CN111801316A - 方法 - Google Patents
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- CN111801316A CN111801316A CN201980016640.2A CN201980016640A CN111801316A CN 111801316 A CN111801316 A CN 111801316A CN 201980016640 A CN201980016640 A CN 201980016640A CN 111801316 A CN111801316 A CN 111801316A
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- ether
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- 238000000034 method Methods 0.000 title claims description 83
- 239000002131 composite material Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 45
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 51
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 48
- LGSAOJLQTXCYHF-UHFFFAOYSA-N tri(propan-2-yl)-tri(propan-2-yl)silyloxysilane Chemical compound CC(C)[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)C(C)C LGSAOJLQTXCYHF-UHFFFAOYSA-N 0.000 claims description 25
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
- 239000003446 ligand Substances 0.000 claims description 18
- 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 17
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 16
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 claims description 16
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 15
- 150000005217 methyl ethers Chemical class 0.000 claims description 15
- 229910052987 metal hydride Inorganic materials 0.000 claims description 14
- 150000004681 metal hydrides Chemical class 0.000 claims description 14
- 238000011065 in-situ storage Methods 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 229910052723 transition metal Inorganic materials 0.000 claims description 12
- 150000003624 transition metals Chemical class 0.000 claims description 12
- 239000000654 additive Substances 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 229910004039 HBF4 Inorganic materials 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 229910052703 rhodium Inorganic materials 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 150000002170 ethers Chemical class 0.000 claims description 4
- 229910052741 iridium Inorganic materials 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052707 ruthenium Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 3
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 claims description 2
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical compound C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 claims description 2
- GYZZZILPVUYAFJ-UHFFFAOYSA-N phanephos Chemical compound C1CC(C(=C2)P(C=3C=CC=CC=3)C=3C=CC=CC=3)=CC=C2CCC2=CC=C1C=C2P(C=1C=CC=CC=1)C1=CC=CC=C1 GYZZZILPVUYAFJ-UHFFFAOYSA-N 0.000 claims description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tri(ortho-tolyl)phosphine Substances CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical class CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- -1 but not limited to Chemical class 0.000 description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 18
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 16
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 16
- KJTULOVPMGUBJS-UHFFFAOYSA-N tert-butyl-[tert-butyl(diphenyl)silyl]oxy-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 KJTULOVPMGUBJS-UHFFFAOYSA-N 0.000 description 16
- WILBTFWIBAOWLN-UHFFFAOYSA-N triethyl(triethylsilyloxy)silane Chemical compound CC[Si](CC)(CC)O[Si](CC)(CC)CC WILBTFWIBAOWLN-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 13
- 125000000217 alkyl group Chemical group 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000010948 rhodium Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 150000001336 alkenes Chemical class 0.000 description 9
- 125000002947 alkylene group Chemical group 0.000 description 9
- QUSKGEMGNZXRRQ-UHFFFAOYSA-N 1,1,1-trichloro-2-(2,2,2-trichloroethoxy)ethane Chemical compound ClC(Cl)(Cl)COCC(Cl)(Cl)Cl QUSKGEMGNZXRRQ-UHFFFAOYSA-N 0.000 description 8
