N-butyl-2-cyclohexylacetamide -Drug Synthesis Database

【结构式】

【分子编号】39003

【品名】N-butyl-2-cyclohexylacetamide

【CA登记号】

【分子式】C₁₂H₂₃NO

【分子量】197.32076

【元素组成】C 73.04% H 11.75% N 7.1% O 8.11%

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：(XIII)

The sulfonation of 4-chlorodiphenyl ether (I) with chlorosulfonic acid in dichloromethane gives the 4-(4-chlorophenoxy)benzenesulfonic acid (II), which is treated with oxalyl chloride and DMF in the same solvent yielding the sulfonyl chloride (III). The reduction of (III) with trimethyl phosphite and KOH in toluene affords the methylsulfanyl derivative (IV), which is chlorinated with SO2Cl2 in dichloromethane to give the chloromethylsulfanyl derivative (V). The condensation of (V) with the silylated enol ether (VI) by means of ZnCl2 and KOH in refluxing dichloromethane yields 4-[4-(4-chlorophenoxy)phenylsulfanylmethyl]tetrahydropyran-4-carboxylic acid (VII), which is treated with oxalyl chloride affording the corresponding acyl chloride (VIII). The reaction of (VIII) with NH2OH in dichloromethane provides the carbohydroxamic acid (IX), which is finally oxidized with oxone (potassium peroxymonosulfate) in N-methyl-2-pyrrolidone/H2O to furnish the target sulfone.

参考文献中间体

合成目标

【1】 Zook, S.E.; Dagnino, R. Jr.; Deason, M.E.; Bender, S.L.; Melnick, M.J. (Agouron Pharmaceuticals, Inc.); Metalloproteinase inhibitors, pharmaceutical compsns. containing them and their pharmaceutical uses, and methods and intermediates useful for their preparation. EP 0874830; JP 2000502330; WO 9720824 .
【2】 Campbell, J.A.; Dvorak, C.A.; Fisher, L.E.; McGrane, P.L. (F. Hoffmann-La Roche AG); Process for preparing 3-arylsulfur hydroxamic acids. EP 0965592 .

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)	39894	1-chloro-4-phenoxybenzene; 4-chlorophenyl phenyl ether	7005-72-3	C₁₂H₉ClO	详情	详情
(II)	39895	4-(4-chlorophenoxy)benzenesulfonic acid		C₁₂H₉ClO₄S	详情	详情
(III)	39896	4-(4-chlorophenoxy)benzenesulfonyl chloride		C₁₂H₈Cl₂O₃S	详情	详情
(IV)	39897	4-chlorophenyl 4-(methylsulfanyl)phenyl ether; 1-(4-chlorophenoxy)-4-(methylsulfanyl)benzene	225652-11-9	C₁₃H₁₁ClOS	详情	详情
(V)	39898	1-[(chloromethyl)sulfanyl]-4-(4-chlorophenoxy)benzene; 4-[(chloromethyl)sulfanyl]phenyl 4-chlorophenyl ether		C₁₃H₁₀Cl₂OS	详情	详情
(VI)	39899	ethoxy(tetrahydro-4H-pyran-4-ylidene)methyl trimethylsilyl ether; [ethoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane		C₁₁H₂₂O₃Si	详情	详情
(VII)	39900	4-([[4-(4-chlorophenoxy)phenyl]sulfanyl]methyl)tetrahydro-2H-pyran-4-carboxylic acid		C₁₉H₁₉ClO₄S	详情	详情
(VIII)	39901	4-([[4-(4-chlorophenoxy)phenyl]sulfanyl]methyl)tetrahydro-2H-pyran-4-carbonyl chloride		C₁₉H₁₈Cl₂O₃S	详情	详情
(IX)	39902	4-([[4-(4-chlorophenoxy)phenyl]sulfanyl]methyl)-N-hydroxytetrahydro-2H-pyran-4-carboxamide		C₁₉H₂₀ClNO₄S	详情	详情
(X)	16829	Diethyl malonate	105-53-3	C₇H₁₂O₄	详情	详情
(XI)	12060	Bis(2-chloroethyl) ether; 1-Chloro-2-(2-chloroethoxy)ethane; 2,2'-Dichlorodiethyl ether	111-44-4	C₄H₈Cl₂O	详情	详情
(XII)	18726	diethyl tetrahydro-4H-pyran-4,4-dicarboxylate		C₁₁H₁₈O₅	详情	详情
(XIII)	39003	N-butyl-2-cyclohexylacetamide		C₁₂H₂₃NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Cyclohexylacetic acid (VII) was converted to acid chloride and then condensed with n-butyl amine to give amide (VIII). Reduction of (VIII) with LiAlH4 afforded secondary amine (IX), which was alkylated with bromide (VI) yielding amino ester (X). After basic hydrolysis of the ester group of (X), the resultant carboxylic acid (XI) was coupled with L-methionine methyl ester (XII) to produce amide (XIII). The methyl ester group of (XIII) was finally hydrolyzed by treatment with LiOH.

参考文献中间体

合成目标

【1】 Donner, B.G.; Janowick, D.A.; Larsen, J.J.; Rosenberg, S.H.; Hamilton, A.D.; Barr, K.J.; Sorensen, B.K.; Augeri, D.J.; Kalvin, D.M.; O'Connor, S.J.; Fakhoury, S.A.; Swenson, R.E.; Liu, G.; Sebti, S.M.; Shen, W. (University of Pittsburgh); Inhibitors of protein isoprenyl transferases. EP 0986384; WO 9850029; WO 9850030; WO 9850031 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	39001	methyl 5-(bromomethyl)-2'-methyl[1,1'-biphenyl]-2-carboxylate		C₁₆H₁₅BrO₂	详情	详情
(VII)	39002	2-cyclohexylacetic acid	5292-21-7	C₈H₁₄O₂	详情	详情
(VIII)	39003	N-butyl-2-cyclohexylacetamide		C₁₂H₂₃NO	详情	详情
(IX)	39004	N-(2-cyclohexylethyl)-1-butanamine; N-butyl-N-(2-cyclohexylethyl)amine		C₁₂H₂₅N	详情	详情
(X)	39005	methyl 5-[[butyl(2-cyclohexylethyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylate		C₂₈H₃₉NO₂	详情	详情
(XI)	39006	5-[[butyl(2-cyclohexylethyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-carboxylic acid		C₂₇H₃₇NO₂	详情	详情
(XII)	17950	D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride	21691-49-6	C₆H₁₃NO₂S	详情	详情
(XIII)	39007	methyl (2S)-2-[[(5-[[butyl(2-cyclohexylethyl)amino]methyl]-2'-methyl[1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate		C₃₃H₄₈N₂O₃S	详情	详情

Extended Information