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【结 构 式】 
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【分子编号】31834 【品名】3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine 【CA登记号】63160-13-4 |
【 分 子 式 】C13H11NO3S 【 分 子 量 】261.30128 【元素组成】C 59.76% H 4.24% N 5.36% O 18.37% S 12.27% |
合成路线1
该中间体在本合成路线中的序号：(V)The protection of the allyl alcohol (I) with dihydropyran and PPTS in dichloromethane gives the tetrahydropyranyl ether (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi and CuCN in THF to yield the adduct (IV). The hydroxylation of (IV) with Davis' oxaziridine, NaHMDS and CSA affords the alcohol (V), which is silylated with Tbdms-OTf and lutidine to provide the silyl ether (VII). The hydrolysis of the oxazolidinone group of (VII) with Et-SH and Et-SK in THF gives the thioester (VIII), which is methylated with Me2CuLi in ethyl ether, yielding the methyl ketone (IX). The condensation of (IX) with phosphonate (X) by means of BuLi in THF affords the diene (XI), which is treated with MgBr2 in ethyl ether in order to eliminate the THP protecting group and obtain the primary alcohol (XII). The sulfonation of (XII) with Ms2O and TEA in dichloromethane gives the mesylate (XIII), which is treated with LiBr in acetone to yield the allyl bromide (XIV). Finally, (XIV) is condensed with methyltriphenylphosphonium bromide (XV) by means of BuLi in THF affording the desired intermediate phosphonium salt (XVI).
| 【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407. |
| 【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 46138 | (Z)-3-iodo-2-methyl-2-propen-1-ol | C4H7IO | 详情 | 详情 | |
| (II) | 46139 | (Z)-3-iodo-2-methyl-2-propenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(Z)-3-iodo-2-methyl-2-propenyl]oxy]tetrahydro-2H-pyran | C9H15IO2 | 详情 | 详情 | |
| (III) | 40307 | (4S)-3-acryloyl-4-benzyl-1,3-oxazolidin-2-one | C13H13NO3 | 详情 | 详情 | |
| (IV) | 46140 | (4S)-4-benzyl-3-[(Z)-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one | C22H29NO5 | 详情 | 详情 | |
| (V) | 31834 | 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine | 63160-13-4 | C13H11NO3S | 详情 | 详情 |
| (VI) | 46141 | (4S)-4-benzyl-3-[(2S,4Z)-2-hydroxy-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one | C22H29NO6 | 详情 | 详情 | |
| (VII) | 46142 | (4S)-4-benzyl-3-[(2S,4Z)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one | C28H43NO6Si | 详情 | 详情 | |
| (VIII) | 46143 | S-ethyl (2S,4Z)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenethioate | C20H38O4SSi | 详情 | 详情 | |
| (IX) | 46144 | (3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(tetrahydro-2H-pyran-2-yloxy)-5-hepten-2-one | C19H36O4Si | 详情 | 详情 | |
| (X) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (XI) | 46145 | 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)-1,5-heptadienyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentenyl ether | C24H41NO3SSi | 详情 | 详情 | |
| (XII) | 40824 | (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol | C19H33NO2SSi | 详情 | 详情 | |
| (XIII) | 46146 | tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1,5-heptadienyl)-2-methyl-1,3-thiazole | C22H39NO2S2Si | 详情 | 详情 | |
| (XIV) | 46147 | 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether | C19H32BrNOSSi | 详情 | 详情 | |
| (XV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XVI) | 46148 | [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide | C38H49BrNOPSSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The protection of the allyl alcohol (I) with dihydropyran and PPTS in dichloromethane gives the tetrahydropyranyl ether (II), which is condensed with the chiral oxazolidinone (III) by means of BuLi and CuCN in THF, yielding the adduct (IV). The hydroxylation of (IV) with Davis' oxaziridine, NaHMDS and CSA affords the alcohol (V), which is silylated with Tbdms-OTf and lutidine, providing the silyl ether (VII). The hydrolysis of the oxazolidinone group of (VII) with Et-SH and Et-SK in THF gives the thioester (VIII), which is methylated with Me2CuLi in ethyl ether, yielding the methyl ketone (IX). The condensation of (IX) with phosphonate (X) by means of BuLi in THF affords the diene (XI), which is treated with MgBr2 in ethyl ether in order to eliminate the THP protecting group and obtain the primary alcohol (XII). The sulfonation of (XII) with Ms2O and TEA in dichloromethane gives the mesylate (XIII), which is treated with LiBr in acetone to yield the allyl bromide (XIV). Finally, (XIV) is condensed with methyltriphenylphosphonium bromide (XV) by means of BuLi in THF affording the desired intermediate phosphonium salt (XVI).
