。 随后加入 50 mL乙酸乙酯, 分液。 水相用 50 mL乙酸乙酯提取, 合并有机相, 饱和食盐水洗涤, 无水硫酸 钠干燥、过滤、浓缩,粗产品通过柱层析得到化合物(4.98 g, 0.0128 mol ),
收率 85 % 。
!H NMR (400 MHz, CDC13) δ 7.87-7.61 (m, 5H), 7.15〜6.94 (m, 1H), 6.88 (d, J = 6.8 Hz, 1H), 5.02 (d, J = 8.9 Hz, 1H), 4.00 - 3.80 (m, 1H), 2.92-2.76 (m, 1H), 2.76-2.64 (m, 1H), 2.64〜 2.44 (m, 2H), 2.06 (d, J = 14.6 Hz, 3H), 1.84 (s, 1H), 1.62 (s, 1H). Ms (M++l): 390. 施例 34
lOO mL三口瓶中, 加入 4.62 g 2,4,5-三氟溴苯(0.022 mol ), 无水四 氢呋喃(50 mL ), 冷却至 -20 V, 氮气保护下慢慢滴加异丙基溴化镁( 22 mmol ) 的四氢呋喃溶液(22 mL, 1M的 THF溶液), 滴加完毕后 -20 V 保温备用。
溴化亚铜-二甲硫醚( 0.41 g, 0.002mol )悬浮于 5 mL无水四氢呋喃, 冷却至 -5 °C, 氮气保护下慢慢滴加上述格式试剂。 15分钟后, 慢慢滴加 吖啶化合物(4.54 g, 0.015 mol ) 的 30 mL四氢呋喃溶液。 5分钟后, 加 入 50 mL饱和氯化铵溶液淬灭反应。 随后加入 50 mL乙酸乙酯, 分液。 水相用 50 mL乙酸乙酯提取, 合并有机相, 饱和食盐水洗涤, 无水硫酸 钠干燥、过滤、 浓缩,粗产品通过柱层析得到化合物(5.07g, 0.012 mol ), 收率 78% 。
!H NMR (400 MHz, CDC13) δ 7.03 (t, J = 10.5 Hz, 1H), 6.91 (t, J = 10.7 Hz, 1H), 5.14 (d, J = 12.6 Hz, 1H), 3.97- 3.85 (m, 1H), 3.82 (d, J = 6.2 Hz, 1H), 3.77〜3.55 (m, 1H), 2.82 (s, 2H), 1.87〜1.68 (m, 1H), 1.63-1.48 (m, 1H), 1.39 (s, 9H), 0.91 (s, 9H), 0.06 (d, J = 4.6 Hz, 6H). Ms (M++1): 434.
lOO mL三口瓶中, 加入 4.62 g 2,4,5-三氟溴苯(0.022 mol ), 无水四 氢呋喃(50 mL ), 冷却至 -20 V, 氮气保护下慢慢滴加异丙基溴化镁( 22 mmol ) 的四氢呋喃溶液(22 mL, 1M的 THF溶液), 滴加完毕后 -20 V 保温备用。
溴化亚铜-二甲硫醚( 0.41 g, 0.002mol )悬浮于 5 mL无水四氢呋喃, 冷却至 -5 °C, 氮气保护下慢慢滴加上述格式试剂。 15分钟后, 慢慢滴加 吖啶化合物(3.46 g, 0.015 mol ) 的 30 mL四氢呋喃溶液。 5分钟后, 加 入 50 mL饱和氯化铵溶液淬灭反应。 随后加入 50 mL乙酸乙酯, 分液。 水相用 50 mL乙酸乙酯提取, 合并有机相, 饱和食盐水洗涤, 无水硫酸 钠干燥、过滤、浓缩,粗产品通过柱层析得到化合物(3.98 g, 0.011 mol ), 收率 73% 。
!H NMR (400 MHz, CDC13) δ 7.01 (t, J = 10.5 Hz, IH), 6.92〜6.88 (m, IH), 5.14 (d, J = 12.6 Hz, IH), 4.50 (s, 2H), 3.95-3.85 (m, IH), 3.82- 3.77 (m, IH), 3.77〜3.55 (m, IH), 3.40 (s, 3H), 2.82 (s, 2H), 1.87〜1.68 (m, IH), 1.63-1.48 (m, IH), 1.39 (s, 9H). Ms (M++l): 364. 施例 36
lOO mL三口瓶中, 加入 4.62 g 2,4,5-三氟溴苯(0.022 mol ), 无水四 氢呋喃(50 mL ), 冷却至 -20 V, 氮气保护下慢慢滴加异丙基溴化镁( 22 mmol ) 的四氢呋喃溶液(22 mL, 1M的 THF溶液), 滴加完毕后 -20 V 保温备用。
溴化亚铜-二甲硫醚( 0.41 g, 0.002mol )悬浮于 5 mL无水四氢呋喃, 冷却至 -5 °C, 氮气保护下慢慢滴加上述格式试剂。 15分钟后, 慢慢滴加 吖啶化合物(4.16 g, 0.015 mol ) 的 30 mL四氢呋喃溶液。 5分钟后, 加 入 50 mL饱和氯化铵溶液淬灭反应。 随后加入 50 mL乙酸乙酯, 分液。 水相用 50 mL乙酸乙酯提取, 合并有机相, 饱和食盐水洗涤, 无水硫酸 钠干燥、过滤、浓缩,粗产品通过柱层析得到化合物(5.41 g, 0.0132 mol ), 收率 88 % 。
!H NMR (400 MHz, CDC13) δ7.53〜7.22 (m, 5H), 7.05 (t, J = 10.5 Hz, 1H), 6.93 (t, J = 10.7 Hz, 1H), 5.12 (d, J = 12.6 Hz, 1H), 3.97-3.85 (m, 1H), 3.82 (d, J = 6.2 Hz, 1H), 3.77〜3.55 (m, 1H), 3.51 (s, 2H),2.82 (s, 2H), 1.87〜1.68 (m, 1H), 1.63-1.48 (m, 1H), 1.39 (s, 9H). Ms (M++l): 410. 施例 37
lOO mL三口瓶中, 加入 4.62 g 2,4,5-三氟溴苯(0.022 mol ), 无水四 氢呋喃(50 mL ), 冷却至 -20 V, 氮气保护下慢慢滴加异丙基溴化镁( 22 mmol ) 的四氢呋喃溶液(22 mL, 1M的 THF溶液), 滴加完毕后 -20 V 保温备用。
