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【结 构 式】 
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【分子编号】16951 【品名】(1R)-1-[(4S,5R)-2,2-dimethyl-5-[(E)-1-tetradecenyl]-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanol 【CA登记号】 |
【 分 子 式 】C40H54O4 【 分 子 量 】598.86636 【元素组成】C 80.22% H 9.09% O 10.69% |
合成路线1
该中间体在本合成路线中的序号：(V)A practical total synthesis of KRN-7000 has been reported: The reaction of D-lyxofuranose (I) with acetone and sulfuric acid gives the acetonide (II), which is tritiated with trityl chloride and pyridine in dichloromethane to the protected lyxose (III). The condensation of (III) with triphenyltridecylphosphonium bromide (IV) by means of butyllithium in THF yields the alcohol (V) with the suitable (2R,3S,4R)-configuration. The mesylation of (V) with mesyl chloride and pyridine affords the mesylate (VI), which is treated with aqueous HCl in dichloromethane to obtain the unsaturated triol (VII). The hydrogenation of (VII) with H2 over Pd-BaSO4 in THF affords (2R,3R,4R)-2-(methanesulfonyloxy)octadecane-1,3,4-triol (VIII), which by reaction with sodium azide in hot DMF yields the corresponding azide (IX). The protection of the primary alcohol of (IX) with trityl chloride and pyridine affords the azide diol (X), which is treated with benzyl bromide and NaH in DMF to give the fully protected triol (XI). The reduction of the azido group of (XI) with H2 over Pd/C in propanol/methanol affords the amine (XII), which is acylated with hexacosanoic acid (XIII) and WSC-HCl yielding the corresponding amide (XIV). Elimination of the trityl group of (XIV) with HCl in methanol/dichloromethane gives the primary alcohol (XV), which is condensed with tetra-O-benzyl-beta-D-galactopyranosyl bromide (XVI) by means of tetrahexylammonium bromide in toluene/DMF yielding the fully benzylated KRN-7000 (XVII). Finally, this compound is debenzylated by a treatment with Pd(OH)2 on charcoal and 4-methylcyclohexene in ethanol.
| 【1】 Morita, M.; Sawa, E.; Yamaji, K.; Sakai, T.; Natori, T.; Koezuka, Y.; Fukushima, H.; Akimoto, K.; Practical total synthesis of (2S,3S,4R)-1-O-(alpha-D-galactopyranosyl)-N-hexacosanoyl-2-amino-1,3,4-octadecanetriol, the antitumorial and immunostimulatory alpha-galactosylceramide, KRN-7000. Biosci Biotech Biochem 1996, 60, 2, 288. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 | |
| (I) | 16948 | (3S,4R,5R)-5-(hydroxymethyl)tetrahydro-2,3,4-furantriol | C5H10O5 | 详情 | 详情 | |
| (II) | 16949 | (3aS,6R,6aS)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-ol | C8H14O5 | 详情 | 详情 | |
| (III) | 16950 | (3aS,6R,6aS)-2,2-dimethyl-6-[(trityloxy)methyl]tetrahydrofuro[3,4-d][1,3]dioxol-4-ol | C27H28O5 | 详情 | 详情 | |
| (IV) | 64686 | triphenyl(tridecyl)phosphonium bromide | C31H42BrP | 详情 | 详情 | |
| (V) | 16951 | (1R)-1-[(4S,5R)-2,2-dimethyl-5-[(E)-1-tetradecenyl]-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanol | C40H54O4 | 详情 | 详情 | |
| (VI) | 16952 | (1R)-1-[(4R,5R)-2,2-dimethyl-5-[(E)-1-tetradecenyl]-1,3-dioxolan-4-yl]-2-(trityloxy)ethyl methanesulfinate | C41H56O5S | 详情 | 详情 | |
| (VII) | 16953 | (1R,2R,3R,4E)-2,3-dihydroxy-1-(hydroxymethyl)-4-heptadecenyl methanesulfinate | C19H38O5S | 详情 | 详情 | |
| (VIII) | 16954 | (1R,2R,3R)-2,3-dihydroxy-1-(hydroxymethyl)heptadecyl methanesulfinate | C19H40O5S | 详情 | 详情 | |
| (IX) | 16955 | (2S,3S,4R)-2-azido-1,3,4-octadecanetriol | C18H37N3O3 | 详情 | 详情 | |
| (X) | 16956 | (1S,2R,3R)-1-azido-1-(trityloxy)-2,3-heptadecanediol | C36H49N3O3 | 详情 | 详情 | |
| (XI) | 16957 | 1-[[[(2S,3S,4R)-2-azido-3,4-bis(benzyloxy)octadecyl]oxy](diphenyl)methyl]benzene; (1R)-1-[(1S,2S)-2-azido-1-(benzyloxy)-3-(trityloxy)propyl]pentadecyl benzyl ether | C51H63N3O3 | 详情 | 详情 | |
| (XII) | 16958 | (2S,3S,4R)-3,4-bis(benzyloxy)-1-(trityloxy)-2-octadecanamine; (1S,2S,3R)-2,3-bis(benzyloxy)-1-[(trityloxy)methyl]heptadecylamine | C51H65NO3 | 详情 | 详情 | |
| (XIII) | 16939 | hexacosanoic acid | 506-46-7 | C26H52O2 | 详情 | 详情 |
| (XIV) | 16960 | N-[(1S,2S,3R)-2,3-bis(benzyloxy)-1-[(trityloxy)methyl]heptadecyl]hexacosanamide | C77H115NO4 | 详情 | 详情 | |
| (XV) | 16961 | N-[(1S,2S,3R)-2,3-bis(benzyloxy)-1-(hydroxymethyl)heptadecyl]hexacosanamide | C58H101NO4 | 详情 | 详情 | |
