CN115536663A - Triracil intermediate and preparation and application thereof - Google Patents
Triracil intermediate and preparation and application thereof Download PDFInfo
- Publication number
- CN115536663A CN115536663A CN202211242477.1A CN202211242477A CN115536663A CN 115536663 A CN115536663 A CN 115536663A CN 202211242477 A CN202211242477 A CN 202211242477A CN 115536663 A CN115536663 A CN 115536663A
- Authority
- CN
- China
- Prior art keywords
- intermediate compound
- compound
- palladium
- reaction
- tert
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940126214 compound 3 Drugs 0.000 claims abstract description 16
- 229940125898 compound 5 Drugs 0.000 claims abstract description 16
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 16
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052802 copper Inorganic materials 0.000 claims abstract description 14
- 239000010949 copper Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 229940125782 compound 2 Drugs 0.000 claims abstract description 10
- 238000005580 one pot reaction Methods 0.000 claims abstract description 9
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 8
- 229940125904 compound 1 Drugs 0.000 claims abstract description 7
- 238000010189 synthetic method Methods 0.000 claims abstract description 7
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 claims abstract description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 150000003138 primary alcohols Chemical class 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 15
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 14
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 11
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 10
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical group I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 9
- 238000001308 synthesis method Methods 0.000 claims description 9
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical group BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 8
- 229940045803 cuprous chloride Drugs 0.000 claims description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 claims description 8
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 7
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 claims description 7
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 7
- 235000011009 potassium phosphates Nutrition 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims 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 claims description 6
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 5
- DORMTBIPKNPJPY-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.IC1=CC=CC=C1 DORMTBIPKNPJPY-UHFFFAOYSA-N 0.000 claims description 5
- 239000012752 auxiliary agent Substances 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].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 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 5
- 239000003446 ligand Substances 0.000 claims description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 4
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- FSNCEEGOMTYXKY-JTQLQIEISA-N Lycoperodine 1 Natural products N1C2=CC=CC=C2C2=C1CN[C@H](C(=O)O)C2 FSNCEEGOMTYXKY-JTQLQIEISA-N 0.000 claims description 4
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000001879 copper Chemical class 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 4
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 4
- 229960002218 sodium chlorite Drugs 0.000 claims description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 4
- GPCHFSKUUKKXAN-UHFFFAOYSA-N tert-butyl n-[[1-[(5-bromo-2-chloropyrimidin-4-yl)amino]cyclohexyl]methyl]carbamate Chemical compound N=1C(Cl)=NC=C(Br)C=1NC1(CNC(=O)OC(C)(C)C)CCCCC1 GPCHFSKUUKKXAN-UHFFFAOYSA-N 0.000 claims description 4
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 4
- UUVRMGSIRLJYNZ-UHFFFAOYSA-N 4-chlorospiro[1,3,5,11-tetrazatricyclo[7.4.0.02,7]trideca-2,4,6,8-tetraene-13,1'-cyclohexane] Chemical compound ClC1=NC2=C(C=C3CNCC4(CCCCC4)N23)C=N1 UUVRMGSIRLJYNZ-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- -1 (5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino Chemical group 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000004537 pulping Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 210000001185 bone marrow Anatomy 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- IMAKHNTVDGLIRY-UHFFFAOYSA-N methyl prop-2-ynoate Chemical compound COC(=O)C#C IMAKHNTVDGLIRY-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- RGUXEWWHSQGVRZ-UHFFFAOYSA-N 3,3-diethoxyprop-1-yne Chemical compound CCOC(C#C)OCC RGUXEWWHSQGVRZ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- 206010065553 Bone marrow failure Diseases 0.000 description 2
- 150000001241 acetals Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RGJNPJRAXMSHKN-UHFFFAOYSA-N 2,4-dichloro-5-iodopyrimidine Chemical compound ClC1=NC=C(I)C(Cl)=N1 RGJNPJRAXMSHKN-UHFFFAOYSA-N 0.000 description 1
- PDGKHKMBHVFCMG-UHFFFAOYSA-N 2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]spiro[7,8-dihydropyrazino[5,6]pyrrolo[1,2-d]pyrimidine-9,1'-cyclohexane]-6-one Chemical compound C1CN(C)CCN1C(C=N1)=CC=C1NC1=NC=C(C=C2N3C4(CCCCC4)CNC2=O)C3=N1 PDGKHKMBHVFCMG-UHFFFAOYSA-N 0.000 description 1
