tert-butyl (2R,3R,4R,5S)-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-formyl-1-pyrrolidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】47667

【品名】tert-butyl (2R,3R,4R,5S)-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-formyl-1-pyrrolidinecarboxylate

【CA登记号】

【分子式】C₃₂H₃₇NO₆

【分子量】531.64892

【元素组成】C 72.29% H 7.01% N 2.63% O 18.06%

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)

The condensation of benzylated D-arabinofuranose (I) with phosphonate (II) in benzene gives the unsaturated ester (III), which is reduced with DIBAL in dichloromethane, yielding the alcohol (IV). The selective monosilylation of (IV) with Tbdms-Cl, TEA and DMAP in DMF affords the silyl ether (V), which is treated with chloromethylsulfonyl chloride and pyridine to provide the sulfonate (VI). The reaction of (VI) with CsOAc and a crown ether in toluene gives the acetate (VII) with inversion of the configuration at the acetoxy group. Hydrolysis of the acetate group with NaOMe in THF yields the alcohol (VIII), which is chloromesylated as before, affording the sulfonate (IX). The treatment of (IX) with HCl in THF eliminates the silyl group, providing the unsaturated alcohol (X), which is epoxidized with tBu-OOH, Ti(OAc)4 and D-(-)-diethyl tartrate to give the chiral epoxide (XI). The reaction of (XI) with sodium azide in DMF yields the azido compound (XII) with the correct steric configuration. The reductive cyclization of (XII) with PPh3, H2 and Pd/C in methanol affords the pyrrolidine (XIII), which is N-protected with Boc2O and TEA in dichloromethane, providing the carbamate (XIV). Oxidative cleavage of the vicinal diol of (XIV) with Pb(OAc)4 in toluene gives the carbaldehyde (XV).

参考文献中间体

合成目标

【1】 Takebayashi, M.; Kajimoto, T.; Kanie, O.; Hiranuma, S.; Kanie, Y.; Wong, C.-H.; A versatile synthetic strategy for the preparation and discovery of new iminocyclitols as inhibitors of glucosidases. J Org Chem 1999, 64, 14, 5280.
【2】 Wong, C.-H.; Liu, J. (Scripps Research Institute); Iminocyclitol inhibitors of hexoaminidase and glycosidase. WO 0068194 .

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)	47654	(3S,4S,5R)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]tetrahydro-2-furanol		C₂₆H₂₈O₅	详情	详情
(II)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(III)	47655	methyl (E,4R,5R,6R)-4,5,7-tris(benzyloxy)-6-hydroxy-2-heptenoate		C₂₉H₃₂O₆	详情	详情
(IV)	47656	(E,4R,5R,6R)-4,5,7-tris(benzyloxy)-2-heptene-1,6-diol		C₂₈H₃₂O₅	详情	详情
(V)	47657	(2R,3R,4R,5E)-1,3,4-tris(benzyloxy)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hepten-2-ol		C₃₄H₄₆O₅Si	详情	详情
(VI)	47658	(1R,2S,3R,4E)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6-[[tert-butyl(dimethyl)silyl]oxy]-4-hexenyl chloromethanesulfonate		C₃₅H₄₇ClO₇SSi	详情	详情
(VII)	47659	(1S,2S,3R,4E)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6-[[tert-butyl(dimethyl)silyl]oxy]-4-hexenyl acetate		C₃₆H₄₈O₆Si	详情	详情
(VIII)	47660	(2S,3R,4R,5E)-1,3,4-tris(benzyloxy)-7-[[tert-butyl(dimethyl)silyl]oxy]-5-hepten-2-ol		C₃₄H₄₆O₅Si	详情	详情
(IX)	47661	(1S,2S,3R,4E)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6-[[tert-butyl(dimethyl)silyl]oxy]-4-hexenyl chloromethanesulfonate		C₃₅H₄₇ClO₇SSi	详情	详情
(X)	47662	(1S,2S,3R,4E)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6-hydroxy-4-hexenyl chloromethanesulfonate		C₂₉H₃₃ClO₇S	详情	详情
(XI)	47663	(1S,2S,3S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-3-[(2S,3R)-3-(hydroxymethyl)oxiranyl]propyl chloromethanesulfonate		C₂₉H₃₃ClO₈S	详情	详情
(XII)	47664	[(2R,3S)-3-[(1S,2R,3R)-3-azido-1,2,4-tris(benzyloxy)butyl]oxiranyl]methanol		C₂₈H₃₁N₃O₅	详情	详情
(XIII)	47665	(1S)-1-[(2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]pyrrolidinyl]-1,2-ethanediol		C₂₈H₃₃NO₅	详情	详情
(XIV)	47666	tert-butyl (2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-[(1S)-1,2-dihydroxyethyl]-1-pyrrolidinecarboxylate		C₃₃H₄₁NO₇	详情	详情
(XV)	47667	tert-butyl (2R,3R,4R,5S)-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-formyl-1-pyrrolidinecarboxylate		C₃₂H₃₇NO₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

