(1S,3S,5S)-1,3-di(2,3-dihydro-1,4-benzodioxin-6-yl)-5-phenyltetrahydro-8H-[1,3]oxazolo[4,3-c][1,4]oxazin-8-one -Drug Synthesis Database

【结构式】

【分子编号】61799

【品名】(1S,3S,5S)-1,3-di(2,3-dihydro-1,4-benzodioxin-6-yl)-5-phenyltetrahydro-8H-[1,3]oxazolo[4,3-c][1,4]oxazin-8-one

【CA登记号】

【分子式】C₂₈H₂₅NO₇

【分子量】487.50904

【元素组成】C 68.98% H 5.17% N 2.87% O 22.97%

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：(III)

The condensation of 2,3-dihydrobenzodioxin-6-carbaldehyde (I) with 5(S)-phenylmorpholin-2-one (I) in refluxing toluene gives the adduct (III), which is treated first with pyrrolidine (IV) in chloroform and then with HCl in refluxing methanol to yield the pyrrolidide (V). The reduction of (V) with LiAlH4 in THF affords compound (VI), which is treated with H2 over Pd/C in THF/methanol/water to provide the aminoalcohol (VII). Finally, the amino group of (VII) is acylated by means of palmitoyl chloride (VIII) and DIEA in dichloromethane to furnish the target palmitoylamide.

参考文献中间体

合成目标

【1】 Hirth, B.H.; Siegel, C. (Genzyme Corp.); Synthesis of UDP-glucose: N-Acylsphingosine glucosyltransferase inhibitors. US 2003050299; WO 0308399 .

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)	61797	2,3-dihydro-1,4-benzodioxine-6-carbaldehyde; 1,4-Benzodioxan-6-carboxaldehyde; 3,4-ethylenedioxybenzaldehyde ;benzodioxane-6-carboxaldehyde	29668-44-8	C₉H₈O₃	详情	详情
(II)	61798	(5S)-5-phenyl-2-morpholinone;5(S)-phenylmorpholin-2-one;(5S)-3,4,5,6-Tetrahydro-5-phenyl-4(H)-1,4-oxazin-2-one	144896-92-4	C₁₀H₁₁NO₂	详情	详情
(III)	61799	(1S,3S,5S)-1,3-di(2,3-dihydro-1,4-benzodioxin-6-yl)-5-phenyltetrahydro-8H-[1,3]oxazolo[4,3-c][1,4]oxazin-8-one		C₂₈H₂₅NO₇	详情	详情
(IV)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(V)	61800	(2R,3R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-2-[(2-hydroxy-1-phenylethyl)amino]-1-(1-pyrrolidinyl)-1-propanone		C₂₃H₂₈N₂O₅	详情	详情
(VI)	61801	(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-3-(1-pyrrolidinyl)-1-propanol		C₂₃H₃₀N₂O₄	详情	详情
(VII)	61802	(1R,2R)-2-amino-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1-pyrrolidinyl)-1-propanol		C₁₅H₂₂N₂O₃	详情	详情
(VIII)	19273	acetyl chloride	75-36-5	C₂H₃ClO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Reaction of bromoacetyl bromide (I) with phenol at 80 °C gives the phenyl ester (II) , which by cyclization with (S)-(+)-phenylglycinol (III), previously treated with DIEA, in acetonitrile provides 5(S)-phenylmorpholin-2-one (IV) . Treatment of compound (IV) with HCl affords the corresponding HCl salt (V), which is reacted with NaHCO3 followed by coupling with benzodioxane-6-carboxaldehyde (VI) in refluxing EtOAc/toluene to yield the oxazine adduct (VII). Oxazine derivative (VII) can also be obtained by direct coupling of 5(S)-phenylmorpholin-2-one (IV) with aldehyde (VI) in refluxing toluene. Opening of adduct (VII) with pyrrolidine (VIII) in CH2Cl2, CHCl3 or refluxing THF followed by addition of HCl in refluxing MeOH leads to 3-(1,4-benzodioxan-6-yl)-3(R)-hydroxy-2(R)-(2-hydroxy-1-phenylethylamino)-1-(pyrrolidin-1-yl)propanone (IX), which is reduced with LiAlH4 in refluxing THF to give diol (X). Cleavage of diol (X) by means of H2 and Pd(OH)2 in the presence of either CF3COOH or HCl in MeOH or EtOH/H2O provides amine (XI), which is finally coupled with octanoic acid N-hydroxysuccinimide ester (XII) in CH2Cl2 . Ester (XII) is prepared by condensation of octanoyl chloride (XIII) with N-hydroxysuccinimide (XIV) by means of Et3N in CH2Cl2 .