- PPJVXZVTPWQOQS-UHFFFAOYSA-N 1-ethoxy-1-(1-ethoxyethoxy)ethane Chemical compound CCOC(C)OC(C)OCC PPJVXZVTPWQOQS-UHFFFAOYSA-N 0.000 description 8
- HCKNRHBSGZMOOF-UHFFFAOYSA-N 1-methoxy-2-methylperoxyethane Chemical compound COCCOOC HCKNRHBSGZMOOF-UHFFFAOYSA-N 0.000 description 8
- SDTORDSXCYSNTD-UHFFFAOYSA-N 1-methoxy-4-[(4-methoxyphenyl)methoxymethyl]benzene Chemical compound C1=CC(OC)=CC=C1COCC1=CC=C(OC)C=C1 SDTORDSXCYSNTD-UHFFFAOYSA-N 0.000 description 8
- POIOOCHMXHKUHV-UHFFFAOYSA-N [nitro-[nitro(phenyl)methoxy]methyl]benzene Chemical compound C=1C=CC=CC=1C([N+](=O)[O-])OC([N+]([O-])=O)C1=CC=CC=C1 POIOOCHMXHKUHV-UHFFFAOYSA-N 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 8
- 229940089960 chloroacetate Drugs 0.000 description 8
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 8
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 8
- RMIODHQZRUFFFF-UHFFFAOYSA-M methoxyacetate Chemical compound COCC([O-])=O RMIODHQZRUFFFF-UHFFFAOYSA-M 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 8
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- AXSFFIVWTMWAEH-UHFFFAOYSA-N dibromo(tritert-butyl)-lambda5-phosphane palladium tritert-butylphosphane Chemical compound [Pd].[Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(Br)(Br)(C(C)(C)C)C(C)(C)C AXSFFIVWTMWAEH-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- QCFAKTACICNQGT-UHFFFAOYSA-N 2-methyl-2-[(2-methylpropan-2-yl)oxymethoxymethoxy]propane Chemical compound CC(C)(C)OCOCOC(C)(C)C QCFAKTACICNQGT-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- NUMQCACRALPSHD-UHFFFAOYSA-N tert-Butyl ethyl ether Natural products CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 4
- YUMSFEDUCCHSIV-UHFFFAOYSA-N 2-methyl-2-methylperoxypropane Chemical compound COOC(C)(C)C YUMSFEDUCCHSIV-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- FUPYEMPPLXGHID-UHFFFAOYSA-N [[dimethoxy(phenyl)methoxy]-dimethoxymethyl]benzene Chemical compound C=1C=CC=CC=1C(OC)(OC)OC(OC)(OC)C1=CC=CC=C1 FUPYEMPPLXGHID-UHFFFAOYSA-N 0.000 description 3
- 125000004419 alkynylene group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000006317 isomerization reaction Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- TYZYRCHEVXXLSJ-UHFFFAOYSA-N phenylmethoxymethoxymethoxymethylbenzene Chemical compound C=1C=CC=CC=1COCOCOCC1=CC=CC=C1 TYZYRCHEVXXLSJ-UHFFFAOYSA-N 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 2
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 2
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical class C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N 1-Heptene Chemical group CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- LGCYVLDNGBSOOW-UHFFFAOYSA-N 2H-benzotriazol-4-ol 1-hydroxybenzotriazole Chemical compound OC1=CC=CC2=C1N=NN2.C1=CC=C2N(O)N=NC2=C1 LGCYVLDNGBSOOW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GVEBZDRVXVMSKI-UHFFFAOYSA-N C1(CCCCC1)P(C1CCCCC1)C1CCCCC1.N1=CC=CC=C1.C1=CCCC=CCC1 Chemical compound C1(CCCCC1)P(C1CCCCC1)C1CCCCC1.N1=CC=CC=C1.C1=CCCC=CCC1 GVEBZDRVXVMSKI-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- VGQOVCHZGQWAOI-YQRHFANHSA-N anthramycin Chemical compound N1[C@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-YQRHFANHSA-N 0.000 description 1
- 229950006345 antramycin Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 125000002993 cycloalkylene group Chemical group 0.000 description 1
- 125000005725 cyclohexenylene group Chemical group 0.000 description 1
- 125000004956 cyclohexylene group Chemical group 0.000 description 1
