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【结 构 式】 
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【分子编号】23694 【品名】butyraldehyde 【CA登记号】123-72-8 |
【 分 子 式 】C4H8O 【 分 子 量 】72.10692 【元素组成】C 66.63% H 11.18% O 22.19% |
合成路线1
该中间体在本合成路线中的序号：(A)From 16alpha-hydroxyprednisolone (III) and n-butyraldehyde (A) in the presence of an acid catalyst. Budesonide is defined as a 1:1 mixture of the two epimers (I) and (II).
| 【1】 Thalen, A.; Brattsand, R.; Synthesis and antiinflammatory properties of budesonide, a new nonhalogenated glucocorticoid with high local activity. Arzneim-Forsch Drug Res 1979, 29, 11, 1687-90. |
| 【2】 Dharma, A.P.; Budesonide. Drugs Fut 1980, 5, 4, 179. |
合成路线2
该中间体在本合成路线中的序号：(XVI)3) The reductocondensation of D-glucose (VIII) and butylamine by means of H2 over Pd/C in ethanol gives N-butylglucamine (IX), which is submitted to a biochemical oxidation by means of Gluconobacter oxidans in water to yield 6-(butylamino)-6-deoxy-a-L-sorbofuranose (X). Finally, this compound is submitted to a reductive cyclization with H2 over Pd/C in ethanol/water. 4) The selective hydrolysis of 1,2:4,6-di-O-isopropylidene-a-L-sorbofuranose (XI) (together with some of its 1,3:4,6-isomer) by means of H2SO4 in methanol gives 1,2-O-isopropylidene-a-L-sorbofuranose (XII), which is treated with tosyl chloride, triethylamine and pyridine to yield the monotosylated sugar (XIII). Reaction of the protected sugar (XIII) with butylamine in hot pyridine/triethylamine affords 6-(butylamino)-6-deoxy-1,2-O-isopropylidene-a-L-sorbofuranose (XIV), which is finally submitted to a reductive cyclization by means of H2 over Pd/C in water. 5) Directly by reductocondensation of 1-deoxynojiri-mycin (XV) with butyraldehyde (XVI) by means of H2 over Pd/C in methanol or with NaBH3CN in methanol/ HCl.
| 【1】 Sorbera, L.A.; Castaner, J.; Bayes, M.; Miglustat. Drugs Fut 2003, 28, 3, 229. |
| 【2】 Landis, B.H.; McLaughlin, J.K.; Heeren, R.; Grabner, R.W.; Wang, P.T.; Bioconversion of N-butylglucamine to 6-deoxy-6-butylamino sorbose by Gluconobacter oxydans. Org Process Res Dev 2002, 6, 4, 547. |
| 【3】 Scaros, M.G.; Prunier, M.L.; Rutter, R.J.; Yonan, P.K.; Grabner, R.; Landis, B.; A new and improved synthesis of N-butyl-1-deoxynojirimycin. Chem Ind (New York 1979) 1994, 53, 41. |
| 【4】 Junge, B.; Puls, W.; Krause, H.P.; Muller, L. (Bayer AG); New 3,4,5-Trihydroxypiperidine derivs., process for their preparation and medicaments and fodder containing them. DE 2758025; EP 0000947 . |
| 【5】 Bryant, M.L.; Koszyk, F.J.; Mueller, R.A.; Partis, R.A. (Pharmacia Corp.); Use of 1-deoxynojirimycin and its derivs. for treating mammals infected with respiratory syncytial virus. WO 9522975 . |
| 【6】 Wang, P.T.; Grabner, R.W.; Landis, B.H.; Prunier, M.L.; Scaros, M.G. (Pharmacia Corp.); Process for producing N-substd.-1-deoxynojirimycin. EP 0477160 . |
| 【7】 Partis, R.A.; Mueller, R.A.; Koszyk, F.J. (Pharmacia Corp.); Antiviral cpds.. US 5310745 . |
| 【8】 Weier, R.M.; Behling, J.R.; Farid, P.; Medich, J.R.; Khanna, I.; Prunier, M.; Scaros, M. (Pharmacia Corp.); Process for preparation of 1,5-(alkylimino)-1,5-dideoxy-D-glucitol and derivs. thereof. WO 9117145 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 23276 | 5-(hydroxymethyl)-1,2,3,4-cyclohexanetetrol | C6H12O6 | 详情 | 详情 | |
