WO2013170778A1 - Intermediate compound for preparing ambrisentan, preparing method thereof, and preparing method of ambrisentan - Google Patents
Intermediate compound for preparing ambrisentan, preparing method thereof, and preparing method of ambrisentan Download PDFInfo
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- WO2013170778A1 WO2013170778A1 PCT/CN2013/075782 CN2013075782W WO2013170778A1 WO 2013170778 A1 WO2013170778 A1 WO 2013170778A1 CN 2013075782 W CN2013075782 W CN 2013075782W WO 2013170778 A1 WO2013170778 A1 WO 2013170778A1
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- solvent
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 178
- 238000000034 method Methods 0.000 title claims abstract description 73
- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 title claims abstract description 32
- 229960002414 ambrisentan Drugs 0.000 title claims abstract description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 237
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 226
- 238000006243 chemical reaction Methods 0.000 claims description 166
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 124
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 123
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 85
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 85
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 72
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 66
- 239000007787 solid Substances 0.000 claims description 60
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 53
- 239000000203 mixture Substances 0.000 claims description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 51
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- 239000002904 solvent Substances 0.000 claims description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 37
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 36
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 33
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 23
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 20
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 19
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000007800 oxidant agent Substances 0.000 claims description 17
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 claims description 17
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 16
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 16
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical group [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 16
- 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 16
- 239000002253 acid Substances 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- ZHPSNGCLCHWTRG-UHFFFAOYSA-N 4,6-dimethyl-2-methylsulfonylpyrimidine Chemical compound CC1=CC(C)=NC(S(C)(=O)=O)=N1 ZHPSNGCLCHWTRG-UHFFFAOYSA-N 0.000 claims description 14
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 13
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 13
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 239000003444 phase transfer catalyst Substances 0.000 claims description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 10
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical group C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 239000003930 superacid Substances 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 8
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 7
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 7
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical group [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 7
- 229960002218 sodium chlorite Drugs 0.000 claims description 7
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 7
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 claims description 6
- 239000000337 buffer salt Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- 239000007853 buffer solution Substances 0.000 claims description 5
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 5
- 230000020477 pH reduction Effects 0.000 claims description 5
- 229920000557 Nafion® Polymers 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- SPOMEWBVWWDQBC-UHFFFAOYSA-K tripotassium;dihydrogen phosphate;hydrogen phosphate Chemical group [K+].[K+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O SPOMEWBVWWDQBC-UHFFFAOYSA-K 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- CIAXFBVXQWOYPA-UHFFFAOYSA-N [C].[K] Chemical group [C].[K] CIAXFBVXQWOYPA-UHFFFAOYSA-N 0.000 claims 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims 1
- 230000001035 methylating effect Effects 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- CMPGARWFYBADJI-UHFFFAOYSA-L tungstic acid Chemical compound O[W](O)(=O)=O CMPGARWFYBADJI-UHFFFAOYSA-L 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 16
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 2
- 239000011734 sodium Substances 0.000 description 116
- 235000019439 ethyl acetate Nutrition 0.000 description 87
- 239000000706 filtrate Substances 0.000 description 83
- 238000001914 filtration Methods 0.000 description 83
- 238000004809 thin layer chromatography Methods 0.000 description 81
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 63
- 239000000243 solution Substances 0.000 description 60
- 239000005457 ice water Substances 0.000 description 50
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 25
- 238000004440 column chromatography Methods 0.000 description 25
- 238000003756 stirring Methods 0.000 description 25
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 23
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 18
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 235000010355 mannitol Nutrition 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 229930195725 Mannitol Natural products 0.000 description 14
- 239000000594 mannitol Substances 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 13
- 238000010025 steaming Methods 0.000 description 13
- 239000006188 syrup Substances 0.000 description 13
- 235000020357 syrup Nutrition 0.000 description 13
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 10
- 241000872931 Myoporum sandwicense Species 0.000 description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 10
- 229910052794 bromium Inorganic materials 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- -1 Methylpyrimidin-2-yl Chemical group 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000012230 colorless oil Substances 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000011592 zinc chloride Substances 0.000 description 6
- 235000005074 zinc chloride Nutrition 0.000 description 6
- 0 *C(OC1)(O[C@@]1C(c1ccccc1)(c1ccccc1)O)I Chemical compound *C(OC1)(O[C@@]1C(c1ccccc1)(c1ccccc1)O)I 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- UROFTPKQEUJFCY-UHFFFAOYSA-N C1CC[CH-]CC1 Chemical compound C1CC[CH-]CC1 UROFTPKQEUJFCY-UHFFFAOYSA-N 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 208000002815 pulmonary hypertension Diseases 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 238000003476 Darzens condensation reaction Methods 0.000 description 3
- 229940118365 Endothelin receptor antagonist Drugs 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000002308 endothelin receptor antagonist Substances 0.000 description 3
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 3
- 238000005562 fading Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- CEMZBWPSKYISTN-YFKPBYRVSA-N methyl (2s)-2-amino-3-methylbutanoate Chemical compound COC(=O)[C@@H](N)C(C)C CEMZBWPSKYISTN-YFKPBYRVSA-N 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- LEIVOMIUGVMEIL-PJKMHFRUSA-N 1-[(2s,4s,5r)-4-hydroxy-5-(hydroxymethyl)-2-iodooxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@]1(I)O[C@H](CO)[C@@H](O)C1 LEIVOMIUGVMEIL-PJKMHFRUSA-N 0.000 description 2
- FJJYHTVHBVXEEQ-UHFFFAOYSA-N 2,2-dimethylpropanal Chemical compound CC(C)(C)C=O FJJYHTVHBVXEEQ-UHFFFAOYSA-N 0.000 description 2
- KXVXRZKXOSZTNV-OAHLLOKOSA-N COC([C@@H](CO)O)(c1ccccc1)c1ccccc1 Chemical compound COC([C@@H](CO)O)(c1ccccc1)c1ccccc1 KXVXRZKXOSZTNV-OAHLLOKOSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 2
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
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- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
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- MGFYSGNNHQQTJW-UHFFFAOYSA-N iodonium Chemical group [IH2+] MGFYSGNNHQQTJW-UHFFFAOYSA-N 0.000 description 1
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- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
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- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
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- 239000010703 silicon Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/28—Preparation of ethers by reactions not forming ether-oxygen bonds from acetals, e.g. by dealcoholysis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
- C07C43/1782—Unsaturated ethers containing hydroxy or O-metal groups containing six-membered aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
- C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
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Abstract
Disclosed are an intermediate IV for preparing ambrisentan, a preparing method of the intermediate, and a preparing method of ambrisentan. The intermediate compound is a compound of S-configuration, and can be directly synthesized into ambrisentan without being split, which overcomes the defects in the prior art, improves the atom utilization rate of synthesis, reduces the cost, and is applicable to industrial production. Also disclosed are other intermediates VI, VII, VIII for preparing ambrisentan, and two preparing methods of ambrisentan.
Description
用于制备安立生坦的中间体化合物及其制备方法、 Intermediate compound for preparing ambrisentan and preparation method thereof,
以及安立生坦的制备 技术领域 And preparation of Anrishengtan
本发明涉及药物化学领域， 具体涉及制备安立生坦的中间体化合物， 以及这 些中间体的制备方法和制备安立生坦的方法。 背景技术 Field of the Invention This invention relates to the field of medicinal chemistry, and in particular to intermediate compounds for the preparation of ambrisentan, as well as processes for the preparation of these intermediates and processes for the preparation of ambrisentan. Background technique
肺动脉高压 (pulmonary arterial hypertension, PAH) 是在病理学上以肺动脉 血管压力异常升高和肺血管床进行性闭塞为主要特征的一类疾病， 最终导致进行 性血管阻力增加和右心衰竭。 目前， 肺动脉高压药物根据作用机制的不同， 主要 分为磷酸二酯酶 -5 (PDE-5 ) 抑制剂、 前列环素和内皮素受体拮抗剂。 其中内皮素 受体拮抗剂能完全与内皮素受体结合， 从而达到延缓疾病恶化的目的， 因此， 近 年对肺动脉高压药物的研究趋向于内皮素受体拮抗剂。 安立生坦 （ambrisentan, Letairis )是由美国 Myogen生物制药公司开发的一种选择性内皮素受体 A拮抗剂， 其化学名为 (+)-(2S)-2-[(4， 6-二甲基嘧啶 -2-基)氧] 3-甲氧基 -3，3-二苯丙酸， 分子式 为 C22H22N2O4， 相对分子量为 378.42。该药以 S-活性构型于 2007年 6月获得美国 FDA批准上市， 2011年 8月中国 肺动脉高压。其结构式如下： Pulmonary arterial hypertension (PAH) is a type of disease characterized by abnormally elevated pulmonary vascular pressure and progressive occlusion of the pulmonary vascular bed pathology, which ultimately leads to an increase in progressive vascular resistance and right heart failure. At present, pulmonary hypertension drugs are mainly classified into phosphodiesterase-5 (PDE-5) inhibitors, prostacyclin and endothelin receptor antagonists depending on the mechanism of action. Among them, endothelin receptor antagonists can completely bind to endothelin receptors, thereby delaying the progression of the disease. Therefore, in recent years, studies on pulmonary hypertension drugs have tended to be endothelin receptor antagonists. Ambrisentan (Lairairs) is a selective endothelin receptor A antagonist developed by Myogen Biopharmaceutical Company of the United States. Its chemical name is (+)-(2S)-2-[(4, 6-II) Methylpyrimidin-2-yl)oxy] 3-methoxy-3,3-diphenylpropionic acid having the formula C 22 H 22 N 2 O 4 and a relative molecular weight of 378.42. The drug was approved by the US FDA in June 2007 with the S-active configuration, and August 2008 Chinese pulmonary hypertension. Its structural formula is as follows:
(S- I ) (S-I)
安立生坦在治疗肺动脉高血压上疗效显著， 对其合成进行研究有着重大意 义。 Anrishengtan has a significant effect on the treatment of pulmonary hypertension, and its synthesis is of great significance.
美国专利 US5703017公开了一系列 3-芳香丙酸衍生物的合成方法。以二苯甲 酮为原料， 经过 Darzens缩合反应、 开环反应、 取代反应得到化合物 I。 其合成路 线如下：
该专利未报到化合物 I拆分出安立生坦 (S- I )的方法。 U.S. Patent No. 5,703,017 discloses the synthesis of a series of 3-aromatic propionic acid derivatives. Starting from benzophenone, a Darzens condensation reaction, a ring opening reaction, and a substitution reaction are carried out to obtain a compound I. The synthetic route is as follows: This patent does not report the method by which Compound I resolves Anrientan (S-I).
美国专利 US5932730公开了一种与 US5703017相似的合成方法， 以二苯甲 酮为原料，经过 Darzens反应、醇解、碱性条件水解、利用 L-脯氨酸甲酯或 (S)-l-(4- 硝基 一的对映异构体。 其方法为： U.S. Patent No. 5,932,730 discloses a synthesis method similar to that of US5703017, which uses benzophenone as a raw material, undergoes Darzens reaction, alcoholysis, alkaline hydrolysis, and utilizes L-valine methyl ester or (S)-l-( The enantiomer of 4-nitro-1. The method is:
US6559338公开了一种利用 (S) -4-氯苯乙胺为拆分剂， 其方法为： US 6,559,338 discloses the use of (S)-4-chlorophenethylamine as a resolving agent by:
专利 WO2010070658公开了一种利用 L-脯氨酸甲酯为拆分剂制备安立生坦
的方法， 其方法为: Patent WO2010070658 discloses a preparation of Anrishengtan using L-valine methyl ester as a resolving agent Method, the method is:
专利 WO2011004402公开了一种新的合成安立生坦的中间体及其制备方法。 利用手性胺为拆分剂，得到的非对映异构体（IX)在强碱性条件下与 4，6-二甲基 -2- Patent WO2011004402 discloses a novel intermediate for the synthesis of ambrisentan and a process for the preparation thereof. Using a chiral amine as a resolving agent, the obtained diastereomer (IX) is strongly basic and 4,6-dimethyl-2-
该方法路线总收率为 24%， 但拆分剂均较为昂贵。 The total route yield of the method is 24%, but the resolving agents are relatively expensive.
目前已有文献报道均采用拆分的方法来制备安立生坦 (S- I )，拆分收率不高， 原子的利用率较低， 增加了成本。 发明内容 At present, it has been reported in the literature that the separation method is used to prepare ambrisentan (S-I), the resolution of the separation is not high, the utilization rate of the atom is low, and the cost is increased. Summary of the invention
本发明的目的是提供了制备安立生坦的中间体化合物， 该中间体化合物为 S 构型的化合物， 可以不经过拆分直接合成安立生坦， 克服了现有技术上的缺陷， 提高合成的原子利用率， 降低成本， 并且适用于工业生产。
本发明利用廉价易得的 D-甘露糖醇为原料， 利用 D-甘露糖醇天然存在的手 性构型构建安立生坦的 2-S-手性中心， 不需经过拆分直接获得高光学纯度 （光学 纯度 ee值大于 99.9%) 的手性中间体， 合成安立生坦。 由于使用拆分剂的方法理 论收率最高不会超过 50%， 有一半的底物不能利用而弃去， 造成大量浪费； 而本 发明的方法是绿色化学方法， 提高合成的原子利用率和合成效率， 该方法操作简 便、 反应条件温和、 收率高， 适合于工业上大规模生产。 本发明还提供了用上述中间体制备安立生坦的方法， 该方法所用原料廉价易 得， 操作简便， 收率高， 适合工业上大规模生产。 第一方面， 本发明提供一种 IV所示的化合物， The object of the present invention is to provide an intermediate compound for preparing ambrisentan, which is a compound of the S configuration, which can directly synthesize ambrisentan without resolution, overcomes the defects of the prior art, and improves the synthesis. Atomic utilization, reduced costs, and suitable for industrial production. The invention utilizes cheap and readily available D-mannitol as a raw material, and constructs a 2-S-chiral center of ambrisentan using a chiral configuration naturally occurring in D-mannitol, and directly obtains high optics without being separated. A chiral intermediate of purity (optical purity ee value greater than 99.9%), synthesizing ambrisentan. Since the theoretical yield of the resolving agent is not more than 50%, half of the substrate can not be used and discarded, resulting in a large amount of waste; and the method of the present invention is a green chemical method to improve the atomic utilization and synthesis of the synthesis. Efficiency, the method is simple in operation, mild in reaction conditions, high in yield, and suitable for industrial mass production. The invention also provides a method for preparing ambrisentan using the above intermediate, the raw material used in the method is cheap and easy to obtain, the operation is simple, the yield is high, and the product is suitable for industrial mass production. In a first aspect, the present invention provides a compound represented by IV,
其中， ！^、 R2各自独立地选自氢原子、 CrC6垸基、 CrC6卤代垸基、 苯基或 被^- 垸氧基、 卤素、 羟基取代的苯基， 或者 和 与它们所连接的碳原子一 起形成 C3-C6环垸基。 among them, ! ^, R 2 are each independently selected from a hydrogen atom, C r C 6 fluorenyl, C r C 6 halodecyl, phenyl or phenyl substituted by ^-decyloxy, halogen, hydroxy, or The attached carbon atoms together form a C 3 -C 6 cyclodecyl group.
在一优选的实施方式中， 和 各自独立地选自氢原子、 甲基、 乙基、丙基、 叔丁基、 三氯甲基、 苯基或 4-甲氧基苯基， 或者 和 与它们所连接的碳原子 一起形成环己基或环戊基。 In a preferred embodiment, and each independently selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, a trichloromethyl group, a phenyl group or a 4-methoxyphenyl group, and The attached carbon atoms together form a cyclohexyl or cyclopentyl group.
在一优选的实施方式中， 是氢， R2三氯甲基、 叔丁基、 苯基或 4-甲氧基苯
在一优选的实施方式中， ^和 均为甲基， 均为乙基或均为11。 In a preferred embodiment, is hydrogen, R 2 trichloromethyl, tert-butyl, phenyl or 4-methoxybenzene In a preferred embodiment, ^ is both methyl, both ethyl or all 11.
在一优选的实施方式中， 所述反应溶剂是有机溶剂中一种或多种或者有机溶 剂与水的混合溶剂。 In a preferred embodiment, the reaction solvent is one or more of organic solvents or a mixed solvent of an organic solvent and water.
在一优选的实施方式中， 所述有机溶剂选自甲醇、 乙醇、 四氢呋喃、 乙腈、 In a preferred embodiment, the organic solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, acetonitrile,
N，N-二甲基甲酰胺、 丙酮、 二氧六环或其混合物。 N,N-dimethylformamide, acetone, dioxane or a mixture thereof.
在一优选的实施方式中， 所述反应是在质子酸或固体超强酸的催化下完成的， 以化合物 III的当量为 1当量计， 质子酸的用量是 0.1~2eq， 优选 0.2~1.8eq， 更优 选 0.3~0.8eq; 固体超强酸的用量是 0.1eq~2.5eq， 优选 0.3~leq; 反应温度是 0°C~100°C， 优选 20°C~80°C ; 反应时间是 lh~60h， 优选 2h~60h。 In a preferred embodiment, the reaction is carried out under the catalysis of a protic acid or a solid super acid, and the amount of the protonic acid is 0.1 to 2 eq, preferably 0.2 to 1.8 eq, based on the equivalent of the compound III. More preferably, it is 0.3~0.8 eq; the amount of solid super acid is 0.1 eq~ 2.5 eq, preferably 0.3~leq; the reaction temperature is 0 °C~100 °C, preferably 20 °C~80 °C; the reaction time is lh~ 60h, preferably 2h~60h.
在一优选的实施方式中， 所述质子酸选自浓硫酸、 浓盐酸、 冰醋酸、 三氟乙 酸、 对甲苯磺酸或其混合物， 所述固体超强酸选自磷钨酸、 磷钼酸、 Nafion 或其 混合物。 第三方面， 本发明提供一种用于制备式 IV所示的化合物的中间体化合物 III， 其结构式如下： In a preferred embodiment, the protic acid is selected from the group consisting of concentrated sulfuric acid, concentrated hydrochloric acid, glacial acetic acid, trifluoroacetic acid, p-toluenesulfonic acid or a mixture thereof, and the solid super acid is selected from the group consisting of phosphotungstic acid, phosphomolybdic acid, Nafion or a mixture thereof. In a third aspect, the present invention provides an intermediate compound III for the preparation of a compound of the formula IV, which has the structural formula:
其中， ！^、 R2各自独立地选自氢原子、 CrC6垸基、 CrC6卤代垸基、 苯基或 被^- 垸氧基、 卤素、 羟基取代的苯基， 或者 和 与它们所连接的碳原子一 起形成 C3-C6环垸基。 among them, ! ^, R 2 are each independently selected from a hydrogen atom, C r C 6 fluorenyl, C r C 6 halodecyl, phenyl or phenyl substituted by ^-decyloxy, halogen, hydroxy, or The attached carbon atoms together form a C 3 -C 6 cyclodecyl group.
在一优选的实施方式中， 和 各自独立地选自氢原子、 甲基、 乙基、丙基、 叔丁基、 三氯甲基、 苯基或 4-甲氧基苯基， 或者 和 与它们所连接的碳原子 一起形成环己基或环戊基。 In a preferred embodiment, and each independently selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, a trichloromethyl group, a phenyl group or a 4-methoxyphenyl group, and The attached carbon atoms together form a cyclohexyl or cyclopentyl group.
在一优选的实施方式中， 是氢， R2三氯甲基、 叔丁基、 苯基或 4-甲氧基苯 基。
在一优选的实施方式中， ^和 均为甲基， 均为乙基或均为11。 第四方面， 本发明提供一种制备式 III所示化合物的方法， 所述方法包括将式In a preferred embodiment, it is hydrogen, R 2 trichloromethyl, tert-butyl, phenyl or 4-methoxyphenyl. In a preferred embodiment, ^ is both methyl, both ethyl or all 11. In a fourth aspect, the present invention provides a method of preparing a compound of Formula III, the method comprising
II所示的化合物在反应溶剂的存在下进行甲基化反应得到式 III所示化合物， The compound represented by II is subjected to methylation reaction in the presence of a reaction solvent to obtain a compound of the formula III.
其中， 、 R2各自独立地选自氢原子、 CrC6垸基、 CrC6卤代垸基、 苯基或 被^- 垸氧基、 卤素、 羟基取代的苯基， 或者 和 与它们所连接的碳原子一 起形成 C3-C6环垸基。 Wherein,, R 2 is independently selected from hydrogen atoms, C r C 6 alkyl with, C r C 6 alkyl with haloalkyl, or phenyl ^ - embankment alkoxy, halo, hydroxy-substituted phenyl group, or and a The carbon atoms to which they are attached together form a C 3 -C 6 cyclodecyl group.
在一优选的实施方式中， 和 各自独立地选自氢原子、 甲基、 乙基、丙基、 叔丁基、 三氯甲基、 苯基或 4-甲氧基苯基， 或者 和 R2与它们所连接的碳原子 一起形成环己基或环戊基。 In a preferred embodiment, and each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, a trichloromethyl group, a phenyl group or a 4-methoxyphenyl group, or an R 2 Together with the carbon atom to which they are attached, a cyclohexyl or cyclopentyl group is formed.
在一优选的实施方式中， 是氢， R2三氯甲基、 叔丁基、 苯基或 4-甲氧基苯 基。 In a preferred embodiment, it is hydrogen, R 2 trichloromethyl, tert-butyl, phenyl or 4-methoxyphenyl.
在一优选的实施方式中， ！^和 R2均为甲基， 均为乙基或均为11。 In a preferred embodiment, ! Both ^ and R 2 are methyl, both ethyl or all 11.
在一优选的实施方式中， 反应溶剂为非质子溶剂， 优选选自四氢呋喃、 二氯 甲垸、 乙酸乙酯、 N，N-二甲基甲酰胺、 甲苯、 环己垸、 氯仿、 二甲苯； 所述甲基 化试剂选自碘甲垸、硫酸二甲酯或碳酸二甲酯；反应温度为 0°C~80°C，优选为 20V ~40°C ; 反应时间是 lh~32h， 优选为 4h~16h。 第五方面， 本发明提供一种制备安立生坦的方法， 其包括如下步骤： a) 将化合物 IV在缓冲盐和溶剂的存在和 TEMPO催化下， 被氧化剂选择性氧 化， 然后进行酸化生成化合物 V； In a preferred embodiment, the reaction solvent is an aprotic solvent, preferably selected from the group consisting of tetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, toluene, cyclohexane, chloroform, xylene; The methylating agent is selected from the group consisting of iodoformin, dimethyl sulfate or dimethyl carbonate; the reaction temperature is 0 ° C ~ 80 ° C, preferably 20 V ~ 40 ° C; the reaction time is lh ~ 32 h, preferably 4h~16h. In a fifth aspect, the present invention provides a process for the preparation of ambrisentan, which comprises the steps of: a) selectively oxidizing an oxidizing agent in the presence of a buffer salt and a solvent and TEMPO, and then acidifying to form a compound V. ;
b) 在碱性条件下和相转移催化剂的存在下， 化合物 V与 4，6-二甲基 -2-甲磺酰 基嘧啶在溶剂中进行取代反应； b) the compound V is subjected to a substitution reaction with 4,6-dimethyl-2-methylsulfonylpyrimidine in a solvent under basic conditions and in the presence of a phase transfer catalyst;
c) 将步骤 b) 的得到的产物进行酸化反应得到安立生坦 S- I， 其反应路线如
c) acidifying the product obtained in step b) to obtain ambrisentan S-I, the reaction route is as follows
S- I 在一优选的实施方式中， 步骤 a)中， 所述溶剂选自乙腈、 四氢呋喃、 N，N-二 甲基甲酰胺、 二氧六环， 优选乙腈、 四氢呋喃， 更优选四氢呋喃； 所述缓冲盐为 KH2PO4-K2HPO4缓冲液， 并且所述缓冲溶液 pH=4~7， 优选 pH=6; 所述氧化剂为 亚氯酸钠， 并且以化合物 IV的当量为 1 当量计， 氧化剂的用量为 l~10eq， 优选 2~6eq，更优选 3~5eq;以化合物 IV的当量为 1当量计， TEMPO的用量 0.001~0.5eq， 优选 0.01~0.3eq， 更优选 0.01~0.1eq; 步骤 a)中的酸化所使用的酸选自稀盐酸、 稀硫酸或稀磷酸； 更优选稀盐酸。 1，2二醇选择性的氧化是一个难题， 对于化合 物 IV， 按照现有的技术， 极易生成脱羧的产物， 本发明中 TEMPO-NaClO2的方法 可以以较高的收率制备出化合物 V。 S-I In a preferred embodiment, in step a), the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran, more preferably tetrahydrofuran; The buffer salt is KH 2 PO 4 -K 2 HPO 4 buffer, and the buffer solution has a pH of 4-7, preferably pH=6; the oxidizing agent is sodium chlorite, and the equivalent of the compound IV is 1 equivalent. The oxidizing agent is used in an amount of from 1 to 10 eq, preferably from 2 to 6 eq, more preferably from 3 to 5 eq. The TEMPO is used in an amount of from 0.001 to 0.5 eq, preferably from 0.01 to 0.3 eq, more preferably from 0.01 to 0.1, based on 1 equivalent of the compound IV. Eq; the acid used in the acidification in step a) is selected from the group consisting of dilute hydrochloric acid, dilute sulfuric acid or dilute phosphoric acid; more preferably dilute hydrochloric acid. The selective oxidation of 1,2 diol is a problem. For compound IV, the decarboxylated product is easily formed according to the prior art. The TEMPO-NaClO 2 method of the present invention can produce compound V in a high yield. .
