tert-butyl(chloro)magnesium -Drug Synthesis Database

【结构式】

【分子编号】15459

【品名】tert-butyl(chloro)magnesium

【CA登记号】677-22-5

【分子式】C₄H₉ClMg

【分子量】116.87316

【元素组成】C 41.11% H 7.76% Cl 30.33% Mg 20.8%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(A)

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

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(III)

Radiolabeled SDZ-FOX-988 has been synthesized as follows: The condensation of 4-bromotoluene (I) with [14C]-cuprous cyanide in DMSO at 180 C gives the labeled 4-methylbenzonitrile (II), which by a Grignard reaction with tert-butylmagnesium chloride in THF yields the ketone (IV). The oxidation of (IV) with KMnO4 in tert-butanol affords the labeled 4-pivaloylbenzoic acid (V), which by reaction with refluxing SOCl2 gives the corresponding acyl chloride (VI). The reaction of (VI) with methoxyamine (VII) and triethylamine in toluene yields the corresponding amide (VIII), which is finally condensed with more acyl chloride (VI), by means of triethylamine in toluene.

参考文献中间体

合成目标

【1】 Sunay, U.B.; Talbot, K.; Prasad, K.; Lee, G.; Jones, L.; Synthesis of [14C2]SDZ FOX 988, a hypoglycemic agent. J Label Compd Radiopharm 1995, 36, 6, 529-35.
【2】 Mealy, N.; Castaner, J.; SDZ-FOX-988. Drugs Fut 1996, 21, 3, 258.

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)	14044	4-Bromotoluene; 1-Bromo-4-methylbenzene	106-38-7	C₇H₇Br	详情	详情
(II)	15458	4-methylbenzonitrile; p-tolunitrile	104-85-8	C₈H₇N	详情	详情
(II)	45171	4-methylbenzonitrile		C₈H₇N	详情	详情
(III)	15459	tert-butyl(chloro)magnesium	677-22-5	C₄H₉ClMg	详情	详情
(IV)	15460	2,2-dimethyl-1-(4-methylphenyl)-1-propanone; 2,2,4'-TRIMETHYLPROPIOPHENONE	30314-44-4	C₁₂H₁₆O	详情	详情
(IV)	45250	2,2-dimethyl-1-(4-methylphenyl)-1-propanone		C₁₂H₁₆O	详情	详情
(V)	15453	4-(2,2-dimethylpropanoyl)benzoic acid		C₁₂H₁₄O₃	详情	详情
(V)	45251	4-(2,2-dimethylpropanoyl)benzoic acid		C₁₂H₁₄O₃	详情	详情
(VI)	15454	4-(2,2-dimethylpropanoyl)benzoyl chloride		C₁₂H₁₃ClO₂	详情	详情
(VI)	45252	4-(2,2-dimethylpropanoyl)benzoyl chloride		C₁₂H₁₃ClO₂	详情	详情
(VII)	15456	4-(2,2-dimethylpropanoyl)-N-methoxybenzamide		C₁₃H₁₇NO₃	详情	详情
(VIII)	15455	(aminooxy)methane; O-methylhydroxylamine	67-62-9	CH₅NO	详情	详情
(VIII)	45253	4-(2,2-dimethylpropanoyl)-N-methoxybenzamide		C₁₃H₁₇NO₃	详情	详情

Extended Information