溴化亚铜-二甲硫醚( 0.41 g, 0.002mol )悬浮于 5 mL无水四氢呋喃, 冷却至 -5 °C, 氮气保护下慢慢滴加上述格式试剂。 15分钟后, 慢慢滴加 吖啶化合物(4.16 g, 0.015 mol ) 的 30 mL四氢呋喃溶液。 5分钟后, 加 入 50 mL饱和氯化铵溶液淬灭反应。 随后加入 50 mL乙酸乙酯, 分液。 水相用 50 mL乙酸乙酯提取, 合并有机相, 饱和食盐水洗涤, 无水硫酸 钠干燥、过滤、浓缩,粗产品通过柱层析得到化合物(4.08 g, 0.0116 mol ), 收率 77 % 。
!H NMR (400 MHz, CDC13) δ7.53〜7.22 (m, 10 H), 7.05 (t, J = 10.5 Hz,
1H), 6.93 (t, J = 10.7 Hz, 1H), 5.12 (d, J = 12.6 Hz, 1H), 3.97-3.85 (m, 1H), 3.82 (d, J = 6.2 Hz, 1H), 3.77〜 3.55 (m, 1H), 3.62 (s, 2H), 3.51 (s, 2H),2.82 (s 2H), 1.87〜1.68 (m, 1H), 1.63-1.48 (m, 1H). Ms (M++1): 400. 实施例 38
三口瓶中, 加入原料(5.07 g, 0.012 mol ), 四氢呋喃 (50 mL ), 室 温下, 加入四丁基氟化铵(3.92 g, 0.015 mol ), 搅拌 2小时, 蒸除溶剂。 加入 50 mL二氯甲烷, 50 mL水, 分液, 有机相分别用稀盐酸、 饱和碳 酸氢钠溶液洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 得到粗产品 (3.64 g, 95 % )。
!H NMR (500 MHz, CDC13) δ 7.05 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 6.6 Hz, 1H), 4.56 (d, J = 9.0 Hz, 1H), 4.13-3.96 (m, 1H), 3.68 (d, J = 6.0 Hz, 2H), 2.85-2.65 (m, 2H), 1.86 (dd, J = 12.4, 7.7 Hz, 1H), 1.68 (s, 1H), 1.42 (s, , 9H). Ms (M++1): 320. 实施例 39
三口瓶中, 加入原料(3.98 g, 0.011 mol ), 二氯曱烷(50 mL )。 室 温下, 加入醋酸(1.2 g, 0.02 mol ), 搅拌 2小时, 加入 50 mL水, 分液, 有机相分别用饱和碳酸氢钠溶液、 稀盐酸洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 得到粗产品 ( 3.41 g, 97 % )。
!H NMR (500 MHz, CDC13) δ 7.05 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 6.6 Hz, 1H), 4.56 (d, J = 9.0 Hz, 1H), 4.13〜3.96 (m, 1H), 3.68 (d, J = 6.0 Hz, 2H)
2.85-2.65 (m, 2H), 1.86 (dd, J = 12.4, 7.7 Hz, 1H), 1.68 (s, 1H), 1.42 (s, , 9H). Ms (M++1): 320. 施例 40
lOO mL三口瓶中, 加入 4.62 g 2,4,5-三氟溴苯(0.022 mol ), 无水四 氢呋喃(50 mL ), 冷却至 -20 V, 氮气保护下慢慢滴加异丙基溴化镁( 22 mmol ) 的四氢呋喃溶液(22 mL, 1M的 THF溶液), 滴加完毕后 -20 V 保温备用。
溴化亚铜-二甲硫醚( 0.41 g, 0.002mol )悬浮于 5 mL无水四氢呋喃, 冷却至 -5 °C, 氮气保护下慢慢滴加上述格式试剂。 15分钟后, 慢慢滴加 吖啶化合物(2.81 g, 0.015 mol ) 的 30 mL四氢呋喃溶液。 5分钟后, 加 入 50 mL饱和氯化铵溶液淬灭反应。 随后加入 50 mL乙酸乙酯, 分液。 水相用 50 mL乙酸乙酯提取, 合并有机相, 饱和食盐水洗涤, 无水硫酸 钠干燥、过滤、浓缩,粗产品通过柱层析得到化合物( 3.69 g, 0.0115 mol ), 收率 77 % 。
!H NMR (500 MHz, CDC13) δ 7.05 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 6.6 Hz, 1H), 4.56 (d, J = 9.0 Hz, 1H), 4.13-3.96 (m, 1H), 3.68 (d, J = 6.0 Hz, 2H), 2.85-2.65 (m, 2H), 1.86 (dd, J = 12.4, 7.7 Hz, 1H), 1.68 (s, 1H), 1.42 (s, , 9H). Ms (M++1): 320. 实施例 41
三口瓶中,加入 35 mL蒸馏水和 5 mL甲醇冷混合溶液悬浮,放置水
盐浴上,加入原料(4.29 g, 0.0123 mol ),然后以注射器小心的抽取 10 mL 碘甲烷加入至上述反应体系, 磁力搅拌反应 30分钟, 底部的碘甲烷变为 无色, 然后撤去水盐浴, 反应体系緩慢升温至室温, 以 TLC检验反应进 度, 待完全反应, 拆除反应装置, 在空气中挥发多余的碘甲烷, 蒸除溶 剂, 得微黄色的固体粗产物。
将所得的固体粗产品加入到双口圆底烧瓶中, 用 20 mL水溶解, 以 恒压滴液漏斗将 1.909 g(0.0227 mol)碳酸氢钠的 10 mL水溶液緩慢滴加至 上述反应液中, 保持反应体系 pH值 3 ~ 6之间, 油浴加热緩慢升温至回 流, TLC跟踪, 反应终点 pH值接近 7, 蒸除溶剂得到粘稠状的微黄色的 胶状物, 加入二氯甲烷(50 mL ), 水(50 mL ), 分液, 有机相分别用饱 和碳酸氢钠溶液、 稀盐酸洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 得到粗 产品 (2.83 g, 72 % )。