| (IX) | 59965 | (3R,4R,5S)-6-(butylamino)-1,2,3,4,5-hexanepentol | C10H23NO5 | 详情 | 详情 | |
| (X) | 59966 | (3S,4S,5S)-5-[(butylamino)methyl]-2-(hydroxymethyl)tetrahydro-2,3,4-furantriol | C10H21NO5 | 详情 | 详情 | |
| (XI) | 59967 | C12H20O6 | 详情 | 详情 | ||
| (XII) | 59968 | (5S,7S,8S,9S)-7-(hydroxymethyl)-2,2-dimethyl-1,3,6-trioxaspiro[4.4]nonane-8,9-diol | C9H16O6 | 详情 | 详情 | |
| (XIII) | 59969 | [(5S,7S,8S,9S)-8,9-dihydroxy-2,2-dimethyl-1,3,6-trioxaspiro[4.4]non-7-yl]methyl 4-methylbenzenesulfonate | C16H22O8S | 详情 | 详情 | |
| (XIV) | 59970 | (5S,7S,8S,9S)-7-[(butylamino)methyl]-2,2-dimethyl-1,3,6-trioxaspiro[4.4]nonane-8,9-diol | C13H25NO5 | 详情 | 详情 | |
| (XV) | 17944 | deoxynojirimycin; (2R,3R,4R,5S)-2-(hydroxymethyl)-3,4,5-piperidinetriol | 19130-96-2 | C6H13NO4 | 详情 | 详情 |
| (XVI) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Synthesis of the aminopyrazole intermediate (XIII): The reaction of butanal (I) with methylhydrazine (II) in dichloromethane in the presence of MgSO4 gives the corresponding hydrazide (III), which is alkylated with ethyl bromoacetate (IV) by means of the polymer-supported base 2-(tert-butylimino)-2-(diethylamino)-1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS-BEMP) (V) and polymer-supported methylamine (VI) to yield the hydrazino ester (VII). Treatment of compound (VII) with an ion exchange tetramethylammonium cyanide resin (VIII) in refluxing ethanol containing a catalytic amount of HOAc affords the adduct (IX), which is dehydrogenated with Pd/C/cyclopentene or MnO2 and treated with a polymer-supported ethyl isocyanate resin (X) in order to eliminate the unreacted product, providing the hydrazone (XI). Cyclization of (XI) by means of PS-BEMP (V) in ethanol gives 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid ethyl ester (XII), which is finally treated with ammonia in methanol to afford the desired pyrazolecarboxamide intermediate (XIII).
| 【1】 Baxendale, I.R.; Ley, S.V.; Polymer-supported reagents for multi-step organic synthesis: Application to the synthesis of sildenafil. Bioorg Med Chem Lett 2000, 10, 17, 1983. |
| 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) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (II) | 12091 | 1-Methylhydrazine; Monomethyl hydrazine | 60-34-4 | CH6N2 | 详情 | 详情 |
| (III) | 44339 | butanal N-methylhydrazone | C5H12N2 | 详情 | 详情 | |
| (IV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (V) | 44344 | N-(tert-butyl)-N-[2-(diethylamino)-1,3-dimethyl-1,3,2lambda(5)-diazaphosphinan-2-ylidene]amine; 2-(tert-butylimino)-N,N-diethyl-1,3-dimethyl-1,3,2lambda(5)-diazaphosphinan-2-amine | C13H31N4P | 详情 | 详情 | |
| (VI) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (VII) | 44340 | ethyl 2-[2-[(E)butylidene]-1-methylhydrazino]acetate | C9H18N2O2 | 详情 | 详情 | |
| (VIII) | 44345 | N,N,N-trimethylmethanaminium cyanide | C5H12N2 | 详情 | 详情 | |
| (IX) | 44341 | ethyl 2-[2-(1-cyanobutyl)-1-methylhydrazino]acetate | C10H19N3O2 | 详情 | 详情 | |
| (X) | 11019 | (Methylimino)(oxo)methane; methyl isocyanate | C2H3NO | 详情 | 详情 | |
| (XI) | 44342 | ethyl 2-[2-[(Z)-1-cyanobutylidene]-1-methylhydrazino]acetate | C10H17N3O2 | 详情 | 详情 | |
| (XII) | 44343 | ethyl 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxylate | C10H17N3O2 | 详情 | 详情 | |
