N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide -Drug Synthesis Database

【结构式】

【分子编号】19587

【品名】N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide

【CA登记号】

【分子式】C₁₅H₁₃BrClNO₄S

【分子量】418.69526

【元素组成】C 43.03% H 3.13% Br 19.08% Cl 8.47% N 3.35% O 15.29% S 7.66%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(XII)

The intermediate 4-(4-chlorophenylsulfonyl)aminocyclohexanone (V) was prepared by two synthetic ways. Reductive condensation of 4,4-diethoxycyclohexanone (I) with benzylamine in the presence of sodium triacetoxyborohydride and AcOH provided the benzylcyclohexylamine (II). Further hydrogenolysis of the N-benzyl group of (II) in the presence of Pd/C and oxalic acid yielded cyclohexylamine (III) as the oxalate salt. Sulfonamide (V) was then obtained by condensation with 4-chlorophenylsulfonyl chloride (IV), followed by hydrolysis of the diethyl acetal with aqueous HCl. lternatively, treatment of trans-4-aminocyclohexanol hydrochloride (VI) with sulfonyl chloride (IV) in the presence of Et3N provided the sulfonamide (VII), which was subsequently oxidized with chromic anhydride and H2SO4 to the target ketone (V). Condensation of this intermediate (V) with ethyl formate in the presence of NaH produced the hydroxymethylene cyclohexanone (VIII), which was submitted to a Wittig reaction with phosphorane (IX) to give the cyclohexylidenpropanoic ester (X). Cyclization of this compound using anhydrous p-toluenesulfonic acid in refluxing toluene furnished pyranone (XI), which by subsequent bromination in acetic acid yielded the 3-bromopyranone (XII). The key tetrahydronaphthalene system (XIV) was then obtained by Diels-Alder reaction with methyl propiolate (XIII) with concomitant decarboxylation at 200 C. Finally, the ester function of (XIV) was reduced to alcohol (XV) with LiAlH4.

参考文献中间体

合成目标

【1】 Cimetière, B.; Dubuffet, T.; Landras, C.; Descombes, J.J.; Simonet, S.; Verbeuren, T.J.; Lavielle, G.; New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 1998, 8, 11, 1381.
【2】 Lavielle, G.; Dubuffet, T.; Muller, O.; Laubie, M.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); 1,2,3,4-Tetrahydronaphthalene, chroman and thiochroman derivs. as antithrombotic agents. CA 2118102; EP 0648741; FR 2711139; JP 1995188155 .

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)	19576	4,4-diethoxycyclohexanone		C₁₀H₁₈O₃	详情	详情
(II)	19577	N-benzyl-4,4-diethoxycyclohexanamine; N-benzyl-N-(4,4-diethoxycyclohexyl)amine		C₁₇H₂₇NO₂	详情	详情
(III)	19578	4,4-diethoxycyclohexanamine; 4,4-diethoxycyclohexylamine		C₁₀H₂₁NO₂	详情	详情
(V)	19580	4-chloro-N-(4-oxocyclohexyl)benzenesulfonamide		C₁₂H₁₄ClNO₃S	详情	详情
(VI)	19581	trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol;	27489-62-9	C₆H₁₃NO	详情	详情
(VII)	19582	4-chloro-N-(4-hydroxycyclohexyl)benzenesulfonamide		C₁₂H₁₆ClNO₃S	详情	详情
(VIII)	19583	4-chloro-N-[3-[(Z)-hydroxymethylidene]-4-oxocyclohexyl]benzenesulfonamide		C₁₃H₁₄ClNO₄S	详情	详情
(IX)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(X)	19585	methyl 3-(5-[[(4-chlorophenyl)sulfonyl]amino]-2-oxocyclohexylidene)propanoate		C₁₆H₁₈ClNO₅S	详情	详情
(XI)	19586	4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide		C₁₅H₁₄ClNO₄S	详情	详情
(XII)	19587	N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide		C₁₅H₁₃BrClNO₄S	详情	详情
(XIII)	19588	methyl propiolate	922-67-8	C₄H₄O₂	详情	详情
(XIV)	19589	methyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenecarboxylate		C₁₈H₁₇BrClNO₄S	详情	详情
(XV)	19590	N-[7-bromo-5-(hydroxymethyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide		C₁₇H₁₇BrClNO₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XII)

