【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% |
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 |