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【结 构 式】 
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【分子编号】63988 【品名】(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 【CA登记号】 |
【 分 子 式 】C17H28FNOSi 【 分 子 量 】309.4993632 【元素组成】C 65.97% H 9.12% F 6.14% N 4.53% O 5.17% Si 9.07% |
合成路线1
该中间体在本合成路线中的序号：(IX)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2
该中间体在本合成路线中的序号：(IX)Diazotization of L-cyclopropylalanine (X) with NaNO2/H2SO4 gives rise to the chiral hydroxy acid (XI). Subsequent treatment of hydroxyacid (XI) with p-methoxybenzyl chloride (XII) in the presence of Et3N furnishes the corresponding p-methoxybenzyl ester (XIII). Hydroxy ester (XIII) is then converted to triflate (XIV), which is further condensed with pyrrolidine (IX) to yield amino ester (XV). Desilylation of (XV) with tetrabutylammonium fluoride affords alcohol (XVI). This is then subjected to Swern oxidation to provide aldehyde (XVII) (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 |
|---|---|---|---|---|---|---|
| (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 | |
| (X) | 65131 | (2S)-2-amino-3-cyclopropylpropanoic acid | C6H11NO2 | 详情 | 详情 | |
| (XI) | 65132 | (2S)-3-cyclopropyl-2-hydroxypropanoic acid | C6H10O3 | 详情 | 详情 | |
| (XII) | 11910 | 4-Methoxybenzyl chloride; 1-(Chloromethyl)-4-methoxybenzene; alpha-Chloro-4-methoxytoluene; 4-(Chloromethyl)phenyl methyl ether | 824-94-2 | C8H9ClO | 详情 | 详情 |
| (XIII) | 65133 | 4-methoxybenzyl (2S)-3-cyclopropyl-2-hydroxypropanoate | C14H18O4 | 详情 | 详情 | |
| (XIV) | 65134 | 4-methoxybenzyl (2S)-3-cyclopropyl-2-{[(trifluoromethyl)sulfonyl]oxy}propanoate | C15H17F3O6S | 详情 | 详情 | |
| (XV) | 65135 | 4-methoxybenzyl (2R)-2-[(3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-fluorophenyl)pyrrolidinyl]-3-cyclopropylpropanoate | C31H44FNO4Si | 详情 | 详情 | |
| (XVI) | 65136 | 4-methoxybenzyl (2R)-3-cyclopropyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-(hydroxymethyl)pyrrolidinyl]propanoate | C25H30FNO4 | 详情 | 详情 | |
| (XVII) | 65137 | 4-methoxybenzyl (2R)-3-cyclopropyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-formylpyrrolidinyl]propanoate | C25H28FNO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)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：(X)Condensation of oxalyl chloride (XI) with N,O-dimethylhydroxylamine produces N,N'-dimethyl-N,N'-dimethoxy oxamide (XII). This is then condensed with cyclobutylmethylmagnesium bromide (XIII) to afford the ketoamide (XIV). Asymmetric keto group reduction employing (R)-alpine borane leads to the (S)-alcohol (XV) in 91% enantiomeric excess. Hydrolysis of the N-methoxyamide function of (XV) to provide hydroxyacid (XVI) is then accomplished employing potassium tert-butoxide in the presence of the equimolecular amount of H2O in THF. Alkylation of hydroxyacid (XVI) with benzyl bromide and Et3N furnishes the corresponding benzyl ester (XVII). Treatment of (XVII) with trifluoromethanesulfonic anhydride gives rise to triflate (XVIII), which is further condensed with pyrrolidine (X) to produce (XIX). After desilylation of (XIX) with tetrabutylammonium fluoride, the resultant alcohol (XX) is oxidized to aldehyde (XXI) under Swern conditions.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XI) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (XII) | 63989 | N-methoxy-2-[methoxy(methyl)amino]-N-methyl-2-oxoacetamide | C6H12N2O4 | 详情 | 详情 | |
| (XIII) | 63990 | bromo(cyclobutylmethyl)magnesium | C5H9BrMg | 详情 | 详情 | |
| (XIV) | 63991 | 3-cyclobutyl-N-methoxy-N-methyl-2-oxopropanamide | C9H15NO3 | 详情 | 详情 | |
| (XV) | 63992 | (2S)-3-cyclobutyl-2-hydroxy-N-methoxy-N-methylpropanamide | C9H17NO3 | 详情 | 详情 | |
| (XVI) | 63993 | (2S)-3-cyclobutyl-2-hydroxypropanoic acid | C7H12O3 | 详情 | 详情 | |
| (XVII) | 63994 | benzyl (2S)-3-cyclobutyl-2-hydroxypropanoate | C14H18O3 | 详情 | 详情 | |
| (XVIII) | 63995 | benzyl (2S)-3-cyclobutyl-2-{[(trifluoromethyl)sulfonyl]oxy}propanoate | C15H17F3O5S | 详情 | 详情 | |
| (XIX) | 63997 | benzyl (2R)-2-[(3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(3-fluorophenyl)pyrrolidinyl]-3-cyclobutylpropanoate | C31H44FNO3Si | 详情 | 详情 | |
| (XX) | 63996 | benzyl (2R)-3-cyclobutyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-(hydroxymethyl)pyrrolidinyl]propanoate | C25H30FNO3 | 详情 | 详情 | |
| (XXI) | 63998 | benzyl (2R)-3-cyclobutyl-2-[(3S,4R)-3-(3-fluorophenyl)-4-formylpyrrolidinyl]propanoate | C25H28FNO3 | 详情 | 详情 |