Setrobuvir;ANA-598;RG-7790, -Drug Synthesis Database

【结构式】

【药物名称】Setrobuvir;ANA-598;RG-7790

【化学名称】N-[3-[(4aR,5S,8R,8aS)-1-(4-Fluorobenzyl)-4-hydroxy-2-oxo-1,2,4a,5,6,7,8,8a-octahydro-5,8-methanoquinolin-3-yl]-1,1-dioxo-4H-1,2,4-benzothiadiazin-7-yl]methanesulfonamide

【CA登记号】

【分子式】C₂₅H₂₅FN₄O₆S₂

【分子量】560.618

【开发单位】Roche

【药理作用】RNA-Directed RNA Polymerase Inhibitor；Treatment of Hepatitis C Virus Infection

合成路线1 合成路线2 合成路线3

合成路线1

Cycloaddition of norbornene (I) with chlorosulfonyl isocyanate (II) in EtOAc or Et2O followed by treatment with aqueous Na2SO3 affords (±)-exo-3-azatricyclo[4.2.1.O2,5]nonan-4-one (III), which by hydrolysis with HCl gives 3-aminonorbornane-2-carboxylic acid hydrochloride (IV). Treatment of amino acid (IV) with EtOH or MeOH by means of SOCl2 at reflux provides the hydrochloride salts of the corresponding ethyl (Va) or methyl (Vb) esters, respectively, which are neutralized with NaHCO3 to yield the free amines (VIa) and (VIb). Resolution of the racemic amino esters (VIa) or (VIb) with (S)-(+)-CSA in EtOAc/EtOH followed by neutralization of the obtained CSA salts (VIIa) or (VIIb) with Na2CO3 or K2CO3 in EtOAc leads to ethyl (VIIIa) or methyl (VIIIb) (1S,2R,3S,4R)-3-aminonorbornane-2-carboxylate, respectively. Alternatively, amino ester (VIIa) can be obtained by ring opening of racemic lactam (III) with EtOH in the presence of (S)-(+)-CSA in EtOAc at 50-75 °C. Reductive alkylation of amines (VIIIa) and (VIIIb) with 4-fluorobenzaldehyde (IX) by means of NaBH3CN and AcOH or NaOAc in EtOH gives the secondary amines (XIa) or (XIb) , which can also be prepared by alkylation of amines (VIII) with 4-fluorobenzyl bromide (Xa) or iodide (XIb) in the presence of Et3N in DMF at 70 °C . N-Acylation of amino esters (XIa) or (XIb) with the carboxylic acid (XII) using as coupling reagents EDC in the presence of DMAP , or NMM in DMF, or DCC in CH2Cl2/DMF, or HATU and NMM in DMF , yields amides (XIIIa) and (XIIIb) . Finally, amide esters (XIII) are submitted to intramolecular Claisen condensation by means of NaOEt in EtOH at 60 °C or Et3N at 60 °C . Alternatively, methyl ester (XIb) can be condensed with the carboxylic acid (XII) in the presence of DCC, NMM and Et3N in DMF at 50 °C , or in acetonitrile .

参考文献中间体

【1】 Tran, C.V., Ruebsam, F., Murphy, D.E. et al. (Anadys Pharmaceuticals, Inc.). 5,6-Dihydro-1H-pyridin-2-one compounds. CA 2682584, EP 2129224, JP 2010523586, US 2010034773, US 7939524, US 8101800, US 2012130068, US 8236948, WO 2008124450.
【2】 Ruebsam, F., Dragovich, P., Webber, S.E., Murphy, D.E., Tran, C.V. (Anadys Pharmaceuticals, Inc.). [1,2,4]Thiadiazine 1,1-dioxide compounds. CN 10236871, US 2009306057, US 80976131, WO 2009152166.
【3】 Dragovich, P.S., Thompson, P.A., Ruebsam, F. (Anadys Pharmaceuticals, Inc.). A method of inhibiting hepatitis C virus by combination of a 5,6-dihydro-1H-pyridin-2-one and one or more additional antiviral compounds. EP 2346329, US 2011229438, WO 2010042834.
【4】 Ruebsam, F., Murphy, D.E., Tran, C.V. et al. Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase. Bioorg Med Chem Lett 2009, 19(22): 6404-12.
【5】 Ruebsam, F., Dragovich, P., Webber, S.E., Murphy, D.E., Tran, C.V. (Anadys Pharmaceuticals, Inc.). [1,2,4]Thiadiazin-3-yl acetic acid compound[[s]] and methods of making the acetic acid compound. US 2012116077, US 8222404.

