CN107266451A - The preparation method of sharp cloth intermediate of auspicious cloth former times - Google Patents
The preparation method of sharp cloth intermediate of auspicious cloth former times Download PDFInfo
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- CN107266451A CN107266451A CN201610212832.9A CN201610212832A CN107266451A CN 107266451 A CN107266451 A CN 107266451A CN 201610212832 A CN201610212832 A CN 201610212832A CN 107266451 A CN107266451 A CN 107266451A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- 239000004744 fabric Substances 0.000 title 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 171
- 239000002904 solvent Substances 0.000 claims description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 239000003054 catalyst Substances 0.000 claims description 18
- 239000007800 oxidant agent Substances 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 16
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 230000003647 oxidation Effects 0.000 claims description 14
- 238000007254 oxidation reaction Methods 0.000 claims description 14
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 230000001590 oxidative effect Effects 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 5
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- NBVHDOZEOGAKLK-UHFFFAOYSA-N [N]=O.CC1C(N(CCC1)C)(C)C Chemical compound [N]=O.CC1C(N(CCC1)C)(C)C NBVHDOZEOGAKLK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 229940117975 chromium trioxide Drugs 0.000 claims description 3
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 3
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 3
- JWIPGAFCGUDKEY-UHFFFAOYSA-L O[Cr](Cl)(=O)=O.C1=CC=NC=C1 Chemical compound O[Cr](Cl)(=O)=O.C1=CC=NC=C1 JWIPGAFCGUDKEY-UHFFFAOYSA-L 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- -1 (tetrahydro-2H-pyran-2-yl)oxy Chemical group 0.000 abstract description 17
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 238000004128 high performance liquid chromatography Methods 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 24
- 239000000243 solution Substances 0.000 description 21
- 239000002585 base Substances 0.000 description 20
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical group [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- VEPTXBCIDSFGBF-UHFFFAOYSA-M tetrabutylazanium;fluoride;trihydrate Chemical compound O.O.O.[F-].CCCC[N+](CCCC)(CCCC)CCCC VEPTXBCIDSFGBF-UHFFFAOYSA-M 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 11
- 230000035484 reaction time Effects 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 9
- 150000002367 halogens Chemical group 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 239000012071 phase Substances 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 8
- 239000010779 crude oil Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical class [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 7
- ADHCEFBFOBDYEC-UHFFFAOYSA-N (2-chloro-7-cyclopentylpyrrolo[2,3-d]pyrimidin-6-yl)methanol Chemical compound OCC1=CC2=CN=C(Cl)N=C2N1C1CCCC1 ADHCEFBFOBDYEC-UHFFFAOYSA-N 0.000 description 6
- SOXVKQLLJZHYTL-UHFFFAOYSA-N 2-chloro-7-cyclopentylpyrrolo[2,3-d]pyrimidine-6-carbaldehyde Chemical compound C12=NC(Cl)=NC=C2C=C(C=O)N1C1CCCC1 SOXVKQLLJZHYTL-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical group [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- PMDDQOHZLBZUSO-UHFFFAOYSA-N 2-chloro-7-cyclopentyl-n,n-dimethylpyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound CN(C)C(=O)C1=CC2=CN=C(Cl)N=C2N1C1CCCC1 PMDDQOHZLBZUSO-UHFFFAOYSA-N 0.000 description 5
- DIVUXBABVYOIOT-UHFFFAOYSA-N 5-bromo-2-chloro-n-cyclopentylpyrimidin-4-amine Chemical compound ClC1=NC=C(Br)C(NC2CCCC2)=N1 DIVUXBABVYOIOT-UHFFFAOYSA-N 0.000 description 5
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 4
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229940126142 compound 16 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- JLRMRTRHBRVQMS-UHFFFAOYSA-N hydrogen peroxide;2-methylpropan-2-ol Chemical compound OO.CC(C)(C)O JLRMRTRHBRVQMS-UHFFFAOYSA-N 0.000 description 4
- 150000007522 mineralic acids Chemical class 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 229950003687 ribociclib Drugs 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 3
- ACQYZSFXPXXIHL-UHFFFAOYSA-N 2-phenylmethoxycarbonyl-3,4-dihydro-1h-isoquinoline-1-carboxylic acid Chemical compound C1CC2=CC=CC=C2C(C(=O)O)N1C(=O)OCC1=CC=CC=C1 ACQYZSFXPXXIHL-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000003999 initiator Substances 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- MRXQMNWIADOAJY-UHFFFAOYSA-M tetrabutylazanium;fluoride;dihydrofluoride Chemical compound F.F.[F-].CCCC[N+](CCCC)(CCCC)CCCC MRXQMNWIADOAJY-UHFFFAOYSA-M 0.000 description 3
- QBVXKDJEZKEASM-UHFFFAOYSA-M tetraoctylammonium bromide Chemical compound [Br-].CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC QBVXKDJEZKEASM-UHFFFAOYSA-M 0.000 description 3
- 150000004684 trihydrates Chemical class 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 2
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 2
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 2
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- XYYYTUCWSSREHK-UHFFFAOYSA-N N1=CC=CC=C1.[N]=O Chemical compound N1=CC=CC=C1.[N]=O XYYYTUCWSSREHK-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
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- 238000009522 phase III clinical trial Methods 0.000 description 1
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- 238000000746 purification Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明属于有机合成和药物合成领域，具体而言涉及一种瑞布昔利布中间体的制备方法，本发明的制备方法，是通过先得到2‑卤代‑7‑环戊基‑6‑(((四氢‑2H‑吡喃‑2‑基)氧基)甲基)‑7H‑吡咯并[2,3‑d]嘧啶后，再经三步反应得到瑞布昔利布中间体2‑卤代‑7‑环戊基‑N,N‑二甲基‑7H‑吡咯并[2,3‑d]嘧啶‑6‑甲酰胺，每一步反应均具有高收率和高纯度，因此整个路线总收率高，明显优于现有技术，且原料容易获得，生产成本低，制备简单易操作，反应试剂对环境友好，特别适合工业化生产。The present invention belongs to the field of organic synthesis and pharmaceutical synthesis, and specifically relates to a preparation method of a rebuciclib intermediate. The preparation method of the present invention is obtained by first obtaining 2-halo-7-cyclopentyl-6- After (((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, rebuciclib intermediate 2 was obtained through three-step reaction ‑Halo‑7‑cyclopentyl‑N,N‑dimethyl‑7H‑pyrrolo[2,3‑d]pyrimidine‑6‑carboxamide, each step reaction has high yield and high purity, so the whole The total yield of the route is high, which is obviously superior to the prior art, and the raw materials are easy to obtain, the production cost is low, the preparation is simple and easy to operate, and the reaction reagent is friendly to the environment, which is especially suitable for industrial production.
Description
技术领域technical field
本发明属于有机合成和药物合成领域，具体涉及一种用于治疗晚期乳腺癌的药物—瑞布昔利布(Ribociclib)的中间体2-卤代-7-环戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺的制备方法及相关中间体。The present invention belongs to the field of organic synthesis and drug synthesis, and in particular relates to an intermediate 2-halogenated-7-cyclopentyl-N,N-dimethoxylate of Ribciclib (Ribociclib), a drug for treating advanced breast cancer. A preparation method of methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and related intermediates.
背景技术Background technique
瑞布昔利布(Ribociclib)是由瑞士诺华公司开发的高度特异性CDK4/CDK6抑制剂，可靶向抑制D1/CDK4、D3/CDK6细胞周期，将细胞周期阻滞于G1期，从而起到抑制肿瘤增殖的作用。临床试验结果表明ribociclib可用于乳腺癌、黑色素瘤、非小细胞肺癌、畸胎瘤、脂肪肉瘤和胶质母细胞瘤的治疗。该药目前处于晚期乳腺癌的Ⅲ期临床试验。Ribociclib (Ribociclib) is a highly specific CDK4/CDK6 inhibitor developed by Novartis, Switzerland. It can target and inhibit the D1/CDK4, D3/CDK6 cell cycle, and block the cell cycle in the G1 phase, thereby playing a role Inhibition of tumor proliferation. The results of clinical trials show that ribociclib can be used in the treatment of breast cancer, melanoma, non-small cell lung cancer, teratoma, liposarcoma and glioblastoma. The drug is currently in phase III clinical trials for advanced breast cancer.
瑞布昔利布的化学名为：7-环戊基-2-(5-哌嗪-1-基-吡啶-2-基氨基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲酰胺，其化学结构式如下所示：The chemical name of rebuciclib is: 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6 -Carboxylic acid dimethylamide, its chemical structural formula is as follows:
WO2010020675公开了瑞布昔利布及其关键中间体2-氯-7-环戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(中间体9)的制备方法，该中间体制备方法如下：。WO2010020675 discloses rebuciclib and its key intermediate 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (intermediate The preparation method of body 9), the preparation method of this intermediate is as follows:.
化合物1与化合物2经亲核芳香取代反应得到化合物3；化合物3与化合物4经Sonogashira反应得到化合物5；化合物5在碱性条件下经环化反应得到嘧啶并吡咯化合物6；化合物6经酸化得到化合物7；化合物7经氧化得到化合物8；化合物8与二甲胺缩合得到关键中间体9。Compound 1 and compound 2 were subjected to nucleophilic aromatic substitution reaction to obtain compound 3; compound 3 and compound 4 were subjected to Sonogashira reaction to obtain compound 5; compound 5 was cyclized under basic conditions to obtain pyrimidopyrrole compound 6; compound 6 was obtained by acidification Compound 7; Compound 7 was oxidized to obtain Compound 8; Compound 8 was condensed with dimethylamine to obtain the key intermediate 9.
WO2012064805公开了中间体9的另一种制备方法，其制备方法如下：WO2012064805 discloses another preparation method of intermediate 9, the preparation method of which is as follows:
化合物1和化合物2经亲核芳香取代反应得到化合物3；化合物3与化合物15经Sonogashira反应得到化合物16；化合物16在碱性条件下发生环化反应得到化合物17；化合物17在二氧化锰和氰化钠存在下先得到中间体18，再得到中间体9。Compound 1 and compound 2 were subjected to nucleophilic aromatic substitution reaction to obtain compound 3; compound 3 and compound 15 were reacted with Sonogashira to obtain compound 16; compound 16 was cyclized under alkaline conditions to obtain compound 17; In the presence of sodium chloride, intermediate 18 was first obtained, and then intermediate 9 was obtained.
