2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】38656

【品名】2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate

【CA登记号】

【分子式】C₉H₁₄Cl₃NO₅

【分子量】322.572

【元素组成】C 33.51% H 4.37% Cl 32.97% N 4.34% O 24.8%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IX)

The isomerization of arecoline (I) with LDA gives 1-methyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester (II), which is reduced with LiAlH4 in THF yielding the carbinol (III). The protection of (III) with trichloroethyl chloroformate (Troc-Cl) and DIEA in toluene affords the demethylated compound (IV), which is treated with K2CO3 in methanol providing 3-(hydroxymethyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid 2,2,2-trichloroethyl ester (V). The silylation of (V) with TBDPSCl and imidazole in DMF gives the silyl ether (VI), which is epoxidized with MCPBA in dichloromethane yielding the epoxide (VII). Epoxide (VII) opening by means of HClO4 in refluxing water affords a diastereomeric mixture of racemates (VIII) and (IX) that could not be separated. The cleavage of the carbamate group of (VIII) and (IX) by means of HCl in water gives a new mixture that could be separated by flash chromatography to furnish the target compound as a racemate. Alternatively, intermediate (IV) is epoxidized with MCPBA in dichloromethane yielding the epoxide (X), which is treated as before.

参考文献中间体

合成目标

【1】 Bols, M.; Hansen, S.U.; Synthesis of (±)-isofagomine and its stereoisomers from arecoline. J Chem Soc - Perkins Trans I 2000, 6, 911.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	13664	1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate	17341-93-4	C₃H₂Cl₄O₂	详情	详情
(I)	38648	methyl 1-methyl-1,2,5,6-tetrahydro-3-pyridinecarboxylate		C₈H₁₃NO₂	详情	详情
(II)	38649	methyl 1-methyl-1,2,3,6-tetrahydro-3-pyridinecarboxylate		C₈H₁₃NO₂	详情	详情
(III)	38650	(1-methyl-1,2,3,6-tetrahydro-3-pyridinyl)methanol		C₇H₁₃NO	详情	详情
(IV)	38651	2,2,2-trichloroethyl 3-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-3,6-dihydro-1(2H)-pyridinecarboxylate		C₁₂H₁₃Cl₆NO₅	详情	详情
(V)	38652	2,2,2-trichloroethyl 3-(hydroxymethyl)-3,6-dihydro-1(2H)-pyridinecarboxylate		C₉H₁₂Cl₃NO₃	详情	详情
(VI)	38653	2,2,2-trichloroethyl 3-([[tert-butyl(diphenyl)silyl]oxy]methyl)-3,6-dihydro-1(2H)-pyridinecarboxylate		C₂₅H₃₀Cl₃NO₃Si	详情	详情
(VII)	38654	2,2,2-trichloroethyl 5-([[tert-butyl(diphenyl)silyl]oxy]methyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate		C₂₅H₃₀Cl₃NO₄Si	详情	详情
(VIII)	38655	2,2,2-trichloroethyl (3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate		C₉H₁₄Cl₃NO₅	详情	详情
(IX)	38656	2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate		C₉H₁₄Cl₃NO₅	详情	详情
(X)	38657	2,2,2-trichloroethyl 5-([[(2,2,2-trichloroethoxy)carbonyl]oxy]methyl)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate		C₁₂H₁₃Cl₆NO₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The condensation of 2-bromo-4-nitrotoluene (I) with phenylboronic acid (II) by means of Pd(OAc)2 in aqueous acetone gives the biphenyl (III), which is oxidized with KMnO4 in aqueous pyridine yielding the biphenyl-2-carboxylic acid (IV). The condensation of (IV) with L-methionine methyl ester (V) by means of EDC and HOBT affords the amide (VI), which is reduced with SnCl2 to give the 5-aminobiphenyl derivative (VII). The reductocondensation of (VII) with N-(tert-butoxycarbonyl)-S-trityl-L-cysteinal (VIII) by means of NaBH3CN affords the secondary amine (IX), which is finally deprotected with HgCl2 and H2S in methanol to furnish the target ester.

