1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone -Drug Synthesis Database

【结构式】

【分子编号】16241

【品名】1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone

【CA登记号】

【分子式】C₂₁H₂₃NO₂

【分子量】321.41916

【元素组成】C 78.47% H 7.21% N 4.36% O 9.96%

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：(IV)

1) The reaction of cis-(1S,2R)-indanediol (I) with acetonitrile and concentrated H2SO4 gives cis-(1S,2R)-1-aminoindan-2-ol (II), which is cyclocondensed with 3-phenylpropionyl chloride (III), isopropenyl methyl ether and triethylamine to yield the acetonide amide (IV). The condensation of amide (IV) with (S)-(+)-glycidyl p-toluenesulfonate (V) in the presence of lithium hexamethyldisylazide (LHS) affords the chiral epoxide (VI), which is condensed with 4-(tert-butoxycarbonyl)-N-tert-butylpiperazine-2(S)-carboxamide (VII) in refluxing isopropyl acetate and deprotected with aqueous HCl to give the dihydroxy-diamide (VIII). Finally, this compound is condensed with 3-(chloromethyl)pyridine (IX) by means of triethylamine in DMF. 2) The amide (IV) can also be alkylated with allyl bromide and butyllithium to the pentenyl amide (X), which is diastereoselectively converted to the chiral iodohydrine (XI) by means of N-iodosuccinimide (NIS). Finally, this compound is cyclized in basic medium, yielding the epoxide (VI), already obtained.

参考文献中间体

合成目标

【1】 Maligres, P.E.; Upadhyay, V.; Rossen, K.; Cianciosi, S.J.; Purick, R.M.; Eng, K.K.; Reamer, R.A.; Askin, D.; Volante, R.P.; Reider, P.J.; Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides: Synthesis of the Merck HIV-1 protease inhibitor epoxide intermediate. Tetrahedron Lett 1995, 36, 13, 2195-8.
【2】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600.
【3】 Askin, D.; Volante, R.P.; Eng, K.K. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502584 .
【4】 Verhoeven, T.R.; Roberts, E.F.; Senanayake, C.H.; Ryan, K.M. (Merck & Co., Inc.); Regiospecific processes to make cis-1-amino-2-alkanol from diol or halohydrin. US 5449830 .
【5】 Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J.; Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett 1994, 35, 5, 673-6.
【6】 Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; et al.; L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem 1994, 37, 21, 3443-51.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
	17354	isopropenyl methyl ether; 2-methoxy-1-propene	116-11-0	C₄H₈O	详情	详情
(I)	16238	(1S,2R)-2,3-dihydro-1H-indene-1,2-diol	67528-22-7	C₉H₁₀O₂	详情	详情
(II)	16239	(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol	126456-43-7	C₉H₁₁NO	详情	详情
(III)	16240	3-phenylpropanoyl chloride; Hydrocinnamoylchloride	645-45-4	C₉H₉ClO	详情	详情
(IV)	16241	1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone		C₂₁H₂₃NO₂	详情	详情
(V)	16242	(2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate	113826-06-5	C₁₀H₁₂O₄S	详情	详情
(VI)	16243	(2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone		C₂₄H₂₇NO₃	详情	详情
(VII)	16244	tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate	150323-35-6	C₁₄H₂₇N₃O₃	详情	详情
(VIII)	16245	(2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide		C₃₀H₄₂N₄O₄	详情	详情
(IX)	15793	3-(Chloromethyl)pyridine	3099-31-8	C₆H₆ClN	详情	详情
(X)	16247	(2S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-penten-1-one		C₂₄H₂₇NO₂	详情	详情
(XI)	16248	(2R,4S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-hydroxy-5-iodo-1-pentanone		C₂₄H₂₈INO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

4) The condensation of the chiral piperazine (VII) with (S)-(+)-glycicyl 3-nitrobenzenesulfonate (XXII) by means of diisopropylethylamine in DMF [or with (S)-glycidol (XXIII), tosyl chloride and NaH] gives the epoxide (XXIV), which is condensed with the propionamide (IV) by means of butyllithium in THF, yielding the protected hydroxyamide (XXV). The deprotection of (XXV) with aqueous HCl affords the dihydroxy-diamide (VIII), already obtained, which is finally alkylated with 3-(chloromethyl)pyridine (IX) as before.

参考文献中间体

合成目标

【1】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600.
【2】 Askin, D.; Reider, P.; Rossen, K.; Varsolona, R.J.; Wells, K.M. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502583 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	16241	1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone		C₂₁H₂₃NO₂	详情	详情
(VII)	16244	tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate	150323-35-6	C₁₄H₂₇N₃O₃	详情	详情
(VIII)	16245	(2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide		C₃₀H₄₂N₄O₄	详情	详情
(IX)	15793	3-(Chloromethyl)pyridine	3099-31-8	C₆H₆ClN	详情	详情
(XXII)	16259	(2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate	115314-14-2	C₉H₉NO₆S	详情	详情
(XXIII)	16260	(R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol	57044-25-4	C₃H₆O₂	详情	详情
(XXIV)	16261	tert-butyl (3S)-3-[(tert-butylamino)carbonyl]-4-[(2R)oxiranylmethyl]tetrahydro-1(2H)-pyrazinecarboxylate		C₁₇H₃₁N₃O₄	详情	详情
(XXV)	16262	tert-butyl (3S)-4-[(2S,4R)-5-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-4-benzyl-2-hydroxy-5-oxopentyl]-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate		C₃₈H₅₄N₄O₆	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

The condensation of indeno[1,2-d]oxazole derivative (I) with (S)-(+)-glycidyl tosylate (II) by means of LiHMDS gives the adduct (III), which is deprotected with HCl to yield the epoxide (IV). Finally, this compound is condensed with the dibenzylpyrrolidone (V) by means of P4 phosphazene base (commercially available) in THF to afford the target amide.

参考文献中间体

合成目标

【1】 Spaltenstein, A.; Cleary, D.G.; Almond, M.R.; Kazmierski, W.M.; Wright, L.L.; Tung, R.D.; Hazen, R.J.; Furfine, E.S.; Salituro, F.G.; Bock, W.J.; Novel inhibitors of HIV protease: Design, synthesis and biological evaluation of picomolar inhibitors containing cyclic P1/P2 scaffolds. Bioorg Med Chem Lett 2000, 10, 11, 1159.
【2】 Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J.; Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett 1994, 35, 5, 673-6.

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)	16241	1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone		C₂₁H₂₃NO₂	详情	详情
(II)	16740	(2S)-(+)-Glycidyl tosylate; (2S)oxiranylmethyl 4-methylbenzenesulfonate	70987-78-9	C₁₀H₁₂O₄S	详情	详情
(III)	16243	(2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone		C₂₄H₂₇NO₃	详情	详情
(IV)	50304	(2R)-2-benzyl-N-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-3-[(2S)oxiranyl]propanamide		C₂₁H₂₃NO₃	详情	详情
(V)	38974	(3S,5R)-3,5-dibenzyl-2-pyrrolidinone		C₁₈H₁₉NO	详情	详情

Extended Information