【结 构 式】 |
【分子编号】31677 【品名】3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile 【CA登记号】 |
【 分 子 式 】C12H13N3O2 【 分 子 量 】231.25424 【元素组成】C 62.33% H 5.67% N 18.17% O 13.84% |
合成路线1
该中间体在本合成路线中的序号:(IX)The iodination of 2-hydroxybenzaldehyde (I) with iodine chloride in dichloromethane gives 2-hydroxy-5-iodobenzaldehyde (II), which is protected with Mem-Cl by means of NaH and 1,3-dimethylperhydropyrimidin-2-one (DMPU) in THF yielding the ether derivative (III). The reduction of (III) with NaBH4 in THF affords the benzyl alcohol (IV), which is brominated with NBS and triphenylphosphine in THF to give the benzyl bromide (V). The condensation of (V) with the protected aminopyrrolidinone (VI) by means of NaH and DMPU in THF yields the benzylpyrrolidinone (VII), which is treated with Zn(CN)2 and palladium tetrakis(triphenylphosphine) in DMF to provide the benzonitrile (VIII). The deprotection of (VIII) with HCl gas in ethyl acetate gives the primary amine (IX), which is sulfonated with 5-(3-pyridyl)thiophene-2-sulfonyl chloride (X) in pyridine yielding the sulfonamide (XI). Finally, this compound is treated first with HCl gas in ethanol, and then with NH3 in methanol to convert the cyano group of (XI) into the amidino group of the target compound. The intermediate sulfonyl chloride (X) has been obtained as follows: The condensation of 3-bromopyridine (XII) with 2-bromothiophene (XIII) by means of Mg and NiCl2 in refluxing ethyl ether gives 2-(3-pyridyl)thiophene (XIV), which is chlorosulfonated by means of BuLi, SO2 and SO2Cl2 in THF to yield intermediate (X).
【1】 McGarry, D.G.; Choi-Sledeski, Y.M.; Green, D.M.; et al.; Sulfonamidopyrrolidinone factor Xa inhibitors: Potency and selectivity enhancements via P-1 and P-2 optimization. J Med Chem 1999, 42, 18, 3572. |
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) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde;2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
(II) | 31671 | 2-hydroxy-5-iodobenzaldehyde | C7H5IO2 | 详情 | 详情 | |
(III) | 31672 | 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde; 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H13IO4 | 详情 | 详情 | |
(IV) | 31673 | [5-iodo-2-[(2-methoxyethoxy)methoxy]phenyl]methanol | C11H15IO4 | 详情 | 详情 | |
(V) | 31674 | 2-[[2-(bromomethyl)-4-iodophenoxy]methoxy]ethyl methyl ether; 2-(bromomethyl)-4-iodo-1-[(2-methoxyethoxy)methoxy]benzene | C11H14BrIO3 | 详情 | 详情 | |
(VI) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
(VII) | 31675 | tert-butyl (3S)-1-[5-iodo-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C20H29IN2O6 | 详情 | 详情 | |
(VIII) | 31676 | tert-butyl (3S)-1-[5-cyano-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C21H29N3O6 | 详情 | 详情 | |
(IX) | 31677 | 3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile | C12H13N3O2 | 详情 | 详情 | |
(X) | 31678 | 5-(3-pyridinyl)-2-thiophenesulfonyl chloride | C9H6ClNO2S2 | 详情 | 详情 | |
(XI) | 31679 | N-[(3S)-1-(5-cyano-2-hydroxybenzyl)-2-oxopyrrolidinyl]-5-(3-pyridinyl)-2-thiophenesulfonamide | C21H18N4O4S2 | 详情 | 详情 | |
(XII) | 13625 | 2-[(3-Methoxyphenyl)sulfanyl]benzoic acid | C14H12O3S | 详情 | 详情 | |
(XIII) | 13681 | 2-Bromothiophene | 1003-09-4 | C4H3BrS | 详情 | 详情 |
(XIV) | 31680 | 3-(2-thienyl)pyridine | C9H7NS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(X)Reaction of salicylaldehyde (I) with iodine monochloride produced 2-hydroxy-5-iodobenzaldehyde (II), which was protected with (2-methoxyethoxy) methyl chloride to give ether (III). Reduction of the aldehyde group of (III) with NaBH4 yielded alcohol (IV) and subsequent treatment with N-bromosuccinimide and triphenylphosphine generated bromide (V). N-Boc-3-aminopyrrolidinone (VII) was prepared by cyclization of (S)-alpha-Boc-2,4-diaminobutyric acid (VI) in the presence of EDC and HOBt. Subsequent alkylation of (VII) with bromide (V) produced the N-benzylpyrrolidinone derivative (VIII). Displacement of iodide group of (VIII) by zinc cyanide gave nitrile (IX). Then, acid cleavage of both Boc and MEM protecting groups furnished intermediate (X).