!H NMR (500 MHz, CDC13) δ 7.05 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 6.6 Hz, 1H), 4.56 (d, J = 9.0 Hz, 1H), 4.13-3.96 (m, 1H), 3.68 (d, J = 6.0 Hz, 2H), 2.85-2.65 (m, 2H), 1.86 (dd, J = 12.4, 7.7 Hz, 1H), 1.68 (s, 1H), 1.42 (s, , 9H). Ms (M++1): 320. 实施例 42
在 250 mL的高压反应釜中, 加入原料 ( 5.41 g, 0.0132 mol )和 50 亳升甲醇, 10 %钯-碳 0.5 g, 于 6个大气压的氢气压力下, 反应 12小时。 随后过滤回收催化剂, 蒸干溶剂, 得到粗产品(4.13 g, 0.0129 mol ), 收 率 98%。
!H NMR (500 MHz, CDC13) δ 7.05 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 6.6 Hz, 1H), 4.56 (d, J = 9.0 Hz, 1H), 4.13-3.96 (m, 1H), 3.68 (d, J = 6.0 Hz, 2H), 2.85-2.65 (m, 2H), 1.86 (dd, J = 12.4, 7.7 Hz, 1H), 1.68 (s, 1H), 1.42 (s, , 9H).
Ms (M +1): 320. 实施例 43
在 250 mL的高压反应釜中,力口入原料(5.11 g, 0.0128 mol )和 50mL 甲醇, 20 %氢氧化钯-碳 0.5 g, 于 50度, 6个大气压的氢气压力下, 反 应 12小时。 随后过滤回收催化剂, 蒸干溶剂, 得到粗产品投入到 100 mL 的圆底烧瓶中, 加入 50 mL二氯甲烷和三乙胺(2.6 g, 0.025mol ), 随后 加入碳酸二叔丁酯( 3.27 g, 0.015mol ), 室温下搅拌 8小时。依次用 50mL 稀盐酸、 50mL水、 50mL饱和食盐水洗涤, 干燥, 过滤, 浓缩得到粗产 品 (3.59 g, O.Ol lmol ), 两步收率 88%。
!H NMR (500 MHz, CDC13) δ 7.05 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 6.6 Hz, 1H), 4.56 (d, J = 9.0 Hz, 1H), 4.13-3.96 (m, 1H), 3.68 (d, J = 6.0 Hz, 2H), 2.85-2.65 (m, 2H), 1.86 (dd, J = 12.4, 7.7 Hz, 1H), 1.68 (s, 1H), 1.42 (s, , 9H). Ms (M++1): 320. 实施 44
三口瓶中,加入 35 mL蒸馏水和 5 mL甲醇冷混合溶液悬浮,放置水 盐浴上,加入原料(4.08 g, 0.0116 mol ),然后以注射器小心的抽取 10 mL 碘甲烷加入至上述反应体系, 磁力搅拌反应 30分钟, 底部的碘甲烷变为 无色, 然后撤去水盐浴, 反应体系緩慢升温至室温, 以 TLC检验反应进 度, 待完全反应, 拆除反应装置, 在空气中挥发多余的碘甲烷, 蒸除溶 剂, 得微黄色的固体粗产物。
将所得的固体粗产品加入到双口圆底烧瓶中, 用 20 mL水溶解, 以 恒压滴液漏斗将 1.91 g(0. 0227 mol)碳酸氢钠的 10 mL水溶液緩慢滴加至 上述反应液中, 保持反应体系 pH值 3 ~ 6之间, 油浴加热緩慢升温至回 流, TLC跟踪, 反应终点 pH值接近 7, 蒸除溶剂得到粘稠状的微黄色的 胶状物, 加入二氯甲烷(50 mL ), 水(50 mL ), 分液, 有机相分别用饱 和碳酸氢钠溶液、 稀盐酸洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 得到粗 产品 ( 2.85 g, 77 % )。
!H NMR (400 MHz, CDC13) δ 8.10 (d, J = 5.4 Hz, 2H), 7.72-7.66 (m, 3H), 7.05 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 6.6 Hz, 1H), 4.51 (d, J = 9.0 Hz, 1H), 4.40 (br, 1H), 4.13-3.96 (m, 1H), 3.68 (d, J = 6.0 Hz, 2H), 2.85-2.65 (m, 2H), 1.86 (dd, J = 12.4, 7.7 Hz, 1H), 1.68 (s, 1H). 实施例 45
三口瓶中,加入 35 mL蒸馏水和 5 mL甲醇冷混合溶液悬浮,放置水 盐浴上, 加入原料 ( 4.98 g, 0.0128 mol ), 然后以注射器小心的抽取 10 mL 碘甲烷加入至上述反应体系, 磁力搅拌反应 30分钟, 底部的碘甲烷变为 无色, 然后撤去水盐浴, 反应体系緩慢升温至室温, 以 TLC检验反应进 度, 待完全反应, 拆除反应装置, 在空气中挥发多余的碘甲烷, 蒸除溶 剂, 得微黄色的固体粗产物。
将所得的固体粗产品加入到双口圆底烧瓶中, 用 20 mL水溶解, 以 恒压滴液漏斗将 1.91 g(0.0227 mol)碳酸氢钠的 10 mL水溶液緩慢滴加至 上述反应液中, 保持反应体系 pH值 3 ~ 6之间, 油浴加热緩慢升温至回 流, TLC跟踪, 反应终点 pH值接近 7, 蒸除溶剂得到粘稠状的微黄色的 胶状物, 加入二氯甲烷(50 mL ), 水(50 mL ), 分液, 有机相分别用饱 和碳酸氢钠溶液、 稀盐酸洗涤, 无水硫酸钠干燥、 过滤、 浓缩, 得到粗
