Otamixaban； FXV-673；XRP-0673, -Drug Synthesis Database

【结构式】

【药物名称】Otamixaban； FXV-673；XRP-0673

【化学名称】2(R)-(3-Amidinobenzyl)-3(R)-[4-(1-oxidopyridin-4-yl)benzamido]butyric acid methyl ester

【CA登记号】193153-04-7, 219672-50-1 (undefined isomer; HCl salt)

【分子式】C₂₅H₂₆N₄O₄

【分子量】446.51037

【开发单位】Aventis Pharma (Originator)

【药理作用】Anticoagulants；Treatment of Acute Coronary Syndrome；Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

The cycloaddition reaction between 4-vinylpyridine (I) and methylcoumalate (II) in hot mesitylene in the presence of Pd/C gives the methyl pyridylbenzoate (III), which is hydrolyzed with NaOH in H2O/MeOH/THF and the resulting carboxylic acid (IV) is converted to the acid chloride (V) upon refluxing with SOCl2 . Acylation of the amino ester (VI) using either pyridylbenzoic acid (IV) by means of TBTU and NMM in DMF or acid chloride (V) in the presence of Et3N in EtOH affords amide (VII), which is then oxidized at the pyridine nitrogen with m-chloroperbenzoic acid or magnesium monoperoxyphthalate in CH2Cl2 to provide the corresponding Noxide (VIII). Finally, nitrile (VIII) is submitted to Pinner reaction with HCl in cold MeOH to afford imidate (IX), followed by heating with methanolic ammonia .

参考文献中间体

【1】 Guertin, K.R., Klein, S.I., Spada, A.P. (sanofi-aventis [FR]). Substituted N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. EP 0906094, JP 2000502710, US 6080767, WO 1997024118.
【2】 Klein, S.I., Guertin, K.R., McGarry, D.G., Gong, Y., Pauls, H.W., Spada, A.P. (sanofi-aventis US LLC). Substituted N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556, EP 0931060, JP 2001500532, WO 1999000356.
【3】 Guertin, K.R., Gardner, C.J., Klein, S.I. et al. Optimization of the betaaminoester class of factor Xa inhibitors. Part 2: Identification of FXV673 as a potent and selective inhibitor with excellent in vivo anticoagulant activity. Bioorg Med Chem Lett 2002, 12(12): 1671-4.
【4】 Teager, D.S., Woodward, R.G. (sanofi-aventis US LLC). Novel crystalline forms of a factor Xa inhibitor. JP 2004521082, US 2003225144, WO 2002028836.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	45857	4-vinylpyridine	C₇H₇N	详情	详情
(II)	58217	methyl 2-oxo-2H-pyran-5-carboxylate; methyl coumalate	C₇H₆O₄	详情	详情
(III)	58218	methyl 4-(4-pyridinyl)benzoate	C₁₃H₁₁NO₂	详情	详情
(IV)	58219	4-(4-pyridinyl)benzoic acid	C₁₂H₉NO₂	详情	详情
(V)	58220	4-(4-pyridinyl)benzoyl chloride	C₁₂H₈ClNO	详情	详情
(VI)	38459	methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate	C₁₃H₁₆N₂O₂	详情	详情
(VII)	58221	methyl (2R,3R)-2-(3-cyanobenzyl)-3-{[4-(4-pyridinyl)benzoyl]amino}butanoate	C₂₅H₂₃N₃O₃	详情	详情
(VIII)	58222	4-[4-({[(1R,2R)-2-(3-cyanobenzyl)-3-methoxy-1-methyl-3-oxopropyl]amino}carbonyl)phenyl]-1-pyridiniumolate	C₂₅H₂₃N₃O₄	详情	详情
(IX)	58223	4-(4-{[((1R,2R)-2-{3-[imino(methoxy)methyl]benzyl}-3-methoxy-1-methyl-3-oxopropyl)amino]carbonyl}phenyl)-1-pyridiniumolate	C₂₆H₂₇N₃O₅	详情	详情

合成路线2

Methyl (R)-3-aminobutyrate (I) is protected as the N-Boc derivative (II) using di-tert-butyl dicarbonate. Diastereoselective alkylation of the lithium enolate of (II) with 3-cyanobenzyl bromide (III) yields adduct (IV). Deprotection of (IV) is then effected by treatment with trifluoroacetic acid, to afford amino ester (V). Alternatively, aminobutyrate (I) is protected as the N-(benzyloxycarbonyl) derivative (VI), which is then alkylated with 3-cyanobenzyl bromide (III) to give (VII). Catalytic hydrogenolysis of (VII) in the presence of Pd/C yields the target intermediate (V).

