(2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine -Drug Synthesis Database

【结构式】

【分子编号】39357

【品名】(2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine

【CA登记号】27527-05-5

【分子式】C₉H₁₇NO₂

【分子量】171.23952

【元素组成】C 63.13% H 10.01% N 8.18% O 18.69%

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：(I)

Synthesis of the dipeptide intermediate (IX): The esterification of D-cyclohexylalanine (I) by means of SOCl2 and methanol gives the methyl ester (II), which is condensed with tert-butyl bromoacetate (III) by means of DIEA in acetonitrile to yield the N-substituted cyclohexylalanine (IV). The reaction of (IV) with Boc2O and DIEA in DMF affords the N-protected compound (V), which is hydrolyzed with NaOH in dioxane/water to provide the free N-substituted cyclohexylalanine (VI). The condensation of (VI) with L-proline benzyl ester (VII) by means of HOBT and DCC in DMF gives the dipeptide (VIII), which is finally debenzylated by means of H2 over Pd/C in methanol to yield the target dipeptide intermediate (IX).

参考文献中间体

合成目标

【1】 Adang, A.E.P.; De Man, A.P.A.; Vogel, G.M.T.; Grootenhuis, P.D.J.; Smit, M.J.; Peters, C.A.M.; Visser, A.; Rewinkel, J.B.M.; van Dinther, T; Lucas, H.; Kelder, J.; van Aelst, S.; Meuleman, D.G.; van Boeckel, C.A.A.; Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics. J Med Chem 2002, 45, 20, 4419.
【2】 Adang, A.E.P.; Peters, J.A.M.; Van Boeckel, C.A.A.; Rewinkel, J.B.M. (Akzo Nobel N.V.); Thrombin inhibitors. WO 9807308 .

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)	39357	(2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine	27527-05-5	C₉H₁₇NO₂	详情	详情
(II)	60226	methyl 2-amino-3-cyclohexylpropanoate		C₁₀H₁₉NO₂	详情	详情
(III)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(IV)	60227	methyl 3-cyclohexyl-2-({2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoate		C₁₆H₂₉NO₄	详情	详情
(V)	60228	methyl 3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoate		C₂₁H₃₇NO₆	详情	详情
(VI)	60229	3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-N-{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}alanine		C₂₀H₃₅NO₆	详情	详情
(VII)	20930	benzyl (2S)-2-pyrrolidinecarboxylate	16652-71-4	C₁₂H₁₅NO₂	详情	详情
(VIII)	60230	phenylmethyl 1-[3-cyclohexyl-2-({[(1,1-dimethylethyl)oxy]carbonyl}{2-[(1,1-dimethylethyl)oxy]-2-oxoethyl}amino)propanoyl]-2-pyrrolidinecarboxylate		C₃₂H₄₈N₂O₇	详情	详情
(IX)	23165	(2S)-1-((2R)-2-[(tert-butoxycarbonyl)[2-(tert-butoxy)-2-oxoethyl]amino]-3-cyclohexylpropanoyl)-2-pyrrolidinecarboxylic acid		C₂₅H₄₂N₂O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

Cyclohexylalanine (XIV) was protected as the Boc derivative (XV) and then coupled with N,O-dimethylhydroxylamine to produce the Weinreb amide (XVI). Reduction of (XVI) with LiAlH4 at -78 C gave aldehyde (XVII) and subsequent addition of tert-butyl isonitrile furnished hydroxy amide (XVIII). After acid hydrolysis of (XVIII), amino acid (XIX) was protected as the N-Boc derivative (XX). This was coupled with benzodioxolylmethyl amine (XXI) yielding amide (XXII). Acid deprotection of the Boc group of (XXII) gave (XXIII), which was further coupled with dipeptide (VII) to generate tripeptide amide (XXIV). Following hydrogenolytic deprotection of the N-nitro group of (XXIV), Swern oxidation of the alcohol group gave rise to the title compound.

参考文献中间体

合成目标

【1】 Semple, J.E.; et al.; Novel, potent, and selective factor Xa inhibitors featuring a hydrophobic P1-ketoamide moiety. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 193.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXIII	39362	(3S)-3-amino-N-(1,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2-hydroxybutanamide		C₁₈H₂₆N₂O₄	详情	详情
(VII)	39350			C₁₆H₂₄N₆O₇S	详情	详情
(XIV)	39357	(2S)-2-amino-3-cyclohexylpropionic acid; L-Cyclohexylalanine	27527-05-5	C₉H₁₇NO₂	详情	详情
(XV)	23050	(2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid		C₁₄H₂₅NO₄	详情	详情
(XVI)	39358	tert-butyl (1S)-1-(cyclohexylmethyl)-2-[methoxy(methyl)amino]-2-oxoethylcarbamate		C₁₆H₃₀N₂O₄	详情	详情
(XVII)	15853	tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate		C₁₄H₂₅NO₃	详情	详情
(XVIII)	39359	tert-butyl (1S)-3-(tert-butylamino)-1-(cyclohexylmethyl)-2-hydroxy-3-oxopropylcarbamate		C₁₉H₃₆N₂O₄	详情	详情
(XIX)	12329	(2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid		C₁₀H₁₉NO₃	详情	详情
(XX)	39360	(3S)-3-[(tert-butoxycarbonyl)amino]-4-cyclohexyl-2-hydroxybutyric acid		C₁₅H₂₇NO₅	详情	详情
(XXI)	33669	1,3-benzodioxol-5-ylmethylamine; 1,3-benzodioxol-5-ylmethanamine; 3,4-Methylendioxybenzylamine	2620-50-0	C₈H₉NO₂	详情	详情
(XXII)	39361	tert-butyl (1S)-3-[(1,3-benzodioxol-5-ylmethyl)amino]-1-(cyclohexylmethyl)-2-hydroxy-3-oxopropylcarbamate		C₂₃H₃₄N₂O₆	详情	详情
(XXIV)	39363			C₃₄H₄₈N₈O₁₀S	详情	详情

Extended Information