- VEYQMURQUFGPLA-UHFFFAOYSA-N 2-chloro-7-[1-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]cyclohexyl]pyrrolo[2,3-d]pyrimidine-6-carboxylic acid Chemical compound OC(=O)C1=CC2=CN=C(Cl)N=C2N1C1(CNC(=O)OC(C)(C)C)CCCCC1 VEYQMURQUFGPLA-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- SIKXIUWKPGWBBF-UHFFFAOYSA-N 5-bromo-2,4-dichloropyrimidine Chemical compound ClC1=NC=C(Br)C(Cl)=N1 SIKXIUWKPGWBBF-UHFFFAOYSA-N 0.000 description 1
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 description 1
- 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 description 1
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102000013698 Cyclin-Dependent Kinase 6 Human genes 0.000 description 1
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- DGEYTDCFMQMLTH-UHFFFAOYSA-N methanol;propan-2-ol Chemical compound OC.CC(C)O DGEYTDCFMQMLTH-UHFFFAOYSA-N 0.000 description 1
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- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
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- 238000011521 systemic chemotherapy Methods 0.000 description 1
- 229950007127 trilaciclib Drugs 0.000 description 1
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Classifications
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- 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
- 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
- C07D487/12—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 three hetero rings
- C07D487/20—Spiro-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a synthetic method of a key intermediate compound 5 of Trasipride, which takes N- (1- ((tertiary compound 1 as an initial raw material, performs Sonogashira coupling with propiolic alcohol under the catalysis of palladium and copper to obtain a compound 2, then performs cyclization reaction to obtain a new compound 3, oxidizes primary alcohol into carboxylic acid to obtain a compound 4, and finally performs one-pot removal of Boc and cyclization to obtain the compound 5.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a novel intermediate of traasiril, a preparation method thereof and a key intermediate of traasiril prepared from the novel intermediate.
Background
Trilaciclib (trade name: cosala) is a cyclin dependent kinase 4/6 (CDK 4/6) inhibitor developed by Protoyor medicine in cooperation with the United states biopharmaceuticals company (G1 Therapeutics) that helps protect Hematopoietic Stem and Progenitor Cells (HSPC) in the bone marrow from chemotherapy-induced myelosuppression. In 8 months 2020, the pioneer pharmaceutical industry bought the right to develop and commercialize all indications of treaxeli in china from G1. Trirasili was approved for sale in the United states at 2 months 2021 for prophylactic administration prior to treatment with a platinum-containing drug in combination with etoposide to reduce the incidence of chemotherapy-induced myelosuppression in a wide-term small cell lung cancer patient who had not previously received systemic chemotherapy. The traasiril comes into the market, becomes the first and only medicine with comprehensive bone marrow protection effect all over the world, solves the long-standing trouble of bone marrow inhibitors caused by chemotherapy, brings treatment hope for more patients, and other indications are also in clinical research.
The chemical name of traasiril is: 2'- ((5- (4-methylpiperazin-1-yl) pyridin-2-yl) amino) -7',8 '-dihydro-6' h-spiro [ cyclohexane-1, 9 '-pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidin-6' -one, the key intermediate formula of which is: 2 '-chloro-7', 8 '-dihydro-6' H-spiro [ cyclohexane-1, 9 '-pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidin-6' -one, wherein their structural formula is as follows:
WO2012061156A reports a synthesis method of key intermediate of traasillide, which uses 5-bromo-2, 4-dichloropyrimidine as a starting material, firstly condenses with 1- ((tert-butoxycarbonyl) aminomethyl) cyclohex-1-amine, then undergoes Sonogashira coupling reaction with 3, 3-diethoxyprop-1-yne, then cyclizes under the action of tetrabutylammonium fluoride (TBAF), removes an acetal protecting group by acetic acid, then oxidizes an aldehyde group by Oxone to obtain 7- (1- ((tert-butoxycarbonyl) aminomethyl) cyclohexyl) -2-chloro-7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid, and finally removes Boc and cyclizes to form lactam in a DCC/DMAP/trifluoroacetic acid system in a one-pot manner to obtain a target product of 2' -chloro-7 ',8' -dihydro-6H-spiro [ cyclohexane-1, 9' -pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidine ] -6' -ketone, wherein the synthesis route is as follows:
the unit price of the 3, 3-diethoxyprop-1-alkyne serving as the raw material in the route is higher, two steps of reactions of acidolysis and oxidation are needed for converting the acetal into the carboxylic acid, the route cost is further increased, and in addition, the Oxone oxidation reaction has certain potential safety hazard when the process is amplified. In a word, the route is overlong, the steps are complicated, the total yield is low, and the method is not suitable for large-scale production.