The intermediate 4-(4-chlorophenylsulfonyl)aminocyclohexanone (V) was prepared by two synthetic ways: 1) Reductive condensation of 4,4-diethoxycyclohexanone (I) with benzylamine in the presence of sodium triacetoxyborohydride and AcOH provided the benzylcyclohexylamine (II). Further hydrogenolysis of the N-benzyl group of (III) in the presence of Pd/C and oxalic acid yielded cyclohexylamine (III) as the oxalate salt. Sulfonamide (V) was then obtained by condensation with 4-chlorophenylsulfonyl chloride (IV), followed by hydrolysis of the diethyl acetal with aqueous HCl. 2) Alternatively, treatment of trans-4-aminocyclohexanol hydrochloride (VI) with sulfonyl chloride (IV) in the presence of Et3N provided the sulfonamide (VII), which was subsequently oxidized with chromic anhydride and H2SO4 to the target ketone (V). 3) Condensation of this intermediate with ethyl formate in the presence of NaH produced the hydroxymethylene cyclohexanone (VIII), which was submitted to a Wittig reaction with phosphorane (IX) to give the cyclohexylidenpropanoic ester (X). Cyclization of this compound using anhydrous p-toluenesulfonic acid in refluxing toluene furnished pyranone (XI), which by subsequent bromination in acetic acid yielded the 3-bromopyranone (XII) (1). The key tetrahydronaphthalene system (XIV) was then obtained by Diels-Alder reaction with refluxing methyl hexynoate (XIII) with concomitant decarboxylation. The ester function of (XIV) was reduced to alcohol (XV) with LiAlH4.

参考文献中间体

合成目标

【1】 Cimetière, B.; Dubuffet, T.; Landras, C.; Descombes, J.J.; Simonet, S.; Verbeuren, T.J.; Lavielle, G.; New tetrahydronaphthalene derivatives as combined thromboxane receptor antagonists and thromboxane synthase inhibitors. Bioorg Med Chem Lett 1998, 8, 11, 1381.
【2】 Lavielle, G.; Dubuffet, T.; Muller, O.; Laubie, M.; Verbeuren, T.; Simonet, S.; Descombes, J.-J. (ADIR et Cie.); 1,2,3,4-Tetrahydronaphthalene, chroman and thiochroman derivs. as antithrombotic agents. CA 2118102; EP 0648741; FR 2711139; JP 1995188155 .

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)	19576	4,4-diethoxycyclohexanone		C₁₀H₁₈O₃	详情	详情
(II)	19577	N-benzyl-4,4-diethoxycyclohexanamine; N-benzyl-N-(4,4-diethoxycyclohexyl)amine		C₁₇H₂₇NO₂	详情	详情
(III)	19578	4,4-diethoxycyclohexanamine; 4,4-diethoxycyclohexylamine		C₁₀H₂₁NO₂	详情	详情
(IV)	15787	4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride	98-60-2	C₆H₄Cl₂O₂S	详情	详情
(V)	19580	4-chloro-N-(4-oxocyclohexyl)benzenesulfonamide		C₁₂H₁₄ClNO₃S	详情	详情
(VI)	19581	trans-4-Aminocyclohexanol；trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol;	27489-62-9	C₆H₁₃NO	详情	详情
(VII)	19582	4-chloro-N-(4-hydroxycyclohexyl)benzenesulfonamide		C₁₂H₁₆ClNO₃S	详情	详情
(VIII)	19583	4-chloro-N-[3-[(Z)-hydroxymethylidene]-4-oxocyclohexyl]benzenesulfonamide		C₁₃H₁₄ClNO₄S	详情	详情
(IX)	14689	Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate	2605-67-6	C₂₁H₁₉O₂P	详情	详情
(X)	19585	methyl 3-(5-[[(4-chlorophenyl)sulfonyl]amino]-2-oxocyclohexylidene)propanoate		C₁₆H₁₈ClNO₅S	详情	详情
(XI)	19586	4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide		C₁₅H₁₄ClNO₄S	详情	详情
(XII)	19587	N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide		C₁₅H₁₃BrClNO₄S	详情	详情
(XIII)	19609	methyl 2-hexynoate	18937-79-6	C₇H₁₀O₂	详情	详情
(XIV)	19610	methyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-2-propyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylate		C₂₁H₂₃BrClNO₄S	详情	详情
(XV)	19611	N-[7-bromo-5-(hydroxymethyl)-6-propyl-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide		C₂₀H₂₃BrClNO₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Bromination of the coumarin derivative (I) with Br2 in DMF afforded the bromo coumarin (II). Diels-Alder cycloaddition between bromo coumarin (II) and ethyl 3-(trimethylsilyl)propiolate (III) with concomitant decarboxylation furnished the tetrahydronaphthalene (IV). After desilylation of (IV) with trifluoroacetic acid, the resultant ester (V) was reduced to alcohol (VI) using the combination LiAlH4-AlCl3. Further oxidation of the alcohol function of (VI) to aldehyde (VII) was performed with 4-benzylpyridinium dichromate (BPDC) in CH2Cl2. Wittig reaction of aldehyde (VII) with methyl (triphenylphosphoranylidene)acetate produced the arylacrylate ester (VIII), which was then reduced to the saturated ester (IX) employing NaBH4 in the presence of CoCl2.

