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【结 构 式】

【分子编号】59950

【品名】(chloromethyl)(dimethyl)silyl isopropyl ether; (chloromethyl)(isopropoxy)dimethylsilane

【CA登记号】

【 分 子 式 】C6H15ClOSi

【 分 子 量 】166.7227

【元素组成】C 43.23% H 9.07% Cl 21.26% O 9.6% Si 16.85%

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:(XX)

The known chiral epoxide (IX) can be synthesized by several different ways shown in the following: 1) 2(S)-Acetoxypropionic acid (XII) is treated first with oxalyl chloride in DMF/CH2Cl2, and then the resultant acyl chloride is submitted to a Friedel-Crafts reaction with 1,3-difluorobenzene (XIII) by means of AlCl3 to provide a 1:1 mixture of a(S)-acetoxypropiophenone (XIV) and a(S)-hydroxy-propiophenone (XV). This mixture is treated with H2SO4 in MeOH to give the pure alcohol (XV). Tosylation of alcohol (XV) with p-toluenesulfonyl chloride in pyridine furnishes tosylate (XVI), which is converted into a(R)-hydroxypropiophenone (XVII) by an SN2 displacement reaction with LiOH in DMF/H2O. Reaction of the hydroxy group of (XVII) with 2,3-dihydropyran (XVIII) and pyridi-nium p-toluenesulfonate (PPTS) in CH2Cl2 gives the protected compound (XIX), which is converted into the silyl alcohol (XXI) by a Grignard reaction with (chloro-methyl)dimethylisopropoxysilane (XX) in the presence of Mg and a small amount of MeI. Oxidative desilylation of (XXI) by means of NaHCO3 and H2O2 in THF/MeOH, followed by hydrolysis with TsOH in MeOH, affords the triol (XXII), which is then mesylated with methanesulfonyl chloride in pyridine to provide the dimesylate (XXIII). Finally, nucleofilic substitution of one mesylate group of (XXIII) with 1H-1,2,4-triazole (XXIV) by means of NaH in DMF with concomitant epoxide formation affords the desired intermediate (IX).

1 Sorbera, L.A.; del Fresno, M.; Rabasseda, X.; CS-758. Drugs Fut 2003, 28, 3, 217.
2 Konos, T.; Miyaoka, T.; Tajima, Y.; Oida, S.; Triazole antifungals. III. Stereocontrolled synthesis of an optically active triazolylmethyloxirane precursor to antifungal oxazolodine derivatives. Chem Pharm Bull 1991, 39, 9, 2241.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IX) 31738 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole C12H11F2N3O 详情 详情
(XII) 10142 (2R)-2-(Acetoxy)propionic acid 18668-00-3 C5H8O4 详情 详情
(XIII) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(XIV) 59948 (1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl acetate C11H10F2O3 详情 详情
(XV) 45571 (2S)-1-(2,4-difluorophenyl)-2-hydroxy-1-propanone C9H8F2O2 详情 详情
(XVI) 59949 (1S)-2-(2,4-difluorophenyl)-1-methyl-2-oxoethyl 4-methylbenzenesulfonate C16H14F2O4S 详情 详情
(XVII) 13100 (2R)-1-(2,4-Difluorophenyl)-2-hydroxy-1-propanone C9H8F2O2 详情 详情
(XVIII) 13684 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran 110-87-2 C5H8O 详情 详情
(XIX) 13102 (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone C14H16F2O3 详情 详情
(XX) 59950 (chloromethyl)(dimethyl)silyl isopropyl ether; (chloromethyl)(isopropoxy)dimethylsilane C6H15ClOSi 详情 详情
(XXI) 59951 (2S,3R)-2-(2,4-difluorophenyl)-1-[isopropoxy(dimethyl)silyl]-3-(tetrahydro-2H-pyran-2-yloxy)-2-butanol C20H32F2O4Si 详情 详情
(XXII) 59952 (2R,3R)-2-(2,4-difluorophenyl)-1,2,3-butanetriol C10H12F2O3 详情 详情
(XXIII) 59953 (1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-[(methylsulfonyl)oxy]propyl methanesulfonate C12H16F2O7S2 详情 详情
(XXIV) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IX)

Coupling between epoxide (I) and amine (II) affords amino alcohol (III). The amino group of (III) is then protected with benzyl chloroformate to provide carbamate (IV). Removal of the N-Boc group of (IV) with trifluoroacetic acid yields amine (V), which is subsequently coupled with N-Boc-L-valine (VI) by means of TBTU to furnish amide (VII). After acidic Boc group cleavage in (VII), the resultant amine (VIII) is acylated by picolinic acid (IX) producing amide (X).

1 Noteberg, D.; et al.; New antimalarials: Design and synthesis of protease inhibitors with effect in cultured parasite-infected human erythrocytes. Drugs Fut 2002, 27, Suppl. A.
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) 23444 tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate C15H21NO3 详情 详情
(II) 58402 (2S)-2-amino-3-(4-bromophenyl)propanamide C9H11BrN2O 详情 详情
(III) 58396 tert-butyl (1S,2S)-3-{[(1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl]amino}-1-benzyl-2-hydroxypropylcarbamate C24H32BrN3O4 详情 详情
(IV) 58397 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl{(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl}carbamate C32H38BrN3O6 详情 详情
(V) 58398 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyl]carbamate C27H30BrN3O4 详情 详情
(VI) 19733 (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid C10H19NO4 详情 详情
(VII) 58399 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl[(2S,3S)-3-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoyl}amino)-2-hydroxy-4-phenylbutyl]carbamate C37H47BrN4O7 详情 详情
(VIII) 58400 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl((2S,3S)-3-{[(2S)-2-amino-3-methylbutanoyl]amino}-2-hydroxy-4-phenylbutyl)carbamate C32H39BrN4O5 详情 详情
(IX) 59950 (chloromethyl)(dimethyl)silyl isopropyl ether; (chloromethyl)(isopropoxy)dimethylsilane C6H15ClOSi 详情 详情
(X) 58401 benzyl (1S)-2-amino-1-(4-bromobenzyl)-2-oxoethyl[(2S,3S)-2-hydroxy-3-({(2S)-3-methyl-2-[(2-pyridinylcarbonyl)amino]butanoyl}amino)-4-phenylbutyl]carbamate C38H42BrN5O6 详情 详情
Extended Information