瑞布昔利布的合成中，中间体9的制备极为关键，已公开的中间体9的制备方法存在如下缺陷：(1)WO2010020675公开的制备方法，化合物3与化合物4制备化合物5反应体系杂质多，不易纯化，产物收率低；化合物5经3步反应制备化合物8，产物均为油状物，步骤较多且不易纯化，导致收率降低；化合物8制备中间体9原料转化率低，因此该路线反应总收率低，操作繁琐，不适用工业化生产。(2)WO2012064805公开的制备方法，化合物3与化合物15制备化合物16反应体系杂质多，产物收率低；化合物16关环反应产生杂质含量多，且难以除去，产物收率低；化合物17制备中间体9的过程中，使用了剧毒的氰化钠，且该反应对二氧化锰的活化性能要求高，反应重现性差，不利于工业化生产。In the synthesis of rebuciclib, the preparation of intermediate 9 is extremely critical, and the disclosed preparation method of intermediate 9 has the following defects: (1) The preparation method disclosed in WO2010020675, compound 3 and compound 4 to prepare compound 5 Reaction system impurities Many, difficult to purify, product yield is low; Compound 5 prepares Compound 8 through 3-step reaction, and product is all oily matter, and step is more and difficult to purify, causes yield to reduce; Compound 8 prepares intermediate 9 raw material conversion rate is low, therefore The total reaction yield of this route is low, the operation is loaded down with trivial details, and is not suitable for industrialized production. (2) In the preparation method disclosed in WO2012064805, the reaction system of compound 3 and compound 15 to prepare compound 16 has many impurities, and the product yield is low; the ring-closing reaction of compound 16 produces many impurities, which are difficult to remove, and the product yield is low; the preparation of compound 17 is intermediate In the process of synthesis 9, highly toxic sodium cyanide was used, and the reaction required high activation performance of manganese dioxide, and the reaction reproducibility was poor, which was not conducive to industrial production.
针对现存的工艺缺陷，开发出工艺简洁、绿色环保、收率高、纯度高且适用于工业化生产的工艺技术，对瑞布昔利布的合成和经济社会效益的提高有着重要的现实意义。In view of the existing process defects, the development of a process technology with simple process, green environmental protection, high yield, high purity and suitable for industrial production has important practical significance for the synthesis of rebuciclib and the improvement of economic and social benefits.
发明内容Contents of the invention
本发明提供一种式Ⅳ化合物的制备方法，包括：式Ⅰ化合物与式Ⅱ化合物在催化剂和碱的存在下进行反应得到式Ⅲ化合物，所述式Ⅲ化合物进行反应得到式Ⅳ化合物，The present invention provides a preparation method of a compound of formula IV, comprising: reacting a compound of formula I and a compound of formula II in the presence of a catalyst and a base to obtain a compound of formula III, and reacting the compound of formula III to obtain a compound of formula IV,
其中X选自卤素，优选为溴、氯或碘，最优选为氯；wherein X is selected from halogen, preferably bromine, chlorine or iodine, most preferably chlorine;
其中Y选自卤素，优选为溴、氯或碘，最优选为溴；wherein Y is selected from halogen, preferably bromine, chlorine or iodine, most preferably bromine;
在本发明的一些具体实施方案中，式Ⅰ化合物为式Ⅰ-1化合物，式Ⅲ化合物为式Ⅲ-1化合物，式Ⅳ化合物为式Ⅳ-1化合物；In some specific embodiments of the present invention, the compound of formula I is the compound of formula I-1, the compound of formula III is the compound of formula III-1, and the compound of formula IV is the compound of formula IV-1;
在本发明的部分实施方式中，所述催化剂为钯催化剂，例如可以是钯(0)和钯(II)催化剂，更具体的，所述钯催化剂选自四(三苯基膦)钯、醋酸钯、1,2-双(二苯膦基)乙烷二氯化钯、1,3-双(二苯膦基)丙烷二氯化钯、1,4-双(二苯膦基)丁烷二氯化钯、二(三苯基膦)二氯化钯、二(氰基苯)二氯化钯、1,1'-双二苯基膦二茂铁二氯化钯或三(二亚苄基丙酮)二钯的一种或一种以上，优选为四(三苯基膦)钯、二(三苯基膦)二氯化钯或二(氰基苯)二氯化钯的一种或一种以上，更优选为四(三苯基膦)钯或二(三苯基膦)二氯化钯的一种或两种，在本发明的一些具体实施方式中，所述催化剂选自四(三苯基膦)钯或二(三苯基膦)二氯化钯；In some embodiments of the present invention, the catalyst is a palladium catalyst, such as palladium (0) and palladium (II) catalyst, more specifically, the palladium catalyst is selected from tetrakis (triphenylphosphine) palladium, acetic acid Palladium, 1,2-bis(diphenylphosphino)ethane palladium dichloride, 1,3-bis(diphenylphosphino)propane palladium dichloride, 1,4-bis(diphenylphosphino)butane Palladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(cyanophenyl)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride or tris(diphenyl One or more of benzylacetone) dipalladium, preferably one of tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride or bis(cyanophenyl)palladium dichloride Or more than one, more preferably one or two of tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride, in some embodiments of the present invention, the catalyst is selected from Tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride;
在本发明的部分实施方式中，所述碱可以是无机碱或者有机碱，更具体的，所述碱选自四丁基氟化铵或其水合物、四正丁基二氢三氟化铵、四丁基磷酸二氢铵、四正辛基溴化铵、四正丁基二氢三氟化铵或其水合物、四丁基溴化铵或甲基三丁基溴化铵的一种或一种以上，优选为四丁基氟化铵或其水合物，更优选为四丁基氟化铵或其三水合物，最优选为四丁基氟化铵三水合物；In some embodiments of the present invention, the base can be an inorganic base or an organic base, more specifically, the base is selected from tetrabutylammonium fluoride or its hydrate, tetra-n-butylammonium dihydrogen trifluoride , tetrabutylammonium dihydrogenphosphate, tetra-n-octylammonium bromide, tetra-n-butyldihydroammonium trifluoride or its hydrate, tetrabutylammonium bromide or methyltributylammonium bromide Or more than one, preferably tetrabutylammonium fluoride or its hydrate, more preferably tetrabutylammonium fluoride or its trihydrate, most preferably tetrabutylammonium fluoride trihydrate;
在本发明的部分实施方式中，所述式Ⅰ化合物与式Ⅱ化合物的摩尔比为1：1-2，也可以为1：1-1.5，在本发明一些具体实施方案中，所述式Ⅰ化合物与式Ⅱ化合物的摩尔比约为1：2或者1：1.5；In some embodiments of the present invention, the molar ratio of the compound of formula I to the compound of formula II is 1:1-2, or 1:1-1.5. In some specific embodiments of the present invention, the molar ratio of the compound of formula I The molar ratio of the compound to the compound of formula II is about 1:2 or 1:1.5;
在本发明的部分实施方式中，所述式Ⅰ化合物与催化剂的摩尔比为1：0.01-0.1，优选1：0.02-0.08，更优选1：0.05-0.06；In some embodiments of the present invention, the molar ratio of the compound of formula I to the catalyst is 1:0.01-0.1, preferably 1:0.02-0.08, more preferably 1:0.05-0.06;
在本发明的部分实施方案中，所述式Ⅰ化合物与碱的摩尔比为1：0.5-10，优选为1：1-10；In some embodiments of the present invention, the molar ratio of the compound of formula I to the base is 1:0.5-10, preferably 1:1-10;
其中所述式Ⅲ化合物可以经分离后进行反应得到式Ⅳ化合物，也可以不经分离进行反应得到式Ⅳ化合物；Wherein the compound of formula III can be reacted to obtain the compound of formula IV after separation, or can be reacted without separation to obtain the compound of formula IV;
在本发明的部分实施方式中，当式Ⅲ化合物经分离后进行反应得到式Ⅳ化合物时，所述式Ⅰ化合物与碱的摩尔比为1：0.5-3，优选为1：1-2.5，最优选为1：1.5-2.5，在本发明的一些具体实施方案中，式Ⅰ化合物与碱的摩尔比约为1：1.5或者1：2.5；In some embodiments of the present invention, when the compound of formula III is separated and reacted to obtain the compound of formula IV, the molar ratio of the compound of formula I to the base is 1:0.5-3, preferably 1:1-2.5, most preferably Preferably it is 1:1.5-2.5. In some specific embodiments of the present invention, the molar ratio of the compound of formula I to the base is about 1:1.5 or 1:2.5;