The reduction of aldehyde (XV) with DIBAL in dichloromethane gives the carbinol (XVI), which is treated with Ms-Cl and TEA to yield the mesylate (XVII). The reaction of (XVII) with sodium azide in DMF affords the corresponding azide (XVIII), which is reduced with H2 over Pd/C in methanol to provide the amino compound (XIX). The reaction of (XIX) with Ac2O in pyridine gives the expected amide (XX), which is treated with TFA to eliminate the carbamate protecting group, thus yielding pyrrolidine (XXI). The reductive methylation of (XXI) with formaldehyde and NaBH3CN in methanol affords the N-methylated pyrrolidine (XXII), which is finally deprotected by hydrogenation with H2 over Pd/C in methanol.

参考文献中间体

合成目标

【1】 Takebayashi, M.; Kajimoto, T.; Kanie, O.; Hiranuma, S.; Kanie, Y.; Wong, C.-H.; A versatile synthetic strategy for the preparation and discovery of new iminocyclitols as inhibitors of glucosidases. J Org Chem 1999, 64, 14, 5280.
【2】 Wong, C.-H.; Liu, J. (Scripps Research Institute); Iminocyclitol inhibitors of hexoaminidase and glycosidase. WO 0068194 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XV)	47667	tert-butyl (2R,3R,4R,5S)-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-formyl-1-pyrrolidinecarboxylate	C₃₂H₃₇NO₆	详情	详情
(XVI)	47668	tert-butyl (2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-(hydroxymethyl)-1-pyrrolidinecarboxylate	C₃₂H₃₉NO₆	详情	详情
(XVII)	47669	tert-butyl (2R,3R,4R,5R)-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-[[(methylsulfonyl)oxy]methyl]-1-pyrrolidinecarboxylate	C₃₃H₄₁NO₈S	详情	详情
(XVIII)	47670	tert-butyl (2R,3R,4R,5R)-2-(azidomethyl)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]-1-pyrrolidinecarboxylate	C₃₂H₃₈N₄O₅	详情	详情
(XIX)	47671	tert-butyl (2R,3R,4R,5R)-2-(aminomethyl)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]-1-pyrrolidinecarboxylate	C₃₂H₄₀N₂O₅	详情	详情
(XX)	47672	tert-butyl (2R,3R,4R,5R)-2-[(acetamido)methyl]-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]-1-pyrrolidinecarboxylate	C₃₄H₄₂N₂O₆	详情	详情
(XXI)	47673	N-([(2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]pyrrolidinyl]methyl)acetamide	C₂₉H₃₄N₂O₄	详情	详情
(XXII)	47674	N-([(2R,3R,4R,5R)-3,4-bis(benzyloxy)-5-[(benzyloxy)methyl]-1-methylpyrrolidinyl]methyl)acetamide	C₃₀H₃₆N₂O₄	详情	详情

Extended Information