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【结 构 式】

【分子编号】27024

【品名】(2R,4R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide

【CA登记号】

【 分 子 式 】C35H46N2O3S

【 分 子 量 】574.82792

【元素组成】C 73.13% H 8.07% N 4.87% O 8.35% S 5.58%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VIII)

The alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is iodinated with I2, KI, KHCO3 with simultaneous cyclization yielding (R,R)-5-(iodomethyl)-3-isobutyltetrahydrofuran-2-one (IV). The condensation of (IV) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid gives (R,R)-3-isobutyl-5-(tritylsulfanylmethyl)tetrahydrofuran-2-one (V). The ring opening of (V) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives (R,R)-4-(tert-butyldimethylsilyloxy)-2-isobutyl-5-(tritylsulfanyl)pentanoic acid (VI), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(R)-hydroxy-5-(triphenylmethylsulfanyl)pen-tanamido]-N,3,3-trimethylbutyramide (VIII). Finally, this compound is detritylated with trifluoroacetic acid (TFA) to afford the target compound.

1 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
42235 Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC 2942-58-7 C5H10NO3P 详情 详情
(I) 25391 (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene;allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 26985 (2R)-2-isobutyl-4-pentenoic acid C9H16O2 详情 详情
(IV) 27021 (3R,5R)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone C9H15IO2 详情 详情
(V) 27022 (3R,5R)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone C28H30O2S 详情 详情
(VI) 27023 (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid C34H46O3SSi 详情 详情
(VII) 18843 (2S)-2-amino-N,3,3-trimethylbutanamide 89226-12-0 C7H16N2O 详情 详情
(VIII) 27024 (2R,4R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide C35H46N2O3S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VIII)

The alkylation of 4(S)-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one (I) with allyl bromide (II) by means of lithium diisopro-pylamide (LDA), followed by hydrolysis with LiOOH gives the chiral pentenoic acid (III), which is iodinated with I2, KI, KHCO3 with simultaneous cyclization yielding (R,R)-5-(iodomethyl)-3-isobutyltetrahydrofuran-2-one (IV). The condensation of (IV) with thioacetic acid by means of NaH, followed by a reductive cleavage and tritylation with triphenylmethanol and trifluoroacetic acid gives (R,R)-3-isobutyl-5-(tritylsulfanylmethyl)tetrahydrofuran-2-one (V). The ring opening of (V) with NaOH, follwed by silylation with tert-butyldimethylsilyl chloride gives (R,R)-4-(tert-butyldimethylsilyloxy)-2-isobutyl-5-(tritylsulfanyl)pentanoic acid (VI), which is condensed with 2(S)-amino-N,3,3-trimethylbutyramide (VII) by means of cyanophosphonic acid diethyl ester and desilylated with tetrabutylammonium fluoride to yield 2(S)-[2(R)-isobutyl-4-(R)-hydroxy-5-(triphenylmethylsulfanyl)pen-tanamido]-N,3,3-trimethylbutyramide (VIII). Finally, compound (VIII) is oxidized with TFA, pyridine, DMSO and EDC, and detritylated with TFA to give the target compound.

1 Levin, J.I.; DiJoseph, J.F.; Killar, L.M.; Sharr, M.A.; Skotnicki, J.S.; Patel, D.V.; Xiao, X.-Y.; Shi, L.; Navre, M.; Campbell, D.A.; The asymmetric synthesis and in vitro characterization of succinyl mercaptoalcohol and mercaptoketone inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 1998, 8, 10, 1163.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
42235 Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC 2942-58-7 C5H10NO3P 详情 详情
(I) 25391 (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one C16H21NO3 详情 详情
(II) 11463 3-Bromo-1-propene; 3-Bromopropene;allyl bromide 106-95-6 C3H5Br 详情 详情
(III) 26985 (2R)-2-isobutyl-4-pentenoic acid C9H16O2 详情 详情
(IV) 27021 (3R,5R)-5-(iodomethyl)-3-isobutyldihydro-2(3H)-furanone C9H15IO2 详情 详情
(V) 27022 (3R,5R)-3-isobutyl-5-[(tritylsulfanyl)methyl]dihydro-2(3H)-furanone C28H30O2S 详情 详情
(VI) 27023 (2R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-isobutyl-5-(tritylsulfanyl)pentanoic acid C34H46O3SSi 详情 详情
(VII) 18843 (2S)-2-amino-N,3,3-trimethylbutanamide 89226-12-0 C7H16N2O 详情 详情
(VIII) 27024 (2R,4R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-4-hydroxy-2-isobutyl-5-(tritylsulfanyl)pentanamide C35H46N2O3S 详情 详情
Extended Information