2-(4-nitrophenyl)acetic acid -Drug Synthesis Database

【结构式】

【分子编号】30305

【品名】2-(4-nitrophenyl)acetic acid

【CA登记号】104-03-0

【分子式】C₈H₇NO₄

【分子量】181.14792

【元素组成】C 53.04% H 3.89% N 7.73% O 35.33%

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：(I)

The reaction of 4-nitrophenylacetic acid (I) with formaldehyde and dimethylamine in water gives 2-(4-nitrophenyl)-3-(dimethylamino)propionic acid (II), which by treatment with refluxing concentrated HCl is converted into 2-(4-nitrophenyl)acrylic acid (III). The esterification of (III) with methanol and p-toluenesulfonic acid yields the corresponding methyl ester (IV), which is reduced with H2 over Pd/C in ethanol to afford methyl 2-(4-aminophenyl)propionate (V). The alkylation of (V) with 2-methylallyl chloride (VI) by means of pyridine in refluxing ethanol gives methyl 2-[4-(2-methylallylamino)phenyl]propionate (VII), which is finally hydrolyzed with NaOH in refluxing methanol.

参考文献中间体

合成目标

【1】 Dumaitre, B.; et al.; Synthesis of some analgesic and antiinflammatory 4-aminophenylacetic and 4-aminophenylacetic and 2-(4-aminophenyl)propionic acid derivatives. Eur J Med Chem - Chim Ther 1979, 14, 3, 207-214.
【2】 Bouchara, E. (Laboratoires du Dr. E. Bouchara); Nouveau procede de preparation de derives de l'acide phenylacetique. FR 2289180 .
【3】 Serradell, M.N.; Castaner, J.; Alminoprofen. Drugs Fut 1984, 9, 3, 165.

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)	30305	2-(4-nitrophenyl)acetic acid	104-03-0	C₈H₇NO₄	详情	详情
(II)	30306	N,N-dimethyl-2-(4-nitrophenyl)-beta-alanine		C₁₁H₁₄N₂O₄	详情	详情
(III)	30307	2-(4-nitrophenyl)acrylic acid		C₉H₇NO₄	详情	详情
(IV)	30308	methyl 2-(4-nitrophenyl)acrylate		C₁₀H₉NO₄	详情	详情
(V)	13912	methyl 2-(4-aminophenyl)propanoate	39718-97-3	C₁₀H₁₃NO₂	详情	详情
(VI)	12127	3-Chloro-2-methyl-1-propene; Isobutenyl chloride	563-47-3	C₄H₇Cl	详情	详情
(VII)	30309	methyl 2-[4-[(2-methyl-2-propenyl)amino]phenyl]propanoate		C₁₄H₁₉NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

6-O-Methylerythromycin A (I) was converted to a mixture of (E)- and (Z)-oximes upon treatment with hydroxylamine in refluxing MeOH. Beckmann rearrangement of the required (Z)-isomer (II) in the presence of tosyl chloride and NaHCO3 led to the macrocyclic lactam (III). Smooth acidic hydrolysis of (III) selectively removed the 3-cladinose moiety. The 3-decladinosyl derivative (IV) was then protected as the 2' acetate (V) employing Ac2O in the presence of NaHCO3. Subsequent acylation of the 3-hydroxyl group of (V) with the mixed anhydride prepared from 4-nitrophenylacetic acid (VI) and pivaloyl chloride furnished ester (VII). Finally, methanolysis of the acetate ester group of (VII) provided the title compound.

参考文献中间体

合成目标

【1】 Alihodzic, S.; et al.; Synthesis and antibacterial activity of isomeric 15-membered azalides. 40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2001, Abst 1177.
【2】 Kobrehel, G.; Lazarevski, G.; Kelneric, Z. (Pliva dd); 15-Membered lactams ketolides with antibacterial activity. EP 1070077; JP 2002510701; US 6110965; WO 9951616 .
【3】 Kobrehel, G.; Lazarevski, G.; Alihodzic, S.; Mutak, S. (Pliva dd); Novel 8a- and 9a-15-membered lactams. EP 1181298; WO 0063223 .

