-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-[3(R)-[N-[N-[1-Amidino-2-hydroxypiperidin-3(S)-yl]carbamoylmethyl]carbamoyl]-3-(benzylsulfonamido)propyl]pyrazine-2-carboxamide

【CA登记号】

【分子式】C₂₄H₃₃N₉O₆S

【分子量】575.65131

【开发单位】Corvas (Originator)

【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors

合成路线1 合成路线2

合成路线1

Nalpha-(Benzyloxycarbonyl)-1,4-diaminobutyric acid (I) was protected as the Nomega-Boc derivative (II) and then coupled to glycine ethyl ester (III) by means of EDC and HOBt to produce dipeptide (IV). Hydrogenolysis of the benzyloxycarbonyl group of (IV) to give (V), followed by condensation with alpha-toluenesulfonyl chloride (VI) gave sulfonamide (VII). Side-chain deprotection of (VII) with HCl liberated amine (VIII), which was acylated with 2-pyrazinecarboxylic acid (IX) to afford amide (X). Saponification of the ethyl ester of (X) with LiOH gave carboxylic acid (XI).

参考文献中间体

【1】 Ho, J.Z.; et al.; Exploration solid-phase synthesis of factor Xa inhibitors: Discovery and application of P3-heterocyclic amides as novel types of non-basic arginine surrogates. Bioorg Med Chem Lett 1999, 9, 24, 3459.

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)	37250	(2R)-4-amino-2-[[(benzyloxy)carbonyl]amino]butyric acid	62234-40-6	C₁₂H₁₆N₂O₄	详情	详情
(II)	37251	(2R)-2-[[(benzyloxy)carbonyl]amino]-4-[(tert-butoxycarbonyl)amino]butyric acid		C₁₇H₂₄N₂O₆	详情	详情
(III)	10309	ethyl 2-aminoacetate; Glycine ethyl ester	459-73-4	C₄H₉NO₂	详情	详情
(IV)	37252	ethyl 2-([(2R)-2-[[(benzyloxy)carbonyl]amino]-4-[(tert-butoxycarbonyl)amino]butanoyl]amino)acetate		C₂₁H₃₁N₃O₇	详情	详情
(V)	37253	ethyl 2-([(2R)-2-amino-4-[(tert-butoxycarbonyl)amino]butanoyl]amino)acetate		C₁₃H₂₅N₃O₅	详情	详情
(VI)	25151	phenylmethanesulfonyl chloride	1939-99-7	C₇H₇ClO₂S	详情	详情
(VII)	37254	ethyl 2-([(2R)-2-[(benzylsulfonyl)amino]-4-[(tert-butoxycarbonyl)amino]butanoyl]amino)acetate		C₂₀H₃₁N₃O₇S	详情	详情
(VIII)	37255	ethyl 2-([(2R)-4-amino-2-[(benzylsulfonyl)amino]butanoyl]amino)acetate		C₁₅H₂₃N₃O₅S	详情	详情
(IX)	37256	2-pyrazinecarboxylic acid; Pyrazinoic acid	98-97-5	C₅H₄N₂O₂	详情	详情
(X)	37257	ethyl 2-([(2R)-2-[(benzylsulfonyl)amino]-4-[(2-pyrazinylcarbonyl)amino]butanoyl]amino)acetate		C₂₀H₂₅N₅O₆S	详情	详情
(XI)	37258	2-([(2R)-2-[(benzylsulfonyl)amino]-4-[(2-pyrazinylcarbonyl)amino]butanoyl]amino)acetic acid		C₁₈H₂₁N₅O₆S	详情	详情

合成路线2

The carboxylic acid (XI) was coupled with Ngamma-Pmc-argininol (XII) giving (XIII). Deprotection of the Pmc group of (XIII) with trifluoroacetic acid provided the free guanidine (XIV). Finally, Swern oxidation of the primary alcohol of (XIV) with concomitant cyclization of the resulting aldehyde furnished the title compound.

参考文献中间体

【1】 Ho, J.Z.; et al.; Exploration solid-phase synthesis of factor Xa inhibitors: Discovery and application of P3-heterocyclic amides as novel types of non-basic arginine surrogates. Bioorg Med Chem Lett 1999, 9, 24, 3459.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	37258	2-([(2R)-2-[(benzylsulfonyl)amino]-4-[(2-pyrazinylcarbonyl)amino]butanoyl]amino)acetic acid	C₁₈H₂₁N₅O₆S	详情	详情
(XII)	37259	N-((E)-amino[[(4S)-4-amino-5-hydroxypentyl]amino]methylidene)-2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromene-6-sulfonamide	C₂₀H₃₆N₄O₄S	详情	详情
(XIII)	37260	N-[(3R)-4-[(2-[[(1S)-4-[(amino[[(2,2,5,7,8-pentamethyl-3,4,4a,8a-tetrahydro-2H-chromen-6-yl)sulfonyl]imino]methyl)amino]-1-(hydroxymethyl)butyl]amino]-2-oxoethyl)amino]-3-[(benzylsulfonyl)amino]-4-oxobutyl]-2-pyrazinecarboxamide	C₃₈H₅₅N₉O₉S₂	详情	详情
(XIV)	37261	N-[(3R)-4-[(2-[[(1S)-4-[[amino(imino)methyl]amino]-1-(hydroxymethyl)butyl]amino]-2-oxoethyl)amino]-3-[(benzylsulfonyl)amino]-4-oxobutyl]-2-pyrazinecarboxamide	C₂₄H₃₅N₉O₆S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)