4-fluorobenzylamine; (4-fluorophenyl)methanamine -Drug Synthesis Database

【结构式】

【分子编号】31095

【品名】4-fluorobenzylamine; (4-fluorophenyl)methanamine

【CA登记号】140-75-0

【分子式】C₇H₈FN

【分子量】125.1456632

【元素组成】C 67.18% H 6.44% F 15.18% N 11.19%

与该中间体有关的原料药合成路线共 6 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5 合成路线6

合成路线1

该中间体在本合成路线中的序号：(III)

The reaction of 2,6-dichloro-3-nitropyridine (I) with ammonia yields 2-amino-3-nitro-chloropyridine (II). 4-Fluorobenzylamine (III) reacts in dioxane and in the presence of triethylamine with (II), resulting in the 2-amino-3-nitro-6-p-fluorobenzylamine derivative (IV). The latter is hydrated and in situ the 3-amino group is condensed with ethyl chloroformate leading to the stable 2-amino-3-carbethoxyamino-6-(p-fluorobenzylamino)pyridine (Flupirtine).

参考文献中间体

合成目标

【1】 Thiele, K.; Steinmetz, G.; Bebenburg, W.v.; Chem Ztg 1979, 103, 10, 387.
【2】 Bebenburg, W.v.; Engel, J.; Sheldrick, W.S.; Thiele, K.; Chem Ztg 1981, 105, 10, 217.
【3】 Castaner, J.; Serradell, M.N.; Blancafort, P.; Flupirtine. Drugs Fut 1983, 8, 9, 773.

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)	13574	2,6-Dichloro-3-nitropyridine	16013-85-7	C₅H₂Cl₂N₂O₂	详情	详情
(II)	13575	6-Chloro-3-nitro-2-pyridinamine; 2-Amino-6-chloro-3-nitropyridine; 6-Chloro-3-nitro-2-pyridinylamine	27048-04-0	C₅H₄ClN₃O₂	详情	详情
(III)	31095	4-fluorobenzylamine; (4-fluorophenyl)methanamine	140-75-0	C₇H₈FN	详情	详情
(IV)	13576	N(6)-(4-Fluorobenzyl)-3-nitro-2,6-pyridinediamine; N-(6-Amino-5-nitro-2-pyridinyl)-N-(4-fluorobenzyl)amine		C₁₂H₁₁FN₄O₂	详情	详情
(V)	13577	N(6)-(4-Fluorobenzyl)-2,3,6-pyridinetriamine; 2-Amino-6-[(4-fluorobenzyl)amino]-3-pyridinylamine		C₁₂H₁₃FN₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：

D-19050 can be obtained in a 5-step synthesis starting from 2,6-dichloropyridine (I): Compound (I) is nitrated with HNO3/H2SO4 yielding 2,6-dichloro-3-nitropyridine (II). Subsequent reaction with ammonia and 4-fluorobenzylamine leads to 2-amino-3-nitro-6-(4-fluorobenzylamino)pyridine (IV), which is hydrogenated using Raney Nickel as catalyst to the corresponding 3-amino derivative (V). This is not isolated, but reacted with (prop-1-en-3-yl)chloroformate to give D-19050.

参考文献中间体

合成目标

【1】 Engel, J.; Emig, P.; Szelenyi, I.; Nickel, B.; Weischer, K.H.; D-19050. Drugs Fut 1989, 14, 6, 511.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	31095	4-fluorobenzylamine; (4-fluorophenyl)methanamine	140-75-0	C₇H₈FN	详情	详情
(I)	13573	2,6-Dichloropyridine	2402-78-0	C₅H₃Cl₂N	详情	详情
(II)	13574	2,6-Dichloro-3-nitropyridine	16013-85-7	C₅H₂Cl₂N₂O₂	详情	详情
(III)	13575	6-Chloro-3-nitro-2-pyridinamine; 2-Amino-6-chloro-3-nitropyridine; 6-Chloro-3-nitro-2-pyridinylamine	27048-04-0	C₅H₄ClN₃O₂	详情	详情
(IV)	13576	N(6)-(4-Fluorobenzyl)-3-nitro-2,6-pyridinediamine; N-(6-Amino-5-nitro-2-pyridinyl)-N-(4-fluorobenzyl)amine		C₁₂H₁₁FN₄O₂	详情	详情
(V)	13577	N(6)-(4-Fluorobenzyl)-2,3,6-pyridinetriamine; 2-Amino-6-[(4-fluorobenzyl)amino]-3-pyridinylamine		C₁₂H₁₃FN₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：