产品 ( 3.10 g, 76 % )。
!H NMR (400 MHz, CDC13) δ 7.87〜7.61 (m, 5H), 7.05 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 6.6 Hz, 1H), 4.56 (d, J = 9.0 Hz, 1H), 4.40 (br, 1H), 4.13-3.96 (m, 1H), 3.68 (d, J = 6.0 Hz, 2H), 2.85- 2.65 (m, 2H), 1.86 (dd, J = 12.4, 7.7 Hz, 1H), 1.68 (s, 1H). 实施例 46
在装有恒压滴液漏斗, 温度计的三口烧瓶中加入粗产物醇 (5.6 g, 0.0175 mol), 75 mL二氯甲烷和 50 mL NaHC03(5%溶液), TEMPO ( 0.28g, 1.75 mmol ) , NaBr (0.18 g , 1.75 mmol)。 于 0。C下滴加 NaClO(50 mmol, 74mL, 5 反应 2小时结束。 加入 10 mL饱和硫代硫酸钠, 用 2 N盐酸 中和至 pH = 2-3 , 二氯甲烷 50 mL萃取 3次, 合并有机相。 无水硫酸镁 干燥过滤, 减压除去溶剂。 得到的固体粗产品用甲醇重结晶, 得到类白 色固体(5.24 g, 0.0157 mol ), 收率 90%。
!H NMR (500 MHz, CDC13) δ 7.09 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 6.7 Hz, 1H), 5.03 (d, J = 4.0 Hz, 1H), 4.36 (s, 1H), 3.06 -2.75 (m, 3H), 2.62 (dd, J = 16.4, 5.6 Hz, 1H), 2.50 (d, J = 8.2 Hz, 1H), 1.33 (s, 9H). Ms(M++l): 334. 实施例 47
在装有恒压滴液漏斗, 温度计的三口烧瓶中加入粗产物醇 (6.5 g, 0.0175 mol), 75 mL二氯甲烷和 50 mL NaHC03(5%溶液), TEMPO( 0.28 g, 1.75 mmol ) , NaBr (0.18 g, 1.75 mmol),于 0 °C下滴加 NaCIO (50 mmol, 74
mL, 5 反应 2小时结束。 加入 10 mL饱和硫代硫酸钠, 用 2 N HC1 中 和至 pH = 2-3 , 二氯甲烷 50 mL萃取 3次, 合并有机相。 无水硫酸镁干 燥过滤, 减压除去溶剂。 得到的固体粗产品用甲醇重结晶, 得到类白色 固体 5.76 g, 收率 85%。
!H NMR (400 MHz, CDC13) δ7.87〜7.61 (m, 5Η), 7.09 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 6.7 Hz, 1H), 5.03 (d, J = 4.0 Hz, 1H), 4.36 (s, 1H), 3.06- 2.75 (m, 3H), 2.62 (dd, J = 16.4, 5.6 Hz, 1H), 2.47 (d, J = 8.2 Hz, 1H), 2.35 (s: 3 H). Ms(M++l): 388. 实施例 48
在装有恒压滴液漏斗, 温度计的三口烧瓶中加入粗产物醇 (5.65 g, 0.0175 mol), 75 mL二氯甲烷和 50 mL NaHC03(5%溶液), TEMPO( 0.28 g, 1.75 mmol ) , NaBr (0.18 g, 1.75 mmol),于 0 °C下滴加 NaCIO (50 mmol, 74 mL, 5 反应 2小时结束, 加入 10 mL饱和硫代硫酸钠, 用 2 N盐酸中 和至 pH = 2-3 , 二氯甲烷 50 mL萃取 3次, 合并有机相。 无水硫酸镁干 燥过滤, 减压除去溶剂。 得到的固体粗产品用甲醇重结晶, 得到类白色 固体(5.43 g, 0.0161 mol ), 收率 92 %。
!H NMR (400 MHz, CDC13) δ 8.10 (d, J = 5.4 Hz, 2H), 7.72-7.66 (m, 3H), 7.09 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 6.7 Hz, 1H), 5.03 (d, J = 4.0 Hz, 1H), 4.36 (s, 1H), 3.06-2.75 (m, 3H), 2.62 (dd, J = 16.4, 5.6 Hz, 1H), 2.50 (d, J = 8.2 Hz, 1H). Ms(M++l): 338. 实施例 49
在装有恒压滴液漏斗, 温度计的三口烧瓶中加入粗产物醇 (6.28 g, 0.0175 mol), 75 mL 二氯甲烷和 50 mL NaHC03(5%溶液), TEMPO ( 0.28g. l.75 mmol ) , NaBr(0.18 g ,1.75 mmol) , 于 0°C下滴加 NaCIO (50 mmol,74ml 5%)。反应 2小时结束。加入 10 mL饱和硫代硫酸钠,用 2N 盐 酸中和至 pH = 2-3 , 二氯甲烷 50 mL萃取 3次, 合并有机相。 无水硫酸 镁干燥过滤, 减压除去溶剂。 得到的固体粗产品用甲醇重结晶, 得到类 白色固体(5.74 g, 0.0154 mol ), 收率 88 %。
!H NMR (400 MHz, CDC13) δ7.87〜7.61 (m, 5H), 7.09 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 6.7 Hz, 1H), 5.03 (d, J = 4.0 Hz, 1H), 4.36 (s, 1H), 3.06- 2.75 (m, 3H), 2.62 (dd, J = 16.4, 5.6 Hz, 1H), 2.47 (d, J = 8.2 Hz, 1H).