参考文献中间体

合成目标

【1】 Cimetiere, B.; et al.; Discovery of new combined 5-HT2 and TP-receptor antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 57.

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)	19586	4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide		C₁₅H₁₄ClNO₄S	详情	详情
(II)	19587	N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide		C₁₅H₁₃BrClNO₄S	详情	详情
(III)	23898	ethyl 3-(trimethylsilyl)-2-propynoate	29394-58-9	C₈H₁₄O₂Si	详情	详情
(IV)	49920	ethyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-2-(trimethylsilyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxylate		C₂₂H₂₇BrClNO₄SSi	详情	详情
(V)	49921	ethyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenecarboxylate		C₁₉H₁₉BrClNO₄S	详情	详情
(VI)	19590	N-[7-bromo-5-(hydroxymethyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide		C₁₇H₁₇BrClNO₃S	详情	详情
(VII)	19591	N-(7-bromo-5-formyl-1,2,3,4-tetrahydro-2-naphthalenyl)-4-chlorobenzenesulfonamide		C₁₇H₁₅BrClNO₃S	详情	详情
(VIII)	49922	methyl (E)-3-(3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)-2-propenoate		C₂₀H₁₉BrClNO₄S	详情	详情
(IX)	49923	methyl 3-(3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate		C₂₀H₂₁BrClNO₄S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

参考文献中间体

合成目标

【1】 Cimetiere, B.; et al.; Discovery of new combined 5-HT2 and TP-receptor antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 57.

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)	19586	4-chloro-N-(2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)benzenesulfonamide		C₁₅H₁₄ClNO₄S	详情	详情
(II)	19587	N-(3-bromo-2-oxo-5,6,7,8-tetrahydro-2H-chromen-6-yl)-4-chlorobenzenesulfonamide		C₁₅H₁₃BrClNO₄S	详情	详情
(III)	23898	ethyl 3-(trimethylsilyl)-2-propynoate	29394-58-9	C₈H₁₄O₂Si	详情	详情
(IV)	49920	ethyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-2-(trimethylsilyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxylate		C₂₂H₂₇BrClNO₄SSi	详情	详情
(V)	49921	ethyl 3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenecarboxylate		C₁₉H₁₉BrClNO₄S	详情	详情
(VI)	19590	N-[7-bromo-5-(hydroxymethyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-4-chlorobenzenesulfonamide		C₁₇H₁₇BrClNO₃S	详情	详情
(VII)	19591	N-(7-bromo-5-formyl-1,2,3,4-tetrahydro-2-naphthalenyl)-4-chlorobenzenesulfonamide		C₁₇H₁₅BrClNO₃S	详情	详情
(VIII)	49922	methyl (E)-3-(3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)-2-propenoate		C₂₀H₁₉BrClNO₄S	详情	详情
(IX)	49923	methyl 3-(3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate		C₂₀H₂₁BrClNO₄S	详情	详情

Extended Information