- 125000004979 cyclopentylene group Chemical group 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- LZWLLMFYVGUUAL-UHFFFAOYSA-L ditert-butyl(cyclopenta-1,3-dien-1-yl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1.CC(C)(C)P(C(C)(C)C)C1=CC=C[CH-]1 LZWLLMFYVGUUAL-UHFFFAOYSA-L 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000003269 fluorescent indicator Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- XZMMPTVWHALBLT-UHFFFAOYSA-N formaldehyde;rhodium;triphenylphosphane Chemical compound [Rh].O=C.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 XZMMPTVWHALBLT-UHFFFAOYSA-N 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- BDDWSAASCFBVBK-UHFFFAOYSA-N rhodium;triphenylphosphane Chemical compound [Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 BDDWSAASCFBVBK-UHFFFAOYSA-N 0.000 description 1
- QQZMDXUEROTLLD-UHFFFAOYSA-N rhodium;triphenylphosphane Chemical compound [Rh].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 QQZMDXUEROTLLD-UHFFFAOYSA-N 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Substances [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 229910006384 μ-Br Inorganic materials 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/44—Palladium
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/46—Ruthenium, rhodium, osmium or iridium
- B01J23/462—Ruthenium
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/46—Ruthenium, rhodium, osmium or iridium
- B01J23/464—Rhodium
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- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
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- B01J23/468—Iridium
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
一种由式(II)化合物:(II)合成式(I)化合物:(I)的方法,其中R8(i)为ProtO3;或(ii)在式(I)中为式(A1)基团并且在式(II)中为式(A2)基团:(A1),(A2)。
Description
本发明涉及一种合成可用作内不饱和的吡咯并苯并二氮杂卓的合成中的中间体的化合物的方法。
背景技术
特司林(Tesirine)和相关的2,3不饱和的吡咯并苯并二氮杂卓通常是通过将体系的C环中的酮的三氟甲磺酰化,然后引入自由基(诸如甲基或芳基)来制成,这种方法在Tiberghien2016和WO 2014/057074中对特司林进行了描述:
到特司林的整个途径需要31个步骤,并且希望通过减少步骤数并且增加总体产率来改善特司林和相关化合物的合成。
具体实施方式
本发明提供了一种从对应外不饱和的烯烃的途径中的到关键内不饱和的烯烃的异构途径。
本发明的第一方面提供了一种从式II化合物:
合成式I化合物:
的方法,其中
RA为H或ProtO1;
R8:
(i)为ProtO3;或
(ii)在式(I)中为式A1基团并且在式(II)中为式A2基团:
其中RB为H或ProtO2;
R7选自C1-4烷基和苄基;
R17选自C1-4烷基和苄基;
Y为C3-12亚烷基,其链可被一个或多个选自O、S和NRN2(其中RN2为H或C1-4烷基)的杂原子或者选自苯和吡啶的芳环中断;
ProtO1、ProtO2和ProtO3独立地为在反应条件下不为不稳定的羟基保护基。
所述方法是使用催化剂在任选加入添加剂的情况下进行的。
因此,当R8为ProtO3时,反应为:
当R8在式(I)中为式A1基团并且在式(II)中为式A2基团时,反应为:
针对烯烃的异构使用催化为已知的。例如,Rh催化剂可用于安曲霉素(anthramycin)的合成中的内双键的异构(Kitamura 2004):
本发明避免了使用烷基铃木反应来生成式(I)化合物的需要。通过这样做,可增加总体产率。此外,从可商购获得的起始材料的化合物(I)的途径可以减少2至4个步骤。
本发明的第二方面提供了一种式IIa化合物:
其中R7选自C1-4烷基和苄基;并且
RA为H或ProtO1;
ProtO1和ProtO3独立地为在本发明的第一方面的反应条件下不为不稳定的羟基保护基。
定义
C1-4烷基:如本文所用,术语“C1-4烷基”关于通过从具有1至4个碳原子的饱和烃化合物的碳原子上除去氢原子所获得的单价基团。
饱和烷基的实例包括但不限于甲基(C1)、乙基(C2)、丙基(C3)和丁基(C4)。
饱和直链烷基的实例包括但不限于甲基(C1)、乙基(C2)、正丙基(C3)和正丁基(C4)。
饱和支链烷基的实例包括但不限于异丙基(C3)、异丁基(C4)、仲丁基(C4)和叔丁基(C4)。
苄基:-CH2-苯基。
C3-12亚烷基:如本文所用,术语“C3-12亚烷基”关于通过除去具有3至12个碳原子(除非另外指定)的烃化合物的两个氢原子(两个氢原子来自同一碳原子,或者一个氢原子来自两个不同碳原子的每一个)所获得的双齿部分,所述化合物可为脂族或脂环族并且可为饱和、部分不饱和或完全不饱和的。因此,术语“亚烷基”包括下面所讨论的亚类亚烯基、亚炔基、亚环烷基等。
直链饱和的C3-12亚烷基的实例包括但不限于-(CH2)n-,其中n为3至12的整数,例如-CH2CH2CH2-(亚丙基)、-CH2CH2CH2CH2-(亚丁基)、-CH2CH2CH2CH2CH2-(亚戊基)和-CH2CH2CH2CH-2CH2CH2CH2-(亚庚基)。
支链饱和的C3-12亚烷基的实例包括但不限于-CH(CH3)CH2-、-CH(CH3)CH2CH2-、-CH(CH3)CH2CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH(CH3)CH2CH2-、-CH(CH2CH3)-、-CH(CH2CH3)CH2-和-CH2CH(CH2CH3)CH2-。
直链部分不饱和的C3-12亚烷基(C3-12亚烯基和亚炔基)的实例包括但不限于-CH=CH-CH2-、-CH2-CH=CH2-、-CH=CH-CH2-CH2-、-CH=CH-CH2-CH2-CH2-、-CH=CH-CH=CH-、-CH=CH-CH=CH-CH2-、-CH=CH-CH=CH-CH2-CH2-、-CH=CH-CH2-CH=CH-、-CH=CH-CH2-CH2-CH=CH-和-CH2-C≡C-CH2-。
支链部分不饱和的C3-12亚烷基(C3-12亚烯基和亚炔基)的实例包括但不限于-C(CH3)=CH-、-C(CH3)=CH-CH2-、-CH=CH-CH(CH3)-和-C≡C-CH(CH3)-。
脂环族饱和的C3-12亚烷基(C3-12亚环烷基)的实例包括但不限于亚环戊基(例如亚环戊-1,3-基)和亚环己基(例如亚环己-1,4-基)。
脂环族部分不饱和的C3-12亚烷基(C3-12亚环烷基)的实例包括但不限于亚环戊烯基(例如4-亚环戊烯-1,3-基)、亚环己烯基(例如2-亚环己烯-1,4-基;3-亚环己烯-1,2-基;2,5-亚环己二烯-1,4-基)。
当C3-12亚烷基被杂原子中断时,下标是指包含杂原子的链中的原子数。例如,链-C2H4-O-C2H4-为C5基团。
在反应条件下不为不稳定的羟基保护基:羟基保护基在本领域中是众所周知的,例如,在Wuts和Greene 2007中。适合用于本发明的那些基团包括取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