Ms(M++l): 374. 实 50
在 50 mL圆底烧瓶中加入 20 mL,分别加入苯基丁酸衍生物( 3.32 g, 0.01 mol )和三氮唑并哌嗪盐酸盐 ( 228 g, 0.01 mol ), 用水盐浴冷却反应 体系的温度到 0 °C, 加入 1-羟基苯并三氮唑( 1.62 g, 0.012mol ), 1-乙基 -3- ( 3-二甲基氨基丙基)碳酰亚胺盐酸盐 (2.29 g, 0.012 mol ), 滴加三 乙胺 3 g, 常温搅拌反应 24 h, 反应液用 3x20 mL蒸馏水洗涤, 有机层用 无水硫酸镁干燥 1小时, 过滤出干燥剂, 浓缩得到 4.81g, 收率 95%。
[a] D20 = + 22.2 (c 1.0, CHC13). M.p. 188-191°C. IR (cm-1): 3374, 2897, 1686, 1635, 1519, 1368, 1164, 1128, 1016. !H NMR (400 MHz, CDC13) δ 7.18 〜7.05 (m, 1H), 7.02 - 6.85 (m, 1H), 5.31 (s, 1H), 5.15〜 4.76 (m, 2H), 4.43〜3.78 (m, 5H), 2.98-2.92 (m, 2H), 2.71-2.61 (m, 2H), 1.36 (s, 9H). ESI-MS: 508.0 (M+ +1). HRMS Calcd. for: C21H23F6N503Na (M + Na)+ requires 530.1598, found 530.1604.
实
在 50 mL圆底烧瓶中加入 20 mL,分别加入苯基丁酸衍生物( 3.87 g, 0.01 mol)和三氮唑并哌嗪盐酸盐 ( 228 g, 0.01 mol), 用水盐浴冷却反应 体系的温度到 0 °C, 加入 1-羟基苯并三氮唑( 1.62 g, 0.012mol), 1-乙基 -3- (3-二甲基氨基丙基)碳酰亚胺盐酸盐 (2.29 g, 0.012 mol), 滴加三 乙胺 3 g, 常温搅拌反应 24 h, 反应液用 3x20 mL蒸馏水洗涤, 有机层用 无水硫酸镁干燥 1小时, 过滤出干燥剂, 浓缩得到 5.1 g, 收率 91%。
在 50 mL圆底烧瓶中加入 20 mL二氯甲烷, 分别加入苯基丁酸衍生 物 ( 3.37 g, 0.01 mol )和三氮唑并哌嗪盐酸盐 ( 228 g, 0.01 mol ), 用水盐 浴冷却反应体系的温度到 0 V , 加入 1-羟基苯并三氮唑 ( 1.62 g, 0.012mol), 1-乙基 -3-(3-二甲基氨基丙基)碳酰亚胺盐酸盐(2.29g, 0.012 mol), 滴加三乙胺 3 g, 常温搅拌反应 24 h, 反应液用 3x20 mL蒸馏水洗 涤, 有机层用无水硫酸镁干燥 1小时, 过滤出干燥剂, 浓缩得到 4.7 g, 收率 92%。
3
在 50 mL圆底烧瓶中加入 20 mL二氯甲烷, 分别加入苯基丁酸衍生 物 ( 3.23 g, 0.01 mol )和三氮唑并哌嗪盐酸盐 ( 228 g, 0.01 mol ), 用水盐 浴冷却反应体系的温度到 0 V , 加入 1-羟基苯并三氮唑 ( 1.62 g, 0.012mol ), 1-乙基 -3- ( 3-二甲基氨基丙基)碳酰亚胺盐酸盐(2.29 g, 0.012 mol ), 滴加三乙胺 3 g, 常温搅拌反应 24 h, 反应液用 3x20 mL蒸馏水洗 涤, 有机层用无水硫酸镁干燥 1小时, 过滤出干燥剂, 浓缩得到 4.67 g, 收率 94%。
在 50 mL圆底烧瓶中加入 20 mL二氯甲烷, 分别加入苯基丁酸衍生 物( 3.73 g, 0.01 mol )和三氮唑并哌嗪盐酸盐 ( 228 g, 0.01 mol ), 用水盐 浴冷却反应体系的温度到 0 V , 加入 1-羟基苯并三氮唑 ( 1.62 g, 0.012mol ), 1-乙基 -3- ( 3-二甲基氨基丙基)碳酰亚胺盐酸盐(2.29 g, 0.012 mol ), 滴加三乙胺 3 g, 常温搅拌反应 24 h, 反应液用 3x20 mL蒸馏水洗 涤, 有机层用无水硫酸镁干燥 1小时, 过滤出干燥剂, 浓缩得到 4.64 g, 收率 85%。 实施例 55
在 250 mL圆底烧瓶中加入原料 (5.07 g, 10 mmol),加甲醇 50mL溶解, 取浓盐酸:甲醇 =l:5(v/v)的混合溶液 50 mL加入圆底烧瓶中, 室温下搅拌 2.5小时后, TCL跟踪监测至反应完全(用纯乙酸乙酯走板,原料 Rf= 0.85,
产物 Rf= 0.25 ), 浓缩蒸干圆底烧瓶中的溶剂, 加入 2 mol/L的氨水中和, 用 3x l00mL的乙酸乙酯萃取水相, 合并有机相, 并用 200 mL的饱和食 盐水洗涤, 用无水硫酸镁干燥 1小时, 过滤, 浓缩得到油状物。
向上述粗产品中加入 60 mL的无水乙醇, 再加入 10 mL水, 将反应 混合物加热到 80 °C, 加入 1.5 g的浓磚酸, 搅拌反应 2小时后, 降至室 温, 搅拌 18 h, 析出固体, 过滤, 即得其磷酸盐 4.39 g, 两步反应的收率 87 %。