参考文献中间体

合成目标

【1】 Dellaria, J.F. Jr., Santarsiero, B.D. Enantioselective synthesis of alphaamino acid derivatives via the stereoselective alkylation of a homochiral glycine enolate synthon. J Org Chem 1989, 54(16): 3916-26.
【2】 Siegel, C., Hirth, B.H. (Genzyme Corp.). Synthesis of UDP-glucose:N-acylsphingosine glucosyltransferase inhibitors. CA 2453978, EP 1409467, EP 2067775, JP 2005255686, JP 2005502635, JP 2010095546, US 2003050299, US 6855830, WO 2003008399.

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)	14005	2-Bromoacetyl bromide; Bromoacetyl bromide	598-21-0	C₂H₂Br₂O	详情	详情
(II)	69187	phenyl 2-bromoacetate;Phenyl bromoacetate;alpha-Phenyl Bromoacetate;Phenyl a-bromoacetate;bromoacetic acidphenyl ester	620-72-4	C₈H₇BrO₂	详情	详情
(III)	10973	(2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol	20989-17-7	C₈H₁₁NO	详情	详情
(IV)	61798	(5S)-5-phenyl-2-morpholinone;5(S)-phenylmorpholin-2-one;(5S)-3,4,5,6-Tetrahydro-5-phenyl-4(H)-1,4-oxazin-2-one	144896-92-4	C₁₀H₁₁NO₂	详情	详情
(V)	69188	5(S)-phenylmorpholin-2-one hydrochloride		C₁₀H₁₁NO₂.HCl	详情	详情
(VI)	61797	2,3-dihydro-1,4-benzodioxine-6-carbaldehyde; 1,4-Benzodioxan-6-carboxaldehyde; 3,4-ethylenedioxybenzaldehyde ;benzodioxane-6-carboxaldehyde	29668-44-8	C₉H₈O₃	详情	详情
(VII)	61799	(1S,3S,5S)-1,3-di(2,3-dihydro-1,4-benzodioxin-6-yl)-5-phenyltetrahydro-8H-[1,3]oxazolo[4,3-c][1,4]oxazin-8-one		C₂₈H₂₅NO₇	详情	详情
(VIII)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(IX)	61800	(2R,3R)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-2-[(2-hydroxy-1-phenylethyl)amino]-1-(1-pyrrolidinyl)-1-propanone		C₂₃H₂₈N₂O₅	详情	详情
(X)	61801	(1R,2R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-[(2-hydroxy-1-phenylethyl)amino]-3-(1-pyrrolidinyl)-1-propanol		C₂₃H₃₀N₂O₄	详情	详情
(XI)	61802	(1R,2R)-2-amino-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(1-pyrrolidinyl)-1-propanol		C₁₅H₂₂N₂O₃	详情	详情
(XII)	69189	octanoic acid N-hydroxysuccinimide ester;2,5-Dioxopyrrolidin-1-yl octanoate;Caprylic acid N-hydroxysuccinimide ester;N-(Octanoyloxy)succinimide;N-Hydroxysuccinimidyl caprylate	14464-30-3	C₁₂H₁₉NO₄	详情	详情
(XIII)	11123	Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride	111-64-8	C₈H₁₅ClO	详情	详情
(XIV)	10264	1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione	6066-82-6	C₄H₅NO₃	详情	详情

Extended Information