催化剂:适合用于本发明的催化剂为包含金属氢化物的催化剂或者能够原位形成金属氢化物的催化剂。这些催化剂含有过渡金属,包括但不限于Ru、Ir、Rh和Pd。
添加剂:任选的添加剂可选自:
(a)适合与所述催化剂组合来原位生成金属氢化物的化合物;
(b)碱;
(c)催化剂的附加配体。
另外的优选项
RA
在一些实施方案中,RA为ProtO1。
在其他实施方案中,RA为H。
RB
在一些实施方案中,RB为ProtO2。
在其他实施方案中,RB为H。
RA和RB
在一些实施方案中,RA为ProtO1,并且RB为ProtO2。
在其他实施方案中,RA为H并且RB为H。
R7
在一些实施方案中,R7为C1-4烷基。在这些实施方案中的一些实施方案中,R7为甲基。在这些实施方案中的其他实施方案中,R7为乙基。
在一些实施方案中,R7为苄基。
R8
在一些实施方案中,R8为ProtO3。
在其他实施方案中,R8在式(I)中为式A1基团并且在式(II)中为式A2基团。
R17
在一些实施方案中,R17为C1-4烷基。在这些实施方案中的一些实施方案中,R17为甲基。在这些实施方案中的其他实施方案中,R17为乙基。
在一些实施方案中,R17为苄基。
Y
在一些实施方案中,Y为不中断的C3-12亚烷基。在这些实施方案中的一些实施方案中,Y为-(CH2)n-,其中n为3至12的整数。特别地,Y可选自-(CH2)3-和-(CH2)5-。
羟基保护基
在一些实施方案中,ProtO3正交于ProtO1。
在一些实施方案中,ProtO2和ProtO1相同。
ProtO1可选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
适合的取代的甲醚包括但不限于甲氧基甲醚(MOM)、β-甲氧基乙氧基甲醚(MEM)、苄氧基甲醚、叔丁氧基甲醚和甲硅烷氧基甲醚。
适合的取代的乙醚(除了含有不饱和性的乙醚)包括但不限于1-乙氧基乙醚、2-羟乙醚、1-[2-(三甲基甲硅烷基)乙氧基]乙醚、2,2,2-三氯乙醚、2-三甲基甲硅烷基乙醚和叔丁醚。
适合的甲氧基取代的苄醚包括但不限于对甲氧基苄醚、二甲氧基苄醚和硝基苄醚。
适合的甲硅烷基醚包括但不限于三甲基甲硅烷基醚(TMS)、三乙基甲硅烷基醚(TES)、叔丁基二甲基甲硅烷基醚(TBS)、叔丁基二苯基甲硅烷基醚(TBDPS)和三异丙基甲硅烷基醚(TIPS)。
适合的乙酸酯包括但不限于氯乙酸酯、甲氧基乙酸酯、苯氧基乙酸酯和苯甲酸酯。
在一些实施方案中,ProtO1为甲硅烷基醚,并且特别是TBS。
ProtO2可选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
适合的取代的甲醚包括但不限于甲氧基甲醚(MOM)、β-甲氧基乙氧基甲醚(MEM)、苄氧基甲醚、叔丁氧基甲醚和甲硅烷氧基甲醚。
适合的取代的乙醚(除了含有不饱和性的乙醚)包括但不限于1-乙氧基乙醚、2-羟乙醚、1-[2-(三甲基甲硅烷基)乙氧基]乙醚、2,2,2-三氯乙醚、2-三甲基甲硅烷基乙醚和叔丁醚。
适合的甲氧基取代的苄醚包括但不限于对甲氧基苄醚、二甲氧基苄醚和硝基苄醚。
适合的甲硅烷基醚包括但不限于三甲基甲硅烷基醚(TMS)、三乙基甲硅烷基醚(TES)、叔丁基二甲基甲硅烷基醚(TBS)、叔丁基二苯基甲硅烷基醚(TBDPS)和三异丙基甲硅烷基醚(TIPS)。
适合的乙酸酯包括但不限于氯乙酸酯、甲氧基乙酸酯、苯氧基乙酸酯和苯甲酸酯。
在一些实施方案中,ProtO2为甲硅烷基醚,并且特别是TBS。
ProtO3可选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
适合的取代的甲醚包括但不限于甲氧基甲醚(MOM)、β-甲氧基乙氧基甲醚(MEM)、苄氧基甲醚、叔丁氧基甲醚和甲硅烷氧基甲醚。
适合的取代的乙醚(除了含有不饱和性的乙醚)包括但不限于1-乙氧基乙醚、2-羟乙醚、1-[2-(三甲基甲硅烷基)乙氧基]乙醚、2,2,2-三氯乙醚、2-三甲基甲硅烷基乙醚和叔丁醚。
适合的甲氧基取代的苄醚包括但不限于对甲氧基苄醚、二甲氧基苄醚和硝基苄醚。
适合的甲硅烷基醚包括但不限于三甲基甲硅烷基醚(TMS)、三乙基甲硅烷基醚(TES)、叔丁基二甲基甲硅烷基醚(TBS)、叔丁基二苯基甲硅烷基醚(TBDPS)和三异丙基甲硅烷基醚(TIPS)。
适合的乙酸酯包括但不限于氯乙酸酯、甲氧基乙酸酯、苯氧基乙酸酯和苯甲酸酯。
在一些实施方案中,ProtO3为甲硅烷基醚,并且特别是TIPS。
催化剂
适合用于本发明的催化剂为含有金属氢化物的催化剂或者能够原位形成金属氢化物的催化剂。这些催化剂含有过渡金属,包括但不限于Ru、Ir、Rh和Pd。在一些实施方案中,过渡金属为Pd。在其他实施方案中,过渡金属为Ru。在其他实施方案中,过渡金属为Rh。在其他实施方案中,过渡金属为Ir。
在一些实施方案中,催化剂包含P配体,诸如但不限于(叔丁基)3P和Ph3P。
在一些实施方案中,催化剂为能够形成包含PdH(PRP 3)X的活性物种的催化剂,其中每个RP独立地选自叔丁基和苯基,并且X为卤素(例如I、Br、Cl)。
感兴趣的特定催化剂包括但不限于以下:
Grubbs I:
亚苄基-双(三环己基膦)二氯化钌、双(三环己基膦)亚苄基二氯化钌(IV)、二氯(亚苄基)双(三环己基膦)钌(II)
Grubbs II:
(1,3-双(2,4,6-三甲基苯基)-2-亚咪唑啉基)二氯(苯基亚甲基)(三环己基膦)钌、亚苄基[1,3-双(2,4,6-三甲基苯基)-2-亚咪唑啉基]二氯(三环己基膦)钌、二氯[1,3-双(2,4,6-三甲基苯基)-2-亚咪唑啉基](亚苄基)(三环己基膦)钌(II)
Crabtrees催化剂:
(1,5-环辛二烯)(吡啶)(三环己基膦)-Ir(I)PF6、
六氟磷酸铱(I)(1,5-环辛二烯)-(吡啶)-(三环己基膦)复合物、
[Ir(cod)(PCy3)(py)]PF6
RuHCl(CO)PPh3:
Ru-42
RhH(CO)PPh3:
Rh-42
羰基三(三苯基膦)氢化铑(I)、
氢化羰基-三(三苯基膦)-铑(I)、
铑单羰基氢三(三苯基膦)、
三(三苯基膦)羰基氢化铑(I)、三(三苯基膦)氢化羰基铑、
反式-羰基(氢化)三(三苯基膦)铑
Rh(COD)2BF4:
四氟硼酸铑(I)1,5-环辛二烯复合物
Pd-113:
二-μ-溴双(三叔丁基膦)二钯(I)
{Pd(μ-Br)[P(tBu)3]}2
Pd-118:
Pd(dtbpf)Cl2
二氯[1,1’-双(二叔丁基膦基)二茂铁]钯(II)
阳离子CpRu(Pr3)
乙腈(环戊二烯基)[2-(二异丙基膦基)-4-(叔丁基)-1-甲基-1H-咪唑]六氟磷酸钌(II)
(tBu3P)2Pd(HCl)
感兴趣的催化剂还可通过金属源和适当的配体的反应原位生成。感兴趣的金属源和配体包括但不限于以下:
金属源
配体
在一些实施方案中,催化剂选自Pd-113和((tBu)3P)2Pd(HCl)。在这些实施方案中的一些实施方案中,催化剂为Pd-113。
添加剂:任选的添加剂可选自:
(a)适合与所述催化剂组合来原位生成金属氢化物的化合物;
(b)碱;
(c)催化剂的附加配体。
适合与催化剂组合来原位生成金属氢化物的化合物包括但不限于:Et3SiH、iPrCOCl和n-BuOH。
适合用于本发明的碱包括但不限于Et3N。
催化剂的附加配体包括但不限于PPh3和P(t-Bu)3。
反应条件
考虑到所采用的反应温度,反应可在任何适合的溶剂中进行。可优选的是,溶剂不为醇。在一些实施方案中,溶剂为甲苯。
反应可在适合的温度下进行。在一些实施方案中,反应温度可在5℃与120℃之间。最低温度可为5℃、10℃、15℃、20℃、30℃、40℃、50℃或60℃。最高温度可为120℃、110℃、100℃、90℃、80℃或75℃。在一些实施方案中,反应可以在70℃下进行。
反应可进行一定量的时间以达到所需的转化。在一些实施方案中,反应时间可在半小时与48小时之间。最短时间可为30分钟、1小时、2小时、4小时或8小时。最长反应时间可为48小时、36小时、24小时或22小时。在一些实施方案中,反应时间可为2小时至22小时。
催化剂可以1mol%至30mol%的式(II)起始化合物的相对量加入。最小相对量可为1mol%、1.25mol%、1.5mol%、2mol%、2.5mol%或5mol%。最大相对量可为30mol%、25mol%、20mol%、15mol%或10mol%。
考虑到所需产物,反应可在适合的气氛条件下进行。可为优选的是,气氛不主要包含氢气。在一些实施方案中,反应可在基本上惰性的气氛下进行。气氛可主要包含氮气或可主要包含氩气。气氛中氧气的最大量可为100,000ppm、50,000ppm、10,000ppm、1,000ppm、100ppm或10ppm。大气中水的最大量可为10,000ppm、1,000ppm、100ppm、10ppm或1ppm。
在本发明的第一方面的一些实施方案中,提供了一种由式II化合物:
合成式I化合物:
的方法,其中R8:
