咨询热线:028-85335741
药品资讯网--新药研发行业门户!

  • PD-6735, LY-156735,118702-11-7,C14-H17-Cl-N2-O2,N-[2(R)-(6-C--药物合成数据库
  • 发布时间:2004-10-25 来源:本站整理
  • 【药物名称】
    PD-6735, LY-156735
    【化学名】
    N-[2(R)-(6-Chloro-5-methoxy-1H-indol-3-yl)propyl]acetamide
    【CAS登记号】
    118702-11-7
    【结构式】
    PD-6735, LY-156735,118702-11-7,C14-H17-Cl-N2-O2,N-[2(R)-(6-C--药物合成数据库
    【分子式】
    C14-H17-Cl-N2-O2
    【分子量】
    280.757
    【原研厂家】
    Lilly (Originator), Phase 2 Discovery (Licensee)
    【作用类别】
    PSYCHOPHARMACOLOGIC DRUGS, Sedative/Hypnotics, Sleep Disorders, Treatment of, Melatonin MT1 Agonists, Melatonin MT2 Agonists
    【研发状态】
    Phase II
    【合成情况】
     
    〖来源〗
    AU 8810979; EP 0281242; US 4997845
    〖合成路线〗
    〖标题〗
    Alkylmelatonins
    〖合成方法〗
    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.
    〖作者〗
    Flaugh, M.E. (Eli Lilly and Company)
    〖参考〗
    Flaugh, M.E. (Eli Lilly and Company); Alkylmelatonins. AU 8810979; EP 0281242; US 4997845
    〖出处〗
    AU 8810979; EP 0281242; US 4997845,,():
    〖备注〗
    〖来源〗
    AU 8810979; EP 0281242; US 4997845
    〖合成路线〗
    〖标题〗
    Alkylmelatonins
    〖合成方法〗
    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.
    〖作者〗
    Flaugh, M.E. (Eli Lilly and Company)
    〖参考〗
    Flaugh, M.E. (Eli Lilly and Company); Alkylmelatonins. AU 8810979; EP 0281242; US 4997845
    〖出处〗
    AU 8810979; EP 0281242; US 4997845,,():
    〖备注〗
赞助商链接

推荐专业资料
赞助商链接