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)	68649	bicyclo[2.2.1]hept-2-ene		C₇H₁₀	详情	详情
(Va)	68657	(±)-(1S,2R,3S,4R)-ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride		C₁₀H₁₇NO₂.HCl	详情	详情
(Vb)	68658	(±)-(1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride		C₉H₁₅NO₂.HCl	详情	详情
(VIa)	68655	(±)-(1S,2R,3S,4R)-ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate		C₁₀H₁₇NO₂	详情	详情
(VIb)	68656	(±)-(1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate		C₉H₁₅NO₂	详情	详情
(VIIa)	68652	(1S,2R,3S,4R)-ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate		C₁₀H₁₇NO₂.C₁₀H₁₆O₄S	详情	详情
(VIIb)	68651	(1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate		C₉H₁₅NO₂S.C₁₀H₁₆O₄S	详情	详情
(VIIIa)	68654	(1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate		C₁₀H₁₇NO₂	详情	详情
(VIIIb)	68653	(1S,2R,3S,4R)ethyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate		C₉H₁₅NO₂	详情	详情
(Xa)	24611	1-(bromomethyl)-4-fluorobenzene	459-46-1	C₇H₆BrF	详情	详情
(Xb)	23601	1-fluoro-4-(iodomethyl)benzene		C₇H₆FI	详情	详情
(XIa)	68660	(1S,2R,3S,4R)-ethyl 3-((4-fluorobenzyl)amino)bicyclo[2.2.1]heptane-2-carboxylate		C₁₇H₂₂FNO₂	详情	详情
(XIb)	68661	(1S,2R,3S,4R)-methyl 3-((4-fluorobenzyl)amino)bicyclo[2.2.1]heptane-2-carboxylate		C₁₆H₂₀FNO₂	详情	详情
(XIIIa)	68663	(1S,2R,3S,4R)-ethyl 3-(N-(4-fluorobenzyl)-2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetamido)bicyclo[2.2.1]heptane-2-carboxylate		C₂₇H₃₁FN₄O₇S₂	详情	详情
(XIIIb)	68664	(1S,2R,3S,4R)-methyl 3-(N-(4-fluorobenzyl)-2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetamido)bicyclo[2.2.1]heptane-2-carboxylate		C₂₆H₂₉FN₄O₇S₂	详情	详情
(II)	14101	Chlorosulfonyl isocyanate	1189-71-5	CClNO₃S	详情	详情
(III)	68650	(±)-exo-3-azatricyclo[4.2.1.O^2.5 nonan-4-one;(1S,2R,5S,6R)-3-azatricyclo[4.2.1.0^2.5]nonan-4-one		C₈H₁₁NO	详情	详情
(IV)	68659	(±)-(1S,2R,3S,4R)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid hydrochloride		C₈H₁₃NO₂.HCl	详情	详情
(IX)	12337	4-fluorobenzaldehyde	459-57-4	C₇H₅FO	详情	详情
(XII)	68662	2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetic acid		C₁₀H₁₁N₃O₆S₂	详情	详情