| (XIII) | 15627 | 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide; 4-amino-1-methyl-3-propyl-5-pyrazolecarboxamide | 139756-02-8 | C8H14N4O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)This compound has been obtained by several related ways: 1. The selective reduction of 6alpha,9alpha-difluoro-16alpha-prednisolone (I) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,16alpha,17alpha,21-tetrahydroxypregn-4-ene-3,20-dione (II), which is cyclized with butanal (III) catalyzed by HClO4 in dioxane to yield the butylidenedioxy derivative (IV) as a diastereomeric mixture. Finally, the desired (R)-diastereomer is separated by column chromatography over Sephadex LH-20. 2. By selective reduction of 16alpha,17alpha-((R)-butylidenedioxy)-6alpha,9alpha-difluoro-11beta,21-dihydroxypregna-1,4-diene-3,20-dione (V) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol. 3. The selective reduction of fluocinolone acetonide (VI) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,21-dihydroxy-16alpha,17alpha-(isopropylidenedioxy)pregen-4-ene-3,20-dione (VII), which is then treated with butanal (III) and HClO4 over SiO2 in heptane.
| 【1】 Andersson, P.; Axelsson, B.; Brattssand, R.; Thalen, A. (AstraZeneca plc); Novel steroids. JP 1994505232; US 5674861; US 5939409; WO 9213872 . |
| 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) | 47567 | (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H26F2O6 | 详情 | 详情 | |
| (II) | 47568 | (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H28F2O6 | 详情 | 详情 | |
| (III) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (IV) | 47569 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C25H34F2O6 | 详情 | 详情 | |
| (V) | 47570 | (4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C25H32F2O6 | 详情 | 详情 | |
| (VI) | 46292 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C24H30F2O6 | 详情 | 详情 | |
| (VII) | 47571 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C24H32F2O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)The intermediate 16alpha,17alpha-((R)-butylidenedioxy)-6alpha,9alpha-difluoro-11beta,21-dihydroxypregn-4-ene-3,20-dione (V) has been obtained in several related ways: 1. The selective reduction of 6alpha, 9alpha-difluoro-16alpha-prednisolone (I) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,16alpha,17alpha,21-tetrahydroxypregn-4-ene-3,20-dione (II), which is cyclized with butanal (III) catalyzed by HClO4 in dioxane to yield the butylidenedioxy derivative (IV) as a diastereomeric mixture. Finally, the desired (R)-diastereomer, the intermediate (V), is separated by column chromatography over Sephadex LH-20. 2. The selective reduction of 16alpha,17alpha-((R)-butylidenedioxy)-6alpha,9alpha-difluoro-11beta,21-dihydroxypregna-1,4-diene-3,20-dione (VI) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol also yields intermediate (V). 3. The selective reduction of fluocinolone acetonide (VII) with H2 over tris(triphenylphosphine)rhodium chloride catalyst in ethanol gives 6alpha,9alpha-difluoro-11beta,21-dihydroxy-16alpha,17alpha-(isopropylidenedioxy)pregen-4-ene-3,20-dione (VIII), which is then treated with butanal (III) and HClO4 over SiO2 in heptane to afford intermediate (V). The target compound is finally obtained by esterification of intermediate (V) with hexadecanoyl chloride (IX) in pyridine.
