Trospectomycin sulfate, U-63366F, Spexil, -Drug Synthesis Database

【结构式】

【药物名称】Trospectomycin sulfate, U-63366F, Spexil

【化学名称】(2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-2-Butyl-4a,7,9-trihydroxy-6,8-bis(methylamino)decahydropyrano[2,3-b][1,4]benzodioxin-4-one sulfate (1:1) pentahydrate
　　　　　　6'-Propylspectinomycin sulfate pentahydrate

【CA登记号】88851-61-0, 88669-04-9 (anhydrous free base)

【分子式】C₁₇H₄₂N₂O₁₆S

【分子量】562.59209

【开发单位】Pfizer (Originator)

【药理作用】Antibiotics, Anti-Helicobacter Pylori Agents, ANTIINFECTIVE THERAPY, Antiulcer Drugs, GASTROINTESTINAL DRUGS, Treatment of Septic Shock

合成路线1 合成路线2 合成路线3

合成路线1

1) The condensation of N,N'-di(benzyloxycarbonyl)actinamine (I) with the L-glucose nitrosodimer (II) in DMF gives the oxime adduct (III), which is cyclized by means of aqueous HCl yielding the hemiketal triacetate (IV). The treatment of (IV) with anhydrous KHCO3 in acetonitrile affords the enone acetate (V), which is deacetylated with K2HPO4 in methanol to give N,N'-di(benzyloxycarbonyl)dehydrospectinomycin (VI). The hydrogenation of (VI) with H2 over Pd/BaSO4 in pyridine - isopropanol yields free spectinomycin (VII), which is protected again with benzyloxycarbonyl chloride as usual to give N,N'-di(benzyloxycarbonyl)spectinomycin (VIII). The formylation of (VIII) with formic acid - acetic anhydride gives the 2,6-di-O-formyl derivative (IX), which by treatment with acetic anhydride and dimethylaminopyridine (DMAP) is converted into the enol acetate (X). The reaction of (X) with dibromodimethylhydantoin (DBMH) in refluxing CCl4 under visible light illumination affords the unsaturated ketone (XI), which is treated with dimethylformamide dimethyl acetal in hot DMF, yielding the dimethylaminovinylene compound (XII).

参考文献中间体

【1】 White, D.R.; Mizsak, S.A.; Birkenmeyer, R.D.; Thomas, R.C.; Wiley, V.H.; The stereospecific synthesis of spectinomycin. Tetrahedron Lett 1979, 30, 2737-40.
【2】 White, D.R. (Pharmacia Corp.); 6'-Alkylspectinomycins. DE 3308196; US 4532336 .
【3】 Cain, G.A.; White, D.R.; The synthesis of trospectomycin (6'-n-propylspectinomycin, U-63,366F). Tetrahedron Lett 1989, 30, 12, 1469-72.
【4】 White, D.R.; Maring, C.J.; Cain, G.A.; Synthesis and in vitro antibacterial properties of alkylspectinomycin analogs. J Antibiot 1983, 36, 3, 339-42.
【5】 Castaner, J.; Patoia, L.; Trospectomycin Sulfate. Drugs Fut 1991, 16, 4, 323.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11984	N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal	4637-24-5	C₅H₁₃NO₂	详情	详情
(I)	10759	(1R,3S,4R,6S)-3-[Carboxy(methyl)amino]-2,4,5,6-tetrahydroxycyclohexyl(methyl)carbamic acid		C₁₀H₁₈N₂O₈	详情	详情
(II)	10760	(2S,3R,4S,5S,6S)-3-(acetoxy)-2-[(acetoxy)methyl]-5-[[[[(2S,3S,4S,5R,6S)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-chlorotetrahydro-2H-pyran-3-yl](oxo)-lambda(5)-azanylidene]methylene](oxo)-lambda(5)-azanyl]-6-chlorotetrahydro-2H-pyran-4-yl acetate		C₂₅H₃₂Cl₂N₂O₁₆	详情	详情
(III)	10761	(2S,3S,4S,6R)-3-(acetoxy)-2-[(acetoxy)methyl]-6-([(2R,3S,5R,6S)-3,5-bis[[(benzyloxy)carbonyl](methyl)amino]-2,4,6-trihydroxycyclohexyl]oxy)-5-(hydroxyimino)tetrahydro-2H-pyran-4-yl acetate		C₃₆H₄₅N₃O₁₆	详情	详情
(IV)	10762	(2S,3S,4R,4aS,5aS,6R,7R,8S,9R,9aS,10aR)-3-(acetoxy)-2-[(acetoxy)methyl]-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-4a,7,9-trihydroxydecahydro-2H-pyrano[2,3-b][1,4]benzodioxin-4-yl acetate		C₃₆H₄₄N₂O₁₆	详情	详情
(V)	10763	(5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-7,9-dihydroxy-2-methyl-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate		C₃₂H₃₆N₂O₁₂	详情	详情
(VI)	10764	benzyl (4aR,5aR,6S,7S,8R,9S,9aR,10aR)-6-[[(benzyloxy)carbonyl](methyl)amino]-4a,7,9-trihydroxy-2-methyl-4-oxo-4a,5a,6,7,8,9,9a,10a-octahydro-4H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate		C₃₀H₃₄N₂O₁₁	详情	详情
(VII)	10765	(2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-4a,7,9-Trihydroxy-2-methyl-6,8-bis(methylamino)decahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4-one		C₁₄H₂₄N₂O₇	详情	详情
(VIII)	10766	benzyl (2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-6-[[(benzyloxy)carbonyl](methyl)amino]-4a,7,9-trihydroxy-2-methyl-4-oxodecahydro-2H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate		C₃₀H₃₆N₂O₁₁	详情	详情
(IX)	10767	benzyl (2R,4aR,5aR,6R,7R,8R,9S,9aS,10aS)-6-[[(benzyloxy)carbonyl](methyl)amino]-7,9-bis(formyloxy)-4a-hydroxy-2-methyl-4-oxodecahydro-2H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate		C₃₂H₃₆N₂O₁₃	详情	详情
(X)	10768	(2R,4aS,5aR,6R,7R,8R,9S,9aS,10aS)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-7,9-bis(formyloxy)-4a-hydroxy-2-methyl-4a,5a,6,7,8,9,9a,10a-octahydro-2H-pyrano[2,3-b][1,4]benzodioxin-4-yl acetate		C₃₄H₃₈N₂O₁₄	详情	详情
(XI)	10769	(5aR,6R,7R,8R,9S,9aS,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-7,9-bis(formyloxy)-2-methyl-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate		C₃₄H₃₆N₂O₁₄	详情	详情
(XII)	10770	(5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-[(E)-2-(dimethylamino)ethenyl]-7,9-dihydroxy-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate		C₃₅H₄₁N₃O₁₂	详情	详情

