AS-601811, -Drug Synthesis Database

【结构式】

【药物名称】AS-601811

【化学名称】4,8-Dimethyl-2,3,5,6-tetrahydro-1H-benzo[c]quinolizin-3-one

【CA登记号】194979-95-8

【分子式】C₁₅H₁₇NO

【分子量】227.30884

【开发单位】Serono (Originator), Università degli Studi di Firenze (Originator)

【药理作用】Acne Therapy, DERMATOLOGIC DRUGS, ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Hirsutism Therapy, Steroid 5alpha-Reductase Type 1 Inhibitors

合成路线1 合成路线2

合成路线1

Acylation of p-toluidine (I) with 3-chloropropionyl chloride afforded the beta-chloroamide (II), which was cyclized to dihydroquinolinone (III) by treatment with AlCl3 at 120 C. After protection of the N atom of (III) as the tert-butyl carbamate (IV), reduction of the 2-oxo group by NaBH4 in ethanol at -25 C, followed by acidic quench with ethanolic HCl, afforded the N-Boc-2-ethoxy derivative (V). The tandem Mannich-Michael cyclization of the alpha-ethoxycarbamate (V) with the (silyloxy)diene (VII) (derived from 1-penten-3-one (VI) in the presence of trimethylsilyl triflate) furnished the benzoquinolizinone (VIII) as a mixture of diastereoisomers. Finally, oxidation of this mixture with mercuric acetate afforded the desired delta-4 unsaturated compound.

参考文献中间体

【1】 Machetti, F.; Scarpi, D.; Guarna, A.; Occhiato, E.G.; Benzo[c]quinolizin-3-ones: A novel class of potent and selective nonsteroidal inhibitors of human steroid 5alpha-reductase 1. J Med Chem 2000, 43, 20, 3718.
【2】 Guarna, A.; Serio, M. (Applied Research Systems ARS Holdings NV); Benzo[c]quinolizine derivs., their preparation and use as 5alpha-reductases inhibitors. EP 0880520; JP 2000504680; WO 9729107 .

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)	31228	p-toluidine; 4-methylphenylamine	106-49-0	C₇H₉N	详情	详情
(II)	43925	3-chloro-N-(4-methylphenyl)propanamide		C₁₀H₁₂ClNO	详情	详情
(III)	43926	6-methyl-3,4-dihydro-2(1H)-quinolinone		C₁₀H₁₁NO	详情	详情
(IV)	43927	tert-butyl 6-methyl-2-oxo-3,4-dihydro-1(2H)-quinolinecarboxylate		C₁₅H₁₉NO₃	详情	详情
(V)	43928	tert-butyl 2-ethoxy-6-methyl-3,4-dihydro-1(2H)-quinolinecarboxylate		C₁₇H₂₅NO₃	详情	详情
(VI)	43930	1-penten-3-one	1629-58-9	C₅H₈O	详情	详情
(VII)	43929	trimethylsilyl (Z)-1-vinyl-1-propenyl ether; trimethyl[[(Z)-1-vinyl-1-propenyl]oxy]silane		C₈H₁₆OSi	详情	详情
(VIII)	43931	4,8-dimethyl-1,2,4,4a,5,6-hexahydro-3H-pyrido[1,2-a]quinolin-3-one		C₁₅H₁₉NO	详情	详情

合成路线2

The reaction of 6-methyl-1,2,3,4-tetrahydroquinolin-2-one (I) with Lawesson's reagent in refluxing toluene gives 6-methyl-1,2,3,4-tetrahydroquinolin-2-thione (II), which is condensed with ethyl vinyl ketone (III) by means of K2CO3 or DBU in THF to yield the addition product (IV). The reaction of (IV) with dimethyl sulfate in refluxing toluene affords the thioiminium ion (V), which, without isolation, is cyclized to the target compound by reaction with DBU in refluxing toluene.

参考文献中间体

【1】 Guarna, A.; et al.; Modification of the aza-robinson annulation for the synthesis of 4-methyl-benzol[c]quinoliin-3-ones. Potent inhibitors of steroid 5alpha-reductase 1. J Org Chem 2000, 65, 23, 8093.

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)	43926	6-methyl-3,4-dihydro-2(1H)-quinolinone		C₁₀H₁₁NO	详情	详情
(II)	50344	6-methyl-3,4-dihydro-2(1H)-quinolinethione		C₁₀H₁₁NS	详情	详情
(III)	43930	1-penten-3-one	1629-58-9	C₅H₈O	详情	详情
(IV)	50345	1-[6-methyl-2-thioxo-3,4-dihydro-1(2H)-quinolinyl]-3-pentanone		C₁₅H₁₉NOS	详情	详情
(V)	50346	6-methyl-2-(methylsulfanyl)-1-(3-oxopentyl)-3,4-dihydroquinolinium		C₁₆H₂₂NOS	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)