在本发明的部分实施方式中，当式Ⅲ化合物经分离后进行反应得到式Ⅳ化合物时，式Ⅲ化合物进行反应得到式Ⅳ化合物是在第二碱的存在下进行的，在本发明的部分实施方式中，所述第二碱选自四丁基氟化铵或其水合物、四正丁基二氢三氟化铵、四丁基磷酸二氢铵、四正辛基溴化铵、四正丁基二氢三氟化铵或其水合物、四丁基溴化铵或甲基三丁基溴化铵的一种或一种以上，优选为四丁基氟化铵或其水合物，更优选为四丁基氟化铵或其三水合物，最优选为四丁基氟化铵三水合物；所述式Ⅲ化合物与第二碱的摩尔比为1：0.5-10，优选为1：1-5，在本发明的一些具体实施方案中，式Ⅲ化合物与第二碱的摩尔比约为1：2；In some embodiments of the present invention, when the compound of formula III is separated and reacted to obtain the compound of formula IV, the reaction of the compound of formula III to obtain the compound of formula IV is carried out in the presence of a second base. In some embodiments of the present invention In the mode, the second base is selected from tetrabutylammonium fluoride or its hydrate, tetra-n-butylammonium dihydrogen trifluoride, tetrabutylammonium dihydrogenphosphate, tetra-n-octylammonium bromide, tetra-n-octylammonium One or more of butyl dihydroammonium trifluoride or its hydrate, tetrabutyl ammonium bromide or methyl tributyl ammonium bromide, preferably tetrabutyl ammonium fluoride or its hydrate, more It is preferably tetrabutylammonium fluoride or its trihydrate, most preferably tetrabutylammonium fluoride trihydrate; the molar ratio of the compound of formula III to the second base is 1:0.5-10, preferably 1: 1-5, in some specific embodiments of the present invention, the molar ratio of the compound of formula III to the second base is about 1:2;
在本发明的部分实施方式中，当式Ⅲ化合物不经分离进行反应得到式Ⅳ化合物时，所述式Ⅰ化合物与碱的摩尔比可以为1：2.5-10，优选为1：3-10，最优选为1：4-10，在本发明的一些具体实施方案中，式Ⅰ化合物与碱的摩尔比约为1：5；In some embodiments of the present invention, when the compound of formula III is reacted without isolation to obtain the compound of formula IV, the molar ratio of the compound of formula I to the base can be 1:2.5-10, preferably 1:3-10, Most preferably 1:4-10, in some specific embodiments of the present invention, the molar ratio of the compound of formula I to the base is about 1:5;
在本发明的部分实施方式中，当式Ⅲ化合物不经分离进行反应得到式Ⅳ化合物时，所述碱可以一次性加入反应体系，也可以分次加入反应体系，例如可以分两次加入反应体系；In some embodiments of the present invention, when the compound of formula III is reacted without separation to obtain the compound of formula IV, the base can be added to the reaction system at one time, or can be added to the reaction system in stages, for example, it can be added to the reaction system twice ;
在本发明的部分实施方式中，上述制备方法在合适的溶剂存在下进行，在本发明的部分实施方式中，所述溶剂选自四氢呋喃、二氧六环、乙腈、甲苯、二甲亚砜、N,N-二甲基甲酰胺的一种或一种以上，优选为四氢呋喃或N,N-二甲基甲酰胺，最优选为四氢呋喃；In some embodiments of the present invention, the above-mentioned preparation method is carried out in the presence of a suitable solvent. In some embodiments of the present invention, the solvent is selected from tetrahydrofuran, dioxane, acetonitrile, toluene, dimethyl sulfoxide, One or more kinds of N,N-dimethylformamide, preferably tetrahydrofuran or N,N-dimethylformamide, most preferably tetrahydrofuran;
在本发明的部分实施方式中，当式Ⅲ化合物经分离后进行反应得到式Ⅳ化合物时，式Ⅲ化合物的制备和式Ⅳ化合物的制备可以根据需要分别选择合适的溶剂，在本发明的部分实施方式中，所述溶剂选自四氢呋喃、二氧六环、乙腈、甲苯、二甲亚砜或N,N-二甲基甲酰胺的一种或一种以上，优选四氢呋喃或N,N-二甲基甲酰胺，最优选为四氢呋喃；In some embodiments of the present invention, when the compound of formula III is separated and reacted to obtain the compound of formula IV, the preparation of the compound of formula III and the preparation of the compound of formula IV can respectively select appropriate solvents according to the needs, and in the partial implementation of the present invention In the method, the solvent is selected from one or more of tetrahydrofuran, dioxane, acetonitrile, toluene, dimethyl sulfoxide or N,N-dimethylformamide, preferably tetrahydrofuran or N,N-dimethylformamide methyl formamide, most preferably tetrahydrofuran;
在本发明的部分实施方式中，所述反应温度为50-100℃，在本发明的一些具体实施方案中，所述温度是75℃或者反应体系的沸点；In some embodiments of the present invention, the reaction temperature is 50-100°C, and in some specific embodiments of the present invention, the temperature is 75°C or the boiling point of the reaction system;
当式Ⅲ化合物经分离后进行反应得到式Ⅳ化合物时，式Ⅲ化合物的制备和式Ⅳ化合物的制备可以根据需要分别选择合适的反应温度，例如可以是50-100℃，在本发明的一些具体实施方案中，所述温度是75℃或者反应体系的沸点；When the compound of formula III is separated and reacted to obtain the compound of formula IV, the preparation of the compound of formula III and the preparation of the compound of formula IV can respectively select appropriate reaction temperature according to needs, for example, it can be 50-100 ° C. In some specific embodiments of the present invention In an embodiment, the temperature is 75° C. or the boiling point of the reaction system;
上述制备方法可以根据需要选择合适的反应时间，在本发明的部分实施方案中，反应时间为0.5-48小时，优选为12-24小时。In the above preparation method, an appropriate reaction time can be selected according to needs. In some embodiments of the present invention, the reaction time is 0.5-48 hours, preferably 12-24 hours.
另一方面，本发明提供了一种式Ⅴ化合物的制备方法，包括式Ⅳ化合物进行反应制备式Ⅴ化合物，In another aspect, the present invention provides a method for preparing a compound of formula V, which comprises reacting a compound of formula IV to prepare a compound of formula V,
其中式Ⅳ化合物通过如前所述的式Ⅳ化合物的制备方法制备；Wherein the compound of formula IV is prepared by the preparation method of the compound of formula IV as described above;
其中X选自卤素，优选为溴或氯，最优选为氯；在本发明的一些具体实施方案中，式Ⅳ化合物为式Ⅳ-1化合物，式Ⅴ化合物为式Ⅴ-1化合物；Wherein X is selected from halogen, preferably bromine or chlorine, most preferably chlorine; in some embodiments of the present invention, the compound of formula IV is the compound of formula IV-1, and the compound of formula V is the compound of formula V-1;
在本发明的部分实施方式中，所述反应是在酸的存在下进行的；其中所述酸选自有机酸或无机酸，其中有机酸选自甲酸、乙酸、三氟乙酸、甲磺酸、对甲苯磺酸或三氟甲烷磺酸的一种或者一种以上，无机酸选自盐酸、氢溴酸、硫酸、磷酸或硝酸的一种或者一种以上，优选为甲磺酸、盐酸、对甲苯磺酸、三氟乙酸或三氟甲烷磺酸的一种或者一种以上，最优选为盐酸；In some embodiments of the present invention, the reaction is carried out in the presence of an acid; wherein the acid is selected from organic acids or inorganic acids, wherein the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, One or more of p-toluenesulfonic acid or trifluoromethanesulfonic acid, one or more of inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid, preferably methanesulfonic acid, hydrochloric acid, p- One or more of toluenesulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid, most preferably hydrochloric acid;
在本发明的部分实施方式中，式Ⅴ化合物与酸的摩尔比为1：5-20，优选为1：5-15，更优选为1：10-12；In some embodiments of the present invention, the molar ratio of the compound of formula V to the acid is 1:5-20, preferably 1:5-15, more preferably 1:10-12;
在本发明的部分实施方式中，式Ⅴ化合物的制备在合适的溶剂存在下进行，所述溶剂选自四氢呋喃、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、二氯甲烷、甲醇、乙醇、正丙醇、二氧六环、乙腈、甲苯、二甲亚砜、N,N-二甲基甲酰胺或上述溶剂的混合溶剂，优选四氢呋喃、乙酸乙酯、二氯甲烷、甲醇，最优选为乙酸乙酯或四氢呋喃；In some embodiments of the present invention, the preparation of the compound of formula V is carried out in the presence of a suitable solvent selected from tetrahydrofuran, ethyl acetate, n-propyl acetate, isopropyl acetate, dichloromethane, methanol, ethanol , n-propanol, dioxane, acetonitrile, toluene, dimethyl sulfoxide, N,N-dimethylformamide or a mixed solvent of the above solvents, preferably tetrahydrofuran, ethyl acetate, dichloromethane, methanol, most preferably is ethyl acetate or tetrahydrofuran;
在本发明的部分实施方式中，所述反应温度为5-30℃，优选为15-30℃，在本发明的一些具体实施方案中，所述反应温度为25℃；In some embodiments of the present invention, the reaction temperature is 5-30°C, preferably 15-30°C, and in some specific embodiments of the present invention, the reaction temperature is 25°C;
式Ⅴ化合物的制备可以根据需要选择合适的反应时间，在本发明的部分实施方案中，反应时间为0.5-24小时，优选为5-12小时，在本发明的一些具体实施方案中，反应时间为8小时。The preparation of formula V compound can select suitable reaction time according to needs, and in some embodiments of the present invention, reaction time is 0.5-24 hour, is preferably 5-12 hour, and in some specific embodiments of the present invention, reaction time for 8 hours.
再一方面，本发明提供了一种式Ⅵ化合物的制备方法，包括式Ⅴ化合物经氧化制备式Ⅵ化合物，In another aspect, the present invention provides a method for preparing a compound of formula VI, comprising preparing the compound of formula VI by oxidation of the compound of formula V,
其中式Ⅴ化合物通过如前所述的式Ⅴ化合物的制备方法制备。Wherein the compound of formula V is prepared by the preparation method of the compound of formula V as described above.