在一优选的实施方式中， 步骤 b)中， 所述溶剂选自乙腈、 四氢呋喃、 N，N-二 甲基甲酰胺、 二氧六环， 优选乙腈、 四氢呋喃， 更优选四氢呋喃， 所述碱性条件 是通过加入碱来实现的， 所述碱选自碳酸钾、 碳酸钠、 氢氧化钠、 氨基钠， 更优 选氢氧化钠； 所述相转移催化剂选自四丁基氯化铵、 四丁基溴化铵、 四丁基碘化 铵、 四丁基硫酸氢铵、 苄基三甲基氯化铵或甲基三辛基氯化铵 (Aliquat 336)， 更优 选四丁基硫酸氢铵。 In a preferred embodiment, in step b), the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran, more preferably tetrahydrofuran, the basicity The condition is achieved by adding a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, sodium amide, more preferably sodium hydroxide; the phase transfer catalyst is selected from the group consisting of tetrabutylammonium chloride, tetrabutyl Ammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride or methyltrioctyl ammonium chloride (Aliquat 336), more preferably tetrabutylammonium hydrogen sulfate.
在一优选的实施方式中， 步骤 c)中， 所述酸化反应所使用的酸选自稀盐酸、 稀硫酸、 稀磷酸， 更优选稀盐酸。 第六方面， 本发明提供一种制备安立生坦的方法， 其包括如下步骤： a) 化合物 IV与酰氯 R3-C1在溶剂和碱的存在下进行反应生成化合物 VI， 其中 选自特戊酰基、 苯甲酰基或苯环的 4位上被羟基、 卤素、 CrC6垸基或 CrC6垸
氧基取代的苯甲酰基， 更优选特戊酰基或苯甲酰基； In a preferred embodiment, in the step c), the acid used in the acidification reaction is selected from the group consisting of dilute hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid, and more preferably dilute hydrochloric acid. In a sixth aspect, the present invention provides a process for the preparation of ambrisentan, which comprises the steps of: a) reacting compound IV with an acid chloride R 3 -C1 in the presence of a solvent and a base to form compound VI, wherein is selected from the group consisting of pivaloyl At the 4-position of the benzoyl or phenyl ring, hydroxy, halogen, C r C 6 fluorenyl or C r C 6垸 An oxy-substituted benzoyl group, more preferably a pivaloyl group or a benzoyl group;
b) 在碱性条件和相转移催化剂的存在下， 化合物 VI与 4，6-二甲基 -2-甲磺酰基 嘧啶取代反应生成化合物 νπ; b) in the presence of basic conditions and a phase transfer catalyst, the compound VI is substituted with 4,6-dimethyl-2-methylsulfonylpyrimidine to form the compound νπ;
c) 在碱性条件和溶剂的存在下， 将化合物 ΥΠ脱去酰基生成化合物珊； d) 在溶剂的存在下， 用氧化剂将化合物 W【氧化得到化合物 S- I， c) removing the acyl group to form the compound in the presence of a basic condition and a solvent; d) oxidizing the compound W with an oxidizing agent to obtain a compound S-I in the presence of a solvent,
在一优选的实施方式中， 步骤 b)中， 所述溶剂选自乙腈、 四氢呋喃、 N，N-二 甲基甲酰胺、 二氧六环， 优选乙腈、 四氢呋喃或其混合物， 更优选四氢呋喃； 所 述碱性条件是通过加入碱来实现的， 所述碱选自碳酸钾、 碳酸钠、 氢氧化钠、 氨 基钠， 更优选氢氧化钠； 所述相转移催化剂优选四丁基氯化铵、 四丁基溴化铵、 四丁基碘化铵、 四丁基硫酸氢铵、 苄基三甲基氯化铵或甲基三辛基氯化铵 (Aliquat 336), 更优选四丁基硫酸氢铵。 In a preferred embodiment, in step b), the solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran or a mixture thereof, more preferably tetrahydrofuran; The basic condition is achieved by adding a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, sodium amide, more preferably sodium hydroxide; the phase transfer catalyst is preferably tetrabutylammonium chloride, four Butyl ammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride or methyltrioctyl ammonium chloride (Aliquat 336), more preferably tetrabutylammonium hydrogen sulfate .
在一优选的实施方式中， 步骤 c)中， 所述的溶剂选自二氯甲垸、 乙酸乙酯、 甲醇、 乙醇或其混合物， 更优选甲醇、 甲醇与二氯甲垸； 所述碱性条件是通过加
入碱来实现的， 所述碱选自氢氧化钠、 碳酸钾、 碳酸钠、 甲醇钠或乙醇钠， 更优 选甲醇钠。 In a preferred embodiment, in the step c), the solvent is selected from the group consisting of dichloromethane, ethyl acetate, methanol, ethanol or a mixture thereof, more preferably methanol, methanol and dichloromethane; the basicity Condition is by adding The base is selected from the group consisting of sodium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide or sodium ethoxide, more preferably sodium methoxide.
在一优选的实施方式中， 步骤 d)中， 所述的溶剂选自二氯甲垸、 氯仿或其混 合物， 所述的氧化剂选自戴斯-马丁氧化剂或 Pt。 第七方面， 本发明提供一种用于制备 S- I的中间体化合物 VI或 νπ或珊， 其结 构式分别如下： In a preferred embodiment, in step d), the solvent is selected from the group consisting of chloroform, chloroform or a mixture thereof, and the oxidizing agent is selected from the group consisting of a Dess-Martin oxidizing agent or Pt. In a seventh aspect, the present invention provides an intermediate compound VI or νπ or sapon for the preparation of S-I, the structural formulas of which are as follows:
π 珊 π 珊
其中 优选特戊酰基、 苯甲酰基或苯环的 4位上被羟基、 卤素、 CrC6垸基 或^- 垸氧基取代的苯甲酰基， 更优选特戊酰基、 苯甲酰基。 发明详述 Wherein the 4-position is preferably a pivaloyl group, a benzoyl group, or a benzene ring substituted by hydroxy, halo, C r C 6 alkyl with or ^ - embankment substituted benzoyl group, more preferably a pivaloyl group, a benzoyl group. Detailed description of the invention
在本说明书中使用以下术语。 这些术语如下定义： The following terms are used in this specification. These terms are defined as follows:
本文所用的术语"烷基"除非另有说明， 包括具有直链、 支链的饱和单 价烃基。 优选 CrC6烷基， 例如甲基、 乙基、 丙基、 叔丁基。 The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having a straight chain, branched chain. Preferably C r C 6 alkyl, such as methyl, ethyl, propyl, t-butyl.
"环烷基"表示环状的饱和单价烃基，优选 c3-c2Q环烷基，更优选 c3-c6 环烷基， 例如环丙基、 环丁基、 环己基、 环戊基。 "Cycloalkyl" means a cyclic saturated monovalent hydrocarbon group, preferably a c 3 -c 2Q cycloalkyl group, more preferably a c 3 -c 6 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclohexyl group or a cyclopentyl group.
"卤代烷基"表示被卤素原子取代的如上述所定义的烷基， 优选 crc6 卤代烷基， 例如三氟甲基、 三氯甲基等。 The "haloalkyl group" means an alkyl group as defined above which is substituted by a halogen atom, preferably a c r c 6 haloalkyl group such as a trifluoromethyl group, a trichloromethyl group or the like.
本文使用的术语 "芳基"除非另作说明， 包括通过除去芳烃中的一个氢 得到的有机基团， 如苯基或萘基。 The term "aryl" as used herein, unless otherwise specified, includes an organic group, such as phenyl or naphthyl, obtained by removal of one hydrogen from an aromatic hydrocarbon.
除非另作说明， 本文所述的"烷基"、 "环烷基"、 "芳基"、各自任选独立 地被 1-3个取代基取代， 所述取代基选自： 氰基、 ¾素、 羟基、 硝基或 d-C6 院基或。广。6院氧基。
术语 "R"和 " S"指所画的化学结构中不对称碳原子上取代基的特定立 体化学构型。 术语 "Me"表示甲基。 具体实施方式 Unless otherwise specified, "alkyl", "cycloalkyl", "aryl", as used herein, are each optionally independently substituted with from 1 to 3 substituents selected from the group consisting of: cyano, 3⁄4 Or a hydroxy, nitro or dC 6 hospital base or. wide. 6 hospital oxygen. The terms "R" and "S" refer to a specific stereochemical configuration of a substituent on an asymmetric carbon atom in the chemical structure depicted. The term "Me" means a methyl group. detailed description
本发明提供了制备安立生坦及 体化合物 IV， 其结构式如下: The present invention provides the preparation of ambrisentan and a compound IV having the following structural formula:
采用该中间体制备安立生坦， 不经过拆分， 原子经济性高。 本发明进一步提供了如式 IV所示的化合物的制备方法， 该方法包括由式 III所 示的化合物在反应溶 保护基得到式 IV所示的化合物， The intermediate is used to prepare ambrisentan, which has high atomic economy without being separated. The present invention further provides a process for the preparation of a compound of the formula IV, which comprises obtaining a compound of the formula IV from a compound of the formula III in a reaction-soluble protecting group,
其中， ！^、 R2各自独立地选自氢原子、 CrC6垸基、 CrC6卤代垸基、 苯基或 被^- 垸氧基、 卤素、 羟基取代的苯基， 或者 和 与它们所连接的碳原子一 起形成 C3-C6环垸基， 更优选地， 和 各自独立地选自氢原子、 甲基、 乙基、 丙基、 叔丁基、 三氯甲基、 苯基或 4-甲氧基苯基， 或者 和 与它们所连接的 碳原子一起形成环己基或环戊基；进一步优选地， 是氢， R2三氯甲基、叔丁基、 苯基或 4-甲氧基苯基， 最优选地， R n 均为甲基， 均为乙基或均为11。 among them, ! ^, R 2 are each independently selected from a hydrogen atom, C r C 6 fluorenyl, C r C 6 halodecyl, phenyl or phenyl substituted by ^-decyloxy, halogen, hydroxy, or The attached carbon atoms together form a C 3 -C 6 cyclodecyl group, more preferably, and each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, a trichloromethyl group, a phenyl group or 4-methoxyphenyl, or together with the carbon atom to which they are attached, form a cyclohexyl or cyclopentyl group; further preferably, hydrogen, R 2 trichloromethyl, tert-butyl, phenyl or 4-methyl Most preferably, R n is a methyl group, both ethyl or all 11.
上面所述的反应溶剂是有机溶剂中一种或多种或者有机溶剂与水的混合溶 剂， 所述的有机溶剂选自甲醇、 乙醇、 四氢呋喃、 乙腈、 N，N-二甲基甲酰胺、 丙 酮、 二氧六环。
上面所述的反应是在质子酸或固体超强酸的催化下完成的， 质子酸选自浓硫 酸、 浓盐酸、 冰醋酸、 三氟乙酸、 对甲苯磺酸， 优选为浓硫酸、 冰醋酸、 对甲苯 磺酸； 固体超强酸选自磷钨酸、 磷钼酸、 Nafion等。 以化合物 III的当量为 1 当量 计， 质子酸的用量是 0.1~2eq， 优选 0.2~1.8eq， 更优选 0.3~0.8eq; 以化合物 III的 当量为 1 当量计， 固体超强酸的用量是 0.1eq~2.5eq， 优选 0.3~leq。 反应温度是 0 °C ~ 100 °C， 优选 20 °C ~80 °C。 反应时间是 1 h~60h， 优选 2h~60h。 The reaction solvent described above is one or more of an organic solvent or a mixed solvent of an organic solvent and water, and the organic solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, acetone. , dioxane. The reaction described above is carried out under the catalysis of a protic acid or a solid super acid selected from the group consisting of concentrated sulfuric acid, concentrated hydrochloric acid, glacial acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, preferably concentrated sulfuric acid, glacial acetic acid, and Toluenesulfonic acid; the solid super acid is selected from the group consisting of phosphotungstic acid, phosphomolybdic acid, Nafion and the like. The amount of the protonic acid is 0.1 to 2 eq, preferably 0.2 to 1.8 eq, more preferably 0.3 to 0.8 eq, based on the equivalent of the compound III. The amount of the solid super acid is 0.1 eq based on the equivalent of the compound III. ~2.5 eq, preferably 0.3~leq. The reaction temperature is from 0 ° C to 100 ° C, preferably from 20 ° C to 80 ° C. The reaction time is from 1 h to 60 h, preferably from 2 h to 60 h.
本发明进一步提供了一种用于制备如式 IV所示的化合物的中间体化合物 III， 其结构式如下： The present invention further provides an intermediate compound III for the preparation of a compound of the formula IV, which has the formula:
其中， ！^、 R2各自独立地选自氢原子、 CrC6垸基、 CrC6卤代垸基、 苯基或 被^- 垸氧基、 卤素、 羟基取代的苯基， 或者 和 与它们所连接的碳原子一 起形成 c3-c6环垸基， 更优选地， 和 各自独立地选自氢原子、 甲基、 乙基、 丙基、 叔丁基、 三氯甲基、 苯基或 4-甲氧基苯基， 或者 和 R2与它们所连接的 碳原子一起形成环己基或环戊基；进一步优选地， 是氢， 三氯甲基、叔丁基、 苯基或 4-甲氧基苯基， 最优选地， ！^和 R2均为甲基， 均为乙基或均为11。 本发明还提供了式 III所示化合物的制备方法， 所述方法包括将式 II所示的化 合物在反应溶剂的存在下进行甲基化反应得到式 III所示化合物， among them, ! ^, R 2 are each independently selected from a hydrogen atom, C r C 6 fluorenyl, C r C 6 halodecyl, phenyl or phenyl substituted by ^-decyloxy, halogen, hydroxy, or The attached carbon atoms together form a c 3 -c 6 cyclodecyl group, more preferably, and each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, a trichloromethyl group, a phenyl group or 4-methoxyphenyl, or together with R 2 and the carbon atom to which they are attached, form a cyclohexyl or cyclopentyl group; further preferably, hydrogen, trichloromethyl, tert-butyl, phenyl or 4-methyl Oxyphenyl groups, most preferably, ! Both ^ and R 2 are methyl, both ethyl or all 11. The present invention also provides a process for the preparation of the compound of the formula III, which comprises subjecting a compound of the formula II to methylation in the presence of a reaction solvent to obtain a compound of the formula III.
其中， 、 R2各自独立地选自氢原子、 CrC6垸基、 CrC6卤代垸基、 苯基或 被^- 垸氧基、 卤素、 羟基取代的苯基， 或者 和 与它们所连接的碳原子一
起形成 C3-C6环垸基， 更优选地， 和 各自独立地选自氢原子、 甲基、 乙基、 丙基、 叔丁基、 三氯甲基、 苯基或 4-甲氧基苯基， 或者 和 R2与它们所连接的 碳原子一起形成环己基或环戊基；进一步优选地， 是氢， R2三氯甲基、叔丁基、 苯基或 4-甲氧基苯基， 最优选地， R n 均为甲基， 均为乙基或均为11。 Wherein,, R 2 is independently selected from hydrogen atoms, C r C 6 alkyl with, C r C 6 alkyl with haloalkyl, or phenyl ^ - embankment alkoxy, halo, hydroxy-substituted phenyl group, or and a The carbon atom to which they are attached Forming a C 3 -C 6 cyclodecyl group, more preferably, and each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, a trichloromethyl group, a phenyl group or a 4-methoxy group Phenyl, or R 2 together with the carbon atom to which they are attached form a cyclohexyl or cyclopentyl group; further preferably, hydrogen, R 2 trichloromethyl, tert-butyl, phenyl or 4-methoxybenzene Most preferably, R n is methyl, both ethyl or all 11.
其中式 II所示的化合物可按现有技术文献公开的方法制得。 The compound of the formula II can be obtained by a method disclosed in the prior art.
上述反应溶剂为非质子溶剂， 优选四氢呋喃、 二氯甲垸、 乙酸乙酯、 N，N-二 甲基甲酰胺、 甲苯、 环己垸、 氯仿、 二甲苯， 更优选四氢呋喃、 二氯甲垸、 甲苯； 甲基化试剂优选为碘甲垸、硫酸二甲酯、碳酸二甲酯；反应温度优选为 20°C~80°C， 更优选 20 V -40 V 反应时间是 1 h~32h， 优选 4h~ 16h。 本发明还提供了两种安立生坦的制备方法： The above reaction solvent is an aprotic solvent, preferably tetrahydrofuran, dichloromethane, ethyl acetate, N,N-dimethylformamide, toluene, cyclohexane, chloroform, xylene, more preferably tetrahydrofuran, dichloromethane, Toluene; methylating agent is preferably iodonium, dimethyl sulfate, dimethyl carbonate; the reaction temperature is preferably 20 ° C ~ 80 ° C, more preferably 20 V - 40 V reaction time is 1 h ~ 32 h, preferably 4h~ 16h. The invention also provides two preparation methods of ambrisentan:
方法一共经过三步反应。 步骤一： 将化合物 IV在缓冲盐和溶剂的存在和 TEMPO 催化下， 被氧化剂选择性氧化， 然后进行酸化生成化合物 V；步骤二： 在 碱性条件下和相转移催化剂的存在下， 化合物 V与 4，6-二甲基 -2-甲磺酰基嘧啶在 溶剂中进行取代反应；步骤三： 将步骤二得到的产物进行酸化反应得到安立生坦 S- I， 其反应路线如下： The method involves a total of three steps. Step 1: Compound IV is selectively oxidized by an oxidizing agent in the presence of a buffer salt and a solvent and TEMPO catalyzed, and then acidified to form Compound V; Step 2: Under basic conditions and in the presence of a phase transfer catalyst, Compound V and 4,6-Dimethyl-2-methanesulfonylpyrimidine is subjected to a substitution reaction in a solvent; Step 3: The product obtained in the second step is subjected to an acidification reaction to obtain Anritan S-I, and the reaction route is as follows:
S- I 上述步骤一， 反应所用的溶剂是本领域技术人员已知的溶剂， 包括乙腈、 四 氢呋喃、 N，N-二甲基甲酰胺、 二氧六环， 优选乙腈、 四氢呋喃， 更优选四氢呋喃。 本反应所用的缓冲盐为缓冲溶液，优选 KH2PO4-K2HPO4缓冲液，缓冲溶液 pH=4~7， 优选 pH=6。 步骤一所用的氧化剂为亚氯酸钠， 用量为化合物 IV的 l~10eq， 优选 2~6eq， 更优选 3~5eq。 步骤一所用的催化剂为 TEMPO, 以化合物 IV的当量为 1
当量计， TEMPO的用量为 0.001~0.5eq， 优选 0.01~0.3eq， 更优选 0.01~0.1eq。 步 骤一所用的酸优选稀盐酸、 稀硫酸、 稀磷酸， 更优选稀盐酸。 S-I In the above step 1, the solvent used in the reaction is a solvent known to those skilled in the art, and includes acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran, more preferably tetrahydrofuran. The buffer salt used in the reaction is a buffer solution, preferably a KH 2 PO 4 -K 2 HPO 4 buffer, and the buffer solution has a pH of 4 to 7, preferably pH = 6. The oxidizing agent used in the first step is sodium chlorite in an amount of from 1 to 10 eq, preferably from 2 to 6 eq, more preferably from 3 to 5 eq, of the compound IV. The catalyst used in the first step is TEMPO, and the equivalent of the compound IV is 1. The amount of TEMPO used is 0.001 to 0.5 eq, preferably 0.01 to 0.3 eq, more preferably 0.01 to 0.1 eq. The acid used in the first step is preferably dilute hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid, more preferably dilute hydrochloric acid.
上述步骤二， 所用的溶剂是本领域技术人员已知的溶剂， 包括乙腈、 四氢呋 喃、 N，N-二甲基甲酰胺、 二氧六环， 优选乙腈、 四氢呋喃， 更优选四氢呋喃。 步 骤二所用的碱选自碳酸钾、 碳酸钠、 氢氧化钠、 氨基钠， 更优选氢氧化钠。 步骤 二所用的相转移催化剂选自四丁基氯化铵、 四丁基溴化铵、 四丁基碘化铵、 四丁 基硫酸氢铵、 苄基三甲基氯化铵或甲基三辛基氯化铵 （Aliquat 336), 更优选四丁 基硫酸氢铵。 In the above step two, the solvent used is a solvent known to those skilled in the art, and includes acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran, and more preferably tetrahydrofuran. The base used in the second step is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, sodium amide, and more preferably sodium hydroxide. The phase transfer catalyst used in the second step is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride or methyltrisin. Ammonium chloride (Aliquat 336), more preferably tetrabutylammonium hydrogen sulfate.
上述步骤三， 所用的酸优选稀盐酸、 稀硫酸、 稀磷酸， 更优选稀盐酸。 方法二有四步反应。 In the above step three, the acid used is preferably dilute hydrochloric acid, dilute sulfuric acid, dilute phosphoric acid, more preferably dilute hydrochloric acid. Method 2 has a four-step reaction.
步骤一：化合物 IV与酰氯 R3-C1在溶剂的存在下于碱性条件下进行反应生成化 合物 VI， 其中 选自特戊酰基、 苯甲酰基或苯环的 4位上被羟基、 卤素、 CrC6 垸基或 CrC6垸氧基取代的苯甲酰基， 更优选特戊酰基或苯甲酰基； Step 1: Compound IV is reacted with an acid chloride R 3 -C1 in the presence of a solvent under basic conditions to form compound VI, which is selected from the 4-position of pivaloyl, benzoyl or benzene ring by hydroxyl group, halogen, C r C 6 fluorenyl or C r C 6 methoxy-substituted benzoyl group, more preferably pivaloyl or benzoyl;
步骤二: 在碱性条件和相转移催化剂的存在下， 化合物 VI与 4，6-二甲基 -2-甲 磺酰基嘧啶取代反应生成化合物 νπ ; Step 2: Compound VI is substituted with 4,6-dimethyl-2-methylsulfonylpyrimidine in the presence of basic conditions and a phase transfer catalyst to form compound νπ;
步骤三： 在碱性条件和溶剂的存在下， 将化合物 νπ脱去酰基生成化合物珊； 步骤四： 在溶剂的存在下， 用氧化剂将化合物 W【氧化得到化合物 S- I， 反应路线如下：
Step 3: Deprotecting the compound νπ to form a compound in the presence of a basic condition and a solvent; Step 4: Compound W is oxidized with an oxidizing agent to obtain a compound S-I in the presence of a solvent, and the reaction route is as follows:
上述步骤一中， 所用的溶剂优选二氯甲垸、 乙酸乙酯、 四氢呋喃、 N，N-二甲 基甲酰胺、 氯仿、 四氢呋喃、 乙腈， 更优选二氯甲垸、 四氢呋喃。 步骤一的碱性 条件是通过加入碱来实现的， 所述碱优选吡啶、 三乙胺、 碳酸钾、 碳酸钠， 更优 选吡啶、三乙胺。其中 优选特戊酰基、 苯甲酰基或苯环的 4位上被羟基、 卤素、 CrC6垸基或 CrC6垸氧基取代的苯甲酰基， 更优选特戊酰基或苯甲酰基。 In the above step 1, the solvent to be used is preferably dichloromethane, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, chloroform, tetrahydrofuran or acetonitrile, more preferably dichloromethane, tetrahydrofuran. The basic condition of the first step is achieved by adding a base, preferably pyridine, triethylamine, potassium carbonate or sodium carbonate, more preferably pyridine or triethylamine. Wherein the 4-position is preferably a pivaloyl group, a benzoyl group, or a benzene ring substituted by hydroxy, halo, C r C 6 alkyl with C r C 6 embankment or substituted benzoyl group, more preferably a pivaloyl group or benzoyl .