| 【1】 White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M.; Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D. J Am Chem Soc 2001, 123, 23, 5407. |
| 【2】 White, J.D.; et al.; A highly stereoselective synthesis of epothilone B. J Org Chem 1999, 64, 3, 684. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 46138 | (Z)-3-iodo-2-methyl-2-propen-1-ol | C4H7IO | 详情 | 详情 | |
| (II) | 46139 | (Z)-3-iodo-2-methyl-2-propenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(Z)-3-iodo-2-methyl-2-propenyl]oxy]tetrahydro-2H-pyran | C9H15IO2 | 详情 | 详情 | |
| (III) | 40307 | (4S)-3-acryloyl-4-benzyl-1,3-oxazolidin-2-one | C13H13NO3 | 详情 | 详情 | |
| (IV) | 46140 | (4S)-4-benzyl-3-[(Z)-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one | C22H29NO5 | 详情 | 详情 | |
| (V) | 31834 | 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine | 63160-13-4 | C13H11NO3S | 详情 | 详情 |
| (VI) | 46141 | (4S)-4-benzyl-3-[(2S,4Z)-2-hydroxy-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one | C22H29NO6 | 详情 | 详情 | |
| (VII) | 46142 | (4S)-4-benzyl-3-[(2S,4Z)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenoyl]-1,3-oxazolidin-2-one | C28H43NO6Si | 详情 | 详情 | |
| (VIII) | 46143 | S-ethyl (2S,4Z)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexenethioate | C20H38O4SSi | 详情 | 详情 | |
| (IX) | 46144 | (3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-(tetrahydro-2H-pyran-2-yloxy)-5-hepten-2-one | C19H36O4Si | 详情 | 详情 | |
| (X) | 44442 | diethyl (2-methyl-1,3-thiazol-4-yl)methylphosphonate | C9H16NO3PS | 详情 | 详情 | |
| (XI) | 46145 | 4-[(1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(tetrahydro-2H-pyran-2-yloxy)-1,5-heptadienyl]-2-methyl-1,3-thiazole; tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-5-(tetrahydro-2H-pyran-2-yloxy)-3-pentenyl ether | C24H41NO3SSi | 详情 | 详情 | |
| (XII) | 40824 | (2Z,5S,6E)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-(2-methyl-1,3-thiazol-4-yl)-2,6-heptadien-1-ol | C19H33NO2SSi | 详情 | 详情 | |
| (XIII) | 46146 | tert-butyl(dimethyl)silyl (1S,3Z)-4-methyl-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl ether; 4-((1E,3S,5Z)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-7-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-1,5-heptadienyl)-2-methyl-1,3-thiazole | C22H39NO2S2Si | 详情 | 详情 | |
| (XIV) | 46147 | 4-((1E,3S,5Z)-7-bromo-3-[[tert-butyl(dimethyl)silyl]oxy]-2,6-dimethyl-1,5-heptadienyl)-2-methyl-1,3-thiazole; (1S,3Z)-5-bromo-4-methyl-1-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-3-pentenyl tert-butyl(dimethyl)silyl ether | C19H32BrNOSSi | 详情 | 详情 | |
| (XV) | 30484 | Methyl(triphenyl)phosphonium bromide | 1779-49-3 | C19H18BrP | 详情 | 详情 |
| (XVI) | 46148 | [(3Z,6S,7E)-6-[[tert-butyl(dimethyl)silyl]oxy]-3,7-dimethyl-8-(2-methyl-1,3-thiazol-4-yl)-3,7-octadienyl](triphenyl)phosphonium bromide | C38H49BrNOPSSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)Treatment of ethyl 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate (I) with ammonium hydroxide provided the aminopyrimidine (II). After reduction of the ethyl ester (II) to alcohol (III) with LiAlH4, oxidation with MnO2 in chloroform yielded aldehyde (IV). Wittig condensation of (IV) with phosphorane (V) afforded the unsaturated ester (VI), which was cyclized to the pyridopyrimidinone (VII) upon treatment with DBU in diisopropylethylamine. Then, alkylation of (VII) with 2-iodopropane in the presence of NaH in DMF gave rise to the 8-isopropyl pyridopyrimidinone (VIII). Subsequent oxidation of the sulfide group of (VIII) to sulfoxide (X) was carried out employing trans-2-(phenylsulfonyl)-3-phenyloxaziridine (IX). Finally, displacement of the methylsulfinyl group of (X) with 4-(4-methylpiperazin-1-yl)aniline (XI) at 175 C yielded the title compound.
