Lafutidine, FRG-8813, Stogar, Protecadin, -Drug Synthesis Database

【结构式】

【药物名称】Lafutidine, FRG-8813, Stogar, Protecadin

【化学名称】(±)-2-(Furfurylsulfinyl)-N-[4-[4-(piperidin-1-ylmethyl)pyridin-2-yloxy]-2(Z)butenyl]acetamide

【CA登记号】118288-08-7

【分子式】C₂₂H₂₉N₃O₄S

【分子量】431.55813

【开发单位】UCB Japan (Originator), Taiho (Licensee)

【药理作用】Antiulcer Drugs, Gastric Antisecretory Drugs, GASTROINTESTINAL DRUGS, Histamine H2 Receptor Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

1) The reaction of 2-bromo-4-(piperidin-1-ylmethyl)pyridine (I) with 4-amino-2(Z)-buten-1-ol (II) by means of NaH in THF gives 4-[4-(piperidin-1-ylmethyl)pyridin-2-yloxy]-2(Z)-buten-1-amine (III), which is then condensed with 2-(2-furylmethylsulfinyl)acetic acid (IV) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDCD) in dichloromethane.

参考文献中间体

【1】 Hirakawa, N.; Kashiwaba, N.; Matsumoto, H.; Hosoda, A.; Sekine, Y.; Isowa, Y.; Yamaura, T.; Sekine, A.; Nishikawa, M. (UCB Japan); Pyridyloxy derivs. EP 0282077; JP 1988225371; JP 1989230556; JP 1989230576; US 4912101 .
【2】 Graul, A.; Prous, J.; Castaner, J.; Lafutidine. Drugs Fut 1994, 19, 9, 835.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	13021	2-Bromo-4-(1-piperidinylmethyl)pyridine	C₁₁H₁₅BrN₂	详情	详情
(II)	13022	(Z)-4-Amino-2-buten-1-ol	C₄H₉NO	详情	详情
(III)	13023	(Z)-4-[[4-(1-Piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-amine; (Z)-4-[[4-(1-Piperidinylmethyl)-2-pyridinyl]oxy]-2-butenylamine	C₁₅H₂₃N₃O	详情	详情
(IV)	13024	2-[(2-Furylmethyl)sulfinyl]acetic acid	C₇H₈O₄S	详情	详情

合成路线2

The condensation of 2-chloro-4-(piperidin-1-ylmethyl)pyridine (V) with 4-(tetrahydropyranyloxy)-2(Z)-buten-1-ol (VI) by means of NaH in THF gives 4-(piperidin-1-ylmethyl)-2-[4-(tetrahydropyranyloxy)-2(Z)-butenyloxy)pyridine (VII), which is deprotected with 4-methylbenzenesulfonic acid in methanol, yielding the free butenol (VIII). The acylation of (VIII) with methanesulfonyl chloride in toluene affords the corresponding mesylate (IX), which is finally condensed with 2-(2-furylmethylsulfonyl)acetamide (X) (obtained from the corresponding 4-nitrophenyl ester (XI) with ammonia) by means of potassium tert-butoxide in toluene.

参考文献中间体

【1】 Iwata, H.; Matsumoto, H.; Matsumoto, M.; Sekine, Y.; Nishimura, M.; Hosoda, A. (UCB Japan); Methods of producing amino butene derivs. EP 0582304; JP 1994192195 .
【2】 Graul, A.; Prous, J.; Castaner, J.; Lafutidine. Drugs Fut 1994, 19, 9, 835.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	13025	2-Chloro-4-(1-piperidinylmethyl)pyridine	C₁₁H₁₅ClN₂	详情	详情
(VI)	13026	(Z)-4-(Tetrahydro-2H-pyran-2-yloxy)-2-buten-1-ol	C₉H₁₆O₃	详情	详情
(VII)	13027	4-(1-Piperidinylmethyl)-2-pyridinyl (Z)-4-(tetrahydro-2H-pyran-2-yloxy)-2-butenyl ether; 4-(1-Piperidinylmethyl)-2-[[(Z)-4-(tetrahydro-2H-pyran-2-yloxy)-2-butenyl]oxy]pyridine	C₂₀H₃₀N₂O₃	详情	详情
(VIII)	13028	(Z)-4-[[4-(1-Piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol	C₁₅H₂₂N₂O₂	详情	详情
(IX)	13029	(Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-butenyl methanesulfonate	C₁₆H₂₄N₂O₄S	详情	详情
(X)	13030	2-[(2-Furylmethyl)sulfinyl]acetamide	C₇H₉NO₃S	详情	详情
(XI)	13031	4-nitrophenyl 2-[(2-furylmethyl)sulfinyl]acetate	C₁₃H₁₁NO₆S	详情	详情