The patent publication No. CN111867592A improves the synthesis method, 5-iodine-2, 4-dichloropyrimidine is used as a starting material, and is firstly condensed with 1- ((tert-butoxycarbonyl) aminomethyl) cyclohex-1-amine, then methyl propiolate with higher activity is used for replacing 3, 3-diethoxyprop-1-yne to participate in Sonogashira coupling reaction, then cyclization is carried out under the action of TBAF, and finally Boc is removed and cyclization is carried out under the action of trifluoroacetic acid in a one-pot method to obtain a target product, wherein the synthesis route is as follows:
although the reaction steps are shortened in the route, the starting materials of 5-iodo-2, 4-dichloropyrimidine and methyl propiolate are high in material price, and the methyl propiolate is high in activity, self-polymerization is easy to occur under the action of alkali, the conversion rate of the starting materials participating in the Sonogashira coupling reaction is low, so that the total yield of the route is low, and the cost is high. In conclusion, the method for synthesizing the key intermediate 2 '-chloro-7', 8 '-dihydro-6' H-spiro [ cyclohexane-1, 9 '-pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidine ] -6' -ketone of traasiril has the advantages of simple process route, high yield, low cost and suitability for industrial production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel intermediate of the traasimide and a key intermediate compound 5 prepared from the intermediate, and the intermediate has the advantages of simple process route, low cost, suitability for industrial production and the like.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a traasiril intermediate compound 3 has a structural formula as follows:
the invention also relates to a synthesis method of the Trasipride intermediate compound 3, which adopts the following technical scheme:
a synthetic method of a traasiril intermediate compound 3 comprises the following steps:
(1) The starting material compound 1 is coupled with propiolic alcohol under the action of palladium and copper catalysts and alkali to obtain an intermediate compound 2:
(2) Cyclizing the intermediate compound 2 under the action of copper salt and alkali or TBAF to obtain an intermediate compound 3;
preferably, the palladium catalyst used in the coupling reaction in step (1) is selected from palladium-carbon, palladium acetate, palladium dichloride, dichlorobis (triphenylphosphine) palladium, pd (dppf) Cl 2 Or tetrakis (triphenylphosphine) palladium; the copper catalyst is selected from cuprous iodide, cuprous chloride or cuprous bromide; no ligand or ligand selected from triphenylphosphine, tricyclohexylphosphine, and tri-tert-butylphosphine; the base is selected from triethylamine, diisopropylethylamine, triethylenediamine, and 1, 8-diazabicyclo [5.4.0]]Undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the reaction solvent used is selected from methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene; the reaction temperature is 0-130 ℃.
Preferably, TBAF is selected as a cyclization reagent in the cyclization reaction of the step (2); the solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, dichloromethane, tetrahydrofuran, 1, 4-dioxane or acetonitrile; the reaction temperature is 25-90 ℃.
Preferably, the cyclization reaction in the step (2) adopts a copper catalyst and closes a ring under the action of alkali, wherein the copper catalyst is selected from cuprous iodide, cuprous chloride or cuprous bromide; the base is selected from triethylamine, diisopropylethylamine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone or DMPU; the reaction temperature is 50-130 ℃.
