|
【结 构 式】 
|
【分子编号】30839 【品名】(2S)-2-(6-methoxy-2-naphthyl)propionic acid;(S)-naproxen;(S)-6-Methoxy-alpha-methyl-2-naphthaleneacetic acid 【CA登记号】22204-53-1 |
【 分 子 式 】C14H14O3 【 分 子 量 】230.26336 【元素组成】C 73.03% H 6.13% O 20.84% |
合成路线1
该中间体在本合成路线中的序号：(S)(+)-(II)The synthesis of the intermediates, the chiral amines (R)(-)-1,2-dimethylpropylamine (R)(-)-(I) and (S)(+)-1,2-dimethylpropylamine (S)(+)-(I) has been performed as follows: (R)(-)-1,2-Dimethylpropylamine (R)(-)-(I): The reaction of racemic 1,2-dimethylpropylamine (rac)(I) with 2(S)-(6-methoxynaphthalen-2-yl)propionic acid (S)(+)-(II) (S-naproxen) in ethanol gives the ammonium salt (III) as a diastereomeric mixture from which the (R,S)-diastereomer is obtained by successive crystallizations. Finally, this diastereomer is treated with NaOH in water to obtain the target (R)(-)-amine (R)(-)-(I). (S)(+)-1,2-Dimethylpropylamine (S)(+)-(I): The reaction of racemic 1,2-dimethylpropylamine (rac)-(I) with 2(S)-hydroxy-2-phenylacetic acid (S)(+)-(IV) (S-mandelic acid) in ethanol gives the ammonium salt (V) as a diastereomeric mixture from which the (S,S)-diastereomer is obtained by successive crystallizations. Finally, this diastereomer is treated with NaOH in water to obtain the target (S)(+)-amine (S)(+)-(I).
| 【1】 de Tullio, P.; Khelili, S.; Lebrun, P.; et al.; Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2'-butylamino)-4H- and 3-(3'-methyl-2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers. Bioorg Med Chem 1999, 7, 8, 1513. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (S)(+)-(IV) | 12563 | (2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid | 17199-29-0 | C8H8O3 | 详情 | 详情 |
| (S)(+)-(II) | 30839 | (2S)-2-(6-methoxy-2-naphthyl)propionic acid;(S)-naproxen;(S)-6-Methoxy-alpha-methyl-2-naphthaleneacetic acid | 22204-53-1 | C14H14O3 | 详情 | 详情 |
| rac-(I) | 38919 | 1,2-dimethylpropylamine; 3-methyl-2-butanamine | C5H13N | 详情 | 详情 | |
| (R)(-)-(I) | 38922 | (1R)-1,2-dimethylpropylamine; (2R)-3-methyl-2-butanamine | C5H13N | 详情 | 详情 | |
| (S)(+)-(I) | 38923 | (1S)-1,2-dimethylpropylamine; (2S)-3-methyl-2-butanamine | C5H13N | 详情 | 详情 | |
| (III) | 38920 | 3-methyl-2-butanaminium (2S)-2-(6-methoxy-2-naphthyl)propanoate | C19H27NO3 | 详情 | 详情 | |
| (V) | 38921 | 3-methyl-2-butanaminium (2S)-2-hydroxy-2-phenylethanoate | C13H21NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The title compound was prepared by coupling of 2-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethanol (I) with (S)-naproxen (II) by means of DCC and HOBt in acetonitrile.
| 【1】 Hellberg, M.R.; Namil, A.; Delgado, P.; David, K.C.; Kessler, T.L.; Graff, G.; Haggard, K.S.; Nixon, J.C.; Novel esters and amides of nonsteroidal antiinflammatory carboxylic acids as antioxidants and antiproliferative agents. J Med Chem 1999, 42, 2, 267. |
| 【2】 Hellberg, M.; Graff, G.; Gamache, D.A.; Nixon, J.C.; Garner, W.H. (Alcon Laboratories, Inc.); Esters and amides of non-steroidal anti-inflammatory carboxylic acids which may be used as anti-oxidants, 5-lipoxygenase inhibitors and non-steroidal anti-inflammatory products. EP 0799219; JP 1998511663; WO 9620187 . |
合成路线3
该中间体在本合成路线中的序号：(I)Chlorination of (S)-naproxen (I) with SOCl2 by means of Et3N in cyclohexane at 60 °C affords the acyl chloride (II) , which is condensed with 4-hydroxybutyl nitrate (III) in CH2Cl2 at 40 °C directly or after pretreatment of nitrate (III) with K2CO3 in CH2Cl2 or toluene, or CaCO3 or CaAl2Si2O8 in CH2Cl2 .