其中X选自卤素，优选为溴或氯，最优选为氯；在本发明的一些具体实施方案中，式Ⅴ化合物为式Ⅴ-1化合物，式Ⅵ化合物为式Ⅵ-1化合物；Wherein X is selected from halogen, preferably bromine or chlorine, most preferably chlorine; in some embodiments of the present invention, the compound of formula V is the compound of formula V-1, and the compound of formula VI is the compound of formula VI-1;
其中式Ⅵ化合物的制备可以根据需要选择合适的氧化条件，所述氧化条件选自(i)、(ii)、(iii)、(iv)或者(v)的氧化条件中的一种：(i)碱性条件下DMSO为氧化剂，低温下在溶剂中与草酰氯协同氧化；所述碱选自三乙胺或N,N-二异丙基乙胺；所述溶剂选自二氯甲烷、四氢呋喃、乙醚或乙酸乙酯，优选二氯甲烷；所述低温为-60～-80℃，优选-60～-70℃；(ii)氯铬酸吡啶为氧化剂，在溶剂存在下氧化；所述溶剂选自二氯甲烷、四氢呋喃、乙醚或乙酸乙酯，优选二氯甲烷；(iii)(1,1,1-三乙酰氧基)-1,1-二氢-1,2-苯碘酰-3(1H)-酮为氧化剂，在溶剂存在下氧化；所述溶剂选自二氯甲烷、四氢呋喃、乙醚或乙酸乙酯，优选二氯甲烷；(iv)三氧化铬、硫酸与水制备的琼斯氧化剂，在溶剂存在下氧化；所述溶剂选自二氯甲烷、四氢呋喃、乙醚或乙酸乙酯，优选二氯甲烷；(v)四甲基哌啶氮氧化物、溴化物、次氯酸钠在碱性条件下为氧化剂，在溶剂存在下氧化；所述溴化物选自溴化钠或溴化钾；所述碱选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、磷酸钠、磷酸钾、磷酸氢钠或磷酸氢钾，优选碳酸氢钠或碳酸氢钾；所述溶剂选自四氢呋喃、二氧六环、乙腈或丙酮，优选四氢呋喃；在本发明的一些具体实施方案中，所述氧化条件为(v)的氧化条件；Wherein the preparation of the compound of formula VI can select suitable oxidation conditions as required, and the oxidation conditions are selected from one of (i), (ii), (iii), (iv) or (v) oxidation conditions: (i ) DMSO is an oxidizing agent under alkaline conditions, and is oxidized synergistically with oxalyl chloride in a solvent at low temperature; the base is selected from triethylamine or N,N-diisopropylethylamine; the solvent is selected from dichloromethane, tetrahydrofuran , ether or ethyl acetate, preferably dichloromethane; the low temperature is -60 to -80°C, preferably -60 to -70°C; (ii) pyridinium chlorochromate is an oxidizing agent, oxidized in the presence of a solvent; the solvent Selected from dichloromethane, tetrahydrofuran, diethyl ether or ethyl acetate, preferably dichloromethane; (iii) (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodide- 3(1H)-ketone is an oxidizing agent, which is oxidized in the presence of a solvent; the solvent is selected from dichloromethane, tetrahydrofuran, ether or ethyl acetate, preferably dichloromethane; (iv) Jones prepared from chromium trioxide, sulfuric acid and water Oxidant, oxidation under the existence of solvent; Said solvent is selected from dichloromethane, tetrahydrofuran, ether or ethyl acetate, preferably dichloromethane; (v) tetramethylpiperidine nitrogen oxide, bromide, sodium hypochlorite are in alkaline condition The following is an oxidizing agent, which is oxidized in the presence of a solvent; the bromide is selected from sodium bromide or potassium bromide; the alkali is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, phosphoric acid Sodium hydrogen or potassium hydrogen phosphate, preferably sodium bicarbonate or potassium bicarbonate; The solvent is selected from tetrahydrofuran, dioxane, acetonitrile or acetone, preferably tetrahydrofuran; In some specific embodiments of the present invention, the oxidation condition is (v) oxidation conditions;
其中式Ⅵ化合物的制备任选在氮气或氩气的保护下进行；Wherein the preparation of the compound of formula VI is optionally carried out under the protection of nitrogen or argon;
式Ⅵ化合物的制备可以根据需要选择合适的反应时间，在本发明的部分实施方案中，反应时间为0.5-48小时，优选为5-24小时，在本发明的一些具体实施方案中，反应时间为12小时。The preparation of the compound of formula VI can select the appropriate reaction time according to the needs, in some embodiments of the present invention, the reaction time is 0.5-48 hours, preferably 5-24 hours, in some specific embodiments of the present invention, the reaction time for 12 hours.
还一方面，本发明提供了一种式Ⅶ化合物的制备方法，包括式Ⅵ化合物与N,N-二甲基甲酰胺进行反应制备式Ⅶ化合物，In another aspect, the present invention provides a method for preparing the compound of formula VII, which comprises reacting the compound of formula VI with N,N-dimethylformamide to prepare the compound of formula VII,
其中式Ⅵ化合物通过如前所述的式Ⅵ化合物的制备方法制备；Wherein the compound of formula VI is prepared by the preparation method of the compound of formula VI as described above;
其中X选自卤素，优选为溴或氯，最优选为氯；在本发明的一些具体实施方案中，式Ⅵ化合物为式Ⅵ-1化合物，式Ⅶ化合物为式Ⅶ-1化合物；Wherein X is selected from halogen, preferably bromine or chlorine, most preferably chlorine; in some embodiments of the present invention, the compound of formula VI is the compound of formula VI-1, and the compound of formula VII is the compound of formula VII-1;
在本发明的部分实施方式中，所述反应是在自由基引发剂和氧化剂存在下进行的；In some embodiments of the present invention, the reaction is carried out in the presence of a free radical initiator and an oxidizing agent;
在本发明的部分实施方式中，所述自由基引发剂选自过氧化氢叔丁醇、二叔丁基过氧化物、过氧化苯甲酸叔丁酯、过氧化二苯甲酰、过氧化二异丙苯、过氧化氢异丙苯、偶氮二异丁腈或过氧化环己酮，优选过氧化氢叔丁醇或二叔丁基过氧化物的一种或一种以上，最优选为过氧化氢叔丁醇；In some embodiments of the present invention, the free radical initiator is selected from tert-butyl hydroperoxide, di-tert-butyl peroxide, tert-butyl peroxybenzoate, dibenzoyl peroxide, di-tert-butyl peroxide Cumene, cumene hydroperoxide, azobisisobutyronitrile or cyclohexanone peroxide, preferably one or more of tert-butanol hydroperoxide or di-tert-butyl peroxide, most preferably tert-butanol hydroperoxide;
在本发明的部分实施方式中，所述氧化剂选自碘、碘化亚铜、氯化亚铜、氧化铜、氯化银、溴化银、碘化银或醋酸银，优选为碘或碘化亚铜，最优选为碘；In some embodiments of the present invention, the oxidant is selected from iodine, cuprous iodide, cuprous chloride, cupric oxide, silver chloride, silver bromide, silver iodide or silver acetate, preferably iodine or cuprous iodide , most preferably iodine;
在本发明的部分实施方式中，所述式Ⅵ化合物与N,N-二甲基甲酰胺的摩尔比为1：20-100，优选为1：30-80，最优选为1：50-60；In some embodiments of the present invention, the molar ratio of the compound of formula VI to N,N-dimethylformamide is 1:20-100, preferably 1:30-80, most preferably 1:50-60 ;
在本发明的部分实施方式中，反应温度为50-100℃，优选为60-90℃，最优选为70-80℃，在本发明的一些具体实施方案中，所述反应温度为70℃或80℃；In some embodiments of the present invention, the reaction temperature is 50-100°C, preferably 60-90°C, most preferably 70-80°C, and in some specific embodiments of the present invention, the reaction temperature is 70°C or 80°C;
式Ⅵ化合物的制备可以根据需要选择合适的反应时间，在本发明的部分实施方案中，反应时间为0.5-48小时，优选为10-36小时，在本发明的一些具体实施方案中，反应时间为24小时。The preparation of the compound of formula VI can select the appropriate reaction time according to the needs, in some embodiments of the present invention, the reaction time is 0.5-48 hours, preferably 10-36 hours, in some specific embodiments of the present invention, the reaction time for 24 hours.
再一方面，本发明提供了一种式Ⅶ化合物的制备方法，包括：In another aspect, the present invention provides a method for preparing a compound of formula VII, comprising:
(1)式Ⅰ化合物与式Ⅱ化合物在催化剂和碱的存在下进行反应得到式Ⅲ化合物，所述式Ⅲ化合物进行反应得到式Ⅳ化合物，(1) The compound of formula I reacts with the compound of formula II in the presence of a catalyst and a base to obtain a compound of formula III, and the compound of formula III reacts to obtain a compound of formula IV,
(2)式Ⅳ化合物进行反应制备式Ⅴ化合物，(2) formula IV compound reacts to prepare formula V compound,
(3)式Ⅴ化合物经氧化制备式Ⅵ化合物，(3) the compound of formula V is oxidized to prepare the compound of formula VI,
(4)式Ⅵ化合物与N,N-二甲基甲酰胺进行反应制备式Ⅶ化合物，(4) reacting the compound of formula VI with N,N-dimethylformamide to prepare the compound of formula VII,
其中X选自卤素，优选为溴、氯或碘，最优选为氯；wherein X is selected from halogen, preferably bromine, chlorine or iodine, most preferably chlorine;
其中Y选自卤素，优选为溴、氯或碘，最优选为溴；wherein Y is selected from halogen, preferably bromine, chlorine or iodine, most preferably bromine;
在本发明的部分实施方式中，所述步骤(1)的催化剂为钯催化剂，例如可以是钯(0)和钯(II)催化剂，更具体的，所述钯催化剂选自四(三苯基膦)钯、醋酸钯、1,2-双(二苯膦基)乙烷二氯化钯、1,3-双(二苯膦基)丙烷二氯化钯、1,4-双(二苯膦基)丁烷二氯化钯、二(三苯基膦)二氯化钯、二(氰基苯)二氯化钯、1,1'-双二苯基膦二茂铁二氯化钯或三(二亚苄基丙酮)二钯的一种或一种以上，优选为四(三苯基膦)钯、二(三苯基膦)二氯化钯或二(氰基苯)二氯化钯的一种或一种以上，更优选为四(三苯基膦)钯或二(三苯基膦)二氯化钯的一种或两种，在本发明的一些具体实施方式中，所述催化剂选自四(三苯基膦)钯或二(三苯基膦)二氯化钯；In some embodiments of the present invention, the catalyst of the step (1) is a palladium catalyst, such as a palladium (0) and palladium (II) catalyst, more specifically, the palladium catalyst is selected from tetrakis (triphenyl) Phosphine) palladium, palladium acetate, 1,2-bis(diphenylphosphino)ethane palladium dichloride, 1,3-bis(diphenylphosphino)propane palladium dichloride, 1,4-bis(diphenyl Phosphino)butanepalladium dichloride, bis(triphenylphosphine)palladium dichloride, bis(cyanophenyl)palladium dichloride, 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride or one or more of tris(dibenzylideneacetone)dipalladium, preferably tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride or bis(cyanobenzene)dichloro One or more of palladium chloride, more preferably one or two of tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride, in some embodiments of the present invention, The catalyst is selected from tetrakis(triphenylphosphine)palladium or bis(triphenylphosphine)palladium dichloride;