The invention also relates to a synthesis method for preparing a key intermediate compound 5 from the intermediate compound 3, which adopts the following technical means:
the synthetic method of the traasiril intermediate compound 5 comprises the following steps
(1) Oxidizing the intermediate compound 3 under the action of an oxidant to obtain an intermediate compound 4;
(2) Removing Boc from the intermediate compound 4 under the action of acid and cyclizing by a one-pot method to obtain an intermediate compound 5;
preferably, the oxidation reaction in the step (1) is carried out by a TEMPO catalytic oxidation method, wherein the oxidant is selected from NBS, NCS, dibromohydantoin, iodobenzene acetate, sodium hypochlorite, sodium chlorite or TCCA; no auxiliary agent is added or an auxiliary agent selected from sodium bicarbonate, sulfamic acid, sodium bromide or isobutene is added to improve the conversion rate; the reaction solvent is selected from tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, toluene, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether; the reaction temperature is-20-90 ℃.
Preferably, the Boc removal and one-pot cyclization reaction acid in the step (2) is selected from hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid; the reaction solvent is selected from methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, toluene, xylene, chlorobenzene or trifluorotoluene; the reaction temperature is 0-150 ℃.
The invention also relates to a synthesis method of the Trasipride intermediate compound 5, which adopts the following technical scheme:
a synthetic method of a traasiril intermediate compound 5 is characterized in that N- (1- ((tert-butoxycarbonyl) aminomethyl) cyclohexyl) -5-bromo-2-chloropyrimidine-4-amine compound 1 is used as a starting material, the compound and propiolic alcohol are subjected to Sonogashira coupling under the catalysis of palladium and copper to obtain a compound 2, then a cyclization reaction is completed under the action of copper salt and alkali or TBAF to obtain a compound 3, primary alcohol is oxidized into carboxylic acid to obtain a compound 4, and finally Boc is removed in a one-pot method and cyclization is carried out to obtain a target product 2 '-chloro-7', 8 '-dihydro-6' H-spiro [ cyclohexane-1, 9 '-pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidine ] -6' -ketone compound 5. The route is as follows:
compared with the prior art, the synthesis method of the intermediate compound 5 of the traasiril optimizes the process, shortens the route steps, improves the route efficiency, has cheap and easily obtained propiolic alcohol raw materials, has simple step of converting the propiolic alcohol raw materials into carboxylic acid, and obviously reduces the process cost. The route is simple to operate, the total yield is high, the purity of the obtained product is high, and the route is suitable for large-scale production.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
Adding N- (1- ((tert-butoxycarbonyl) aminomethyl) cyclohexyl) -5-bromo-2-chloropyrimidine-4-amine compound 1 (41.97g, 100mmol), propiolic alcohol (11.21g, 200mmol), diisopropylethylamine DIPEA (25.85g, 200mmol) and isopropanol (420 mL) into a three-neck flask, uniformly stirring, switching nitrogen gas for 3 times in vacuum, adding cuprous iodide (190mg, 1mmol) and dichlorobis (triphenylphosphine) palladium (702mg, 1mmol) under the protection of nitrogen gas, heating to 55-60 ℃ after the addition, reacting for 6-8 hours, filtering after the reaction is finished, adding most isopropanol, adding 420mL of water, pulping, filtering, collecting a filter cake, and drying to obtain compound 2 (32.66g, 82.7%).
1 HNMR(500MHz,DMSO-d6)δ8.04(s,1H),6.85-7.04(m,1H),5.65-5.77(m,1H),5.32-5.41(m,1H),4.31-4.47(m,2H),3.25-3.44(m,2H),2.04-2.17(m,2H),1.15-1.62(m,17H)。
MS(ESI)m/z=395.1[M+H] + 。
In example 1; the alkali diisopropylethylamine can be triethylamine, triethylene diamine, or 1, 8-diazabicyclo [5.4.0]Undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the solvent isopropanol can be replaced by methanol, ethanol, tert-butanol, tert-amyl alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene; the copper catalyst cuprous iodide can be replaced by cuprous chloride or cuprous bromide; the palladium catalyst dichlorobis (triphenylphosphine) palladium can be palladium carbon, palladium acetate, palladium dichloride, pd (dppf) Cl 2 Or tetrakis (triphenylphosphine) palladium; triphenylphosphine, tricyclohexylphosphine, or tri-tert-butylphosphine ligand may be added during the reaction.