By treatment of (S)-naproxen (I) with KHCO3 in DMF followed by condensation with either 4-nitrooxybutyl tosylate (IVa) or 4-bromobutyl nitrate (IVb) in the presence of KI .
Esterification of (S)-naproxen (I) with 1,4-butanediol (V) in the presence of H2SO4 or NaHSO4·H2O in toluene at 80 °C gives (S)-naproxen 4-hydroxybutyl ester (VI), which is then converted to: a) the mesylate (VII) by mesylation with MsCl by means of Et3N or Nmethylmorpholine (NMM) in toluene; b) the tosylate (IXa) by reaction with tosyl chloride (VIIIa) by means of either DMAP and Et3N in toluene or NMM in EtOAc; and c) the chlorobenzenesulfonate (IXb) by treatment with 4-chlorobenzenesulfonyl chloride (VIIIb) by means of NMM in acetonitrile. Finally, esters (VII), (IXa) and (IXb) are nitrated with NaNO3 or LiNO3 in the presence or absence of Bu4NNO3 or Bu4NHSO4 in various solvents, such as N-methylpyrrolidone (NMP), sulfolane and tetramethylurea, among others .
| 【1】 Hack, A., Weingartner, G., Kramer, M. (NicOX SA). Process for preparing 1,4-butanediol mononitrate. WO 2009000723. |
| 【2】 Benedini, F., Tarquini, A., Castaldi, G., Oldani, E. (NicOX SA). Process for the preparation of naproxene nitroxyalkylesters. CA 2380116, EP 1200386, EP 1384707, JP 2003506425, US 2005119339, US 6700011, US 7238829, WO 2001010814. |
| 【3】 Del Soldato, P., Santus, G., Benedini, F. (NicOX SA). Process for preparing nitrooxyderivative of naproxen. CA 2497187, EP 1532098, JP 2005536558, US 2006173005, US 7199258, WO2004020384. |
| 【4】 Belli, A., Cannata, V., Villa, M., Hedberg, M., Westermark, A., Fonduca, T. (AstraZeneca AB). New process. CA 2465697, EP 1451140, JP 2005510557, US 2005234123, WO 2003045896. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 69254 | 4-(nitrooxy)butyl 4-methylbenzenesulfonate | C11H15NO6S | 详情 | 详情 | |
| (IVb) | 69255 | 4-bromobutyl nitrate;4-Nitrooxybutyl bromide;4-bromo-1-Butanol nitrate | 146563-40-8 | C4H8BrNO3 | 详情 | 详情 |
| (VIIIa) | 13975 | p-Toluenesulfonyl chloride;p-tosyl chloride;Toluene-4-sulfonyl chloride;4-Toluene sulfochloride;tosyl chloride; 4-Methylbenzenesulfonyl chloride | 98-59-9 | C7H7ClO2S | 详情 | 详情 |
| (VIIIb) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (IXa) | 69258 | (S)-4-(tosyloxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C25H28O6S | 详情 | 详情 | |
| (IXb) | 69259 | (S)-4-(((4-chlorophenyl)sulfonyl)oxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C24H25ClO6S | 详情 | 详情 | |
| (I) | 30839 | (2S)-2-(6-methoxy-2-naphthyl)propionic acid;(S)-naproxen;(S)-6-Methoxy-alpha-methyl-2-naphthaleneacetic acid | 22204-53-1 | C14H14O3 | 详情 | 详情 |
| (II) | 69252 | (S)-2-(6-methoxynaphthalen-2-yl)propanoyl chloride | C14H13ClO2 | 详情 | 详情 | |
| (III) | 69253 | 4-hydroxybutyl nitrate | C4H9NO4 | 详情 | 详情 | |
| (V) | 43160 | 1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol | 110-63-4 | C4H10O2 | 详情 | 详情 |
| (VI) | 69256 | (S)-4-hydroxybutyl 2-(6-methoxynaphthalen-2-yl)propanoate | C18H22O4 | 详情 | 详情 | |
| (VII) | 69257 | (S)-4-((methylsulfonyl)oxy)butyl 2-(6-methoxynaphthalen-2-yl)propanoate | C19H24O6S | 详情 | 详情 |