|
【结 构 式】 
|
【分子编号】25556 【品名】N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-benzyl-N-(methoxymethyl)(trimethylsilyl)methanamine 【CA登记号】1871-96-1 |
【 分 子 式 】C13H23NOSi 【 分 子 量 】237.41726 【元素组成】C 65.77% H 9.76% N 5.9% O 6.74% Si 11.83% |
合成路线1
该中间体在本合成路线中的序号：(II)The 1,3-dipolar addition of the unsaturated ester (I) with tertiary amine (II) by means of TFA gives the trans pyrrolidinecarboxylic acid methyl ester (III), which is hydrolyzed with NaOH to the corresponding racemic trans free acid (IV). The optical resolution of (IV) with (R)-alpha-methylbenzylamine affords the (2S,3S)-(IV), which is treated with SOCl2 in dichloromethane giving the acyl chloride (V). The reaction of (V) with ammonia yields the amide (VI), which is reduced with LiAlH4 in THF providing the aminomethyl pyrrolidine (VII). The protection of the primary amino group of (VII) with tert-butoxycarbonyl anhydride gives the carbamate (VIII), which is debenzylated by hydrogenolysis with H2 over Pd/C affording the pyrrolidine (IX). The condensation of (IX) with the protected quinolonecarboxylic acid (X) by means of triethylamine in DMSO gives the amino protected quinolone (XI), which is finally deprotected with trifluoroacetic acid as usual.
| 【1】 Fukui, H.; Shibata, T.; Naito, T.; Nakano, J.; Maejima, T.; Senda, H.; Iwatani, W.; Tatsumi, Y.; Suda, M.; Arika, T.; Synthesis and antibacterial activity of novel 7-(3-substituted-3 or 4-trifluoromethyl-1-pyrrolidinyl)-8-methoxyfluoroquinolones. Bioorg Med Chem Lett 1998, 8, 20, 2833. |
| 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) | 25555 | ethyl (E)-4,4,4-trifluoro-2-butenoate | 74499-23-3 | C6H7F3O2 | 详情 | 详情 |
| (II) | 25556 | N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-benzyl-N-(methoxymethyl)(trimethylsilyl)methanamine | 1871-96-1 | C13H23NOSi | 详情 | 详情 |
| (III) | 25557 | methyl (3S,4S)-1-benzyl-4-(trifluoromethyl)-3-pyrrolidinecarboxylate | C14H16F3NO2 | 详情 | 详情 | |
| (IV) | 25558 | (3S,4S)-1-benzyl-4-(trifluoromethyl)-3-pyrrolidinecarboxylic acid | C13H14F3NO2 | 详情 | 详情 | |
| (V) | 25559 | (3S,4S)-1-benzyl-4-(trifluoromethyl)-3-pyrrolidinecarbonyl chloride | C13H13ClF3NO | 详情 | 详情 | |
| (VI) | 25560 | (3S,4S)-1-benzyl-4-(trifluoromethyl)-3-pyrrolidinecarboxamide | C13H15F3N2O | 详情 | 详情 | |
| (VII) | 25561 | [(3R,4S)-1-benzyl-4-(trifluoromethyl)pyrrolidinyl]methanamine; [(3R,4S)-1-benzyl-4-(trifluoromethyl)pyrrolidinyl]methylamine | C13H17F3N2 | 详情 | 详情 | |
| (VIII) | 25562 | tert-butyl [(3R,4S)-1-benzyl-4-(trifluoromethyl)pyrrolidinyl]methylcarbamate | C18H25F3N2O2 | 详情 | 详情 | |
| (IX) | 25563 | tert-butyl [(3S,4S)-4-(trifluoromethyl)pyrrolidinyl]methylcarbamate | C11H19F3N2O2 | 详情 | 详情 | |
| (X) | 25564 | 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid boron difluoride compkex | C14H10BF4NO4 | 详情 | 详情 | |
| (XI) | 25565 | 7-[(3R,4S)-3-[[(tert-butoxycarbonyl)amino]methyl]-4-(trifluoromethyl)pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C25H29F4N3O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)m-Fluorocinnamic acid (I) is coupled to (S)-4-benzyloxazolidin-2-one (II), via the corresponding mixed anhydride with pivaloyl chloride, to furnish the N-cinnamoyl oxazolidinone (III). Cycloaddition of (III) with N-methoxymethyl-N-trimethylsilylmethyl benzylamine (IV) in the presence of trifluoroacetic acid produces a mixture of the diastereoisomeric pyrrolidines (V) and (VI), separable by column chromatography. The desired isomer (V) is then reduced by means of LiAlH4 to the primary alcohol (VII), which is further protected by silylation with t-butyldimethylsilyl chloride. The resultant silyl ether (VIII) is then subjected to benzyl group cleavage under transfer hydrogenation conditions, producing pyrrolidine (IX) (1).