(i)为ProtO3;或
(ii)在式(I)中为式A1基团并且在式(II)中为式A2基团:
R7选自C1-4烷基和苄基;
R17选自C1-4烷基和苄基;
Y为C3-12亚烷基,其链可被一个或多个选自O、S和NRN2(其中RN2为H或C1-4烷基)的杂原子或者选自苯和吡啶的芳环中断;
ProtO1、ProtO2和ProtO3独立地为在反应条件下不为不稳定的羟基保护基。
在本发明的第二方面的一些实施方案中,提供了一种式IIa化合物:
其中R7选自C1-4烷基和苄基;
ProtO1和ProtO3独立地为在本发明的第一方面的反应条件下不为不稳定的羟基保护基。
实施例
以下实施例仅提供以说明本发明并且不旨在限制如本文描述的本发明的范围。
缩略词
DMF-二甲基甲酰胺
THF-四氢呋喃
EtOAc-乙酸乙酯
Boc2O-二碳酸二叔丁酯
TBAF-四正丁基氟化铵
HOBt-羟基苯并三唑
DIC-N,N'-二异丙基碳二亚胺
rt-室温
Vols-1ml中的1g材料为1体积
一般信息
如所指示,使用Biotage Isolera 1TM,使用用己烷/EtOAc或CH2Cl2/MeOH混合物的梯度洗脱进行快速色谱法,直到所有UV活性组分从管柱洗脱。每当观察到UV活性材料的大量洗脱时,手动保持梯度。使用薄层色谱法(TLC),使用Merck Kieselgel 60F254硅胶检查级分的纯度,其中荧光指示剂在铝板上。除非另外说明,否则TLC的可视化是用UV光或碘蒸气实现的。萃取和色谱溶剂购自VWR U.K.并且在没有进一步纯化的情况下即使用。所有精细化学品均购自Sigma-Aldrich或VWR。
分析的LC/MS条件(用于反应监测和纯度测定)如下:使用ShimadzuLCMS-2020进行正模式电喷雾质谱法。所用的流动相为溶剂A(含0.1%甲酸的H2O)和溶剂B(含0.1%甲酸的CH3CN)。
LCMS-A:3分钟运行的梯度:初始组合物在25秒内保持5%B,然后在1分钟35秒的时间段内从5%B增加至100%B。将组合物在100%B下保持50秒,然后在5秒内返回至5%B并且保持5秒。梯度运行的总持续时间为3.0分钟,流速为0.8mL/min。管柱:在50℃下,WatersAcquityBEH Shield RP18 1.7μm 2.1x 50mm,安装有Waters AcquityBEH Shield RP18 VanGuard前置柱,130A,1.7μm,2.1mm x 5mm
LCMS-B:15分钟运行的梯度:初始组合物在1分钟内保持5%B,然后在9分钟的时间段内从5%B增加至100%B。将组合物在100%B下保持2分钟,然后在10秒内返回至5%B并且保持2分钟50秒。梯度运行的总持续时间为15.0分钟,流速为0.6mL/分钟。在254nm、223nm和214nm处监测检测。ACE Excel 2C18-AR,2μ,3.0x 100mm安装有Waters AcquityBEH Shield RP18 VanGuard前置柱,130A,1.7μm,2.1mm x 5mm。
起始材料的合成
(i)(S)-1-(5-甲氧基-2-硝基-4-((三异丙基甲硅烷基)氧基)苯甲酰基)-4-亚甲
基吡咯烷-2-羧酸甲酯(3)
圆底烧瓶中装入磁力搅拌器、THF(15mL)、1(1.89g,5.118mmol,1.0当量)、HOBt(761mg,5.630mmol,1.1当量)、DIC(872μL,5.630mmol,1.1当量)和i-Pr2NEt(1.96mL,11.26mmol,2.2当量),并将混合物搅拌10min。分批加入2(1.00g,5.630mmol,1.1当量),并将反应混合物搅拌1h。将反应用CH2Cl2稀释,用0.2N HCl溶液洗涤,将有机物经MgSO4干燥,并在中真空浓缩。快速柱色谱法(20-30%在己烷中的EtOAc)得到呈黄色油状物的所需产物(1.19g,47%)。LCMS-A:2.00min(ES+)m/z 493[M+H]+,515[M+Na]+
(ii)(S)-(2-(羟甲基)-4-亚甲基吡咯烷-1-基)(5-甲氧基-2-硝基-4-((三异丙基
甲硅烷基)氧基)苯基)甲酮(4)
圆底烧瓶中装入磁力搅拌器、THF(15mL)、3(1.17g,2.383mmol,1.0当量),并将搅拌的混合物冷却至0℃。谨慎地加入LiBH4(156mg,7.149mmol,3.0当量),并且将混合物在0℃下搅拌1h并在rt下再搅拌1.5h。通过加入冰冷的H2O将反应淬灭,并用1N HCl将pH调节至约6。用CH2Cl2萃取水性混合物,将有机物合并,经MgSO4干燥,并在真空中浓缩,以得到呈黄色泡沫的所需产物(1.06g,96%),其在没有进一步纯化的情况下即使用。LCMS-A:1.92min(ES+)m/z 465[M+H]+,487[M+Na]+
(iii)(S)-(2-((((叔丁基二甲基甲硅烷基)氧基)甲基)-4-亚甲基吡咯烷-1-基)
(5-甲氧基-2-硝基-4-((三异丙基甲硅烷基)氧基)苯基)甲酮(5)
圆底烧瓶中装入磁力搅拌器、CH2Cl2(10mL)、4(1.06g,2.281mmol,1.0当量)、咪唑(467mg,6.858mmol,3.0当量)、TBSCl(517mg,3.429mmol,1.5当量),并搅拌1h,于是LCMS指示反应完成。将反应混合物过滤,滤液用H2O、盐水洗涤,经MgSO4干燥并在真空中浓缩。快速柱色谱法(20-30%在己烷中的EtOAc)得到呈黄色油状物的产物(1.27g,96%)。LCMS-A:2.30min(ES+)m/z 579[M+H]+,601[M+Na]+
实施例1
基于100mg规模的烯烃,以24孔板格式在4mL小瓶中进行反应,所述小瓶位于惰性化手套箱(<10ppm O2和<1ppm H2O)中。用手称重金属源(如果是空气不敏感的)或使用位于手套箱内部的Quantos称重机器人将金属源作为固体进行分配。将搅拌盘加入到每个小瓶中。
将起始材料(2g)溶解在无水脱气甲苯(总计10mL)中,并将500μL分配到每个小瓶中。(100mg/反应)。然后用下面反应计划中所说明的溶剂将每个小瓶补足至2mL。然后加入液体添加剂(反应2和5)。对除反应4(在MeOH中,保持在60℃)以外的所有反应,将反应密封,并在60℃下加热4小时,然后在100℃下再加热18小时。22小时之后制备用于uPLC/MS分析的样品。
HPLC条件/取样
λ=220nm
(A1)在H2O中的TFA(0.03v/v%)和(B1)在CH3CN中的TFA(0.03v/v%)
在G64 uPLC上运行。(PC_306)
取样:取样15μL反应混合物,稀释至1.0mL MeCN:水(4:1)中,0.5L进样量。
转化量计算如下:
*比较例
结果
实施例2
以96孔板格式在1mL小瓶中进行反应,所述小瓶位于惰性化手套箱(<10ppm O2和<1ppm H2O)中。通过在惰性手套箱内部的Quantos称重机器人将配体(双齿为12mol%并且单齿为20mol%)和Pd-113作为固体进行预称重。
将Pd源(10mol%)、IS(4-4'-二叔丁基联苯,10mol%)作为0.01M储备溶液(CHCl3)分配到96孔小瓶中。使用位于手套箱内部的Genevac EZ-2蒸发载体溶剂。将搅拌盘加入到每个小瓶中。制备烯烃起始材料的溶液(998mg,在20mL甲苯中),单独或与Et3SiH(27.7μL)一起以得到100mol%烯烃和10mol%Et3SiH,或与iPrCOCl(18.3μL)一起以得到100mol%烯烃和10mol%iPrCOCl。在每个小瓶中加入579μL每种溶液,以提供每个反应28.9mg烯烃。将Et3N(1.4μL,20mol%)加入到含有作为其HBF4盐的配体的每个小瓶中。将反应密封并在80℃下加热20小时。在反应结束时制备用于uPLC/MS分析的样品(如下)。
HPLC条件/取样
λ=220nm
(A1)在H2O中的TFA(0.03v/v%)和(B1)在CH3CN中的TFA(0.03v/v%)
在G64 uPLC上运行。(PC_306)
取样:取样15μL反应混合物,稀释至1.0mL MeCN:水(4:1)中,0.5μL进样量。
结果
实施例3
基于100mg规模的烯烃,以24孔板格式在4mL小瓶中进行反应,所述小瓶位于惰性化手套箱(<10ppm O2和<1ppm H2O)中。用手称重Grubbs II,然后将小瓶放入手套箱环境中。使用位于手套箱内部的Quantos称重机器人将所有其他固体作为固体进行分配。将搅拌盘加入到每个小瓶中。
将起始材料(1.4g,1当量)溶解在无水脱气甲苯(总计14mL)中,并将1mL分配到每个小瓶中。(100mg/反应和10mol%内标)。然后加入用于反应5和反应6的液体添加剂。对所有反应,将反应密封并在70℃下加热18小时。在30分钟、2小时和18小时时制备用于uPLC/MS分析的样品(如下)。
在30分钟时的结果
在2小时时的结果
在18小时时的结果
实施例4
