Sufentanil citrate, R-33800, R-30730(free base), Sufenta, -Drug Synthesis Database

【结构式】

【药物名称】Sufentanil citrate, R-33800, R-30730(free base), Sufenta

【化学名称】N-[4-(Methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidyl]propionanilide citrate

【CA登记号】60561-17-3, 56030-54-7 (free base)

【分子式】C₂₈H₃₈N₂O₉S

【分子量】578.68706

【开发单位】Janssen (Originator), Taylor (Licensee)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Opioid Analgesics

合成路线1 合成路线2 合成路线3

合成路线1

The esterification of 1-benzyl-4-(phenylamino)piperidine-4-carboxylic acid (I) with ethanol and H2SO4 gives the corresponding ethyl ester (II), which is reduced with LiAlH2(OCH2CH2OCH3)2 in benzene affording 1-benzyl-4-(phenylamino)piperidine-4-methanol (III) The methylation of (III) with methyl iodide and NaH in HMPA yields 1-benzyl-4-methoxymethyl-4-(phenylamino)piperidine (IV), which is refluxed with propionic anhydride (A) to give N-[4-(methoxymethyl)-1-benzyl-4-piperidyl]propionanilide (V). The hydrogenolysis of (V) with H2 over Raney-Ni in methanol yields N-[4-(methoxymethyl)-4-piperidyl]propionanilide (VI), which is finally condensed with 2-thiopheneethanol methanesulfonate (B) by means of Na2CO3 in methyl isobutyl ketone.

参考文献中间体

【1】 Van Daele, P.G.H.; et al.; Synthetic analgesics: N-(1-[2-arylethyl]-4-substituted-4-piperidinyl)-N-arylalkanamides. Arzneim-Forsch Drug Res 1976, 26, 8, 1521.
【2】 Castaner, J.; Arrigoni-Martelli, E.; Sufentanil. Drugs Fut 1977, 2, 5, 334.

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)	20095	propionic anhydride	123-62-6	C₆H₁₀O₃	详情	详情
(B)	33889	2-(2-thienyl)-1-ethanol; Thiophene-2-ethanol	5402-55-1	C₆H₈OS	详情	详情
(I)	33884	4-anilino-1-benzyl-4-piperidinecarboxylic acid		C₁₉H₂₂N₂O₂	详情	详情
(II)	33885	ethyl 4-anilino-1-benzyl-4-piperidinecarboxylate		C₂₁H₂₆N₂O₂	详情	详情
(III)	33886	(4-anilino-1-benzyl-4-piperidinyl)methanol		C₁₉H₂₄N₂O	详情	详情
(IV)	33887	N-[1-benzyl-4-(methoxymethyl)-4-piperidinyl]-N-phenylamine; 1-benzyl-4-(methoxymethyl)-N-phenyl-4-piperidinamine		C₂₀H₂₆N₂O	详情	详情
(V)	33888	N-[1-benzyl-4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide		C₂₃H₃₀N₂O₂	详情	详情
(VI)	32220	N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide		C₁₆H₂₄N₂O₂	详情	详情

合成路线2

A total synthesis of sufentanil has been described: The cyclization of 2-(2-thienyl)ethylamine (I) with allyltrimethylsilane (II) and formaldehyde gives 4-hydroxy-1-[2-(2-thienyl)ethyl]piperidine (III), which is oxidized with oxalyl chloride in DMSO/dichloromethane to 1-[2-(2-thienyl)ethyl]piperidin-4-one (IV). The epoxidation of (IV) by means of trimethylsulfonium iodide and the sodium salt of DMSO yields the spiro-epoxide (V), which is opened with aniline (VI) and boron trifluoride ethearate giving a 1.8:1 mixture of 4-(hydroxymethyl)-4-(phenylamino)piperidine (VII) and 4-hydroxy-4-(phenylamino)piperidine (VIII) that are conveniently separated. The methylation of the OH group of (VII) with diazomethane and SiO2 affords the methoxymethyl compound (IX), which is finally acylated with propionic anhydride to provide sufentanil.

参考文献中间体

【1】 Park, H.J.; Jeon, R.O.; Ryu, J.S.; Hyun, S.S.; Suh, Y.G.; Shin, D.Y.; Total synthesis of sufentanil. Arch Pharmacal Res 1999, 22, 4, 398.

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)	35253	2-(2-thienyl)ethylamine; 2-(2-thienyl)-1-ethanamine; 2-Thiophene ethylamine	30433-91-1	C₆H₉NS	详情	详情
(II)	15775	Allyltrimethylsilane; allyl(trimethyl)silane	762-72-1	C₆H₁₄Si	详情	详情
(III)	35254	1-[2-(2-thienyl)ethyl]-4-piperidinol		C₁₁H₁₇NOS	详情	详情
(IV)	35255	1-[2-(2-thienyl)ethyl]-4-piperidinone		C₁₁H₁₅NOS	详情	详情
(V)	35256	6-[2-(2-thienyl)ethyl]-1-oxa-6-azaspiro[2.5]octane		C₁₂H₁₇NOS	详情	详情
(VI)	12294	Aniline; Phenylamine	62-53-3	C₆H₇N	详情	详情
(VII)	35257	[4-anilino-1-[2-(2-thienyl)ethyl]-4-piperidinyl]methanol		C₁₈H₂₄N₂OS	详情	详情
(VIII)	35258	4-(anilinomethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinol		C₁₈H₂₄N₂OS	详情	详情
(IX)	35259	N-[4-(methoxymethyl)-1-[2-(2-thienyl)ethyl]-4-piperidinyl]-N-phenylamine; 4-(methoxymethyl)-N-phenyl-1-[2-(2-thienyl)ethyl]-4-piperidinamine		C₁₉H₂₆N₂OS	详情	详情

合成路线3

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 2-(2-thienyl)ethyl mesylate (VIII) by means of K2CO3 in refluxing acetonitrile yields the adduct (XI), which is methylated with NaH and CH3I in THF to afford the methoxy derivative (X). Finally, this compound is acylated with propionyl chloride (XI) in chloroform to provide the target compound.

参考文献中间体

【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)	49685	2-(2-thienyl)ethyl methanesulfonate		C₇H₁₀O₃S₂	详情	详情
(IX)	35257	[4-anilino-1-[2-(2-thienyl)ethyl]-4-piperidinyl]methanol		C₁₈H₂₄N₂OS	详情	详情
(X)	49686	1-[2-(5-ethyl-2-thienyl)ethyl]-4-(methoxymethyl)-N-phenyl-4-piperidinamine; N-[1-[2-(5-ethyl-2-thienyl)ethyl]-4-(methoxymethyl)-4-piperidinyl]-N-phenylamine		C₂₁H₃₀N₂OS	详情	详情
(XI)	15967	propanoyl chloride; propionyl chloride	79-03-8	C₃H₅ClO	详情	详情

Extended Information