| (XVI) | 16962 | (2R,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-2-[(benzyloxy)methyl]-6-bromotetrahydro-2H-pyran; benzyl (2R,3R,4S,5R,6R)-3,5-bis(benzyloxy)-2-[(benzyloxy)methyl]-6-bromotetrahydro-2H-pyran-4-yl ether | C34H35BrO5 | 详情 | 详情 | |
| (XVII) | 16963 | N-[(1S,2S,3R)-2,3-bis(benzyloxy)-1-[([(2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]oxy)methyl]heptadecyl]hexacosanamide | C92H135NO9 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)The reaction of 3-chlorotetrafluoropyridine (I) with sodium tert-butoxide in THF gives 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine (II), which is dechlorinated with H2 over Pearlman's catalyst in methanol yielding 4-(tert-butoxy)-2,3,6-trifluoropyridine (III). The methylation of (III) with methyl iodide and lithium diethylamide (LDA) in THF affords 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine (IV), which is treated with hydrazine in refluxing propanol to give 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with 2-bromo-2-cyclopropylacetopnitrile (VI) by means of LDA in THF yields the expected condensation product (VII), which is treated with TFA to eliminate the tert-butyl protecting group and with POCl3 in DMF to afford the 4-chloropyridyl derivative (VIII). The hydrolysis of the nitrile group of (VIII) with HCl in ethanol gives the corresponding acetate ester (IX), which is reduced with LiAlH4 in THF to the alcohol (X). The oxidation of (X) with oxalyl chloride in DMSO/dichloromethane yields the aldehyde (XI), which is cyclized with diethyl malonate (XII) by means of piperidine in refluxing acetic acid, followed by heating at 220 C C in Dowtherm to afford 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (XIII). The condensation of (XIII) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) by means of triethylamine in DMF gives the expected condensation product (XV), which is methylated with methyl iodide and sodium hexamethyldisylazane (Na-HMDS) in THF yielding the N-methyl derivative (XVI). The hydrolysis of the ester group of (XVI) with LiOH in THF/water provides the corresponding free acid (XVII), which is finally deprotected with HCl in acetic acid. The synthesis of the intermediate 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) has already been described in the first synthesis of compound no. 268134 (see scheme 26813401a).
| 【1】 Or, Y.S.; Armiger, Y.-L.; Fung, A. (Abbott Laboratories Inc.); Pyridone antibiotic with improved safety profile. US 5977133; WO 0010998 . |
| 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) | 16189 | (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoic acid | C10H8O3S | 详情 | 详情 | |
| (II) | 16820 | 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine; tert-butyl 3-chloro-2,5,6-trifluoro-4-pyridinyl ether | C9H9ClF3NO | 详情 | 详情 | |
| (III) | 16821 | 4-(tert-butoxy)-2,3,6-trifluoropyridine; tert-butyl 2,3,6-trifluoro-4-pyridinyl ether | C9H10F3NO | 详情 | 详情 | |
| (IV) | 16822 | tert-butyl 2,3,6-trifluoro-5-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine | C10H12F3NO | 详情 | 详情 | |
| (V) | 16823 | tert-butyl 2,5-difluoro-3-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine | C10H13F2NO | 详情 | 详情 | |
| (VI) | 31629 | 2-bromo-2-cyclopropylacetonitrile | C5H6BrN | 详情 | 详情 | |
| (VII) | 16825 | 2-[4-(tert-butoxy)-5-fluoro-3-methyl-2-pyridinyl]-2-cyclopropylacetonitrile | C15H19FN2O | 详情 | 详情 | |
| (VIII) | 16826 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile | C11H10ClFN2 | 详情 | 详情 | |
| (IX) | 16827 | ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate | C13H15ClFNO2 | 详情 | 详情 | |
| (X) | 31627 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropyl-1-ethanol | C11H13ClFNO | 详情 | 详情 | |
| (XI) | 16828 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde | C11H11ClFNO | 详情 | 详情 | |
| (XII) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XIII) | 16831 | ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C16H15ClFNO3 | 详情 | 详情 | |
| (XIV) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (XV) | 26950 | ethyl 8-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C27H34FN3O5 | 详情 | 详情 | |
| (XVI) | 16951 | (1R)-1-[(4S,5R)-2,2-dimethyl-5-[(E)-1-tetradecenyl]-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanol | C40H54O4 | 详情 | 详情 | |
| (XVII) | 31628 | 8-[(7S)-7-[(tert-butoxycarbonyl)(methyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid | C26H32FN3O5 | 详情 | 详情 |