【结 构 式】 |
【分子编号】31675 【品名】tert-butyl (3S)-1-[5-iodo-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate 【CA登记号】 |
【 分 子 式 】C20H29IN2O6 【 分 子 量 】520.36461 【元素组成】C 46.16% H 5.62% I 24.39% N 5.38% O 18.45% |
合成路线1
该中间体在本合成路线中的序号:(VII)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:(VIII)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:(VIII)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 |