PD-6735, LY-156735, -Drug Synthesis Database

【结构式】

【药物名称】PD-6735, LY-156735

【化学名称】N-[2(R)-(6-Chloro-5-methoxy-1H-indol-3-yl)propyl]acetamide

【CA登记号】118702-11-7

【分子式】C₁₄H₁₇ClN₂O₂

【分子量】280.75679

【开发单位】Lilly (Originator), Phase 2 Discovery (Licensee)

【药理作用】PSYCHOPHARMACOLOGIC DRUGS, Sedative/Hypnotics, Sleep Disorders, Treatment of, Melatonin MT1 Agonists, Melatonin MT2 Agonists

合成路线1 合成路线2

合成路线1

The condensation of 6-chloro-5-methoxy-1H-indole (I) with Meldrum's acid (II) and acetaldehyde (III) catalyzed by L-proline in acetonitrile gives the adduct (IV), which is treated with Cu and ethanol in refluxing pyridine to yield 3-(6-chloro-5-methoxy-1H-indol-3-yl)butyric acid ethyl ester (V). The reaction of (V) with hydrazine at 140 C affords the hydrazide (VI), which is treated with NaNO2 and Ac-OH to provide the corresponding azide that, without isolation, is thermolyzed and rearranged in toluene at 80?C to give 7-chloro-6-methoxy-4-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-1-one (VII). The cleavage of the lactam ring of (VII) with KOH in refluxing ethanol/water yields 3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole-2-carboxylic acid (VIII). The decarboxylation of (VIII) by means of refluxing aq. 3M HCl affords 3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole (IX), which is finally acylated with acetic anhydride and pyridine in toluene to provide the target 6-chloromelatonin as a racemic compound.

参考文献中间体

【1】 Flaugh, M.E. (Eli Lilly and Company); Alkylmelatonins. AU 8810979; EP 0281242; US 4997845 .

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)	56744	6-chloro-1H-indol-5-yl methyl ether; 6-chloro-5-methoxy-1H-indole		C₉H₈ClNO	详情	详情
(II)	14738	Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester	2033-24-1	C₆H₈O₄	详情	详情
(III)	11974	Acetaldehyde	75-07-0	C₂H₄O	详情	详情
(IV)	56745	5-[1-(6-chloro-5-methoxy-1H-indol-3-yl)ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione		C₁₇H₁₈ClNO₅	详情	详情
(V)	56746	ethyl 3-(6-chloro-5-methoxy-1H-indol-3-yl)butanoate		C₁₅H₁₈ClNO₃	详情	详情
(VI)	56747	3-(6-chloro-5-methoxy-1H-indol-3-yl)butanohydrazide		C₁₃H₁₆ClN₃O₂	详情	详情
(VII)	56748	7-chloro-6-methoxy-4-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-one		C₁₃H₁₃ClN₂O₂	详情	详情
(VIII)	56749	3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole-2-carboxylic acid		C₁₃H₁₅ClN₂O₃	详情	详情
(IX)	56750	2-(6-chloro-5-methoxy-1H-indol-3-yl)-1-propanamine; 2-(6-chloro-5-methoxy-1H-indol-3-yl)propylamine		C₁₂H₁₅ClN₂O	详情	详情

