1-chloro-4-[(chlorocarbonyl)oxy]benzene -Drug Synthesis Database

【结构式】

【分子编号】17779

【品名】1-chloro-4-[(chlorocarbonyl)oxy]benzene

【CA登记号】7693-45-0

【分子式】C₇H₄Cl₂O₂

【分子量】191.01296

【元素组成】C 44.02% H 2.11% Cl 37.12% O 16.75%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(C)

Pyridine-3-carboxaldehyde O-methyloxime (I) is prepared either by methylation of 3-pyridinealdoxime sodium salt or by condensation of 3-pyridinecarboxaldehyde with methoxylamine in water. Quaternization of (I) with ethyl iodide gives 3-(methoxyiminomethyl)-1-ethylpyridinium iodide (II), which is reduced by means of sodium borohydride in methanol to 1-ethyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde O-methyloxime (III). Cleavage of the ethyl group is obtained by reaction with 4-chlorophenylchloroformate in refluxing dichloroethane to yield RU 47213. Ru 47213 is obtained as pure (E)-isomer. Under UV irradiation in toluene it is partially converted into the sterically unfavored (Z)-isomer.

参考文献中间体

合成目标

【1】 Barzaghi, F.; Galliani, G.; Toja, E.; RU 47213. Drugs Fut 1994, 19, 5, 454.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	12849	Nicotinaldehyde; 3-Pyridinecarboxaldehyde	500-22-1	C₆H₅NO	详情	详情
(D)	16170	1,2-dichloroethane	107-06-2	C₂H₄Cl₂	详情	详情
(B)	31260	nicotinaldehyde oxime	1193-92-6	C₆H₆N₂O	详情	详情
(I)	12850	Nicotinaldehyde O-methyloxime		C₇H₈N₂O	详情	详情
(II)	31259	1-ethyl-3-[(methoxyimino)methyl]pyridinium iodide		C₉H₁₃IN₂O	详情	详情
(III)	31261	1-ethyl-1,2,5,6-tetrahydro-3-pyridinecarbaldehyde O-methyloxime		C₉H₁₆N₂O	详情	详情
(C)	17779	1-chloro-4-[(chlorocarbonyl)oxy]benzene	7693-45-0	C₇H₄Cl₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Treatment of quinoline (I) with ethynylmagnesium bromide (II) in THF at low temperature, and then with 4-chlorophenyl chloroformate (III) gave carbamate (IV). Subsequent deprotection of tert-butyldimethylsilyl group with p-toluenesulfonic acid yielded allyl alcohol (V), and this was stereoselectively epoxidized with m-chloroperbenzoic acid to give epoxyalcohol (VI). Coupling of (VI) with vinyl chloride (VII) in the presence of Pd(0)-CuI catalyst provided the enediyne compound (VIII). This was oxidized with Dess-Martin periodinane reagent to the aldehyde (IX). Finally, CsF-promoted cyclization in the presence of acetic anhydride provided the title compound as a 2:1 mixture of diastereoisomers, which could not be separated.

参考文献中间体

合成目标

【1】 Unno, R.; et al.; Structure-activity relationships of cyclic enediynes related to dynemicin A-I. Synthesis and antitumor activity of 9-acetoxy enediynes equipped with aryl carbamate moieties. Bioorg Med Chem 1997, 5, 5, 883.