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)	18631	(3R,4S,5R,6R,7R,9R,11R,12R,13S,14R)-6-[[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-14-ethyl-12,13-dihydroxy-4-[[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy]-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione		C₃₈H₆₉NO₁₃	详情	详情
(II)	55084	(3R,4S,5R,6R,7R,9R,11S,12R,13S,14R)-6-{[(3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-14-ethyl-12,13-dihydroxy-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-7-methoxy-3,5,7,9,11,13-hexamethyl-2,10-oxacyclotetradecanedione 10-oxime		C₃₈H₇₀N₂O₁₃	详情	详情
(III)	55085	(2R,3S,4R,5R,8R,10R,11R,12R,13S,14R)-11-{[(3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-3,4-dihydroxy-13-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-10-methoxy-3,5,8,10,12,14-hexamethyl-1-oxa-7-azacyclopentadecane-6,15-dione		C₃₈H₇₀N₂O₁₃	详情	详情
(IV)	55086	(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-{[(3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-3,4,13-trihydroxy-10-methoxy-3,5,8,10,12,14-hexamethyl-1-oxa-7-azacyclopentadecane-6,15-dione		C₃₀H₅₆N₂O₁₀	详情	详情
(V)	55087	(3R,4S,6R)-4-(dimethylamino)-2-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,13-trihydroxy-10-methoxy-3,5,8,10,12,14-hexamethyl-6,15-dioxo-1-oxa-7-azacyclopentadecan-11-yl]oxy}-6-methyltetrahydro-2H-pyran-3-yl acetate		C₃₂H₅₈N₂O₁₁	详情	详情
(VI)	30305	2-(4-nitrophenyl)acetic acid	104-03-0	C₈H₇NO₄	详情	详情
(VII)	55089	(2R,3S,4R,5R,8R,10R,11R,12R,13S,14R)-11-{[(3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl]oxy}-2-ethyl-3,4-dihydroxy-10-methoxy-3,5,8,10,12,14-hexamethyl-6,15-dioxo-1-oxa-7-azacyclopentadecan-13-yl 2-(4-nitrophenyl)acetate		C₄₀H₆₃N₃O₁₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(X)

Coupling of p-nitrophenylacetic acid (IX) with p-toluenesulfonamide (X) using CDI provided the N-acyl sulfonamide (XI). The nitro group of (XI) was then reduced by catalytic hydrogenation to furnish aniline (XII). Reductive condensation of aniline (XII) with aldehyde (VIII) in the presence of NaBH(OAc)3 gave rise to amine (XIII). Finally, simultaneous removal of the O-silyl and N-Boc protecting groups of (XIII) was accomplished by treatment with 4 N aqueous HCl.

参考文献中间体

合成目标

【1】 Uehling, D.E.; Donaldson, K.H.; Deaton, D.N.; Hyman, C.E.; Sugg, E.E.; Barret, D.G.; Hughes, R.G.; Reitter, B.; Adkison, K.K.; Lancaster, M.E.; Lee, F.; Hart, R.; Paulik, M.A.; Sherman, B.W.; True, T.; Cowan, C.; Synthesis and evaluation of potent and selective beta3 adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres. J Med Chem 2002, 45, 3, 567.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	59936	tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl[(1R)-1-methyl-2-oxoethyl]carbamate		C₂₂H₃₆ClNO₄Si	详情	详情
(IX)	59937	4-methylbenzenesulfonamide	70-55-3	C₇H₉NO₂S	详情	详情
(X)	30305	2-(4-nitrophenyl)acetic acid	104-03-0	C₈H₇NO₄	详情	详情
(XI)	59938	4-methyl-N-[2-(4-nitrophenyl)acetyl]benzenesulfonamide		C₁₅H₁₄N₂O₅S	详情	详情
(XII)	59939	N-[2-(4-aminophenyl)acetyl]-4-methylbenzenesulfonamide		C₁₅H₁₆N₂O₃S	详情	详情
(XIII)	59940	tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl{(1R)-1-methyl-2-[4-(2-{[(4-methylphenyl)sulfonyl]amino}-2-oxoethyl)anilino]ethyl}carbamate		C₃₇H₅₂ClN₃O₆SSi	详情	详情

Extended Information