在本发明的部分实施方式中，所述步骤(1)的碱可以是无机碱或者有机碱，更具体的，所述碱选自四丁基氟化铵或其水合物、四正丁基二氢三氟化铵、四丁基磷酸二氢铵、四正辛基溴化铵、四正丁基二氢三氟化铵或其水合物、四丁基溴化铵或甲基三丁基溴化铵的一种或一种以上；优选为四丁基氟化铵或其水合物，更优选为四丁基氟化铵或其三水合物，最优选为四丁基氟化铵三水合物；In some embodiments of the present invention, the base in the step (1) can be an inorganic base or an organic base, more specifically, the base is selected from tetrabutylammonium fluoride or its hydrate, tetra-n-butyldi Ammonium hydrogen trifluoride, tetrabutyl ammonium dihydrogen phosphate, tetra-n-octyl ammonium bromide, tetra-n-butyl ammonium dihydrogen trifluoride or its hydrate, tetrabutyl ammonium bromide or methyl tributyl bromide One or more than one ammonium chloride; preferably tetrabutylammonium fluoride or its hydrate, more preferably tetrabutylammonium fluoride or its trihydrate, most preferably tetrabutylammonium fluoride trihydrate ;
在本发明的部分实施方式中，所述步骤(1)中式Ⅰ化合物与式Ⅱ化合物的摩尔比为1：1-2，也可以为1：1-1.5，在本发明一些具体实施方案中，所述式Ⅰ化合物与式Ⅱ化合物的摩尔比约为1：2或者1：1.5；In some embodiments of the present invention, the molar ratio of the compound of formula I to the compound of formula II in the step (1) is 1:1-2, or 1:1-1.5. In some specific embodiments of the present invention, The molar ratio of the compound of formula I to the compound of formula II is about 1:2 or 1:1.5;
在本发明的部分实施方式中，所述步骤(1)中式Ⅰ化合物与催化剂的摩尔比为1：0.01-0.1，优选1：0.02-0.08，更优选1：0.05-0.06；In some embodiments of the present invention, the molar ratio of the compound of formula I to the catalyst in the step (1) is 1:0.01-0.1, preferably 1:0.02-0.08, more preferably 1:0.05-0.06;
在本发明的部分实施方案中，所述步骤(1)中式Ⅰ化合物与碱的摩尔比为1：0.5-10；In some embodiments of the present invention, the molar ratio of the compound of formula I to the base in the step (1) is 1:0.5-10;
其中步骤(1)中所述式Ⅲ化合物可以经分离后进行反应得到式Ⅳ化合物，也可以不经分离进行反应得到式Ⅳ化合物；Wherein the compound of formula III described in step (1) can be reacted to obtain the compound of formula IV after separation, and can also be reacted without separation to obtain the compound of formula IV;
在本发明的部分实施方式中，步骤(2)的反应是在酸的存在下进行的；其中所述酸选自有机酸或无机酸，其中有机酸选自甲酸、乙酸、三氟乙酸、甲磺酸、对甲苯磺酸或三氟甲烷磺酸的一种或者一种以上，无机酸选自盐酸、氢溴酸、硫酸、磷酸或硝酸的一种或者一种以上，优选为甲磺酸、盐酸、对甲苯磺酸、三氟乙酸或三氟甲烷磺酸的一种或者一种以上，最优选为盐酸；In some embodiments of the present invention, the reaction in step (2) is carried out in the presence of an acid; wherein the acid is selected from organic acids or inorganic acids, wherein the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, formic acid One or more of sulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid, one or more of inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid, preferably methanesulfonic acid, One or more of hydrochloric acid, p-toluenesulfonic acid, trifluoroacetic acid or trifluoromethanesulfonic acid, most preferably hydrochloric acid;
在本发明的部分实施方式中，步骤(2)中式Ⅴ化合物与酸的摩尔比为1：5-20，优选为1：5-15，更优选为1：10-12；In some embodiments of the present invention, the molar ratio of the compound of formula V to the acid in step (2) is 1:5-20, preferably 1:5-15, more preferably 1:10-12;
其中步骤(3)可以根据需要选择合适的氧化条件，所述氧化条件选自以下(i)、(ii)、(iii)、(iv)或者(v)中的一种：(i)碱性条件下DMSO为氧化剂，低温下在溶剂中与草酰氯协同氧化；所述碱选自三乙胺或N,N-二异丙基乙胺；所述溶剂选自二氯甲烷、四氢呋喃、乙醚或乙酸乙酯，优选二氯甲烷；所述低温为-60～-80℃，优选-60～-70℃；(ii)氯铬酸吡啶为氧化剂，在溶剂存在下氧化；所述溶剂选自二氯甲烷、四氢呋喃、乙醚或乙酸乙酯，优选二氯甲烷；(iii)(1,1,1-三乙酰氧基)-1,1-二氢-1,2-苯碘酰-3(1H)-酮为氧化剂，在溶剂存在下氧化；所述溶剂选自二氯甲烷、四氢呋喃、乙醚或乙酸乙酯，优选二氯甲烷；(iv)三氧化铬、硫酸与水制备的琼斯氧化剂，在溶剂存在下氧化；所述溶剂选自二氯甲烷、四氢呋喃、乙醚或乙酸乙酯，优选二氯甲烷；(v)四甲基哌啶氮氧化物、溴化物、次氯酸钠在碱性条件下为氧化剂，在溶剂存在下氧化；所述溴化物选自溴化钠或溴化钾；所述碱选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、磷酸钠、磷酸钾、磷酸氢钠或磷酸氢钾，优选碳酸氢钠或碳酸氢钾；所述溶剂选自四氢呋喃、二氧六环、乙腈或丙酮，优选四氢呋喃；在本发明的一些具体实施方案中，所述氧化条件为(v)的氧化条件；Wherein step (3) can select suitable oxidation condition according to need, and described oxidation condition is selected from one of following (i), (ii), (iii), (iv) or (v): (i) alkaline Under conditions, DMSO is an oxidizing agent, and it is oxidized synergistically with oxalyl chloride in a solvent at low temperature; the base is selected from triethylamine or N,N-diisopropylethylamine; the solvent is selected from dichloromethane, tetrahydrofuran, ether or Ethyl acetate, preferably dichloromethane; the low temperature is -60 to -80°C, preferably -60 to -70°C; (ii) pyridinium chlorochromate is an oxidant, oxidized in the presence of a solvent; the solvent is selected from two Chloromethane, tetrahydrofuran, diethyl ether or ethyl acetate, preferably dichloromethane; (iii) (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodyl-3(1H )-ketone is an oxidizing agent, which is oxidized in the presence of a solvent; the solvent is selected from dichloromethane, tetrahydrofuran, ether or ethyl acetate, preferably dichloromethane; (iv) Jones oxidizing agent prepared by chromium trioxide, sulfuric acid and water, in Oxidation in the presence of a solvent; the solvent is selected from dichloromethane, tetrahydrofuran, ether or ethyl acetate, preferably dichloromethane; (v) tetramethylpiperidine nitrogen oxide, bromide, sodium hypochlorite are oxidants under alkaline conditions , oxidized in the presence of a solvent; the bromide is selected from sodium bromide or potassium bromide; the base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate or Potassium hydrogen phosphate, preferably sodium bicarbonate or potassium bicarbonate; The solvent is selected from tetrahydrofuran, dioxane, acetonitrile or acetone, preferably tetrahydrofuran; In some specific embodiments of the present invention, the oxidation condition is (v) oxidation conditions;
其中步骤(4)是在自由基引发剂和氧化剂存在下进行的；Wherein step (4) is carried out in the presence of free radical initiator and oxidizing agent;
在本发明的部分实施方式中，步骤(4)中的式Ⅵ化合物与N,N-二甲基甲酰胺的摩尔比为1：20-100，优选为1：30-80，最优选为1：50-60。In some embodiments of the present invention, the molar ratio of the compound of formula VI to N,N-dimethylformamide in step (4) is 1:20-100, preferably 1:30-80, most preferably 1 : 50-60.
还一方面，本发明的提供了式Ⅲ化合物和式Ⅳ化合物或其盐，In another aspect, the present invention provides a compound of formula III and a compound of formula IV or a salt thereof,
其中X选自卤素，优选为溴或氯，最优选为氯。wherein X is selected from halogen, preferably bromine or chlorine, most preferably chlorine.
还一方面，本发明提供了式Ⅲ化合物或式Ⅳ化合物或其盐在制备式Ⅶ化合物的用途。In another aspect, the present invention provides the use of the compound of formula III or the compound of formula IV or a salt thereof in the preparation of the compound of formula VII.
还一方面，本发明提供了式Ⅲ化合物或式Ⅳ化合物或其盐在制备瑞布昔利布的用途。In another aspect, the present invention provides the use of the compound of formula III or IV or a salt thereof in the preparation of rebuciclib.
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes that said event or circumstance occurs and that it does not.
本文单独或组合使用的术语“卤素”或“卤代”是指氟、氯、溴和碘。The term "halogen" or "halo" as used herein, alone or in combination, refers to fluorine, chlorine, bromine and iodine.
本申请中，式Ⅰ化合物、式Ⅰ-1化合物和式Ⅱ化合物可通过现有技术的方法制备，也可来源于市售，本发明实施例使用的式Ⅰ-1化合物和式Ⅱ化合物来源于市售。In this application, the compound of formula I, the compound of formula I-1 and the compound of formula II can be prepared by the methods of the prior art, or can be obtained from the market. The compounds of formula I-1 and formula II used in the examples of the present invention are derived from commercially available.
在本申请中，所述反应可选地在溶剂中进行，本申请中所使用的所有溶剂是市售的，无需进一步纯化即可使用，反应一般是在惰性氮气下、无水溶剂中进行的。In this application, the reaction is optionally carried out in a solvent. All solvents used in this application are commercially available and can be used without further purification. The reaction is generally carried out under an inert nitrogen atmosphere in an anhydrous solvent. .
化合物经手工或者软件命名，市售化合物采用供应商目录名称。Compounds were manually or The software is named, and the commercially available compounds adopt the supplier catalog name.
在本申请中，质子核磁共振数据记录在BRUKER DRX-400(400MHz)分光仪上，化学位移以四甲基硅烷低场处的(ppm)表示；质谱是在Agilent-Q-Tofmicro YA019上测定。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。HPLC色谱柱采用Waters SymmetryC18(4.6×250mm，5μm)，流动相A为0.05％的三氟乙酸水溶液，流动相B为0.05％的三氟乙酸乙腈溶液。薄层层析硅胶板采用烟台芝罘黄务硅胶开发试验厂制的HSG-F254高效薄层层析硅胶预制板。In this application, the proton NMR data were recorded on a BRUKER DRX-400 (400MHz) spectrometer, and the chemical shifts were expressed in ppm at the downfield of tetramethylsilane; the mass spectrum was determined on Agilent-Q-Tofmicro YA019. The mass spectrometer is equipped with an electrospray ionization source (ESI) operating in positive or negative mode. The HPLC chromatographic column adopts Waters Symmetry C18 (4.6×250 mm, 5 μm), the mobile phase A is 0.05% trifluoroacetic acid aqueous solution, and the mobile phase B is 0.05% trifluoroacetic acid acetonitrile solution. The thin-layer chromatography silica gel plate adopts the HSG-F254 high-efficiency thin-layer chromatography silica gel prefabricated plate manufactured by Yantai Zhifu Huangwu Silica Gel Development and Experimental Factory.
