Buprenorphine hydrochloride, IX-1003, TSN-09(tape), UM-952, NIH-8805, CL-112302, Probuphine, Transtec, Subutex, Temgesic, Buprex, Buprenex, -Drug Synthesis Database

【结构式】

【药物名称】Buprenorphine hydrochloride, IX-1003, TSN-09(tape), UM-952, NIH-8805, CL-112302, Probuphine, Transtec, Subutex, Temgesic, Buprex, Buprenex

【化学名称】21-Cyclopropyl-7alpha-[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6,14-endo-ethano-6,7,8,14-tetrahydrooripavine hydrochloride
　　　　　　21-Cyclopropyl-7alpha-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydrooripavine hydrochloride
　　　　　　17-(Cyclopropylmethyl)-alpha-(1,1-dimethylethyl)-4,5-epoxy-3-hydroxy-6-methoxy-alpha-methyl-6,14-ethenomorphinan-7-methanol hydrochloride

【CA登记号】53152-21-9, 52485-79-7 (free base)

【分子式】C₂₉H₄₂ClNO₄

【分子量】504.11539

【开发单位】Reckitt & Colman (Originator), Grünenthal (Not Determined), Teijin (Not Determined), Essex (Licensee), Nastech (Licensee), Roche (Licensee), DrugAbuse Sciences (Formulation), Ionix Pharmaceuticals (Formulation), Titan (Formulation), Schering-Plough (Distr

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Opioid Analgesics, Treatment of Opioid Dependency, TREATMENT OF POISONING, DRUG ABUSE & DEPENDENCY, Treatment of Substance Dependency, delta-Opioid Antagonists, kappa-Opioid Antagonists, mu-Opioid Agonists

合成路线1

The hydrogenation of 7-acetyl-6,14-endoetheno-6,7,8,14-tetrahydrothebaine (I) with H2 over Pd/C in acetic acid gives the corresponding endo-ethano derivative (II), which by a Grignard reaction with tertbutyl-magnesium chloride (A) in ether-benzene yields 7alpha-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydrothebaine (III). The reaction of III with BrCN in CH2Cl2 affords 7alpha-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-N-cyano-6,7,8,14-tetrahydronorthebaine (IV), which is treated with KOH in ethylene glycol at 170 C to give 7alpha(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydronorthebaine (V). This compound is treated first with cyclopropylcarbonyl chloride (B) in CH2Cl2 containing triethylamine, followed by a reduction with LiAlH4 in refluxing THF yielding N-cyclopropylmethyl-7alpha-(2-hydroxy-3,3-dimethyl-2-butyl)-6,14-endo-ethano-6,7,8,14-tetrahydro-northebaine (VI). Finally, (VI) is demethylated with KOH in diethylene glycol at 210-220 C.

参考文献中间体

【1】 Bentley, K.W.; Thebaine and Oripavine derivatives. CH 558362; DE 1620206; FR 6395M; GB 1136214 .
【2】 Castaner, J.; Paton, D.M.; Buprenorphine. Drugs Fut 1977, 2, 9, 570.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	14061	Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride	4023-34-1	C₄H₅ClO	详情	详情
(A)	15459	tert-butyl(chloro)magnesium	677-22-5	C₄H₉ClMg	详情	详情
(I)	33912	1-[(1R,2S,6R,14R,15S,16S)-11,15-dimethoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11,18-tetraen-16-yl]-1-ethanone		C₂₃H₂₇NO₄	详情	详情
(II)	33913	1-[(1S,2S,6R,14R,15S,16S)-11,15-dimethoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-1-ethanone		C₂₃H₂₉NO₄	详情	详情
(III)	33914	(2R)-2-[(1S,2S,6R,14R,15S,16R)-11,15-dimethoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol		C₂₇H₃₉NO₄	详情	详情
(IV)	33915	(2R)-2-[(1S,2S,6R,14R,15S,16R)-5-cyano-11,15-dimethoxy-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol		C₂₇H₃₆N₂O₄	详情	详情
(V)	33916	(2R)-2-[(1S,2S,6R,14R,15S,16R)-11,15-dimethoxy-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol		C₂₆H₃₇NO₄	详情	详情
(VI)	33917	(2R)-2-[(1S,2S,6R,14R,15S,16R)-5-(cyclopropylmethyl)-11,15-dimethoxy-13-oxa-5-azahexacyclo[13.2.2.1(2,8).0(1,6).0(2,14).0(12,20)]icosa-8(20),9,11-trien-16-yl]-3,3-dimethyl-2-butanol		C₃₀H₄₃NO₄	详情	详情

Extended Information