| 【1】 Dobrusin, E.M.; Fattacy, A.; Boschelli, D.H.; Fry, D.W.; Wu, Z.; Doherty, A.M.; Kallmeyer, S.T.; Barvian, M.R. (Pfizer Inc.); Pyrido[2,3-d]pyrimidines and 4-aminopyrimidines as inhibitors of cellular proliferation. WO 9833798 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 18198 | ethyl 4-chloro-2-(methylsulfanyl)-5-pyrimidinecarboxylate; ETHYL 4-CHLORO-2-METHYLTHIO-5-PYRIMIDINECARBOXYLATE | 5909-24-0 | C8H9ClN2O2S | 详情 | 详情 |
| (II) | 31828 | ethyl 4-amino-2-(methylsulfanyl)-5-pyrimidinecarboxylate | C8H11N3O2S | 详情 | 详情 | |
| (III) | 31829 | [4-amino-2-(methylsulfanyl)-5-pyrimidinyl]methanol | C6H9N3OS | 详情 | 详情 | |
| (IV) | 31830 | 4-amino-2-(methylsulfanyl)-5-pyrimidinecarbaldehyde | C6H7N3OS | 详情 | 详情 | |
| (V) | 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 |
| (VI) | 31831 | ethyl (E)-3-[4-amino-2-(methylsulfanyl)-5-pyrimidinyl]-2-propenoate | C10H13N3O2S | 详情 | 详情 | |
| (VII) | 31832 | 2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one | C8H7N3OS | 详情 | 详情 | |
| (VIII) | 31833 | 8-isopropyl-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one | C11H13N3OS | 详情 | 详情 | |
| (IX) | 31834 | 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine | 63160-13-4 | C13H11NO3S | 详情 | 详情 |
| (X) | 31835 | 8-isopropyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one | C11H13N3O2S | 详情 | 详情 | |
| (XI) | 31836 | 4-(4-methyl-1-piperazinyl)phenylamine; 4-(4-methyl-1-piperazinyl)aniline | C11H17N3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)Condensation of S-methylisothiourea (I) and cyano acetate derivative (II) by means of NaOMe in MeOH affords pyrimidine derivative (III), whose hydroxy group is converted into chloro by means of refluxing POCl3, yielding derivative (IV). Alkylation of (IV) with cyclopentylamine (V) and Et3N in CH2Cl2 provides derivative (VI), whose nitrile group is then reduced by means of LiAlH4 in THF to afford aminomethyl compound (VII). Treatment of (VII) with 1,1-carbonyldiimidazole (CDI) in refluxing THF gives pyrimidopyrimidinone (VIII), whose methylsulfanyl group is oxidized with 3-phenyl-2-(phenylsulfonyl)oxaziridine (IX) in CHCl3 to afford methyl sulfoxide derivative (X). Displacement of the methyl sulfoxide group of (X) with substituted aniline (XI) in TFA/acetonitrile yields 3,4-dihydropyrimidopyrimidinone (XII), which is finally oxidized by means of KOtBu in THF or DMSO.
