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【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%

与该中间体有关的原料药合成路线共 3 条

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
Extended Information