合成路线2

Reduction of (XII) with sodium cyanoborohydride in methanolic HCl gives the 2-dimethylaminoethyl compound (XIII), which is treated with m-chloroperbenzoic acid in ethylacetate - Skellysolve B to afford the vinyl derivative (XIV). The reaction of (XIV) with ethylmagnesium bromide and CuBr2 in THF affords the protected propyl-dehydrospectinomycin (XV), which is hydrogenated with lithium tri-sec-butyl borohydride in THF to afford the propyl-spectinomycin (XVI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol. 2) The silylation of the dimethylaminovinylene compound (XII) with trimethylsilylchloride and hexamethyldisilazane in THF gives the silylated compound (XVII), which is treated with ethylmagnesium bromide to yield the 1-butenyl derivative (XVIII). The elimination of the silyl groups of (XVIII) with HF in acetonitrile affords N,N'-di(benzyloxycarbonyl)tetradehydrotrospectomycin (XIX), which is then hydrogenated with H2 over Pd/BaSO4 as before.

参考文献中间体

【1】 White, D.R.; Mizsak, S.A.; Birkenmeyer, R.D.; Thomas, R.C.; Wiley, V.H.; The stereospecific synthesis of spectinomycin. Tetrahedron Lett 1979, 30, 2737-40.
【2】 White, D.R. (Pharmacia Corp.); 6'-Alkylspectinomycins. DE 3308196; US 4532336 .
【3】 Cain, G.A.; White, D.R.; The synthesis of trospectomycin (6'-n-propylspectinomycin, U-63,366F). Tetrahedron Lett 1989, 30, 12, 1469-72.
【4】 White, D.R.; Maring, C.J.; Cain, G.A.; Synthesis and in vitro antibacterial properties of alkylspectinomycin analogs. J Antibiot 1983, 36, 3, 339-42.
【5】 Castaner, J.; Patoia, L.; Trospectomycin Sulfate. Drugs Fut 1991, 16, 4, 323.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	10770	(5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-[(E)-2-(dimethylamino)ethenyl]-7,9-dihydroxy-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate	C₃₅H₄₁N₃O₁₂	详情	详情
(XIII)	10771	(5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-[2-(dimethylamino)ethyl]-7,9-dihydroxy-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate	C₃₅H₄₃N₃O₁₂	详情	详情
(XIV)	10772	(5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-7,9-dihydroxy-4-oxo-2-vinyl-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate	C₃₃H₃₆N₂O₁₂	详情	详情
(XV)	10773	(5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-butyl-7,9-dihydroxy-4-oxo-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate	C₃₅H₄₂N₂O₁₂	详情	详情
(XVI)	10774	benzyl (2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-6-[[(benzyloxy)carbonyl](methyl)amino]-2-butyl-4a,7,9-trihydroxy-4-oxodecahydro-2H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate	C₃₃H₄₂N₂O₁₁	详情	详情
(XVII)	10775	(5aR,6S,7S,8R,9S,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-[(E)-2-(dimethylamino)ethenyl]-4-oxo-7,9-bis[(trimethylsilyl)methyl]-5a,6,7,8,9,9a-hexahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4(10aH)-yl acetate	C₄₃H₆₁N₃O₁₀Si₂	详情	详情
