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【结 构 式】

【分子编号】13127

【品名】2-Bromopropionyl bromide; 2-Bromopropanoyl bromide

【CA登记号】563-76-8

【 分 子 式 】C3H4Br2O

【 分 子 量 】215.87216

【元素组成】C 16.69% H 1.87% Br 74.03% O 7.41%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(A)

Compound can be prepared in two different ways both starting from 2,6-xylidine (I): 1) By condensation of (I) with N-carbobenzoxyalanine (B) by means of dicyclohexylcarbodiimide in methylenechloride giving N-(carbobenzoxyalanyl)xylidine (II), which is then hydrogenated over Pd/C in ethanol - methylene chloride. 2) By condensation of (I) with 2-bromopropionyl bromide (A) by means of sodium acetate in acetic acid giving 2-bromo-2',6'-propionoxylidide (III), which is then treated with NH3 in alcohol water.

1 Boyes, R.N.; et al.; Propionamide derivative a method of making it and therapeutic compositions containing it. DE 2235745; FR 2147277; GB 1374367; NL 7210418 .
2 Boyes, R.N.; et al.; Primary amino acylanilides methods of making the same and use as antiarrhythmic drugs. DE 2400540; ES 422085; FR 2213065; GB 1461602; JP 49116034 .
3 Hillier, K.; Castaner, J.; Tocainide. Drugs Fut 1977, 2, 2, 141.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 13127 2-Bromopropionyl bromide; 2-Bromopropanoyl bromide 563-76-8 C3H4Br2O 详情 详情
(B) 61217 CBZ-DL-Alanine; 2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-DL-alanine; Carbobenzyloxy-DL-alanine 4132-86-9 C11H13NO4 详情 详情
(I) 17527 2,6-Xylidine; 2,6-Dimethylaniline; 2,6-Dimethylphenylamine 87-62-7 C8H11N 详情 详情
(II) 33595 benzyl 2-(2,6-dimethylanilino)-1-methyl-2-oxoethylcarbamate C19H22N2O3 详情 详情
(III) 33594 2-bromo-N-(2,6-dimethylphenyl)propanamide C11H14BrNO 详情 详情

合成路线2

该中间体在本合成路线中的序号:(II)

A new synthesis of the active (R,R)-isomer of SM-8668 has been reported: The Friedel-Crafts condensation of 1,3-difluorobenzene (I) with 2-bromopropionyl bromide (II) by means of AlCl3 gives the corresponding propiophenone (III), which is treated with sodium methylmercaptide to yield 2',4'-difluoro-2-(methylsulfanyl)propiophenone (IV). The reaction of (IV) with trimethylsulfoxonium chloride affords the epoxide (V) as a D,L-threo-mixture of isomers, which is treated with a chiral carboxylic acid (VI), giving the diastereomeric mixture of esters (VII). The separation of the isomers by column chromatography or fractional crystallization affords the (2R,3R)-isomer (VIII), which by hydrolysis with NaOH is converted to the diol (IX). The epoxidation of the diol (IX) with mesyl chloride, NaOH and benzyltriethylammonium chloride yields the (2R,3R)-epoxide (X), which is condensed with 1,2,4-triazole (XI) by means of NaOH to give the precursor (XII). Finally, this compound is oxidized with H2O2 and sodium tungstate.

1 Tanio, T.; Miyauchi, H.; Ohashi, N.; Synthesis and antifungal activities of optically active isomers of SM-8668. Bioorg Med Chem Lett 1995, 5, 9, 933.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(D,L-threo(V)) 13130 (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl methyl sulfide; (2R)-2-(2,4-Difluorophenyl)-2-[(1R)-1-(methylsulfanyl)ethyl]oxirane C11H12F2OS 详情 详情
(D,L-threo(VII) 13132 (2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-(methylsulfanyl)butyl acetate C13H16F2O3S 详情 详情
(I) 13095 m-Difluorobenzene; 1,3-Difluorobenzene 372-18-9 C6H4F2 详情 详情
(II) 13127 2-Bromopropionyl bromide; 2-Bromopropanoyl bromide 563-76-8 C3H4Br2O 详情 详情
(III) 13128 2-Bromo-1-(2,4-difluorophenyl)-1-propanone C9H7BrF2O 详情 详情
(IV) 13129 1-(2,4-Difluorophenyl)-2-(methylsulfanyl)-1-propanone C10H10F2OS 详情 详情
(IX) 13133 (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfanyl)-1,2-butanediol C11H14F2O2S 详情 详情
(X) 13130 (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl methyl sulfide; (2R)-2-(2,4-Difluorophenyl)-2-[(1R)-1-(methylsulfanyl)ethyl]oxirane C11H12F2OS 详情 详情
(XI) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(XII) 13108 (2R,3R)-2-(2,4-Difluorophenyl)-3-(methylsulfanyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol C13H15F2N3OS 详情 详情

合成路线3

该中间体在本合成路线中的序号:(XIV)

The reaction of 2-hydroxybenzamide (XI) with cyclohexanone (XII) by means of Ts-OH in toluene gives the spiranic benzoxazine (XIII), which is condensed with 2-bromopropionyl bromide (XIV) by means of pyridine in toluene, yielding the corresponding acylated benzoxazine (XV). The condensation of (XV) with chiral azetidinone (XVI) by means of Zn in refluxing THF affords the adduct (XVII), which is finally hydrolyzed with LiOH and H2O2 to furnish the target azetidinonepropionic acid (I).

