(3aR,8aS)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole -Drug Synthesis Database

【结构式】

【分子编号】32764

【品名】(3aR,8aS)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole

【CA登记号】

【分子式】C₉H₁₀BNO

【分子量】158.99554

【元素组成】C 67.99% H 6.34% B 6.8% N 8.81% O 10.06%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(II)

The enantioselective reduction of phenacyl bromide (I) with BH3.S(CH3)2 in THF catalyzed by the chiral borolidine (II) (obtained by reaction of (1R,2S)-1-amino-2-indanol (III) with BH3.S(CH3)2 in THF) gives the (R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (IV), which is reduced with H2 over PtO2 in THF/toluene yielding the corresponding amino derivative (V). The reaction of (V) with formic acid and Ac2O affords the formamide (VI), which is condensed with the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) in THF/methanol providing the protected target compound (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol. The intermediate the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) has been obtained by reductocondensation of 1-(4-methoxyphenyl)-2-propanone (IX) and benzylamine by hydrogenation with H2 over Pd/C in methanol yielding racemic N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (X), which is submitted to optical resolution with (S)-mandelic acid to obtain the desired (R)-enantiomer (VII).

参考文献中间体

合成目标

【1】 Hett, R.; et al.; Large-scale synthesis of enantio- and diastereomerically pure (R,R)-formoterol. Org Process Res Dev 1998, 2, 2, 96.
【2】 Hett, R.; Senanayake, C.H.; Fang, K.Q.; Wald, S.A.; Redmon, M.P.; Gao, Y. (Sepracor Inc.); Formoterol process. US 6040344 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(I)	32763	1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanone		C₁₅H₁₂BrNO₄	详情	详情
(II)	32764	(3aR,8aS)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole		C₉H₁₀BNO	详情	详情
(III)	27559	(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol		C₉H₁₁NO	详情	详情
(IV)	32765	(1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol	188690-82-6	C₁₅H₁₄BrNO₄	详情	详情
(V)	32766	(1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-bromo-1-ethanol		C₁₅H₁₆BrNO₂	详情	详情
(VI)	32767	2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenylformamide		C₁₆H₁₆BrNO₃	详情	详情
(VII)	32738	tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate		C₃₄H₄₈N₂O₆S₂	详情	详情
(VIII)	32769	5-((1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide		C₃₃H₃₆N₂O₄	详情	详情
(IX)	10038	4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone	122-84-9	C₁₀H₁₂O₂	详情	详情
(X)	32770	N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine; N-benzyl-1-(4-methoxyphenyl)-2-propanamine		C₁₇H₂₁NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The synthesis of the chiral borolidine catalyst (II) starting from indoline (I), as well as the enantioselective reduction of 4'-(benzyloxy)-3'-nitrophenacyl bromide (III), catalyzed by borolidine (II), and using various borane complexes (borane/dimethylsulfide, borane/THF and borane/diethylaniline), has been studied in order to solve the problems presented in large-scale synthesis. The conclusions of the study are that the complex borane/diethylaniline (DEANB) is the most suitable reagent for large-scale reduction of phenacyl bromide (III) since the chemical hazards and inconsistent reagent quality of the borane/THF and borane/dimethylsulfide complexes disqualified their use in large-scale processes. The best reaction conditions of the reduction with this complex are presented.

参考文献中间体

合成目标

【1】 Wilkinson, H.S.; et al.; Diethylanilineborane: A practical, safe, and consistent-quality borane source for the large-scale enantioselective reduction of a ketone intermediate in the synthesis of (R,R)-formoterol. Org Process Res Dev 2002, 6, 2, 146.

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)	27559	(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol		C₉H₁₁NO	详情	详情
(II)	32764	(3aR,8aS)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole		C₉H₁₀BNO	详情	详情
(III)	32763	1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanone		C₁₅H₁₂BrNO₄	详情	详情
(IV)	32765	(1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol	188690-82-6	C₁₅H₁₄BrNO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

By reduction of a mixture of 1-(3-formylamino-4-hydroxyphenyl)-2-aminoethanol (VIII) and 1-(4-methoxyphenyl)-2-propanone (IX) with H2 over Pt in ethanol, followed by a treatment with fumaric acid (A).

参考文献中间体

合成目标

【1】 Tanoury GJ, Hett R,Kessler D,et aL 2002. Taking advantage of polymorphism to effect an impurity removalt: development of a thermodynamic crystal form of (R,R)-fonnoterol tartnte. Org Proc Res Dev,6 (6)．855~862
【1】 Murase, K.; et al.; JP 7512040 .
【2】 Castaner, J.; Weetman, D.F.; BD 40A. Drugs Fut 1977, 2, 10, 639.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	23808	Fumaric acid; (E)-2-butenedioic acid	110-17-8	C₄H₄O₄	详情	详情
(I)	66381	(1R,2S)-1-Amino-2-indanol	7480-35-5	C₉H₁₁NO	详情	详情
(II)	32764	(3aR,8aS)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole		C₉H₁₀BNO	详情	详情
(III)	32765	(1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol	188690-82-6	C₁₅H₁₄BrNO₄	详情	详情
(IV)	32766	(1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-bromo-1-ethanol		C₁₅H₁₆BrNO₂	详情	详情
(V)	32767	2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenylformamide		C₁₆H₁₆BrNO₃	详情	详情
(VI)	32738	tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate		C₃₄H₄₈N₂O₆S₂	详情	详情
(VII)	32769	5-((1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide		C₃₃H₃₆N₂O₄	详情	详情
(VIII)	33905	5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenylformamide		C₉H₁₂N₂O₃	详情	详情
(VIII)	66382	N-[2-Hydroxy-5-[1(R)-hydroxy-2-[2-(4-methoxyphenyl)-1(R)-methylethylamino]ethyl]phenyl]formamide	67346-49-0	C₁₉H₂₄N₂O₄	详情	详情
(IX)	10038	4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone	122-84-9	C₁₀H₁₂O₂	详情	详情

Extended Information