本发明的制备方法，式Ⅰ化合物通过与2-(丙-2-炔-1-基氧基)四氢-2H-呋喃反应得到式Ⅲ化合物，式Ⅲ化合物经分离或不经分离继续反应得到式Ⅳ化合物，所得产物进行后续反应依次得到式Ⅴ化合物、式Ⅵ化合物和式Ⅶ化合物，每一步反应均具有高收率和高纯度，因此整个路线总收率高，明显优于现有技术，且原料容易获得，生产成本低，制备简单易操作，反应试剂对环境友好，特别适合工业化生产。In the preparation method of the present invention, the compound of the formula I is reacted with 2-(prop-2-yn-1-yloxy)tetrahydro-2H-furan to obtain the compound of the formula III, and the compound of the formula III is obtained through separation or continuous reaction without separation The compound of formula IV, the obtained product undergoes subsequent reactions to obtain the compound of formula V, the compound of formula VI and the compound of formula VII in sequence. Each step of the reaction has high yield and high purity, so the total yield of the whole route is high, which is obviously better than the prior art. Moreover, the raw materials are easy to obtain, the production cost is low, the preparation is simple and easy to operate, and the reaction reagent is environmentally friendly, which is especially suitable for industrial production.
具体实施方式detailed description
以下实施例对本发明技术方案作进一步非限制性的详细说明。它们不应该被认为是对本发明范围的限制，而只是本发明的示例性说明和典型代表。本发明中使用的溶剂、试剂和原料等均为市售化学纯或分析纯产品。The following examples illustrate the technical solution of the present invention in further non-limiting detail. They should not be considered as limiting the scope of the invention, but only illustrative and typical of the invention. The solvents, reagents and raw materials used in the present invention are commercially available chemically pure or analytically pure products.
实施例1：2-氯-N-环戊基-5-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)嘧啶-4-胺(式Ⅲ-1化合物)的制备Example 1: 2-Chloro-N-cyclopentyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidine-4- Preparation of amine (compound of formula Ⅲ-1)
依次将5-溴-2-氯-N-环戊基嘧啶-4-胺(60g，218mmol)、四丁基氟化铵三水合物(103g，326mmol)、二(三苯基膦)二氯化钯(7.6g，10.85mmol)和无水四氢呋喃(550mL)加入反应瓶中，氮气保护，加入2-(丙-2-炔-1-基氧基)四氢-2H-呋喃(式Ⅱ化合物)(45.6g，325.5mmol)，回流反应24小时后，HPLC分析，反应完全。将反应液冷却到室温，减压蒸馏除去四氢呋喃，加入乙酸乙酯(500mL)，依次用饱和硫酸氢钠(400mL×3)、水(400mL×3)、饱和食盐水(400mL×1)洗涤。将有机相分离后减压浓缩得到粗品油状物，硅胶柱层析，流动相为石油醚/乙酸乙酯＝10：1，得到64.5g淡棕色油状物2-氯-N-环戊基-5-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)嘧啶-4-胺，收率：88.2％，HPLC分析纯度为96.2％。5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (60g, 218mmol), tetrabutylammonium fluoride trihydrate (103g, 326mmol), bis(triphenylphosphine) dichloro Palladium chloride (7.6g, 10.85mmol) and anhydrous tetrahydrofuran (550mL) were added to the reaction flask, under nitrogen protection, 2-(prop-2-yn-1-yloxy)tetrahydro-2H-furan (compound of formula II ) (45.6g, 325.5mmol), after reflux reaction for 24 hours, HPLC analysis showed that the reaction was complete. The reaction solution was cooled to room temperature, tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (500 mL) was added, and washed successively with saturated sodium bisulfate (400 mL×3), water (400 mL×3), and saturated brine (400 mL×1). The organic phase was separated and concentrated under reduced pressure to obtain a crude oil. Silica gel column chromatography, the mobile phase was petroleum ether/ethyl acetate = 10:1, and 64.5 g of light brown oil 2-chloro-N-cyclopentyl-5 -(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidin-4-amine, yield: 88.2%, purity by HPLC analysis: 96.2%.
1H-NMR(400MHz,CDCl3):δ＝8.05(1H,s),5.71(1H,s),4.87-4.85(1H,t,J＝7.0Hz),4.52-4.51(2H,d,J＝7.0Hz),4.47-4.39(1H,m),3.91-3.85(1H,m),3.58-3.54(1H,m),1.76-1.41(14H,m)。 1 H-NMR (400MHz, CDCl 3 ): δ=8.05(1H,s), 5.71(1H,s), 4.87-4.85(1H,t,J=7.0Hz), 4.52-4.51(2H,d,J =7.0Hz), 4.47-4.39 (1H, m), 3.91-3.85 (1H, m), 3.58-3.54 (1H, m), 1.76-1.41 (14H, m).
MS m/z[ESI]:336.1[M+1]+。MS m/z [ESI]: 336.1 [M+1] + .
实施例2：2-氯-N-环戊基-5-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)嘧啶-4-胺(式Ⅲ-1化合物)的制备Example 2: 2-Chloro-N-cyclopentyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidine-4- Preparation of amine (compound of formula Ⅲ-1)
依次将5-溴-2-氯-N-环戊基嘧啶-4-胺(20g，72.3mmol)、四丁基氟化铵三水合物(57g，180.8mmol)、四(三苯基膦)钯(4.2g，3.62mmol)和无水四氢呋喃(300mL)加入反应瓶中，氮气保护，加入2-(丙-2-炔-1-基氧基)四氢-2H-呋喃(20.3g，144.6mmol)，75℃反应20小时后，HPLC分析，反应完全。将反应液冷却到室温，减压蒸馏除去四氢呋喃，加入乙酸乙酯(300mL)，依次用饱和硫酸氢钠(200mL×3)、水(200mL×3)、饱和食盐水(200mL×1)洗涤。将有机相分离后减压浓缩得到粗品油状物，硅胶柱层析分离，流动相为石油醚/乙酸乙酯＝10：1，得到19.5g淡棕色油状物2-氯-N-环戊基-5-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)嘧啶-4-胺，收率：80.0％，HPLC分析纯度为96.8％。5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (20g, 72.3mmol), tetrabutylammonium fluoride trihydrate (57g, 180.8mmol), tetrakis (triphenylphosphine) Palladium (4.2g, 3.62mmol) and anhydrous tetrahydrofuran (300mL) were added to the reaction flask, and under nitrogen protection, 2-(prop-2-yn-1-yloxy)tetrahydro-2H-furan (20.3g, 144.6 mmol), after reacting for 20 hours at 75°C, HPLC analysis showed that the reaction was complete. The reaction solution was cooled to room temperature, tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300 mL) was added, and washed successively with saturated sodium bisulfate (200 mL×3), water (200 mL×3), and saturated brine (200 mL×1). The organic phase was separated and concentrated under reduced pressure to obtain a crude oil, which was separated by silica gel column chromatography, and the mobile phase was petroleum ether/ethyl acetate = 10:1 to obtain 19.5 g of light brown oil 2-chloro-N-cyclopentyl- 5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidin-4-amine, yield: 80.0%, purity by HPLC analysis: 96.8% .
实施例3：2-氯-N-环戊基-5-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)嘧啶-4-胺(式Ⅲ-1化合物)的制备Example 3: 2-Chloro-N-cyclopentyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidine-4- Preparation of amine (compound of formula Ⅲ-1)
依次将5-溴-2-氯-N-环戊基嘧啶-4-胺(30g，108.5mmol)、四丁基氟化铵(70.8g，271.3mmol)、二(三苯基膦)二氯化钯(7.6g，10.85mmol)和无水四氢呋喃(300mL)加入反应瓶中，氮气保护，加入2-(丙-2-炔-1-基氧基)四氢-2H-呋喃(22.8g，162.8mmol)，75℃反应20小时后，HPLC分析，反应完全。将反应液冷却到室温，减压蒸馏除去四氢呋喃，加入乙酸乙酯(300mL)，依次用饱和硫酸氢钠(200mL×3)、水(200mL×3)、饱和食盐水(200mL×1)洗涤。将有机相分离后减压浓缩得到粗品油状物，硅胶柱层析分离，流动相为石油醚/乙酸乙酯＝10：1，得到32.6g淡棕色油状物2-氯-N-环戊基-5-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)嘧啶-4-胺，收率：89.1％，HPLC分析纯度为97.4％。5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (30g, 108.5mmol), tetrabutylammonium fluoride (70.8g, 271.3mmol), bis(triphenylphosphine) dichloro Palladium chloride (7.6g, 10.85mmol) and anhydrous tetrahydrofuran (300mL) were added to the reaction flask, under nitrogen protection, 2-(prop-2-yn-1-yloxy)tetrahydro-2H-furan (22.8g, 162.8mmol), after reacting at 75°C for 20 hours, HPLC analysis showed that the reaction was complete. The reaction solution was cooled to room temperature, tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300 mL) was added, and washed successively with saturated sodium bisulfate (200 mL×3), water (200 mL×3), and saturated brine (200 mL×1). The organic phase was separated and concentrated under reduced pressure to obtain a crude oil, which was separated by silica gel column chromatography, and the mobile phase was petroleum ether/ethyl acetate = 10:1 to obtain 32.6 g of light brown oil 2-chloro-N-cyclopentyl- 5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidin-4-amine, yield: 89.1%, purity by HPLC analysis: 97.4% .
实施例4：2-氯-7-环戊基-6-(((四氢-2H-吡喃-2-基)氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(式Ⅳ-1化合物)的制备Example 4: 2-Chloro-7-cyclopentyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Formula IV-1 compound) preparation
依次将2-氯-N-环戊基-5-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)嘧啶-4-胺(64.5g，192.5mmol)、四丁基氟化铵(配制成1mol/L的四氢呋喃溶液，150mL)和无水四氢呋喃(50mL)加入反应瓶中，氮气保护，90℃回流反应12小时，HPLC分析，反应完全。将反应液冷却到室温，减压蒸馏除去四氢呋喃，加入乙酸乙酯(300mL)，依次用饱和硫酸氢钠(200mL×3)、水(200mL×3)、饱和食盐水(200mL×1)洗涤。将有机相分离后减压浓缩得到粗品油状物，硅胶柱层析分离，流动相为石油醚/乙酸乙酯＝5：1，得到54.2g淡棕色油状物2-氯-7-环戊基-6-(((四氢-2H-吡喃-2-基)氧基)甲基)-7H-吡咯并[2,3-d]嘧啶，收率：84.0％，HPLC分析纯度为98.5％。Sequentially 2-chloro-N-cyclopentyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidin-4-amine ( 64.5g, 192.5mmol), tetrabutylammonium fluoride (prepared as 1mol/L tetrahydrofuran solution, 150mL) and anhydrous tetrahydrofuran (50mL) were added to the reaction flask, nitrogen protection, 90 ° C reflux reaction for 12 hours, HPLC analysis, The response is complete. The reaction solution was cooled to room temperature, tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300 mL) was added, and washed successively with saturated sodium bisulfate (200 mL×3), water (200 mL×3), and saturated brine (200 mL×1). The organic phase was separated and concentrated under reduced pressure to obtain a crude oil, which was separated by silica gel column chromatography, and the mobile phase was petroleum ether/ethyl acetate = 5:1 to obtain 54.2 g of light brown oil 2-chloro-7-cyclopentyl- 6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, yield: 84.0%, purity by HPLC analysis: 98.5%.