| 【1】 Mills, S.G.; Kim, D.; Hale, J.; MacCoss, M.; Berk, S.; Chapman, K.; Lynch, C.; Caldwell, C.; Willoughby, C.; Rosauer, K. (Merck & Co., Inc.); Pyrrolidine modulators of chemokine receptor activity. US 6265434; WO 0059503 . |
| 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) | 63980 | m-Fluorocinnamic acid; (E)-3-(3-fluorophenyl)-2-propenoic acid | C9H7FO2 | 详情 | 详情 | |
| (II) | 25351 | (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone | 102029-44-7 | C10H11NO2 | 详情 | 详情 |
| (III) | 63983 | (4S)-4-benzyl-3-[(E)-3-(3-fluorophenyl)-2-propenoyl]-1,3-oxazolidin-2-one | C19H16FNO3 | 详情 | 详情 | |
| (IV) | 25556 | N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-benzyl-N-(methoxymethyl)(trimethylsilyl)methanamine | 1871-96-1 | C13H23NOSi | 详情 | 详情 |
| (V) | 63985 | (4S)-4-benzyl-3-{[(3R,4S)-1-benzyl-4-(3-fluorophenyl)pyrrolidinyl]carbonyl}-1,3-oxazolidin-2-one | C28H27FN2O3 | 详情 | 详情 | |
| (VI) | 63984 | (4S)-4-benzyl-3-{[(3S,4R)-1-benzyl-4-(3-fluorophenyl)pyrrolidinyl]carbonyl}-1,3-oxazolidin-2-one | C28H27FN2O3 | 详情 | 详情 | |
| (VII) | 63986 | [(3R,4S)-1-benzyl-4-(3-fluorophenyl)pyrrolidinyl]methanol | C18H20FNO | 详情 | 详情 | |
| (VIII) | 65130 | (3R,4S)-1-benzyl-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-fluorophenyl)pyrrolidine; [(3R,4S)-1-benzyl-4-(3-fluorophenyl)pyrrolidinyl]methyl tert-butyl(dimethyl)silyl ether | C24H34FNOSi | 详情 | 详情 | |
| (IX) | 63988 | (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-fluorophenyl)pyrrolidine; tert-butyl(dimethyl)silyl [(3R,4S)-4-(3-fluorophenyl)pyrrolidinyl]methyl ether | C17H28FNOSi | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)3-Fluorocinnamic acid (I) is activated as the mixed anhydride (II) with pivaloyl chloride and subsequently coupled to the lithium anion of (S)-4-benzyloxazolidin-2-one (III) to provide the N-acyl oxazolidinone (IV). Cycloaddition of the cinnamoyl derivative (IV) with N-methoxymethyl-N-trimethylsilylmethyl benzylamine (V) in the presence of trifluoroacetic acid gives rise to a diastereomeric mixture of trans-pyrrolidines (VI) and (VII), separable by column chromatography. The desired isomer (VII) is then reduced by LiAlH4 to alcohol (VIII), which is further protected as the silyl ether (IX). Debenzylation of (IX) by transfer hydrogenolysis with ammonium formate and Pearlman's catalyst furnishes pyrrolidine (X).
