-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】exo-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(8- methyl-8-azabicyclo[3.2.1]oct-3-yl)-2(Z),4(E)-pentadienamide

【CA登记号】

【分子式】C₂₂H₂₅Cl₂N₃O₂

【分子量】434.36945

【开发单位】SmithKline Beecham

【药理作用】METABOLIC DRUGS, TREATMENT OF BONE DISEASES

合成路线1 合成路线2

合成路线1

Condensation of dichloronitrotoluene (I) with diethyl oxalate in the presence of KOEt afforded phenylpyruvate (II), and subsequent reductive cyclization gave indole-2-carboxylate (VI). Alternatively, condensation of 3,4-dichlorophenyl hydrazine (III) with ethyl pyruvate (IV) provided hydrazone (V). Then, Fischer indole synthesis with p-TsOH in refluxing toluene yielded a mixture of 5,6-dichloroindole (VI) and the corresponding 4,5-dichloroindole. Ester reduction using LiAlH4 in THF afforded alcohol (VII), which was subsequently oxidized to aldehyde (VIII) with MnO2 in Et2O. Condensation of (VIII) with phosphonate (IX) in the presence of NaH provided E-indolylpropenoate (X). Then, the sequence of DIBAH reduction, followed by oxidation of the resulting allyl alcohol (XI) with MnO2 in EtOAc furnished aldehyde (XII).

参考文献中间体

【1】 Consolandi, E.; Nadler, G.; Gagliardi, S.; et al.; 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2, 4-pentadienamides: Novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. J Med Chem 1998, 41, 10, 1568.
【2】 Farina, C.; Gagliardi, S.; Parini, C.; Pinza, M.; Nadler, G.M.M.G.; Morvan, M.J.-M. (SmithKline Beecham SpA); Indole derivs. useful in the treatment of osteoporosis. JP 1998512251; WO 9621644 .

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)	19088	1,2-dichloro-4-methyl-5-nitrobenzene		C₇H₅Cl₂NO₂	详情	详情
(II)	19089	ethyl 3-(4,5-dichloro-2-nitrophenyl)-2-oxopropanoate		C₁₁H₉Cl₂NO₅	详情	详情
(III)	19090	1-(3,4-dichlorophenyl)hydrazine		C₆H₆Cl₂N₂	详情	详情
(IV)	12135	ethyl 2-oxopropanoate; Ethyl pyruvate	617-35-6	C₅H₈O₃	详情	详情
(V)	19092	ethyl 2-[(Z)-2-(3,4-dichlorophenyl)hydrazono]propanoate		C₁₁H₁₂Cl₂N₂O₂	详情	详情
(VI)	19093	ethyl 5,6-dichloro-1H-indole-2-carboxylate		C₁₁H₉Cl₂NO₂	详情	详情
(VII)	19094	(5,6-dichloro-1H-indol-2-yl)methanol		C₉H₇Cl₂NO	详情	详情
(VIII)	19095	5,6-dichloro-1H-indole-2-carbaldehyde		C₉H₅Cl₂NO	详情	详情
(IX)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(X)	19097	ethyl (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenoate		C₁₃H₁₁Cl₂NO₂	详情	详情
(XI)	19098	(E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propen-1-ol		C₁₁H₉Cl₂NO	详情	详情
(XII)	19099	(E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenal		C₁₁H₇Cl₂NO	详情	详情

合成路线2

Bromination of methyl methoxyacetate (XIII) with NBS in the presence of benzoyl peroxide in refluxing CCl4 gave (XIV), which was treated with triphenylphosphine to produce the phosphonium salt (XV). Then, phosphonium salt (XV) was condensed with aldehyde (XII) in the presence of DBU in THF to afford indolylpentadienoate (XVI). Finally, ester (XVI) was hydrolyzed to acid (XVII) and then condensed with amine (XVIII) to provide the title amide.

参考文献中间体

【1】 Consolandi, E.; Nadler, G.; Gagliardi, S.; et al.; 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2, 4-pentadienamides: Novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. J Med Chem 1998, 41, 10, 1568.
【2】 Farina, C.; Gagliardi, S.; Parini, C.; Pinza, M.; Nadler, G.M.M.G.; Morvan, M.J.-M. (SmithKline Beecham SpA); Indole derivs. useful in the treatment of osteoporosis. JP 1998512251; WO 9621644 .

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)	19099	(E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenal		C₁₁H₇Cl₂NO	详情	详情
(XIII)	19100	methyl 2-methoxyacetate	6290-49-9	C₄H₈O₃	详情	详情
(XIV)	19101	methyl 2-bromo-2-methoxyacetate		C₄H₇BrO₃	详情	详情
(XV)	19102	(1,2-dimethoxy-2-oxoethyl)(triphenyl)phosphonium bromide		C₂₂H₂₂BrO₃P	详情	详情
(XVI)	19103	methyl (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate		C₁₅H₁₃Cl₂NO₃	详情	详情
(XVII)	19104	(2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid		C₁₄H₁₁Cl₂NO₃	详情	详情
(XVIII)	19105	(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine		C₈H₁₆N₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)