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【结 构 式】

【分子编号】45888

【品名】(2R)-2-[[(benzyloxy)amino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide

【CA登记号】

【 分 子 式 】C22H37N3O3

【 分 子 量 】391.5542

【元素组成】C 67.49% H 9.52% N 10.73% O 12.26%

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:(IX)

Claisen reaction between ethyl caproate (I) and ethyl formate (II) in the presence of NaOEt affords formyl derivative (III), which is then condensed with O-benzyl hydroxylamine hydrochloride (IV) by means of NaOAc in EtOH/H2O to yield derivative (V). Hydrolysis of the ethyl ester moiety of (V) by treatment with aqueous NaOH in MeOH provides carboxylic acid (VI), which is coupled to tert-leucine N,N-dimethylamide (VII) by means of EDC and HOAt to furnish compound (VIII). Reduction of the oxime moiety of (VIII) with NaCNBH3 in HOAc affords a mixture of diastereoisomers from which (R)-(IX) is separated by flash chromatography. Finally, treatment of (R)-(IX) with N-formyl-benzotriazole (HCOBt) in THF provides formamide (X), whose benzyl group is then removed by hydrogenation over Pd/C in MeOH.

1 Spavold, Z.M.; Launchbury, S.; Clements, J.M.; Hunter, M.G.; Davies, S.J.; Pratt, L.M.; Beckett, R.P.; Whittaker, M. (British Biotech Pharmaceuticals Ltd.); Antibacterial agents. WO 9939704 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIIIa) 45887 (2R)-2-[[(benzyloxy)imino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide C22H35N3O3 详情 详情
(VIIIb) 45890 (2S)-2-[[(benzyloxy)imino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide C22H35N3O3 详情 详情
(I) 51702 Ethyl caproate; Ethyl n-Caproate; Caproic acid ethyl ester; n-Caproic acid ethylester; Capronic Ether; Isoamyl acetate; Hexanoic acid ethyl ester; Ethyl hexanoate 123-66-0 C8H16O2 详情 详情
(II) 16602 ethyl formate 109-94-4 C3H6O2 详情 详情
(III) 45886 (2S)-2-amino-N,N,3,3-tetramethylbutanamide C8H18N2O 详情 详情
(IV) 14640 O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene 622-33-3 C7H9NO 详情 详情
(V) 45884 ethyl 2-[[(benzyloxy)imino]methyl]hexanoate C16H23NO3 详情 详情
(VI) 45885 2-[[(benzyloxy)imino]methyl]hexanoic acid C14H19NO3 详情 详情
(VII) 45886 (2S)-2-amino-N,N,3,3-tetramethylbutanamide C8H18N2O 详情 详情
(IX) 45888 (2R)-2-[[(benzyloxy)amino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide C22H37N3O3 详情 详情
(X) 45889 (2R)-2-[[(benzyloxy)(formyl)amino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide C23H37N3O4 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IX)

Alternatively, compound (R)-(IX) can be obtained as follows: treatment of butylmalonic acid (XI) with formaldehyde (XII) in ethanol in the presence of piperidine provides 2-butyl acrylic acid (XIII), which is converted into oxazolidinone derivative (XVI) by first reaction with pivaloyl chloride (XIV) and Et3N in THF followed by treatment with derivative (XV) and BuLi in THF. Oxazolidinone (XVI) is then enantioselectively condensed with O-benzylhydroxylamine (XVII) and treated with p-TsOH to afford a single diastereoisomer (XVIII), which is then hydrolyzed with LiOH in THF to yield (XIX). Finally, hexanoic acid (XIX) is coupled to tert-Leucine-N,N-dimethylamide (VII) by means of EDC and HOBt in DMF.

1 Spavold, Z.M.; Launchbury, S.; Clements, J.M.; Hunter, M.G.; Davies, S.J.; Pratt, L.M.; Beckett, R.P.; Whittaker, M. (British Biotech Pharmaceuticals Ltd.); Antibacterial agents. WO 9939704 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 45886 (2S)-2-amino-N,N,3,3-tetramethylbutanamide C8H18N2O 详情 详情
(IX) 45888 (2R)-2-[[(benzyloxy)amino]methyl]-N-[(1S)-1-[(dimethylamino)carbonyl]-2,2-dimethylpropyl]hexanamide C22H37N3O3 详情 详情
(XI) 45891 2-butylmalonic acid 534-59-8 C7H12O4 详情 详情
(XII) 22075 Formaldehyde; Paraformaldehyde 1118-66-7 CH2O 详情 详情
(XIII) 45892 2-[(ethylsulfanyl)methyl]acrylic acid C6H10O2S 详情 详情
(XIV) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(XV) 45893 (4S)-4-benzyl-5,5-dimethyl-1,3-oxazolidin-2-one C12H15NO2 详情 详情
(XVI) 45894 (4S)-4-benzyl-3-[2-[(ethylsulfanyl)methyl]acryloyl]-5,5-dimethyl-1,3-oxazolidin-2-one C18H23NO3S 详情 详情
(XVII) 14640 O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene 622-33-3 C7H9NO 详情 详情
(XVIII) 45895 (4S)-4-benzyl-3-[(2R)-3-[(benzyloxy)amino]-2-[(ethylsulfanyl)methyl]propanoyl]-5,5-dimethyl-1,3-oxazolidin-2-one C25H32N2O4S 详情 详情
(XIX) 45897 3-[4-[2-(benzyloxy)ethoxy]phenyl]-2-ethoxypropanamide C20H25NO4 详情 详情
Extended Information