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【结 构 式】

【分子编号】22776

【品名】(2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol

【CA登记号】

【 分 子 式 】C6H12F3NO

【 分 子 量 】171.1626296

【元素组成】C 42.1% H 7.07% F 33.3% N 8.18% O 9.35%
与该中间体有关的原料药合成路线共 3 条
合成路线1合成路线2合成路线3

合成路线1

该中间体在本合成路线中的序号：(VII)

Removal of the N-(benzyloxycarbonyl) group from the protected dipeptide (I) by catalytic hydrogenolysis provided the dipeptide Val-Pro-O-t-Bu (II), which was N-acylated with anisoyl chloride (III) to afford anisoyl dipeptide (IV). The tert-butyl ester group of (IV) was then cleaved using trifluoroacetic acid to afford (VI). Alternatively, the intermediate (VI) could be obtained from unprotected Val-Pro-OH (V) by treatment with trimethylsilyl chloride and subsequent acylation of the silyl ester with acid chloride (III). The anisoyl dipeptide (VI) was further condensed with racemic threo-aminoalcohol (VII), either in the presence of EDC and HOBt or via conversion to the mixed anhydride with isobutyl chloroformate, to furnish the corresponding peptide amide (VIII) as a diastereomeric mixture. Subsequent oxidation of the alcohol group of (VIII) to the trifluoromethyl ketone (IX) was carried out using a modified Pfitzner-Moffat procedure in the presence of DMSO, EDC and dichloroacetic acid or with KMnO4 in basic medium. The desired S,S,S-isomer was isolated from the epimeric mixture after repeated crystallizations.

参考文献 中间体
合成目标
【1】 Bohnert, C.M.; Bernstein, P.R.; Veale, C.A.; et al.; Orally active trifluoromethyl ketone inhibitors of. J Med Chem 1997, 40, 20, 3173.
【2】 Pegg, S.J.; Sependa, G.J.; Davies, E.P.; Veale, C.A. (AstraZeneca plc); Diastereomeric pure trifluoromethyl ketone peptide. EP 0743953; JP 1997508902; US 5739157; US 6037363; WO 9521855 .
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) 22770 tert-butyl (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate C22H32N2O5 详情 详情
(II) 22771 tert-butyl (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-2-pyrrolidinecarboxylate C14H26N2O3 详情 详情
(III) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(IV) 22773 tert-butyl (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-2-pyrrolidinecarboxylate C22H32N2O5 详情 详情
(V) 22774 (2S)-1-[(2S)-2-amino-3-methylbutanoyl]-2-pyrrolidinecarboxylic acid C10H18N2O3 详情 详情
(VI) 22775 (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-2-pyrrolidinecarboxylic acid C18H24N2O5 详情 详情
(VII) 22776 (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol C6H12F3NO 详情 详情
(VIII) 22777 (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)-2-pyrrolidinecarboxamide C24H34F3N3O5 详情 详情
(IX) 22778 (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)-2-pyrrolidinecarboxamide C24H32F3N3O5 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XVII)

An alternative synthesis has been reported employing pure (2R,3S)-aminoalcohol (XVII). Treatment of isobutyl iodide (X) with sodium nitrite in the presence of urea in DMF afforded 2-methyl-1-nitropropane (XI). Further condensation of fluoral hydrate (XII) with this nitrocompound using K2CO3 provided a diastereomeric mixture of nitroalcohols (XIII). Fractional crystallization from pentane yielded the racemic threo-nitroalcohol (XIV), which was converted to the alredy reported racemic threo-aminoalcohol (VII) by catalytic hydrogenation. This compound (VII) was treated with triphosgene and NaOH to produce oxazolidone (XV). After conversion of (XV) to the corresponding lithium salt with BuLi at -70 C, its condensation with (-)-menthyl chloroformate gave a diastereomeric mixture of carbamates, from which the desired isomer (XVI) was isolated by fractional crystallization from ether/hexane. The chiral auxiliary and the oxazolidone ring were then cleaved by hydrolysis with KOH yielding the (2R,3S)-aminoalcohol (XVII)(1). The coupling of (XVII) with the amino protected dipeptide (XVIII) (obtained by treatment of peptide (I) with trifluoroacetic acid) afforded dipeptide amide (XIX), The N-(benzyloxycarbonyl) protecting group of (XIX) was subsequently removed by catalytic hydrogenation, and the resulting amino compound was condensed with anisoyl chloride (III) to furnish the anisoyl dipeptide (XX). Finally, oxidation of the alcohol group of (XX) using the modified Pfitner-Moffat procedure produced some epimerization of the resulting ketone, the oxidation with KMnO4 in the presence of NaOH yielded the target S,S,S-peptide.