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)	17777	tert-butyl(dimethyl)silyl 4-quinolinylmethyl ether; 4-([[tert-butyl(dimethyl)silyl]oxy]methyl)quinoline		C₁₆H₂₃NOSi	详情	详情
(II)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(III)	17779	1-chloro-4-[(chlorocarbonyl)oxy]benzene	7693-45-0	C₇H₄Cl₂O₂	详情	详情
(IV)	17780	4-chlorophenyl (2R)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-ethynyl-1(2H)-quinolinecarboxylate		C₂₅H₂₈ClNO₃Si	详情	详情
(V)	17781	4-chlorophenyl (2R)-2-ethynyl-4-(hydroxymethyl)-1(2H)-quinolinecarboxylate		C₁₉H₁₄ClNO₃	详情	详情
(VI)	17782	4-chlorophenyl (1aS,2S,7bS)-2-ethynyl-7b-(hydroxymethyl)-1a,7b-dihydrooxireno[2,3-c]quinoline-3(2H)-carboxylate		C₁₉H₁₄ClNO₄	详情	详情
(VII)	17783	[(Z)-4-chloro-3-buten-1-ynyl](trimethyl)silane		C₇H₁₁ClSi	详情	详情
(VIII)	17784	4-chlorophenyl (1aS,2S,7bS)-7b-(hydroxymethyl)-2-[(Z)-6-(trimethylsilyl)-3-hexene-1,5-diynyl]-1a,7b-dihydrooxireno[2,3-c]quinoline-3(2H)-carboxylate		C₂₆H₂₄ClNO₄Si	详情	详情
(IX)	17785	4-chlorophenyl (1aS,2S,7bR)-7b-formyl-2-[(Z)-6-(trimethylsilyl)-3-hexene-1,5-diynyl]-1a,7b-dihydrooxireno[2,3-c]quinoline-3(2H)-carboxylate		C₂₆H₂₂ClNO₄Si	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Treatment of 4-chlorophenyl chloroformate (I) with N-(4-chlorophenyl) hydroxylamine (II) produced the N-hydroxycarbamate (III). This was condensed with glutathione (IV) to afford thiocarbamate (V). Finally, both carboxylate groups of (V) were esterified in ethanolic HCl to provide the target diethyl ester.

参考文献中间体

合成目标

【1】 Sentz, D.L.; Kavarana, M.J.; O'Neill, H.B.; Wang, H.; Eiseman, J.L.; Sharkey, E.M.; Creighton, D.J.; Pharmacokinetics and antitumor properties in tumor-bearing mice of an enediol analogue inhibitor of glyoxalase I. Cancer Chemotherapy and Pharmacology 2000, 46, 2, 156.
【2】 Kavarana, M.J.; Kovaleva, E.G.; Creighton, D.J.; Wollman, M.B.; Eiseman, J.L.; Mechanism-based competitive inhibitors of glyoxalase I: Intracellular delivery, in vitro antitumor activities, and stabilities in human serum and mouse serum. J Med Chem 1999, 42, 2, 221.
【3】 Muthy, N.S.R.K.; et al.; S-(N-Aryl-N-hydroxycarbamoyl)glutathione derivatives are tight-binding inhibitors of Glyoxalase I and Slow Substrates for Glyoxalase II. J Med Chem 1994, 37, 14, 2161-2166.
【4】 Creighton, D.J.; Hamilton, D.S. (University of Maryland); Glutathione N-hydroxycarbamoyl thioesters and method of inhibiting neoplastic growth. US 5616563; WO 9600061 .

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)	17779	1-chloro-4-[(chlorocarbonyl)oxy]benzene	7693-45-0	C₇H₄Cl₂O₂	详情	详情
(II)	29435	1-chloro-4-(hydroxyamino)benzeneN-(4-chlorophenyl)hydroxylamine		C₆H₆ClNO	详情	详情
(III)	29438	4-chlorophenyl 4-chlorophenyl(hydroxy)carbamate		C₁₃H₉Cl₂NO₃	详情	详情
(IV)	29436	(2S)-2-amino-5-[[(1R)-2-[(carboxymethyl)amino]-2-oxo-1-(sulfanylmethyl)ethyl]amino]-5-oxopentanoic acid	70-18-8	C₁₀H₁₇N₃O₆S	详情	详情
(V)	29437	(2S)-2-amino-5-([(1R)-2-[(carboxymethyl)amino]-1-[([[4-chloro(hydroxy)anilino]carbonyl]sulfanyl)methyl]-2-oxoethyl]amino)-5-oxopentanoic acid		C₁₇H₂₁ClN₄O₈S	详情	详情

Extended Information