上述步骤二中， 反应所用的溶剂是本领域技术人员已知的溶剂， 包括乙腈、 四氢呋喃、 N，N-二甲基甲酰胺、 二氧六环， 优选乙腈、 四氢呋喃， 更优选四氢呋 喃。 步骤二的碱性条件是通过加入碱来实现的， 所述碱选自碳酸钾、 碳酸钠、 氢 氧化钠、 氨基钠， 更优选氢氧化钠。 步骤二所用的相转移催化剂选自四丁基氯化 铵、 四丁基溴化铵、 四丁基碘化铵、 四丁基硫酸氢铵、 苄基三甲基氯化铵、 甲基 三辛基氯化铵 （Aliquat 336)等， 更优选四丁基硫酸氢铵 In the above step two, the solvent used in the reaction is a solvent known to those skilled in the art, and includes acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, preferably acetonitrile, tetrahydrofuran, and more preferably tetrahydrofuran. The basic condition of step two is achieved by the addition of a base selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, sodium amide, more preferably sodium hydroxide. The phase transfer catalyst used in the second step is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, methyltrisin. Ammonium chloride (Aliquat 336), etc., more preferably tetrabutylammonium hydrogen sulfate
上述步骤三中， 所用溶剂选自二氯甲垸、 乙酸乙酯、 甲醇、 乙醇中一种或几 种， 更优选甲醇、 甲醇与二氯甲垸。 步骤三的碱性条件是通过加入碱来实现的， 所述碱选自氢氧化钠、 碳酸钾、 碳酸钠、 甲醇钠或乙醇钠， 更优选甲醇钠。 In the above step three, the solvent to be used is one or more selected from the group consisting of dichloromethane, ethyl acetate, methanol, and ethanol, and more preferably methanol, methanol, and dichloromethane. The basic condition of step three is achieved by the addition of a base selected from the group consisting of sodium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide or sodium ethoxide, more preferably sodium methoxide.
上述步骤四中， 所用溶剂选自二氯甲垸、 乙酸乙酯、 甲醇、 乙醇中一种或几 种， 更优选二氯甲垸、 氯仿。 所用的氧化剂选自戴斯-马丁氧化剂或 Pt。
本发明进一步提供了一种用于制备 S- 1的中间体化合物 VI、 vn、 w【， 其结构 式分别如下： In the above step four, the solvent used is one or more selected from the group consisting of dichloromethane, ethyl acetate, methanol, and ethanol, and more preferably dichloromethane, chloroform. The oxidizing agent used is selected from the group consisting of Dess-Martin Oxidizer or Pt. The present invention further provides an intermediate compound VI, vn, w for preparing S-1, and the structural formulas thereof are as follows:
π 珊 π 珊
其中其中 优选特戊酰基、 苯甲酰基或苯环的 4位上被羟基、 卤素、 CrC6 垸基或 CrC6垸氧基取代的苯甲酰基， 更优选特戊酰基、 苯甲酰基。 下面结合具体实施例， 进一步阐述本发明。 应理解， 这些实施例仅用于说明 本发明而不用于限制本发明的范围。 下列实施例中未注明具体条件的实验方法， 通常按照常规条件。 除非另外说明， 否则份数和百分比为重量百分比。 Wherein the 4-position wherein preferably a pivaloyl group, a benzoyl group, or a benzene ring substituted by hydroxy, halo, C r C 6 alkyl with C r C 6 embankment or substituted benzoyl group, and more preferably pivaloyl, benzoyl Acyl group. The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in which the specific conditions are not indicated in the following examples are usually in accordance with conventional conditions. Parts and percentages are by weight unless otherwise stated.
实施例中所用的原料或试剂除特别说明之外， 均市售可得。 The starting materials or reagents used in the examples are commercially available unless otherwise specified.
实施例中所述的室温均指 20〜35 。 除非特别指出， 所述的试剂不经纯化直 接使用。所有溶剂均购自商业化供应商， 例如奧德里奇 (Aldrich), 并且不经处理就 可使用。 反应通过 TLC分析和 /或通过 LC-MS分析， 通过起始材料的消耗来判断 反应的终止。 分析用的薄层层析 (TLC)是在预涂覆硅胶 60 F254 0.25毫米板的玻璃 板 (EMD化学品公司 (EMD Chemicals))上进行的， 用 UV光 (254nm)和 /或硅胶上的 碘显象， 和 /或与 TLC染色物如醇制磷钼酸、 水合茚三酮溶液、 高锰酸钾溶液或硫 酸高铈溶液一起加热。 The room temperature described in the examples means 20 to 35. Unless otherwise indicated, the reagents described are used directly without purification. All solvents were purchased from commercial suppliers, such as Aldrich, and were used without treatment. The reaction is judged by TLC analysis and/or by LC-MS, and the termination of the reaction is judged by the consumption of the starting material. Thin layer chromatography (TLC) for analysis was performed on precoated silica gel 60 F254 0.25 mm plate glass plates (EMD Chemicals) using UV light (254 nm) and/or silica gel. Iodine imaging, and/or heating with TLC dyes such as alcoholic phosphomolybdic acid, ninhydrin solution, potassium permanganate solution or sorghum sulfate solution.
1H-NM 谱是在万瑞安-默丘利 -VX400 (Varian Mercury- VX400)仪上， 在 400MHz操作下记录的。 NMR谱从 CDC13溶液 (单位 ppm)中得到， 用氯仿作为参 比的标准物 (对质子为 7.27ppm)， 或内标的四甲基甲硅垸 (0.00ppm)。 其它的 NMR 溶剂可按需使用。 若报道峰多重性时， 使用下列缩写： s (单峰)、 d (双峰)、 t (三重 峰)、 m (多重峰)、 br (加宽的峰)、 bs (宽单峰)、 dd (成对的双峰)、 dt (成对的三重峰)。 偶合常数记录为赫兹 (Hz)。 The 1H-NM spectrum was recorded on a Varian Mercury-VX400 instrument at 400 MHz operation. NMR spectra obtained from CDC1 3 solution (in ppm) with chloroform as the reference standard (7.27 ppm for the proton), or a silicon internal standard tetramethylsilane embankment (0.00ppm). Other NMR solvents can be used as needed. When peak multiplicity is reported, the following abbreviations are used: s (single peak), d (double peak), t (triplet), m (multiple peak), br (widened peak), bs (wide single peak), Dd (paired doublet), dt (paired triplet). The coupling constant is recorded in Hertz (Hz).
化合物的 ee值是通过 aglinentl lOO高效液相色谱仪， 大赛璐 AD-H手性色谱
柱进行测定， 流动相条件 MeOH:H2O=95:5，波长 230nm， 流速 lmL/min。 The ee value of the compound is determined by aglinentl lOO high performance liquid chromatography, Daisy 璐AD-H chiral chromatography The column was measured, and the mobile phase conditions were MeOH:H 2 O = 95:5, wavelength 230 nm, flow rate 1 mL/min.
所述的合成途径和实验过程中使用了许多常见的化学缩写： PE表示石 油醚， EA表示乙酸乙酯， DCM表示二氯甲垸， MeOH表示甲醇。 式 Π所示的化合物可按现有技术文献公开的方法制得， 本发明参考路线如 Many common chemical abbreviations are used in the synthetic routes and experiments: PE for petroleum ether, EA for ethyl acetate, DCM for dichloromethane, and MeOH for methanol. The compound of the formula 可 can be obtained by the method disclosed in the prior art document, and the reference route of the present invention is as
上述制备式 II的路线以及制备方法可参考的文献： （1) J.CHEM.SOC, PERKIN The above-mentioned routes for preparing Formula II and the preparation methods can be referred to: (1) J.CHEM.SOC, PERKIN
TRANS 1 : Organic and Bio-Organic Chemistry 1986， 765. (2) Synth. 1988， 10， 790. (3) Tetrahedron: Asym. 2000, 11， 4885. TRANS 1 : Organic and Bio-Organic Chemistry 1986, 765. (2) Synth. 1988, 10, 790. (3) Tetrahedron: Asym. 2000, 11, 4885.
式中， 、 R2各自独立地选自氢原子、 CrC6垸基、 CrC6卤代垸基、 苯基或 被^- 垸氧基、 卤素、 羟基取代的苯基， 或者 和 与它们所连接的碳原子一 起形成 C3-C6环垸基， 更优选地， 和 各自独立地选自氢原子、 甲基、 乙基、 丙基、 叔丁基、 三氯甲基、 苯基或 4-甲氧基苯基， 或者 和 R2与它们所连接的 碳原子一起形成环己基或环戊基；进一步优选地， 是氢， R2三氯甲基、叔丁基、 苯基或 4-甲氧基苯基， 最优选地， ！^和 R2均为甲基， 均为乙基或均为11。 本发明实施例 la~3a 提供了当 RfR^Me 时， 式 II所示的化合物（当 RfR^Me时， 式 II所示的化合物也成为式 Π -a所示的化合物)的制备方法。 其中 实施例 la-3a的反应路线如下所示： Wherein,, R 2 is independently selected from hydrogen atoms, C r C 6 alkyl with, C r C 6 alkyl with haloalkyl, or phenyl ^ - embankment alkoxy, halo, hydroxy-substituted phenyl, or and Together with the carbon atom to which they are attached, a C 3 -C 6 cyclodecyl group is formed, more preferably, and each independently selected from a hydrogen atom, a methyl group, an ethyl group, a propyl group, a t-butyl group, a trichloromethyl group, a benzene group Or a 4-methoxyphenyl group, or together with R 2 and the carbon atom to which they are attached, form a cyclohexyl or cyclopentyl group; further preferably, hydrogen, R 2 trichloromethyl, tert-butyl, phenyl Or 4-methoxyphenyl, most preferably, ! Both ^ and R 2 are methyl, both ethyl or all 11. In the examples la~3a of the present invention, a method of preparing a compound of the formula II (when RfR^Me, the compound of the formula II is also a compound represented by the formula Π-a) is provided when RfR^Me. The reaction route of the example la-3a is as follows:
甘露糖醇 X-a XI- a II-a 实施例 la Mannitol Xa XI- a II-a Example la
称取甘露糖醇 80g (0.44mol) 和氯化锌 480g (3.5mol) , 溶于 1000ml丙酮
20°C下搅拌反应 14h。 TLC (PE: EA=1 :2) 监测， 反应完毕。 称取 500g碳酸钾溶 解在 1000ml水中， 将碳酸钾的水溶液和 1.5L二氯甲垸加入到体系中搅拌 30min， 过滤、 滤渣用 lOOmL二氯甲垸洗涤， 水相用 500ml二氯甲垸萃取， 合并有机相， 有机相用饱和食盐水 300mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到淡黄色固体（化合物 X-a) 125 加入 150ml异丙醚和 100ml石油醚， 80°C 加热， 冷却至室温， 得白色固体 49g。 收率 43%。 其结构鉴定数据如下： Weigh 80g (0.44mol) of mannitol and 480g (3.5mol) of zinc chloride, dissolved in 1000ml of acetone The reaction was stirred at 20 ° C for 14 h. TLC (PE: EA = 1:2) was monitored and the reaction was completed. Weigh 500g of potassium carbonate dissolved in 1000ml of water, add potassium carbonate aqueous solution and 1.5L of dichloromethane to the system and stir for 30min, filter, filter residue washed with 100mL of dichloromethane, and the aqueous phase is extracted with 500ml of dichloromethane. The organic phases were combined organic phase was washed once with 300mL saturated brine, dried over anhydrous Na 2 SO 4. Filtration, the filtrate was evaporated to dryness to give a pale-yellow solid (Compound Xa). </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; The yield was 43%. Its structural identification data is as follows:
MS: [M+H]+: 263.18[M+Na]+: 303 实施例 2a MS: [M+H] + : 263.18 [M+Na] + : 303 Example 2a
称取 （化合物 X-a) 48.3g (0.18mol)， 溶于 480mL二氯甲垸。 依次加入水 (Compound X-a) 48.3 g (0.18 mol) was weighed and dissolved in 480 mL of dichloromethane. Add water in turn
33ml和 NaIO4 49.5g (0.23mol) , 于 20°C搅拌反应 5h。 TLC (PE: EA=1 :1 )监测， 反应完毕。 过滤、 40°C旋蒸后， 加入 （甲醇： 水 =9:1 ) 混合液 500ml和碳酸氢钠 70g (0. 83mol)，冰水浴下滴加溴素 18.8ml (0.36mol)，于 20°C搅拌反应过夜， TLC (PE: EA=4:1 )检测， 磷钼酸显色， 冰水浴下加饱和硫代硫酸钠 15ml， 体系完全 褪色， 加入二氯甲垸 700ml， 水 300ml分液， 有机相用饱和食盐水 300mL洗涤一 次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色液体（化合物 XI-a) 44.3g。 33 ml and NaIO 4 49.5 g (0.23 mol) were stirred at 20 ° C for 5 h. TLC (PE: EA=1:1) was monitored and the reaction was completed. After filtration and steaming at 40 ° C, 500 ml of a mixture of (methanol: water = 9:1) and 70 g of sodium hydrogencarbonate (0.03 mol) were added, and 18.8 ml (0.36 mol) of bromine was added dropwise thereto in an ice water bath at 20°. C stirred the reaction overnight, TLC (PE: EA = 4:1) detection, phosphomolybdic acid coloration, adding 15 ml of saturated sodium thiosulfate under ice water bath, the system completely faded, adding 700 ml of dichloromethane, 300 ml of water, The organic phase was washed once with 300 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give 44.3 g of a colorless liquid (Compound XI-a).
MS: [M+H]+:161.08; 实施例 3a MS: [M+H] + : 161.08; Example 3a
称取溴代苯 97ml (0.97mol) 滴加到镁屑 25g ( l.Omol) 禾卩 THF400ml中， 回 流 30min后， 称取 （化合物 XI-a) 44.3g (0.28mol) 的四氢呋喃 100ml溶液， 滴加 到体系中， 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 反应完毕。 加入饱和 氯化铵溶液 30ml后过滤、 滤渣用 50ml乙酸乙酯洗涤， 滤液用 500mL乙酸乙酯稀 释后， 饱和食盐水 200mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到白色固体 80.3g， 力 P 240ml无水乙醇， 70°C加热， 冷却至室温后过滤， 得白色 固体 （化合物 Π -a) 57g, 收率 54.4%。 97 ml (0.97 mol) of bromobenzene was added dropwise to a solution of 25 g of magnesium granules (1.0 mol) and 400 ml of THF. After refluxing for 30 min, a solution of 44.3 g (0.28 mol) of tetrahydrofuran in 100 ml of the compound (XI-a) was weighed. It was added to the system, and the reaction was stirred at 20 ° C overnight, and TLC (PE: EA = 4:1) was detected, and the reaction was completed. After adding 30 ml of a saturated ammonium chloride solution, it was filtered, and the residue was washed with 50 ml of ethyl acetate. The filtrate was diluted with ethyl acetate (500 mL), and then washed twice with saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a white solid (yield: EtOAc, EtOAc, EtOAc: EtOAc (EtOAc)
MS:[M+Na]+:307.20 本发明实施例 lb~3b提供了当 = =Η时， 式 II所示的化合物 (当 = =Η
时，式 II所示的化合物也成为式 Π -b所示的化合物)的制备方法。其中实施例 lb-3b 的
MS: [M+Na] + : 307.20 Inventive Examples lb~3b provide the compound of formula II when ==Η (when ==Η In the case, the compound represented by the formula II is also a method for producing a compound represented by the formula Π-b. Wherein the embodiment lb-3b
甘露糖醇 X-b XI- b II-b Mannitol X-b XI- b II-b
实施例 lb Example lb
称取甘露糖醇 8g (0.044mol) 和氯化锌 9.6g (0.07mol)， 溶于 80mlDMF中， 加入三聚甲醛 15.8g (0.18mol)后， 20°C下搅拌反应 14h。 TLC (PE: EA=1 :2)监 测， 反应完毕。 称取 10g碳酸钾溶解在 50ml水中， 将碳酸钾的水溶液和 200ml 二氯甲垸加入到体系中搅拌 30min， 过滤、 滤渣用 50mL二氯甲垸洗涤， 水相用 100ml二氯甲垸萃取， 合并有机相， 有机相用饱和食盐水 100mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到淡黄色固体 （化合物 X-b) 6.2g。 柱层 析 PE: EA=3:1， 得白色固体 5.8g。 收率 56.8%。 其结构鉴定数据如下： 8 g (0.044 mol) of mannitol and 9.6 g (0.07 mol) of zinc chloride were weighed and dissolved in 80 ml of DMF. After adding 15.8 g (0.18 mol) of triacetal, the reaction was stirred at 20 ° C for 14 h. TLC (PE: EA = 1:2) was monitored and the reaction was completed. Weigh 10g of potassium carbonate dissolved in 50ml of water, add potassium carbonate aqueous solution and 200ml of dichloromethane to the system and stir for 30min, filter, filter residue washed with 50mL of dichloromethane, the aqueous phase is extracted with 100ml of dichloromethane, and combined The organic phase was washed once with 100 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a pale yellow solid (Comp. Xb) 6.2 g. Column chromatography PE: EA = 3:1, 5.8 g of white solid. The yield was 56.8%. Its structural identification data is as follows:
[M+Na]+: 229.12。 实施例 2b [M+Na] + : 229.12. Example 2b
称取 （化合物 Xb) 4.3g (0.02mol)， 溶于 43mL二氯甲垸。 依次加入水 3ml 禾口 NaIO4 8.5g (0.04mol), 于 20°C搅拌反应 5h。 TLC (PE: EA=1 : 1 ) 监测， 反应 完毕。 过滤、 40°C旋蒸后， 加入 （甲醇： 水 =9:1 ) 混合液 50ml和碳酸氢钠 7g (0. 08mol)， 冰水浴下滴加溴素 1.9ml (0.04mol)， 于 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 磷钼酸显色， 冰水浴下加饱和硫代硫酸钠 5ml， 体系完全褪色， 加入二氯甲垸 40ml， 水 30ml分液， 有机相用饱和食盐水 30mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色液体 （化合物 XI-b) 3.6g。 (Compound Xb) 4.3 g (0.02 mol) was weighed and dissolved in 43 mL of dichloromethane. 3 ml of water and 8.5 g (0.04 mol) of NaIO 4 were sequentially added thereto, and the reaction was stirred at 20 ° C for 5 hours. TLC (PE: EA=1: 1) was monitored and the reaction was completed. After filtration and steaming at 40 ° C, 50 ml of a mixture of (methanol: water = 9:1) and 7 g of sodium hydrogencarbonate (0.08 mol) were added, and 1.9 ml (0.04 mol) of bromine was added dropwise in an ice water bath at 20 °. C stirred the reaction overnight, TLC (PE: EA = 4:1) detection, phosphomolybdic acid coloration, adding 5 ml of saturated sodium thiosulfate under ice water bath, the system completely faded, adding 40 ml of dichloromethane, 30 ml of water, The organic phase was washed once with 30 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a colorless liquid (Compound XI-b) 3.6 g.
MS: [M+H]+: 133.08; 实施例 3b MS: [M+H] + : 133.08; Example 3b
称取溴代苯 5.2ml (0.05mol) 滴加到镁屑 0.7g (0.05mol) 禾卩 THF30ml中， 回流 30min后， 称取 (化合物 Xlb) 3.6g (0.025mol) 的四氢呋喃 20ml溶液， 滴加
到体系中， 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 反应完毕。 加入饱和 氯化铵溶液 10ml后过滤、 滤渣用 20ml乙酸乙酯洗涤， 滤液用 50mL乙酸乙酯稀 释后， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得 到白色固体 5.1g，柱层析 PE: EA=6:1，得白色固体（化合物 II -b) 4.8g，收率 82.7%。 5.2 ml (0.05 mol) of bromobenzene was added dropwise to 0.7 g (0.05 mol) of magnesium sulphate and 30 ml of THF. After refluxing for 30 min, a solution of (Compound X lb) 3.6 g (0.025 mol) in tetrahydrofuran 20 ml was weighed and added dropwise. In the system, the reaction was stirred at 20 ° C overnight, and TLC (PE: EA = 4:1) was detected, and the reaction was completed. After adding 10 ml of a saturated ammonium chloride solution, it was filtered, and the residue was washed with 20 ml of ethyl acetate. The filtrate was diluted with 50 mL of ethyl acetate, and then washed twice with saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a white solid (yield: 5.1 g, EtOAc: EtOAc: EtOAc:
MS:[M+Na]+:279.20 本发明实施例 lc~3c提供了当 RfR^Et时， 式 II所示的化合物 (当 RfR^Et 时，式 II所示的化合物也成为式 Π -c所示的化合物)的制备方法。其中实施例 lc-3c 的反应路线如下所示： MS: [M+Na] + : 279.20 Inventive Examples lc~3c provide a compound of formula II when RfR^Et (when RfR^Et, the compound of formula II also becomes formula Π-c Process for the preparation of the compounds shown). The reaction route of Example lc-3c is as follows:
甘露糖醇 实施例 lc Mannitol Example lc
称取甘露糖醇 8g (0.044mol) 和氯化锌 9.6g (0.07mol)， 溶于 80mlDMF中， 加入 3-戊酮 15.1g后， 20°C下搅拌反应 16ho TLC (PE: EA=1 :2)监测， 反应完毕。 称取 10g碳酸钾溶解在 50ml水中，将碳酸钾的水溶液和 200ml二氯甲垸加入到体 系中搅拌 30min，过滤、滤渣用 50mL二氯甲垸洗涤，水相用 100ml二氯甲垸萃取， 合并有机相， 有机相用饱和食盐水 100mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到淡黄色固体 （化合物 X-c) 6.2g。 柱层析 PE: EA=3:1 , 得白 色固体 5.0g。 收率 36.1%。 其结构鉴定数据如下： 8 g (0.044 mol) of mannitol and 9.6 g (0.07 mol) of zinc chloride were weighed and dissolved in 80 ml of DMF. After adding 15.1 g of 3-pentanone, the reaction was stirred at 20 ° C for 16 ho TLC (PE: EA = 1: 2) Monitoring, the reaction is completed. Weigh 10g of potassium carbonate dissolved in 50ml of water, add potassium carbonate aqueous solution and 200ml of dichloromethane to the system and stir for 30min, filter, filter residue washed with 50mL of dichloromethane, the aqueous phase is extracted with 100ml of dichloromethane, and combined The organic phase was washed once with 100 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give 6.2 g of pale yellow solid (Comp. Xc). Column chromatography PE: EA = 3:1 afforded 5.0 g as a white solid. The yield was 36.1%. Its structural identification data is as follows:
[M+Na]+: 341. 20 实施例 2c [M+Na] + : 341. 20 Example 2c
称取（化合物 X-c) 4.3g (0.016mol), 溶于 43mL二氯甲垸。依次加入水 3ml 禾口 NaIO4 6.4g (0.03mol), 于 20°C搅拌反应 8h。 TLC (PE: EA=1 : 1 ) 监测， 反应
完毕。 过滤、 40°C旋蒸后， 加入 （甲醇： 水 =9:1 ) 混合液 50ml和碳酸氢钠 lO.lg (0. 12mol)，冰水浴下滴加溴素 1.9ml (0.04mol)，于 20°C搅拌反应过夜， TLC CPE: EA=4:1 ) 检测， 磷钼酸显色， 冰水浴下加饱和硫代硫酸钠 5ml， 体系完全褪色， 加入二氯甲垸 40ml， 水 30ml分液， 有机相用饱和食盐水 30mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色液体 （化合物 XI-c) 3.1g。 (Compound Xc) 4.3 g (0.016 mol) was weighed and dissolved in 43 mL of dichloromethane. Water (3 ml) and NaIO 4 6.4 g (0.03 mol) were successively added, and the reaction was stirred at 20 ° C for 8 h. TLC (PE: EA=1: 1) monitoring, reaction Finished. After filtration and steaming at 40 ° C, 50 ml of a mixture of (methanol: water = 9:1) and sodium bicarbonate 10 g (0.12 mol) were added, and 1.9 ml (0.04 mol) of bromine was added dropwise in an ice water bath. Stirring at 20 ° C overnight, TLC CPE: EA = 4:1) detection, phosphomolybdic acid coloration, adding 5 ml of saturated sodium thiosulfate under ice water bath, the system is completely fading, adding 40 ml of dichloromethane, 30 ml of water The organic phase was washed once with 30 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a colorless liquid (Compound XI-c), 3.1 g.
