methyl 2-[4-[(tert-butoxycarbonyl)amino]cyclohexyl]acetate -Drug Synthesis Database

【结构式】

【分子编号】33035

【品名】methyl 2-[4-[(tert-butoxycarbonyl)amino]cyclohexyl]acetate

【CA登记号】

【分子式】C₁₄H₂₅NO₄

【分子量】271.35684

【元素组成】C 61.97% H 9.29% N 5.16% O 23.58%

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：(III)

Esterification of trans-4-aminocyclohexylacetic acid (I), followed by protection of the resulting amino ester (II) with di-tert-butyl dicarbonate, afforded carbamate (III). Ester (III) reduction using DIBAL then gave aldehyde (IV) (1,2). 6-Cyano-1,2,3,4-tetrahydroisoquinoline (VII) was prepared by acylation of 6-bromotetrahydroisoquinoline (V) with trifluoroacetic anhydride to give amide (VI). Bromide displacement in (VI) with CuCN in NMP, followed by hydrolysis of the trifluoroacetamido group, furnished (VII) (1). Reductive condensation between amine (VII) and aldehyde (IV) in the presence of NaBH(OAc)3 gave adduct (VIII). The Boc protecting group of (VIII) was then removed by treatment with trifluoroacetic acid, yielding amine (IX). This was finally coupled with 4-quinolinecarboxylic acid (X) by means of EDC and HOBt.

参考文献中间体

合成目标

【2】 Branch, C.L.; Stemp, G.; Johnson, C.N. (SmithKline Beecham plc); Tetrahydroisoquinoline derivs. as modulators of dopamine D3 receptors. EP 0983244; WO 9850364 .
【1】 Branch, C.L.; Stemp, G.; Ashmeade, T.; et al.; Design and synthesis of trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011): A potent and selective dopamine D3 receptor antagonist with high oral bioavailability and CNS penetration in the rat. J Med Chem 2000, 43, 9, 1878.

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)	33033	2-(4-aminocyclohexyl)acetic acid		C₈H₁₅NO₂	详情	详情
(II)	33034	methyl 2-(4-aminocyclohexyl)acetate		C₉H₁₇NO₂	详情	详情
(III)	33035	methyl 2-[4-[(tert-butoxycarbonyl)amino]cyclohexyl]acetate		C₁₄H₂₅NO₄	详情	详情
(IV)	33036	tert-butyl 4-(2-oxoethyl)cyclohexylcarbamate		C₁₃H₂₃NO₃	详情	详情
(V)	45796	6-bromo-1,2,3,4-tetrahydroisoquinoline		C₉H₁₀BrN	详情	详情
(VI)	45797	1-[6-bromo-3,4-dihydro-2(1H)-isoquinolinyl]-2,2,2-trifluoro-1-ethanone		C₁₁H₉BrF₃NO	详情	详情
(VII)	45798	1,2,3,4-tetrahydro-6-isoquinolinecarbonitrile		C₁₀H₁₀N₂	详情	详情
(VIII)	45799	tert-butyl 4-[2-[6-cyano-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]cyclohexylcarbamate		C₂₃H₃₃N₃O₂	详情	详情
(IX)	45800	2-[2-(4-aminocyclohexyl)ethyl]-1,2,3,4-tetrahydro-6-isoquinolinecarbonitrile		C₁₈H₂₅N₃	详情	详情
(X)	45801	4-quinolinecarboxylic acid	486-74-8	C₁₀H₇NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIII)

An alternative procedure started from trans-4-aminocyclohexylacetic acid hydrogen sulfate (XI), which was esterified with methanol and sulfuric acid to give aminoester (XII). Protection of the amino group of (XII) as the tert-butyl carbamate (XIII), followed by ester reduction with DIBAL gave rise to aldehyde (XIV). Reductive condensation of (XIV) with tetrahydroisoquinoline (IV) provided (XV). The Boc group of (XV) was then cleaved with trifluoroacetic acid to furnish the trans amine (XVI). This was finally converted to the target compound by coupling with indole-2-carboxylic acid (X) as above.

参考文献中间体

合成目标

【1】 Stokker, G.E.; Preparation of 1,2,3,4-tetrahydroisoquinolines lacking electron donating groups - an intramolecular cyclization complementary to the Pictet-Spengler reaction. Tetrahedron Lett 1996, 37, 31, 5453.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	33026	1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile		C₁₀H₁₀N₂	详情	详情
(X)	25226	1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid	1477-50-5	C₉H₇NO₂	详情	详情
(XI)	33033	2-(4-aminocyclohexyl)acetic acid		C₈H₁₅NO₂	详情	详情
(XII)	33034	methyl 2-(4-aminocyclohexyl)acetate		C₉H₁₇NO₂	详情	详情
(XIII)	33035	methyl 2-[4-[(tert-butoxycarbonyl)amino]cyclohexyl]acetate		C₁₄H₂₅NO₄	详情	详情
(XIV)	33036	tert-butyl 4-(2-oxoethyl)cyclohexylcarbamate		C₁₃H₂₃NO₃	详情	详情
(XV)	33037	tert-butyl 4-[2-[7-cyano-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]cyclohexylcarbamate		C₂₃H₃₃N₃O₂	详情	详情
(XVI)	33038	2-[2-(4-aminocyclohexyl)ethyl]-1,2,3,4-tetrahydro-7-isoquinolinecarbonitrile		C₁₈H₂₅N₃	详情	详情

Extended Information