KML-010, -Drug Synthesis Database

【结构式】

【药物名称】KML-010

【化学名称】8-[4-(4-Fluorophenyl)-4-oxobutyl]-1-methyl-1,3,8-triazaspiro[4.5]decan-4-one dihydrochloride

【CA登记号】1045-22-3, 217635-62-6 (free base), 217635-65-9 (labeled)

【分子式】C₁₈H₂₆Cl₂FN₃O₂

【分子量】406.33122

【开发单位】Albany Medical College (Originator), Virginia Commonwealth University (Originator)

【药理作用】Antidepressants, Antipsychotic Drugs, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT2A Antagonists

合成路线1 合成路线2

合成路线1

The title compound is prepared by two related methods. N-Benzyl-4-piperidone (I) is condensed with KCN and MeNH2.HCl to produce amino nitrile (II). Partial hydrolysis of nitrile (II) with H2SO4 furnishes amide (III). Condensation of the amino amide (III) with triethyl orthoformate gives rise to the spiro imidazolinone (IV). Catalytic hydrogenation of the imidazoline double bond of (IV) and simultaneous N-benzyl group hydrogenolysis gives rise to 1-methyl-1,3,8-triazaspiro[4,5]decan-4-one (V). This is finally alkylated with 4'-fluoro-4-chlorobutyrophenone (VI) to yield the desired compound (1,2).

参考文献中间体

【1】 Metwally, K.A.; Dukat, M.; Egan, C.T.; Smith, C.; Dupre, A.; Gauthier, C.B.; Herrick-Davis, K.; Teitler, M.; Glennon, R.A.; Spiperone: Influence of spiro ring substituents on 5-HT2A serotonin receptor binding. J Med Chem 1998, 41, 25, 5084.
【2】 Janssen, P.A.J. (Janssen Pharmaceutica NV); 2,4,8-Triaza-spiro(4,5)dec-2-enes. US 3155669 .

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)	15720	1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one	3612-20-2	C₁₂H₁₅NO	详情	详情
(II)	64576	1-benzyl-4-(methylamino)-4-piperidinecarbonitrile		C₁₄H₁₉N₃	详情	详情
(III)	22019	1-benzyl-4-(methylamino)-4-piperidinecarboxamide	1024-11-9	C₁₄H₂₁N₃O	详情	详情
(IV)	64577	8-benzyl-1-methyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one		C₁₅H₁₉N₃O	详情	详情
(V)	64578	1-methyl-1,3,8-triazaspiro[4.5]decan-4-one		C₈H₁₅N₃O	详情	详情
(VI)	35864	4-chloro-1-(4-fluorophenyl)-1-butanone	3874-54-2	C₁₀H₁₀ClFO	详情	详情

合成路线2

Similarly, the condensation of N-benzyl-4-piperidone (I) with KCN in the presence of NH4Cl provides amino nitrile (II), which is further hydrolyzed to amide (III) with 95% H2SO4. Cyclization of amino amide (III) with formamide under acidic conditions yields the spiro imidazolinone (IV), which is further reduced to imidazolidinone (V) employing NaBH4 in hot MeOH. Debenzylation of (V) with H2 and Pd/C provides 1,3,8-triazaspiro[4,5]decan-4-one (VI). Then, alkylation of (VI) with 4'-fluoro-4-chlorobutyrophenone (VII) by means of K2CO3 and catalytic KI in methyl isobutyl ketone furnishes (VIII). The imidazolidinone ring of (VIII) is finally methylated with iodomethane and KOH to produce the title compound (2).

参考文献中间体

【1】 Metwally, K.A.; Dukat, M.; Egan, C.T.; Smith, C.; Dupre, A.; Gauthier, C.B.; Herrick-Davis, K.; Teitler, M.; Glennon, R.A.; Spiperone: Influence of spiro ring substituents on 5-HT2A serotonin receptor binding. J Med Chem 1998, 41, 25, 5084.

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)	15720	1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one	3612-20-2	C₁₂H₁₅NO	详情	详情
(II)	64579	4-amino-1-benzyl-4-piperidinecarbonitrile		C₁₃H₁₇N₃	详情	详情
(III)	64580	4-amino-1-benzyl-4-piperidinecarboxamide		C₁₃H₁₉N₃O	详情	详情
(IV)	64581	8-benzyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one		C₁₄H₁₇N₃O	详情	详情
(V)	64582	8-benzyl-1,3,8-triazaspiro[4.5]decan-4-one		C₁₄H₁₉N₃O	详情	详情
(VI)	64583	1,3,8-triazaspiro[4.5]decan-4-one		C₇H₁₃N₃O	详情	详情
(VII)	35864	4-chloro-1-(4-fluorophenyl)-1-butanone	3874-54-2	C₁₀H₁₀ClFO	详情	详情
(VIII)	64584	8-[4-(4-fluorophenyl)-4-oxobutyl]-1,3,8-triazaspiro[4.5]decan-4-one		C₁₇H₂₂FN₃O₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)