NNC-45-0095, -Drug Synthesis Database

【结构式】

【药物名称】NNC-45-0095

【化学名称】1-Ethyl-2-(4-hydroxyphenyl)pyrrolo[2,1,5-cd]indolizine
　　　　　　4-(1-Ethylpyrrolo[2,1,5-cd]indolizin-2-yl)phenol

【CA登记号】217318-90-6

【分子式】C₁₈H₁₅NO

【分子量】261.32635

【开发单位】Novo Nordisk (Originator)

【药理作用】Bone Diseases, Treatment of, METABOLIC DRUGS, Treatment of Osteoporosis, Estrogen Agonists

合成路线1 合成路线2

合成路线1

The title compound has been prepared by two related procedures. Alkylation of 2-propylpyridine (I) with 4-methoxyphenacyl bromide (II) in refluxing acetone gave the pyridinum salt (III), which was further cyclized to the indolizine (IV) using aqueous NaHCO3. Condensation of (IV) with dimethyl acetylenedicarboxylate (V), followed by oxidation with 2,3-dichloro-5,6-dicyanoquinone furnished the tricyclic system (VI). Hydrolysis of the diester of (VI) and subsequent decarboxylation of the resulting diacid (VII) produced the methoxy derivative (VIII). Finally, demethylation of (VIII) using AlCl3 and ethanethiol gave rise to the title phenol compound.

参考文献中间体

【1】 Christiansen, L.B.; Kanstrup, A.; Jacobsen, P.; Jorgensen, A.S.; Bury, P.S. (Novo Nordisk A/S); Pyrrolo[2,1,5-cd]indolizine derivs. useful in the prevention or treatment of estrogen related diseases or syndromes. EP 0986560; US 6075036; WO 9855482 .

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)	39281	2-propylpyridine	622-39-9	C₈H₁₁N	详情	详情
(II)	21991	2-Methoxyphenacyl bromide; 2-bromo-1-(4-methoxyphenyl)-1-ethanone	2632-13-5	C₉H₉BrO₂	详情	详情
(III)	39282	1-[2-(4-methoxyphenyl)-2-oxoethyl]-2-propylpyridinium bromide		C₁₇H₂₀BrNO₂	详情	详情
(IV)	39283	4-(1-ethyl-2-indolizinyl)phenyl methyl ether; 1-ethyl-2-(4-methoxyphenyl)indolizine		C₁₇H₁₇NO	详情	详情
(V)	24551	Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester	762-42-5	C₆H₆O₄	详情	详情
(VI)	39284	dimethyl 4-ethyl-3-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate		C₂₃H₂₁NO₅	详情	详情
(VII)	39285	4-ethyl-3-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid		C₂₁H₁₇NO₅	详情	详情
(VIII)	39286	1-ethyl-2-(4-methoxyphenyl)pyrrolo[2,1,5-cd]indolizine; 4-(1-ethylpyrrolo[2,1,5-cd]indolizin-2-yl)phenyl methyl ether		C₁₉H₁₇NO	详情	详情

合成路线2

In a very close procedure, alkylation of 2-propylpyridine (I) was effected with 4-benzyloxyphenacyl bromide (IX). The resulting pyridinium salt (X) was cyclized with NaHCO3 to give (XI), which was then condensed with dimethyl acetylenedicarboxylate (V) as before to give the tricyclic system (XII). Hydrolysis of diester (XII) to diacid (XIII), followed by decarboxylation with copper in hot quinoline yielded (XIV). The benzyl protecting group of (XIV) was then removed by catalytic hydrogenolysis in the presence of Pd/C.

参考文献中间体

【1】 Wassermann, K.; Kanstrup, A.; Jorgensen, A.S.; Bain, S.; Naerum, L.; Jacobsen, P.; Christiansen, L.B.; Bury, P.S.; Thorpe, S.M.; Synthesis and pharmacology of a novel pyrrolo[2,1,5-cd] indolizine (NNC 45-0095), a high affinity non-steroidal agonist for the estrogen receptor. Bioorg Med Chem Lett 2000, 10, 4, 399.

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)	39281	2-propylpyridine	622-39-9	C₈H₁₁N	详情	详情
(V)	24551	Dimethyl acetylenedicarboxylate; Dimethyl 2-butynedioate;Acetylenedicarboxylic acid dimethyl ester	762-42-5	C₆H₆O₄	详情	详情
(IX)	36424	1-[4-(benzyloxy)phenyl]-2-bromo-1-ethanone		C₁₅H₁₃BrO₂	详情	详情
(X)	39287	1-[2-[4-(benzyloxy)phenyl]-2-oxoethyl]-2-propylpyridinium bromide		C₂₃H₂₄BrNO₂	详情	详情
(XI)	39288	benzyl 4-(1-ethyl-2-indolizinyl)phenyl ether; 2-[4-(benzyloxy)phenyl]-1-ethylindolizine		C₂₃H₂₁NO	详情	详情
(XII)	39289	dimethyl 3-[4-(benzyloxy)phenyl]-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylate		C₂₉H₂₅NO₅	详情	详情
(XIII)	39290	3-[4-(benzyloxy)phenyl]-4-ethylpyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid		C₂₇H₂₁NO₅	详情	详情
(XIV)	39291	2-[4-(benzyloxy)phenyl]-1-ethylpyrrolo[2,1,5-cd]indolizine; benzyl 4-(1-ethylpyrrolo[2,1,5-cd]indolizin-2-yl)phenyl ether		C₂₅H₂₁NO	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)