benzyl 6-oxo-5,6,7,8-tetrahydro-2-naphthalenylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】36984

【品名】benzyl 6-oxo-5,6,7,8-tetrahydro-2-naphthalenylcarbamate

【CA登记号】

【分子式】C₁₈H₁₇NO₃

【分子量】295.33792

【元素组成】C 73.2% H 5.8% N 4.74% O 16.25%

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：(XII)

A new process for the preparation of emtricitabine has been described: The esterification of 2-butene-1,4-diol (I) with butyryl chloride and DMAP in pyridine gives the diester (II), which by ozonolysis with O3 in methanol provides the hemiacetal (III). Cyclization of (III) with 2-mercaptoacetic acid in refluxing toluene affords racemic 2-(butyryloxymethyl)-1,3-oxathiolan-5-one (V), which is submitted to optical resolution to afford the (R)-enantiomer (VI). The reduction of (VI) with Li(t-BuO)3AlH, followed by acetylation with acetic anhydride gives 5-(acetoxy)-2(R)-(butyryloxy)-1,3-oxathiolane (VII), which by treatment with HCl in dichloroethane is converted into 2(R)-(butyryloxy)-5-chloro-1,3-oxathiolane (VIII). Condensation of (VIII) with 5-fluoro-bis(trimethylsilyl)cytosine (IX) obtained by silylation of cytosine (X) with HMDS by means of NaHCO3 in dichloroethane gives a diastereomeric mixture of the butyrate nucleosides (XI), which is hydrolyzed with butylamine in methanol yielding the corresponding diastereomeric mixture of the (2R,5S)-isomer, emtricitabine, and the (2R,5R)-isomer (XII). This mixture is separated by crystallization of the corresponding hydrochlorides obtained by treatment with HCl in methanol/dioxane.

参考文献中间体

合成目标

【1】 Almond, M.; Painter, G.R.; Liotta, D.C.; Cleary, D.; Soria, J. (Emory University; Triangle Pharmaceuticals, Inc.); Method of manufacture of 1,3-oxathiolane nucleosides. WO 0009494 .

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)	36965	(Z)-2-butene-1,4-diol	6117-80-2	C₄H₈O₂	详情	详情
(II)	36966	(Z)-4-(butyryloxy)-2-butenyl butyrate		C₁₂H₂₀O₄	详情	详情
(III)	39681	2-hydroxy-2-methoxyethyl butyrate		C₇H₁₄O₄	详情	详情
(IV)	18524	2-sulfanylacetic acid	68-11-1	C₂H₄O₂S	详情	详情
(V)	36968	(5-oxo-1,3-oxathiolan-2-yl)methyl butyrate		C₈H₁₂O₄S	详情	详情
(VI)	39682	[(2R)-5-oxo-1,3-oxathiolan-2-yl]methyl butyrate		C₈H₁₂O₄S	详情	详情
(VII)	39683	[(2R)-5-(acetoxy)-1,3-oxathiolan-2-yl]methyl butyrate		C₁₀H₁₆O₅S	详情	详情
(VIII)	39685	[(2R)-5-chloro-1,3-oxathiolan-2-yl]methyl butyrate		C₈H₁₃ClO₃S	详情	详情
(IX)	36959	5-fluoro-N-(trimethylsilyl)-2-[(trimethylsilyl)oxy]-4-pyrimidinamine; N-[5-fluoro-2-[(trimethylsilyl)oxy]-4-pyrimidinyl]-N-(trimethylsilyl)amine		C₁₀H₂₀FN₃OSi₂	详情	详情
(X)	16747	4-amino-5-fluoro-2(1H)-pyrimidinone; 5-fluorocytosine	2022-85-7	C₄H₄FN₃O	详情	详情
(XI)	36970	(rac)-[(2R,5S)-5-[4-amino-5-fluoro-2-oxo-1(2H)-pyrimidinyl]-1,3-oxathiolan-2-yl]methyl butyrate		C₁₂H₁₆FN₃O₄S	详情	详情
(XII)	36984	benzyl 6-oxo-5,6,7,8-tetrahydro-2-naphthalenylcarbamate		C₁₈H₁₇NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Tetralone (I) was reduced with NaBH4 and the resulting alcohol (II) was dehydrated with p-TsOH in refluxing toluene to yield the dihydronaphthalene (III). Oxidation of (III) with N-methylmorpholine N-oxide and OsO4 produced diol (IV), which was converted to the 2-tetralone (V) by acid-catalyzed rearrangement. The unstable tetralone (V) was condensed with the sodium salt of tert-butyl diethyl phosphonoacetate (VI) providing a mixture of olefin isomers (VII). Catalytic hydrogenation of the olefin (VIIa-c) with simultaneous removal of the carbobenzoxy group furnished the aminotetralin (VIII). This was coupled with 4-cyanobenzoic acid (IX) using EDC to give amide (X). Addition of H2S to the nitrile group of (X), followed by S-methylation provided (XI). Then, displacement of the methylthio group of (XI) by ammonium acetate and further treatment with di-tert-butyl dicarbonate yielded the Boc-protected benzamidine (XII). Deprotection with trifluoroacetic acid produced the amidino acid (XIII), which was finally esterified with EtOH and HCl.

