1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one -Drug Synthesis Database

【结构式】

【分子编号】14721

【品名】1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one

【CA登记号】

【分子式】C₅H₉BrN₄O

【分子量】221.05682

【元素组成】C 27.17% H 4.1% Br 36.15% N 25.35% O 7.24%

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：(VIII)

The reaction of 4-oxopiperidine-1-carboxylic acid ethyl ester (I) with CHCl3, benzyl triethylammonium chloride and NaOH in THF/water gives the spirooxirane (II), which is treated with aniline (III) and NaOH to yield the anilide (IV). The methylation of the amide nitrogen by means of NaH and CH3I in THF affords the methylated anilide (V). The reaction of (V) with KOH in refluxing isopropanol causes elimination of its ethoxycarbonyl group, providing compound (VI), which is reduced with lithium triethylborohydride in THF to give 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII). The condensation of (VII) with tetrazolone derivative (VIII) by means of KI in refluxing acetonitrile (or propionitrile) yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (XII). Finally, this compound is acylated with propionyl chloride (XIII) in chloroform to provide the target compound. The intermediate tetrazolone derivative (VIII) has been obtained by reaction of 1-ethyl-4,5-dihydro-1H-tetrazol-5-one (IX) with 1,2-dibromoethane (X) by means of TEA in acetonitrile.

参考文献中间体

合成目标

【1】 Killgore, J.K.; Jacob, M. (Mallinckrodt Medical Inc.); New methods for the syntheses of alfentanil, sufentanil and remifentanil. WO 0140184 .

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)	13486	Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone	29976-53-2	C₈H₁₃NO₃	详情	详情
(II)	49678	ethyl 2,2-dichloro-1-oxa-6-azaspiro[2.5]octane-6-carboxylate		C₉H₁₃Cl₂NO₃	详情	详情
(III)	12294	Aniline; Phenylamine	62-53-3	C₆H₇N	详情	详情
(IV)	49679	ethyl 4-anilino-4-(anilinocarbonyl)-1-piperidinecarboxylate		C₂₁H₂₅N₃O₃	详情	详情
(V)	49680	ethyl 4-anilino-4-[(methylanilino)carbonyl]-1-piperidinecarboxylate		C₂₂H₂₇N₃O₃	详情	详情
(VI)	49681	4-anilino-N-methyl-N-phenyl-4-piperidinecarboxamide		C₁₉H₂₃N₃O	详情	详情
(VII)	49682	(4-anilino-4-piperidinyl)methanol		C₁₂H₁₈N₂O	详情	详情
(VIII)	14721	1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₅H₉BrN₄O	详情	详情
(IX)	32218	1-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one	69048-98-2	C₃H₆N₄O	详情	详情
(X)	10252	1,2-Dibromoethane; Ethylene dibromide	106-93-4	C₂H₄Br₂	详情	详情
(XI)	49683	1-[2-[4-anilino-4-(hydroxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₁₇H₂₆N₆O₂	详情	详情
(XII)	49684	1-[2-[4-anilino-4-(methoxymethyl)-1-piperidinyl]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₁₈H₂₈N₆O₂	详情	详情
(XIII)	15967	propanoyl chloride; propionyl chloride	79-03-8	C₃H₅ClO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

Condensation of 1-benzyl-4-piperidone (I) with 2-fluoroaniline (II) affords imine (III). Addition of phenyllithium (IV) to imine (III) gives amine (V), which is acylated with propionyl chloride and the resultant amide (VI) is debenzylated via 1-chloroethyl chloroformate in refluxing 1,2-dichloroethane followed by methanolysis to give (VII). Amine (VII)) is alkylated with 1-(2-bromoethyl)-4-ethyl-4,5-dihydro-1H-tetrazol-5-one(VIII) to yield A-3665. A-3665 hydrochloride is precipitated with dry HCl gas in ethyl ether.

参考文献中间体

合成目标

【1】 Kudzma, L.V.; Spencer, H.K.; Severnak, S.A. (BOC Health Care, Inc.); 4-Phenyl-4-[N-(phenyl)amido]piperidine derivs. and methods employing such cpds. AU 8824558; EP 0315405; JP 1990015061; JP 1990152963; US 4791121; US 4921864 .
【2】 Kudzma, L.V.; Ossipov, M.H.; Benvenga, M.J.; Spaulding, T.C.; Rudo, F.G.; A-3665. Drugs Fut 1990, 15, 6, 559.