[ ]D 20 = - 22.8 (c 1.0, CHC13). M.p. 108-112 。C. IR (cm-1): 3360, 2870, 1644, 1517, 1437, 1342, 1237, 1140, 941, 808. !H NMR (400 MHz, CDC13) 67.19-7.02 (m, 1H), 7.02- 6.81 (m, 1H) 5.06 (dd, J = 50.1, 18.2 Hz, 1H), 4.95 (s, 2H), 4.43〜 3.77 (m, 5H), 3.60 (s, 1H), 2.92〜 2.28 (m, 4H). ESI-MS: 408.0 (M+ +1). HRMS Calcd. for: C16H15F6N5ONa (M ++Na)+ requires 430.1082, found 430.1087. 实施例 56
在 250 mL圆底烧瓶中加入原料 (5.61 g, 10 mmol), 醋酸 50 mL和浓盐 酸 25 mL搅拌下溶解, 并逐渐加热到回流搅拌 3小时后, TCL跟踪监测至 反应完全, 冷却反应体系到室温后, 将反应体系到入 200 g碎水中, 用 6 N 的氢氧化钠溶解调节反应体系的 pH = 10, 用 3x 100 mL的乙酸乙酯萃取水 相, 合并有机相, 并用 200 mL的饱和食盐水洗涤, 用无水硫酸镁干燥 1 小时, 过滤, 浓缩得到油状物。
向上述粗产品中加入 60 mL的无水乙醇, 再加入 10 mL水, 将反应混 合物加热到 80 °C, 加入 1.5 g的浓磚酸, 搅拌反应 2小时后, 降至室温, 搅 拌 18 h, 析出固体, 过滤, 即得其磷酸盐 3.25 g, 两步反应的收率 65 %。
实施例 57
在 100 mL圆底烧瓶中加入原料 (5.11 g, lO mmol), 加乙醇 50 mL溶解, 取乙醇钠 (3.4 g, 50 mmol)加入圆底烧瓶中, 室温下搅拌 7.5小时后, TCL 跟踪监测至反应完全, 浓缩蒸干圆底烧瓶中的溶剂, 加入 100 mL水, 用 3x l00mL的二氯甲烷萃取水相, 合并有机相, 并用 200 mL的饱和食盐水 洗涤, 用无水硫酸镁干燥 1小时, 过滤, 浓缩得到油状物。
向上述粗产品中加入 60 mL的无水乙醇, 再加入 10 mL水, 将反应混 合物加热到 80 °C, 加入 1.5 g的浓磚酸, 搅拌反应 2小时后, 降至室温, 搅 拌 18 h, 析出固体, 过滤, 即得其磷酸盐 3.78 g, 两步反应的收率 75 %。 实施例 58
在高压反应釜中加入原料 ( 4.97 g, 10 mmol )、 10%Pd/C (0.5 g)和 120 mL的甲醇中, 用氢气置换其中的空气三到四次, 调整氢气压力为 6 atm, 温度为 45〜50 °C, 搅拌反应 10小时, 反应完成后, 过滤回收催化剂, 减压 除去溶剂后即得粗产品;
向上述粗产品中加入 60 mL的无水乙醇, 再加入 10 mL水, 将反应混 合物加热到 80 °C, 加入 1.5 g的浓磚酸, 搅拌反应 2小时后, 降至室温, 搅 拌 18 h, 析出固体, 过滤, 即得其磷酸盐 4.7 g, 两步反应的收率 93 %。
实施例 59
在 250 mL圆底烧瓶中加入原料 (5.47 g, 10 mmol), 醋酸 50 mL和浓盐 酸 25 mL搅拌下溶解, 并逐渐加热到回流搅拌 3小时后, TCL跟踪监测至 反应完全, 冷却反应体系到室温后, 将反应体系到入 200 g碎水中, 用 6 N 的氢氧化钠溶解调节反应体系的 pH = 10, 用 3x 100 mL的乙酸乙酯萃取水 相, 合并有机相, 并用 200 mL的饱和食盐水洗涤, 用无水硫酸镁干燥 1 小时, 过滤, 浓缩得到油状物。
向上述粗产品中加入 60 mL的无水乙醇, 再加入 10 mL水, 将反应混 合物加热到 80 °C, 加入 1.5 g的浓磚酸, 搅拌反应 2小时后, 降至室温, 搅 拌 18 h, 析出固体, 过滤, 即得其磷酸盐 3.5 g, 两步反应的收率 70 %。
Claims
1、 一种绝对构型为 R的吖啶类化合物 (1), 其结构式如下所示:
R2
I
N
R1
I
其中 R1为 -CH2SR3, R3选自 d-C4的烷基; 或 R1为 -CH2OR4, R4选 自氢、 甲基、 取代的甲基、 甲氧基苯基、 乙基、 苄基、 取代的苄基或硅 醚基;
其中所述取代的甲基选自甲氧基甲基、 甲硫基甲基、 苄氧甲基、 对 甲氧苄氧甲基、 2-甲氧基乙氧基甲基、 2-三甲硅基乙氧甲基或四氢吡喃基; 所述取代的苄基选自对甲氧基苄基、 3,4-二甲氧基苄基或对硝基苄 基;
所述硅醚基选自三甲基硅基、 三乙基硅基、 三异丙基硅基、 叔丁基 二甲基硅基、 叔丁基二苯基硅基、 二苯基甲基硅基或叔丁基甲氧基苯基 硅基;
R2选自氢、 甲酸酯基、 酰基、 磺酰基或烷基;
其中所述甲酸酯基选自甲酸甲酯基、 甲酸乙酯基、 9-芴基甲氧叛基、 2-氯 -3-茚基甲氧羰基、 2,2,2-三氯乙氧羰基、 2-三甲基硅基乙氧羰基、 高 苄氧羰基、 叔丁氧羰基、 苄氧羰基或烯丙氧羰基;
所述酰基选自甲酰基、 乙酰基、 三氟乙酰基或苯甲酰基;
所述磺酰基选自苯磺酰基或三氟甲磺酰基;
所述烷基选自苄基或 4-甲氧基苄基。
2、根据权利要求 1所述的绝对构型为 R的吖啶类化合物 (1), 其特征 在于,
R1为 -CH2SR3, R3为甲基; 或 R1为 -CH2OR4, R4选自氢、 甲氧基甲 基、 苄基、 对硝基苄基、 叔丁基二甲基硅基或叔丁基二苯基硅基;