合成路线2

The intermediate diazonium salt (XIII) has been obtained as follows: the hydrogenation of 3-chloro-4-methoxynitrobenzene (XI) with H2 over Pt/Al2O3 in toluene gives the corresponding aniline (XII), which is diazotized with NaNO2/HCl and treated with sodium tetrafluoroborate to yield the target diazonium salt intermediate (XIII). The reduction of pulegone (I) with H2 over Pd/C gives the menthol (II), which is oxidized with CrO3/H2SO4 to yield 3(R),7-dimethyl-6-oxooctanoic acid (IV), which can also be obtained by direct oxidation of (l)-menthol (III) under the same conditions. The oxidation of (IV) with trifluoroperacetic acid (trifluoroacetic anhydride/H2O2) in dichloromethane yields the 3(R)-methylhexanedioic acid isopropyl monoester (V), which is treated with NaOEt in ethanol to obtain the corresponding ethyl monoester (VI). The reaction of (VI) with diethyl carbonate, EtONa, and "Adogen 464" (a phase transfer catalyst) in ethanol affords 5,5-bis(ethoxycarbonyl)-3(S)-methylpentanoic acid (VII), which is treated with oxalyl chloride to provide the expected acyl chloride (VIII). The reaction of (VIII) with sodium azide and benzyl alcohol gives the intermediate azide that rearranges to the benzyl carbamate (IX). The reductive cyclization of (IX) with H2 over Pd/C in ethanol yields 5(R)-methyl-2-oxopiperidine-3-carboxylic acid ethyl ester (X), which is condensed with the intermediate diazonium salt (XIII) to afford the hydrazono derivative (XIV). The cyclization of (XIV) in hot formic acid provides 7-chloro-6-methoxy-4(R)-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-1-one (XV), which is treated with KOH In refluxing ethanol/water to cleave the lactam ring, yielding 3-(2-amino-1(R)-methylethyl)-6-chloro-5-methoxy-1H-indole-2-carboxylic acid (XVI). The decarboxylation of (XVI) by means of refluxing 3M HCl affords 3-(2-amino-1(R)-methylethyl)-6-chloro-5-methoxy-1H-indole (XVII), which is finally acylated with Ac2O and pyridine in toluene to provide the target 6-chloromelatonin as a pure enantiomer.

参考文献中间体

【1】 Flaugh, M.E. (Eli Lilly and Company); Alkylmelatonins. AU 8810979; EP 0281242; US 4997845 .

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)	56751	(5R)-5-methyl-2-(1-methylethylidene)cyclohexanone		C₁₀H₁₆O	详情	详情
(II)	56766	(5R)-2-isopropyl-5-methylcyclohexanol		C₁₀H₂₀O	详情	详情
(III)	56752	(3R)-3,7-dimethyl-6-oxooctanoic acid		C₁₀H₁₈O₃	详情	详情
(IV)	56767	(2S,5R)-2-isopropyl-5-methylcyclohexanol		C₁₀H₂₀O	详情	详情
(V)	56753	(3R)-6-isopropoxy-3-methyl-6-oxohexanoic acid		C₁₀H₁₈O₄	详情	详情
(VI)	56754	(3R)-6-ethoxy-3-methyl-6-oxohexanoic acid		C₉H₁₆O₄	详情	详情
(VII)	56755	(3R)-6-ethoxy-5-(ethoxycarbonyl)-3-methyl-6-oxohexanoic acid		C₁₂H₂₀O₆	详情	详情
(VIII)	56756	diethyl 2-[(2R)-4-chloro-2-methyl-4-oxobutyl]malonate		C₁₂H₁₉ClO₅	详情	详情
(IX)	56757	diethyl 2-((2R)-3-{[(benzyloxy)carbonyl]amino}-2-methylpropyl)malonate		C₁₉H₂₇NO₆	详情	详情
(X)	56758	ethyl (5R)-5-methyl-2-oxo-3-piperidinecarboxylate		C₉H₁₅NO₃	详情	详情
(XI)	56759	2-Chloro-4-nitroanisole; 3-Chloro-4-methoxynitrobenzene	4920-79-0	C₇H₆ClNO₃	详情	详情
(XII)	56760	3-chloro-4-methoxyaniline; 3-Chloro-p-anisidine	5345-54-0	C₇H₈ClNO	详情	详情
(XIII)	56761			C₇H₆BClF₄N₂O	详情	详情
(XIV)	56762	(5R)-5-methyl-2,3-piperidinedione 3-[N-(3-chloro-4-methoxyphenyl)hydrazone]		C₁₃H₁₆ClN₃O₂	详情	详情
(XV)	56763	(4R)-7-chloro-6-methoxy-4-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-one		C₁₃H₁₃ClN₂O₂	详情	详情
(XVI)	56764	3-[(1R)-2-amino-1-methylethyl]-6-chloro-5-methoxy-1H-indole-2-carboxylic acid		C₁₃H₁₅ClN₂O₃	详情	详情
(XVII)	56765	(2R)-2-(6-chloro-5-methoxy-1H-indol-3-yl)-1-propanamine; (2R)-2-(6-chloro-5-methoxy-1H-indol-3-yl)propylamine		C₁₂H₁₅ClN₂O	详情	详情

Extended Information