| 【1】 Mills, S.G.; Kim, D.; Hale, J.; MacCoss, M.; Berk, S.; Chapman, K.; Lynch, C.; Caldwell, C.; Willoughby, C.; Kim, R.M. (Merck & Co., Inc.); Pyrrolidine modulators of chemokine receptor activity. US 6498161; WO 0059498 . |
| 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) | 63980 | m-Fluorocinnamic acid; (E)-3-(3-fluorophenyl)-2-propenoic acid | C9H7FO2 | 详情 | 详情 | |
| (II) | 63981 | 1,1-dimethylpropanoic (E)-2-(3-fluorophenyl)-2-propenoic anhydride | C14H15FO3 | 详情 | 详情 | |
| (III) | 63982 | (4S)-4-benzyl-1,3-oxazolidin-2-one | C10H11NO2 | 详情 | 详情 | |
| (IV) | 63983 | (4S)-4-benzyl-3-[(E)-3-(3-fluorophenyl)-2-propenoyl]-1,3-oxazolidin-2-one | C19H16FNO3 | 详情 | 详情 | |
| (V) | 25556 | N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-benzyl-N-(methoxymethyl)(trimethylsilyl)methanamine | 1871-96-1 | C13H23NOSi | 详情 | 详情 |
| (VI) | 63984 | (4S)-4-benzyl-3-{[(3S,4R)-1-benzyl-4-(3-fluorophenyl)pyrrolidinyl]carbonyl}-1,3-oxazolidin-2-one | C28H27FN2O3 | 详情 | 详情 | |
| (VII) | 63985 | (4S)-4-benzyl-3-{[(3R,4S)-1-benzyl-4-(3-fluorophenyl)pyrrolidinyl]carbonyl}-1,3-oxazolidin-2-one | C28H27FN2O3 | 详情 | 详情 | |
| (VIII) | 63986 | [(3R,4S)-1-benzyl-4-(3-fluorophenyl)pyrrolidinyl]methanol | C18H20FNO | 详情 | 详情 | |
| (IX) | 63987 | 1-[(1S,2S)-4-benzyl-2-propylcyclopentyl]-3-methylbenzene | C22H28 | 详情 | 详情 | |
| (X) | 63988 | (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-fluorophenyl)pyrrolidine; tert-butyl(dimethyl)silyl [(3R,4S)-4-(3-fluorophenyl)pyrrolidinyl]methyl ether | C17H28FNOSi | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Acid-catalyzed cycloaddition of the chiral acryloyl oxazolidine derivative (I) with amine (II) affords a diastereomeric mixture of trans pyrrolidines (III) and (IV). The desired isomer (IV) is then reduced by DIBAL to the intermediate aldehyde (V)
| 【1】 Pyrrolidine antagonists of the CCR3 chemokine receptor. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 250. |
| 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) | 63496 | 4-(phenylmethyl)-3-[3-(3-thiophenyl)acryloyl]-1,3-oxazolidin-2-one | C17H15NO3S | 详情 | 详情 | |
| (II) | 25556 | N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine; N-benzyl-N-(methoxymethyl)(trimethylsilyl)methanamine | 1871-96-1 | C13H23NOSi | 详情 | 详情 |
| (III) | 63498 | 4-(phenylmethyl)-3-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]carbonyl}-1,3-oxazolidin-2-one | C26H26N2O3S | 详情 | 详情 | |
| (IV) | 63499 | 4-(phenylmethyl)-3-{[1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinyl]carbonyl}-1,3-oxazolidin-2-one | C26H26N2O3S | 详情 | 详情 | |
| (V) | 63500 | 1-(phenylmethyl)-4-(3-thiophenyl)-3-pyrrolidinecarbaldehyde | C16H17NOS | 详情 | 详情 |