| 【1】 Axelsson, B.; Brattsand, R.; Kallstrom, L.; Thalen, A. (AstraZeneca plc); Novel steroid esters. JP 1994505233; US 5614514; US 5888995; WO 9213873 . |
| 【2】 Andersson, P.; Axelsson, B.; Brattssand, R.; Thalen, A. (AstraZeneca plc); Novel steroids. JP 1994505232; US 5674861; US 5939409; WO 9213872 . |
| 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) | 47567 | (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H26F2O6 | 详情 | 详情 | |
| (II) | 47568 | (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-17-glycoloyl-11,16,17-trihydroxy-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | C21H28F2O6 | 详情 | 详情 | |
| (III) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (IV) | 47569 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C25H34F2O6 | 详情 | 详情 | |
| (V) | 47572 | (4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C25H34F2O6 | 详情 | 详情 | |
| (VI) | 47570 | (4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C25H32F2O6 | 详情 | 详情 | |
| (VII) | 46292 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C24H30F2O6 | 详情 | 详情 | |
| (VIII) | 47571 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C24H32F2O6 | 详情 | 详情 | |
| (IX) | 16480 | Palmitoyl Chloride; hexadecanoyl chloride | 112-67-4 | C16H31ClO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)Hydrolysis of the known acetonide (I) with formic acid at 80 C afforded the trihydroxy compound (II) (1). Subsequent ketalization of (II) with butyraldehyde (III) in the presence of perchloric acid provided the butylidene ketal (IVa-b) as a 4:1 mixture of R/S epimers at C-20. Selective hydrogenation of the 1-2 double bond of (IVa-b) by iron pentacaarbonyl/sodium hydroxide gave (V). The carboxylate group of (V) was then activated as the mixed anhydride (VI) by reaction with diethyl chlorophosphate and Et3N. Condensation of anhydride (VI) with the sodium salt of N-hydroxypyridine-2-thione (VII) produced the pyridyl ester (VIII). Photolysis of ester (VIII) by irradiation with a tungsten lamp in the presence of dimethyl disulfide gave rise to the target methyl thioether as a diastereomeric mixture. The major (20R)-epimer was finally isolated by preparative HPLC.
| 【1】 Ashton, M.J.; et al.; Anti-inflammatory 17beta-thioalkyl-16alpha, 17alpha-ketal and -acetal androstanes: A new class of airway selective steroids for the treatment of asthma. J Med Chem 1996, 39, 25, 4888. |
| 【2】 Ashton, M.J.; Karlsson, S.J.-A.; Vacher, B.Y.J.; Withnall, M.T. (Aventis Pharma SA); New steroids. EP 0675897; JP 1996504806; WO 9414834 . |
| 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) | 59446 | (4aS,4bR,5S,6aS,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a,8,8-tetramethyl-2-oxo-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-6b-carboxylic acid | C23H28F2O6 | 详情 | 详情 | |
| (II) | 59447 | (6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-11,16,17-trihydroxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid | C20H24F2O6 | 详情 | 详情 | |
| (III) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (IV) | 59448 | (4aS,4bR,5S,6aS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-6b-carboxylic acid | C24H30F2O6 | 详情 | 详情 | |
| (V) | 59449 | (4aS,4bR,5S,6aS,8S,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-6b-carboxylic acid | C24H30F2O6 | 详情 | 详情 | |
| (VI) | 47372 | (4aS,4bR,5S,6aS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,3,4,4a,4b,5,6,6a,9a,10,10a,10b,11,12-tetradecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxole-6b-carboxylic acid | C24H32F2O6 | 详情 | 详情 | |
| (VII) | 59450 | [(4aS,4bR,5S,6aS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-6-yl]carbonyl diethyl phosphate | C28H39F2O9P | 详情 | 详情 | |
| (VIII) | 59451 | sodium 2-thioxo-1(2H)-pyridinolate | C5H4NNaOS | 详情 | 详情 | |
| (IX) | 59452 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-8-propyl-6b-({[2-thioxo-1(2H)-pyridinyl]oxy}carbonyl)-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C29H33F2NO6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VIII)Acylation of Meldrum's acid (I) with propionyl chloride (II) in the presence of pyridine gave propionyl derivative (III). Subsequent ring opening of (III) with ethanethiol (IV), followed by decarboxylation provided S-ethyl 3-oxothiovalerate (V). Propyl 3-amino-3-phenyl-2-propenoate (VII) was prepared by reaction of benzoylacetate (VI) with ammonium acetate in refluxing ethanol. Then, Hantzsch condensation of ketothioester (V), beta-enaminoester (VII), and butyraldehyde (VIII) in EtOH at 80 C in a sealed tube furnished the dihydropyridine (IX). Finally, oxidation of (IX) using chloranil (X) in boiling THF gave the target pyridine.
