deoxynojirimycin; (2R,3R,4R,5S)-2-(hydroxymethyl)-3,4,5-piperidinetriol -Drug Synthesis Database

【结构式】

【分子编号】17944

【品名】deoxynojirimycin; (2R,3R,4R,5S)-2-(hydroxymethyl)-3,4,5-piperidinetriol

【CA登记号】19130-96-2

【分子式】C₆H₁₃NO₄

【分子量】163.17356

【元素组成】C 44.17% H 8.03% N 8.58% O 39.22%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XV)

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.

参考文献中间体

合成目标

【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2

该中间体在本合成路线中的序号：(V)

Treatment of propargyl alcohol (I) with two equivalents of butyllithium in THF, followed by chlorotrimethylsilane, and then with methanol and a catalytic amount of distannoxane, gave 3-(trimethylsilyl)-2-propyn-1-ol (II). Partial reduction of acetylenic triple bond with sodium bis(2-methoxyethoxy)aluminum hydride afforded the expected (E)-olefin (III), which on treatment with methanesulfonyl chloride and triethylamine in dichloromethane provided mesylate (IV). Finally, alkylation of 1-deoxynojirimycin (V) with mesylate (IV) in the presence of triethylamine gave the title compound.

参考文献中间体

合成目标

【1】 Lesur, B.; et al.; New deoxynojirimycin derivatives as potent inhibitors of intestinal alpha-glucohydrolases. Bioorg Med Chem Lett 1997, 7, 3, 355-360.
【2】 Lesur, B.; Ducep, J.-B.; Danzin, C. (Merrell Pharmaceuticals, Inc.); Novel nojirimycin derivs.. EP 0453692; EP 0454580; JP 1993086072; US 5252587; US 5536732 .

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)	16664	Propargyl Alcohol; 2-propyn-1-ol	107-19-7	C₃H₄O	详情	详情
(II)	17941	3-Trimethylsilylpropargyl alcohol; 3-(trimethylsilyl)-2-propyn-1-ol	5272-36-6	C₆H₁₂OSi	详情	详情
(III)	17942	(E)-3-(trimethylsilyl)-2-propen-1-ol; trans-3-(Trimethylsilyl)allyl alcohol	59376-64-6	C₆H₁₄OSi	详情	详情
(IV)	17943	(E)-3-(trimethylsilyl)-2-propenyl methanesulfonate		C₇H₁₆O₃SSi	详情	详情
(V)	17944	deoxynojirimycin; (2R,3R,4R,5S)-2-(hydroxymethyl)-3,4,5-piperidinetriol	19130-96-2	C₆H₁₃NO₄	详情	详情

Extended Information