合成路线2

Chlorination of 2-chloro-5-nitrobenzenesulfonic acid (XIV) with SOCl2 in refluxing DMF gives the sulfonyl chloride (XV), which is converted to the corresponding sulfonamide (XVI) by treatment with NH4OH in toluene/THF. Amination of the chloro sulfonamide (XVI) with (NH4)2CO3 and NH4OH in the presence of CuSO4 at 118 °C leads to 2-amino-5-nitrobenzenesulfonamide (XVII). Alternatively, chlorination of 2-amino-5-nitrobenzenesulfonic acid (XVIII) using POCl3 in sulfolane at 110-120 °C provides the corresponding sulfonyl chloride (XIX), which is treated with NH4OH to yield sulfonamide (XVII). Reduction of the nitro moiety of compound (XVII) with H2 over Pd/C in the presence of MsOH in EtOH/H2O at 55 °C affords 2,5-diaminobenzenesulfonamide mesylate (XX), which can also be obtained by chloride substitution in 2-chloro-5-nitrobenzenesulfonamide (XVI) with benzylamine by means of Et3N in acetonitrile at 92 °C, followed by hydrogenolysis of the resulting 2-(benzylamino)-5-nitrobenzenesulfonamide (XXI) over Pd/C in the presence of MsOH in THF/EtOH/H2O. Selective N-sulfonylation of diamine (XX) with methanesulfonyl chloride (XXII) and pyridine in CH2Cl2 or acetonitrile gives rise to 2-amino-5-(methylsulfonamido)benzenesulfonamide (XXIII), which is then condensed with either methyl malonyl chloride (XXIV) in THF or ethyl malonyl chloride (XXV) in DMF/Et2O or DMA , yielding amides (XXVI) or (XXVII). Finally, carbamoyl sulfonamides (XXVI) and (XXVII) are cyclized and simultaneously hydrolyzed by treatment with NaOH (XII) .

参考文献中间体

【1】 Tran, C.V., Ruebsam, F., Murphy, D.E. et al. (Anadys Pharmaceuticals, Inc.). 5,6-Dihydro-1H-pyridin-2-one compounds. CA 2682584, EP 2129224, JP 2010523586, US 2010034773, US 7939524, US 8101800, US 2012130068, US 8236948, WO 2008124450.
【2】 Dragovich, P.S., Thompson, P.A., Ruebsam, F. (Anadys Pharmaceuticals, Inc.). A method of inhibiting hepatitis C virus by combination of a 5,6-dihydro-1H-pyridin-2-one and one or more additional antiviral compounds. EP 2346329, US 2011229438, WO 2010042834.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	68662	2-(7-(methylsulfonamido)-1,1-dioxido-4H-benzo[e][1,2,4]thiadiazin-3-yl)acetic acid		C₁₀H₁₁N₃O₆S₂	详情	详情
(XIV)	68665	2-chloro-5-nitrobenzenesulfonic acid;2-Chloro-5-nitrobenzene sulfonic acid;p-Nitrochlorobenzene-o-sulfonic acid;2-chloro-5-nitro-Benzenesulfonic acid;2-chloro-5-nitrobenzenesulphonic acid	96-73-1	C₆H₄ClNO₅S	详情	详情
(XV)	43034	2-chloro-5-nitrobenzenesulfonyl chloride;2-Chloro-5-nitro-benzenesulfonyl chloride;2-Chloro-5-nitrophenylsulfonyl chloride;6-Chloro-3-nitrobenzenesulfonyl chloride	4533-95-3	C₆H₃Cl₂NO₄S	详情	详情
(XVI)	43035	2-chloro-5-nitrobenzenesulfonamide	96-72-0	C₆H₅ClN₂O₄S	详情	详情
(XVII)	68666	2-amino-5-nitrobenzenesulfonamide		C₆H₇N₃O₄S	详情	详情
(XVIII)	68668	2-amino-5-nitrobenzenesulfonic acid	96-75-3	C₆H₆N₂O₅S	详情	详情
(XIX)	68667	2-amino-5-nitrobenzene-1-sulfonyl chloride		C₆H₅ClN₂O₄S	详情	详情
(XX)	68669	2,5-diaminobenzenesulfonamide mesylate;2,5-diaminobenzenesulfonamide methanesulfonate		C₆H₉N₃O₂S.CH₄O₃S	详情	详情
(XXI)	68670	2-(benzylamino)-5-nitrobenzenesulfonamide		C₁₃H₁₃N₃O₄S	详情	详情
(XXII)	13467	Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride	124-63-0	CH₃ClO₂S	详情	详情
(XXIII)	68671	2-amino-5-(methylsulfonamido)benzenesulfonamide		C₇H₁₁N₃O₄S₂	详情	详情
(XXIV)	50272	Malonic acid monomethyl ester chloride; Methyl (chloroformyl)acetate; Methyl malonyl chloride ;Methyl 3-chloro-3-oxopropionate	37517-81-0	C₄H₅ClO₃	详情	详情
(XXV)	13188	ethyl 3-chloro-3-oxopropanoate; 2-Ethoxycarbonylacetyl chloride; Ethyl malonyl chloride	36239-09-5	C₅H₇ClO₃	详情	详情
(XXVI)	68672	methyl 3-((4-(methylsulfonamido)-2-sulfamoylphenyl)amino)-3-oxopropanoate		C₁₁H₁₅N₃O₇S₂	详情	详情
(XXVII)	68673	ethyl 3-((4-(methylsulfonamido)-2-sulfamoylphenyl)amino)-3-oxopropanoate		C₁₂H₁₇N₃O₇S₂	详情	详情