| 【1】 Li, A.-H.; Moro, S.; Melman, N.; Ji, X.D.; Jacobson, K.A.; Structure-activity relationships and molecular mod. J Med Chem 1998, 41, 17, 3186. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 21391 | D-aspartic acid; (2R)-2-aminobutanedioic acid | 1783-96-6 | C4H7NO4 | 详情 | 详情 |
| (I) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (II) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (III) | 23689 | 2,2-dimethyl-5-propionyl-1,3-dioxane-4,6-dione | C9H12O5 | 详情 | 详情 | |
| (IV) | 23712 | 1-ethanethiol; ethylhydrosulfide | 75-08-1 | C2H6S | 详情 | 详情 |
| (V) | 23696 | S-ethyl 3-oxopentanethioate | C7H12O2S | 详情 | 详情 | |
| (VI) | 23692 | propyl 3-oxo-3-phenylpropanoate | C12H14O3 | 详情 | 详情 | |
| (VII) | 23693 | propyl (E)-3-amino-3-phenyl-2-propenoate | C12H15NO2 | 详情 | 详情 | |
| (VIII) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (IX) | 23695 | propyl 6-ethyl-5-[(ethylsulfanyl)carbonyl]-2-phenyl-4-propyl-1,4-dihydro-3-pyridinecarboxylate | C23H31NO3S | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)Ketal exchange of acetonide (I) with butyraldehyde (II) under acidic conditions provides the corresponding butylidene ketal (III). The primary alcohol group of (III) is then mesylated with methanesulfonyl chloride in pyridine to furnish (IV). Subsequent displacement of the mesylate group of (IV) by racemic alpha-mercapto-gamma-butyrolactone (V) gives rise to a mixture of the title compound along with its (R)-epimer (VI), which can be separated employing preparative HPLC. (1,2)
| 【1】 Angell, R.M.; Biggadike, K.; Farrell, R.M.; Flack, S.S.; Hancock, A.P.; Irving, W.R.; Lynn, S.M.; Procopiou, P.A.; Novel glucocorticoid antedrugs possessing a 21-(gamma-lactone) ring. J Chem Soc - Perkins Trans I 2002, 6, 831. |
| 【2】 Farrell, R.M.; Biggadike, K. (Glaxo Wellcome Inc.); 21-(2-Oxo-tetrahydrofuran)-thio pregnane derivs., a process for their production and pharmaceutical compsns. containing them. US 6013244; WO 9724367 . |
| 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) | 47571 | (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a,8,8-tetramethyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C24H32F2O6 | 详情 | 详情 | |
| (II) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (III) | 47572 | (4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-6b-glycoloyl-5-hydroxy-4a,6a-dimethyl-8-propyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one | C25H34F2O6 | 详情 | 详情 | |
| (IV) | 64290 | 2-[(4aS,4bR,5S,6aS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-2-oxo-8-propyl-2,3,4,4a,4b,5,6,6a,9a,10,10a,10b,11,12-tetradecahydro-6bH-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-6-yl]-2-oxoethyl methanesulfonate | C26H36F2O8S | 详情 | 详情 | |
| (V) | 46294 | 3-sulfanyldihydro-2(3H)-furanone | C4H6O2S | 详情 | 详情 | |
| (VI) | 64291 | (4aS,4bR,5S,6aS,6bS,8R,9aR,10aS,10bS,12S)-4b,12-difluoro-5-hydroxy-4a,6a-dimethyl-6b-(2-{[(3R)-2-oxotetrahydro-3-furanyl]sulfanyl}acetyl)-8-propyl-3,4,4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-tetradecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2 | C29H38F2O7S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(IV)Preparation of the 15-methylerythromycin A precursor (XI) is accomplished by a chemobiosynthetic approach, utilizing the diketide surrogate (IX). Synthesis of (IX) is carried out as follows. Acylation of (S)-4-benzyl-2-oxazolidinone (I) with propionyl chloride (II) affords the N-propionyl oxazolidinone (III). Diastereoselective aldol condensation of (III) with butyraldehyde (IV) employing dibutylboron triflate leads to adduct (V). Deacetylation of cysteamine hydrochloride (VI) with Ac2O provides (VII). Then, selective hydrolysis of the thioester function of (VII) under alkaline conditions provides thiol (VIII). Condensation of the acyl oxazolidinone (V) with thiol (VIII) in the presence of AlMe3 gives rise to the thioester substrate (IX) (1). Incubation of a recombinant Streptomyces coelicolor strain with the diketide surrogate (IX) leads to the production of 6-deoxy-15-methylerythronolide B (X). Subsequent bioconversion of the aglycone (X) in a Saccharopolyspora erythraea strain affords the desired 15-methylerythromycin A (XI).
