Renzapride hydrochloride, ATL-1251, AZM-112, BRL-24924, -Drug Synthesis Database

【结构式】

【药物名称】Renzapride hydrochloride, ATL-1251, AZM-112, BRL-24924

【化学名称】(±)-endo-4-Amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide hydrochloride

【CA登记号】112727-80-7 (free base), 88721-77-1 (free base;no stereoch.)

【分子式】C₁₆H₂₃Cl₂N₃O₂

【分子量】360.28661

【开发单位】GlaxoSmithKline (Originator), Alizyme (Licensee)

【药理作用】GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, 5-HT3 Antagonists, 5-HT4 Agonists

合成路线1 合成路线2

合成路线1

A new synthesis of renzapride has been described: The reaction of 1-azabicyclo[3.3.1]nonan-4-one (I) with hydroxylamine and pyridine in refluxing ethanol gives the corresponding oxime (II), which is reduced with Na in refluxing pentanol yielding a mixture of the exo- and endo-amines (IIIa and IIIb). The acylation of this mixture with 4-acetamido-5-chloro-2-methoxybenzoylchloride (IV) and triethylamine in toluene affords a mixture of the exo- and endo-amides (Va and Vb), which are separated by column chromatography over alumina. The endo-isomer (Va) is finally deacetylated with NaOH in refluxing ethanol. It is obtained as crystals, m.p. > 260 C.

参考文献中间体

【1】 Hadley, M.S.; Smith, D.M.; Watts, E.A.; Joiner, K.T.; Martin, R.T.; Sanger, G.J.; Smith, G.E.; King, F.D.; Smith, P.; Turner, D.H.; Substituted benzamides with conformationally restricted side chains.5. Azabicyclo[x.y.z]derivatives as 5-HT4 receptor agonists and gastric motility stimulants. J Med Chem 1993, 36, 6, 683.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IIIa)	11629	(R)-1-Azabicyclo[3.3.1]non-4-ylamine; (R)-1-Azabicyclo[3.3.1]nonan-4-amine	C₈H₁₆N₂	详情	详情
(IIIb)	11630	(S)-1-Azabicyclo[3.3.1]nonan-4-amine; (S)-1-Azabicyclo[3.3.1]non-4-ylamine	C₈H₁₆N₂	详情	详情
(Va)	11632	4-(Acetamido)-N-(1-azabicyclo[3.3.1]non-4-yl)-5-chloro-2-methoxybenzamide	C₁₈H₂₄ClN₃O₃	详情	详情
(Vb)	11633	4-(Acetamido)-N-(1-azabicyclo[3.3.1]non-4-yl)-5-chloro-2-methoxybenzamide	C₁₈H₂₄ClN₃O₃	详情	详情
(I)	11627	1-Azabicyclo[3.3.1]nonan-4-one	C₈H₁₃NO	详情	详情
(II)	11628	1-Azabicyclo[3.3.1]nonan-4-one oxime	C₈H₁₄N₂O	详情	详情
(IV)	11631	4-(Acetamido)-5-chloro-2-methoxybenzoyl chloride	C₁₀H₉Cl₂NO₃	详情	详情

合成路线2

The reaction of 1-azabicyclo[3.3.1]nonan-4-one (I) with hydroxyamine gives the corresponding oxime (II), which is reduced with LiAlH4 in THF yielding 4-amino-1-azabicyclo [3.3.1]nonane (III). Finally, this compound is condensed with 4-amino-5-chloro-2-methoxybenzoylchloride (IV).

参考文献中间体

【1】 King, F.D. (SmithKline Beecham plc); Azabicyclo compounds, useful as intermediates. EP 0094742; JP 5194513; JP 58188885; US 4857647 .
【2】 Serradell, M.N.; Castaner, R.M.; Castaner, J.; BRL-24924. Drugs Fut 1987, 12, 11, 1009.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	11627	1-Azabicyclo[3.3.1]nonan-4-one	C₈H₁₃NO	详情	详情
(II)	11628	1-Azabicyclo[3.3.1]nonan-4-one oxime	C₈H₁₄N₂O	详情	详情
(III)	11629	(R)-1-Azabicyclo[3.3.1]non-4-ylamine; (R)-1-Azabicyclo[3.3.1]nonan-4-amine	C₈H₁₆N₂	详情	详情
(IV)	28152	4-amino-5-chloro-2-methoxybenzoyl chloride	C₈H₇Cl₂NO₂	详情	详情

Extended Information