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【结 构 式】 
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【分子编号】17415 【品名】(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one 【CA登记号】464-49-3 |
【 分 子 式 】C10H16O 【 分 子 量 】152.23644 【元素组成】C 78.9% H 10.59% O 10.51% |
合成路线1
该中间体在本合成路线中的序号：(I)1NK-104 in its open and lactone forms has been synthesized by several different ways: 1) Lactone form: The reaction of 1(R),7,7-trimethylbicyclo[2.2.1]heptan-2-one (I) with 1-naphthylmagnesium bromide (II) gives the tertiary alcohol (III), which by reaction with SOCl2 and then with NaHCO3 yields 2-(1-naphthyl)-1(R),7,7-trimethylbicyclo[2.2.1]heptene (IV). Hydroboration of (IV) with BH3 followed by oxidation with H2O2 affords 4(S),7,7-trimethyl-3exo-(1-naphthyl)bicyclo[2.2.1]heptan-2exo-ol (V), which is submitted to transesterification with methyl acetoacetate (VI) and dimethyl-aminopyridine (DMAP) to give the corresponding ester (VII). The condensation of (VII) with N-methoxy-N-methyl-3-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-2(E)-propenamide (VIII) by means of NaH yields the corresponding chiral 3,5-dioxoheptenoic acid ester (IX), which is selectively reduced first with diisobutylaluminum hy-dride acid (DIBAL) and then with diethylmethoxyborane and sodium borohydride affording the 3(R),5(S)-dihydroxyheptenoic ester (X). Finally, this compound is saponified with NaOH and treated with acetic acid/sodium acetate. The intermediate amide (VIII) is obtained by condensation of 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde (XI) with N-methoxy-N-methylacetamide (XII) by means of butyllithium to the hydroxy propionamide (XIII), which is then dehydrated with methanesulfonyl chloride and triethylamine in the usual way).
| 【1】 Castaner, J.; Sorbera, L.A.; Leeson, P.A.; NK-104. Drugs Fut 1998, 23, 8, 847-859. |
| 【2】 Guntor, B.; Kaiyama, T.; Arai, K.; Minami, T.; Suzuki, M.; Kobara, Y.; Sakota, R. (Nissan Chemical Industry, Ltd.; Sagami Chemical Research Center); Optically active ß,*-diketo acid esters and their reduced forms. JP 1994025092 . |
| 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) | 17415 | (1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one | 464-49-3 | C10H16O | 详情 | 详情 |
| (II) | 17416 | bromo(1-naphthyl)magnesium | C10H7BrMg | 详情 | 详情 | |
| (III) | 17417 | (1R,2S,4R)-1,7,7-trimethyl-2-(1-naphthyl)bicyclo[2.2.1]heptan-2-ol | C20H24O | 详情 | 详情 | |
| (IV) | 17418 | 1-[(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-en-2-yl]naphthalene | C20H22 | 详情 | 详情 | |
| (V) | 17419 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]heptan-2-ol | C20H24O | 详情 | 详情 | |
| (VI) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (VII) | 17421 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl 3-oxobutanoate | C24H28O3 | 详情 | 详情 | |
| (VIII) | 17422 | (E)-3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-N-methoxy-N-methyl-2-propenamide | C23H21FN2O2 | 详情 | 详情 | |
| (IX) | 17423 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dioxo-6-heptenoate | C45H42FNO4 | 详情 | 详情 | |
| (X) | 17424 | (1S,2R,3R,4S)-4,7,7-trimethyl-3-(1-naphthyl)bicyclo[2.2.1]hept-2-yl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dihydroxy-6-heptenoate | C45H46FNO4 | 详情 | 详情 | |
| (XI) | 17425 | 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarbaldehyde | 121660-37-5 | C19H14FNO | 详情 | 详情 |
