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【结 构 式】 
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【分子编号】32115 【品名】(2,4-dimethoxyphenyl)methanamine; 2,4-dimethoxybenzylamine 【CA登记号】20781-21-9 |
【 分 子 式 】C9H13NO2 【 分 子 量 】167.20776 【元素组成】C 64.65% H 7.84% N 8.38% O 19.14% |
合成路线1
该中间体在本合成路线中的序号：(XX)Pyrrolidinone (XXVI): The selective hydrolysis of the known methyl ester (XIV) with NaOH in methanol/water gives the corresponding carboxylic acid (XV), which is coupled with the chiral oxazolidinone (XVI) by means of pivaloyl chloride and Et3N in THF to yield the amide (XVII). The regiocontrolled alkylation of (XVII) with allyl iodide and NaN(SiMe3)2 in THF affords the allyl derivative (XVIII), which is submitted to ozonolysis in dichloromethane to provide the aldehyde (XIX). The condensation of (XIX) with 2,4-dimethoxybenzylamine (XX) yields imine (XXI), which by a reductive cyclization with NaBH3CN in THF/EtOH affords pyrrolidinone (XXII). Cleavage of the oxazolidine ring of (XXII) with TsOH in hot methanol gives the amino alcohol (XXIII), which is oxidized with oxalyl chloride in DMSO to the aldehyde (XXIV). Finally, this compound is condensed with triethyl phosphonoacetate (XXV) by means of NaN(SiMe3)2 in THF to provide the desired pyrrolidinone (XXVI).
| 【1】 Dragovich, P.S.; Prins, T.J.; Zhou, R.; et al.; Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as L-glutamine replacements. J Med Chem 1999, 42, 7, 1213. |
| 【2】 Graul, A.; Castañer, J.; AG-7088. Drugs Fut 2000, 25, 1, 9. |
| 【3】 Meyer, M.D.; Daanen, J.F.; Ehrlich, P.P.; Ralston, J.W. (Abbott Laboratories Inc.); 3-Phenylpyrrole alpha-1 adrenergic cpds.. WO 9957122 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 | |
| (XIV) | 32109 | tert-butyl (4S)-4-(3-methoxy-3-oxopropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C14H25NO5 | 详情 | 详情 | |
| (XV) | 32110 | 3-[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]propionic acid | C13H23NO5 | 详情 | 详情 | |
| (XVI) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (XVII) | 32111 | tert-butyl (4S)-4-[3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C23H32N2O6 | 详情 | 详情 | |
| (XVIII) | 32113 | tert-butyl (4S)-4-((2S)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-pentenyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C26H36N2O6 | 详情 | 详情 | |
| (XIX) | 32114 | tert-butyl (4S)-4-((2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-oxobutyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C25H34N2O7 | 详情 | 详情 | |
| (XX) | 32115 | (2,4-dimethoxyphenyl)methanamine; 2,4-dimethoxybenzylamine | 20781-21-9 | C9H13NO2 | 详情 | 详情 |
| (XXI) | 32116 | tert-butyl (4S)-4-[(2R)-2-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-[(2,4-dimethoxybenzyl)imino]butyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C34H45N3O8 | 详情 | 详情 | |
| (XXII) | 32117 | tert-butyl (4S)-4-[[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate | C24H36N2O6 | 详情 | 详情 | |
| (XXIII) | 32118 | tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-(hydroxymethyl)ethylcarbamate | C21H32N2O6 | 详情 | 详情 | |
| (XXIV) | 32119 | tert-butyl (1S)-2-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-1-formylethylcarbamate | C21H30N2O6 | 详情 | 详情 | |
| (XXV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (XXVI) | 32105 | ethyl (E,4S)-4-[(tert-butoxycarbonyl)amino]-5-[(3S)-1-(2,4-dimethoxybenzyl)-2-oxopyrrolidinyl]-2-pentenoate | C25H36N2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Pregnenolone acetate (I) was reduced with NaBH4 to give alcohol (II), which was subsequently protected as the silyl ether (III) by means of tert-butyl dimethylsilyl chloride and imidazole. Allylic oxidation of (III) with tert-butyl hydroperoxide and chromium hexacarbonyl produced the unsaturated ketone (IV). Addition of methylmagnesium chloride to (IV), with concomitant cleavage of the acetate ester, yielded diol (V), and further Oppenauer oxidation using cyclohexanone and aluminum triisopropoxide generated dienone (VI). Selective reduction of one double bond of (VI) to give enone (VII) was achieved by transfer hydrogenation with cyclohexene and Pd/C. Oxidative cleavage of the A ring of (VII) with NaIO4 and KMnO4 to give (VIII), followed by HF-promoted desilylation furnished the 7beta-methylpregnane seco-acid (IX). This was cyclized with 2,4-dimethoxybenzyl amine (X) affording the azasteroid (XI).