【1】 Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; McGarry, D.G.; Davis, R.S.; Spada, A.P. (Aventis Pharma SA); Substd. sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide cpds.. EP 0894088; JP 2000505815; US 5731315; WO 9824784 . |
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) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde;2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
(II) | 31671 | 2-hydroxy-5-iodobenzaldehyde | C7H5IO2 | 详情 | 详情 | |
(III) | 31672 | 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde; 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H13IO4 | 详情 | 详情 | |
(IV) | 31673 | [5-iodo-2-[(2-methoxyethoxy)methoxy]phenyl]methanol | C11H15IO4 | 详情 | 详情 | |
(V) | 31674 | 2-[[2-(bromomethyl)-4-iodophenoxy]methoxy]ethyl methyl ether; 2-(bromomethyl)-4-iodo-1-[(2-methoxyethoxy)methoxy]benzene | C11H14BrIO3 | 详情 | 详情 | |
(VI) | 29493 | (2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyric acid | C9H18N2O4 | 详情 | 详情 | |
(VII) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
(VIII) | 31675 | tert-butyl (3S)-1-[5-iodo-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C20H29IN2O6 | 详情 | 详情 | |
(IX) | 31676 | tert-butyl (3S)-1-[5-cyano-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C21H29N3O6 | 详情 | 详情 | |
(X) | 31677 | 3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile | C12H13N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(X)Thienylacrylic acid (XII), prepared from thiophene aldehyde (XI), was activated as the mixed anhydride with ethyl chloroformate and then treated with NaN3 to yield acyl azide (XIII). Cyclization of (XIII) in the presence of Bu3P in boiling diphenyl ether generated the thienopyridine system (XIV). Chlorination of (XIV) with POCl3 afforded the chloro derivative (XV). After lithium-bromine exchange with n-butyllithium, the resulting organolithium derivative (XVI) was treated with SO2 and further oxidized to sulfonyl chloride (XVII) with SO2Cl2. Coupling of (XVII) with aminopyrrolidinone (X) yielded sulfonamide (XVIII). Conversion of the nitrile of (XVIII) to the corresponding imidate (XIX), followed by reaction with ammonia produced benzamidine (XX). Finally, hydrogenolytic dechlorination of (XX) over Pd/C provided the title compound.
【1】 Ewing, W.R.; Davis, R.S.; Becker, M.R.; et al.; Synthesis, SAR and in vivo activity of novel thienopyridine sulfonamide pyrrolidinones as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 18, 2753. |
【2】 Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; McGarry, D.G.; Davis, R.S.; Spada, A.P. (Aventis Pharma SA); Substd. sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide cpds.. EP 0894088; JP 2000505815; US 5731315; WO 9824784 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(X) | 31677 | 3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile | C12H13N3O2 | 详情 | 详情 | |
(XI) | 31660 | 5-bromo-3-thiophenecarbaldehyde | C5H3BrOS | 详情 | 详情 | |
(XII) | 38299 | (E)-3-(5-bromo-3-thienyl)-2-propenoic acid | C7H5BrO2S | 详情 | 详情 | |
(XIII) | 38300 | (E)-3-(5-bromo-3-thienyl)-2-propenoyl azide | C7H4BrN3OS | 详情 | 详情 | |
(XIV) | 38301 | 2-bromothieno[2,3-c]pyridin-7(6H)-one | C7H4BrNOS | 详情 | 详情 | |
(XV) | 38302 | 2-bromo-7-chlorothieno[2,3-c]pyridine | C7H3BrClNS | 详情 | 详情 | |
(XVI) | 38303 | (7-chlorothieno[2,3-c]pyridin-2-yl)lithium | C7H3ClLiNS | 详情 | 详情 | |
(XVII) | 38304 | 7-chlorothieno[2,3-c]pyridine-2-sulfonyl chloride | C7H3Cl2NO2S2 | 详情 | 详情 | |
(XVIII) | 38305 | 7-chloro-N-[(3S)-1-(5-cyano-2-hydroxybenzyl)-2-oxopyrrolidinyl]thieno[2,3-c]pyridine-2-sulfonamide | C19H15ClN4O4S2 | 详情 | 详情 | |
(XIX) | 38306 | ethyl 3-[((3S)-3-[[(7-chlorothieno[2,3-c]pyridin-2-yl)sulfonyl]amino]-2-oxopyrrolidinyl)methyl]-4-hydroxybenzenecarboximidoate | C21H21ClN4O5S2 | 详情 | 详情 | |
(XX) | 38307 | 3-[((3S)-3-[[(7-chlorothieno[2,3-c]pyridin-2-yl)sulfonyl]amino]-2-oxopyrrolidinyl)methyl]-4-hydroxybenzenecarboximidamide | C19H18ClN5O4S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(X)Reaction of salicylaldehyde (I) with iodine monochloride produced 2-hydroxy-5-iodobenzaldehyde (II), which was protected with (2-methoxyethoxy) methyl chloride to give ether (III). Reduction of the aldehyde group of (III) with NaBH4 yielded alcohol (IV) and subsequent treatment with N-bromosuccinimide and triphenylphosphine generated bromide (V). N-Boc-3-aminopyrrolidinone (VII) was prepared by cyclization of (S)-alpha-Boc-2,4-diaminobutyric acid (VI) in the presence of EDC and HOBt. Subsequent alkylation of (VII) with bromide (V) produced the N-benzylpyrrolidinone derivative (VIII). Displacement of iodide group of (VIII) by zinc cyanide gave nitrile (IX). Then, acid cleavage of both Boc and MEM protecting groups furnished intermediate (X).