D-19274 can be obtained in a 6-step synthesis starting from 2,6-dichloropyridine (I). Compound (I) is nitrated with HNO3/H2SO4 yielding 2,6-dichloro-3-nitropyridine (II). Subsequent reaction with ammonia and 4-fluorobenzylamine leads to 2-amino-3-nitro-6-(4-fluorobenzylamino)pyridine (IV), which is hydrogenated using Raney Nickel as catalyst to the corresponding 3-amino derivative (V), which reacts with 2-bromoethyl chloroformate to 2-bromoethyl [N-(2-amino-6-(4-fluorobenzylamino)pyridin-3-yl)]carbamate hydrochloride (VI). (VI) is then treated with excess NaOH at 35 C, followed by treatment with isopropanol HCl to give the desired D-19274.

参考文献中间体

合成目标

【1】 Engel, J.; Emig, P.; Nickel, B.; Szelenyi, I. (Asta Medica AG); 3-(N-heterocyclyl)-2,6-diaminopyridines and N-oxides, their preparation and their use as medicines. DE 3915184; EP 0343429; JP 1990017186; US 4923858 .
【2】 Emig, P.; Engel, J.; Nickel, B.; Szelenyi, I.; Werner, U.; D-19274. Drugs Fut 1990, 15, 3, 223.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	31095	4-fluorobenzylamine; (4-fluorophenyl)methanamine	140-75-0	C₇H₈FN	详情	详情
	63775	1-bromo-2-[(chlorocarbonyl)oxy]ethane		C₃H₄BrClO₂	详情	详情
(I)	13573	2,6-Dichloropyridine	2402-78-0	C₅H₃Cl₂N	详情	详情
(II)	13574	2,6-Dichloro-3-nitropyridine	16013-85-7	C₅H₂Cl₂N₂O₂	详情	详情
(III)	13575	6-Chloro-3-nitro-2-pyridinamine; 2-Amino-6-chloro-3-nitropyridine; 6-Chloro-3-nitro-2-pyridinylamine	27048-04-0	C₅H₄ClN₃O₂	详情	详情
(IV)	13576	N(6)-(4-Fluorobenzyl)-3-nitro-2,6-pyridinediamine; N-(6-Amino-5-nitro-2-pyridinyl)-N-(4-fluorobenzyl)amine		C₁₂H₁₁FN₄O₂	详情	详情
(V)	13577	N(6)-(4-Fluorobenzyl)-2,3,6-pyridinetriamine; 2-Amino-6-[(4-fluorobenzyl)amino]-3-pyridinylamine		C₁₂H₁₃FN₄	详情	详情
(VI)	13578	2-bromoethyl 2-amino-6-[(4-fluorobenzyl)amino]-3-pyridinylcarbamate		C₁₅H₁₆BrFN₄O₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(V)