Example 2
Adding N- (1- ((tert-butoxycarbonyl) aminomethyl) cyclohexyl) -5-bromo-2-chloropyrimidine-4-amine compound 1 (41.97g, 100mmol), propiolic alcohol (11.21g, 200mmol), diisopropylethylamine DIPEA (25.85g, 200mmol) and ethanol (420 mL) into a three-neck flask, uniformly stirring, switching nitrogen for 3 times in vacuum, adding cuprous iodide (190mg, 1mmol) and 10% palladium carbon (1064mg, 1mmol) under the protection of nitrogen, heating to 55-60 ℃ after finishing the addition, reacting for 6-8 hours, filtering to recover palladium carbon after the reaction is finished, removing most ethanol, adding 420mL of water, pulping, filtering, collecting a filter cake, and drying to obtain intermediate formula 2 (30.21g, 76.5%).
In example 1; the alkali diisopropylethylamine can be triethylamine, triethylene diamine, or 1, 8-diazabicyclo [5.4.0]Undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the solvent ethanol can be replaced by isopropanol methanol, tert-butanol, tert-amyl alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene; the copper catalyst cuprous iodide can be replaced by cuprous chloride or cuprous bromide; the palladium-carbon catalyst can be dichlorobis (triphenylphosphine) palladium, palladium acetate, palladium dichloride, pd (dppf) Cl 2 Or tetrakis (triphenylphosphine) palladium; triphenylphosphine, tricyclohexylphosphine, or tri-tert-butylphosphine ligand may be added during the reaction.
Example 3
Compound 2 (39.49g, 100mmol) and N-methylpyrrolidone NMP (197 mL) were added to a three-necked flask, and after stirring, nitrogen was switched in under vacuum for 3 times, cuprous chloride (990mg, 10mmol) and 1, 8-diazabicyclo [5.4.0] undec-7-ene DBU (3.04g, 20mmol) were added under nitrogen protection, and after completion of the addition, the temperature was raised to 110 to 120 ℃ for reaction overnight. After the reaction is finished, 395mL of water is added to quench the reaction, the aqueous phase is extracted by ethyl acetate (395 mL), the combined organic phases are washed by water for 2 times (99 mL), dried by sodium sulfate, filtered, concentrated to a small volume, slowly added with petroleum ether, cooled to 0-5 ℃, pulped, filtered, collected filter cake and dried to obtain an intermediate formula 3 (34.67g, 87.8%).
1 HNMR(500MHz,DMSO-d6)δ8.83(s,1H),7.42-7.54(m,1H),6.53(s,1H)5.48-5.57(m,1H),4.62-4.72(m,2H),3.75-3.85(m,2H),2.67-2.85(m,2H),1.58-1.80(m,4H),1.37-1.54(m,13H)ppm.
MS(ESI)m/z=395.1[M+H] + 。
In example 3, cuprous chloride, a copper catalyst, can be replaced with cuprous iodide or cuprous bromide; the base 1, 8-diazabicyclo [5.4.0] undec-7-ene may be replaced by triethylamine, diisopropylethylamine, triethylenediamine, potassium carbonate, sodium carbonate or potassium phosphate; the solvent N-methylpyrrolidone can be replaced by dimethylformamide, dimethylacetamide, dimethyl sulfoxide or DMPU.
Example 4
Compound 2 (39.49g, 100mmol) and THF (395 mL) were added to a three-necked flask, TBAF trihydrate (94.65g, 300mmol) was added, and after the addition, the temperature was raised to 55 to 60 ℃ for reaction overnight. After the reaction is finished, 395mL of water is added to quench the reaction, the aqueous phase is extracted by ethyl acetate (395 mL), the combined organic phases are washed by water for 2 times (98 mL), dried by sodium sulfate, filtered, concentrated to a small volume, slowly added with petroleum ether (316 mL), cooled to 0-5 ℃, pulped, filtered, collected filter cake and dried to obtain an intermediate formula 3 (33.37g, 84.5%).
In example 4, the solvent tetrahydrofuran may be replaced with dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, 1, 4-dioxane or acetonitrile.