【1】 Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; McGarry, D.G.; Davis, R.S.; Spada, A.P. (Aventis Pharma SA); Substd. sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide cpds.. EP 0894088; JP 2000505815; US 5731315; WO 9824784 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
40670 | 2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride | 3970-21-6 | C4H9ClO2 | 详情 | 详情 | |
(I) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde;2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
(II) | 31671 | 2-hydroxy-5-iodobenzaldehyde | C7H5IO2 | 详情 | 详情 | |
(III) | 31672 | 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde; 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H13IO4 | 详情 | 详情 | |
(IV) | 31673 | [5-iodo-2-[(2-methoxyethoxy)methoxy]phenyl]methanol | C11H15IO4 | 详情 | 详情 | |
(V) | 31674 | 2-[[2-(bromomethyl)-4-iodophenoxy]methoxy]ethyl methyl ether; 2-(bromomethyl)-4-iodo-1-[(2-methoxyethoxy)methoxy]benzene | C11H14BrIO3 | 详情 | 详情 | |
(VI) | 29493 | (2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyric acid | C9H18N2O4 | 详情 | 详情 | |
(VII) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
(VIII) | 31675 | tert-butyl (3S)-1-[5-iodo-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C20H29IN2O6 | 详情 | 详情 | |
(IX) | 31676 | tert-butyl (3S)-1-[5-cyano-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C21H29N3O6 | 详情 | 详情 | |
(X) | 31677 | 3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile | C12H13N3O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(X)The reaction of 5-chlorothieno[3,2-b]pyridine (XI) with n-BuLi and SO2 in THF and further oxidation with SO2Cl2 gives sulfonyl chloride (XII), which was coupled with aminopyrrolidinone (X) by means of TEA in dichloromethane to yield sulfonamide (XIII). Conversion of the nitrile of (XIII) to the corresponding imidate with HCl in methanol, followed by reaction with ammonia produced benzamidine (XIV). Finally, hydrogenolytic dechlorination of (XIV) over Pd/C provided the title compound.
【1】 Ewing, W.R.; Davis, R.S.; Becker, M.R.; et al.; Synthesis, SAR and in vivo activity of novel thienopyridine sulfonamide pyrrolidinones as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 18, 2753. |
【2】 Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; McGarry, D.G.; Davis, R.S.; Spada, A.P. (Aventis Pharma SA); Substd. sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide cpds.. EP 0894088; JP 2000505815; US 5731315; WO 9824784 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(X) | 31677 | 3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile | C12H13N3O2 | 详情 | 详情 | |
(XI) | 38295 | 5-chlorothieno[3,2-b]pyridine | C7H4ClNS | 详情 | 详情 | |
(XII) | 38296 | 5-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride | C7H3Cl2NO2S2 | 详情 | 详情 | |
(XIII) | 38297 | 5-chloro-N-[(3S)-1-(5-cyano-2-hydroxybenzyl)-2-oxopyrrolidinyl]thieno[3,2-b]pyridine-2-sulfonamide | C19H15ClN4O4S2 | 详情 | 详情 | |
(XIV) | 38298 | 3-[((3S)-3-[[(5-chlorothieno[3,2-b]pyridin-2-yl)sulfonyl]amino]-2-oxopyrrolidinyl)methyl]-4-hydroxybenzenecarboximidamide | C19H18ClN5O4S2 | 详情 | 详情 |