MS: [M+H]+:189.10 实施例 3c MS: [M+H] + : 189.10 Example 3c
称取溴代苯 4.1ml (0.04mol) 滴加到镁屑 lg (0.04mol) 禾卩 THF30ml中， 回 流 30min后， 称取 （化合物 XI-c) 4.0g (0.02mol) 的四氢呋喃 20ml溶液， 滴加到 体系中， 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 反应完毕。 加入饱和氯 化铵溶液 10ml后过滤、 滤渣用 20ml乙酸乙酯洗涤， 滤液用 50mL乙酸乙酯稀释 后， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到 白色固体 5.7g， 柱层析 PE: EA=6:1， 得白色固体（化合物 Π -c) 5.3g， 收率 88.3%。 Weigh 4.1ml (0.04mol) of bromobenzene into 30ml of magnesium granules lg (0.04mol) and THF, and reflux for 30min, then weigh (Compound XI-c) 4.0g (0.02mol) of tetrahydrofuran 20ml solution, drop It was added to the system, and the reaction was stirred at 20 ° C overnight, and TLC (PE: EA = 4:1) was detected, and the reaction was completed. After adding 10 ml of a saturated ammonium chloride solution, it was filtered, and the residue was washed with 20 ml of ethyl acetate. The filtrate was diluted with 50 mL of ethyl acetate, and then washed twice with saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a white solid (yield: 5.7 g, EtOAc: EtOAc: EtOAc:
MS:[M+Na]+:335.14 本发明实施例 ld~3d提供了当 R^Me, 2=Pr时，式 II所示的化合物 (当 R^Me. R2=Pr时， 式 II所示的化合物也成为式 Π -d所示的化合物)的制备方法。 其中实施 例 l -3c的反应路线如下所示： MS: [M+Na] + : 335.14 Inventive Examples ld~3d provide a compound of formula II when R^Me, 2 =Pr (when R^Me.R 2 =Pr, formula II The compound shown also becomes a preparation method of the compound represented by the formula Π-d. The reaction route of Example 1-3c is as follows:
实施例 Id Example Id
称取甘露糖醇 8g (0.044mol) 和氯化锌 9.6g (0.07mol)， 溶于 80mlDMF中， 加入 2-戊酮 15.1g后， 20°C下搅拌反应 32h。 TLC (PE: EA=1 :2)监测， 反应完毕。 称取 10g碳酸钾溶解在 50ml水中，将碳酸钾的水溶液和 200ml二氯甲垸加入到体 系中搅拌 30min，过滤、滤渣用 50mL二氯甲垸洗涤，水相用 100ml二氯甲垸萃取，
合并有机相， 有机相用饱和食盐水 100mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到淡黄色固体 （化合物 X-d) 6.0g。 柱层析 PE: EA=3:1 , 得白 色固体 4.8g。 收率 34.3%。 其结构鉴定数据如下： 8 g (0.044 mol) of mannitol and 9.6 g (0.07 mol) of zinc chloride were weighed and dissolved in 80 ml of DMF. After adding 15.1 g of 2-pentanone, the reaction was stirred at 20 ° C for 32 h. TLC (PE: EA = 1:2) was monitored and the reaction was completed. Weigh 10g of potassium carbonate dissolved in 50ml of water, add potassium carbonate aqueous solution and 200ml of dichloromethane to the system and stir for 30min, filter, filter residue washed with 50mL of dichloromethane, the aqueous phase is extracted with 100ml of dichloromethane. The organic phase was combined, and the organic phase was washed once with brine (100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a pale yellow solid (Comp. Column chromatography PE: EA = 3:1, 4.8 g of white solid. The yield was 34.3%. Its structural identification data is as follows:
[M+Na]+: 341. 20 实施例 2d [M+Na] + : 341. 20 Example 2d
称取（化合物 X-d) 3.2g (O.Olmol), 溶于 32mL二氯甲垸。 依次加入水 3ml 禾口 NaIO4 4.3g (0.02mol), 于 20°C搅拌反应 8h。 TLC (PE: EA=1 : 1 ) 监测， 反应 完毕。 过滤、 40°C旋蒸后， 加入 （甲醇： 水 =9:1 ) 混合液 50ml和碳酸氢钠 lO.lg (0. 12mol)，冰水浴下滴加溴素 1.9ml (0.04mol)，于 20°C搅拌反应过夜， TLC CPE: EA=4:1 ) 检测， 磷钼酸显色， 冰水浴下加饱和硫代硫酸钠 5ml， 体系完全褪色， 加入二氯甲垸 40ml， 水 30ml分液， 有机相用饱和食盐水 30mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色液体 （化合物 XI-d) 3.0g。 (Compound Xd) 3.2 g (O.Olmol) was weighed and dissolved in 32 mL of dichloromethane. 3 ml of water and 4.3 g (0.02 mol) of NaIO 4 were sequentially added thereto, and the reaction was stirred at 20 ° C for 8 hours. TLC (PE: EA=1: 1) was monitored and the reaction was completed. After filtration and steaming at 40 ° C, 50 ml of a mixture of (methanol: water = 9:1) and sodium bicarbonate 10 g (0.12 mol) were added, and 1.9 ml (0.04 mol) of bromine was added dropwise in an ice water bath. Stirring at 20 ° C overnight, TLC CPE: EA = 4:1) detection, phosphomolybdic acid coloration, adding 5 ml of saturated sodium thiosulfate under ice water bath, the system is completely fading, adding 40 ml of dichloromethane, 30 ml of water The organic phase was washed once with 30 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a colorless liquid (Compound XI-d) 3.0 g.
MS: [M+H]+:189.10 实施例 3d MS: [M+H] + : 189.10 Example 3d
称取溴代苯 4.1ml (0.04mol) 滴加到镁屑 lg (0.04mol) 禾卩 THF30ml中， 回 流 30min后， 称取 （化合物 XI-d) 4.0g (0.02mol) 的四氢呋喃 20ml溶液， 滴加到 体系中， 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 反应完毕。 加入饱和氯 化铵溶液 10ml后过滤、 滤渣用 20ml乙酸乙酯洗涤， 滤液用 50mL乙酸乙酯稀释 后， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到 白色固体 5.7g， 柱层析 PE: EA=6:1，得白色固体（化合物 Π -d) 4.8g， 收率 75.0%。 Weigh 4.1ml (0.04mol) of bromobenzene into 30ml of magnesium granules lg (0.04mol) and THF, and reflux for 30min, then weigh (Compound XI-d) 4.0g (0.02mol) of tetrahydrofuran 20ml solution, drop It was added to the system, and the reaction was stirred at 20 ° C overnight, and TLC (PE: EA = 4:1) was detected, and the reaction was completed. After adding 10 ml of a saturated ammonium chloride solution, it was filtered, and the residue was washed with 20 ml of ethyl acetate. The filtrate was diluted with 50 mL of ethyl acetate, and then washed twice with saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a white solid (yield: 5.7 g, EtOAc: EtOAc: EtOAc: EtOAc:
MS:[M+Na]+:335.14 本发明实施例 le~3e提供了当 =Η， 2=t-Bu时，式 II所示的化合物 (当 =Η，MS: [M+Na] + : 335.14 Inventive Examples le~3e provide a compound of formula II when =Η, 2 = t-Bu (when =Η,
R2=t-Bu时， 式 II所示的化合物也成为式 Π -e所示的化合物)的制备方法。 其中实 施例 le-3e的反应路线如下所示：
When R 2 = t-Bu, the compound of the formula II is also a method for producing a compound represented by the formula Π -e . The reaction route of the example le-3e is as follows:
甘露糖醇 Mannitol
实施例 le Example le
称取甘露糖醇 8g (0.044mol) 和氯化锌 9.6g (0.07mol)， 溶于 80mlDMF中， 加入 2，2-二甲基丙醛 15.1g (0.18mol)后， 20 °C下搅拌反应 32h。 TLC (PE: EA=1 :2) 监测， 反应完毕。 称取 10g碳酸钾溶解在 50ml水中， 将碳酸钾的水溶液和 200ml 二氯甲垸加入到体系中搅拌 30min， 过滤、 滤渣用 50mL二氯甲垸洗涤， 水相用 100ml二氯甲垸萃取， 合并有机相， 有机相用饱和食盐水 100mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到淡黄色固体（化合物 X-e) 6.2g。 柱层析 PE: EA=3:1， 得白色固体 4.5g。 收率 32.1%。 其结构鉴定数据如下： 8 g (0.044 mol) of mannitol and 9.6 g (0.07 mol) of zinc chloride were weighed, dissolved in 80 ml of DMF, and 15.1 g (0.18 mol) of 2,2-dimethylpropanal was added, and the reaction was stirred at 20 ° C. 32h. TLC (PE: EA = 1:2) was monitored and the reaction was completed. Weigh 10g of potassium carbonate dissolved in 50ml of water, add potassium carbonate aqueous solution and 200ml of dichloromethane to the system and stir for 30min, filter, filter residue washed with 50mL of dichloromethane, the aqueous phase is extracted with 100ml of dichloromethane, and combined The organic phase was washed once with 100 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a pale-yellow solid (Compound Xe) 6.2 g. Column chromatography PE: EA = 3:1 afforded 4.5 g of white solid. The yield was 32.1%. Its structural identification data is as follows:
[M+Na]+: 341. 20 实施例 2e [M+Na] + : 341. 20 Example 2e
称取（化合物 X-e) 3.2g (O.Olmol) , 溶于 32mL二氯甲垸。 依次加入水 3ml 禾口 NaIO4 4.3g (0.02mol), 于 20°C搅拌反应 8h。 TLC (PE: EA=1 : 1 ) 监测， 反应 完毕。 过滤、 40°C旋蒸后， 加入 （甲醇： 水 =9:1 ) 混合液 50ml和碳酸氢钠 lO.lg (0. 12mol)，冰水浴下滴加溴素 1.9ml (0.04mol)，于 20°C搅拌反应过夜， TLC CPE: EA=4:1 ) 检测， 磷钼酸显色， 冰水浴下加饱和硫代硫酸钠 5ml， 体系完全褪色， 加入二氯甲垸 40ml， 水 30ml分液， 有机相用饱和食盐水 30mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色液体 （化合物 XI-e) 2.8g。 (Compound Xe) 3.2 g (O.Olmol) was weighed and dissolved in 32 mL of dichloromethane. 3 ml of water and 4.3 g (0.02 mol) of NaIO 4 were sequentially added thereto, and the reaction was stirred at 20 ° C for 8 hours. TLC (PE: EA=1: 1) was monitored and the reaction was completed. After filtration and steaming at 40 ° C, 50 ml of a mixture of (methanol: water = 9:1) and sodium bicarbonate 10 g (0.12 mol) were added, and 1.9 ml (0.04 mol) of bromine was added dropwise in an ice water bath. Stirring at 20 ° C overnight, TLC CPE: EA = 4:1) detection, phosphomolybdic acid coloration, adding 5 ml of saturated sodium thiosulfate under ice water bath, the system is completely fading, adding 40 ml of dichloromethane, 30 ml of water The organic phase was washed once with 30 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give 2.8 g (yield: Compound XI-e).
MS: [M+H]+:189.10 实施例 3e MS: [M+H] + : 189.10 Example 3e
称取溴代苯 2.1ml (0.02mol) 滴加到镁屑 0.5g (0.02mol) 禾卩 THF30ml中， 回流 30min后， 称取 （化合物 XI-e) 2.0g (O.Olmol) 的四氢呋喃 20ml溶液， 滴加
到体系中， 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 反应完毕。 加入饱和 氯化铵溶液 10ml后过滤、 滤渣用 20ml乙酸乙酯洗涤， 滤液用 50mL乙酸乙酯稀 释后， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得 到白色固体 2.6g，柱层析 PE: EA=6:1，得白色固体（化合物 II -e) 2.6g，收率 83.9%。 2.1 ml (0.02 mol) of bromobenzene was added dropwise to 0.3 g (0.02 mol) of magnesium granules and 30 ml of THF. After refluxing for 30 min, a solution of (Compound XI-e) 2.0 g (O.Omol) in tetrahydrofuran (20 ml) was weighed. , dripping In the system, the reaction was stirred at 20 ° C overnight, and TLC (PE: EA = 4:1) was detected, and the reaction was completed. After adding 10 ml of a saturated ammonium chloride solution, it was filtered, and the residue was washed with 20 ml of ethyl acetate. The filtrate was diluted with 50 mL of ethyl acetate, and then washed twice with saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give 2.6 g of white solid. EtOAc (EtOAc: EtOAc)
MS:[M+Na]+:335.14 本发明实施例 lf~3f提供了当 RfH, 2=CC13时，式 II所示的化合物 (当 RfH, R2=CC13时， 式 II所示的化合物也成为式 Π -f 所示的化合物)的制备方法。 其中实 施 lc-3c的反应路线如下所示： MS: [M+Na] + : 335.14 The lf~3f of the present invention provides a compound of the formula II when RfH, 2 = CC1 3 (when RfH, R 2 = CC1 3 , formula II) The compound also becomes a preparation method of the compound represented by the formula Π-f. The reaction route for implementing lc-3c is as follows:
实施例 if Example if
称取甘露糖醇 8g (0.044mol) 和氯化锌 9.6g (0.07mol)， 溶于 80mlDMF中， 加入三氯乙醛 25.9g后， 30°C下搅拌反应 32h。 TLC (PE: EA=1 :2)监测， 反应完 毕。称取 10g碳酸钾溶解在 50ml水中， 将碳酸钾的水溶液和 200ml二氯甲垸加入 到体系中搅拌 30min， 过滤、滤渣用 50mL二氯甲垸洗涤， 水相用 100ml二氯甲垸 萃取， 合并有机相， 有机相用饱和食盐水 100mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到淡黄色固体（化合物 X-f) 14.2g。 柱层析 PE: EA=3:1， 得白色固体 12.5g。 收率 65.1%。 其结构鉴定数据如下： 8 g (0.044 mol) of mannitol and 9.6 g (0.07 mol) of zinc chloride were weighed and dissolved in 80 ml of DMF. After adding 25.9 g of trichloroacetaldehyde, the reaction was stirred at 30 ° C for 32 h. TLC (PE: EA = 1:2) was monitored and the reaction was completed. Weigh 10g of potassium carbonate dissolved in 50ml of water, add potassium carbonate aqueous solution and 200ml of dichloromethane to the system and stir for 30min, filter, filter residue washed with 50mL of dichloromethane, the aqueous phase is extracted with 100ml of dichloromethane, and combined The organic phase was washed once with 100 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a pale yellow solid (Compound Xf) 14.2 g. Column chromatography PE: EA = 3:1 gave a white solid (12.5 g). The yield was 65.1%. Its structural identification data is as follows:
[M+Na]+: 460. 88 实施例 2f [M+Na] + : 460. 88 Example 2f
称取 （化合物 Xf) 4.4g (O.Olmol) , 溶于 32mL二氯甲垸。 依次加入水 3ml 禾口 NaIO4 4.3g (0.02mol), 于 20°C搅拌反应 8h。 TLC (PE: EA=1 : 1 ) 监测， 反应 完毕。 过滤、 40°C旋蒸后， 加入 （甲醇： 水 =9:1 ) 混合液 50ml和碳酸氢钠 lO.lg
(0. 12mol)，冰水浴下滴加溴素 1.9ml (0.04mol)，于 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 磷钼酸显色， 冰水浴下加饱和硫代硫酸钠 5ml， 体系完全褪色， 加入二氯甲垸 40ml， 水 30ml分液， 有机相用饱和食盐水 30mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色液体 （化合物 XI-f) 3.7g。 Weighed (Compound Xf) 4.4 g (O.Olmol) in 32 mL of dichloromethane. 3 ml of water and 4.3 g (0.02 mol) of NaIO 4 were sequentially added thereto, and the reaction was stirred at 20 ° C for 8 hours. TLC (PE: EA=1: 1) was monitored and the reaction was completed. After filtration and 40 ° C rotary evaporation, add (methanol: water = 9:1) mixture 50 ml and sodium bicarbonate lO. (0. 12mol), 1.9 ml (0.04 mol) of bromine was added dropwise in an ice water bath, and the reaction was stirred at 20 ° C overnight, TLC (PE: EA = 4:1) was detected, the phosphomolybdic acid was colored, and the ice water bath was added. Saturated sodium thiosulfate 5 ml, the system was completely faded, 40 ml of dichloromethane was added, 30 ml of water was separated, and the organic phase was washed once with 30 mL of saturated brine, dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give 3.7 g (yield: Compound XI-f).
MS: [M+H]+:248.94 实施例 3f MS: [M+H] + : 248.94 Example 3f
称取溴代苯 2.1ml (0.02mol) 滴加到镁屑 0.5g (0.02mol) 禾卩 THF30ml中， 回流 30min后， 称取 （化合物 XI-f) 2.5g (O.Olmol) 的四氢呋喃 20ml溶液， 滴加 到体系中， 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 反应完毕。 加入饱和 氯化铵溶液 10ml后过滤、 滤渣用 20ml乙酸乙酯洗涤， 滤液用 50mL乙酸乙酯稀 释后， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得 到白色固体 2.8g，柱层析 PE: EA=6:1，得白色固体（化合物 II -f) 2.7g，收率 73.0%。 Weigh 2.1 ml (0.02 mol) of bromobenzene dropwise to 0.3 g (0.02 mol) of magnesium sulphate and 30 ml of THF. After refluxing for 30 min, weigh out (Compound XI-f) 2.5 g (O.Omol) of tetrahydrofuran 20 ml solution. , dropwise addition to the system, stirring at 20 ° C overnight, TLC (PE: EA = 4:1) detection, the reaction is completed. After adding 10 ml of a saturated ammonium chloride solution, it was filtered, and the residue was washed with 20 ml of ethyl acetate. The filtrate was diluted with 50 mL of ethyl acetate, and then washed twice with saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a white solid (yield: 2.8 g, EtOAc: EtOAc: EtOAc:
MS:[M+Na]+:395.01 本发明实施例 lg~3g提供了当 R^I^ RfPh时， 式 II所示的化合物 (当 =Η， R2=Ph时， 式 II所示的化合物也成为式 Π -f所示的化合物)的制备方法。 其中实施 例 l MS: [M+Na] + :395.01 Inventive Examples lg~3g provide the compound of formula II when R^I^RfPh (when =Η, R 2 =Ph, the compound of formula II) It is also a method for producing a compound represented by the formula Π-f. Wherein embodiment l
实施例 lg Example lg
称取甘露糖醇 8g (0.044mol)和对甲苯磺酸 1.5g (0.008mol)，溶于 80mlDMF 中， 加入苯甲醛缩二甲醇 26.7g后， 40°C下搅拌反应 24h。 TLC (PE: EA=1 :2)监 测， 反应完毕。 称取 10g碳酸钾溶解在 50ml水中， 将碳酸钾的水溶液和 200ml 二氯甲垸加入到体系中搅拌 30min， 过滤、 滤渣用 50mL二氯甲垸洗涤， 水相用
100ml二氯甲垸萃取， 合并有机相， 有机相用饱和食盐水 100mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到淡黄色固体 （化合物 X-g) 12.2g。 柱层 析 PE: EA=3:1， 得白色固体 10.3g。 收率 65.6%。 其结构鉴定数据如下： 8 g (0.044 mol) of mannitol and 1.5 g (0.008 mol) of p-toluenesulfonic acid were weighed and dissolved in 80 ml of DMF. After adding 26.7 g of benzaldehyde dimethylacetal, the reaction was stirred at 40 ° C for 24 h. TLC (PE: EA = 1:2) was monitored and the reaction was completed. Weigh 10g of potassium carbonate dissolved in 50ml of water, add potassium carbonate aqueous solution and 200ml of dichloromethane to the system and stir for 30min, filter, filter residue washed with 50mL of dichloromethane, water phase The organic phase was extracted with 100 ml of dichloromethane, and the organic phase was washed once with 100 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a pale yellow solid (Comp. Xg) 12.2 g. Column chromatography PE: EA = 3:1 afforded 10.3 g of white solid. The yield was 65.6%. Its structural identification data is as follows:
[M+Na]+: 381.14。 实施例 2g [M+Na] + : 381.14. Example 2 g
称取（化合物 Xg) 5.0g (O.O mol), 溶于 50mL二氯甲垸。 依次加入水 5ml 和 NaIO4 5.5g (0.03mol), 于 20°C搅拌反应 2h。 TLC (PE: EA=1 : 1 ) 监测， 反应 完毕。 过滤、 40°C旋蒸后， 加入（甲醇： 水 =9:1 )混合液 50ml和碳酸氢钠 4.2g (0. 05mol)， 冰水浴下滴加溴素 1.5ml (0.03mol), 于 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 磷钼酸显色， 冰水浴下加饱和硫代硫酸钠 5ml， 体系完全褪色， 加入二氯甲垸 40ml， 水 30ml分液， 有机相用饱和食盐水 30mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色液体 （化合物 XI-g) 3.4g。 Weighed (Compound Xg) 5.0 g (OO mol), dissolved in 50 mL of dichloromethane. 5 ml of water and 5.5 g of NaIO 4 (0.03 mol) were successively added, and the reaction was stirred at 20 ° C for 2 h. TLC (PE: EA=1: 1) was monitored and the reaction was completed. After filtration and steaming at 40 ° C, 50 ml of a mixture of (methanol: water = 9:1) and 4.2 g (0.0 mmol) of sodium hydrogencarbonate were added, and 1.5 ml (0.03 mol) of bromine was added dropwise in an ice water bath at 20 Stir the reaction overnight at °C, TLC (PE: EA=4:1) detection, phosphomolybdic acid coloration, add 5 ml of saturated sodium thiosulfate under ice water bath, the system completely faded, add 40 ml of dichloromethane, 30 ml of water The organic phase was washed once with 30 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give 3.4 g (yield: Compound XI-g).
MS: [M+H]+:209.07; 实施例 3g MS: [M+H] + : 209.07; Example 3 g
称取溴代苯 4.2ml (0.04mol) 滴加到镁屑 l .Og (0.04mol) 和 THF30ml中， 回流 30min后， 称取 （化合物 XI-g) 4.2g (0.02mol) 的四氢呋喃 20ml溶液， 滴加 到体系中， 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 反应完毕。 加入饱和 氯化铵溶液 10ml后过滤、 滤渣用 20ml乙酸乙酯洗涤， 滤液用 50mL乙酸乙酯稀 释后， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得 到白色固体 6.4g，柱层析 PE: EA=6:1，得白色固体（化合物 II -g) 6.1g，收率 92.4%。 4.2 ml (0.04 mol) of bromobenzene was added dropwise to magnesium granules of 1.0 g (0.04 mol) and 30 ml of THF. After refluxing for 30 min, a solution of 4.2 g (0.02 mol) of tetrahydrofuran in 20 ml was weighed (compound XI-g). The mixture was added dropwise to the system, and the reaction was stirred at 20 ° C overnight, and TLC (PE: EA = 4:1) was detected and the reaction was completed. After adding 10 ml of a saturated ammonium chloride solution, it was filtered, and the residue was washed with 20 ml of ethyl acetate. The filtrate was diluted with 50 mL of ethyl acetate, and then washed twice with saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give 6.4 g (yield: EtOAc: EtOAc: EtOAc:
MS:[M+Na]+:355.20 MS: [M+Na] + : 355.20
OMe OMe
本发明实施例 lh~3h提供了当 =Η， 2= T 时， 式 II所示的化合物 (当
OMe i=H, 2= T 时， 式 II所示的化合物也成为式 II -h所示的化合物)的制备方法。 其中实施例 lh-3h的反应路线如下所示： In the examples of the present invention, lh~3h provide the compound of formula II when =Η, 2 = T (when When OMe i = H, 2 = T, the compound of the formula II is also a method for preparing the compound of the formula II - h). The reaction route of the examples 1h-3h is as follows:
称取甘露糖醇 8g (0.044mol)和对甲苯磺酸 1.5g (0.008mol)，溶于 80mlDMF 中，加入 4-甲氧基苯甲醛缩二甲醇 32.3g后， 40°C下搅拌反应 24h。TLC(PE: EA=l :2) 监测， 反应完毕。 称取 10g碳酸钾溶解在 50ml水中， 将碳酸钾的水溶液和 200ml 二氯甲垸加入到体系中搅拌 30min， 过滤、 滤渣用 50mL二氯甲垸洗涤， 水相用 100ml二氯甲垸萃取， 合并有机相， 有机相用饱和食盐水 100mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到淡黄色固体 （化合物 X-h) 13.1g。 柱层 析 PE: EA=3:1， 得白色固体 9.7g。 收率 56.7%。 其结构鉴定数据如下： 8 g (0.044 mol) of mannitol and 1.5 g (0.008 mol) of p-toluenesulfonic acid were weighed and dissolved in 80 ml of DMF. After adding 32.3 g of 4-methoxybenzaldehyde dimethylacetal, the reaction was stirred at 40 ° C for 24 h. TLC (PE: EA=l:2) was monitored and the reaction was completed. Weigh 10g of potassium carbonate dissolved in 50ml of water, add potassium carbonate aqueous solution and 200ml of dichloromethane to the system and stir for 30min, filter, filter residue washed with 50mL of dichloromethane, the aqueous phase is extracted with 100ml of dichloromethane, and combined The organic phase was washed once with 100 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a pale yellow solid (Comp. Column chromatography PE: EA = 3:1, 9.7 g of white solid. The yield was 56.7%. Its structural identification data is as follows:
[M+Na]+: 443.14。 实施例 2h [M+Na] + : 443.14. Example 2h
称取（化合物 X-h) 5.4g (0.013mol)， 溶于 50mL二氯甲垸。依次加入水 5ml 和 NaIO4 5.5g (0.03mol), 于 20°C搅拌反应 2h。 TLC (PE: EA=1 : 1 ) 监测， 反应 完毕。 过滤、 40°C旋蒸后， 加入（甲醇： 水 =9:1 )混合液 50ml和碳酸氢钠 4.2g (0. 05mol)， 冰水浴下滴加溴素 1.5ml (0.03mol), 于 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 磷钼酸显色， 冰水浴下加饱和硫代硫酸钠 5ml， 体系完全褪色，
加入二氯甲垸 40ml， 水 30ml分液， 有机相用饱和食盐水 30mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色液体 （化合物 XI-h) 4.1g。(Compound Xh) 5.4 g (0.013 mol) was weighed and dissolved in 50 mL of dichloromethane. 5 ml of water and 5.5 g of NaIO 4 (0.03 mol) were successively added, and the reaction was stirred at 20 ° C for 2 h. TLC (PE: EA=1: 1) was monitored and the reaction was completed. After filtration and steaming at 40 ° C, 50 ml of a mixture of (methanol: water = 9:1) and 4.2 g (0.0 mmol) of sodium hydrogencarbonate were added, and 1.5 ml (0.03 mol) of bromine was added dropwise in an ice water bath at 20 The reaction was stirred overnight at °C, TLC (PE: EA=4:1) was detected, the phosphomolybdic acid was developed, and 5 ml of saturated sodium thiosulfate was added in an ice water bath, and the system completely faded. 40 ml of dichloromethane was added, and 30 ml of water was separated, and the organic phase was washed once with 30 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a colorless liquid ( Compound XI-h) 4.1 g.