将钯-113(二溴双(三叔丁基膦基)二钯(I))(48mg,0.062mmol,0.07当量)加入到起始材料(518mg,0.89mmol,1.0当量)和三乙基硅烷(17.2μL,0.107mmol,0.12当量)在无水甲苯(8mL)中的溶液中。将反应在70℃、氩气下搅拌2小时。LC/MS显示起始材料的完全转化。通过在减压下的旋转蒸发除去甲苯,并将残余物通过快速管柱色谱法(硅胶;isolerabiotage ultra 25g,梯度为80/20至0/100己烷/乙酸乙酯v/v)纯化。收集纯级分并合并,并且通过在减压下的旋转蒸发除去过量洗脱液,以得到所需产物(210mg,40%)。通过LC的纯度:90%
LCMS-B:10.86min;(ES+)m/z(相对强度)601.35([M+Na]+.,100)。
质子NMR与已发表的文献光谱相同。旋光度在已发表的文献值的实验误差范围内(如与-100°相比的-89°)。手性SFC分析表明产物为对映体纯的。
实施例5
用于此实施例的起始材料在Gregson 2001中作为化合物16发表。
[4-[3-[4-[(2S)-2-(羟甲基)-4-甲基-2,3-二氢吡咯-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯基]-[(2S)-2-(羟甲基)-4-甲基-2,3-二氢吡咯-1-基]甲酮的制备
在惰性气氛下,将[4-[3-[4-[(2S)-2-(羟甲基)-4-亚甲基-吡咯烷-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯基]-[(2S)-2-(羟甲基)-4-亚甲基-吡咯烷-1-基]甲酮(100mg,0.15mmol)和二溴双(三叔丁基膦)二钯(I)(3.31mg,0.0004mmol)混合在无水脱气甲苯(1.5mL)中。将反应混合物加热至75℃并保持24h。将第二部分二溴双(三叔丁基膦)二钯(I)(2.95mg,0.0004mmol)加入反应混合物中,并将其在75℃下再保持20h。将反应混合物冷却至20℃。
乙酸[(2S)-1-[4-[3-[4-[(2S)-2-(乙酰氧基甲基)-4-亚甲基-吡咯烷-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯甲酰]-4-亚甲基-吡咯烷-2-基]甲酯的制备
将乙酸酐(0.72ml,7.61mmol)加入到[4-[3-[4-[(2S)-2-(羟甲基)-4-亚甲基-吡咯烷-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯基]-[(2S)-2-(羟甲基)-4-亚甲基-吡咯烷-1-基]甲酮(1.00g,1.52mmol)和三乙胺(0.85mL,6.09mmol)在2-甲基四氢呋喃(15mL)中的搅拌溶液中。将反应混合物在20℃下保持20h。将反应混合物用水(5.0mL)洗涤3次,并在真空下除去溶剂。通过硅胶色谱法纯化反应材料,以得到呈黄色油状物的乙酸[(2S)-1-[4-[3-[4-[(2S)-2-(乙酰氧基甲基)-4-亚甲基-吡咯烷-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯甲酰]-4-亚甲基-吡咯烷-2-基]甲酯(0.83g,73.6%);1H NMR(500MHz,DMSO-d6)δppm 1.17(t,J=7.13Hz,1H)1.86-2.07(m,6H)2.27(br t,J=5.72Hz,1H)2.34-2.44(m,1H)2.52-2.55(m,1H)2.71-2.84(m,1H)3.69-3.85(m,3H)3.87-4.22(m,9H)4.29(br t,J=5.76Hz,3H)4.32-4.44(m,1H)4.53-4.58(m,1H)4.94(br s,1H)5.02(br s,1H)5.07-5.12(m,1H)5.12-5.17(m,1H)5.76(s,1H)7.07(s,1H)7.23(s,1H)7.73-7.77(m,1H)。
乙酸[(2S)-1-[4-[3-[4-[(2S)-2-(乙酰氧基甲基)-4-亚甲基-吡咯烷-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯甲酰]-4-亚甲基-吡咯烷-2-基]甲酯的制备
在惰性气氛下,将乙酸[(2S)-1-[4-[3-[4-[(2S)-2-(乙酰氧基甲基)-4-亚甲基-吡咯烷-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯甲酰]-4-亚甲基-吡咯烷-2-基]甲酯(78.4mg,0.11mmol)和二溴双(三叔丁基膦)二钯(I)(2.66mg,0.0003mmol)混合在无水脱气甲苯(1.5mL)中。将反应混合物加热至75℃,并保持44h。将第二部分二溴双(三叔丁基膦)二钯(I)(2.85mg,0.0004mmol)加入反应混合物中,并将其在75℃下再保持20h。将反应混合物冷却至20℃。
[4-[3-[4-[(2S)-2-[[叔丁基(二甲基)甲硅烷基]氧基甲基]-4-亚甲基-吡咯烷-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯基]-[(2S)-2-[[叔丁基(二甲基)甲硅烷基]氧基甲基]-4-亚甲基-吡咯烷-1-基]甲酮的制备
将叔丁基二甲基氯硅烷(1.18g,7.61mmol)加入到[4-[3-[4-[(2S)-2-(羟甲基)-4-亚甲基-吡咯烷-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯基]-[(2S)-2-(羟甲基)-4-亚甲基-吡咯烷-1-基]甲酮(1.00g,1.52mmol)和三乙胺(1.28mL,9.14mmol)在2-甲基四氢呋喃(15mL)中的搅拌溶液中。将反应加热至50℃并在此温度下保持6h。将附加的三乙胺(1.28mL,9.14mmol)和叔丁基二甲基氯硅烷(1.18g,7.61mmol)加入到反应中,并将反应混合物在50℃下再保持16h。将反应混合物冷却至20℃。将反应混合物用水(5.0mL)洗涤3次,并在真空下除去溶剂。通过硅胶色谱法纯化反应材料,以得到呈黄色固体的[4-[3-[4-[(2S)-2-[[叔丁基(二甲基)甲硅烷基]氧基甲基]-4-亚甲基-吡咯烷-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯基]-[(2S)-2-[[叔丁基(二甲基)甲硅烷基]氧基甲基]-4-亚甲基-吡咯烷-1-基]甲酮(0.88g,65.3%);1H NMR(400MHz,DMSO-d6)δppm-0.29--0.22(m,6H)-0.08(s,1H)0.61-0.66(m,10H)0.81(s,17H)1.10(t,J=7.11Hz,2H)1.91(s,2H)2.11-2.27(m,3H)2.34-2.40(m,1H)2.44-2.53(m,2H)2.55-2.73(m,3H)3.15(t,J=9.59Hz,1H)3.29(dd,J=10.18,3.72Hz,1H)3.39-3.49(m,2H)3.51-3.59(m,1H)3.63-3.86(m,16H)3.95(q,J=7.11Hz,2H)4.16-4.31(m,9H)4.83(br s,2H)4.92(br s,2H)5.03(br d,J=11.53Hz,2H)6.93(s,2H)7.14(s,1H)7.63-7.70(m,3H)。
[4-[3-[4-[(2S)-2-[[叔丁基(二甲基)甲硅烷基]氧基甲基]-4-甲基-2,3-二氢吡咯-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯基]-[(2S)-2-[[叔丁基(二甲基)甲硅烷基]氧基甲基]-4-甲基-2,3-二氢吡咯-1-基]甲酮的制备
在惰性气氛下,将[4-[3-[4-[(2S)-2-[[叔丁基(二甲基)甲硅烷基]氧基甲基]-4-亚甲基-吡咯烷-1-羰基]-2-甲氧基-5-硝基-苯氧基]丙氧基]-5-甲氧基-2-硝基-苯基]-[(2S)-2-[[叔丁基(二甲基)甲硅烷基]氧基甲基]-4-亚甲基-吡咯烷-1-基]甲酮(100mg,0.15mmol)和二溴双(三叔丁基膦)二钯(I)(2.48mg,0.0003mmol)混合在无水脱气甲苯(1.5mL)中。将反应混合物加热至75℃并保持24h。将第二部分二溴双(三叔丁基膦)二钯(I)(2.41mg,0.0003mmol)加入反应混合物中,并将其在75℃下再保持20h。将反应混合物冷却至20℃。
参考文献
发明陈述
1.一种由式II化合物:
合成式I化合物:
的方法,其中
RA为H或ProtO1;
R8:
(i)为ProtO3;或
(ii)在式(I)中为式A1基团并且在式(II)中为式A2基团:
其中RB为H或ProtO2;
R7选自C1-4烷基和苄基;