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)	15750	(6R,7R)-3-[(acetoacetoxy)methyl]-7-[[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid		C₁₇H₁₈N₆O₈S₂	详情	详情
(II)	22296	2-fluorophenylamine; 2-fluoroaniline	348-54-9	C₆H₆FN	详情	详情
(III)	13865	N-(1-Benzyl-4-piperidinylidene)-N-(2-fluorophenyl)amine; N-(1-Benzyl-4-piperidinylidene)-2-fluoroaniline		C₁₈H₁₉FN₂	详情	详情
(IV)	24014	Phenyllithium	591-51-5	C₆H₅Li	详情	详情
(V)	13866	N-(1-Benzyl-4-phenyl-4-piperidinyl)-N-(2-fluorophenyl)amine; 1-Benzyl-N-(2-fluorophenyl)-4-phenyl-4-piperidinamine		C₂₄H₂₅FN₂	详情	详情
(VI)	13867	N-(1-Benzyl-4-phenyl-4-piperidinyl)-N-(2-fluorophenyl)propanamide		C₂₇H₂₉FN₂O	详情	详情
(VII)	13868	N-(2-Fluorophenyl)-N-(4-phenyl-4-piperidinyl)propanamide		C₂₀H₂₃FN₂O	详情	详情
(VIII)	14721	1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₅H₉BrN₄O	详情	详情

合成路线3

该中间体在本合成路线中的序号：(III)

The synthesis of tritium-labeled brifentanil has been described: The hydrogenolysis of 1-benzyl-3-methylpiperidin-4-one (I) with H2 over Pd/C in ethanol gives the free piperidone (II), which is condensed with 1-(2-bromoethyl)-4-ethyl-4,5-dihydro-1H-tetrazol-5-one (III) by means of NaI and Na2CO3 in acetonitrile, yielding the condensation product (IV). The reductocondensation of (IV) with 4-bromo-2-fluoroaniline by means of NaBH3CN and HCl in methanol affords the substituted aniline (VI), which is acylated with 2-methoxyacetyl chloride (VII) and submitted to chromatographic (HPLC) separation to obtain the cis-isomer of bromobrifentanil (VIII). Finally, this compound is submitted to debromination with tritium gas and Pd/C in ethanol to afford [3H]-brifentanil.

参考文献中间体

合成目标

【1】 Nugent, R.P.; Huang, B.S.; Filer, C.N.; The synthesis of [fluorophenyl-H-3(N)]ocfentanil and [fluorophenyl-H-3(N)]brifentanil. J Label Compd Radiopharm 1995, 36, 11, 1019.

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)	14714	1-Benzyl-3-methyl-4-piperidone; 1-benzyl-3-methyltetrahydro-4(1H)-pyridinone	34737-89-8	C₁₃H₁₇NO	详情	详情
(II)	14720	3-methyltetrahydro-4(1H)-pyridinone		C₆H₁₁NO	详情	详情
(III)	14721	1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₅H₉BrN₄O	详情	详情
(IV)	14722	1-[2-(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,3,4-tetraazol-1-yl)ethyl]-3-methyltetrahydro-4(1H)-pyridinone		C₁₁H₁₉N₅O₂	详情	详情
(V)	14723	4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline	367-24-8	C₆H₅BrFN	详情	详情
(VI)	14724	1-[2-[4-(4-bromo-2-fluoroanilino)-3-methylpiperidino]ethyl]-4-ethyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one		C₁₇H₂₄BrFN₆O	详情	详情
(VII)	13429	2-Methoxyacetyl chloride; Methoxyacetyl chloride	38870-89-2	C₃H₅ClO₂	详情	详情
(VIII)	14726	N-(4-bromo-2-fluorophenyl)-N-[(3R,4S)-1-[2-(4-ethyl-5-oxo-4,5-dihydro-1H-1,2,3,4-tetraazol-1-yl)ethyl]-3-methylhexahydro-4-pyridinyl]-2-methoxyacetamide		C₂₀H₂₈BrFN₆O₃	详情	详情

Extended Information