实施例 li Example li
称取甘露糖醇 8g (0.044mol)和对甲苯磺酸 1.5g (0.008mol)，溶于 80mlDMF 中， 加入环戊酮 14.7g后， 40°C下搅拌反应 24h。 TLC (PE: EA=1 :2)监测， 反应 完毕。称取 10g碳酸钾溶解在 50ml水中， 将碳酸钾的水溶液和 200ml二氯甲垸加 入到体系中搅拌 30min， 过滤、滤渣用 50mL二氯甲垸洗涤， 水相用 100ml二氯甲 垸萃取， 合并有机相， 有机相用饱和食盐水 100mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到淡黄色固体（化合物 X-i) lO.lgo 柱层析 PE: EA=3:1，
得白色固体 7.8g。 收率 56.5%。 其结构鉴定数据如下： 8 g (0.044 mol) of mannitol and 1.5 g (0.008 mol) of p-toluenesulfonic acid were weighed and dissolved in 80 ml of DMF. After adding 14.7 g of cyclopentanone, the reaction was stirred at 40 ° C for 24 h. TLC (PE: EA = 1:2) was monitored and the reaction was completed. Weigh 10g of potassium carbonate dissolved in 50ml of water, add potassium carbonate aqueous solution and 200ml of dichloromethane to the system and stir for 30min, filter, filter residue washed with 50mL of dichloromethane, the aqueous phase is extracted with 100ml of dichloromethane, and combined The organic phase was washed once with 100 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was spun dry to give a pale-yellow solid (Compound Xi) lO.lgo column chromatography PE: EA=3:1, A white solid was obtained 7.8 g. The yield was 56.5%. Its structural identification data is as follows:
[M+Na]+: 337.14。 实施例 2i [M+Na] + : 337.14. Example 2i
称取（化合物 X-i) 4.1g (O.O mol), 溶于 50mL二氯甲垸。 依次加入水 5ml 和 NaIO4 5.5g (0.03mol), 于 20°C搅拌反应 2h。 TLC (PE: EA=1 : 1 ) 监测， 反应 完毕。 过滤、 40°C旋蒸后， 加入（甲醇： 水 =9:1 )混合液 50ml和碳酸氢钠 4.2g (0. 05mol)， 冰水浴下滴加溴素 1.5ml (0.03mol), 于 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 磷钼酸显色， 冰水浴下加饱和硫代硫酸钠 5ml， 体系完全褪色， 加入二氯甲垸 40ml， 水 30ml分液， 有机相用饱和食盐水 30mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色液体 （化合物 XI-i) 3.3g。 Weigh (Compound Xi) 4.1 g (OO mol), dissolved in 50 mL of dichloromethane. 5 ml of water and 5.5 g of NaIO 4 (0.03 mol) were successively added, and the reaction was stirred at 20 ° C for 2 h. TLC (PE: EA=1: 1) was monitored and the reaction was completed. After filtration and steaming at 40 ° C, 50 ml of a mixture of (methanol: water = 9:1) and 4.2 g (0.0 mmol) of sodium hydrogencarbonate were added, and 1.5 ml (0.03 mol) of bromine was added dropwise in an ice water bath at 20 Stir the reaction overnight at °C, TLC (PE: EA=4:1) detection, phosphomolybdic acid coloration, add 5 ml of saturated sodium thiosulfate under ice water bath, the system completely faded, add 40 ml of dichloromethane, 30 ml of water The organic phase was washed once with 30 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was spun dry to give a colorless liquid (Compound XI-i) 3.3 g.
MS: [M+H]+: 187.07 实施例 3i MS: [M+H] + : 187.07 Example 3i
称取溴代苯 4.2ml (0.04mol) 滴加到镁屑 l .Og (0.04mol) 和 THF30ml中， 回流 30min后， 称取 （化合物 XI-i) 3.7g (0.02mol) 的四氢呋喃 20ml溶液， 滴加 到体系中， 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 反应完毕。 加入饱和 氯化铵溶液 10ml后过滤、 滤渣用 20ml乙酸乙酯洗涤， 滤液用 50mL乙酸乙酯稀 释后， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得 到白色固体 4.6g，柱层析 PE: EA=6:1，得白色固体（化合物 II -i) 4.4g，收率 71.0%。 4.2 ml (0.04 mol) of bromobenzene was added dropwise to magnesium granules of 1.0 g (0.04 mol) and 30 ml of THF. After refluxing for 30 min, a solution of 3.7 g (0.02 mol) of tetrahydrofuran (20 ml) was weighed (compound XI-i). The mixture was added dropwise to the system, and the reaction was stirred at 20 ° C overnight, and TLC (PE: EA = 4:1) was detected and the reaction was completed. After adding 10 ml of a saturated ammonium chloride solution, it was filtered, and the residue was washed with 20 ml of ethyl acetate. The filtrate was diluted with 50 mL of ethyl acetate, and then washed twice with saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give 4.6 g (yield: EtOAc: EtOAc: EtOAc:
MS:[M+Na]+:333.14 本发明实施例 lj~3j提供了当 、 R2与相连碳原子形成六元环时， 式 II所示 的化合物 (当 Ri、 R2与相连碳原子形成六元环时， 式 II所示的化合物也成为式 Π -j 所示的化合物)的制备方法。 其中实施例 lj-3j的反应路线如下所示：：
MS: [M+Na] + : 333.14 Inventive Examples lj~3j provide a compound of formula II when R 2 forms a six-membered ring with a bonded carbon atom (when Ri, R 2 and associated carbon atoms are formed) In the case of a six-membered ring, the compound of the formula II is also a method for producing a compound represented by the formula Π-j. The reaction route of the examples lj-3j is as follows:
实施例 lj Example lj
称取甘露糖醇 8g (0.044mol)和对甲苯磺酸 1.5g (0.008mol)，溶于 80mlDMF 中， 加入环己酮 17.2g后， 25°C下搅拌反应 16h。 TLC (PE: EA=1 :2)监测， 反应 完毕。称取 10g碳酸钾溶解在 50ml水中， 将碳酸钾的水溶液和 200ml二氯甲垸加 入到体系中搅拌 30min， 过滤、滤渣用 50mL二氯甲垸洗涤， 水相用 100ml二氯甲 垸萃取， 合并有机相， 有机相用饱和食盐水 100mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到淡黄色固体（化合物 X-j ) lO. l go 柱层析 PE: EA=3:1， 得白色固体 8.1g。 收率 50.0%。 其结构鉴定数据如下： 8 g (0.044 mol) of mannitol and 1.5 g (0.008 mol) of p-toluenesulfonic acid were weighed and dissolved in 80 ml of DMF. After adding 17.2 g of cyclohexanone, the reaction was stirred at 25 ° C for 16 h. TLC (PE: EA = 1:2) was monitored and the reaction was completed. Weigh 10g of potassium carbonate dissolved in 50ml of water, add potassium carbonate aqueous solution and 200ml of dichloromethane to the system and stir for 30min, filter, filter residue washed with 50mL of dichloromethane, the aqueous phase is extracted with 100ml of dichloromethane, and combined The organic phase was washed once with 100 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a pale-yellow solid (Compound Xj). </ RTI></RTI></RTI></RTI></RTI></RTI></RTI> EA = 3:1. The yield was 50.0%. Its structural identification data is as follows:
[M+Na]+: 365.14 实施例 2j [M+Na] + : 365.14 Example 2j
称取（化合物 X-j ) 5.0g (0.014mol)， 溶于 50mL二氯甲垸。 依次加入水 5ml 和 NaIO4 5.5g (0.03mol), 于 20°C搅拌反应 2h。 TLC (PE: EA=1 : 1 ) 监测， 反应 完毕。 过滤、 40°C旋蒸后， 加入（甲醇： 水 =9:1 )混合液 50ml和碳酸氢钠 4.2g (0. 05mol)， 冰水浴下滴加溴素 1.5ml (0.03mol), 于 20°C搅拌反应过夜， TLC (PE: EA=4:1 ) 检测， 磷钼酸显色， 冰水浴下加饱和硫代硫酸钠 5ml， 体系完全褪色， 加入二氯甲垸 40ml， 水 30ml分液， 有机相用饱和食盐水 30mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色液体 （化合物 XI-j ) 3.8g。 (Compound Xj) 5.0 g (0.014 mol) was weighed and dissolved in 50 mL of dichloromethane. 5 ml of water and 5.5 g of NaIO 4 (0.03 mol) were successively added, and the reaction was stirred at 20 ° C for 2 h. TLC (PE: EA=1: 1) was monitored and the reaction was completed. After filtration and steaming at 40 ° C, 50 ml of a mixture of (methanol: water = 9:1) and 4.2 g (0.0 mmol) of sodium hydrogencarbonate were added, and 1.5 ml (0.03 mol) of bromine was added dropwise in an ice water bath at 20 Stir the reaction overnight at °C, TLC (PE: EA=4:1) detection, phosphomolybdic acid coloration, add 5 ml of saturated sodium thiosulfate under ice water bath, the system completely faded, add 40 ml of dichloromethane, 30 ml of water The organic phase was washed once with 30 mL of saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give 3.8 g of a colorless liquid (Compound XI-j).
MS: [M+H]+:201.07; 实施例 3j MS: [M+H] + : 201.07; Example 3j
称取溴代苯 5.3ml (0.05mol) 滴加到镁屑 1.3g (0.05mol) 禾卩 THF30ml中， 回流 30min后， 称取 （化合物 Xlj ) 5.1g (0.024mol) 的四氢呋喃 20ml溶液， 滴加
到体系中， 20°C搅拌反应过夜， TLC (PE: EA=4: 1 ) 检测， 反应完毕。 加入饱和 氯化铵溶液 10ml后过滤、 滤渣用 20ml乙酸乙酯洗涤， 滤液用 50mL乙酸乙酯稀 释后， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得 到白色固体 7.8g，柱层析 PE: EA=6: 1，得白色固体（化合物 Π -j ) 7.4g，收率 91.3%。 Weigh 5.3 ml (0.05 mol) of bromobenzene into 0.3 g (0.05 mol) of magnesium sulphate and concentrate in 30 ml of THF. After refluxing for 30 min, weigh out (Compound Xlj) 5.1 g (0.024 mol) of tetrahydrofuran 20 ml solution, add dropwise In the system, the reaction was stirred at 20 ° C overnight, and TLC (PE: EA = 4:1) was detected, and the reaction was completed. After adding 10 ml of a saturated ammonium chloride solution, it was filtered, and the residue was washed with 20 ml of ethyl acetate. The filtrate was diluted with 50 mL of ethyl acetate, and then washed twice with saturated brine and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give a white solid (yield: 7.8 g, EtOAc: EtOAc: EtOAc:
MS:[M+Na]+:347.20 本发明实施例 4a-5a提供了式 IV化合物的制备方法MS: [M+Na] + : 347.20 Inventive Example 4a-5a provides a method of preparing a compound of formula IV
-5a的反应路线如下所示： The reaction route for -5a is as follows:
实施例 4a Example 4a
称取 （化合物 Π -a) 50g (0.18mol)， 溶于 500mL 四氢呋喃中， 冰水浴下加 入 NaH 17.5g(0.44mol)于 20°C下搅拌反应 30min后，滴加碘甲垸 16.4ml(0.26mol)。 TLC (PE: EA=15: 1 ) 监测， 反应完毕。 冰水浴下， 加入 20mL饱和氯化铵后， 搅 拌 30min， 体系浓缩后， 用 500mL乙酸乙酯稀释， 饱和食盐水 200mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色油状物 （化合物 Ill-a) 61.2g, 直接下一步。 Weighed (Compound Π-a) 50g (0.18mol), dissolved in 500mL of tetrahydrofuran, added NaH 17.5g (0.44mol) under ice water bath, stirred at 20 ° C for 30min, then added dropwise iodoformam 16.4ml (0.26) Mol). TLC (PE: EA=15: 1) was monitored and the reaction was completed. Under ice-water bath, 20 mL of saturated ammonium chloride was added, and the mixture was stirred for 30 minutes. After concentration, the mixture was concentrated, diluted with ethyl acetate (500 mL), and washed twice with saturated brine (200 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to give 61.2 g (yield of Compound Ill-a) as a colorless oil.
MS:[M+Na]+:321.14 实施例 5a MS: [M+Na] + : 321.14 Example 5a
称取 （化合物 ΙΠ-a) 61.2g, 溶于 300mL甲醇： 水 =20: 1的溶液中。 滴加浓硫 酸 2.8ml (0.05mol)， 于 25°C搅拌反应 40h。 TLC (PE: EA=15: 1 ) 监测， 反应完 毕。 加饱和碳酸钠溶液调节 PH=9后， 加入 500ml乙酸乙酯和 100ml水稀释滤液 后， 用饱和食盐水 150mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 经柱层析 （PE: EA=4: 1 ) 得到白色糖浆状物 （化合物 IV ) 41.2g， 收率 77.8%。
Ή NM : δ 3.12 (s, 3H), 3.38 (dd,lH), 3.64 (d, 1H)， 4.65 (m, 1H)， 7.28-7.49 (m.61.2 g of the compound (ΙΠ-a) was weighed and dissolved in a solution of 300 mL of methanol: water = 20:1. 2.8 ml (0.05 mol) of concentrated sulfuric acid was added dropwise, and the reaction was stirred at 25 ° C for 40 h. TLC (PE: EA=15: 1) was monitored and the reaction was completed. After adjusting the pH of the saturated sodium carbonate solution, the filtrate was diluted with 500 ml of ethyl acetate and 100 ml of water, and then washed once with 150 mL of saturated brine, and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was spun dry, and then purified by column chromatography (PE: EA = 4: 1) to afford 41.2 g of a white syrup (Compound IV), yield 77.8%. Ή NM : δ 3.12 (s, 3H), 3.38 (dd, lH), 3.64 (d, 1H), 4.65 (m, 1H), 7.28-7.49 (m.
10H) 10H)
MS:[M+Na]+:281.13 本发明实施例 4b-5b提供了式 IV化合物的制备方法 MS: [M+Na] + : 281.13 Inventive Example 4b-5b provides a method for preparing a compound of formula IV
以下实施例 4b-5b的反应路线如下所示： The reaction schemes of the following Examples 4b-5b are as follows:
实施例 4b Example 4b
称取 （化合物 lib) 2.6g (O.Olmol), 溶于 20mL四氢呋喃中， 冰水浴下加入 NaH 1.2g (0.03mol) 于 20°C下搅拌反应 30min后， 滴加碘甲垸 1.3ml (0.02mol), 20°C下反应 lh后。 TLC (PE: EA=15:1 ) 监测， 反应完毕。 冰水浴下， 加入 5mL 饱和氯化铵后， 搅拌 30min， 体系浓缩后， 用 30mL 乙酸乙酯稀释， 饱和食盐水 15mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色油状物 （化 合物 Illb) 2.9g， 直接下一步。 Weigh (Compound lib) 2.6g (O.Olmol), dissolved in 20mL of tetrahydrofuran, add NaH 1.2g (0.03mol) under ice water bath, stir the reaction at 20 °C for 30min, add dropwise iodothymidine 1.3ml (0.02 Mol), after reacting at 20 ° C for 1 h. TLC (PE: EA=15:1) was monitored and the reaction was completed. Under ice cooling, after adding 5mL saturated ammonium chloride, stirred for 30min, after the system was concentrated, diluted with 30mL ethyl acetate, washed once with saturated brine 15mL, dried over anhydrous Na 2 SO 4. After filtration, the filtrate was dried to give 2.9 g (yield of compound 111b).
MS:[M+Na]+:293.13 MS: [M+Na] + : 293.13
实施例 5b Example 5b
称取 （化合物 Illb) 2.7g， 溶于 30mL乙醇： 水 =10:1 的溶液中。 滴加浓盐酸 0.08ml (0.001mol,0.1eq), 于 20°C搅拌反应 10h。 TLC (PE: EA=15:1 ) 监测， 反 应完毕。 加饱和碳酸钠溶液调节 PH=9后， 加入 20ml乙酸乙酯和 10ml水稀释滤 液后， 用饱和食盐水 10mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 经柱层析 （PE: EA=4:1 ) 得到白色糖浆状物 （化合物 IV ) 1.86g， 收率 72.3%。 Weigh (Compound Illb) 2.7 g, dissolved in 30 mL of ethanol: water = 10:1 solution. 0.08 ml (0.001 mol, 0.1 eq) of concentrated hydrochloric acid was added dropwise, and the reaction was stirred at 20 ° C for 10 h. TLC (PE: EA=15:1) was monitored and the reaction was completed. After adjusting the pH of the saturated sodium carbonate solution, the filtrate was diluted with 20 ml of ethyl acetate and 10 ml of water, and then washed once with 10 mL of saturated brine, and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was dried to dryness, and then purified by column chromatography (PE: EA = 4:1) to give a white syrup (Compound IV) 1.86 g, yield 72.3%.
MS:[M+Na]+:281.13 本发明实施例 4c-5c提供了式 IV化合物的制备方法
-5C的反应路线如下所示: MS: [M+Na] + : 281.13 Inventive Examples 4c-5c provide a method of preparing a compound of formula IV The reaction route for -5C is as follows:
IIIc 实施例 4c IIIc Example 4c
称取 （化合物 li e) 3.3g (O.Olmol) , 溶于 20mL的 DMF中， 冰水浴下加入 NaH 1.2g(0.03mol)于 20°C下搅拌反应 30min后，滴加硫酸二甲酯 1.4ml(0.015mol， 1.5eq)， 25°C下反应 10h后。 TLC (PE: EA=15:1 ) 监测， 反应完毕。 冰水浴下， 加入 20mL饱和氯化铵后， 搅拌 30min， 体系浓缩后， 用 50mL乙酸乙酯稀释， 饱 和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色 油状物 （化合物 IIIc) 3.6g, 直接下一步。 Weighed (Compound Li e) 3.3g (O.Olmol), dissolved in 20mL of DMF, added NaH 1.2g (0.03mol) under ice water bath and stirred at 20 ° C for 30min, then add dimethyl sulfate 1.4 Ml (0.015 mol, 1.5 eq), after reacting at 25 ° C for 10 h. TLC (PE: EA=15:1) was monitored and the reaction was completed. Under ice-water bath, after adding 20 mL of saturated ammonium chloride, the mixture was stirred for 30 min, and the system was concentrated, diluted with 50 mL of ethyl acetate, washed once with 20 mL of saturated brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was dried to give 3.6 g (yel.
MS:[M+Na]+:335.14 实施例 5c MS: [M+Na]+: 335.14 Example 5c
称取 （化合物 IIIc) 3.3g, 溶于 30mL四氢呋喃： 水 =15:1 的溶液中。 滴加冰 醋酸 Llml (0.02mol, 2eq)， 于 30°C搅拌反应 60h。 TLC (PE: EA=15:1 ) 监测， 反应完毕。 加饱和碳酸钠溶液调节 PH=9后， 加入 20ml乙酸乙酯和 10ml水稀释 滤液后， 用饱和食盐水 10mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干 后， 经柱层析（PE: EA=4:1 )得到白色糖浆状物（化合物 IV ) 1.56g， 收率 60.3%。 3.3 g of (Compound IIIc) was weighed and dissolved in a solution of 30 mL of tetrahydrofuran:water = 15:1. Ice lactic acid (1 ml) (0.02 mol, 2 eq) was added dropwise, and the mixture was stirred at 30 ° C for 60 h. TLC (PE: EA=15:1) was monitored and the reaction was completed. After adjusting the pH of the saturated sodium carbonate solution, the filtrate was diluted with 20 ml of ethyl acetate and 10 ml of water, and then washed once with 10 mL of saturated brine, and dried over anhydrous Na? After filtration, the filtrate was spun dry, and then purified by column chromatography (PE: EA = 4:1) to give a white syrup (Compound IV) 1.56 g, yield 60.3%.
MS:[M+Na]+:281.13 本发明实施例 4d-5d提供了式 IV化合物的制备方法 MS: [M+Na]+: 281.13 Inventive Examples 4d-5d provide a method for preparing a compound of formula IV
以下实施例 4d-5d的反应路线如下所示：
The reaction schemes of the following Examples 4d-5d are as follows:
li d Illd Li d Illd
实施例 4d Example 4d
称取 （化合物 li d) 3.2g (O.Olmol) , 溶于 20mL的 DMF中， 冰水浴下加入 NaH 1.2g(0.03mol)于 20°C下搅拌反应 30min后，滴加碳酸二甲酯 1.7ml(0.02mol， 2eq)， 80°C下反应 32h后。 TLC (PE: EA=15:1 ) 监测， 反应完毕。 冰水浴下， 加 入 20mL饱和氯化铵后， 搅拌 30min， 体系浓缩后， 用 50mL乙酸乙酯稀释， 饱和 食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色油 状物 （化合物 Illd) 3.4g， 直接下一步。 Weighed (Compound Li d) 3.2g (O.Olmol), dissolved in 20mL of DMF, added NaH 1.2g (0.03mol) under ice water bath and stirred at 20 ° C for 30min, then add dimethyl carbonate 1.7 Ml (0.02 mol, 2 eq), after reaction at 80 ° C for 32 h. TLC (PE: EA=15:1) was monitored and the reaction was completed. Under ice water bath, 20 mL of saturated ammonium chloride was added, and the mixture was stirred for 30 minutes. After concentration, the mixture was concentrated, diluted with 50 mL of ethyl acetate, and then washed twice with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was dried to give 3.4 g (yield of compound Illd) as a colorless oil.
MS:[M+Na]+:349.17 实施例 5d MS: [M+Na]+: 349.17 Example 5d
称取 （化合物 Illd) 3.3g, 溶于 30mL DMF: 水 =20:1的溶液中。 滴加三氟乙 酸 0.11ml (0.0015mol,0.15eq) , 于 40°C搅拌反应 lh。 TLC (PE: EA=15:1 ) 监测， 反应完毕。 加饱和碳酸钠溶液调节 PH=9后， 加入 20ml乙酸乙酯和 10ml水稀释 滤液后， 用饱和食盐水 10mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干 后， 经柱层析（PE: EA=4:1 )得到白色糖浆状物（化合物 IV ) 1.12g， 收率 43.6%。 Weigh (Compound Illd) 3.3g, dissolved in 30mL DMF: water = 20:1 solution. 0.11 ml (0.0015 mol, 0.15 eq) of trifluoroacetic acid was added dropwise, and the reaction was stirred at 40 ° C for lh. TLC (PE: EA=15:1) was monitored and the reaction was completed. After adjusting the pH of the saturated sodium carbonate solution, the filtrate was diluted with 20 ml of ethyl acetate and 10 ml of water, and then washed once with 10 mL of saturated brine, and dried over anhydrous Na? After filtration, the filtrate was dried to dryness, and then purified by column chromatography (PE: EA = 4:1) to give white syrup (Comp. IV) 1.12 g, yield 43.6%.