| (XII) | 17426 | N-methoxy-N-methylacetamide | 78191-00-1 | C4H9NO2 | 详情 | 详情 |
| (XIII) | 17427 | 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3-hydroxy-N-methoxy-N-methylpropanamide | C23H23FN2O3 | 详情 | 详情 | |
| (XLVI) | 64696 | (4R,6S)-6-{(E)-2-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]ethenyl}-4-hydroxytetrahydro-2H-pyran-2-one | C25H22FNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIX)An alternative method, suitable for large-scale synthesis, has been described: The chloromethylation of 4'-hydroxyacetophenone (XII) using formaldehyde and HCl gave (XIII). Displacement of the chloride group with NaCN provided nitrile (XIV), which was further hydrolyzed to the carboxylic acid (XV). Esterification of (XV) with methanol and sulfuric acid yields (XVI), whose phenolic hydroxyl group was protected as the benzyl ether (XVII) by alkylation with benzyl chloride. Subsequent bromination of ketone (XVII) yielded the phenacyl bromide (XVIII). The chiral amino alcohol (XX) was prepared from (-)-camphor (XIX) by ketone oxidation in position alpha with SeO2, followed by condensation with hydroxylamine and reduction with LiAlH4. Asymmetric reduction of the bromo ketone (XVIII) with borane in the presence of aluminum triethoxide and the chiral auxiliary (XX) provided the desired (R)-bromohydrin (XXI). The hydroxyl groups of (XXI) were then protected by silylation with tert-butyldimethylsilyl chloride, yielding (XXII). Condensation of the silyl-protected bromide (XXII) with (S)-2[(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl)oxy]-N,N-dimethylacetamide (XXIII) furnished adduct (XXIV).
| 【1】 Yanagi, T.; et al.; The practical synthesis of a uterine relaxant, bis (2-{[2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylacetamide)sulfate (KUR-1246). Chem Pharm Bull 2001, 49, 8, 1018. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 18123 | 1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone | 99-93-4 | C8H8O2 | 详情 | 详情 |
| (XIII) | 39615 | 1-[3-(chloromethyl)-4-hydroxyphenyl]-1-ethanone | C9H9ClO2 | 详情 | 详情 | |
| (XIV) | 50683 | 2-(5-acetyl-2-hydroxyphenyl)acetonitrile | C10H9NO2 | 详情 | 详情 | |
| (XV) | 50684 | 2-(5-acetyl-2-hydroxyphenyl)acetic acid | C10H10O4 | 详情 | 详情 | |
| (XVI) | 50685 | methyl 2-(5-acetyl-2-hydroxyphenyl)acetate | C11H12O4 | 详情 | 详情 | |
| (XVII) | 50686 | methyl 2-[5-acetyl-2-(benzyloxy)phenyl]acetate | C18H18O4 | 详情 | 详情 | |
| (XVIII) | 50687 | methyl 2-[2-(benzyloxy)-5-(2-bromoacetyl)phenyl]acetate | C18H17BrO4 | 详情 | 详情 | |
| (XIX) | 17415 | (1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one | 464-49-3 | C10H16O | 详情 | 详情 |
| (XX) | 50688 | (1R,2S,3R,4S)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol | C10H19NO | 详情 | 详情 | |
| (XXI) | 50689 | (1R)-1-[4-(benzyloxy)-3-(2-hydroxyethyl)phenyl]-2-bromo-1-ethanol | C17H19BrO3 | 详情 | 详情 | |
| (XXII) | 50690 | ([(1R)-1-[4-(benzyloxy)-3-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl]-2-bromoethyl]oxy)(tert-butyl)dimethylsilane; benzyl 4-((1R)-2-bromo-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl ether | C29H47BrO3Si2 | 详情 | 详情 | |
| (XXIII) | 50691 | 2-[[(7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenyl]oxy]-N,N-dimethylacetamide | C14H20N2O2 | 详情 | 详情 | |
| (XXIV) | 50692 | 2-([(7S)-7-[((2R)-2-[4-(benzyloxy)-3-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy)-N,N-dimethylacetamide | C43H66N2O5Si2 | 详情 | 详情 |