Arundic acid, ONO-2506PO, ONO-2506, Proglia, Cereact, -Drug Synthesis Database

【结构式】

【药物名称】Arundic acid, ONO-2506PO, ONO-2506, Proglia, Cereact

【化学名称】2(R)-Propyloctanoic acid

【CA登记号】185517-21-9, 31080-41-8 (racemate), 161089-52-7 (racemate, Na salt)

【分子式】C₁₁H₂₂O₂

【分子量】186.29679

【开发单位】Ono (Originator)

【药理作用】Alzheimer's Dementia, Treatment of , Amyotrophic Lateral Sclerosis, Agents for, Antiparkinsonian Drugs, Cerebrovascular Diseases, Treatment of, Cognition Disorders, Treatment of, Extrapyramidal Disorders, Treatment of, Neurodegenerative Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of

合成路线1 合成路线2

合成路线1

The acylation of (-)-2,10-camphorsultam (II) with octanoyl chloride (I) provides the N-octanoyl sultam (III). Diastereoselective alkylation of the lithium enolate of (III) with allyl bromide (IV) gives rise to the (2S)-2-propenoyloctanoyl sultam (V). Hydrolysis of the N-acyl sultam (V) to furnish acid (VI) is then effected by treatment with hydrogen peroxide-tetrabutylammonium hydroxide. Finally, catalytic hydrogenation of the unsaturated acid (VI) in the presence of either Pd/C or Pt/C yields the required (R)-2-propyloctanoic acid. Alternatively, the title compound is obtained by hydrogenation of the N-acyl sultam (V) to the saturated derivative (VII), followed by hydrolytic removal of the camphorsultam moiety.

参考文献中间体

【1】 Hasegawa, T.; Kawanaka, Y.; Kasamatsu, E.; Iguchi, Y.; Yonekawa, Y.; Okamoto, M.; Ohta, C.; Hashimoto, S.; Ohuchida, S.; Process development of ONO-2506: A therapeutic agent for stroke and Alzheimer's disease. Org Process Res Dev 2003, 7, 2, 168.
【2】 Hasegawa, T.; Yamamoto, H.; A practical synthesis of optically active (R)-2-propyloctanoic acid: Therapeutic agent for Alzheimer's disease. Bull Chem Soc Jpn 2000, 73, 2, 423.
【3】 Hasegawa, T.; Yamamoto, H.; A practical removal method of camphorsultam. Synlett 1998, 8, 882.
【4】 Yamamoto, H. (Ono Pharmaceutical Co., Ltd.); Novel intermediates and processes for the preparation of optically active octanoic acid derivs.. EP 1078921; US 6333415; WO 9958513 .

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)	11123	Octanoyl chloride; n-Caprylyl chloride;Capryloyl chloride	111-64-8	C₈H₁₅ClO	详情	详情
(II)	58242	(1S,5R,7R)-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione		C₁₀H₁₇NO₂S	详情	详情
(III)	58243	(1S,5R,7R)-10,10-dimethyl-4-octanoyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione		C₁₈H₃₁NO₃S	详情	详情
(IV)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(V)	58244	(1S,5R,7R)-4-[(2S)-2-hexyl-4-pentenoyl]-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione		C₂₁H₃₅NO₃S	详情	详情
(VI)	58245	(1S,5R,7R)-10,10-dimethyl-4-[(2R)-2-propyloctanoyl]-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione		C₂₁H₃₇NO₃S	详情	详情
(VII)	58246	(2S)-2-hexyl-4-pentenoic acid		C₁₁H₂₀O₂	详情	详情

合成路线2

In a related procedure, the N-octanoyl sultam (I) is alkylated by propargyl bromide (II) to produce (III). Hydrolysis of (III) by means of hydrogen peroxide-tetrabutylammonium hydroxide or lithium hydroxide-hydrogen peroxide furnishes acid (IV). Then, catalytic hydrogenation of the propargyloctanoic acid (IV) in the presence of either Pd/C or Pt/C provides the title compound.

参考文献中间体

【1】 Hasegawa, T.; Yamamoto, H.; A practical synthesis of optically active (R)-2-propyloctanoic acid: Therapeutic agent for Alzheimer's disease. Bull Chem Soc Jpn 2000, 73, 2, 423.
【2】 Yamamoto, H. (Ono Pharmaceutical Co., Ltd.); Novel intermediates and processes for the preparation of optically active octanoic acid derivs.. EP 1078921; US 6333415; WO 9958513 .
【3】 Iguchi, Y.; Yamaguchi, K.; Toda, N. (Ono Pharmaceutical Co., Ltd.; Tokyo Kasei Kogyo Co., Ltd.); Process for the preparation of (2R)-2-propyloctanoic acid. EP 1153910; WO 0048982 .

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)	58243	(1S,5R,7R)-10,10-dimethyl-4-octanoyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione		C₁₈H₃₁NO₃S	详情	详情
(II)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(III)	58247	(1S,5R,7R)-4-[(2S)-2-hexyl-4-pentynoyl]-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione		C₂₁H₃₃NO₃S	详情	详情
(IV)	58248	(2S)-2-hexyl-4-pentynoic acid		C₁₁H₁₈O₂	详情	详情

Extended Information