MS:[M+Na]+:281.13 MS: [M+Na]+: 281.13
称取 （化合物 li e) 3.1g (O.Olmol) , 溶于 20mL的 DMF中， 冰水浴下加入 NaH 1.2g (0.03mol) 于 20°C下搅拌反应 30min后， 滴加碘甲垸 1.3ml (0.02mol), 30°C下反应 16h后。 TLC (PE: EA=15:1 )监测， 反应完毕。冰水浴下， 加入 20mL 饱和氯化铵后， 搅拌 30min， 体系浓缩后， 用 50mL 乙酸乙酯稀释， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色油状物 （化 合物 Ille) 4.0g， 直接下一步。 Weighed (Compound Li e) 3.1g (O.Olmol), dissolved in 20mL of DMF, added NaH 1.2g (0.03mol) under ice water bath, stirred at 20 ° C for 30min, then added dropwise iodothymidine 1.3ml (0.02 mol), after reacting at 30 ° C for 16 h. TLC (PE: EA = 15:1) was monitored and the reaction was completed. After adding 20 mL of saturated ammonium chloride to the ice water bath, the mixture was stirred for 30 minutes, and the mixture was concentrated, diluted with 50 mL of ethyl acetate, and washed twice with saturated brine (20 mL) and dried over anhydrous Na? After filtration, the filtrate was dried to give a colorless oil (yield Ille) 4.0 g.
MS:[M+Na]+:395.14 实施例 5e MS: [M+Na]+: 395.14 Example 5e
称取 （化合物 Ille) 3.3g, 溶于 30mL丙酮： 水 =15:1的溶液中。 滴加对甲苯 磺酸 0.57g (0.003mol,0.3eq), 于 60°C搅拌反应 4h。 TLC (PE: EA=15:1 ) 监测， 反应完毕。 加饱和碳酸钠溶液调节 PH=9后， 加入 20ml乙酸乙酯和 10ml水稀释 滤液后， 用饱和食盐水 10mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干 后， 经柱层析（PE: EA=4:1 )得到白色糖浆状物（化合物 IV ) 1.89g， 收率 73.1%。 Weigh (Compound Ille) 3.3g, dissolved in 30mL of acetone: water = 15:1 solution. 0.57 g (0.003 mol, 0.3 eq) of p-toluenesulfonic acid was added dropwise, and the reaction was stirred at 60 ° C for 4 h. TLC (PE: EA=15:1) was monitored and the reaction was completed. After adjusting the pH of the saturated sodium carbonate solution, the filtrate was diluted with 20 ml of ethyl acetate and 10 ml of water, and then washed once with 10 mL of saturated brine, and dried over anhydrous Na? After filtration, the filtrate was dried to dryness, and then purified by column chromatography (PE: EA = 4:1) to yield white syrup (Compound IV) 1.89 g, yield 73.1%.
MS:[M+Na]+:281.13 本发明实施例 4f-5f提供了式 IV化合物的制备方法 MS: [M+Na]+: 281.13 Inventive Example 4f-5f provides a method for preparing a compound of formula IV
-5f的反应路线如下所示: The reaction route for -5f is as follows:
实施例 4f Example 4f
称取 （化合物 II f) 3.9g (O.Olmol) , 溶于 20mL的 DMF中， 冰水浴下加入 NaH 1.2g(0.03mol)于 20°C下搅拌反应 30min后，滴加碳酸二甲酯 1.7ml(0.02mol， 2eq)， 48°C下反应 27h后。 TLC (PE: EA=15:1 ) 监测， 反应完毕。 冰水浴下， 加
入 20mL饱和氯化铵后， 搅拌 30min， 体系浓缩后， 用 50mL乙酸乙酯稀释， 饱和 食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色油 状物 （化合物 Illf) 4.0g， 直接下一步。 Weighed (Compound II f) 3.9g (O.Olmol), dissolved in 20mL of DMF, added NaH 1.2g (0.03mol) under ice water bath and stirred at 20 ° C for 30min, then add dimethyl carbonate 1.7 Ml (0.02 mol, 2 eq), after reaction at 48 ° C for 27 h. TLC (PE: EA=15:1) was monitored and the reaction was completed. Under the ice water bath, add After 20 mL of saturated ammonium chloride was added, the mixture was stirred for 30 minutes, and the mixture was concentrated, diluted with 50 mL of ethyl acetate, and washed twice with saturated brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was dried to give a colorless oil (Compound Illf) 4.0 g.
MS:[M+Na]+:409.07 实施例 5f MS: [M+Na]+: 409.07 Example 5f
称取 （化合物 Illf) 3.9g， 溶于 30mL二氧六环： 水 =20:1 的溶液中。 滴加磷 钨酸 0.28g (0.001mol,0.1eq), 于 45°C搅拌反应 30h。 TLC (PE: EA=15:1 ) 监测， 反应完毕。 加饱和碳酸钠溶液调节 PH=9后， 加入 20ml乙酸乙酯和 10ml水稀释 滤液后， 用饱和食盐水 10mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干 后， 经柱层析（PE: EA=4:1 )得到白色糖浆状物（化合物 IV ) 1.38g， 收率 53.3%。 Weigh (Compound Illf) 3.9 g, dissolved in 30 mL of dioxane: water = 20:1 solution. 0.28 g (0.001 mol, 0.1 eq) of phosphotungstic acid was added dropwise, and the reaction was stirred at 45 ° C for 30 h. TLC (PE: EA=15:1) was monitored and the reaction was completed. After adjusting the pH of the saturated sodium carbonate solution, the filtrate was diluted with 20 ml of ethyl acetate and 10 ml of water, and then washed once with 10 mL of saturated brine, and dried over anhydrous Na? After filtration, the filtrate was dried to dryness, and then purified by column chromatography (PE: EA = 4:1) to give white syrup (Compound IV) 1.38 g, yield 53.3%.
MS:[M+Na]+:281.13 本发明实施例 4 -5g提供了式 IV化合物的制备方法
MS: [M+Na]+: 281.13 Inventive Example 4 - 5 g provides a method for preparing a compound of formula IV
实施例 4g Example 4 g
称取 （化合物 Il g) 3.4g (O.Olmol), 溶于 20mL的四氢呋喃中， 冰水浴下加 入 NaH 1.2g (0.03mol) 于 20°C下搅拌反应 30min 后， 滴加硫酸二甲酯 1.4ml (0.015mol, 1.5eq)， 65°C下反应 32h后。 TLC (PE: EA=15: 1 )监测， 反应完毕。 冰水浴下， 加入 20mL饱和氯化铵后， 搅拌 30min， 体系浓缩后， 用 50mL乙酸乙 酯稀释， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色油状物 （化合物 Illg) 3.8g， 直接下一步。 Weighed (Compound Il g) 3.4g (O.Olmol), dissolved in 20mL of tetrahydrofuran, added NaH 1.2g (0.03mol) under ice water bath and stirred at 20 ° C for 30min, then add dimethyl sulfate 1.4 Ml (0.015 mol, 1.5 eq), after reaction at 65 ° C for 32 h. TLC (PE: EA = 15: 1) was monitored and the reaction was completed. Under ice water bath, 20 mL of saturated ammonium chloride was added, and the mixture was stirred for 30 minutes. After concentration, the system was concentrated, diluted with 50 mL of ethyl acetate, washed once with 20 mL of saturated brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was dried to give 3.8 g, m.
MS:[M+Na]+:369.16
实施例 5g MS: [M+Na]+: 369.16 Example 5 g
称取 （化合物 Illg) 3.9g， 溶于 30mL 甲醇： 乙醇： 水 =10:10: 1的溶液中。 滴加磷钼酸 0.18g (0.001mol,0.1eq), 于 0°C搅拌反应 30h。 TLC (PE: EA=15: 1 ) 监测， 反应完毕。 加饱和碳酸钠溶液调节 PH=9后， 加入 20ml乙酸乙酯和 10ml 水稀释滤液后， 用饱和食盐水 10mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤 液旋干后， 经柱层析 （PE: EA=4:1 ) 得到白色糖浆状物 （化合物 IV ) 1.22g， 收率 47.4%。 Weighed (Compound Illg) 3.9 g, dissolved in 30 mL of methanol: ethanol: water = 10:10:1 solution. 0.18 g (0.001 mol, 0.1 eq) of phosphomolybdic acid was added dropwise, and the reaction was stirred at 0 ° C for 30 h. TLC (PE: EA=15: 1) was monitored and the reaction was completed. After adjusting the pH of the saturated sodium carbonate solution, the filtrate was diluted with 20 ml of ethyl acetate and 10 ml of water, and then washed once with 10 mL of saturated brine and dried over anhydrous Na? After filtration, the filtrate was dried and purified by column chromatography (PE: EA = 4:1) to yield white syrup (Comp. IV) 1.22 g, yield 47.4%.
MS:[M+Na]+:281.13 本发明实施例 4h-5h提供了式 IV化合物的制备方法 MS: [M+Na]+: 281.13 Inventive Example 4h-5h provides a method for preparing a compound of formula IV
-5h的反应路线如下所示: The reaction route for -5h is as follows:
实施例 4h Example 4h
称取 （化合物 Ilh) 3.7g (O.Olmol) , 溶于 20mL的 DMF中， 冰水浴下加入 Weigh (Compound Ilh) 3.7g (O.Olmol), dissolve in 20mL of DMF, add in ice water bath
NaH 1.2g(0.03mol)于 20°C下搅拌反应 30min后，滴加硫酸二甲酯 1.4ml(0.015mol， 1.5eq)， 50°C下反应 12h后。 TLC (PE: EA=15:1 ) 监测， 反应完毕。 冰水浴下， 加入 20mL饱和氯化铵后， 搅拌 30min， 体系浓缩后， 用 50mL乙酸乙酯稀释， 饱 和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色 油状物 （化合物 Ii ) 4.1g， 直接下一步。 After stirring NaH 1.2 g (0.03 mol) at 20 ° C for 30 min, dimethyl sulfate 1.4 ml (0.015 mol, 1.5 eq) was added dropwise, and reacted at 50 ° C for 12 h. TLC (PE: EA=15:1) was monitored and the reaction was completed. Under ice-water bath, after adding 20 mL of saturated ammonium chloride, the mixture was stirred for 30 min, and the system was concentrated, diluted with 50 mL of ethyl acetate, washed once with 20 mL of saturated brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was dried to give a colorless oil (Comp.
MS:[M+Na]+:399.17 实施例 5h MS: [M+Na]+: 399.17 Example 5h
称取 （化合物 Iim ) 3.9g， 溶于 30mL 甲醇： 水 =15: 1 的溶液中。 滴加
Nafion0.22g, 于 20°C搅拌反应 16h。 TLC (PE: EA=15: 1 )监测， 反应完毕。 加饱 和碳酸钠溶液调节 PH=9后， 加入 20ml乙酸乙酯和 10ml水稀释滤液后， 用饱和 食盐水 10mL洗涤一次，无水 Na2SO4干燥。过滤，将滤液旋干后，经柱层析（PE: EA=4: 1 ) 得到白色糖浆状物 （化合物 IV ) 0.8g， 收率 31.8%。 Weigh (Compound Iim) 3.9 g, dissolved in 30 mL of methanol: water = 15:1 solution. Drop Nafion 0.22 g, and the reaction was stirred at 20 ° C for 16 h. TLC (PE: EA = 15: 1) was monitored and the reaction was completed. After adjusting the pH = 9 with a saturated sodium carbonate solution, the filtrate was diluted with 20 ml of ethyl acetate and 10 ml of water, and then washed once with 10 mL of saturated brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was spin-dried, and then subjected to column chromatography (PE: EA = 4:1) to obtain a white syrup (Compound IV) 0.8 g, yield 31.8%.
MS:[M+Na]+:281.13 本发明实施例 4i-5i提供了式 IV化合物的制备方法 MS: [M+Na]+: 281.13 Inventive Example 4i-5i provides a method for preparing a compound of formula IV
-5i的反应路线如下所示: The reaction route for -5i is as follows:
实施例 4i Example 4i
称取 （化合物 Il i) 3.1g (O.Olmol) , 溶于 20mL的四氢呋喃中， 冰水浴下加 入 NaH 1.2g ( 0.03mol) 于 20°C下搅拌反应 30min 后， 滴加硫酸二甲酯 1.4ml (0.015mol， 1.5eq)， 72°C下反应 12h后。 TLC (PE: EA=15: 1 )监测， 反应完毕。 冰水浴下， 加入 20mL饱和氯化铵后， 搅拌 30min， 体系浓缩后， 用 50mL乙酸乙 酯稀释， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色油状物 （化合物 Illi) 3.5g， 直接下一步。 Weigh (Compound Il i) 3.1g (O.Olmol), dissolved in 20mL of tetrahydrofuran, add NaH 1.2g (0.03mol) under ice water bath and stir the reaction at 20 °C for 30min, then add dimethyl sulfate 1.4 Ml (0.015 mol, 1.5 eq), after reaction at 72 ° C for 12 h. TLC (PE: EA = 15: 1) was monitored and the reaction was completed. Under ice water bath, 20 mL of saturated ammonium chloride was added, and the mixture was stirred for 30 minutes. After concentration, the system was concentrated, diluted with 50 mL of ethyl acetate, washed once with 20 mL of saturated brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was spun dry to give a colorless oil (Comp. Illi) 3.5 g.
MS:[M+Na]+:347.14 实施例 5i MS: [M+Na]+: 347.14 Example 5i
称取 （化合物 Illi) 3.2g， 溶于 30mL 甲醇： 水 =15: 1的溶液中。 滴加磷钼酸 Weigh (Compound Illi) 3.2g, dissolved in 30mL of methanol: water = 15: 1 solution. Adding phosphomolybdic acid
45.6g (0.025mol,2.5eq) , 于 10°C搅拌反应 1.5h。 TLC (PE: EA=15: 1 ) 监测， 反 应完毕。 加饱和碳酸钠溶液调节 PH=9后， 加入 20ml乙酸乙酯和 10ml水稀释滤 液后， 用饱和食盐水 10mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 经柱层析 （PE: EA=4: 1 ) 得到白色糖浆状物 （化合物 IV ) 0.54g， 收率 20.8%。 45.6 g (0.025 mol, 2.5 eq), and stirred at 10 ° C for 1.5 h. TLC (PE: EA=15: 1) monitoring, the reaction is completed. After adjusting the pH of the saturated sodium carbonate solution, the filtrate was diluted with 20 ml of ethyl acetate and 10 ml of water, and then washed once with 10 mL of saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was spun dry, and then purified by column chromatography (PE: EA = 4:1) to yield white syrup (Comp.
MS:[M+Na]+:281.13
本发明实施例 4j-5j提供了式 IV化合物的制备方法MS: [M+Na]+: 281.13 Inventive Example 4j-5j provides a method for preparing a compound of formula IV
-5j的反应路线如下所示: The reaction route for -5j is as follows:
实施例 4j Example 4j
称取 （化合物 Ilj ) 3.3g (O.Olmol) , 溶于 20mL的四氢呋喃中， 冰水浴下加 入 NaH 1.2g (0.03mol) 于 20°C下搅拌反应 30min 后， 滴加硫酸二甲酯 1.4ml (0.015mol, 1.5eq)， 20°C下反应 18h后。 TLC (PE: EA=15: 1 )监测， 反应完毕。 冰水浴下， 加入 20mL饱和氯化铵后， 搅拌 30min， 体系浓缩后， 用 50mL乙酸乙 酯稀释， 饱和食盐水 20mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 得到无色油状物 （化合物 Illj ) 3.7g， 直接下一步。 Weigh (Compound Ilj) 3.3g (O.Olmol), dissolved in 20mL of tetrahydrofuran, add NaH 1.2g (0.03mol) under ice water bath, stir the reaction at 20 °C for 30min, then add dimethyl sulfate 1.4ml (0.015 mol, 1.5 eq), after 18 h at 20 ° C. TLC (PE: EA = 15: 1) was monitored and the reaction was completed. Under ice water bath, 20 mL of saturated ammonium chloride was added, and the mixture was stirred for 30 minutes. After concentration, the system was concentrated, diluted with 50 mL of ethyl acetate, washed once with 20 mL of saturated brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was dried to give 3.7 g (yield of compound Illj) as a colorless oil.
MS:[M+Na]+:361.14 实施例 5j MS: [M+Na]+: 361.14 Example 5j
称取 （化合物 Illj ) 3.4g， 溶于 30mL 甲醇： 水 =15: 1的溶液中。 滴加磷钨酸 Weigh (Compound Illj) 3.4g, dissolved in 30mL of methanol: water = 15: 1 solution. Adding phosphotungstic acid
2.8g (0.001mol,0.1eq)和磷钼酸 1.8g (0.001mol,0.1eq), 于 80°C搅拌反应 4h。 TLC (PE: EA=15: 1 ) 监测， 反应完毕。 加饱和碳酸钠溶液调节 PH=9后， 加入 20ml 乙酸乙酯和 10ml水稀释滤液后， 用饱和食盐水 10mL洗涤一次， 无水 Na2SO4干 燥。 过滤， 将滤液旋干后， 经柱层析 （PE: EA=4:1 ) 得到白色糖浆状物 （化合物 IV ) 0.65g, 收率 25·3%。 2.8 g (0.001 mol, 0.1 eq) and 1.8 g (0.001 mol, 0.1 eq) of phosphomolybdic acid were stirred at 80 ° C for 4 h. TLC (PE: EA=15: 1) was monitored and the reaction was completed. After adjusting the pH of the saturated sodium carbonate solution, the filtrate was diluted with 20 ml of ethyl acetate and 10 ml of water, and then washed once with 10 mL of brine, and dried over anhydrous Na? After filtration, the filtrate was spun dry, and then subjected to column chromatography (PE: EA = 4:1) to obtain white syrup (Compound IV) 0.65 g, yield 25.5%.
MS:[M+Na]+:281.13 安立生坦的制备 (反应过程 1) (实施例 6-14)
MS: [M+Na]+: 281.13 Preparation of ambrisentan (Reaction Process 1) (Examples 6-14)
S- I 反应过程 1 S-I reaction process 1
实施例 6 Example 6
称取 （化合物 IV ) 8.6g (33mmol), 溶于 70mL 四氢呋喃中。 依次加入 3g KH2PO4和 6g K2HPO4的 35ml水溶液、 TEMPO 52mmg (0.3mmol)、 亚氯酸钠 12g (0.13mol)， 于 25下搅拌反应 14h。 TLC (PE: EA=2:1 ) 监测， 反应完毕。 冰水 浴下， 滴加饱和亚硫酸钠， 100ml乙酸乙酯稀释后， 滴加浓盐酸调节 PH=2后， 用 200mL 乙酸乙酯和 50ml水稀释后， 再用饱和食盐水 150mL洗涤， 无水 Na2SO4 干燥。 过滤， 将滤液旋干后， 环己垸重结晶， 得 (化合物 V)白色固体 10.2g， 收率 74.5%, 光学纯度 99.95 % ee 。 (Compound IV) 8.6 g (33 mmol) was weighed and dissolved in 70 mL of tetrahydrofuran. 3 g of KH 2 PO 4 and 6 g of K 2 HPO 4 in 35 ml of water, TEMPO 52 mmg (0.3 mmol), and sodium chlorite 12 g (0.13 mol) were successively added, and the reaction was stirred at 25 ° for 14 h. TLC (PE: EA=2:1) was monitored and the reaction was completed. Under ice-water bath, add saturated sodium sulfite, dilute with 100 ml of ethyl acetate, add concentrated hydrochloric acid dropwise to adjust pH = 2, dilute with 200 mL of ethyl acetate and 50 ml of water, and then wash with 150 mL of saturated brine, anhydrous Na 2 SO 4 dry. After filtration, the filtrate was spun dry, and the cyclohexanide was recrystallized to give (Compound V) white solid 10.2 g, yield 74.5%, optical purity 99.95 % ee.
MS: [M+Na]+:295.15 实施例 7 MS: [M+Na] + : 295.15 Example 7
称取（化合物 V ) 0.2g (24mmol)，溶于 2mL 四氢呋喃。依次加入 50%NaOH 水溶液 lml， 4，6-二甲基 -2-甲磺酰基嘧啶 0.14g (24mmol)， 四丁基硫酸氢铵 12mg (0.03mmol) , 于 25°C下搅拌反应 4h。 TLC (DCM: MeOH=9:l ) 监测， 反应完 毕。 体系加水稀释后， 滴加盐酸搅拌， 析出固体后过滤， 得到淡黄色固体 （安立 生坦 S- I ) 0.15g， 收率 53.6% (Compound V) 0.2 g (24 mmol) was weighed and dissolved in 2 mL of tetrahydrofuran. Then, 1 ml of a 50% aqueous NaOH solution, 4,6-dimethyl-2-methylsulfonylpyrimidine 0.14 g (24 mmol), tetrabutylammonium hydrogen sulfate 12 mg (0.03 mmol) were added, and the reaction was stirred at 25 ° C for 4 h. TLC (DCM: MeOH = 9:1) was monitored and the reaction was completed. After the system was diluted with water, the mixture was stirred with hydrochloric acid, and the solid was separated and filtered to give a pale-yellow solid (Ansine S-I) 0.15 g, yield 53.6%
MS:[M+Na]+:401.13 MS: [M+Na] + : 401.13
1H NM : (DMSO) 52.35 (s, 6H)， 3.38 (s, 3H), 6.15(s, 1H)， 6.95 (s, 1H)， 1H NM : (DMSO) 52.35 (s, 6H), 3.38 (s, 3H), 6.15(s, 1H), 6.95 (s, 1H),
7.20-7.38 (m, 10H) 实施例 8
将粗品安立生坦 30g (0.08mol) 和异丙醇 189ml和甲醇 21ml加热回流， 热 滤后滤液冷却至 25°C， 搅拌 45分钟， 过滤， 滤饼用异丙醇和甲醇洗涤， 60°C下干 燥， 得安立生坦 (21g， 收率 70%)， 光学纯度 99.97 % ee。 7.20-7.38 (m, 10H) Example 8 The crude ambrisentan 30g (0.08mol) and 189ml of isopropanol and 21ml of methanol were heated to reflux. After hot filtration, the filtrate was cooled to 25 ° C, stirred for 45 minutes, filtered, and the filter cake was washed with isopropyl alcohol and methanol at 60 ° C. Dry, ambrisentan (21 g, yield 70%), optical purity 99.97% ee.
MS: [M+Na]+:401.13 MS: [M+Na] + :401.13
1H NM : (DMSO) 52.35 (s, 6H)， 3.38 (s, 3H), 6.15(s, 1H)， 6.95 (s, 1H)， 7.20-7.38 (m, 10H) 实施例 9 1H NM : (DMSO) 52.35 (s, 6H), 3.38 (s, 3H), 6.15 (s, 1H), 6.95 (s, 1H), 7.20-7.38 (m, 10H) Example 9
称取（化合物 IV ) 2.6g ( lOmmol) ,溶于 30mL 乙腈中。依次加入 lg KH2PO4 禾卩 2g K2HPO4的 10ml水溶液、 TEMPO 0.15g ( lmmol, 0.1eq)、 亚氯酸钠 1.8g (0.02mol， 2eq)， 于 25下搅拌反应 16h。 TLC (PE: EA=2:1 ) 监测， 反应完毕。 冰水浴下，滴加饱和亚硫酸钠， 100ml乙酸乙酯稀释后，滴加浓硫酸调节 PH=2后， 用 50mL 乙酸乙酯和 20ml水稀释后， 再用饱和食盐水 20mL洗涤， 无水 Na2SO4 干燥。 过滤， 将滤液旋干后， 环己垸重结晶， 得 (化合物 V)白色固体 1.96g， 收率 72.1%, 光学纯度 99.95 % ee。 (Compound IV) 2.6 g (10 mmol) was weighed and dissolved in 30 mL of acetonitrile. 10 ml of an aqueous solution of lg KH 2 PO 4 and 2 g of K 2 HPO 4 , TEMPO 0.15 g (1 mmol, 0.1 eq), and sodium chlorite (1.8 g, 0.02 mol, 2 eq) were successively added, and the reaction was stirred at 25 ° for 16 h. TLC (PE: EA=2:1) was monitored and the reaction was completed. Under ice-water bath, add saturated sodium sulfite, dilute with 100 ml of ethyl acetate, add concentrated sulfuric acid dropwise to adjust pH=2, dilute with 50 mL of ethyl acetate and 20 ml of water, then wash with 20 mL of saturated brine, anhydrous Na 2 SO 4 dry. After filtration, the filtrate was spun dry, and the cyclohexanide was recrystallized to give (Compound V) white solid 1.96 g, yield 72.1%, optical purity 99.95% ee.