(XVIII)	10776	benzyl (4aR,5aR,6S,7S,8R,9S,9aR,10aR)-6-[[(benzyloxy)carbonyl](methyl)amino]-2-[(E)-1-butenyl]-4a-hydroxy-4-oxo-7,9-bis[(trimethylsilyl)methyl]-4a,5a,6,7,8,9,9a,10a-octahydro-4H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate	C₃₈H₅₀N₂O₉Si	详情	详情
(XIX)	10777	benzyl (4aR,5aR,6S,7S,8R,9S,9aR,10aR)-6-[[(benzyloxy)carbonyl](methyl)amino]-2-[(E)-1-butenyl]-4a,7,9-trihydroxy-4-oxo-4a,5a,6,7,8,9,9a,10a-octahydro-4H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate	C₃₃H₃₈N₂O₁₁	详情	详情

合成路线3

A new synthesis of trospectomycin has been published: The protection of the amino groups of spectinomycin (I) with benzyl chloroformate gives compound (II), which is treated with trimethylsilylchloride to protect the hydroxyl groups yielding the fully protected compound (III). The reaction of (III) with tert-butyl hydroperoxide makes free the oxo group affording compound (IV), which is converted into the enol ester (V) with allyl chloroformate and LiHMDS. The trans-allylation of (V) in THF by means of Pd under Tsujii conditions gives the protected 3-butenyl derivative (VI), which is finally deprotected and simultaneously hydrogenated with H2 over Pd/Al2O3 in methanol-acetic acid.

参考文献中间体

【1】 Herrinton, P.M.; Hartley, W.M.; Klotz, K.L.; Oxidation and alkylation of spectinomycin derivatives: Synthesis of trospectomycin from spectinomycin. J Org Chem 1993, 58, 3, 678.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	10765	(2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-4a,7,9-Trihydroxy-2-methyl-6,8-bis(methylamino)decahydro-4H-pyrano[2,3-b][1,4]benzodioxin-4-one	C₁₄H₂₄N₂O₇	详情	详情
(II)	10766	benzyl (2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-6-[[(benzyloxy)carbonyl](methyl)amino]-4a,7,9-trihydroxy-2-methyl-4-oxodecahydro-2H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate	C₃₀H₃₆N₂O₁₁	详情	详情
(III)	10780	benzyl (2R,4aS,5aR,6S,7S,8R,9S,9aR,10aS)-6-[[(benzyloxy)carbonyl](methyl)amino]-2-methyl-4,4a,7,9-tetrakis[(trimethylsilyl)methyl]-4a,5a,6,7,8,9,9a,10a-octahydro-2H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate	C₄₆H₇₆N₂O₇Si₄	详情	详情
(IV)	10781	benzyl (2R,4aR,5aR,6S,7S,8R,9S,9aR,10aS)-6-[[(benzyloxy)carbonyl](methyl)amino]-2-methyl-4-oxo-4a,7,9-tris[(trimethylsilyl)methyl]decahydro-2H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate	C₄₂H₆₆N₂O₈Si₃	详情	详情
(V)	10782	(4aS,5aR,6S,7S,8R,9R,9aR,10aR)-6,8-bis[[(benzyloxy)carbonyl](methyl)amino]-2-methylene-4a,7,9-tris[(trimethylsilyl)methyl]-4a,5a,6,7,8,9,9a,10a-octahydro-2H-pyrano[2,3-b][1,4]benzodioxin-4-yl allyl carbonate	C₄₅H₆₆N₂O₁₁Si₃	详情	详情
(VI)	10783	benzyl (2R,4aS,5aR,6R,7R,8R,9S,9aS,10aS)-6-[[(benzyloxy)carbonyl](methyl)amino]-2-(3-butenyl)-4-oxo-4a,7,9-tris[(trimethylsilyl)oxy]decahydro-2H-pyrano[2,3-b][1,4]benzodioxin-8-yl(methyl)carbamate	C₄₀H₅₈N₂O₁₀Si₂	详情	详情

Extended Information