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【结 构 式】 
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【分子编号】50327 【品名】Cyanoethane; Ethyl cyanide; Propionitrile 【CA登记号】107-12-0 |
【 分 子 式 】C26H39NO5 【 分 子 量 】445.5994 【元素组成】C 70.08% H 8.82% N 3.14% O 17.95% |
合成路线1
该中间体在本合成路线中的序号：(IV)The condensation of the choral oxazolidinone (I) with octanal (II) by means of Bu2B-OTf and TEA in dichloromethane gives the chiral alcohol (III), which is protected with DHP and PPTS, yielding the tetrahydropyranyl ether (IV). The cleavage of the chiral adjuvant of (IV) by means of LiOH and H2O2 affords the carboxylic acid (V), which is esterified with (2S)-hydroxy-3-methylbutyric acid benzyl ester (VI) by means of trichlorobenzoyl chloride and TEA to provide the adduct (VII). Elimination of the tetrahydropyranyl protecting group of (VII) by means of Ts-OH gives the hydroxyester (VIII), which is condensed with the chiral amino acid (IX) by means of trichlorobenzoyl chloride as before to yield the triester compound (X). Elimination of the Mom protecting group of (X) by means of Tms-Cl and tetrabutylammonium bromide affords the hydroxy compound (XI), which is hydrogenated with H2 over Pd(OH)2 to provide the carboxylic acid (XII). Elimination of the Boc protecting group of (XII) by means of TFA gives the amino acid (XII), which is finally submitted to a macrocyclization by means of DPPA and DIEA in DMF to yield the target hapalosin.
| 【1】 Hermann, C.; et al.; Total synthesis of hapalosin and two ring expanded analogs. Tetrahedron 2000, 56, 43, 8461. |
| 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) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (II) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (III) | 25715 | (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-1,3-oxazolidin-2-one | C21H31NO4 | 详情 | 详情 | |
| (IV) | 50327 | Cyanoethane; Ethyl cyanide; Propionitrile | 107-12-0 | C26H39NO5 | 详情 | 详情 |
| (V) | 50328 | (2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)decanoic acid | C16H30O4 | 详情 | 详情 | |
| (VI) | 25720 | benzyl (2S)-2-hydroxy-3-methylbutanoate | C12H16O3 | 详情 | 详情 | |
| (VII) | 50329 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)decanoate | C28H44O6 | 详情 | 详情 | |
| (VIII) | 25722 | (1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate | C23H36O5 | 详情 | 详情 | |
| (IX) | 50330 | (3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-(methoxymethoxy)-5-phenylpentanoic acid | C19H29NO6 | 详情 | 详情 | |
| (X) | 50331 | benzyl (6S,7R,11R,12S,15S)-6-benzyl-11-heptyl-15-isopropyl-7-(methoxymethoxy)-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate | C42H63NO10 | 详情 | 详情 | |
| (XI) | 50332 | benzyl (6S,7R,11S,12S,15S)-6-benzyl-11-heptyl-7-hydroxy-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate | C40H59NO9 | 详情 | 详情 | |
| (XII) | 50333 | (6S,7R,11R,12S,15S)-6-benzyl-11-heptyl-7-hydroxy-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oic acid | C33H53NO9 | 详情 | 详情 | |
| (XIII) | 50334 | (2S)-2-[((2S,3R)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoyl)oxy]-3-methylbutyric acid | C28H45NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The alkylation of 4-hydroxy-3-methoxybenzoic acid methyl ester (I) with 3-(4-morpholinyl)propyl chloride (II) and tetrabutylammonium chloride in refluxing butanone gives 3-methoxy-4-[3-(4-morpholinyl)propoxy]benzoic acid methyl ester (III), which is nitrated with HNO3 in hot acetic acid to yield 5-methoxy-4-[3-(4-morpholinyl)propoxy]-2-nitrobenzoic acid methyl ester (IV). The reduction of (III) with H2 over Pd/C in methanol/ethyl acetate to afford the corresponding 2-amino ester (V), which is condensed with dimethylformamide dimethylacetal (VI) by heating at 100 C to provide the 2-(dimethylaminomethyleneamino) derivative (VII). The cyclization of (VII) with acetonitrile (VIII) by means of BuLi and CO2 in THF gives 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-oxo-1,4-dihydroquinoline-3-carbonitrile (IX), which is treated with refluxing SOCl2 to yield the 4-chloroquinoline derivative (X). Finally, this compound is condensed with 2-bromo-5-methoxyaniline by means of pyridine hydrochloride in 2-ethoxyethanol or NaH in THF (or DMF).
| 【1】 Wang, Y.D.; et al.; Inhibition of SRC kinase activity by 4-phenylamino-3-quinolinecarbonitriles, Part 1: optimization of the aniline headpiece at C-4. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 144. |
| 【2】 Tsou, H.-R.; Wissner, A.; Johnson, B.D.; Reich, M.F.; Floyd, M.B. Jr.; Kitchen, D.B. (American Cyanamid Co.); Substituted 3-cyano quinolines. US 6002008 . |
| 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) | 29176 | methyl 4-hydroxy-3-methoxybenzoate | 3943-74-6 | C9H10O4 | 详情 | 详情 |
| (II) | 18691 | 4-(3-chloropropyl)morpholine;N-(3-Chloropropyl)morpholine | 7357-67-7 | C7H14ClNO | 详情 | 详情 |
| (III) | 50321 | methyl 3-methoxy-4-[3-(4-morpholinyl)propoxy]benzoate | C16H23NO5 | 详情 | 详情 | |
| (IV) | 50322 | methyl 5-methoxy-4-[3-(4-morpholinyl)propoxy]-2-nitrobenzoate | C16H22N2O7 | 详情 | 详情 | |
| (V) | 50323 | methyl 2-amino-5-methoxy-4-[3-(4-morpholinyl)propoxy]benzoate | C16H24N2O5 | 详情 | 详情 | |
| (VI) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (VII) | 50324 | methyl 2-[[(E)-(dimethylamino)methylidene]amino]-5-methoxy-4-[3-(4-morpholinyl)propoxy]benzoate | C19H29N3O5 | 详情 | 详情 | |
| (VIII) | 50327 | Cyanoethane; Ethyl cyanide; Propionitrile | 107-12-0 | C26H39NO5 | 详情 | 详情 |
| (IX) | 50325 | 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-oxo-1,4-dihydro-3-quinolinecarbonitrile | C18H21N3O4 | 详情 | 详情 | |
| (X) | 48517 | 4-chloro-6-methoxy-7-[3-(4-morpholinyl)propoxy]-3-quinolinecarbonitrile | C18H20ClN3O3 | 详情 | 详情 | |
| (XI) | 50326 | 2-Bromo-5-methoxyaniline | 129968-11-2 | C7H8BrNO | 详情 | 详情 |