MS: [M+Na]+:295.15 实施例 10 MS: [M+Na] + : 295.15 Example 10
称取 （化合物 V ) 2.8g ( lOmmol), 溶于 2mL 乙腈。 依次加入 50%NaOH 水溶液 lml， 4，6-二甲基 -2-甲磺酰基嘧啶 1.9g ( lOmmol) , 四丁基溴化铵 40mg (O.lmmol) , 于 25°C下搅拌反应 8h。 TLC (DCM: MeOH=9:l )监测， 反应完毕。 体系加水稀释后， 滴加盐酸搅拌， 析出固体后过滤， 得到淡黄色固体 （安立生坦 S- I ) 1.7g， 收率 43.8%， 光学纯度 99.95 % ee。 (Compound V) 2.8 g (10 mmol) was dissolved in 2 mL of acetonitrile. Then, 1 ml of a 50% aqueous NaOH solution, 1.9 g (10 mmol) of 4,6-dimethyl-2-methylsulfonylpyrimidine, and 40 mg (0.1 mmol) of tetrabutylammonium bromide were added thereto, and the mixture was stirred at 25 ° C for 8 hours. TLC (DCM: MeOH = 9:1) was monitored and the reaction was completed. After the system was diluted with water, hydrochloric acid was added dropwise with stirring, and the solid was separated and then filtered to give a pale-yellow solid (Anlishengtan S-I) 1.7 g, yield 43.8%, optical purity 99.95 % ee.
MS:[M+Na]+:401.13 实施例 11 MS: [M+Na] + : 401.13 Example 11
称取 （化合物 IV ) 2.62g ( lOmmol), 溶于 30mL二氧六环中。 依次加入 2g KH2PO4和 lg K2HPO4的 10ml水溶液、 TEMPO 0.75g (5mmol, 0.5eq)、 亚氯酸钠
3.6g (0.02mol, 4eq)， 于 25下搅拌反应 16h。 TLC (PE: EA=2:1 ) 监测， 反应完 毕。冰水浴下，滴加饱和亚硫酸钠， 100ml乙酸乙酯稀释后，滴加浓磷酸调节 PH=2 后，用 50mL 乙酸乙酯和 20ml水稀释后，再用饱和食盐水 20mL洗涤，无水 Na2SO4 干燥。 过滤， 将滤液旋干后， 环己垸重结晶， 得 (化合物 V)白色固体 1.26g， 收率 46.5%, 经 HPLC测定， 纯度大于 99%， 光学纯度 99.96 % ee。 (Compound IV) 2.62 g (10 mmol) was dissolved in 30 mL of dioxane. 2 g of KH 2 PO 4 and lg K 2 HPO 4 in 10 ml of water, TEMPO 0.75 g (5 mmol, 0.5 eq), sodium chlorite 3.6 g (0.02 mol, 4 eq), the reaction was stirred at 25 ° for 16 h. TLC (PE: EA=2:1) was monitored and the reaction was completed. Under ice-water bath, add saturated sodium sulfite, dilute with 100 ml of ethyl acetate, add concentrated phosphoric acid dropwise to adjust pH=2, dilute with 50 mL of ethyl acetate and 20 ml of water, and then wash with saturated brine 20 mL, anhydrous Na 2 SO 4 dry. After filtration, the filtrate was spun dry, and the cyclohexanide was recrystallized to give (Compound V) white solid 1.26 g, yield 46.5%, purity by more than 99%, and optical purity of 99.96% ee.
MS: [M+Na]+:295.15 实施例 12 MS: [M+Na] + : 295.15 Example 12
称取（化合物 V )2.76g ( lOmmol)，溶于 2mL二氧六环。依次加入 50%NaOH 水溶液 lml， 4，6-二甲基 -2-甲磺酰基嘧啶 1.9g ( lOmmol) , 四丁基碘化铵 45mg (O.lmmol) , 于 25°C下搅拌反应 8h。 TLC (DCM: MeOH=9:l )监测， 反应完毕。 体系加水稀释后， 滴加盐酸搅拌， 析出固体后过滤， 得到淡黄色固体 （安立生坦 S- I ) 1.5g， 收率 39.6%， 光学纯度 99.96 % ee。 (Compound V) 2.76 g (10 mmol) was weighed and dissolved in 2 mL of dioxane. Then, 1 ml of a 50% aqueous NaOH solution, 1.9 g (10 mmol) of 4,6-dimethyl-2-methylsulfonylpyrimidine, and 45 mg (0.1 mmol) of tetrabutylammonium iodide were added, and the reaction was stirred at 25 ° C for 8 h. TLC (DCM: MeOH = 9:1) was monitored and the reaction was completed. After the system was diluted with water, hydrochloric acid was added dropwise with stirring, and the solid was separated and filtered to give a pale-yellow solid (Anlishengtan S-I) 1.5 g, yield 39.6%, optical purity 99.96 % ee.
MS:[M+Na]+:401.13 实施例 13 MS: [M+Na] + : 401.13 Example 13
称取 （化合物 IV ) 2.5g ( lOmmol), 溶于 30mL 四氢呋喃中。 依次加入 lg KH2PO4和 2.5g K2HPO4的 10ml水溶液、 TEMPO 1.5mg (O.Olmmol, 0.001eq)、 亚氯酸钠 0.9g ( lOmol, leq)， 于 25下搅拌反应 20h。 TLC (PE: EA=2: 1 ) 监测， 反应完毕。冰水浴下， 滴加饱和亚硫酸钠， 100ml乙酸乙酯稀释后， 滴加浓磷酸调 节 PH=2后， 用 50mL 乙酸乙酯和 20ml水稀释后， 再用饱和食盐水 20mL洗涤， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 环己垸重结晶， 得 (化合物 V)白色固体 1.58g， 收率 56.5%， 经 HPLC测定， 纯度大于 99%。 (Compound IV) 2.5 g (10 mmol) was weighed and dissolved in 30 mL of tetrahydrofuran. 10 ml of an aqueous solution of lg KH 2 PO 4 and 2.5 g of K 2 HPO 4 , TEMPO 1.5 mg (0.1 mmol, 0.001 eq), sodium chlorite 0.9 g (10 mol, leq) were successively added, and the reaction was stirred at 25 ° for 20 h. TLC (PE: EA=2: 1) was monitored and the reaction was completed. Under ice-water bath, add saturated sodium sulfite, dilute with 100 ml of ethyl acetate, add concentrated phosphoric acid dropwise to adjust pH=2, dilute with 50 mL of ethyl acetate and 20 ml of water, then wash with 20 mL of saturated brine, anhydrous Na 2 SO 4 dry. After filtration, the filtrate was spun dry, and the cyclohexanide was recrystallized to give (Compound V) white solid 1.58 g, yield 56.5%, and the purity was more than 99% by HPLC.
MS: [M+Na]+:295.15 实施例 14 MS: [M+Na] + : 295.15 Example 14
称取（化合物 V )2.71g ( lOmmol)，溶于 2mL二氧六环。依次加入 50%NaOH 水溶液 lml， 4，6-二甲基 -2-甲磺酰基嘧啶 1.9g ( lOmmol) , 四丁基氯化铵 38mg
(O.lmmol), 于 25°C下搅拌反应 10h。 TLC (DCM: MeOH=9:l ) 监测， 反应完 毕。 体系加水稀释后， 滴加硫酸搅拌， 析出固体后过滤， 得到淡黄色固体 （安立 生坦 S- I ) 1.3g, 收率 34.5%。 (Compound V) 2.71 g (10 mmol) was weighed and dissolved in 2 mL of dioxane. Add 1 ml of 50% NaOH aqueous solution, 1.9 g (10 mmol) of 4,6-dimethyl-2-methylsulfonylpyrimidine, and 38 mg of tetrabutylammonium chloride. (O.lmmol), the reaction was stirred at 25 ° C for 10 h. TLC (DCM: MeOH = 9:1) was monitored and the reaction was completed. After the system was diluted with water, sulfuric acid was added dropwise with stirring, and the solid was separated and filtered to give a pale-yellow solid (Anrishengtan S-I) 1.3 g, yield: 34.5%.
MS:[M+Na]+:401.13 安立生坦的制备 (反应过程 2) (实施例 15-29) MS: [M+Na] + : 401.13 Preparation of ambrisentan (Reaction Process 2) (Examples 15-29)
反应过程 2 实施例 15-19， R3为苯甲酰基， 反应式如下:
Reaction Scheme 2 Examples 15-19, R 3 is a benzoyl group, and the reaction formula is as follows:
称取 (化合物 IV ) 7.3g (0.03mol), 溶于 48mL二氯甲垸。 加入吡啶 6.8ml (0.08mol)， 冰水浴下滴加苯甲酰氯 3.4ml (0.03mmol)， 滴加完毕后立即加入甲 醇 5ml。体系中加入浓盐酸调节 PH=2后，加入 200二氯甲垸水稀释，依次用 80mL 水洗涤 2次， 80ml饱和碳酸氢钠饱洗涤一次，食盐水 100mL洗涤一次，无水 Na2SO4 干燥。 过滤， 将滤液旋干后， 石油醚打浆， 得到白色固体 （化合物 VI-a) 8.3g， 收 率 81.4%， 经 HPLC测定， 纯度大于 99%， 99.98 % ee。 (Compound IV) 7.3 g (0.03 mol) was weighed and dissolved in 48 mL of dichloromethane. 6.8 ml (0.08 mol) of pyridine was added, and 3.4 ml (0.03 mmol) of benzoyl chloride was added dropwise thereto in an ice water bath, and 5 ml of methanol was added immediately after the dropwise addition. Add concentrated hydrochloric acid to adjust the pH=2, add 200 dichloromethane water to dilute, wash twice with 80mL water, wash once with 80ml saturated sodium bicarbonate, wash once with 100mL brine, dry with anhydrous Na 2 SO 4 . After filtration, the filtrate was spun and the petroleum ether was slurried to give a white solid (Compound VI-a) 8.3 g, yield: 81.4%, purity by more than 99%, 99.98 % ee.
MS:[M+Na]+:385.10 实施例 16 MS: [M+Na] + : 385.10 Example 16
称取 （化合物 VI-a ) 0.2g ( 0.5mmol )， 4，6-二甲基 -2-甲磺酰基嘧啶 O.lg (0.5mmol) , 碳酸钾 38mg (0.3mmol)， DMF 2ml, 80°C加热过夜后， 加入二氯甲 垸 20ml和水 7ml稀释， 食盐水 10mL洗涤， 无水 Na2SO4干燥。 过滤， 将滤液旋 干后， 柱层析得到白色固体 （化合物 Vn-a) 0.13g， 收率 50.4%%， 经 HPLC测定， 纯度大于 99%, 99.98 % ee。 Weighing (Compound VI-a) 0.2g (0.5mmol), 4,6-dimethyl-2-methylsulfonylpyrimidine O.lg (0.5mmol), potassium carbonate 38mg (0.3mmol), DMF 2ml, 80° After heating overnight, 20 ml of dichloromethane was added and 7 ml of water was added, and 10 mL of brine was washed and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was spin-dried, and then purified by column chromatography to yield white solid (Comp. Vn-a) 0.13 g, yield 50.4%%, purity by more than 99%, 99.98 % ee.
MS:[M+Na]+:391.16
实施例 17 MS: [M+Na] + :391.16 Example 17
称取 (化合物 W-a) 1.6g (4.4mmol) , 溶解于 16ml甲醇溶液中， 加入 0.05g 甲醇钠固体， 室温搅拌 2小时后， TLC (PE: EA=2:1 ) 监测， 反应完毕。 乙酸乙 酯水稀释， 食盐水 10mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 柱 层析（PE: EA=2:1 )， 得到白色糖浆状物（化合物珊） 1.5g， 收率 93.7%， 经 HPLC 测定， 纯度大于 99%， 99.98 % ee。 1.6 g (4.4 mmol) was weighed (Compound Wa), dissolved in 16 ml of methanol solution, and added with 0.05 g of sodium methoxide solid. After stirring at room temperature for 2 hours, TLC (PE: EA = 2:1) was monitored and the reaction was completed. It was diluted with ethyl acetate water, washed once with 10 mL of brine, and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was spun dry, and then subjected to column chromatography (PE: EA = 2:1) to obtain a white syrup (compound) 1.5 g, yield 93.7%, purity by HPLC, greater than 99%, 99.98 % ee .
MS:[M+Na]+:387.23 实施例 18 MS: [M+Na]+: 387.23 Example 18
称取 （化合物珊） 5.1g ( 14mmol)， 溶于 30mL二氯甲垸。 0°C下加入戴斯- 马丁氧化剂（Dess-Martin Periodinane) 12g (28mmol), 自然升至室温反应 2h。 TLC (PE: EA=1 :1 ) 监测， 反应完毕。 冰水浴下加入 10%的 Na2S2O3溶液 10ml， 室 温搅拌 10min， 加入 EA50ml后， 分别用饱和 NaHCO3溶液 10ml， 饱和 NaCl溶 液 20ml洗涤， 无水硫酸钠干燥过夜。 过滤、 40°C旋蒸后， 加入异丙醇 20ml加热 回流， 自然冷却至室温后过滤，得固体（安立生坦 S- I ) 3.8g，收率 72.2%， 99.94 % ee0 Weighed (Compound Shan) 5.1g (14mmol), dissolved in 30mL of dichloromethane. Dess-Martin Periodinane 12g (28mmol) was added at 0 ° C, and naturally raised to room temperature for 2 h. TLC (PE: EA=1:1) was monitored and the reaction was completed. 10 ml of a 10% Na2S2O3 solution was added to the ice water bath, and the mixture was stirred at room temperature for 10 min. After adding 50 ml of EA, respectively, 10 ml of a saturated NaHCO3 solution, 20 ml of a saturated NaCl solution, and dried over anhydrous sodium sulfate overnight. After filtration and steaming at 40 ° C, 20 ml of isopropanol was added and heated to reflux, and the mixture was cooled to room temperature, and then filtered to give a solid (amp. s. s. s.) 3.8 g, yield 72.2%, 99.94 % ee 0
MS: [M+Na]+:401.13 实施例 19 MS: [M+Na] + : 401.13 Example 19
称取 （化合物珊） 5.1g ( 14mmol)， 溶于 20ml丙酮和 20ml水的混合液中。 加入 PtO2共 0.16g (0.7mmol), 60°C反应 24h。 TLC (PE: EA=1 :1 ) 监测， 反应完毕。 过滤， 加入 EA50ml后， lmol/L的稀盐酸 5ml酸化， 至 PH等于 2后， 饱和 NaCl 溶液 20ml洗涤， 无水硫酸钠干燥过夜。 过滤、 40°C旋蒸后， 加入异丙醇 20ml加 热回流，自然冷却至室温后过滤，得固体（安立生坦 S- I )3.2g，收率 60.8%， 99.96 % ee。 Weighed (Compound) 5.1 g (14 mmol) in a mixture of 20 ml of acetone and 20 ml of water. A total of 0.16 g (0.7 mmol) of PtO2 was added and reacted at 60 ° C for 24 h. TLC (PE: EA=1:1) was monitored and the reaction was completed. After filtration, after adding 50 ml of EA, 5 ml of 1 mol/L of dilute hydrochloric acid was acidified, and after the pH was equal to 2, 20 ml of a saturated NaCl solution was washed, and dried over anhydrous sodium sulfate overnight. After filtration and steaming at 40 ° C, 20 ml of isopropanol was added and heated to reflux, and the mixture was cooled to room temperature and then filtered to give a solid (amp.s.
MS: [M+Na]+:40L13。 实施例 20-24， R3为特戊酰基， 反应式如下：
MS: [M+Na]+: 40L13. Examples 20-24, R 3 is a pivaloyl group, and the reaction formula is as follows:
实施例 20 Example 20
称取（化合物 IV ) 2.6g (O.Olmol), 溶于 20mL 乙酸乙酯。加入三乙胺 4.1ml (0.03mol)， 冰水浴下滴加特戊酰氯 1.3ml (O.Ol lmmol) , 滴加完毕后立即加入甲 醇 5ml。体系中加入浓盐酸调节 PH=2后， 加入 40二氯甲垸水稀释， 依次用 20mL 水洗涤 2次， 20ml饱和碳酸氢钠饱洗涤一次，食盐水 20mL洗涤一次，无水 Na2SO4 干燥。 过滤， 将滤液旋干后， 石油醚打浆， 得到白色固体 （化合物 VI-b) 2.5g， 收 率 72.3%， 经 HPLC测定， 纯度大于 95%， 99.96 % ee。 (Compound IV) 2.6 g (0. Olmol) was weighed and dissolved in 20 mL of ethyl acetate. After adding 3.1 ml (0.03 mol) of triethylamine, 1.3 ml (O.Ol.lmmol) of pivaloyl chloride was added dropwise thereto in an ice water bath, and 5 ml of methanol was added immediately after the dropwise addition. After adding concentrated hydrochloric acid to the system to adjust pH=2, it was diluted with 40 dichloromethane water, washed twice with 20 mL of water, washed once with 20 ml of saturated sodium hydrogencarbonate, once with 20 mL of brine, and dried with anhydrous Na2SO4. After filtration, the filtrate was spun dry, and petroleum ether was beaten to obtain a white solid (Compound VI-b) 2.5 g, yield 72.3%, purity determined by HPLC, greater than 95%, 99.96 % ee.
MS:[M+Na]+:365.18 实施例 21 MS: [M+Na]+: 365.18 Example 21
称取（化合物 VI-b )3.3g( l Ommol )， 4，6-二甲基 -2-甲磺酰基嘧啶 1.4g( 1 Ommol )， 碳酸钠 0.53g (5mmol)， 乙腈 15ml， 80°C加热过夜后， 加入二氯甲垸 40ml和水 20ml稀释， 食盐水 20mL洗涤， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 柱层析 得到白色固体 （化合物 Vn-b) 2.5g， 收率 56.4%， 经 HPLC测定， 纯度大于 99%， 99.96 % ee。 Weighing (Compound VI-b) 3.3g (10 mmol), 4,6-dimethyl-2-methylsulfonylpyrimidine 1.4g (1 Ommol), sodium carbonate 0.53g (5mmol), acetonitrile 15ml, 80°C after heating overnight, diluted with 20ml of dichloromethane 40ml was added and washed with water, brine 20mL, dried with anhydrous Na 2 SO 4. After filtration, the filtrate was spin-dried, and then subjected to column chromatography to give a white solid (Compound Vn-b) 2.5 g, yield 56.4%, purity by more than 99%, 99.96 % ee.
MS:[M+Na]+:471.16
实施例 22 MS: [M+Na] + : 471.16 Example 22
称取（化合物 Vn-b) 0.5g ( l.lmmol), 溶解于 5ml甲醇中， 加入甲醇钠 10mg， 室温搅拌 2小时， TLC (PE: EA=2:1 ) 监测， 反应完毕。 乙酸乙酯水稀释， 食盐 水 10mL洗涤一次，无水 Na2SO4干燥。过滤，将滤液旋干后，柱层析（PE: EA=2:1 )， 得到白色糖浆状物（化合物 WD 0.26g，收率 64.7%，经 HPLC测定，纯度大于 99%， 99.96 % ee。 (Compound Vn-b) 0.5 g (1.1 mmol) was dissolved in 5 ml of methanol, and 10 mg of sodium methoxide was added thereto, stirred at room temperature for 2 hours, and monitored by TLC (PE: EA = 2:1). It was diluted with ethyl acetate water, washed once with 10 mL of brine, and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was spin-dried and subjected to column chromatography (PE: EA = 2:1) to give a white syrup (Compound WD 0.26 g, yield: 64.7%, purity by more than 99%, 99.96 % ee by HPLC).
MS:[M+Na]+:387.23 实施例 23 MS: [M+Na]+: 387.23 Example 23
称取 （化合物珊） 1.7g (5mmol)， 溶于 20mL氯仿。 0°C下加入戴斯-马丁氧 化剂 （Dess-Martin Periodinane) 4g (9mmol), 自然升至室温反应 4h。 TLC (PE: EA=1 :1 ) 监测， 反应完毕。 冰水浴下加入 10%的 Na2S2O3溶液 10ml， 室温搅拌 lOmin, 加入 EA20ml后， 分别用饱和 NaHCO3溶液 10ml， 饱和 NaCl溶液 20ml 洗涤， 无水硫酸钠干燥过夜。 过滤、 40°C旋蒸后， 加入异丙醇 20ml加热回流， 自 然冷却至室温后过滤， 得固体 （安立生坦 S- I ) 1.18g， 收率 67.2%， 99.95 % ee。 Weighed (Compound) 1.7 g (5 mmol) in 20 mL of chloroform. Dess-Martin Periodinane 4g (9mmol) was added at 0 ° C, and naturally raised to room temperature for 4 h. TLC (PE: EA=1:1) was monitored and the reaction was completed. 10 ml of 10% Na2S2O3 solution was added to the ice water bath, and the mixture was stirred at room temperature for 10 min. After adding 20 ml of EA, respectively, 10 ml of a saturated NaHCO3 solution, 20 ml of a saturated NaCl solution, and dried over anhydrous sodium sulfate overnight. After filtration and steaming at 40 ° C, 20 ml of isopropyl alcohol was added thereto, and the mixture was refluxed, and the mixture was cooled to room temperature, and then filtered to give a solid (Anriline S-I) 1.18 g, yield 67.2%, 99.95 % ee.
MS: [M+Na]+:401.13 实施例 24 MS: [M+Na] + : 401.13 Example 24
称取 （化合物珊） 2.6g (7mmol)， 溶于 10ml丙酮和 10ml水的混合液中。 加 入 Pt共 0.16g (0.7mmol), 40°C反应 24h。 TLC (PE: EA=1 :1 ) 监测， 反应完毕。 过滤， 加入 EA50ml后， lmol/L的稀盐酸 5ml酸化， 至 PH等于 2后， 饱和 NaCl 溶液 20ml洗涤，无水硫酸钠干燥过夜。过滤、 40°C旋蒸后，柱层析（PE: EA=2:1 )， 得固体 （安立生坦 S- I ) 1.6g， 收率 60.8%， 99.94 % ee。 Weighed (Compound) 2.6 g (7 mmol) in a mixture of 10 ml of acetone and 10 ml of water. A total of 0.16 g (0.7 mmol) of Pt was added and reacted at 40 ° C for 24 h. TLC (PE: EA=1:1) was monitored and the reaction was completed. After filtration, after adding EA 50 ml, 5 ml of 1 mol/L of dilute hydrochloric acid was acidified, and after the pH was equal to 2, 20 ml of a saturated NaCl solution was washed and dried over anhydrous sodium sulfate overnight. After filtration and rotary evaporation at 40 ° C, column chromatography (PE: EA = 2:1) gave a solid (Anlishengtan S-I) 1.6 g, yield 60.8%, 99.94 % ee.
MS: [M+Na]+:401.13。 实施例 25-29， R3为对甲氧基苯甲酰基， 反应式如下：
MS: [M+Na]+: 401.13. Examples 25-29, R 3 is p-methoxybenzoyl, and the reaction formula is as follows:
实施例 25 Example 25
称取（化合物 IV )2.6g ( 0.0111 01)，溶于2011 1^1^。加入碳酸钾 13.9g(0.1mol)， 冰水浴下滴加对甲氧基苯甲酰氯 1.5ml (O.Ol lmmol) , 滴加完毕后立即加入甲醇 5ml。 体系中加入浓盐酸调节 PH=2后， 加入 40二氯甲垸水稀释， 依次用 20mL 水洗涤 2次， 20ml饱和碳酸氢钠饱洗涤一次，食盐水 20mL洗涤一次，无水 Na2SO4 干燥。 过滤， 将滤液旋干后， 石油醚打浆， 得到白色固体 （化合物 VI-c) 3.0g， 收 率 77.3%， 经 HPLC测定， 纯度大于 95%， 99.96 % ee。 Weigh (Compound IV) 2.6g (0.0111 01), dissolved in 2011 1^1^. 13.9 g (0.1 mol) of potassium carbonate was added, and 1.5 ml of p-methoxybenzoyl chloride (O.Ol lmmol) was added dropwise thereto in an ice water bath, and 5 ml of methanol was added immediately after the dropwise addition. After adding concentrated hydrochloric acid to the system to adjust pH=2, it was diluted with 40 dichloromethane water, washed twice with 20 mL of water, washed once with 20 ml of saturated sodium hydrogencarbonate, once with 20 mL of brine, and dried with anhydrous Na2SO4. After filtration, the filtrate was spun dry, and petroleum ether was beaten to obtain a white solid (Compound VI-c) 3.0 g, yield 77.3%, purity determined by HPLC, greater than 95%, 99.96 % ee.
MS:[M+Na]+:415.16 实施例 26 MS: [M+Na]+: 415.16 Example 26
称取（化合物 VI-c )3.9g( l Ommol )， 4，6-二甲基 -2-甲磺酰基嘧啶 1.4g ( 1 Ommol )， 氨基钠 0.4g ( lOmmol) , DMF 15ml, 80°C加热过夜后， 加入二氯甲垸 40ml和水 20ml稀释， 食盐水 20mL洗涤， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 柱层 析得到白色固体（化合物 W-C ) 1.8g， 收率 36.4%， 经 HPLC测定， 纯度大于 99%， 99.96 % ee。 Weighed (Compound VI-c) 3.9 g (10 mmol), 4,6-dimethyl-2-methylsulfonylpyrimidine 1.4 g (1 Ommol), sodium amide 0.4 g (10 mmol), DMF 15 ml, 80 ° C After heating overnight, 40 ml of dichloromethane and 20 ml of water were added for dilution, and 20 mL of brine was washed and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was spun dry, and the column was separated to give a white solid (Compound W-C) 1.8 g (yield: 36.4%). The purity was more than 99%, 99.96 % ee by HPLC.