1 Lu, X.; et al.; Process development on (3S,4S)-[(R)-1'((tert-butyldimethylsilyl)oxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone: 1-beta-methylcarbapanem key intermediate. Org Process Res Dev 2001, 5, 2, 186.
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) 30029 (2R)-2-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]propionic acid C14H27NO4Si 详情 详情
(XI) 14652 salicylamide 65-45-2 C7H7NO2 详情 详情
(XII) 11059 Cyclohexanone 108-94-1 C6H10O 详情 详情
(XIII) 46246   C13H15NO2 详情 详情
(XIV) 13127 2-Bromopropionyl bromide; 2-Bromopropanoyl bromide 563-76-8 C3H4Br2O 详情 详情
(XV) 37738 3-(2-Bromo-1-oxopropyl)-spiro[2H-1,3-benzoxazine-2,1'-cyclohexan]-4(3H)-one 158299-05-9 C16H18BrNO3 详情 详情
(XVI) 11687 (2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate C13H25NO4Si 详情 详情
(XVII) 46247   C27H40N2O5Si 详情 详情

合成路线4

该中间体在本合成路线中的序号:(XI)

4-Bromo-3-fluorotoluene (I) is converted into the Grignard reagent (II) with magnesium in boiling Et2O, and subsequently added to cyclopropylacetonitrile (III) to produce ketone (IV). Condensation of (IV) with hydroxylamine affords oxime (V), which is further alkylated with benzyl bromide to yield the O-benzyl oxime (VI). Asymmetric reduction of oxime (VI) with borane in the presence of the aminoalcohol chiral auxiliary (VII) provides the (S)-amine (VIII). Reaction of amine (VIII) with ammonium thiocyanate and benzoyl chloride, followed by treatment with hydrazine hydrate, gives rise to the thiourea (IX). Friedel-Crafts acylation of 4-chloro-2-methoxytoluene (X) with 2-bromopropionyl bromide (XI) employing AlCl3 furnishes the bromo ketone (XII). Then, condensation of thiourea (IX) with bromo ketone (XII) in the presence of Et3N in boiling EtOH gives rise to the aminothiazole (XIII). Finally, alkylation of the amino group of (XIII) with propargyl bromide (XIV) and NaH furnishes the title compound

1 Roger, P.; Gully, D.; Pradines, A.; Fontaine, E.; Geslin, M. (Sanofi-Synthelabo); Aminothiazole derivs. and their use as CRF receptor ligands. EP 1200419; FR 2796380; JP 2003505380; WO 0105776 .
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) 60397 4-bromo-2-fluoro-1-methylbenzene C7H6BrF 详情 详情
(II) 60398 bromo(3-fluoro-4-methylphenyl)magnesium C7H6BrFMg 详情 详情
(III) 16824 2-cyclopropylacetonitrile; Cyclopropylacetonitrile 6542-60-5 C5H7N 详情 详情
(IV) 60399 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-1-ethanone C12H13FO 详情 详情
(V) 60400 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-1-ethanone oxime C12H14FNO 详情 详情
(VI) 60401 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-1-ethanone O-benzyloxime C19H20FNO 详情 详情
(VII) 10103 (2R)-2-Amino-3-methyl-1,1-diphenyl-1-butanol 56755-20-5 (hydrochloride) C17H21NO 详情 详情
(VIII) 60402 (1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-1-ethanamine; (1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethylamine C12H16FN 详情 详情
(IX) 60403 N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]thiourea C13H17FN2S 详情 详情
(X) 60405 5-chloro-2-methylphenyl methyl ether; 4-chloro-2-methoxy-1-methylbenzene C8H9ClO 详情 详情
(XI) 13127 2-Bromopropionyl bromide; 2-Bromopropanoyl bromide 563-76-8 C3H4Br2O 详情 详情
(XII) 60404 2-bromo-1-(2-chloro-4-methoxy-5-methylphenyl)-1-propanone C11H12BrClO2 详情 详情
(XIII) 60406 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-1,3-thiazol-2-amine; N-[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methyl-1,3-thiazol-2-yl]-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]amine C24H26ClFN2OS 详情 详情
(XIV) 23634 acetylene 74-86-2 C2H2 详情 详情
Extended Information