Diclofenac; 2-[2-(2,6-Dichloroanilino)phenyl]acetic acid -Drug Synthesis Database

【结构式】

【分子编号】33701

【品名】Diclofenac; 2-[2-(2,6-Dichloroanilino)phenyl]acetic acid

【CA登记号】

【分子式】C₁₄H₁₁Cl₂NO₂

【分子量】296.15228

【元素组成】C 56.78% H 3.74% Cl 23.94% N 4.73% O 10.8%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VI)

Alkylation of the sodium salt of diclofenac (I) with benzyl bromoacetate (II) in hot DMF yielded the (arylacetoxy)acetate (III). Subsequent hydrogenolysis of the benzyl ester of (III) in the presence of Pd/C gave the title carboxylic acid. Alternatively, the benzyl ester group of (III) was cleaved by means of the combination of chlorotrimethylsilane and sodium iodide. This method of selective ester hydrolysis with in situ generated iodotrimethylsilane was also applied to the corresponding methyl (IV) and tert-butyl (V) esters. In a related procedure, tert-butyl ester (V) was prepared by alkylation of diclofenac (VI) with tert-butyl bromoacetate (VII) in the presence of tertiary amines. Selective cleavage of the tert-butyl ester group of (V) was then performed by treatment with either trifluoroacetic or formic acid.

参考文献中间体

合成目标

【1】 Casas, A.V. (Almirall Prodesfarma, SA); 2-[(2,6-Dichlorophenyl)amino]phenylacetoxyacetyl derivs. and therapeutic compsns. containing same. EP 0119932; US 4548952 .
【2】 Ginebreda Martí, A.; Agustí Cruz, A. (Almirall Prodesfarma, SA); Process for obtaining 2-[(2,6-dichlorophenyl)amino]phenylacetoxyacetic acid. ES 2020146 .
【3】 Schickaneder, H.; Nikolopoulos, A.; Murphy, T.; Process for the preparation of aceclofenac. WO 9955660 .

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)	56535	sodium 2-[2-(2,6-dichloroanilino)phenyl]acetate		C₁₄H₁₀Cl₂NNaO₂	详情	详情
(II)	12869	benzyl 2-bromoacetate	5437-45-6	C₉H₉BrO₂	详情	详情
(III)	56536	2-(benzyloxy)-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate		C₂₃H₁₉Cl₂NO₄	详情	详情
(IV)	56537	2-methoxy-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate		C₁₇H₁₅Cl₂NO₄	详情	详情
(V)	56538	2-(tert-butoxy)-2-oxoethyl 2-[2-(2,6-dichloroanilino)phenyl]acetate		C₂₀H₂₁Cl₂NO₄	详情	详情
(VI)	33701	Diclofenac; 2-[2-(2,6-Dichloroanilino)phenyl]acetic acid		C₁₄H₁₁Cl₂NO₂	详情	详情
(VII)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Treatment of cyclohexanecarboxaldehyde (I) with sulfur monochloride produced the dimeric disulfide (II). After condensation of (II) with 3-amino-1-propanol (III), reduction with NaBH4 afforded diamine (IV). Subsequent N-methylation of (IV) to give (VI) was achieved by condensation with formaldehyde, followed by NaBH4 reduction of the resulting oxazine (V). Reductive cleavage of the disulfide group of (VI) using LiAlH4 provided thiol (VII). Optionally, nitrosation of the sulfhydryl group of (VII) by means of tert-butyl nitrite gave rise to the nitrosothio derivative (VIII). Further coupling of this compound with diclofenac (IX) in the presence of DCC and DMAP furnished the title ester. Alternatively, the title compound was prepared by esterification of mercapto alcohol (VII) with diclofenac, followed by S-nitrosation of the resulting ester (X).

参考文献中间体

合成目标

【1】 Bandarage, U.K.; et al.; Nitrosothiol esters of diclofonecac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs. J Med Chem 2000, 43, 21, 4005.
【2】 Bandarage, U.K.; et al.; NMI-377, a nitric oxide-donating diclofenac derivative with gastroprotective properties. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 81.

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)	33694	cyclohexanecarbaldehyde	2043-61-0	C₇H₁₂O	详情	详情
(II)	33695	1-[(1-formylcyclohexyl)disulfanyl]cyclohexanecarbaldehyde		C₁₄H₂₂O₂S₂	详情	详情
(III)	18522	3-amino-1-propanol	156-87-6	C₃H₉NO	详情	详情
(IV)	33696	3-[([1-[(1-[[(3-hydroxypropyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)amino]-1-propanol		C₂₀H₄₀N₂O₂S₂	详情	详情
(V)	33697	bis[1-(1,3-oxazinan-3-ylmethyl)cyclohexyl] disulfide; 3-[(1-[[1-(1,3-oxazinan-3-ylmethyl)cyclohexyl]disulfanyl]cyclohexyl)methyl]-1,3-oxazinane		C₂₂H₄₀N₂O₂S₂	详情	详情
(VI)	33698	3-[([1-[(1-[[(3-hydroxypropyl)(methyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)(methyl)amino]-1-propanol		C₂₂H₄₄N₂O₂S₂	详情	详情
(VII)	33699	3-[methyl[(1-sulfanylcyclohexyl)methyl]amino]-1-propanol		C₁₁H₂₃NOS	详情	详情
(VIII)	33700	1-[[(3-hydroxypropyl)(methyl)amino]methyl]-N-oxocyclohexanesulfenamide		C₁₁H₂₂N₂O₂S	详情	详情
(IX)	33701	Diclofenac; 2-[2-(2,6-Dichloroanilino)phenyl]acetic acid		C₁₄H₁₁Cl₂NO₂	详情	详情
(X)	33702	3-[methyl[(1-sulfanylcyclohexyl)methyl]amino]propyl 2-[2-(2,6-dichloroanilino)phenyl]acetate		C₂₅H₃₂Cl₂N₂O₂S	详情	详情

Extended Information