| 【1】 Macielag, M.; Abbanat, D.; Ashley, G.; Foleno, B.; Fu, H.; Li, Y.; Wira, E.; Bush, K.; Structure-activity studies of 15-methyl ketolides: Optimization of the heterocyclic substituent. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-1662. |
| 【2】 Hlasta, D.; Khosla, C.; Chu, D.T.W.; Ashley, G.; Henninger, T.C.; Grant, E.B. (Ortho-McNeil Pharmaceutical, Inc.); Ketolide antibacterials. WO 0232918 . |
| 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) | 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 |
| (II) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (III) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (IV) | 23694 | butyraldehyde | 123-72-8 | C4H8O | 详情 | 详情 |
| (V) | 62287 | (4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methylhexanoyl]-1,3-oxazolidin-2-one | C17H23NO4 | 详情 | 详情 | |
| (VI) | 13186 | 2-Aminoethanethiol; 2-Amino-1-ethanethiol; 2-Aminoethylhydrosulfide; Cysteamine | 60-23-1 | C2H7NS | 详情 | 详情 |
| (VII) | 62288 | Ethanethioic acid, S-[2-(acetylamino)ethyl] ester; N,S-DIACETYLCYSTEAMINE; (TM)S-(2-(ACETYLAMINO)ETHYL) ETHANETHIOATE}; N,S-DIACETYL-BETA-MERCAPTOETHYLAMINE; N,s-Diacetylcysteamine; N-2-Mercaptoethylacetamide-acetate; {S-[2-(ACETYLAMINO)ETHYL] ETHANETHIOATE}; N,S-DIACETYLCYSTEAMINE*; N,S-Diacetyl-.beta.-mercaptoethylamine | 1420-88-8 | C6H11NO2S | 详情 | 详情 |
| (VIII) | 20034 | N-(2-sulfanylethyl)acetamide | 1190-73-4 | C4H9NOS | 详情 | 详情 |
| (IX) | 62289 | S-[2-(acetylamino)ethyl] (2S,3R)-3-hydroxy-2-methylhexanethioate | C11H21NO3S | 详情 | 详情 | |
| (X) | 62290 | (3R,4S,5R,6S,7S,9R,11R,12S,13R,14R)-4,6,12-trihydroxy-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione | C22H40O6 | 详情 | 详情 | |
| (XI) | 62291 | (3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-6-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-7,12,13-trihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-pr | C38H69NO13 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(II)The title compound is prepared by reductive alkylation of deoxygalactonojirimycin (I) with butyraldehyde (II) under catalytic hydrogenation conditions in the presence of palladium black and sodium acetate buffer
| 【1】 Platt, F.M.; Neises, G.R.; Dwek, R.A.; Butters, T.D. (Pharmacia Corp.); Novel deoxygalactonojirimycin derivs.. EP 0698012; JP 1996510244; US 5399567; US 6291657; WO 9426714 . |