methyl 3-(3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate -Drug Synthesis Database

【结构式】

【分子编号】49923

【品名】methyl 3-(3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate

【CA登记号】

【分子式】C₂₀H₂₁BrClNO₄S

【分子量】486.81378

【元素组成】C 49.35% H 4.35% Br 16.41% Cl 7.28% N 2.88% O 13.15% S 6.59%

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：(IX)

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2

该中间体在本合成路线中的序号：(IX)

Heck reaction of aryl bromide (IX) with vinyl tributyltin (X) in the presence of palladium catalyst gave the vinyl tetrahydronaphthalene (XI), which was converted to the primary alcohol (XII) by means of hydroboration with borane in THF followed by oxidative treatment with H2O2 and NaOH. Reaction of alcohol (XII) with p-toluenesulfonyl chloride and Et3N produced the corresponding tosylate (XIII) (1). This was then condensed with 6-fluoro-3-(4-piperidinyl)benzisoxazole (XIV), yielding adduct (XV). Finally, basic hydrolysis of the ester group of (XIV) provided the title carboxylic acid.

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.
【2】 Verbeuren, T.; Simonet, S.; Descombes, J.-J.; Cimetiere, B.; Lavielle, G. (ADIR et Cie.); Benzenesulfonamide derivs., process for their preparation and pharmaceutical compsns. containing them. EP 1118610; FR 2803848; JP 2001226353 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	49923	methyl 3-(3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate		C₂₀H₂₁BrClNO₄S	详情	详情
(X)	24920	tributyl(vinyl)stannane；Tributylvinylstannane;Vinyltributylstannane	7486-35-3	C₁₄H₃₀Sn	详情	详情
(XI)	49924	methyl 3-(6-[[(4-chlorophenyl)sulfonyl]amino]-3-vinyl-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate		C₂₂H₂₄ClNO₄S	详情	详情
(XII)	49925	methyl 3-(6-[[(4-chlorophenyl)sulfonyl]amino]-3-formyl-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate		C₂₁H₂₂ClNO₅S	详情	详情
(XIII)	49926	methyl 3-[6-[[(4-chlorophenyl)sulfonyl]amino]-3-(hydroxymethyl)-5,6,7,8-tetrahydro-1-naphthalenyl]propanoate		C₂₁H₂₄ClNO₅S	详情	详情
(XIV)	17910	6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole		C₁₂H₁₃FN₂O	详情	详情
(XV)	49964	methyl 3-(6-[[(4-chlorophenyl)sulfonyl]amino]-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate		C₃₄H₃₇ClFN₃O₅S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IX)

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：(IX)

Heck reaction of aryl bromide (IX) with vinyl tributyltin (X) in the presence of palladium catalyst gave the vinyl tetrahydronaphthalene (XI), which was subjected to oxidative double-bond cleavage to aldehyde (XII) using NaIO4 in the presence of a catalytic amount of OsO4. Aldehyde reduction with NaBH4 provided alcohol (XIII). This was then converted to the corresponding bromide (XIV) by treatment with carbon tetrabromide and triphenylphosphine.

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.
【2】 Verbeuren, T.; Simonet, S.; Descombes, J.-J.; Cimetiere, B.; Lavielle, G. (ADIR et Cie.); Benzenesulfonamide derivs., process for their preparation and pharmaceutical compsns. containing them. EP 1118610; FR 2803848; JP 2001226353 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	49923	methyl 3-(3-bromo-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate		C₂₀H₂₁BrClNO₄S	详情	详情
(X)	24920	tributyl(vinyl)stannane；Tributylvinylstannane;Vinyltributylstannane	7486-35-3	C₁₄H₃₀Sn	详情	详情
(XI)	49924	methyl 3-(6-[[(4-chlorophenyl)sulfonyl]amino]-3-vinyl-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate		C₂₂H₂₄ClNO₄S	详情	详情
(XII)	49925	methyl 3-(6-[[(4-chlorophenyl)sulfonyl]amino]-3-formyl-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate		C₂₁H₂₂ClNO₅S	详情	详情
(XIII)	49926	methyl 3-[6-[[(4-chlorophenyl)sulfonyl]amino]-3-(hydroxymethyl)-5,6,7,8-tetrahydro-1-naphthalenyl]propanoate		C₂₁H₂₄ClNO₅S	详情	详情
(XIV)	49927	methyl 3-(3-(bromomethyl)-6-[[(4-chlorophenyl)sulfonyl]amino]-5,6,7,8-tetrahydro-1-naphthalenyl)propanoate		C₂₁H₂₃BrClNO₄S	详情	详情

Extended Information