R2选自甲酸酯基、 酰基、 磺酰基和烷基; 其中所述甲酸酯基选自甲 酸甲酯基、 叔丁氧羰基、 苄氧羰基或烯丙氧羰基; 所述酰基为苯甲酰基; 所述烷基选自苄基、 4-甲氧基苄基; 所述磺酰基选自苯磺酰基、 三氟甲磺 酰基。
3、根据权利要求 1所述的绝对构型为 R的吖啶类化合物 (1), 其特征 在于, R1为 -CH2SR3, R3为甲基; 或 R1为 -CH2OR4, R4选自氢、 苄基、 叔丁基二甲基硅基; R2选自叔丁氧羰基、 苄基、 苯磺酰基。
其中, R1为 -CH2SR3, R3选自 d-C4的烷基; 或 R1为 -CH2OR4, R4 选自氢、 甲基、 取代的甲基、 甲氧基苯基、 乙基、 苄基、 取代的苄基或 硅醚基;
其中所述取代的甲基选自甲氧基甲基、 甲硫基甲基、 苄氧甲基、 对 甲氧苄氧甲基、 2-甲氧基乙氧基甲基、 2-三甲硅基乙氧甲基或四氢吡喃基; 所述取代的苄基选自对甲氧基苄基、 3,4-二甲氧基苄基或对硝基苄 基;
所述硅醚基选自三甲基硅基、 三乙基硅基、 三异丙基硅基、 叔丁基 二甲基硅基、 叔丁基二苯基硅基、 二苯基甲基硅基或叔丁基甲氧基苯基 硅基;
R2选自氢、 甲酸酯基、 酰基、 磺酰基或烷基;
其中所述甲酸酯基选自甲酸甲酯基、 甲酸乙酯基、 9-芴基甲氧叛基、 2-氯 -3-茚基甲氧羰基、 2,2,2-三氯乙氧羰基、 2-三甲基硅基乙氧羰基、 高 苄氧羰基、 叔丁氧羰基、 苄氧羰基或烯丙氧羰基;
所述酰基选自甲酰基、 乙酰基、 三氟乙酰基或苯甲酰基; 所述磺酰基选自苯磺酰基或三氟甲磺酰基;
所述烷基选自苄基或 4-甲氧基苄基;
R5选自羟基、 磺酸酯、 鹵素;
其中所述的磺酸酯选自甲磺酸酯、 对甲苯磺酸酯或三氟甲磺酸酯; 所述! ¾素选自氯、 溴或捵。
5、 根据权利要求 4所述的方法, 其特征在于, 所述 R1为 -CH2SR3, R3为甲基; 或 R1为 -CH2OR4, R4选自氢、 苄基、 叔丁基二甲基硅基; R2 选自叔丁氧羰基、 苄基、 苯磺酰基; R5选自甲磺酸酯、 对甲苯磺酸酯。
6、 根据权利要求 4或 5所述的方法, 其特征在于, 所述的碱为有机 减或无机减;
其中所述的无机碱选自氢氧化钠、 氢氧化钾、 氢化锂、 氢化钠、 氢 化钾、 氢氧化钙、 碳酸钠、 磷酸钾、 碳酸钾中的一种或多种;
所述的有机碱选自吡啶、 取代吡啶、 哌啶、 1,8-二氮杂双环 [5.4.0]十 一碳 -7-烯、 d-C4脂肪胺、 d-C4脂肪醇钠、 d-C4脂肪醇钾、 丁基 4里、 二 异丙基胺基里、 六甲基二硅烷胺基里、 六甲基二硅烷胺基钠、 六甲基二 硅烷胺基钾中的一种或多种。
7、 根据权利要求 6所述的方法, 其特征在于, 所述的碱为氢化钠、 甲醇钠或两者的混合物。
8、 一种构型为 R的手 :), 其结构式如下:
其中, R1为 -CH2SR3, R3选自 d-C4的烷基; 或 R1为 -CH2OR4, R4 选自氢、 甲基、 取代的甲基、 甲氧基苯基、 乙基、 苄基、 取代的苄基或 硅醚基;
其中所述取代的甲基选自甲氧基甲基、 甲硫基甲基、 苄氧甲基、 对 甲氧苄氧甲基、 2-甲氧基乙氧基甲基、 2-三甲硅基乙氧甲基或四氢吡喃基; 所述取代的苄基选自对甲氧基苄基、 3,4-二甲氧基苄基或对硝基苄 所述硅醚基选自三甲基硅基、 三乙基硅基、 三异丙基硅基、 叔丁基 二甲基硅基、 叔丁基二苯基硅基、 二苯基甲基硅基或叔丁基甲氧基苯基 硅基;
R2选自氢、 甲酸酯基、 酰基、 磺酰基或烷基;
其中所述甲酸酯基选自甲酸甲酯基、 甲酸乙酯基、 9-芴基甲氧叛基、 2-氯 -3-茚基甲氧羰基、 2,2,2-三氯乙氧羰基、 2-三甲基硅基乙氧羰基、 高 苄氧羰基、 叔丁氧羰基、 苄氧羰基或烯丙氧羰基;
所述酰基选自甲酰基、 乙酰基、 三氟乙酰基或苯甲酰基;
所述磺酰基选自苯磺酰基或三氟甲磺酰基;
所述烷基选自苄基或 4-甲氧基苄基。
9、一种权利要求 8所述的构型为 R的手性氨基化合物 (IV)的制备方 法, 包括步骤: 由 2,4,5-三氟苯的金属试剂 (III)与权利要求 1-3任一项所 述的绝对构型为 R型的吖啶类化合物 (I)发生开环反应后, 得到构型为 R 的手性氨
其中, 2,4,5-三氟苯的金属试剂 (III)中的 M选自锂、 铜锂、 溴化镁、 氯化镁或辞。
10、 根据权利要求 9 所述的制备方法, 其特征在于, 所述的 2,4,5- 三氟苯的金属试剂 (III)是 2,4,5-三氟苯溴化镁。
11、 一种西他列汀磷酸盐(X )的制备方法, 其特征在于, 包括以下 步骤:
( 2 ) 由手性氨基化合物 IV)制备得到西他列汀磷酸盐:
其中所述取代的甲基选自甲氧基甲基、 甲硫基甲基、 苄氧甲基、 对 甲氧苄氧甲基、 2-甲氧基乙氧基甲基、 2-三甲硅基乙氧甲基或四氢吡喃基; 所述取代的苄基选自对甲氧基苄基、 3,4-二甲氧基苄基或对硝基苄 基;
所述硅醚基选自三甲基硅基、 三乙基硅基、 三异丙基硅基、 叔丁基 二甲基硅基、 叔丁基二苯基硅基、 二苯基甲基硅基或叔丁基甲氧基苯基 硅基;
R2选自氢、 甲酸酯基、 酰基、 磺酰基或烷基;
其中所述甲酸酯基选自甲酸甲酯基、 甲酸乙酯基、 9-芴基甲氧叛基、 2-氯 -3-茚基甲氧羰基、 2,2,2-三氯乙氧羰基、 2-三甲基硅基乙氧羰基、 高 苄氧羰基、 叔丁氧羰基、 苄氧羰基或烯丙氧羰基;
所述酰基选自甲酰基、 乙酰基、 三氟乙酰基或苯甲酰基;
所述磺酰基选自苯磺酰基或三氟甲磺酰基;
所述烷基选自苄基或 4-甲氧基苄基;