1H-NMR(400MHz,CDCl3):δ＝8.69(1H,s),6.50-6.48(1H,d,J＝7.0Hz),4.90-4.84(2H,m),4.69-4.62(2H,m),3.89-3.83(1H,m),3.58-3.55(1H,m),2.47-2.36(2H,m),2.10-2.04(4H,m),1.75-1.52(8H,m)。 1 H-NMR (400MHz, CDCl 3 ): δ=8.69(1H,s), 6.50-6.48(1H,d,J=7.0Hz), 4.90-4.84(2H,m), 4.69-4.62(2H,m ), 3.89-3.83(1H,m), 3.58-3.55(1H,m), 2.47-2.36(2H,m), 2.10-2.04(4H,m), 1.75-1.52(8H,m).
MS m/z[ESI]:358.2[M+Na]+。MS m/z [ESI]: 358.2 [M+Na] + .
实施例5：2-氯-7-环戊基-6-(((四氢-2H-吡喃-2-基)氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(式Ⅳ-1化合物)的制备Example 5: 2-Chloro-7-cyclopentyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Formula IV-1 compound) preparation
依次将2-氯-N-环戊基-5-(3-((四氢-2H-吡喃-2-基)氧基)丙-1-炔-1-基)嘧啶-4-胺(35g，104.5mmol)和四丁基氟化铵(配制成1mol/L的四氢呋喃溶液，200mL)加入反应瓶中，氮气保护，90℃回流反应12小时，HPLC分析，反应完全。将反应液冷却到室温，减压蒸馏除去四氢呋喃，加入乙酸乙酯(300mL)，依次用饱和硫酸氢钠(200mL×3)、水(200mL×3)、饱和食盐水(200mL×1)洗涤。将有机相分离后减压浓缩得到粗品油状物，硅胶柱层析分离，流动相为石油醚/乙酸乙酯＝5：1，得到30.3g淡棕色油状物2-氯-7-环戊基-6-(((四氢-2H-吡喃-2-基)氧基)甲基)-7H-吡咯并[2,3-d]嘧啶，收率：86.6％，HPLC分析纯度为98.7％。Sequentially 2-chloro-N-cyclopentyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidin-4-amine ( 35g, 104.5mmol) and tetrabutylammonium fluoride (prepared as 1mol/L tetrahydrofuran solution, 200mL) were added to the reaction flask, under nitrogen protection, 90 ° C reflux reaction for 12 hours, HPLC analysis, the reaction was complete. The reaction solution was cooled to room temperature, tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300 mL) was added, and washed successively with saturated sodium bisulfate (200 mL×3), water (200 mL×3), and saturated brine (200 mL×1). The organic phase was separated and concentrated under reduced pressure to obtain a crude oil, which was separated by silica gel column chromatography, and the mobile phase was petroleum ether/ethyl acetate=5:1 to obtain 30.3 g of light brown oil 2-chloro-7-cyclopentyl- 6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, yield: 86.6%, purity by HPLC analysis: 98.7%.
实施例6：2-氯-7-环戊基-6-(((四氢-2H-吡喃-2-基)氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(式Ⅳ-1化合物)的制备Example 6: 2-Chloro-7-cyclopentyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Formula IV-1 compound) preparation
依次将5-溴-2-氯-N-环戊基嘧啶-4-胺(50g，180.8mmol)、四丁基氟化铵三水合物(171g，542.4mmol)、二(三苯基膦)二氯化钯(6.3g，9.04mmol)和无水四氢呋喃(450mL)加入反应瓶中，氮气保护，加入2-(丙-2-炔-1-基氧基)四氢-2H-呋喃(35.5g，253mmol)，回流反应12小时后，补加四丁基氟化铵三水合物(114g，361.6mmol)，继续回流搅拌12小时，HPLC分析，反应完全。将反应液冷却到室温，减压蒸馏除去四氢呋喃，加入乙酸乙酯(500mL)，依次用饱和硫酸氢钠(400mL×3)、水(400mL×3)、饱和食盐水(400mL×1)洗涤。将有机相分离后减压浓缩得到粗品油状物，硅胶柱层析分离，流动相为石油醚/乙酸乙酯＝5：1，得到40.2g淡棕色油状物2-氯-7-环戊基-6-(((四氢-2H-吡喃-2-基)氧基)甲基)-7H-吡咯并[2,3-d]嘧啶，收率：66.0％，HPLC分析纯度为98.2％。5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (50g, 180.8mmol), tetrabutylammonium fluoride trihydrate (171g, 542.4mmol), bis(triphenylphosphine) Palladium dichloride (6.3g, 9.04mmol) and anhydrous tetrahydrofuran (450mL) were added to the reaction flask, under nitrogen protection, 2-(prop-2-yn-1-yloxy)tetrahydro-2H-furan (35.5 g, 253mmol), after reflux reaction for 12 hours, add tetrabutylammonium fluoride trihydrate (114g, 361.6mmol), continue to reflux and stir for 12 hours, HPLC analysis shows that the reaction is complete. The reaction solution was cooled to room temperature, tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (500 mL) was added, and washed successively with saturated sodium bisulfate (400 mL×3), water (400 mL×3), and saturated brine (400 mL×1). The organic phase was separated and concentrated under reduced pressure to obtain a crude oil, which was separated by silica gel column chromatography, and the mobile phase was petroleum ether/ethyl acetate=5:1 to obtain 40.2 g of light brown oil 2-chloro-7-cyclopentyl- 6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, yield: 66.0%, purity by HPLC analysis: 98.2%.
实施例7：2-氯-7-环戊基-6-(((四氢-2H-吡喃-2-基)氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(式Ⅳ-1化合物)的制备Example 7: 2-Chloro-7-cyclopentyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (Formula IV-1 compound) preparation
依次将5-溴-2-氯-N-环戊基嘧啶-4-胺(25g，90.4mmol)、四丁基氟化铵三水合物(142g，452mmol)、二(三苯基膦)二氯化钯(5.2g，4.52mmol)和无水四氢呋喃(230mL)加入反应瓶中，氮气保护，加入2-(丙-2-炔-1-基氧基)四氢-2H-呋喃(19g，135.6mmol)，回流反应24小时，HPLC分析，反应完全。将反应液冷却到室温，减压蒸馏除去四氢呋喃，加入乙酸乙酯(300mL)，依次用饱和硫酸氢钠(200mL×3)、水(200mL×3)、饱和食盐水(200mL×1)洗涤。将有机相分离后减压浓缩得到粗品油状物，硅胶柱层析分离，流动相为石油醚/乙酸乙酯＝5：1，得到19.6g淡棕色油状物2-氯-7-环戊基-6-(((四氢-2H-吡喃-2-基)氧基)甲基)-7H-吡咯并[2,3-d]嘧啶，收率：64.3％，HPLC分析纯度为98.4％。5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (25g, 90.4mmol), tetrabutylammonium fluoride trihydrate (142g, 452mmol), bis(triphenylphosphine) di Palladium chloride (5.2g, 4.52mmol) and anhydrous tetrahydrofuran (230mL) were added to the reaction flask, under nitrogen protection, 2-(prop-2-yn-1-yloxy)tetrahydro-2H-furan (19g, 135.6mmol), reflux reaction for 24 hours, HPLC analysis, the reaction was complete. The reaction solution was cooled to room temperature, tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300 mL) was added, and washed successively with saturated sodium bisulfate (200 mL×3), water (200 mL×3), and saturated brine (200 mL×1). The organic phase was separated and concentrated under reduced pressure to obtain a crude oil, which was separated by silica gel column chromatography, and the mobile phase was petroleum ether/ethyl acetate=5:1 to obtain 19.6 g of light brown oil 2-chloro-7-cyclopentyl- 6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, yield: 64.3%, purity by HPLC analysis: 98.4%.
实施例8：(2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-基)甲醇(式Ⅴ-1化合物)的制备Example 8: Preparation of (2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol (compound of formula V-1)
将2-氯-7-环戊基-6-(((四氢-2H-吡喃-2-基)氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(40g，119.4mmol)和乙酸乙酯(400mL)加入反应瓶中，冷却至10℃，缓慢滴入浓盐酸(40mL)，室温搅拌8小时，HPLC分析反应完全。反应液减压浓缩得到粘稠状物，加入甲醇(50mL)，在室温下将其缓慢滴入10％NaOH(300mL)中，滴入完毕，加入正己烷(100mL)继续搅拌2小时，过滤，滤饼40℃真空干燥12小时得29.4g淡黄色固体(2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-基)甲醇，收率：98.0％，HPLC分析纯度为99.6％。2-Chloro-7-cyclopentyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (40g, 119.4mmol) and ethyl acetate (400mL) were added to the reaction flask, cooled to 10°C, concentrated hydrochloric acid (40mL) was slowly added dropwise, stirred at room temperature for 8 hours, and the reaction was complete by HPLC analysis. The reaction solution was concentrated under reduced pressure to obtain a viscous substance. Methanol (50 mL) was added, and it was slowly dropped into 10% NaOH (300 mL) at room temperature. After the addition was completed, n-hexane (100 mL) was added to continue stirring for 2 hours, and filtered. The filter cake was vacuum-dried at 40°C for 12 hours to obtain 29.4 g of light yellow solid (2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol, yield: 98.0%, The purity by HPLC analysis was 99.6%.