R17选自C1-4烷基和苄基;
Y为C3-12亚烷基,其链可被一个或多个选自O、S和NRN2(其中RN2为H或C1-4烷基)的杂原子或者选自苯和吡啶的芳环中断;
ProtO1、ProtO2和ProtO3独立地为在反应条件下不为不稳定的羟基保护基。
2.根据陈述1所述的方法,其中R7为C1-4烷基。
3.根据陈述2所述的方法,其中R7为甲基。
4.根据陈述2所述的方法,其中R7为乙基。
5.根据陈述1所述的方法,其中R7为苄基。
6.根据陈述1至5中任一项所述的方法,其中RA为ProtO1。
7.根据陈述1至5中任一项所述的方法,其中RA为H。
8.根据陈述1至6中任一项所述的方法,其中ProtO1选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
9.根据陈述8所述的方法,其中ProtO1选自:
(a)甲氧基甲醚(MOM)、β-甲氧基乙氧基甲醚(MEM)、苄氧基甲基、叔丁氧基甲醚和甲硅烷氧基甲醚;
(b)1-乙氧基乙醚、2-羟乙醚、1-[2-(三甲基甲硅烷基)乙氧基]乙醚、2,2,2-三氯乙醚、2-三甲基甲硅烷基乙醚和叔丁醚;
(c)对甲氧基苄醚、二甲氧基苄基和硝基苄醚;
(d)三甲基甲硅烷基醚(TMS)、三乙基甲硅烷基醚(TES)、叔丁基二甲基甲硅烷基醚(TBS)、叔丁基二苯基甲硅烷基醚(TBDPS)和三异丙基甲硅烷基醚(TIPS);
(e)氯乙酸酯、甲氧基乙酸酯、苯氧基乙酸酯和苯甲酸酯。
10.根据陈述8所述的方法,其中ProtO1为甲硅烷基醚。
11.根据陈述10所述的方法,其中ProtO1为叔丁基二甲基甲硅烷基醚(TBS)。
12.根据陈述1至11中任一项所述的方法,其中R8为ProtO3。
13.根据陈述12所述的方法,其中R8选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
14.根据陈述13所述的方法,其中R8选自:
(a)甲氧基甲醚(MOM)、β-甲氧基乙氧基甲醚(MEM)、苄氧基甲基、叔丁氧基甲醚和甲硅烷氧基甲醚;
(b)1-乙氧基乙醚、2-羟乙醚、1-[2-(三甲基甲硅烷基)乙氧基]乙醚、2,2,2-三氯乙醚、2-三甲基甲硅烷基乙醚和叔丁醚;
(c)对甲氧基苄醚、二甲氧基苄基和硝基苄醚;
(d)三甲基甲硅烷基醚(TMS)、三乙基甲硅烷基醚(TES)、叔丁基二甲基甲硅烷基醚(TBS)、叔丁基二苯基甲硅烷基醚(TBDPS)和三异丙基甲硅烷基醚(TIPS);
(e)氯乙酸酯、甲氧基乙酸酯、苯氧基乙酸酯和苯甲酸酯。
15.根据陈述13所述的方法,其中R8为甲硅烷基醚。
16.根据陈述15所述的方法,其中R8为三异丙基甲硅烷基醚(TIPS)。
17.根据陈述1至11中任一项所述的方法,其中R8为式(I)中的式A1基团和式(II)中的式A2基团。
18.根据陈述17所述的方法,其中R17为C1-4烷基。
19.根据陈述18所述的方法,其中R17为甲基。
20.根据陈述18所述的方法,其中R17为乙基。
21.根据陈述17所述的方法,其中R17为苄基。
22.根据陈述17至21中任一项所述的方法,其中Y为不中断的C3-12亚烷基。
23.根据陈述22所述的方法,其中Y为-(CH2)n-,其中n为3至12的整数。
24.根据陈述23所述的方法,其中Y选自-(CH2)3-和-(CH2)5-。
25.根据陈述17至21中任一项所述的方法,其中Y为被芳环中断的C3-12亚烷基。
27.根据陈述17至26中任一项所述的方法,其中RB为ProtO2。
28.根据陈述17至26中任一项所述的方法,其中RB为H。
29.根据陈述17至27中任一项所述的方法,其中ProtO2选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
30.根据陈述29所述的方法,其中ProtO2选自:
(a)甲氧基甲醚(MOM)、β-甲氧基乙氧基甲醚(MEM)、苄氧基甲基、叔丁氧基甲醚和甲硅烷氧基甲醚;
(b)1-乙氧基乙醚、2-羟乙醚、1-[2-(三甲基甲硅烷基)乙氧基]乙醚、2,2,2-三氯乙醚、2-三甲基甲硅烷基乙醚和叔丁醚;
(c)对甲氧基苄醚、二甲氧基苄基和硝基苄醚;
(d)三甲基甲硅烷基醚(TMS)、三乙基甲硅烷基醚(TES)、叔丁基二甲基甲硅烷基醚(TBS)、叔丁基二苯基甲硅烷基醚(TBDPS)和三异丙基甲硅烷基醚(TIPS);
(e)氯乙酸酯、甲氧基乙酸酯、苯氧基乙酸酯和苯甲酸酯。
31.根据陈述29所述的方法,其中ProtO2为甲硅烷基醚。
32.根据陈述29所述的方法,其中ProtO2为叔丁基二甲基甲硅烷基醚(TBS)。
33.根据陈述1至31中任一项所述的方法,其使用催化剂在任选加入添加剂的情况下进行。
34.根据陈述33所述的方法,其中所述催化剂包括金属氢化物或能够原位形成金属氢化物。
35.根据陈述34所述的方法,其中所述催化剂含有选自Ru、Ir、Rh和Pd的过渡金属。
36.根据陈述35所述的方法,其中所述过渡金属为Pd。
37.根据陈述35所述的方法,其中所述过渡金属为Ru。
38.根据陈述35所述的方法,其中所述过渡金属为Rh。
39.根据陈述35所述的方法,其中所述过渡金属为Ir。
40.根据陈述33至39中任一项所述的方法,其中催化剂包括选自(叔丁基)3P和Ph3P的P配体。
41.根据陈述34所述的方法,其中所述催化剂能够形成包括PdH(PRP 3)X的活性物种,其中每个RP独立地选自叔丁基和苯基,并且X为卤代。
42.根据陈述34所述的方法,其中所述催化剂选自:Grubbs I;Grubbs II;Crabtrees催化剂;RuHCl(CO)PPh3;RhH(CO)PPh3;Rh(COD)2BF4;Pd-113;Pd-118;阳离子CpRu(Pr3);和(tBu3P)2Pd(HCl)。
43.根据陈述42所述的方法,其中所述催化剂选自Pd-113和((tBu)3P)2Pd(HCl)。
44.根据陈述43所述的方法,其中所述催化剂为Pd-113。
45.根据陈述34所述的方法,其中所述催化剂通过金属源和适当的配体原位形成,其中所述金属源选自:Pd(OAc)2和Pd(dba)2;并且适当的配体选自:P(OH)(t-Bu)2;P(t-Bu)3.HBF4;PCy3.HBF4;P(t-Bu)2(Me).HBF4;P(O-(2,4-t-Bu)-Ph)3;Xantphos;Phanephos;Ru-phos;P(o-tol)3;和Biphephos。
46.根据陈述33至45中任一项所述的方法,其中所述任选的添加剂选自:
(a)适合与所述催化剂组合来原位生成金属氢化物的化合物;
(b)碱;
(c)所述催化剂的附加配体。
47.根据陈述46所述的方法,其中适合与所述催化剂组合来原位生成金属氢化物的所述化合物选自:Et3SiH、iPrCOCl和n-BuOH。
48.根据陈述46所述的方法,其中所述碱为Et3N。
49.根据陈述46所述的方法,其中所述催化剂的所述附加配体选自PPh3和P(t-Bu)3。
50.根据陈述1至49中任一项所述的方法,其中所述反应在甲苯中进行。
51.根据陈述1至50中任一项所述的方法,其中反应温度在5℃与120℃之间。
52.根据陈述1至51中任一项所述的方法,其中反应时间在半小时与48小时之间。
53.根据陈述1至52中任一项所述的方法,其中所述催化剂以1mol%至30mol%的式(II)起始化合物的相对量加入。
54.根据陈述1至53中任一项所述的方法,其中所述反应在基本上惰性气氛下进行。
55.根据陈述54所述的方法,其中所述基本上惰性气氛主要包含氮气。
56.根据陈述54所述的方法,其中所述基本上惰性气氛主要包含氩气。
57.根据陈述54至56中任一项所述的方法,其中所述基本上惰性气氛包含少于10ppm的氧气。
58.一种式IIa化合物:
其中R7选自C1-4烷基和苄基;并且
RA为H或ProtO1;
ProtO1和ProtO3独立地为在本发明的第一方面的反应条件下不为不稳定的羟基保护基。
59.根据陈述58所述的化合物,其中R7为C1-4烷基。
60.根据陈述59所述的化合物,其中R7为甲基。
61.根据陈述59所述的化合物,其中R7为乙基。
62.根据陈述58所述的化合物,其中R7为苄基。
63.根据陈述58至62中任一项所述的化合物,其中RA为ProtO1。
64.根据陈述58至62中任一项所述的化合物,其中RA为H。
65.根据陈述58至63中任一项所述的化合物,其中ProtO1选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
66.根据陈述65所述的化合物,其中ProtO1选自:
(a)甲氧基甲醚(MOM)、β-甲氧基乙氧基甲醚(MEM)、苄氧基甲基、叔丁氧基甲醚和甲硅烷氧基甲醚;
(b)1-乙氧基乙醚、2-羟乙醚、1-[2-(三甲基甲硅烷基)乙氧基]乙醚、2,2,2-三氯乙醚、2-三甲基甲硅烷基乙醚和叔丁醚;