| 【1】 Harris, G.S.; Tolman, R.L.; Ellsworth, K.P.; Rasmusson, G.H.; Chang, B.C.; Patel, G.F.; Bakshi, R.K.; 3-Oxo-4aza-5alpha-7beta-methylpregnan-20-ethers as inhibitors of human type 1 5alpha-reductase: Synthesis and structure-activity relationship. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 226. |
| 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) | 35173 | (3S,8S,9S,10R,13S,14S,17S)-17-acetyl-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | 1778-02-5 | C23H34O3 | 详情 | 详情 |
| (II) | 35174 | (3S,8S,9S,10R,13S,14S,17S)-17-[(1R)-1-hydroxyethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | 14553-79-8 | C23H36O3 | 详情 | 详情 |
| (III) | 35175 | (3S,8S,9S,10R,13S,14S,17S)-17-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C29H50O3Si | 详情 | 详情 | |
| (IV) | 35176 | (3S,8S,9S,10R,13S,14S,17S)-17-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-10,13-dimethyl-7-oxo-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl acetate | C29H48O4Si | 详情 | 详情 | |
| (V) | 35177 | (3S,8S,9S,10R,13S,14S,17S)-17-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-7,10,13-trimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,7-diol | C28H50O3Si | 详情 | 详情 | |
| (VI) | 35178 | (8S,9S,10R,13S,14S,17S)-17-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-7,10,13-trimethyl-1,2,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C28H46O2Si | 详情 | 详情 | |
| (VII) | 35179 | (7S,8S,9S,10R,13S,14S,17S)-17-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-7,10,13-trimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C28H48O2Si | 详情 | 详情 | |
| (VIII) | 35180 | 3-[(3S,3aS,5aS,6R,9S,9aS,9bS)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-3a,6,9-trimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalen-6-yl]propionic acid | C27H48O4Si | 详情 | 详情 | |
| (IX) | 35181 | 3-[(3S,3aS,5aS,6R,9S,9aS,9bS)-3-[(1R)-1-hydroxyethyl]-3a,6,9-trimethyl-7-oxododecahydro-1H-cyclopenta[a]naphthalen-6-yl]propionic acid | C21H34O4 | 详情 | 详情 | |
| (X) | 32115 | (2,4-dimethoxyphenyl)methanamine; 2,4-dimethoxybenzylamine | 20781-21-9 | C9H13NO2 | 详情 | 详情 |
| (XI) | 35182 | (4aR,4bS,6aS,7S,9aS,9bS,10R)-1-(2,4-dimethoxybenzyl)-7-[(1R)-1-hydroxyethyl]-4a,6a,10-trimethyl-1,3,4,4a,4b,5,6,6a,7,8,9,9a,9b,10-tetradecahydro-2H-indeno[5,4-f]quinolin-2-one | C30H43NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)The aminoazepinone building block (III) can be prepared as follows. 2,4-Dimethoxybenzylamine (XIII) is alkylated with 2,3-dibromopropene (XIV) in the presence of Et3N to yield amine (XV), which is condensed with 2(R)-(benzyloxycarbonylamino)-4-pentenoic acid (XVI) by means of EDC in CH2Cl2 giving amide (XVII). Subsequent coupling of vinyl bromide (XVII) with 2,3-difluorophenylboronic acid (XVIII) in the presence of 1,1’-bis(diphenylphosphino)ferrocenedichloropalladium(II)· CH2Cl2 and Na2CO3 in DMF gives (XIX). Ring-closing olefin metathesis in diene (XIX) utilizing a second-generation Grubbs catalyst generates the azepinone derivative (XX), from which the dimethoxybenzyl group is removed by means of trifluoroacetic acid in CH2Cl2 to provide compound (XXI). Hydrogenation of olefin (XXI) and simultaneous Cbz group cleavage in the presence of Pd/C and Boc2O leads to the Boc-protected aminoperhydroazepinone (XXII). After alkylation of lactam (XXII) with the 2,2,2-trifluoroethyl sulfonate (XXIII) and NaH in DMF, the N-Boc group is removed using trifluoroacetic acid to furnish the target amine (III) (1). Scheme 2.
| 【1】 Burgey, C.S., Deng, Z.J., Williams, T.M., Paone, D.V., Shaw, A.W., Nguyen, D.N. (Merck & Co., Inc.). CGRP receptor antagonists. EP 1638969, JP 2006523697, US 2004229861, US 6953790, WO 2004092166, WO 2004092168. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 65556 | (3R,6S)-3-Amino-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepine | C14H15F5N2O | 详情 | 详情 | |
| (XIII) | 32115 | (2,4-dimethoxyphenyl)methanamine; 2,4-dimethoxybenzylamine | 20781-21-9 | C9H13NO2 | 详情 | 详情 |
| (XIV) | 21748 | 2,3-dibromo-1-propene | 513-31-5 | C3H4Br2 | 详情 | 详情 |
| (XV) | 65562 | C12H16BrNO2 | 详情 | 详情 | ||
| (XVI) | 65563 | Cbz-alpha-Allyl-L-Gly; N-ALPHA-CARBOBENZOXY-L-ALPHA-ALLYL-GLYCINE; CBZ-(S)-2-AMINO-4-PENTENOIC ACID; (S)-2-CBZ-AMINO-4-PENTENOIC ACID | 78553-51-2 | C13H15NO4 | 详情 | 详情 |
| (XVII) | 65564 | C25H29BrN2O5 | 详情 | 详情 | ||
| (XVIII) | 65565 | 2,3-Difluorophenylboronic acid; 2,3-Difluorobenzeneboronic acid | 121219-16-7 | C6H5BF2O2 | 详情 | 详情 |
| (XIX) | 65566 | C31H33F2N2O5 | 详情 | 详情 | ||
| (XX) | 65567 | C29H28F2N2O5 | 详情 | 详情 | ||
| (XXI) | 65568 | C20H18F2N2O3 | 详情 | 详情 | ||
| (XXII) | 65569 | C17H21F2N2O3 | 详情 | 详情 | ||
| (XXIII) | 33474 | 2,2,2-Trifluoroethyl trichloromethanesulfonate; 2,2,2-Trifluoroethyl trichloromethylsulfonate | 23199-56-6 | C3H2Cl3F3O3S | 详情 | 详情 |