M选自锂、 铜锂、 溴化镁、 氯化镁、 辞。
12、 根据权利要求 11 所述的制备方法, 其特征在于, 在步骤(1 ) 之前还包括如下步骤:
其中的 R5选自羟基、磺酸酯、 鹵素; 其中所述磺酸酯选自甲磺酸酯、 对甲苯磺酸酯、 三氟甲磺酸酯, 所述鹵素选自氯、 溴、 碘。
13、 根据权利要求 11或 12所述的制备方法, 其特征在于, 在步骤 ( 2 ) 中,
当手性氨基化合物 (IV)中的 R1为 -CH2OH时, 手性氨基化合物 (IV)就 是 β-氨基醇类化合物 ( V),该化合物先经过氧化反应得到 β-氨基酸类化合 物 (VI);
当手性氨基化合物 (IV)中的 R1为 -CH2SR3, R3选自 d-C4的烷基; 或 R1为 -CH2OR4, R4选自甲基、 取代的甲基、 甲氧基苯基、 乙基、 苄基、 取代的苄基、 硅醚基, 其中所述取代的甲基选自甲氧基甲基、 甲硫基甲 基、 苄氧甲基、 对甲氧苄氧甲基、 2-甲氧基乙氧基甲基、 2-三甲硅基乙氧 甲基、 四氢吡喃基, 所述取代的苄基选自对甲氧基苄基、 3,4-二甲氧基苄 基、 对硝基苄基, 所述硅醚基选自三甲基硅基、 三乙基硅基、 三异丙基 硅基、 叔丁基二甲基硅基、 叔丁基二苯基硅基、 二苯基甲基硅基、 叔丁 基甲氧基苯基硅基时,构型为 R的手性氨基化合物 (IV)先经过脱除硫烷基 或羟基保护基后得到构型为 R的手性 β-氨基醇类化合物 (V:), 然后 β-氨 基醇类化合物(V)经过氧化反应得到 β-氨基酸类化合物 (VI);
14、 根据权利要求 13所述的制备方法, 其特征在于, 步骤(2 ) 中, 将所得的 β-氨基酸类化合物 (VI)与三唑嗪类化合物( VI )进行缩合反 应得到胺基保护的西他列汀衍生物(環),
15、 根据权利要求 14所述的制备方法, 其特征在于, 步骤(2 ) 中, 将所得的胺基保护的西他列汀衍生物(環)经过脱除胺基保护基 R2
再将西他列汀 (IX)与磷酸反应后得到西他列汀磷酸盐;
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WO2013065066A1 (en) * | 2011-11-02 | 2013-05-10 | Cadila Healthcare Limited | Processes for preparing 4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [l,2,41-triazolo[43-a]pyrazin-7(8h)-yl]-l-(2,4,5- trifluorophenyl)butan-2-amine |
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CA2947526A1 (en) * | 2014-02-05 | 2015-08-13 | Stereokem, Inc. (Usa) | Expedient synthesis of sitagliptin |
WO2015145333A1 (en) | 2014-03-26 | 2015-10-01 | Sun Pharmaceutical Industries Limited | Process for the preparation of sitagliptin and its intermediate |
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CN107840840B (zh) * | 2016-09-18 | 2019-11-12 | 西南民族大学 | 一种黄连素重要中间体的合成 |
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CN107540575B (zh) * | 2017-10-13 | 2020-03-20 | 和鼎(南京)医药技术有限公司 | 一种西他列汀中间体的制备方法 |
CN108586346B (zh) | 2018-05-10 | 2019-10-01 | 北京富盛嘉华医药科技有限公司 | 一种生物催化合成西他列汀及其中间体的方法 |
CN113149991A (zh) * | 2020-12-31 | 2021-07-23 | 浙江美诺华药物化学有限公司 | 西他列汀游离碱及西他列汀磷酸盐一水合物的合成方法 |
CN116987012A (zh) * | 2022-04-29 | 2023-11-03 | 凯特立斯(深圳)科技有限公司 | 沙库必曲中间体、其制备方法及其应用 |
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US9187419B2 (en) | 2015-11-17 |
EP2647624B1 (en) | 2016-10-12 |
EP2647624A4 (en) | 2014-04-23 |
US20130281695A1 (en) | 2013-10-24 |
CN102485718B (zh) | 2014-03-26 |
CN102485718A (zh) | 2012-06-06 |
EP2647624A1 (en) | 2013-10-09 |
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