参考文献中间体

合成目标

【1】 Fisher, M.J.; Arfstan, A.E.; Giese, U.; et al.; Fused bicyclic Gly-Asp beta-turn mimics with specific affinity for GPIIb-IIIa. J Med Chem 1999, 42, 23, 4875.
【2】 Fisher, M.J.; Happ, A.M.; Jakubowski, J.A.; Kinnick, M.D.; Kline, A.D.; Morin, J.M. Jr.; Sall, D.J.; Skelton, M.A.; Vasileff, R.T. (Eli Lilly and Company); Glycoprotein IIb/IIIa antagonists. CA 2128348; EP 0635492; JP 1996188564; US 5618843 .
【3】 Fisher, M.J.; Jakubowski, J.A.; Martinelli, M.J.; Morin, J.M. Jr.; Paal, M.; Ruhter, G.; Ruterbories, K.J.; Schotten, T.; Stenzel, W.; Vasileff, R.T. (Eli Lilly and Company); Glycoprotein IIb/IIIa antagonists. EP 0804431; JP 1999502194; WO 9622288 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIa)	36985	tert-butyl 2-(6-[[(benzyloxy)carbonyl]amino]-1,2,3,4-tetrahydro-2-naphthalenyl)acetate		C₂₄H₂₉NO₄	详情	详情
(VIIb)	36986	(E)-tert-butyl 2-[6-[[(benzyloxy)carbonyl]amino]-3,4-dihydro-2(1H)-naphthalenylidene]acetate		C₂₄H₂₇NO₄	详情	详情
(VIIc)	36987	(Z)-tert-butyl 2-[6-[[(benzyloxy)carbonyl]amino]-3,4-dihydro-2(1H)-naphthalenylidene]acetate		C₂₄H₂₇NO₄	详情	详情
(I)	36980	benzyl 5-oxo-5,6,7,8-tetrahydro-2-naphthalenylcarbamate		C₁₈H₁₇NO₃	详情	详情
(II)	36981	benzyl 5-hydroxy-5,6,7,8-tetrahydro-2-naphthalenylcarbamate		C₁₈H₁₉NO₃	详情	详情
(III)	36982	benzyl 7,8-dihydro-2-naphthalenylcarbamate		C₁₈H₁₇NO₂	详情	详情
(IV)	36983	benzyl 5,6-dihydroxy-5,6,7,8-tetrahydro-2-naphthalenylcarbamate		C₁₈H₁₉NO₄	详情	详情
(V)	36984	benzyl 6-oxo-5,6,7,8-tetrahydro-2-naphthalenylcarbamate		C₁₈H₁₇NO₃	详情	详情
(VI)	25637	tert-butyl 2-(diethoxyphosphoryl)acetate	6273-47-8	C₁₀H₂₁O₅P	详情	详情
(VIII)	36988	tert-butyl 2-(6-amino-1,2,3,4-tetrahydro-2-naphthalenyl)acetate		C₁₆H₂₃NO₂	详情	详情
(IX)	36897	4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile	619-65-8	C₈H₅NO₂	详情	详情
(X)	36989	tert-butyl 2-[6-[(4-cyanobenzoyl)amino]-1,2,3,4-tetrahydro-2-naphthalenyl]acetate		C₂₄H₂₆N₂O₃	详情	详情
(XI)	36990	tert-butyl 2-[6-([4-[imino(methylsulfanyl)methyl]benzoyl]amino)-1,2,3,4-tetrahydro-2-naphthalenyl]acetate		C₂₅H₃₀N₂O₃S	详情	详情
(XII)	36991	tert-butyl 2-[6-([4-[[(tert-butoxycarbonyl)amino](imino)methyl]benzoyl]amino)-1,2,3,4-tetrahydro-2-naphthalenyl]acetate		C₂₉H₃₇N₃O₅	详情	详情
(XIII)	36992	2-[6-([4-[amino(imino)methyl]benzoyl]amino)-1,2,3,4-tetrahydro-2-naphthalenyl]acetic acid		C₂₀H₂₁N₃O₃	详情	详情

Extended Information