(1R,2R)-2-(1-pyrrolidinyl)cyclohexanol -Drug Synthesis Database

【结构式】

【分子编号】14637

【品名】(1R,2R)-2-(1-pyrrolidinyl)cyclohexanol

【CA登记号】

【分子式】C₁₀H₁₉NO

【分子量】169.267

【元素组成】C 70.96% H 11.31% N 8.27% O 9.45%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(III)

The condensation of cyclohexene-epoxide (I) with pyrrolidine (II) gives trans-2-(1-pyrrolidinyl)cyclohexanol (III), which by reaction with NaH and methanesulfonyl chloride, and then with benzylamine is converted into trans-2-(1-pyrrolidinyl)-N-benzylcyclohexylamine (IV). The debenzylation of (IV) by hydrogenolysis with H2 over Pd/C affords trans-2-(1-pyrrolidinyl)cyclohexylamine (V), which is formylated with ethyl formate to the corresponding N-formyl-trans-2-(1-pyrrolidinyl)cyclohexylamine (VI). The reduction of (VI) with LiAlH4 in refluxing ether gives trans-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (VII), which is finally condensed with 3,4-dichlorophenylacetic acid (VIII) by means of carbonyl diimidazole (IX) in THF.

参考文献中间体

合成目标

【1】 Blancafort, P.; Castaner, J.; Serradell, M.N.; U-50488. Drugs Fut 1982, 7, 6, 416.
【2】 Szmuszkovicz, J.; 2-Aminocycloaliphatic amide compounds. DE 2749950; ES 463876; FR 2370723; GB 1569225; JP 53063351; JP 61233654; US 4145435 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(B)	16602	ethyl formate	109-94-4	C₃H₆O₂	详情	详情
(I)	17986	7-oxabicyclo[4.1.0]heptane; cyclohexene oxide	286-20-4	C₆H₁₀O	详情	详情
(II)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(III)	14637	(1R,2R)-2-(1-pyrrolidinyl)cyclohexanol		C₁₀H₁₉NO	详情	详情
(IV)	37038	N-phenyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]aniline		C₁₆H₂₄N₂	详情	详情
(V)	37040	(1R,2R)-2-(1-pyrrolidinyl)cyclohexylamine; (1R,2R)-2-(1-pyrrolidinyl)cyclohexanamine		C₁₀H₂₀N₂	详情	详情
(VI)	37011	1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-quinoxalinyl)-2-propen-1-one		C₁₅H₂₀N₂O	详情	详情
(VII)	31357	N-methyl-N-[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]amine; (1R,2R)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine		C₁₁H₂₂N₂	详情	详情
(VIII)	30414	2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid	5807-30-7	C₈H₆Cl₂O₂	详情	详情
(IX)	11353	1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole)	530-62-1	C₇H₆N₄O	详情	详情
(X)	37039	7-azabicyclo[4.1.0]heptane		C₆H₁₁N	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Trapencaine is prepared from 3-(n-pentyloxy)phenylisocyanate and (+)-trans-2-(1-pyrrolidinyl)cyclohexanol in dry benzene or some other inert solvent. Stereochemically pure isomer is obtained by treatment of the pure base with hydrochloric acid, yielding the corresponding salt.

参考文献中间体

合成目标

【1】 Benes, L.; Trapencaine Hydrochloride. Drugs Fut 1991, 16, 7, 627.
【2】 Benes, L.; Borovansky, A.; Kopácová, L.; Alkoxycarbanilic acid esters with high local anaesthetic activity. Arzneim-Forsch Drug Res 1969, 19, 1902-3.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	14636	3-(pentyloxy)phenyl isocyanate; 1-isocyanato-3-(pentyloxy)benzene	C₁₂H₁₅NO₂	详情	详情
(II)	14637	(1R,2R)-2-(1-pyrrolidinyl)cyclohexanol	C₁₀H₁₉NO	详情	详情
(III)	14638	(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl N-[3-(pentyloxy)phenyl]carbamate	C₂₂H₃₄N₂O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

