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【结 构 式】 
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【分子编号】38459 【品名】methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate 【CA登记号】 |
【 分 子 式 】C13H16N2O2 【 分 子 量 】232.28232 【元素组成】C 67.22% H 6.94% N 12.06% O 13.78% |
合成路线1
该中间体在本合成路线中的序号：(X)Protection of methyl (R)-3-aminobutyrate (VI) with di-tert-butyl dicarbonate provided the Boc derivative (VII), which was alkylated with 3-cyanobenzyl bromide (VIII) in the presence of lithium bis(trimethylsilyl)amide at -78 C to afford adduct (IX). Acid deprotection of the Boc group of (IX) yielded amino ester (X). Alternatively, (X) was obtained by protection of methyl 3-aminobutyrate (VI) with benzyl chloroformate, followed by alkylation with 3-cyanobenzyl bromide to give (XI). The carbobenzoxy group of (XI) was then deprotected by hydrogenation over Pd/C. Coupling of amino ester (X) with acid chloride (V) gave rise to amide (XII). Conversion of (XII) to the required amidine was then achieved by treatment with methanolic HCl, followed by reaction of the resulting imidate with ammonia in boiling MeOH. The title compound was isolated after conversion to the trifluoroacetate salt.
| 【1】 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 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| (V) | 38455 | 3',4'-dimethoxy[1,1'-biphenyl]-4-carbonyl chloride | C15H13ClO3 | 详情 | 详情 | |
| (VI) | 38456 | methyl (3R)-3-aminobutanoate | C5H11NO2 | 详情 | 详情 | |
| (VII) | 38457 | methyl (3R)-3-[(tert-butoxycarbonyl)amino]butanoate | C10H19NO4 | 详情 | 详情 | |
| (VIII) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
| (IX) | 38458 | methyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-(3-cyanobenzyl)butanoate | C18H24N2O4 | 详情 | 详情 | |
| (X) | 38459 | methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate | C13H16N2O2 | 详情 | 详情 | |
| (XI) | 38460 | methyl (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-(3-cyanobenzyl)butanoate | C21H22N2O4 | 详情 | 详情 | |
| (XII) | 38461 | methyl (2R,3R)-2-(3-cyanobenzyl)-3-[[(3',4'-dimethoxy[1,1'-biphenyl]-4-yl)carbonyl]amino]butanoate | C28H28N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)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).
| 【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
该中间体在本合成路线中的序号：(V)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.
| 【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 | CAS号 | 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 |
合成路线4
该中间体在本合成路线中的序号：(IV)Nitration of quinazolone (I) by reaction with HNO3/H2SO4 affords 7-chloro-6-nitro-4-quinazolone (II), which is then chlorinated with phosphorus oxychloride (POCl3) to provide quinazoline (III). Selective amination of the quinazoline ring of (III) by reaction with 4-chlorophenethylamine (IV) in isopropanol in the presence of Et3N yields compound (V), which is finally converted into the desired compound by condensation with piperazine (VI) in refluxing butanol in the presence of DIEA. Alternatively the target product can be obtained by the following procedure: Condensation of quinazolone derivative (II) with piperazine (VI) in refluxing butanol in the presence of DIEA affords compound (VII), which is treated with POCl3 and finally subjected to condensation with 4-chlorophenethylamine (IV) in isopropanol in the presence of Et3N.
| 【1】 Matsumoto, M.; Hayashi, H.; Tomizawa, H.; Obara, F.; Nagasaki, T.; Tobe, M.; Isoba, Y.; Structure-activity relationships of quinazoline derivatives: Dual-acting compounds with inhibitory activities toward both TNF-alpha production and T cell proliferation. Bioorg Med Chem Lett 2001, 11, 4, 545. |
| 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) | 50077 | 7-chloro-4(3H)-quinazolinone | C8H5ClN2O | 详情 | 详情 | |
| (II) | 50078 | 7-chloro-6-nitro-4(3H)-quinazolinone | C8H4ClN3O3 | 详情 | 详情 | |
| (III) | 50079 | 4,7-dichloro-6-nitroquinazoline | C8H3Cl2N3O2 | 详情 | 详情 | |
| (IV) | 38459 | methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate | C13H16N2O2 | 详情 | 详情 | |
| (V) | 50080 | N-(7-chloro-6-nitro-4-quinazolinyl)-N-(4-chlorophenethyl)amine; 7-chloro-N-(4-chlorophenethyl)-6-nitro-4-quinazolinamine | C16H12Cl2N4O2 | 详情 | 详情 | |
| (VI) | 10355 | Diethylenediamine; Piperazine | 110-85-0 | C4H10N2 | 详情 | 详情 |
| (VII) | 50081 | 6-nitro-7-(1-piperazinyl)-4(3H)-quinazolinone | C12H13N5O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)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 .
| 【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 | CAS号 | 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 |