| 【1】 Kramer, J.B.; et al.; Synthesis and biological activity of a novel series of pyrimidopyrimidinones as inhibitors of cyclin-dependent kinases. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 40. |
| 【2】 Dobrusin, E.M.; Showalter, H.D.H.; Schroeder, M.C.; Toogood, P.; Kramer, J.B.; Trumpp-Kallmeyer, S.A.; Hamby, J.M. (Pfizer Inc.); Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation. WO 9961444 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIa) | 43041 | ethyl (Z)-2-cyano-3-ethoxy-2-propenoate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (IIb) | 43563 | ethyl (E)-2-cyano-3-ethoxy-2-propenoate；(E)-ethyl 2-cyano-3-ethoxyacrylate | 94-05-3 | C8H11NO3 | 详情 | 详情 |
| (I) | 10272 | [[Amino(imino)methyl]sulfanyl]methane | 2986-19-8 | C2H6N2S | 详情 | 详情 |
| (III) | 43555 | 4-hydroxy-2-(methylsulfanyl)-5-pyrimidinecarbonitrile | C6H5N3OS | 详情 | 详情 | |
| (IV) | 43556 | 4-chloro-2-(methylsulfanyl)-5-pyrimidinecarbonitrile | C6H4ClN3S | 详情 | 详情 | |
| (V) | 28850 | cyclopentanamine | 1003-03-8 | C5H11N | 详情 | 详情 |
| (VI) | 43557 | 4-(cyclopentylamino)-2-(methylsulfanyl)-5-pyrimidinecarbonitrile | C11H14N4S | 详情 | 详情 | |
| (VII) | 43558 | N-[5-(aminomethyl)-2-(methylsulfanyl)-4-pyrimidinyl]-N-cyclopentylamine; 5-(aminomethyl)-N-cyclopentyl-2-(methylsulfanyl)-4-pyrimidinamine | C11H18N4S | 详情 | 详情 | |
| (VIII) | 43559 | 1-cyclopentyl-7-(methylsulfanyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one | C12H16N4OS | 详情 | 详情 | |
| (IX) | 31834 | 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine | 63160-13-4 | C13H11NO3S | 详情 | 详情 |
| (X) | 43560 | 1-cyclopentyl-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one | C12H16N4O2S | 详情 | 详情 | |
| (XI) | 43561 | 1-(4-aminophenyl)-4-piperidinol | C11H16N2O | 详情 | 详情 | |
| (XII) | 43562 | 1-cyclopentyl-7-[4-(4-hydroxy-1-piperidinyl)anilino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one | C22H28N6O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)The condensation of 3-fluoroaniline (I) with 4-fluorobenzonitrile (II) by means of BCl3 and AlCl3 in xylene at 120 C gives the benzophenone (III), which is reduced with hydrazine and KOH in ethyleneglycol at 200 C to yield the diphenylmethane (IV). The acylation of the NH2 group of (IV) with refluxing formic acid affords the formamide (V), which is cyclized by means of PPA and POCl3 in xylene at 100 C to provide the dibenzazepine (VI). The reduction of (VI) with H2 over Pd/C in THF/methanol gives the corresponding dihydro compound (VII), which is oxidized with 3-phenyl-2-(phenylsulfonyl)oxaziridine (VIII) in dichloromethane to yield the N-oxide (IX). Finally, this compound is cyclized with N-allyl-N,N-dimethylamine (X) by heating in toluene at 100 C to afford the target oxazolidine derivative. Alternatively, the cyclization of 5-fluoro-2-hydroxyaniline (XI) with 3-fluorobenzaldehyde (XII) by means of chloroacetic acid at 100 C in methanol or isopropanol gives 7-fluoro-2-(4-fluorophenyl)-2,4-dihydro-1H-3,1-benzoxazine (XIII), which is reduced with NaBH4 in refluxing ethanol to yield N-(3-fluorobenzyl)-N-[2-(hydroxymethyl)-5-fluorophenyl]amine (XIV). Finally, this compound is cyclized by means of H2SO4 in dichloromethane to afford the previously described dihydro-benzodiazepine (VII), which is worked up as before.
