4-(2-fluoroethyl)piperidine -Drug Synthesis Database

【结构式】

【分子编号】28517

【品名】4-(2-fluoroethyl)piperidine

【CA登记号】

【分子式】C₇H₁₄FN

【分子量】131.1933032

【元素组成】C 64.09% H 10.76% F 14.48% N 10.68%

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：(II)

Coupling of N-Boc-p-nitrophenylalanine (I) with 4-(2-fluoroethyl)piperidine (II) by means of 2-benzotriazolyl-1,1,3,3-tetramethyluronium tetrafluoborate (TBTU) gave amide (III) which, after acidic deprotection provided aminoamide (IV). 4-Chloropyridine-3-sulfonyl chloride (VI), generated from 4-hydroxy pyridine-3-sulfonic acid (V) by chlorination with PCl5/POCl3, was coupled with amine (IV) to afford sulfonamide (VII). Further condensation of (VII) with L-phenylalaninol (VIII) produced aminopyridine (IX). Conversion of the alcohol group of (IX) to the corresponding mesylate, followed by displacement with morpholine furnished the N-substituted morpholine (X). The nitro group of (X) was finally reduced to the target aniline by hydrogenation over Pd/C.

参考文献中间体

合成目标

【1】 Ambler, J.; Baker E; Brown, L.; Butler, P.; Farr, D.; Dunnet, K.; Le Grand, D.; Janus, D.; Jones, D.; Menear, K.; Mercer, M.; Smith, G.; Talbot, M.; Tweed, M.; The discovery of orally available thrombin inhibitors: Studies towards the optimisation of CGH1668. Bioorg Med Chem Lett 1998, 8, 24, 3583.

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)	28516	(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-nitrophenyl)propionic acid		C₁₄H₁₈N₂O₆	详情	详情
(II)	28517	4-(2-fluoroethyl)piperidine		C₇H₁₄FN	详情	详情
(III)	28518	tert-butyl (1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethylcarbamate		C₂₁H₃₀FN₃O₅	详情	详情
(IV)	28519	(2S)-2-amino-1-[4-(2-fluoroethyl)-1-piperidinyl]-3-(4-nitrophenyl)-1-propanone		C₁₆H₂₂FN₃O₃	详情	详情
(V)	28520	4-hydroxy-3-pyridinesulfonic acid		C₅H₅NO₄S	详情	详情
(VI)	28521	4-chloro-3-pyridinesulfonyl chloride		C₅H₃Cl₂NO₂S	详情	详情
(VII)	28522	4-chloro-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide		C₂₁H₂₄ClFN₄O₅S	详情	详情
(VIII)	28523	(2S)-2-amino-3-phenyl-1-propanol; L-phenylalanilol; (S)-2-amino-3-phenyl-1-propanol	5267-64-1	C₉H₁₃NO	详情	详情
(IX)	28524	4-[[(1S)-1-benzyl-2-hydroxyethyl]amino]-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide		C₃₀H₃₆FN₅O₆S	详情	详情
(X)	28525	4-[[(1S)-1-benzyl-2-(4-morpholinyl)ethyl]amino]-N-[(1S)-2-[4-(2-fluoroethyl)-1-piperidinyl]-1-(4-nitrobenzyl)-2-oxoethyl]-3-pyridinesulfonamide		C₃₄H₄₃FN₆O₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Alcohol (I) was converted to fluoride (II) by treatment with either diethylaminosulfur trifluoride or the Ishikawa reagent. Subsequent acid cleavage of the Boc protecting group of (III) provided piperidine (VI). Alternatively, alcohol (III) was converted to mesylate (IV), which was displaced with tetrabutylammonium fluoride to afford fluoride (V). The benzamido group of (V) was then hydrolyzed with HCl in aqueous MeOH.