合成路线3

A new synthesis of lafutidine has been described: The condensation of 2-bromopyridine-4-carbaldehyde ethylene ketal (I) with 4-(tetrahydropyranyloxy)-2(Z)-buten-1-ol (II) by means of NaOH, K2CO3 and tetrabutylammonium bisulfate in refluxing toluene gives the corresponding substitution product (III), which by treatment with pyridinium p-toluenesulfonate (PPTS) in hot ethanol yields the 2(Z)-butenol (IV). The reaction of (IV) with SOCl2 and then with potassium phthalimide (V) affords the substituted phthalimide (VI), which by treatment with hydrazine hydrate in refluxing methanol gives the 2(Z)-butenamine (VII). The condensation of (VII) with 2-(2-furylmethylsulfinyl)acetic acid 4-nitrophenyl ester (VIII) in THF yields the expected amide (IX), which is treated with p-toluenesulfonic acid in refluxing acetone/water to eliminate the ethylene ketal protecting group yilding the aldehyde (X). Finally, this compound is reductocondensed with piperidine (XI) by means of NaBH4 in ethanol.

参考文献中间体

【1】 Hosoda, A.; Yamaura, T.; Sekine, Y.; Matsumoto, H.; Hirakawa, N.; Sekine, A.; A novel histamine 2(H2) receptor antagonist with gastroprotective activity. II. Synthesis and pharmacological evaluation of 2-furfuryl-thio and 2-furfurylsulfinyl acetamide derivatives with heteroaromatic rings. Chem Pharm Bull 1998, 46, 4, 616.

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)	27887	2-bromo-4-(1,3-dioxolan-2-yl)pyridine		C₈H₈BrNO₂	详情	详情
(II)	13026	(Z)-4-(Tetrahydro-2H-pyran-2-yloxy)-2-buten-1-ol		C₉H₁₆O₃	详情	详情
(III)	27888	4-(1,3-dioxolan-2-yl)-2-pyridinyl (Z)-4-(tetrahydro-2H-pyran-2-yloxy)-2-butenyl ether		C₁₇H₂₃NO₅	详情	详情
(IV)	27889	(Z)-4-[[4-(1,3-dioxolan-2-yl)-2-pyridinyl]oxy]-2-buten-1-ol		C₁₂H₁₅NO₄	详情	详情
(V)	27890	Potassium phthalimide	1074-82-4	C₈H₄KNO₂	详情	详情
(VI)	27891	2-((Z)-4-[[4-(1,3-dioxolan-2-yl)-2-pyridinyl]oxy]-2-butenyl)-1H-isoindole-1,3(2H)-dione		C₂₀H₁₈N₂O₅	详情	详情
(VII)	27892	(Z)-4-[[4-(1,3-dioxolan-2-yl)-2-pyridinyl]oxy]-2-butenylamine		C₁₂H₁₆N₂O₃	详情	详情
(VIII)	13031	4-nitrophenyl 2-[(2-furylmethyl)sulfinyl]acetate		C₁₃H₁₁NO₆S	详情	详情
(IX)	27893	N-((Z)-4-[[4-(1,3-dioxolan-2-yl)-2-pyridinyl]oxy]-2-butenyl)-2-[(2-furylmethyl)sulfinyl]acetamide		C₁₉H₂₂N₂O₆S	详情	详情
(X)	27894	N-[(Z)-4-[(4-formyl-2-pyridinyl)oxy]-2-butenyl]-2-[(2-furylmethyl)sulfinyl]acetamide		C₁₇H₁₈N₂O₅S	详情	详情
(XI)	10158	Piperidine	110-89-4	C₅H₁₁N	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)