Example 5
3 (39.49g, 100mmol) and dichloromethane (395 mL) are added to a three-neck flask, TEMPO (312mg, 2mmol) and iodobenzene acetate (96.63g, 300mmol) are added, and after the addition, the mixture is stirred at room temperature for 6 to 8 hours, and then heated to 38 to 40 ℃ for reaction overnight. After the reaction, part of dichloromethane was removed by concentration, petroleum ether (316 mL) was slowly added, the mixture was cooled to room temperature and slurried, filtered, and the filter cake was collected and dried to obtain Compound 4 (36.88g, 90.2%).
In example 5, the oxidizing agent iodobenzene acetate can be replaced by NBS, NCS, dibromohydantoin, sodium hypochlorite, sodium chlorite, or TCCA; the reaction solvent dichloromethane can be replaced by tetrahydrofuran, 1, 2-dichloroethane, toluene, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether; an auxiliary agent selected from sodium bicarbonate, sulfamic acid, sodium bromide or isobutene can also be added in the reaction process to improve the conversion rate.
Example 6
3 (39.49g, 100mmol) and dichloromethane (197 mL) were added to a three-necked flask, and after stirring and dissolution, the mixture was cooled in an ice bath, sodium bicarbonate (16.8g, 200mmol) was added, TEMPO (312mg, 2mmol) was added, dibromohydantoin (60.04g, 210mmol) was added in portions, and the mixture was allowed to warm to room temperature for 6 to 8 hours. After the reaction, 10% citric acid solution is added to adjust the pH value to 3-4, partial solid is removed by filtration, liquid separation is carried out, the water phase is extracted by dichloromethane (98 mL) for 1 time, organic phase water (98 mL) is combined for 2 times, anhydrous sodium sulfate is dried, filtered, concentrated, petroleum ether is added after concentration for pulping, solid is separated by filtration, and the compound of formula 4 (35.12g, 85.9%) is obtained by drying.
In example 6, the oxidant dibromohydantoin can be replaced with iodobenzene acetate, NBS, NCS, sodium hypochlorite, sodium chlorite, or TCCA; the reaction solvent dichloromethane can be replaced by tetrahydrofuran, 1, 2-dichloroethane, toluene, ethyl acetate, isopropyl acetate or methyl tertiary butyl ether; sodium bicarbonate may be omitted or sulfamic acid, sodium bromide or isobutylene may be substituted to increase conversion during the reaction.
Example 7
Adding 2 (40.89g, 100mmol) and toluene (409 mL) into a three-neck flask, adding p-toluenesulfonic acid monohydrate (41.85g, 220mmol), heating to reflux, carrying out water-carrying reaction for 8-10 hours, cooling to room temperature after the reaction is finished, adding 5% sodium bicarbonate aqueous solution (205 mL), stirring, separating, washing an organic phase for 1 time, collecting the organic phase, evaporating most of toluene, slowly adding petroleum ether (245 mL), slowly cooling to 0-5 ℃, pulping, filtering, collecting a filter cake, and drying to obtain a target product of the formula 5 (33.37g, 88.1%).
In example 7, the methanesulfonic acid can be replaced by hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid; the reaction solvent toluene can be replaced by methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, xylene, chlorobenzene or trifluorotoluene.
Claims (9)
2. a synthetic method of a traasiril intermediate compound 3 is characterized by comprising the following steps:
(1) The starting material compound 1 is coupled with propiolic alcohol under the action of palladium and copper catalysts and alkali to obtain an intermediate compound 2:
(2) Cyclizing the intermediate compound 2 under the action of copper salt and alkali or TBAF to obtain an intermediate compound 3;
3. the method for synthesizing a traasiride intermediate compound 3 according to claim 2, wherein a palladium catalyst used in the coupling reaction in the step (1) is selected from palladium-carbon, palladium acetate, palladium dichloride, dichlorobis (triphenylphosphine) palladium, and Pd (dppf) Cl 2 Or tetrakis (triphenylphosphine) palladium; the copper catalyst is selected from cuprous iodide, cuprous chloride or cuprous bromide; without addition of ligand or with ligandFrom triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine; the base is selected from triethylamine, diisopropylethylamine, triethylenediamine, and 1, 8-diazabicyclo [5.4.0]]Undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the reaction solvent used is selected from methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, acetonitrile or toluene.
