ChemicalBook CAS DataBase List Indometacin

Indometacin synthesis

9synthesis methods

Product Name:Indometacin
CAS Number:53-86-1
Molecular formula:C19H16ClNO4
Molecular Weight:357.79

Indomethacin, 1-(n-chlorobenzoyl)-5-methoxy-2-methylindol-3-acetic acid (3.2.51), has been synthesized by various methods. All of the proposed methods of synthesis start with 4-methoxyphenylhydrazine. According to the first method, a reaction is done to make indole from phenylhydrazone (3.2.46) by Fischer’s method, using levulinic acid methyl ester as a carbonyl component, hydrogen chloride as a catalyst, and ethanol as a solvent, to give the methyl ester of 5-methoxy-2-methyl-3-indolylacetic acid (3.2.47). This product is hydrolyzed by an alkali into 5-methoxy-2-methyl-3-indolylacetic acid (3.2.48), from which tert-butyl ester of 5-methoxy-2-methyl-3-indolylacetic acid (3.2.49) is formed by using tert-butyl alcohol and zinc chloride in the presence of dicyclohexylcarbodiimide. The resulting product undergoes acylation at the indole nitrogen atom by p-chorobenzoyl chloride in dimethylformamide, using sodium hydride as a base. The resulting tert-butyl ester of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetic acid (3.2.50), further undergoes thermal decomposition to the desired acid, indomethacin (3.2.51) [111,112].

1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-Methoxy-2-Methyl-, ethyl ester

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Yield:53-86-1 657 mg

Reaction Conditions:

with lithium hydroxide monohydrate in water at 25; for 6 h;

Steps:

Indomethacin(10)

LiOH·H₂O(0.2 mmol,) in H₂O (0.5 mL) was added and continuously stirred for 6h at 25 °C followed by extraction of the organic phase with 2M aq. NH₃(2x0.1mL). The aqueous phase was washed withCH₂Cl₂(10 mL). Addition of conc. HCl (0.2 mL) resulted inprecipitation of the product which was filtered off and washed with water. Theproduct was dissolved in a mixture of MeOH/CH₂Cl₂ (1 mL),dried over Na₂SO₄. Filtration and evaporation of thesolvent afforded indomethacin (10;657mg).¹H NMR (400 MHz, CDCl₃)δ 7.68 - 7.63 (m, 2H), 7.50 - 7.44 (m, 2H), 6.95 (d, J = 2.5, 1H), 6.85(d, J = 9.0, 1H), 6.67 (dd, J = 9.0, 2.5, 1H), 3.83 (s, 3H), 3.70(s, 2H), 2.39 (s, 3H).¹³C NMR (101 MHz, CDCl₃)δ 176.22, 168.44, 156.23, 139.51, 136.42, 133.95, 131.35, 130.93, 130.60,129.30, 115.16, 111.94, 111.86, 101.39, 55.88, 30.05, 13.44.

References:

Gong, Tian-Jun;Cheng, Wan-Min;Su, Wei;Xiao, Bin;Fu, Yao [Tetrahedron Letters,2014,vol. 55,# 11,p. 1859 - 1862] Location in patent:supporting information