　 -Drug Synthesis Database

【结构式】

【分子编号】43017

【品名】　

【CA登记号】

【分子式】C₁₁H₂₁N₅O₆

【分子量】319.31784

【元素组成】C 41.38% H 6.63% N 21.93% O 30.06%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XVIII)

Coupling Method 1. Treatment of L-Arginine (XIII) with K2CO3 and assembling to intermediate (VII) affords derivative (XIV). After protection of the piperidine derivative (XV) as its tert-butyl ether (XVI) by means of isobutylene (B) in acidic media, (XVI) is condensed with (XIV) in the presence of Et3N to yield (XVII). Finally, elimination of the protecting groups with TFA, HBr gas or HCl in AcOH affords the desired product. 2. Alternatively, the coupling can be performed by reaction of nitro-protected L-arginine (XVIII) with isobutyl chloroformate in DMF in the presence of NMM, followed by reaction with protected piperidine derivative (XVI) to yield (XIX). Removal of the Boc group with HCl in AcOH or in dichloromethane/AcOH (2:1) and assembling to sulfonyl chloride intermediate (VII) with DIEA in DMF yields protected derivative (XX). Reductive cleavage of the nitro protecting group of (XX) with Pd/C, H2 in MeOH/AcOH/H2O (15:0.1:1), followed by elimination of the t-Bu protecting group in the conditions described above, yields the desired product.

参考文献中间体

合成目标

【1】 Donovan, V.; Brundish, D.; Bull, A.; et al.; Design and synthesis of thrombin inhibitors: Analogues of MD-805 with reduced stereogenicity and improved potency. J Med Chem 1999, 42, 22, 4584.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	15926	2-methyl-1-propene; isobutylene	115-11-7	C₄H₈	详情	详情
(VII)	43006	6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl chloride		C₁₁H₁₃Cl₂NO₂S	详情	详情
(XIII)	22853	Arginine; 2-Amino-5-guanidinopentanoic acid		C₆H₁₄N₄O₂	详情	详情
(XIV)	43011	N(5)-[amino(imino)methyl]-N(2)-[(3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]ornithine		C₁₇H₂₇N₅O₄S	详情	详情
(XV)	43012	2-(4-piperidinyl)-1-ethanol	622-26-4	C₇H₁₅NO	详情	详情
(XVI)	43013	4-[2-(tert-butoxy)ethyl]piperidine; tert-butyl 2-(4-piperidinyl)ethyl ether		C₁₁H₂₃NO	详情	详情
(XVII)	43014	N-[4-[[amino(imino)methyl]amino]-1-([4-[2-(tert-butoxy)ethyl]-1-piperidinyl]carbonyl)butyl]-3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonamide		C₂₈H₄₈N₆O₄S	详情	详情
(XVIII)	43017			C₁₁H₂₁N₅O₆	详情	详情
(XIX)	43015			C₂₂H₄₂N₆O₆	详情	详情
(XX)	43016			C₂₈H₄₇N₇O₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVIII)

Alternatively, piperidine derivative (XV) can be protected as its acetic ester form (XXI) by reaction with AcOH and HCl gas. In this case: 1) Piperidine (XXI) is condensed with (XIV) in the presence of Et3N to yield (XXII). Finally, elimination of the protecting groups with NaOH/MeOH affords the desired product. 2) The coupling can be performed by reaction of nitro-protected L-arginine (XVIII) with isobutyl chloroformate in DMF in the presence of NMM, followed by reaction with protected piperidine derivative (XXI) to yield (XXIII). Removal of the Boc group of (XXIII) with HCl in AcOH or in dichloromethane/AcOH (2:1) and assembling to sulfonyl chloride intermediate (VII) with DIEA in DMF yields protected derivative (XXIV). Reductive cleavage of the nitro protecting group of (XXIV) with Pd/C, H2 in MeOH/AcOH/H2O (15:0.1:1), followed by elimination of the acetyl protecting group in the conditions described above, yields the desired product.

参考文献中间体

合成目标

【1】 Hoyle, W.; Howarth, G.A.; Brundish, D.E.; Kane, P.D.; Walker, C.V.; Hayler, J.; Fullerton, J.D.; Smith, G.P.; Wathey, W.B.; Le Grand, D.M.; Allen, M.C.; Herold, P. (Novartis AG); Trypsin and thrombin inhibitors. EP 0815103; JP 1999502219; WO 9629327 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	43005	3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl chloride		C₁₁H₁₄ClNO₂S	详情	详情
(XIV)	43011	N(5)-[amino(imino)methyl]-N(2)-[(3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]ornithine		C₁₇H₂₇N₅O₄S	详情	详情
(XV)	43012	2-(4-piperidinyl)-1-ethanol	622-26-4	C₇H₁₅NO	详情	详情
(XVIII)	43017			C₁₁H₂₁N₅O₆	详情	详情
(XXI)	43019	2-(4-piperidinyl)ethyl acetate		C₉H₁₇NO₂	详情	详情
(XXII)	43018	2-[1-(5-[[amino(imino)methyl]amino]-2-[[(3,3-dimethyl-1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl]amino]pentanoyl)-4-piperidinyl]ethyl acetate		C₂₆H₄₂N₆O₅S	详情	详情
(XXIII)	43020			C₂₀H₃₆N₆O₇	详情	详情
(XXIV)	43021			C₂₆H₄₁N₇O₇S	详情	详情

Extended Information