| 【1】 Alonso, J.M.; Alcázar, J.; Andrés, J.I.; et al.; Synthesis and structure-activity relationship of 2-(aminoalkyl)-2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine derivatives: A novel series of 5-HT2A/2C receptor antagonists. Part 2. Bioorg Med Chem Lett 2002, 12, 2, 249. |
| 【2】 Sipido, V.K.; Fernandez-Gadea, F.J.; Andres-Gil, J.I.; Meert, T.F.; Gil-Lopetegui, P. (Janssen Pharmaceutica NV); Substd. tetracyclic azepine derivs. which have affinity for 5-HT2 receptors. EP 0789701; JP 1998508308; US 5552399; WO 9614320 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 20697 | 3-fluoroaniline; 3-fluorophenylamine | 372-19-0 | C6H6FN | 详情 | 详情 |
| (II) | 14144 | 4-Fluorobenzonitrile | 1194-02-1 | C7H4FN | 详情 | 详情 |
| (III) | 54726 | (2-amino-4-fluorophenyl)(4-fluorophenyl)methanone | C13H9F2NO | 详情 | 详情 | |
| (IV) | 54727 | 5-fluoro-2-(4-fluorobenzyl)aniline; 5-fluoro-2-(4-fluorobenzyl)phenylamine | C13H11F2N | 详情 | 详情 | |
| (V) | 54728 | 5-fluoro-2-(4-fluorobenzyl)phenylformamide | C14H11F2NO | 详情 | 详情 | |
| (VI) | 54729 | 3,8-difluoro-11H-dibenzo[b,e]azepine | C14H9F2N | 详情 | 详情 | |
| (VII) | 54730 | 3,8-difluoro-6,11-dihydro-5H-dibenzo[b,e]azepine | C14H11F2N | 详情 | 详情 | |
| (VIII) | 31834 | 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine | 63160-13-4 | C13H11NO3S | 详情 | 详情 |
| (IX) | 54731 | 3,8-difluoro-11H-dibenzo[b,e]azepinium-5-olate | C14H9F2NO | 详情 | 详情 | |
| (X) | 54732 | 1-Dimethylamino-2-propene; Allyldimethylamine; N,N-Dimethylallylamine; N-Allyl-N,N-dimethylamine | 2155-94-4 | C5H11N | 详情 | 详情 |
| (XI) | 54733 | 2-amino-4-fluorophenol | C6H6FNO | 详情 | 详情 | |
| (XII) | 18887 | 3-Fluorobenzaldehyde | 456-48-4 | C7H5FO | 详情 | 详情 |
| (XIII) | 54734 | 7-fluoro-2-(3-fluorophenyl)-1,4-dihydro-2H-3,1-benzoxazine | C14H11F2NO | 详情 | 详情 | |
| (XIV) | 54735 | {4-fluoro-2-[(3-fluorobenzyl)amino]phenyl}methanol | C14H13F2NO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Treatment of 6-bromo-8-cyclopentyl-5-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (I) with 2-benzenesulfonyl-3-phenyl-oxaziridine (II) in CH2Cl2 results in the corresponding sulfoxide (III) . Subsequent displacement of the methylsulfinyl group of compound (III) with 2-amino-5-(4-Boc-1-piperazinyl)pyridine (IV) in boiling toluene provides the diarylamine adduct (V), which is subjected to Stille coupling with (ethoxyvinyl)tributylstannane (VI) in the presence of Pd(PPh3)4 to give the ethoxyvinyl derivative (VII). Finally, compound (VII) is submitted to simultaneous enol ether hydrolysis and cleavage of the Boc-protecting group by means of HCl in CH2Cl2 .
| 【1】 Toogood, P.L., Harvey, P.J., Repine, J.T. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Med Chem 2005, 48(7): 2388-406. |
| 【2】 Barvian, M.R., Quin, J. III, Sheehan, D.J. et al. (Pfizer Inc.). 2-(Pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones. EP 1470124, JP 2005519909, US 2003149001, US 6936612, WO 2003062236. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 68142 | 6-bromo-8-cyclopentyl-5-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one | C14H16BrN3OS | 详情 | 详情 | |
| (II) | 31834 | 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine;2-(Phenylsulfonyl)-3-phenyloxaziridine;2-Benzenesulfonyl-3-phenyloxaziridine;3-Phenyl-2-phenylsulfonyloxaziridine;3-Phenyl-N-phenylsulfonyloxaziridine;N-(Phenylsulfonyl)phenyloxaziridine;N-Benzenesulfonyl-3-phenyloxaziridine | 63160-13-4 | C13H11NO3S | 详情 | 详情 |
| (III) | 68143 | 6-bromo-8-cyclopentyl-5-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one | C14H16BrN3O2S | 详情 | 详情 | |
| (IV) | 68144 | tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate | C14H22N4O2 | 详情 | 详情 | |
| (V) | 68145 | tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate | C27H34BrN7O3 | 详情 | 详情 | |
| (VI) | 19760 | ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane | 97674-02-7 | C16H34OSn | 详情 | 详情 |
| (VII) | 61701 | tert-butyl 4-(6-((8-cyclopentyl-6-(1-ethoxyvinyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate | C31H41N7O4 | 详情 | 详情 |