(c)对甲氧基苄醚、二甲氧基苄基和硝基苄醚;
(d)三甲基甲硅烷基醚(TMS)、三乙基甲硅烷基醚(TES)、叔丁基二甲基甲硅烷基醚(TBS)、叔丁基二苯基甲硅烷基醚(TBDPS)和三异丙基甲硅烷基醚(TIPS);
(e)氯乙酸酯、甲氧基乙酸酯、苯氧基乙酸酯和苯甲酸酯。
66.根据陈述65所述的化合物,其中ProtO1为甲硅烷基醚。
67.根据陈述67所述的化合物,其中ProtO1为叔丁基二甲基甲硅烷基(TBS)。
68.根据陈述58至67中任一项所述的化合物,其中ProtO3选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
69.根据陈述68所述的化合物,其中ProtO3选自:
(a)甲氧基甲醚(MOM)、β-甲氧基乙氧基甲醚(MEM)、苄氧基甲基、叔丁氧基甲醚和甲硅烷氧基甲醚;
(b)1-乙氧基乙醚、2-羟乙醚、1-[2-(三甲基甲硅烷基)乙氧基]乙醚、2,2,2-三氯乙醚、2-三甲基甲硅烷基乙醚和叔丁醚;
(c)对甲氧基苄醚、二甲氧基苄基和硝基苄醚;
(d)三甲基甲硅烷基醚(TMS)、三乙基甲硅烷基醚(TES)、叔丁基二甲基甲硅烷基醚(TBS)、叔丁基二苯基甲硅烷基醚(TBDPS)和三异丙基甲硅烷基醚(TIPS);
(e)氯乙酸酯、甲氧基乙酸酯、苯氧基乙酸酯和苯甲酸酯。
70.根据陈述68所述的化合物,其中ProtO3为甲硅烷基醚。
71.根据陈述70所述的化合物,其中ProtO3为三异丙基甲硅烷基醚(TIPS)。
Claims (28)
2.根据权利要求1所述的方法,其中R7选自甲基和苄基。
3.根据权利要求1或权利要求2所述的方法,其中RA为H。
4.根据权利要求1或权利要求2所述的方法,其中RA为ProtO1,并且ProtO1选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
5.根据权利要求4所述的方法,其中ProtO1为叔丁基二甲基甲硅烷基醚(TBS)。
6.根据权利要求1至5中任一项所述的方法,其中R8为ProtO3,并且其选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
7.根据权利要求6所述的方法,其中R8为三异丙基甲硅烷基醚(TIPS)。
8.根据权利要求1至5中任一项所述的方法,其中R8在式(I)中为式A1基团并且在式(II)中为式A2基团。
9.根据权利要求8所述的方法,其中R17选自甲基和苄基。
11.根据权利要求8至10中任一项所述的方法,其中RB为H。
12.根据权利要求8至10中任一项所述的方法,其中RB为ProtO2,并且ProtO2选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
13.根据权利要求12所述的方法,其中ProtO2为叔丁基二甲基甲硅烷基醚(TBS)。
14.根据权利要求1至13中任一项所述的方法,其使用催化剂在任选加入添加剂的情况下进行。
15.根据权利要求14所述的方法,其中所述催化剂包括金属氢化物或能够原位形成金属氢化物。
16.根据权利要求15所述的方法,其中所述催化剂含有选自Ru、Ir、Rh和Pd的过渡金属。
17.根据权利要求14至16中任一项所述的方法,其中催化剂包括选自(叔丁基)3P和Ph3P的P配体。
18.根据权利要求14所述的方法,其中所述催化剂能够形成包括PdH(PRP 3)X的活性物种,其中每个RP独立地选自叔丁基和苯基,并且X为卤代。
19.根据权利要求14所述的方法,其中所述催化剂选自:Grubbs I;Grubbs II;Crabtrees催化剂;RuHCl(CO)PPh3;RhH(CO)PPh3;Rh(COD)2BF4;Pd-113;Pd-118;阳离子CpRu(Pr3);和(tBu3P)2Pd(HCl)。
20.根据权利要求9所述的方法,其中所述催化剂为Pd-113。
21.根据权利要求14所述的方法,其中所述催化剂通过金属源和适当的配体原位形成,其中所述金属源选自:Pd(OAc)2和Pd(dba)2;并且适当的配体选自:P(OH)(t-Bu)2;P(t-Bu)3.HBF4;PCy3.HBF4;P(t-Bu)2(Me).HBF4;P(O-(2,4-t-Bu)-Ph)3;Xantphos;Phanephos;Ru-phos;P(o-tol)3和Biphephos。
22.根据权利要求14至21中任一项所述的方法,其中所述任选的添加剂选自:
(a)适合与所述催化剂组合来原位生成金属氢化物的化合物;
(b)碱;
(c)所述催化剂的附加配体。
23.根据权利要求1至22中任一项所述的方法,其中所述反应在基本上惰性气氛下进行,所述基本上惰性气氛选自:
(a)主要包含氮气的气氛;
(b)主要包含氩气的气氛;
(c)主要包含氮气或氩气和少于10ppm氧气的气氛。
25.根据权利要求24所述的化合物,其中R7选自甲基和苄基。
26.根据权利要求24或权利要求25所述的化合物,其中ProtO1和ProtO3选自取代的甲醚、取代的乙醚(除了含有不饱和性的乙醚)、甲氧基取代的苄醚、甲硅烷基醚和乙酸酯。
27.根据权利要求26所述的化合物,其中ProtO1为叔丁基二甲基甲硅烷基醚(TBS)。
28.根据权利要求26或权利要求27所述的化合物,其中ProtO3为三异丙基甲硅烷基醚(TIPS)。
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2019
- 2019-03-01 EP EP19708832.1A patent/EP3759071A1/en not_active Withdrawn
- 2019-03-01 WO PCT/EP2019/055116 patent/WO2019166615A1/en unknown
- 2019-03-01 CN CN201980016640.2A patent/CN111801316A/zh active Pending
- 2019-03-01 US US16/977,072 patent/US11352324B2/en active Active
- 2019-03-01 KR KR1020207026719A patent/KR20200128046A/ko not_active Application Discontinuation
- 2019-03-01 JP JP2020545525A patent/JP2021515760A/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2000012508A2 (en) * | 1998-08-27 | 2000-03-09 | Spirogen Limited | Pyrrolbenzodiazepines |
WO2014057074A1 (en) * | 2012-10-12 | 2014-04-17 | Spirogen Sàrl | Pyrrolobenzodiazepines and conjugates thereof |
WO2017059289A1 (en) * | 2015-10-02 | 2017-04-06 | Genentech, Inc. | Pyrrolobenzodiazepine antibody drug conjugates and methods of use |
WO2017201132A2 (en) * | 2016-05-18 | 2017-11-23 | Mersana Therapeutics, Inc. | Pyrrolobenzodiazepines and conjugates thereof |
Non-Patent Citations (1)
Title |
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ANNABEL C. MURPHY ET AL.: "Concise, Stereoselective Route to the Four Diastereoisomers of 4-Methylproline" * |
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JP2021515760A (ja) | 2021-06-24 |
US11352324B2 (en) | 2022-06-07 |
EP3759071A1 (en) | 2021-01-06 |
GB201803342D0 (en) | 2018-04-18 |
KR20200128046A (ko) | 2020-11-11 |
WO2019166615A1 (en) | 2019-09-06 |
US20200399215A1 (en) | 2020-12-24 |
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