参考文献中间体

合成目标

【1】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	43453	tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate	C₁₂H₂₃NO₃	详情	详情
(II)	43454	tert-butyl 4-(2-fluoroethyl)-1-piperidinecarboxylate	C₁₂H₂₂FNO₂	详情	详情
(III)	43455	[4-(2-hydroxyethyl)-1-piperidinyl](phenyl)methanone	C₁₄H₁₉NO₂	详情	详情
(IV)	43456	2-(1-benzoyl-4-piperidinyl)ethyl methanesulfonate	C₁₅H₂₁NO₄S	详情	详情
(V)	43457	[4-(2-fluoroethyl)-1-piperidinyl](phenyl)methanone	C₁₄H₁₈FNO	详情	详情
(VI)	28517	4-(2-fluoroethyl)piperidine	C₇H₁₄FN	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

Amine intermediate (XIV) has been obtained as follows: N-(Carbobenzoxy)-L-aspartic acid alpha-benzyl ester (VII) was converted to acid chloride (VIII) and then coupled to 2-aminophenyl disulfide (IX) to afford the bis-amide (X). Reductive cleavage of the disulfide group of (X), followed by basic cyclization, produced the benzothiazole (XI) (2). Hydrolysis of the benzyl ester group of (XI) and subsequent coupling of the resulting carboxylic acid (XII) with piperidine (VI) gave amide (XIII). The carbobenzoxy group of (XII) was then cleaved with HBr in HOAc, yielding intermediate amine (XIV).

参考文献中间体

合成目标

【1】 Baettig, U.; et al.; The design and synthesis of thrombin inhibitors: Analogues of MD805 containing non-polar surrogates for arginine at the P1 position. Bioorg Med Chem Lett 2000, 10, 14, 1563.
【2】 Smith, G.P.; Brundish, D.E.; Menear, K.A.; Walker, C.V.; Herold, P.; Fullerton, J.D.; Allen, M.C.; Le Grand, D.M.; Kane, P.D.; Cockcroft, X.-L.; Wathey, W.B.; Butler, P.I.; Hatto, J.D.I.; Hayler, J.D. (Novartis AG); Tetrahydroquinoline inhibitors of trypsin and thrombin. GB 2312674 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	28517	4-(2-fluoroethyl)piperidine		C₇H₁₄FN	详情	详情
(VII)	43458	(3S)-4-(benzyloxy)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid	4779-31-1	C₁₉H₁₉NO₆	详情	详情
(VIII)	43459	benzyl (2S)-2-[[(benzyloxy)carbonyl]amino]-4-chloro-4-oxobutanoate		C₁₉H₁₈ClNO₅	详情	详情
(IX)	43460	2-[(2-aminophenyl)disulfanyl]aniline; 2-[(2-aminophenyl)disulfanyl]phenylamine	1141-88-4	C₁₂H₁₂N₂S₂	详情	详情
(X)	43461	benzyl (2S)-4-[2-([2-[((3S)-4-(benzyloxy)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutanoyl)amino]phenyl]disulfanyl)anilino]-2-[[(benzyloxy)carbonyl]amino]-4-oxobutanoate		C₅₀H₄₆N₄O₁₀S₂	详情	详情
(XI)	43462	benzyl (2S)-3-(1,3-benzothiazol-2-yl)-2-[[(benzyloxy)carbonyl]amino]propanoate		C₂₅H₂₂N₂O₄S	详情	详情
(XII)	43463	(2S)-3-(1,3-benzothiazol-2-yl)-2-[[(benzyloxy)carbonyl]amino]propionic acid		C₁₈H₁₆N₂O₄S	详情	详情
(XIII)	43464	benzyl (1S)-1-(1,3-benzothiazol-2-ylmethyl)-2-[4-(2-fluoroethyl)-1-piperidinyl]-2-oxoethylcarbamate		C₂₅H₂₈FN₃O₃S	详情	详情
(XIV)	43465	(2S)-2-amino-3-(1,3-benzothiazol-2-yl)-1-[4-(2-fluoroethyl)-1-piperidinyl]-1-propanone		C₁₇H₂₂FN₃OS	详情	详情

Extended Information