UIC-PI, UIC-94-003, -Drug Synthesis Database

【结构式】

【药物名称】UIC-PI, UIC-94-003

【化学名称】N-[1(S)-Benzyl-2(R)-hydroxy-3-[N-isobutyl-N-(4-methoxyphenylsulfonyl)amino]propyl]carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester

【CA登记号】206362-00-7

【分子式】C₂₈H₃₈N₂O₈S

【分子量】562.68766

【开发单位】Finch Univ. Health Sci./Chicago Med Sch. (Originator), University of Illinois (Originator), University of the Pacific (Originator), Sequoia Pharmaceuticals (Not Determined)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors

合成路线1 合成路线2

合成路线1

The Grignard reaction of vinyloxirane (I) with phenylmagnesium bromide and CuCN in THF gives 4-phenyl-2-buten-1-ol (II), which is submitted to a Sharpless epoxidation with t-BuOOH and Ti(Oi-Pr)4 in dichloromethane in the presence of (-)-diethyl tartrate [(-)-DET] yielding the chiral epoxide (III). The reaction of (III) with Ti(Oi-Pr)2(N3)2 in refluxing benzene affords the 3(S)-azido-4-phenylbutane-1,2(S)-diol (IV), which is epoxidized with 2-acetoxy-2-methylpropionyl chloride (A) and NaOMe in THF to give the chiral azidoepoxide (V). The reaction of (V) with isobutylamine (VI) in hot isopropanol yields the secondary amine (VII), which is condensed with 4-methoxyphenylsulfonyl chloride (VIII) in pyridine affording the sulfonamide (IX). The reduction of the azido group of (IX) with H2 over Pd/C in methanol provides (X) with a primary amino group that is finally condensed with the succinimidinyl carbonate (XI) by means of triethylamine in acetonitrile.

参考文献中间体

【1】 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687.
【2】 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 .
【3】 Ghosh, A.K.; et al.; Potent HIV protease inhibitors: The development of tetrahydrofuranylglycines as novel P2-ligands and pyrazine amides as P3-ligands. J Med Chem 1993, 36, 16, 2300.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	17616	bromo(phenyl)magnesium; Phenyl Magnesium Bromide	100-58-3	C₆H₅BrMg	详情	详情
(A)	32808	2-chloro-1,1-dimethyl-2-oxoethyl acetate	40635-66-3	C₆H₉ClO₃	详情	详情
(I)	32805	2-vinyloxirane	930-22-3	C₄H₆O	详情	详情
(II)	32806	(E)-4-phenyl-2-buten-1-ol		C₁₀H₁₂O	详情	详情
(III)	32807	[(2R,3S)-3-benzyloxiranyl]methanol	116949-62-3	C₁₀H₁₂O₂	详情	详情
(IV)	14544	(2S,3S)-3-azido-4-phenyl-1,2-butanediol		C₁₀H₁₃N₃O₂	详情	详情
(V)	14547	(1S)-1-[(2S)oxiranyl]-2-phenylethyl azide; (2S)-2-[(1S)-1-azido-2-phenylethyl]oxirane		C₁₀H₁₁N₃O	详情	详情
(VI)	13306	2-Methyl-1-propanamine; Isobutylamine	78-81-9	C₄H₁₁N	详情	详情
(VII)	32809	(2R,3S)-3-azido-1-(isobutylamino)-4-phenyl-2-butanol		C₁₄H₂₂N₄O	详情	详情
(VIII)	15719	4-methoxybenzenesulfonyl chloride	98-68-0	C₇H₇ClO₃S	详情	详情
(IX)	32810	N-[(2R,3S)-3-azido-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide		C₂₁H₂₈N₄O₄S	详情	详情
(X)	32811	N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-methoxybenzenesulfonamide		C₂₁H₃₀N₂O₄S	详情	详情
(XI)	32812	1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione		C₁₁H₁₃NO₇	详情	详情

合成路线2

The intermediate succinimidinyl carbonate (XI) has been obtained as follows: The reaction of 2,3-dihydrofuran (XII) with N-iodosuccinimide (NIS) and propargyl alcohol (XIII) in dichloromethane gives trans-3-iodo-2-(propargyloxy)tetrahydrofuran (XIV), which is cyclized by means of Bu3SnH and AIBN in hot toluene yielding the methylenic compound (XV). The ozonolysis of (XV) with O3, followed by reduction with NaBH4 in ethanol affords the racemic alcohol (XVI), which is submitted to an enantioselective acylation with Ac2O and lipase 30 to obtain the chiral alcohol (3R,3aS,6aR)-(XVI). Finally, this compound is treated with disuccinimidinyl carbonate and triethylamine in acetonitrile to provide the target intermediate (XI).

参考文献中间体

【1】 Ghosh, A.K.; Kincaid, J.F.; Cho, W.; Walters, D.E.; Krishnan, K.; Hussain, K.A.; Koo, Y.; Cho, H.; Rudall, C.; Holland, L.; Buthod, J.; Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998, 8, 6, 687.
【2】 Hussain, K.A.; Gulnik, S.V.; Ghosh, A.K.; Erickson, J.W. (University of Illinois; US Department of Health & Human Services); Multi-drug resistant retroviral protease inhibitors and associated methods. WO 9967254 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(rac)-(XVI)	32815	(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol		C₆H₁₀O₃	详情	详情
3R,3aS,6aR-XVI)	32815	(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol		C₆H₁₀O₃	详情	详情
(XI)	32812	1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione		C₁₁H₁₃NO₇	详情	详情
(XII)	22766	2,3-dihydrofuran	1191-99-7	C₄H₆O	详情	详情
(XIII)	16664	Propargyl Alcohol; 2-propyn-1-ol	107-19-7	C₃H₄O	详情	详情
(XIV)	32813	(2R,3S)-3-iodo-2-(2-propynyloxy)tetrahydrofuran; (2R,3S)-3-iodotetrahydro-2-furanyl 2-propynyl ether		C₇H₉IO₂	详情	详情
(XV)	32814	(3aS,6aR)-3-methylenehexahydrofuro[2,3-b]furan		C₇H₁₀O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)