1H-NMR(400MHz,CDCl3):δ＝8.61(1H,s),6.40(1H,s),4.97-4.89(1H,m),4.81(2H,s),2.42-2.36(2H,m),2.10-2.07(4H,m),1.72-1.71(2H,m)。 1 H-NMR (400MHz, CDCl 3 ): δ=8.61(1H,s), 6.40(1H,s), 4.97-4.89(1H,m), 4.81(2H,s), 2.42-2.36(2H,m ), 2.10-2.07(4H,m), 1.72-1.71(2H,m).
MS m/z[ESI]:252.1[M+H]+。MS m/z [ESI]: 252.1 [M+H] + .
实施例9：(2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-基)甲醇(式Ⅴ-1化合物)的制备Example 9: Preparation of (2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol (compound of formula V-1)
将2-氯-7-环戊基-6-(((四氢-2H-吡喃-2-基)氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(20g，59.7mmol)和四氢呋喃(200mL)加入反应瓶中，冷却至10℃，缓慢滴入浓盐酸(20mL)，室温搅拌8小时，HPLC分析反应完全。反应液减压浓缩得到粘稠状物，加入甲醇(30mL)，在室温下将其缓慢滴入10％NaOH(150mL)中，滴入完毕，加入正己烷(60mL)继续搅拌2小时，过滤，滤饼40℃真空干燥12小时得14.6g淡黄色固体(2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-基)甲醇，收率：97.3％，HPLC分析纯度为99.2％。2-Chloro-7-cyclopentyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (20g, 59.7mmol) and tetrahydrofuran (200mL) were added to the reaction flask, cooled to 10°C, concentrated hydrochloric acid (20mL) was slowly added dropwise, stirred at room temperature for 8 hours, and the reaction was complete by HPLC analysis. The reaction solution was concentrated under reduced pressure to obtain a viscous substance. Methanol (30 mL) was added, and it was slowly dropped into 10% NaOH (150 mL) at room temperature. After the addition was completed, n-hexane (60 mL) was added to continue stirring for 2 hours, and filtered. The filter cake was vacuum-dried at 40°C for 12 hours to obtain 14.6 g of light yellow solid (2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol, yield: 97.3%, Purity by HPLC analysis was 99.2%.
实施例10：2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-甲醛(式Ⅵ-1化合物)的制备Example 10: Preparation of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (compound of formula VI-1)
依次将(2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-基)甲醇(20.0g，80mmol)、NaBr(0.82g，8mmol)、四甲基哌啶氮氧化物(0.13g，0.8mmol)和四氢呋喃(300mL)加入反应瓶中，氮气保护，冰浴下缓慢滴入次氯酸钠溶液(5.2％0.806M 150mL，120mmol，用饱和碳酸氢钠调pH至9.5)，滴加完毕后室温搅拌12小时，HPLC分析反应完全，依次用10％柠檬酸(200mL×1，加入KI 0.02当量)、10％硫代硫酸钠(200mL×3)、水(200mL×3)、饱和食盐水(200mL×1)洗涤。有机相减压浓缩得到17.1g白色固体2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-甲醛，收率：86.0％，HPLC分析纯度为96.8％。(2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol (20.0g, 80mmol), NaBr (0.82g, 8mmol), tetramethylpiper Pyridine nitrogen oxide (0.13g, 0.8mmol) and tetrahydrofuran (300mL) were added to the reaction flask, under nitrogen protection, sodium hypochlorite solution (5.2% 0.806M 150mL, 120mmol) was slowly added dropwise under ice bath, and the pH was adjusted to 9.5 with saturated sodium bicarbonate ), stirred at room temperature for 12 hours after the dropwise addition was completed, and the reaction was complete by HPLC analysis. ), washed with saturated brine (200mL×1). The organic phase was concentrated under reduced pressure to obtain 17.1 g of white solid 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde, the yield: 86.0%, and the purity by HPLC analysis was 96.8%.
1H-NMR(400MHz,CDCl3):δ＝9.93(1H,s),8.98(1H,s),7.31(1H,s),5.79-5.70(1H,m),2.25-1.72(8H,m)。 1 H-NMR (400MHz, CDCl 3 ): δ=9.93(1H,s), 8.98(1H,s), 7.31(1H,s), 5.79-5.70(1H,m), 2.25-1.72(8H,m ).
MS m/z[ESI]:250.4[M+H]+。MS m/z [ESI]: 250.4 [M+H] + .
实施例11：2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-甲醛(式Ⅵ-1化合物)的制备Example 11: Preparation of 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (compound of formula VI-1)
依次将(2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-基)甲醇(10.0g，40mmol)、KBr(0.5g，4mmol)、四甲基哌啶氮氧化物(0.07g，0.4mmol)和四氢呋喃(150mL)加入反应瓶中，氮气保护，冰浴下缓慢滴入次氯酸钠溶液(5.2％0.806M 150mL，60mmol，用饱和碳酸氢钠调pH至9.5)，滴加完毕后室温搅拌12小时，HPLC分析反应完全，依次用10％柠檬酸(100mL×1，加入KI 0.02当量)、10％硫代硫酸钠(100mL×3)、水(100mL×3)、饱和食盐水(100mL×1)洗涤。有机相减压浓缩得到8.6g白色固体2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-甲醛，收率：86.8％，HPLC分析纯度为96.2％。(2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol (10.0g, 40mmol), KBr (0.5g, 4mmol), tetramethylpiper Pyridine nitrogen oxide (0.07g, 0.4mmol) and tetrahydrofuran (150mL) were added to the reaction flask, under nitrogen protection, sodium hypochlorite solution (5.2% 0.806M 150mL, 60mmol) was slowly added dropwise under ice bath, and the pH was adjusted to 9.5 with saturated sodium bicarbonate ), stirred at room temperature for 12 hours after the dropwise addition was completed, and the reaction was complete by HPLC analysis. ), washed with saturated brine (100mL×1). The organic phase was concentrated under reduced pressure to obtain 8.6 g of white solid 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde, the yield: 86.8%, and the purity by HPLC analysis was 96.2%.
实施例12：2-氯-7-环戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(式Ⅶ-1化合物)的制备Example 12: Preparation of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (compound of formula VII-1)
依次将2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-甲醛(12.0g，48mmol)、碘(2.4g，9.6mmol)和N,N-二甲基甲酰胺(200mL)加入至反应瓶中，氮气保护，缓慢滴入过氧化氢叔丁醇(70％水溶液，26.3mL，192mmol)，滴入完毕后70℃反应24小时，HPLC分析反应完全。将反应液冷却到室温，向反应液中缓慢滴入饱和硫代硫酸钠溶液(100mL)，滴入完毕后，用乙酸乙酯(200mL×3)萃取，合并有机相，依次用水(200mL×1)、饱和食盐水(200mL×1)洗涤，有机相减压浓缩得淡棕色粗品，石油醚/乙酸乙酯重结晶得到10.2g淡黄色固体2-氯-7-环戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺，收率72.8％，HPLC分析纯度为98.9％。2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (12.0g, 48mmol), iodine (2.4g, 9.6mmol) and N,N-dimethyl Add methyl formamide (200mL) into the reaction flask, under nitrogen protection, slowly drop in tert-butanol hydroperoxide (70% aqueous solution, 26.3mL, 192mmol), react at 70°C for 24 hours after the dropwise addition, HPLC analysis shows that the reaction is complete. The reaction solution was cooled to room temperature, and the saturated sodium thiosulfate solution (100 mL) was slowly added dropwise to the reaction solution. After the addition was completed, it was extracted with ethyl acetate (200 mL×3), the organic phases were combined, and water (200 mL×1 ), saturated brine (200mL×1), and the organic phase was concentrated under reduced pressure to obtain a light brown crude product, which was recrystallized from petroleum ether/ethyl acetate to obtain 10.2 g of light yellow solid 2-chloro-7-cyclopentyl-N,N- Dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, yield 72.8%, HPLC analysis purity 98.9%.
1H-NMR(400MHz,CDCl3):δ＝8.77(1H,s),6.51(1H,s),4.90-4.82(1H,m),3.17-3.07(6H,s),2.38-2.33(2H,m),2.08-2.03(4H,m),1.68-1.65(2H,m)。 1 H-NMR (400MHz, CDCl 3 ): δ=8.77(1H,s), 6.51(1H,s), 4.90-4.82(1H,m), 3.17-3.07(6H,s), 2.38-2.33(2H ,m), 2.08-2.03(4H,m), 1.68-1.65(2H,m).
MS m/z[ESI]:293.1[M+H]+。MS m/z [ESI]: 293.1 [M+H] + .
实施例13：2-氯-7-环戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺(式Ⅶ-1化合物)的制备Example 13: Preparation of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (compound of formula VII-1)
依次将2-氯-7-环戊基-7H-吡咯并[2,3-d]嘧啶-6-甲醛(10.0g，40mmol)、碘(2.0g，8mmol)和N,N-二甲基甲酰胺(150mL)加入至反应瓶中，氮气保护，缓慢滴入过氧化氢叔丁醇(70％水溶液，27.3mL，200mmol)，滴入完毕后80℃反应24小时，HPLC分析反应完全。将反应液冷却到室温，向反应液中缓慢滴入饱和硫代硫酸钠溶液(80mL)，滴入完毕后，用乙酸乙酯(200mL×3)萃取，合并有机相，依次用水(200mL×1)、饱和食盐水(200mL×1)洗涤，有机相减压浓缩得淡棕色粗品，石油醚/乙酸乙酯重结晶得到8.8g淡黄色固体2-氯-7-环戊基-N,N-二甲基-7H-吡咯并[2,3-d]嘧啶-6-甲酰胺，收率75.2％，HPLC分析纯度为99.2％。2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (10.0g, 40mmol), iodine (2.0g, 8mmol) and N,N-dimethyl Add formamide (150mL) into the reaction flask, under nitrogen protection, slowly drop into tert-butanol hydroperoxide (70% aqueous solution, 27.3mL, 200mmol), react at 80°C for 24 hours after dropping, HPLC analysis shows that the reaction is complete. The reaction solution was cooled to room temperature, and the saturated sodium thiosulfate solution (80 mL) was slowly dripped into the reaction solution. After the addition was completed, it was extracted with ethyl acetate (200 mL×3), the organic phases were combined, and water (200 mL×1 ), saturated brine (200mL×1), and the organic phase was concentrated under reduced pressure to obtain a light brown crude product, which was recrystallized from petroleum ether/ethyl acetate to obtain 8.8 g of light yellow solid 2-chloro-7-cyclopentyl-N,N- Dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide, the yield is 75.2%, and the HPLC analysis purity is 99.2%.
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