参考文献中间体

【1】 Guertin, K.R.; Klein, S.I.; Spada, A.P. (Aventis Pharma SA); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. EP 0906094; JP 2000502710; US 6080767; WO 9724118 .
【2】 Gong, Y.; Guertin, K.R.; McGarry, D.G.; Pauls, H.W.; Klein, S.I.; Spada, A.P. (Aventis Pharmaceuticals, Inc.); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556; EP 0931060; WO 9900356 .

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)	38456	methyl (3R)-3-aminobutanoate		C₅H₁₁NO₂	详情	详情
(II)	38457	methyl (3R)-3-[(tert-butoxycarbonyl)amino]butanoate		C₁₀H₁₉NO₄	详情	详情
(III)	13244	alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile	28188-41-2	C₈H₆BrN	详情	详情
(IV)	38458	methyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-(3-cyanobenzyl)butanoate		C₁₈H₂₄N₂O₄	详情	详情
(V)	38459	methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate		C₁₃H₁₆N₂O₂	详情	详情
(VI)	58216	methyl (3R)-3-{[(benzyloxy)carbonyl]amino}butanoate		C₁₃H₁₇NO₄	详情	详情
(VII)	38460	methyl (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-(3-cyanobenzyl)butanoate		C₂₁H₂₂N₂O₄	详情	详情

合成路线3

The cycloaddition reaction between 4-vinylpyridine (VIII) and methyl coumalate (IX) in hot mesitylene gives rise to the pyridyl benzoate (X). After saponification of the ester group of (X), the resultant carboxylic acid (XI) is converted to acid chloride (XII) by treatment with SOCl2. Acylation of amino ester (V) by acid chloride (XII) affords amide (XIII). The pyridine N of (XIII) is then oxidized to the corresponding N-oxide (XIV) employing m-chloroperbenzoic acid. Finally, conversion of the cyano group of (XIV) into the title amidine is accomplished by Pinner reaction, via formation of the intermediate imidate (XV), which is subsequently treated with methanolic ammonia.

参考文献中间体

【1】 Guertin, K.R.; et al.; Optimization of the beta-aminoester class of factor Xa inhibitors. Part 2: Identification of FXV673 as a potent and selective inhibitor with excellent in vivo anticoagulant activity. Bioorg Med Chem Lett 2002, 12, 12, 1671.
【2】 Guertin, K.R.; Klein, S.I.; Spada, A.P. (Aventis Pharma SA); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. EP 0906094; JP 2000502710; US 6080767; WO 9724118 .
【3】 Gong, Y.; Guertin, K.R.; McGarry, D.G.; Pauls, H.W.; Klein, S.I.; Spada, A.P. (Aventis Pharmaceuticals, Inc.); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556; EP 0931060; WO 9900356 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(V)	38459	methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate	C₁₃H₁₆N₂O₂	详情	详情
(VIII)	45857	4-vinylpyridine	C₇H₇N	详情	详情
(IX)	58217	methyl 2-oxo-2H-pyran-5-carboxylate; methyl coumalate	C₇H₆O₄	详情	详情
(X)	58218	methyl 4-(4-pyridinyl)benzoate	C₁₃H₁₁NO₂	详情	详情
(XI)	58219	4-(4-pyridinyl)benzoic acid	C₁₂H₉NO₂	详情	详情
(XII)	58220	4-(4-pyridinyl)benzoyl chloride	C₁₂H₈ClNO	详情	详情
(XIII)	58221	methyl (2R,3R)-2-(3-cyanobenzyl)-3-{[4-(4-pyridinyl)benzoyl]amino}butanoate	C₂₅H₂₃N₃O₃	详情	详情
(XIV)	58222	4-[4-({[(1R,2R)-2-(3-cyanobenzyl)-3-methoxy-1-methyl-3-oxopropyl]amino}carbonyl)phenyl]-1-pyridiniumolate	C₂₅H₂₃N₃O₄	详情	详情
(XV)	58223	4-(4-{[((1R,2R)-2-{3-[imino(methoxy)methyl]benzyl}-3-methoxy-1-methyl-3-oxopropyl)amino]carbonyl}phenyl)-1-pyridiniumolate	C₂₆H₂₇N₃O₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)