Nitration of 3-chlorobenzoic acid (I) with KNO3 and H2SO4 produced 2,4-dinitro-5-chlorobenzoic acid (II) which, after conversion to acid chloride (III), was reacted with ammonia to give amide (IV). Displacement of the chlorine of (IV) with 4-fluorobenzylamine (V) furnished aminobenzamide (VI). The nitro groups were then reduced by hydrogenation over PtO2, and the resulting triamine (VII) was cyclized to benzimidazole (VIII) by means of formic acid. 5-Bromo-2-propoxybenzoic acid (X) was prepared from 5-bromosalicylic acid (IX) by alkylation with n-propyl iodide. Coupling of carboxylic acid (X) with amine (VIII) using EDC and HOBt afforded amide (XI), which was cyclized to the imidazoquinazoline (XII) in the presence of potassium tert-butoxide. Substitution of the bromine atom of (XII) with cuprous cyanide in NMP yielded nitrile (XIII). This was finally converted to the desired amide by hydrolysis to the carboxylic acid, followed by coupling with ammonia in the presence of EDC.

参考文献中间体

合成目标

【1】 Normandin, D.; Zhu, Y.; Rotella, D.P.; Sun, Z.; Macor, J.E.; Seliger, L.; Krupinski, J.; Pongrac, R.; N-3-Substituted imidazoquinazolinones: Potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction. J Med Chem 2000, 43, 7, 1257.
【2】 Weller, H.N. III; Rotella, D.P.; Yevich, J.P.; Cushman, D.W.; Macor, J.E. (Bristol-Myers Squibb Co.); Quinazolinone inhibitors of cGMP phosphodiesterase. US 6087368; WO 9964004 .

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)	38849	m-chlorobenzoic acid; 3-chlorobenzoic acid	535-80-8	C₇H₅ClO₂	详情	详情
(II)	38850	5-chloro-2,4-dinitrobenzoic acid		C₇H₃ClN₂O₆	详情	详情
(III)	38851	5-chloro-2,4-dinitrobenzoyl chloride		C₇H₂Cl₂N₂O₅	详情	详情
(IV)	38852	5-chloro-2,4-dinitrobenzamide		C₇H₄ClN₃O₅	详情	详情
(V)	31095	4-fluorobenzylamine; (4-fluorophenyl)methanamine	140-75-0	C₇H₈FN	详情	详情
(VI)	38853	5-[(4-fluorobenzyl)amino]-2,4-dinitrobenzamide		C₁₄H₁₁FN₄O₅	详情	详情
(VII)	38854	2,4-diamino-5-[(4-fluorobenzyl)amino]benzamide		C₁₄H₁₅FN₄O	详情	详情
(VIII)	38855	5-amino-1-(4-fluorobenzyl)-1H-benzimidazole-6-carboxamide		C₁₅H₁₃FN₄O	详情	详情
(IX)	38856	5-bromo-2-hydroxybenzoic acid	89-55-4	C₇H₅BrO₃	详情	详情
(X)	38857	5-bromo-2-propoxybenzoic acid		C₁₀H₁₁BrO₃	详情	详情
(XI)	38858	5-[(5-bromo-2-propoxybenzoyl)amino]-1-(4-fluorobenzyl)-1H-benzimidazole-6-carboxamide		C₂₅H₂₂BrFN₄O₃	详情	详情
(XII)	38859	6-(5-bromo-2-propoxyphenyl)-1-(4-fluorobenzyl)-1,7-dihydro-8H-imidazo[4,5-g]quinazolin-8-one		C₂₅H₂₀BrFN₄O₂	详情	详情
(XIII)	38860	3-[1-(4-fluorobenzyl)-8-oxo-7,8-dihydro-1H-imidazo[4,5-g]quinazolin-6-yl]-4-propoxybenzonitrile		C₂₆H₂₀FN₅O₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(XIII)

The pyrazolopyridopyrimidine tricyclic system (XII) was generated by acylation of amine (X) with acid chloride (XI), followed by base-mediated cyclization. Displacement of the remaining chloride of (XII) with p-fluorobenzyl amine (XIII) afforded (XIV). The p-methoxybenzyl group of (XIV) was finally removed by treatment with trifluoroacetic acid yielding the title compound.