合成路线3

Intermediate (XIb) can also be prepared by the following route. Desymmetrization of cis-5-norbornene-exo-2,3-dicarboxylic anhydride (XXVIII) with MeOH in the presence of quinine in toluene/CCl4 at –55 °C affords (1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]-hept-5-ene-2-carboxylic acid (XXIX). Activation of carboxylic acid (XXIX) with ClCOOEt in the presence of Et3N in THF followed by reaction of the resulting mixed anhydride with NaN3 results in the corresponding acyl azide, which then undergoes Curtius rearrangement in refluxing benzene to produce isocyanate (XXX). Without isolation, isocyanate (XXX) is treated with benzyl alcohol in the presence of Et3N in refluxing CH2Cl2 to give the Cbz-protected amine (XXXI). Reduction and deprotection of norbornene derivative (XXXI) with H2 over Pd/C in EtOAc followed by treatment with HCl in Et2O/dioxane gives the saturated amino ester (Vb), which is submitted to reductive alkylation with 4-fluorobenzaldehyde (IX) by means of NaBH3CN and NaOAc in MeOH .

参考文献中间体

【1】 Tran, C.V., Ruebsam, F., Murphy, D.E. et al. (Anadys Pharmaceuticals, Inc.). 5,6-Dihydro-1H-pyridin-2-one compounds. CA 2682584, EP 2129224, JP 2010523586, US 2010034773, US 7939524, US 8101800, US 2012130068, US 8236948, WO 2008124450.
【2】 Dragovich, P.S., Thompson, P.A., Ruebsam, F. (Anadys Pharmaceuticals, Inc.). A method of inhibiting hepatitis C virus by combination of a 5,6-dihydro-1H-pyridin-2-one and one or more additional antiviral compounds. EP 2346329, US 2011229438, WO 2010042834.
【3】 Ruebsam, F., Murphy, D.E., Tran, C.V. et al. Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase. Bioorg Med Chem Lett 2009, 19(22): 6404-12.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Vb)	68658	(±)-(1S,2R,3S,4R)-methyl 3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride		C₉H₁₅NO₂.HCl	详情	详情
(XIb)	68661	(1S,2R,3S,4R)-methyl 3-((4-fluorobenzyl)amino)bicyclo[2.2.1]heptane-2-carboxylate		C₁₆H₂₀FNO₂	详情	详情
(IX)	12337	4-fluorobenzaldehyde	459-57-4	C₇H₅FO	详情	详情
(XXVIII)	11171	(1R,2R,6S,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione		C₉H₈O₃	详情	详情
(XXIX)	68674	(1S,2S,3R,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]-hept-5-ene-2-carboxylic acid		C₁₀H₁₂O₄	详情	详情
(XXX)	68675			C₁₀H₁₁NO₃	详情	详情
(XXXI)	68676	(1S,2S,3R,4R)-methyl 3-(((benzyloxy)carbonyl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxylate		C₁₇H₁₉NO₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)