MS:[M+Na]+:521.22
实施例 27 MS: [M+Na]+:521.22 Example 27
称取 （化合物 W-c) 0.4g ( l.lmmol) , 溶于 4ml甲醇溶液中， 加入 8mg甲醇 钠， 室温搅拌 3小时， TLC (PE: EA=2:1 ) 监测， 反应完毕。 乙酸乙酯水稀释， 食盐水 10mL洗涤一次， 无水 Na2SO4干燥。 过滤， 将滤液旋干后， 柱层析 （PE: EA=2:1 )， 得到白色糖浆状物（化合物珊） 0.28g， 收率 68.7%， 经 HPLC测定， 纯 度大于 99%， 99.96 % ee。 (Compound W-c) 0.4 g (1.1 mmol) was dissolved in 4 ml of methanol solution, and 8 mg of sodium methoxide was added thereto, stirred at room temperature for 3 hours, and monitored by TLC (PE: EA = 2:1). It was diluted with ethyl acetate water, washed once with 10 mL of brine, and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was spun dry, and then subjected to column chromatography (PE: EA = 2:1) to obtain white syrup (compound) 0.28 g, yield 68.7%, purity by HPLC, greater than 99%, 99.96 % ee .
MS:[M+Na]+:387.23 实施例 28 MS: [M+Na]+: 387.23 Example 28
称取 （化合物珊） 1.7g (5mmol)， 溶于 20mL氯仿。 0°C下加入戴斯-马丁氧 化剂 （Dess-Martin Periodinane) 4g (9mmol), 自然升至室温反应 4h。 TLC (PE: EA=1 :1 ) 监测， 反应完毕。 冰水浴下加入 10%的 Na2S2O3溶液 10ml， 室温搅拌 lOmin, 加入 EA20ml后， 分别用饱和 NaHCO3溶液 10ml， 饱和 NaCl溶液 20ml 洗涤， 无水硫酸钠干燥过夜。 过滤、 40°C旋蒸后， 加入异丙醇 20ml加热回流， 自 然冷却至室温后过滤， 得固体 （安立生坦 S- I ) 1.18g， 收率 67.2%， 99.96 % ee。 Weighed (Compound) 1.7 g (5 mmol) in 20 mL of chloroform. Dess-Martin Periodinane 4g (9mmol) was added at 0 ° C, and naturally raised to room temperature for 4 h. TLC (PE: EA=1:1) was monitored and the reaction was completed. 10 ml of 10% Na2S2O3 solution was added to the ice water bath, and the mixture was stirred at room temperature for 10 min. After adding 20 ml of EA, respectively, 10 ml of a saturated NaHCO3 solution, 20 ml of a saturated NaCl solution, and dried over anhydrous sodium sulfate overnight. After filtration and steaming at 40 ° C, 20 ml of isopropanol was added and heated to reflux, and the mixture was cooled to room temperature and then filtered to give a solid (amp., s.
MS: [M+Na]+:401.13 实施例 29 MS: [M+Na]+: 401.13 Example 29
称取 （化合物珊） 2.6g (7mmol)， 溶于 10ml丙酮和 10ml水的混合液中。 加 入 Pt共 0.16g (0.7mmol), 40°C反应 24h。 TLC (PE: EA=1 :1 ) 监测， 反应完毕。 过滤， 加入 EA50ml后， lmol/L的稀盐酸 5ml酸化， 至 PH等于 2后， 饱和 NaCl 溶液 20ml洗涤，无水硫酸钠干燥过夜。过滤、 40°C旋蒸后，柱层析（PE: EA=2:1 )， 得固体 （安立生坦 S- I ) 1.6g， 收率 60.8%， 99.96 % ee。 Weighed (Compound) 2.6 g (7 mmol) in a mixture of 10 ml of acetone and 10 ml of water. A total of 0.16 g (0.7 mmol) of Pt was added and reacted at 40 ° C for 24 h. TLC (PE: EA=1:1) was monitored and the reaction was completed. After filtration, after adding EA 50 ml, 5 ml of 1 mol/L of dilute hydrochloric acid was acidified, and after the pH was equal to 2, 20 ml of a saturated NaCl solution was washed and dried over anhydrous sodium sulfate overnight. After filtration and rotary evaporation at 40 ° C, column chromatography (PE: EA = 2:1) gave a solid (Anlishengtan S-I) 1.6 g, yield 60.8%, 99.96% ee.
MS: [M+Na]+:40L13。 实施例 30
MS: [M+Na]+: 40L13. Example 30
IV 称取（化合物 IV ) 8.6g (33mmol) ,溶于 70mL 四氢呋喃中。加入 3g KH2PO4 和 6g K2HPO4的 35ml水溶液、 TEMPO 52mmg(0.3mmol)、次氯酸钠 9.7g(0.13mol)， 四丁基氯化铵 0.9g， 室温下搅拌反应 12h。 TLC (PE: EA=2:1 ) 监测， 反应完毕。 冰水浴下，滴加饱和亚硫酸钠， 100ml乙酸乙酯稀释后，滴加浓盐酸调节 PH=2后， 用 200mL 乙酸乙酯和 50ml水稀释后，再用饱和食盐水 150mL洗涤，无水 Na2SO4 干燥。 过滤， 将滤液旋干后， 环己垸重结晶， 得 (化合物 V " )白色固体 6.5g， 收率 81%。 IV (Compound IV) 8.6 g (33 mmol) was dissolved in 70 mL of tetrahydrofuran. 3 g of KH 2 PO 4 and 6 g of K 2 HPO 4 in 35 ml of water, TEMPO 52 mmg (0.3 mmol), sodium hypochlorite 9.7 g (0.13 mol), and tetrabutylammonium chloride 0.9 g were added, and the reaction was stirred at room temperature for 12 h. TLC (PE: EA=2:1) was monitored and the reaction was completed. Under ice-water bath, add saturated sodium sulfite, dilute with 100 ml of ethyl acetate, add concentrated hydrochloric acid dropwise to adjust pH=2, dilute with 200 mL of ethyl acetate and 50 ml of water, then wash with 150 mL of saturated brine, anhydrous Na 2 SO 4 dry. After filtration, the filtrate was spun dry, and the cyclohexane was recrystallized to give (Compound V " ) 6.5 g of a white solid, yield 81%.
MS: [M+Na]+:265.1 应当明白， 前述内容是例举和解释性的， 它仅供阐述本发明和其优选的实施 方式用。 通过常规的实验， 所述领域的技术人员能容易地了解在不背离本发明精 神做出明显的修饰和改变。
MS: [M+Na] + : 265.1 It is to be understood that the foregoing is illustrative and illustrative, and is intended to illustrate the invention and its preferred embodiments. It will be apparent to those skilled in the art that <RTIgt;</RTI><RTIgt;</RTI><RTIgt;
Claims
1. 一种如式 IV所示的化合物 1. A compound represented by formula IV
2. 一种制备如权利要求 1 所述的式 IV所示的化合物的方法， 该方法包括由 式 III所示的化合物在 IV所示的化合物， 2. A method for preparing a compound represented by formula IV as claimed in claim 1, the method comprising a compound represented by formula III in a compound represented by IV,
其中， ！^、 R2各自独立地选自氢原子、 CrC6垸基、 CrC6卤代垸基、 苯基或 被^- 垸氧基、 卤素、 羟基取代的苯基， 或者 和 与它们所连接的碳原子一 起形成 C3-C6环垸基。 in, ! ^ and R 2 are each independently selected from a hydrogen atom, C r C 6 alkyl group, C r C 6 halogenated alkyl group, phenyl or phenyl group substituted by ^-alkyloxy group, halogen, hydroxyl group, or a combination with them The attached carbon atoms together form a C 3 -C 6 cycloalkyl group.
3. 如权利要求 2所述的方法，其特征在于， 和 各自独立地选自氢原子、 甲基、 乙基、 丙基、 叔丁基、 三氯甲基、 苯基或 4-甲氧基苯基， 或者 和 与 它们所连接的碳原子一起形成环己基或环戊基。 3. The method of claim 2, wherein and are each independently selected from a hydrogen atom, methyl, ethyl, propyl, tert-butyl, trichloromethyl, phenyl or 4-methoxy phenyl, or together with the carbon atom to which they are attached form cyclohexyl or cyclopentyl.
4. 如权利要求 2所述的方法， 其特征在于， 是氢， 选自三氯甲基、 叔 丁基、 苯基或 4-甲氧基苯基。 4. The method of claim 2, wherein is hydrogen and is selected from trichloromethyl, tert-butyl, phenyl or 4-methoxyphenyl.
5. 如权利要求 2所述的方法， 其特征在于， 和 均为甲基， 均为乙基或 均为 H。 5. The method of claim 2, wherein and are both methyl, both are ethyl or both are H.
6. 如权利要求 2-5中任一项所述的方法， 其特征在于， 所述反应溶剂是有机 溶剂中一种或多种或者有机溶剂与水的混合溶剂。 6. The method according to any one of claims 2 to 5, characterized in that the reaction solvent is one or more organic solvents or a mixed solvent of organic solvents and water.
7. 如权利要求 6中所述的方法，其特征在于，所述有机溶剂选自甲醇、乙醇、 四氢呋喃、 乙腈、 N，N-二甲基甲酰胺、 丙酮、 二氧六环或其混合物。 7. The method of claim 6, wherein the organic solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, acetone, dioxane or mixtures thereof.
8. 如权利要求 2-5中任一项所述的方法， 其特征在于， 所述反应是在质子酸
或固体超强酸的催化下完成的， 以化合物 III的当量为 1 当量计， 质子酸的用量是 8. The method according to any one of claims 2 to 5, characterized in that the reaction is carried out in a protonic acid Or it is completed under the catalysis of solid super acid. Taking the equivalent of compound III as 1 equivalent, the dosage of protonic acid is
0.1~2eq; 固体超强酸的用量是 0.1eq~2.5eq; 反应温度是 0°C~100°C； 反应时间是 lh~60h。 0.1~2eq; the dosage of solid super acid is 0.1eq~2.5eq; the reaction temperature is 0°C~100°C; the reaction time is 1h~60h.
9. 如权利要求 8所述的方法，其特征在于，所述质子酸选自浓硫酸、浓盐酸、 冰醋酸、 三氟乙酸、 对甲苯磺酸或其混合物， 所述固体超强酸选自磷钨酸、 磷钼 酸、 Nafion或其混合物。 9. The method of claim 8, wherein the protonic acid is selected from concentrated sulfuric acid, concentrated hydrochloric acid, glacial acetic acid, trifluoroacetic acid, p-toluenesulfonic acid or a mixture thereof, and the solid super acid is selected from phosphorus Tungstic acid, phosphomolybdic acid, Nafion or mixtures thereof.
10. 一种用于制备式 IV所示的化合物的中间体化合物 III， 其结构式如下： 10. An intermediate compound III used to prepare the compound represented by formula IV, its structural formula is as follows:
其中， 、 R2各自独立地选自氢原子、 CrC6垸基、 CrC6卤代垸基、 苯基或 被^- 垸氧基、 卤素、 羟基取代的苯基， 或者 和 与它们所连接的碳原子一 起形成 C3-C6环垸基。 Among them, R 2 is each independently selected from a hydrogen atom, C r C 6 alkyl group, C r C 6 halogenated alkyl group, phenyl group or phenyl group substituted by ^-alkyloxy group, halogen, hydroxyl group, or and The carbon atoms to which they are attached together form a C 3 -C 6 cycloalkyl group.
11 如权利要求 10所述的方法， 其特征在于， 和 R2各自独立地选自氢原 子、 甲基、 乙基、 丙基、 叔丁基、 三氯甲基、 苯基或 4-甲氧基苯基， 或者 ！^和 与它们所连接的碳原子一起形成环己基或环戊基。 11 The method of claim 10, wherein R and R are each independently selected from a hydrogen atom, methyl, ethyl, propyl, tert-butyl, trichloromethyl, phenyl or 4-methoxy phenyl, or! ^ and together with the carbon atoms to which they are attached form cyclohexyl or cyclopentyl.
12. 如权利要求 10所述的方法， 其特征在于， ！^和 均为甲基， 均为乙基 或均为 H。 12. The method of claim 10, characterized in that,! ^ and are both methyl, both are ethyl or both are H.
13. 一种制备式 III所示化合物的方法， 所述方法包括将式 II所示的化合物在 反应溶剂的存在下 III所示化合物， 13. A method for preparing a compound represented by formula III, the method comprising: converting a compound represented by formula II into a compound represented by formula III in the presence of a reaction solvent,
其中， ！^、 R2各自独立地选自氢原子、 CrC6垸基、 CrC6卤代垸基、 苯基或 被^- 垸氧基、 卤素、 羟基取代的苯基， 或者 和 与它们所连接的碳原子一
起形成 C3-C6环垸基。 in, ! ^ and R 2 are each independently selected from a hydrogen atom, C r C 6 alkyl group, C r C 6 halogenated alkyl group, phenyl or phenyl group substituted by ^-alkyloxy group, halogen, hydroxyl group, or a combination with them The carbon atom attached Together they form a C 3 -C 6 cycloalkyl group.
14 如权利要求 13所述的方法， 其特征在于， 和 R2各自独立地选自氢原 子、 甲基、 乙基、 丙基、 叔丁基、 三氯甲基、 苯基或 4-甲氧基苯基， 或者 ！^和 与它们所连接的碳原子一起形成环己基或环戊基。 14 The method of claim 13, wherein R and R are each independently selected from a hydrogen atom, methyl, ethyl, propyl, tert-butyl, trichloromethyl, phenyl or 4-methoxy phenyl, or! ^ and together with the carbon atoms to which they are attached form cyclohexyl or cyclopentyl.
15. 如权利要求 13所述的方法， 其特征在于， 和 均为甲基， 均为乙基 或均为 H。 15. The method of claim 13, wherein and are both methyl, both are ethyl or both are H.
16. 如权利要求 13-15中任一项所述的方法， 其特征在于， 反应溶剂为非质 子溶剂； 所述甲基化试剂选自碘甲垸、 硫酸二甲酯或碳酸二甲酯； 反应温度为 0°C~80°C ; 反应时间是 lh~32h。 16. The method according to any one of claims 13 to 15, wherein the reaction solvent is an aprotic solvent; the methylating reagent is selected from methyl iodide, dimethyl sulfate or dimethyl carbonate; The reaction temperature is 0°C~80°C; the reaction time is 1h~32h.
17. 一种制备安立生坦的方法， 其包括如下步骤： 17. A method for preparing ambrisentan, which includes the following steps:
a) 将化合物 IV在缓冲盐和溶剂的存在和 TEMPO催化下，被氧化剂选择性氧 化， 然后进行酸化生成化合物 V； a) Compound IV is selectively oxidized by an oxidant in the presence of buffer salt and solvent and catalyzed by TEMPO, and then acidified to generate compound V;
b) 在碱性条件下和相转移催化剂的存在下，化合物 V与 4，6-二甲基 -2-甲磺酰 基嘧啶在溶剂中进行取代反应； b) Under alkaline conditions and in the presence of a phase transfer catalyst, compound V undergoes a substitution reaction with 4,6-dimethyl-2-methanesulfonylpyrimidine in a solvent;
c) 将步骤 b) 的得到的产物进行酸化反应得到安立生坦 S- I， 其反应路线如 c) Acidify the product obtained in step b) to obtain ambrisentan S-I. The reaction route is as follows:
S- I S-I
18. 如权利要求 17的方法， 步骤 a)中， 所述溶剂选自乙腈、 四氢呋喃、 N，N- 二甲基甲酰胺、 二氧六环； 所述缓冲盐为 KH2PO4-K2HPO4缓冲液， 并且所述缓冲 溶液 pH=4~7; 所述氧化剂为亚氯酸钠， 并且以化合物 IV的当量为 1当量计， 氧化 剂的用量为 l~10eq; 以化合物 IV的当量为 1当量计， TEMPO的用量 0.001~0.5eq; 步骤 a)中的酸化所使用的酸选自稀盐酸、 稀硫酸或稀磷酸。 18. The method of claim 17, in step a), the solvent is selected from acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane; the buffer salt is KH 2 PO 4 -K 2 HPO 4 buffer solution, and the buffer solution pH=4~7; the oxidizing agent is sodium chlorite, and based on the equivalent of compound IV being 1 equivalent, the amount of oxidizing agent is 1~10 eq; taking the equivalent of compound IV being Based on 1 equivalent, the dosage of TEMPO is 0.001~0.5eq; the acid used in the acidification in step a) is selected from dilute hydrochloric acid, dilute sulfuric acid or dilute phosphoric acid.
19. 如权利要求 17的方法， 步骤 b)中， 所述溶剂选自乙腈、 四氢呋喃、 N，N- 二甲基甲酰胺、 二氧六环， 所述碱性条件是通过加入碱来实现的， 所述碱选自碳
酸钾、 碳酸钠、 氢氧化钠、 氨基钠； 所述相转移催化剂选自四丁基氯化铵、 四丁 基溴化铵、 四丁基碘化铵、 四丁基硫酸氢铵、 苄基三甲基氯化铵或甲基三辛基氯 化铵 (Aliquat 336)。 19. The method of claim 17, in step b), the solvent is selected from acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, and the alkaline condition is achieved by adding a base , the base is selected from carbon Potassium acid, sodium carbonate, sodium hydroxide, sodium amide; the phase transfer catalyst is selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyl Trimethylammonium chloride or methyltrioctylammonium chloride (Aliquat 336).
20. 如权利要求 17的方法， 步骤 c)中， 所述酸化反应所使用的酸选自稀盐 酸、 稀硫酸、 稀磷酸。 20. The method of claim 17, in step c), the acid used in the acidification reaction is selected from dilute hydrochloric acid, dilute sulfuric acid, and dilute phosphoric acid.
21. 一种制备安立生坦的方法， 其包括如下步骤： 21. A method for preparing ambrisentan, which includes the following steps:
a) 化合物 IV与酰氯 R3-C1在溶剂的存在下于碱性条件下进行反应生成化合物 VI， 其中 选自特戊酰基、 苯甲酰基或苯环的 4位上被羟基、 卤素、 CrC6垸基 或 CrC6垸氧基取代的苯甲酰基； a) Compound IV reacts with acid chloride R 3 -C1 in the presence of a solvent under alkaline conditions to generate compound VI, in which the 4-position of the benzene ring is selected from pivaloyl, benzoyl or benzene ring is covered with hydroxyl, halogen, C r C 6 alkyl or C r C 6 alkoxy substituted benzoyl group;
b) 在碱性条件和相转移催化剂的存在下，化合物 VI与 4，6-二甲基 -2-甲磺酰基 嘧啶取代反应生成化合物 νπ ; b) In the presence of alkaline conditions and a phase transfer catalyst, compound VI is substituted with 4,6-dimethyl-2-methanesulfonyl pyrimidine to form compound νπ;
c) 在碱性条件和溶剂的存在下， 将化合物 ΥΠ脱去酰基生成化合物珊； d) 在溶剂的存在下， 用氧化剂将化合物 W【氧化得到化合物 S- I， c) In the presence of alkaline conditions and a solvent, remove the acyl group from compound YΠ to generate compound S-I; d) In the presence of a solvent, oxidize compound W with an oxidizing agent to obtain compound S-I,
22. 如权利要求 21所述的方法， 步骤 a)中， 所述溶剂选自二氯甲垸、 乙酸 乙酯、 四氢呋喃、 N，N-二甲基甲酰胺、 氯仿、 乙腈或其混合物； 所述碱性条件是 通过加入碱来实现的， 所述碱选自吡啶、 三乙胺、 碳酸钾、 碳酸钠。 22. The method of claim 21, in step a), the solvent is selected from dichloromethane, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, chloroform, acetonitrile or mixtures thereof; The alkaline conditions are achieved by adding a base, and the base is selected from the group consisting of pyridine, triethylamine, potassium carbonate, and sodium carbonate.
23. 如权利要求 21所述的方法， 步骤 b)中， 所述溶剂选自乙腈、 四氢呋喃、
N，N-二甲基甲酰胺、 二氧六环； 所述碱性条件是通过加入碱来实现的， 所述碱选 自碳酸钾、 碳酸钠、 氢氧化钠、 氨基钠； 所述相转移催化剂优选四丁基氯化铵、 四丁基溴化铵、 四丁基碘化铵、 四丁基硫酸氢铵、 苄基三甲基氯化铵或甲基三辛 基氯化铵 (Aliquat 336)。 23. The method of claim 21, in step b), the solvent is selected from acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dioxane; The alkaline condition is achieved by adding a base, and the base is selected from potassium carbonate, sodium carbonate, sodium hydroxide, and sodium amide; the phase transfer The catalyst is preferably tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride or methyl trioctyl ammonium chloride (Aliquat 336 ).
24. 如权利要求 21所述的方法， 步骤 c)中， 所述的溶剂选自二氯甲垸、 乙 酸乙酯、 甲醇、 乙醇或其混合物； 所述碱性条件是通过加入碱来实现的， 所述碱 选自氢氧化钠、 碳酸钾、 碳酸钠、 甲醇钠或乙醇钠。 24. The method of claim 21, in step c), the solvent is selected from dichloromethane, ethyl acetate, methanol, ethanol or a mixture thereof; the alkaline condition is achieved by adding a base , the base is selected from sodium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide or sodium ethoxide.
25. 如权利要求 21所述的方法， 步骤 d)中， 所述的溶剂选自二氯甲垸、 氯 仿或其混合物， 所述的氧化剂选自戴斯-马丁氧化剂或 Pt。 25. The method of claim 21, in step d), the solvent is selected from dichloromethane, chloroform or a mixture thereof, and the oxidizing agent is selected from Dess-Martin oxidant or Pt.
26. 一种 如下： 26. One is as follows:
π 珊 π Shan
其中 选自特戊酰基、 苯甲酰基或苯环的 4位上被羟基、 卤素、 CrC6垸基 或 CrC6垸氧基取代的苯甲酰基。
Among them, it is selected from pivaloyl group, benzoyl group or benzoyl group substituted at the 4-position of the benzene ring by hydroxyl, halogen, C r C 6 alkyl group or C r C 6 alkoxy group.
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| EP3800184A1 (en) * | 2019-09-24 | 2021-04-07 | Henkel AG & Co. KGaA | Acetal / ketal-based fragrance and insect repellent precursor compounds |
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| CN103709106A (en) * | 2013-12-06 | 2014-04-09 | 石家庄博策生物科技有限公司 | Stereoselectivity preparation method for Letairis |
| CN104844524A (en) * | 2015-05-18 | 2015-08-19 | 宁波人健医药化工有限公司 | Synthetic method of ambrisentan |
| CN109705042B (en) * | 2017-10-26 | 2021-12-21 | 正大天晴药业集团股份有限公司 | Preparation method of ambrisentan |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011004402A2 (en) * | 2009-07-10 | 2011-01-13 | Cadila Healthcare Limited | Improved process for the preparation of ambrisentan and novel intermediates thereof |
| CN102276536A (en) * | 2011-06-10 | 2011-12-14 | 中国科学院化学研究所 | Preparation method of optically pure (+)-ambrisentan and optically pure (+)-darusentan |
| WO2012017441A1 (en) * | 2010-08-04 | 2012-02-09 | Natco Pharma Limited | Improved process to prepare s-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid |
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| WO2011004402A2 (en) * | 2009-07-10 | 2011-01-13 | Cadila Healthcare Limited | Improved process for the preparation of ambrisentan and novel intermediates thereof |
| WO2012017441A1 (en) * | 2010-08-04 | 2012-02-09 | Natco Pharma Limited | Improved process to prepare s-2-hydroxy-3-methoxy-3,3-diphenyl propionic acid |
| CN102276536A (en) * | 2011-06-10 | 2011-12-14 | 中国科学院化学研究所 | Preparation method of optically pure (+)-ambrisentan and optically pure (+)-darusentan |
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| KR20180108367A (en) * | 2017-03-24 | 2018-10-04 | 한양대학교 산학협력단 | Alicyclic acid compounds, ester derivatives thereof and polymers thereof |
| KR101967532B1 (en) * | 2017-03-24 | 2019-04-10 | 한양대학교 산학협력단 | Alicyclic acid compounds, ester derivatives thereof and polymers thereof |
| EP3800184A1 (en) * | 2019-09-24 | 2021-04-07 | Henkel AG & Co. KGaA | Acetal / ketal-based fragrance and insect repellent precursor compounds |
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