SK&F-105685, -Drug Synthesis Database

【结构式】

【药物名称】SK&F-105685

【化学名称】N,N-Dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine dihydrochloride
　　　　　　2-[3-(Dimethylamino)propyl]-8,8-dipropyl-2-azaspiro[4.5]decane dihydrochloride

【CA登记号】124796-27-6, 123018-34-8 (free base)

【分子式】C₂₀H₄₂Cl₂N₂

【分子量】381.47714

【开发单位】GlaxoSmithKline (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Immunosuppressants, Non-Steroidal Antiinflammatory Drugs

合成路线1 合成路线2

合成路线1

The hindered base, diisobutylamine, was used in the Stork enamine synthesis of valeraldehyde (I) with allyl bromide to yield the desired aldehyde (II) following acidic hydrolysis and subsequent hydrogenation. Acid-catalyzed annelation of (II) with methyl vinyl ketone provided 4,4-dipropylcyclohex-2-enone which upon hydrogenation gave (III). Piperidine-catalyzed condensation of ethyl cyanoacetate with (III) gave cyanoester (IV). Michael addition of KCN followed by acidic hydrolysis gave diacid (V). Treatment of diacid (V) with acetic anhydride gave desired anhydride (VI), which was condensed with N,N-dimethylaminopropylamine to yield the desired imide (VII). Lithium aluminum hydride reduction of the imide (VII) gave the desired diamine which was treated with anhydrous HCl/ethanol to give the required dihydrochloride salt, SK&F 105685.

参考文献中间体

【1】 Curphey, T.J.; Chu, C.C.C.; Hung, J.C.; A study of the alkylation of enamines derived from sterically hindered amines. J Org Chem 1975, 40, 607-14.
【2】 Flaugh, M.E.; Crowell, T.A.; Farlow, D.S.; Acid-catalyzed annelation of alpha-alkyl aldehydes and alpha,beta-unsaturated ketones. A one-pot synthesis of 4,4-dimethyl-2-cyclohexen-1-one. J Org Chem 1980, 45, 5399-400.
【3】 Schwartz, D.A.; Badger, A.M.; SK&F-105685. Drugs Fut 1991, 16, 9, 815.

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)	13409	n-Valeraldehyde; Pentanal	110-62-3	C₅H₁₀O	详情	详情
(II)	13410	2-Propylpentanal		C₈H₁₆O	详情	详情
(III)	13411	4,4-Dipropylcyclohexanone	123018-62-2	C₁₂H₂₂O	详情	详情
(IV)	13412	ethyl 2-cyano-2-(4,4-dipropylcyclohexylidene)acetate		C₁₇H₂₇NO₂	详情	详情
(V)	13413	1-(Carboxymethyl)-4,4-dipropylcyclohexanecarboxylic acid		C₁₅H₂₆O₄	详情	详情
(VI)	13414	8,8-Dipropyl-2-oxaspiro[4.5]decane-1,3-dione		C₁₅H₂₄O₃	详情	详情
(VII)	13415	2-[3-Ddimethylamino)propyl]-8,8-dipropyl-2-azaspiro[4.5]decane-1,3-dione		C₂₀H₃₆N₂O₂	详情	详情

合成路线2

The synthesis of two different forms of tritiated SK&F-105685 has been described: 1) The reaction of SK&F-105685 (I) with mercuric acetate and perchloric acid gives the corresponding iminium perchlorate (II), which is then reduced with NaBT4 in ethanol yielding the tritium derivative at C-1. 2) The reductive tritiation of the 8-allyl-2-[3-(dimethylamino)propyl]-8-propyl-2-azaspiro[4.5]decane (III) with tritium gas over Pd/C in ethanol gives the ditritiated compound at the propyl.

参考文献中间体

【1】 Landvatter, S.W.; Heys, J.R.; Senderoff, S.G.; Synthesis of the tritium labelled azaspirane: SK&F 105685. J Label Compd Radiopharm 1993, 33, 12, 1113.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	13416	N-[3-(8,8-Dipropyl-2-azaspiro[4.5]dec-2-yl)propyl]-N,N-dimethylamine; 3-(8,8-Dipropyl-2-azaspiro[4.5]dec-2-yl)-N,N-dimethyl-1-propanamine	C₂₀H₄₀N₂	详情	详情
(II)	13417	2-[3-(Dimethylamino)propyl]-8,8-dipropyl-2-azoniaspiro[4.5]dec-1-ene	C₂₀H₃₉N₂	详情	详情
(III)	13419	N-[3-(8-Allyl-8-propyl-2-azaspiro[4.5]dec-2-yl)propyl]-N,N-dimethylamine; 3-(8-Allyl-8-propyl-2-azaspiro[4.5]dec-2-yl)-N,N-dimethyl-1-propanamine	C₂₀H₃₈N₂	详情	详情

Extended Information