参考文献中间体

合成目标

【1】 Bi, Y.; et al.; The discovery of novel, potent and selective PDE5 inhibitors. Bioorg Med Chem Lett 2001, 11, 18, 2461.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	51148	4-amino-6-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[3,4-b]pyridine-5-carboxamide		C₁₅H₁₄ClN₅O₂	详情	详情
(XI)	51149	5-[[(3R)-3-(dimethylamino)pyrrolidinyl]sulfonyl]-2-propoxybenzoyl chloride		C₁₆H₂₃ClN₂O₄S	详情	详情
(XII)	51150	5-chloro-2-(5-[[(3R)-3-(dimethylamino)pyrrolidinyl]sulfonyl]-2-propoxyphenyl)-8-(4-methoxybenzyl)-3,8-dihydro-4H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-4-one		C₃₁H₃₄ClN₇O₅S	详情	详情
(XIII)	31095	4-fluorobenzylamine; (4-fluorophenyl)methanamine	140-75-0	C₇H₈FN	详情	详情
(XIV)	51151	2-(5-[[(3R)-3-(dimethylamino)pyrrolidinyl]sulfonyl]-2-propoxyphenyl)-5-[(4-fluorobenzyl)amino]-8-(4-methoxybenzyl)-3,8-dihydro-4H-pyrazolo[4',3':5,6]pyrido[4,3-d]pyrimidin-4-one		C₃₈H₄₁FN₈O₅S	详情	详情

合成路线6

该中间体在本合成路线中的序号：(VI)

Mitsunobu coupling between isopropyl 3-(hydroxymethyl)pyridine-2-carboxylate (I) and N-tosyl glycine methyl ester (II) affords amino diester (III). Diester (III) is subsequently converted to the naphthyridine (IV) under Dieckmann cyclization conditions. Bromination of naphthyridine (IV) by means of N-bromosuccinimide provides (V). The methyl ester group of (V) is then displaced with 4-fluorobenzylamine (VI) to furnish amide (VII). Finally, copper-catalyzed displacement of the bromide (VII) with butanesultam (VIII) provides the title compound.

参考文献中间体

合成目标

【1】 Young, S.D.; Guare, J.P.; Wai, J.S.; Fisher, T.E.; Perlow, D.S.; Anthony, N.J.; Egbertson, M.; Gomez, R.P.; Kuo, M.S.; Tran, L.; Zhuang, L.; Langford, H.M.; Melamed, J.Y.; Bennett, J.J.; Embrey, M.; Jolly, S.M.; Funk, T.W. (Merck & Co., Inc.); Aza- and polyaza-naphthalenyl carboxamides useful as HIV integrase inhibitors. WO 0230930; WO 0230931 .

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)	57743	isopropyl 3-(hydroxymethyl)-2-pyridinecarboxylate		C₁₀H₁₃NO₃	详情	详情
(II)	57744	methyl 2-{[(4-methylphenyl)sulfonyl]amino}acetate	2645-02-5	C₁₀H₁₃NO₄S	详情	详情
(III)	57745	isopropyl 3-({(2-methoxy-2-oxoethyl)[(4-methylphenyl)sulfonyl]amino}methyl)-2-pyridinecarboxylate		C₂₀H₂₄N₂O₆S	详情	详情
(IV)	57746	methyl 8-hydroxy[1,6]naphthyridine-7-carboxylate		C₁₀H₈N₂O₃	详情	详情
(V)	57747	methyl 5-bromo-8-hydroxy[1,6]naphthyridine-7-carboxylate		C₁₀H₇BrN₂O₃	详情	详情
(VI)	31095	4-fluorobenzylamine; (4-fluorophenyl)methanamine	140-75-0	C₇H₈FN	详情	详情
(VII)	57748	5-bromo-N-(4-fluorobenzyl)-8-hydroxy[1,6]naphthyridine-7-carboxamide		C₁₆H₁₁BrFN₃O₂	详情	详情
(VIII)	57749	1lambda~6~,2-thiazinane-1,1-dione		C₄H₉NO₂S	详情	详情

Extended Information