By refluxing a solution of equimolecular quantities of 3-pentyloxyphenyl isocyanate (I) and trans-2-(1-pyrrolidinyl)cyclohexanol (II) in toluene. The obtained pentacaine base is transformed to the hydrochloride by treatment of an ether solution of anhydrous hydrogen chloride (1,2). The starting amino-alcohol (II) is prepared from cyclohexanol (III), which is first dehydrated to cyclohexene (IV). The following addition of HClO gives trans-2-chlorocyclohexanol (V), which, in turn is dehydrochlorinated to 1,2-epoxycyclohexane (VI). Final addition of pyrrolidine (A) yields the required intermediate (II).

参考文献中间体

合成目标

【1】 Castaner, J.; Pentacaine. Drugs Fut 1976, 1, 8, 379.
【2】 Subert, J.; et al.; Studies on local anesthetics. XLVIII. Preliminary analytical evaluation of the substance K-1902 (pentacaine). Cesk Farm 1975, 24, 5.
【3】 Benes, L.; Borovansky, A.; Kopácová, L.; Basische trans- und cis-Cyklohexylester substituierter Alkoxycarbanilsäuren. XLI. Studien über Lokalanästhetika. Arch Pharm 1972, 305, 648.
【4】 Benes, L.; Borovansky, A.; Kopácová, L.; Alkoxycarbanilic acid esters with high local anaesthetic activity. Arzneim-Forsch Drug Res 1969, 19, 1902-3.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(I)	14636	3-(pentyloxy)phenyl isocyanate; 1-isocyanato-3-(pentyloxy)benzene		C₁₂H₁₅NO₂	详情	详情
(II)	14637	(1R,2R)-2-(1-pyrrolidinyl)cyclohexanol		C₁₀H₁₉NO	详情	详情
(III)	11306	Cyclohexanol	108-93-0	C₆H₁₂O	详情	详情
(IV)	40446	1-cyclohexene	110-83-8	C₆H₁₀	详情	详情
(V)	40447	(1R,2R)-2-chlorocyclohexanol	1561-86-0	C₆H₁₁ClO	详情	详情
(VI)	40448	(1R,6R)-7-oxabicyclo[4.1.0]heptane		C₆H₁₀O	详情	详情

合成路线4

该中间体在本合成路线中的序号：(III)

Opening of cyclohexene oxide (I) with pyrrolidine (II) in aqueous K2CO3 yielded the racemic trans-2-(1-pyrrolidinyl)cyclohexanol (III). Subsequent Mitsunobu coupling of (III) with phenol (IV) in the presence of DEAD and PPh3 produced ether (V). The intermediate acid chloride (VI) was then prepared by ester hydrolysis, followed by treatment with SOCl2.

参考文献中间体

合成目标

【1】 McCowan, J.R.; Sall, D.J.; Gifford-Moore, D.S.; Takeuchi, K.; Denney, M.L.; Kohn, T.J.; Smith, G.F.; Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[b]thiophenes. Bioorg Med Chem Lett 1999, 9, 5, 759.

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)	17986	7-oxabicyclo[4.1.0]heptane; cyclohexene oxide	286-20-4	C₆H₁₀O	详情	详情
(II)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(III)	14637	(1R,2R)-2-(1-pyrrolidinyl)cyclohexanol		C₁₀H₁₉NO	详情	详情
(IV)	29176	methyl 4-hydroxy-3-methoxybenzoate	3943-74-6	C₉H₁₀O₄	详情	详情
(V)	29177	methyl 3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoate		C₁₉H₂₇NO₄	详情	详情
(VI)	29178	3-methoxy-4-[[(1R,2R)-2-(1-pyrrolidinyl)cyclohexyl]oxy]benzoyl chloride		C₁₈H₂₄ClNO₃	详情	详情

Extended Information