参考文献 中间体
合成目标
【1】 Bohnert, C.M.; Bernstein, P.R.; Veale, C.A.; et al.; Orally active trifluoromethyl ketone inhibitors of. J Med Chem 1997, 40, 20, 3173.
【2】 Pegg, S.J.; Sependa, G.J.; Davies, E.P.; Veale, C.A. (AstraZeneca plc); Diastereomeric pure trifluoromethyl ketone peptide. EP 0743953; JP 1997508902; US 5739157; US 6037363; WO 9521855 .
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) 22770 tert-butyl (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate C22H32N2O5 详情 详情
(III) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(VII) 22776 (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol C6H12F3NO 详情 详情
(X) 18168 1-iodo-2-methylpropane 513-38-2 C4H9I 详情 详情
(XI) 11782 2-Methyl-1-nitropropane C4H9NO2 详情 详情
(XII) 22781 2,2,2-trifluoro-1,1-ethanediol 421-53-4 C2H3F3O2 详情 详情
(XIII) 11783 1,1,1-Trifluoro-4-methyl-3-nitro-2-pentanol C6H10F3NO3 详情 详情
(XIV) 22783 (2R,3S)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol C6H10F3NO3 详情 详情
(XV) 22784 (4S,5R)-4-isopropyl-5-(trifluoromethyl)-1,3-oxazolidin-2-one C7H10F3NO2 详情 详情
(XVI) 22785 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (4S,5R)-4-isopropyl-2-oxo-5-(trifluoromethyl)-1,3-oxazolidine-3-carboxylate C18H28F3NO4 详情 详情
(XVII) 22776 (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol C6H12F3NO 详情 详情
(XVIII) 22787 (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid C18H24N2O5 详情 详情
(XIX) 22788 benzyl (1S)-2-methyl-1-[[(2S)-2-([[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino]carbonyl)pyrrolidinyl]carbonyl]propylcarbamate C24H34F3N3O5 详情 详情
(XX) 22789 (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-N-[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]-2-pyrrolidinecarboxamide C24H34F3N3O5 详情 详情

合成路线3

该中间体在本合成路线中的序号：(VII)

An alternative synthesis has been reported employing pure (2R,3S)-aminoalcohol (XVII). Treatment of isobutyl iodide (X) with sodium nitrite in the presence of urea in DMF afforded 2-methyl-1-nitropropane (XI). Further condensation of fluoral hydrate (XII) with this nitrocompound using K2CO3 provided a diastereomeric mixture of nitroalcohols (XIII). Fractional crystallization from pentane yielded the racemic threo-nitroalcohol (XIV), which was converted to the alredy reported racemic threo-aminoalcohol (VII) by catalytic hydrogenation. This compound (VII) was treated with triphosgene and NaOH to produce oxazolidone (XV). After conversion of (XV) to the corresponding lithium salt with BuLi at -70 C, its condensation with (-)-menthyl chloroformate gave a diastereomeric mixture of carbamates, from which the desired isomer (XVI) was isolated by fractional crystallization from ether/hexane. The chiral auxiliary and the oxazolidone ring were then cleaved by hydrolysis with KOH yielding the (2R,3S)-aminoalcohol (XVII)(1). The coupling of (XVII) with the amino protected dipeptide (XVIII) (obtained by treatment of peptide (I) with trifluoroacetic acid) afforded dipeptide amide (XIX), The N-(benzyloxycarbonyl) protecting group of (XIX) was subsequently removed by catalytic hydrogenation, and the resulting amino compound was condensed with anisoyl chloride (III) to furnish the anisoyl dipeptide (XX). Finally, oxidation of the alcohol group of (XX) using the modified Pfitner-Moffat procedure produced some epimerization of the resulting ketone, the oxidation with KMnO4 in the presence of NaOH yielded the target S,S,S-peptide.

参考文献 中间体
合成目标
【1】 Bohnert, C.M.; Bernstein, P.R.; Veale, C.A.; et al.; Orally active trifluoromethyl ketone inhibitors of. J Med Chem 1997, 40, 20, 3173.
【2】 Pegg, S.J.; Sependa, G.J.; Davies, E.P.; Veale, C.A. (AstraZeneca plc); Diastereomeric pure trifluoromethyl ketone peptide. EP 0743953; JP 1997508902; US 5739157; US 6037363; WO 9521855 .
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) 22770 tert-butyl (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylate C22H32N2O5 详情 详情
(III) 22671 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride 100-07-2 C8H7ClO2 详情 详情
(VII) 22776 (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol C6H12F3NO 详情 详情
(X) 18168 1-iodo-2-methylpropane 513-38-2 C4H9I 详情 详情
(XI) 11782 2-Methyl-1-nitropropane C4H9NO2 详情 详情
(XII) 22781 2,2,2-trifluoro-1,1-ethanediol 421-53-4 C2H3F3O2 详情 详情
(XIII) 11783 1,1,1-Trifluoro-4-methyl-3-nitro-2-pentanol C6H10F3NO3 详情 详情
(XIV) 22783 (2R,3S)-1,1,1-trifluoro-4-methyl-3-nitro-2-pentanol C6H10F3NO3 详情 详情
(XV) 22784 (4S,5R)-4-isopropyl-5-(trifluoromethyl)-1,3-oxazolidin-2-one C7H10F3NO2 详情 详情
(XVI) 22785 (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (4S,5R)-4-isopropyl-2-oxo-5-(trifluoromethyl)-1,3-oxazolidine-3-carboxylate C18H28F3NO4 详情 详情
(XVII) 22776 (2R,3S)-3-amino-1,1,1-trifluoro-4-methyl-2-pentanol C6H12F3NO 详情 详情
(XVIII) 22787 (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)-2-pyrrolidinecarboxylic acid C18H24N2O5 详情 详情
(XIX) 22788 benzyl (1S)-2-methyl-1-[[(2S)-2-([[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]amino]carbonyl)pyrrolidinyl]carbonyl]propylcarbamate C24H34F3N3O5 详情 详情
(XX) 22789 (2S)-1-[(2S)-2-[(4-methoxybenzoyl)amino]-3-methylbutanoyl]-N-[(1S,2R)-3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl]-2-pyrrolidinecarboxamide C24H34F3N3O5 详情 详情
Extended Information