4. The synthesis method of the Trasipride intermediate compound 3 according to claim 2, wherein the cyclization reaction in the step (2) adopts TBAF as a cyclization reagent; the solvent is selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, tetrahydrofuran, 1, 4-dioxane or acetonitrile.
5. The synthesis method of the Trasipride intermediate compound 3 according to claim 2, wherein the cyclization reaction in the step (2) is performed by using a copper catalyst and closing a ring under the action of alkali, wherein the copper catalyst is selected from cuprous iodide, cuprous chloride or cuprous bromide; the base is selected from triethylamine, diisopropylethylamine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, sodium carbonate or potassium phosphate; the solvent is selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone or DMPU.
6. A synthetic method of a traasiril intermediate compound 5 comprises the following steps
(1) Oxidizing the intermediate compound 3 under the action of an oxidant to obtain an intermediate compound 4;
(2) Removing Boc from the intermediate compound 4 under the action of acid and cyclizing by a one-pot method to obtain an intermediate compound 5;
7. the method for synthesizing the traasiril intermediate compound 5 according to claim 6, wherein the oxidation reaction in the step (1) is carried out by a TEMPO catalytic oxidation method, wherein the oxidant is selected from NBS, NCS, dibromohydantoin, iodobenzene acetate, sodium hypochlorite, sodium chlorite or TCCA; no auxiliary agent is added or an auxiliary agent selected from sodium bicarbonate, sulfamic acid, sodium bromide or isobutene is added to improve the conversion rate; the reaction solvent is selected from tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, toluene, ethyl acetate, isopropyl acetate or methyl tert-butyl ether.
8. The synthesis method of the traasiril intermediate compound 5 according to claim 6, wherein hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid or trifluoromethanesulfonic acid is selected as the de-Boc and one-pot cyclization reaction acid in the step (2); the reaction solvent is selected from methanol, ethanol, isopropanol, tert-butanol, tert-amyl alcohol, dichloromethane, tetrahydrofuran, 1, 2-dichloroethane, toluene, xylene, chlorobenzene or trifluorotoluene.
9. A synthetic method of a traasiril intermediate compound 5 is characterized in that N- (1- ((tert-butoxycarbonyl) aminomethyl) cyclohexyl) -5-bromo-2-chloropyrimidine-4-amine compound 1 is used as a starting material, the compound and propiolic alcohol are subjected to Sonogashira coupling under the catalysis of palladium and copper to obtain a compound 2, then a cyclization reaction is completed under the action of copper salt and alkali or TBAF to obtain a compound 3, primary alcohol is oxidized into carboxylic acid to obtain a compound 4, and finally Boc is removed in a one-pot method and cyclization is carried out to obtain a target product 2 '-chloro-7', 8 '-dihydro-6' H-spiro [ cyclohexane-1, 9 '-pyrazino [1',2':1,5] pyrrolo [2,3-d ] pyrimidine ] -6' -ketone compound 5, wherein the route is as follows:
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012061156A1 (en) * | 2010-10-25 | 2012-05-10 | Tavares Francis X | Cdk inhibitors |
CN111867592A (en) * | 2018-01-04 | 2020-10-30 | G1治疗公司 | Heterocyclic compounds for the treatment of abnormal cell proliferation |
Non-Patent Citations (2)
Title |
---|
FRANCIS A. J. KERDESKY: "Synthesis and 5-lipoxygenase inhibitory activity of 5-hydroperoxy-6, 8, 11, 14-eicosatetraenoic acid analogs", JOURNAL OF MEDICINAL CHEMISTRY, vol. 30, no. 7, pages 1177, XP055952668, DOI: 10.1021/jm00390a010 * |
LEILEI WANG: "Concise synthesis of pyrrolo[2, 3-d]pyrimidine derivatives via the Cu-catalyzed coupling reaction", GREEN CHEMISTRY LETTERS AND REVIEWS, vol. 10, no. 1, pages 42 - 47, XP055657782, DOI: 10.1080/17518253.2016.1275822 * |
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