参考文献中间体

合成目标

【1】 Fossum, R.D.; Marugan, J.J.; Vogt, A.; Qian, Y.; Sebti, S.M.; Hamilton, A.D.; Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. Bioorg Med Chem 1999, 7, 12, 3011.
【2】 Sebti, S.; Hamilton, A. (University of Pittsburgh); Inhibitors of prenyl transferases. JP 1998512266; WO 9621456 .

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)	38642	2-bromo-1-methyl-4-nitrobenzene	7745-93-9	C₇H₆BrNO₂	详情	详情
(II)	16593	Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide	98-80-6	C₆H₇BO₂	详情	详情
(III)	38643	2-methyl-5-nitro-1,1'-biphenyl		C₁₃H₁₁NO₂	详情	详情
(IV)	38644	5-nitro[1,1'-biphenyl]-2-carboxylic acid		C₁₃H₉NO₄	详情	详情
(V)	17950	D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride	21691-49-6	C₆H₁₃NO₂S	详情	详情
(VI)	38645	methyl (2S)-4-(methylsulfanyl)-2-[[(5-nitro[1,1'-biphenyl]-2-yl)carbonyl]amino]butanoate		C₁₉H₂₀N₂O₅S	详情	详情
(VII)	38656	2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate		C₉H₁₄Cl₃NO₅	详情	详情
(VIII)	17953	tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate		C₂₇H₂₉NO₃S	详情	详情
(IX)	38647	methyl (2S)-2-[[(5-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino][1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate		C₄₆H₅₁N₃O₅S₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

The condensation of 2-bromo-4-nitrotoluene (I) with phenylboronic acid (II) by means of Pd(OAc)2 in aqueous acetone gives the biphenyl (III), which is oxidized with KMnO4 in aqueous pyridine yielding the biphenyl-2-carboxylic acid (IV). The condensation of (IV) with L-methionine methyl ester (V) by means of EDC and HOBT affords the amide (VI), which is reduced with SnCl2 to give the 5-aminobiphenyl derivative (VII). The reductocondensation of (VII) with N-(tert-butoxycarbonyl)-S-trityl-L-cysteinal (VIII) by means of NaBH3CN affords the secondary amine (IX), which is finally deprotected and hydrolyzed first with LiOH and THF and then with TFA and Et3SiH in dichloromethane to furnish the target free acid.

参考文献中间体

合成目标

【1】 Fossum, R.D.; Marugan, J.J.; Vogt, A.; Qian, Y.; Sebti, S.M.; Hamilton, A.D.; Probing the hydrophobic pocket of farnesyltransferase: Aromatic substitution of CAAX peptidomimetics leads to highly potent inhibitors. Bioorg Med Chem 1999, 7, 12, 3011.
【2】 Sebti, S.; Hamilton, A. (University of Pittsburgh); Inhibitors of prenyl transferases. JP 1998512266; WO 9621456 .

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)	38642	2-bromo-1-methyl-4-nitrobenzene	7745-93-9	C₇H₆BrNO₂	详情	详情
(II)	16593	Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide	98-80-6	C₆H₇BO₂	详情	详情
(III)	38643	2-methyl-5-nitro-1,1'-biphenyl		C₁₃H₁₁NO₂	详情	详情
(IV)	38644	5-nitro[1,1'-biphenyl]-2-carboxylic acid		C₁₃H₉NO₄	详情	详情
(V)	17950	D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride	21691-49-6	C₆H₁₃NO₂S	详情	详情
(VI)	38645	methyl (2S)-4-(methylsulfanyl)-2-[[(5-nitro[1,1'-biphenyl]-2-yl)carbonyl]amino]butanoate		C₁₉H₂₀N₂O₅S	详情	详情
(VII)	38656	2,2,2-trichloroethyl (3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-1-piperidinecarboxylate		C₉H₁₄Cl₃NO₅	详情	详情
(VIII)	17953	tert-butyl (1R)-1-formyl-2-(tritylsulfanyl)ethylcarbamate		C₂₇H₂₉NO₃S	详情	详情
(IX)	38647	methyl (2S)-2-[[(5-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propyl]amino][1,1'-biphenyl]-2-yl)carbonyl]amino]-4-(methylsulfanyl)butanoate		C₄₆H₅₁N₃O₅S₂	详情	详情

Extended Information