5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid

To a stirring solution of 1 (19.4 g, 100 mmol) in methanol (100 mL) and water (400 mL) was added 5N KOH solution (200mL). The reaction mixture was heated to refluxing and stirred for 3 h. Cooled to room temperature, the mixture was adjusted to pH 3 with 5N HCl, and then filtered. The precipitate was washed with water and dried in vacuo to give the title compound 2 (15.5 g, 94 percent) as an yellowish brown solid.5-Formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). 5-Formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). [0168] 5-Formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). The mixture was refluxed for 3 hours, cooled to room temperature and acidified with 6 N hydrochloric acid to pH 3. The solid was collected by filtration, washed with water and dried in a vacuum oven overnight to give 1.6 g (93percent) of 5-formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ 12.09 (s, br, 2H, NH COOH), 9.59 (s, 1H, CHO), 2.44 (s, 3H, CH3), 2.40 (s, 3H, CH3).Step (iv): Preparation of 5-formyl-2, 4-dimethyI-lH-pyrrole-3-carboxylic acid (V):Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition runnel and reflux condenser were charged 5-formyl-2, 4- dimethyl- lH-pyrrole-3-carboxylic acid ethyl ester (IV) (0.6 Kg; 3.09 mole), methanol (2.0 L) and aqueous KOH solution (prepared by dissolving 450 g KOH in 1.8 L of water), stirred well and raised the reaction mass temperature to 60-70° C and maintained for 4-6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the excess solvent was removed under diminished pressure and the resulting product was diluted with water and extracted with ethylacetate. The aqueous layer was separated and the pH adjusted to 4.0 with cone. HCl. The resulting solution was stirred over night at 25-30° C. The product was filtered and washed with water. The product was dried at 60° C. Dry Weight: 0.483 Kg Yield: 93.5percent HPLC purity: 99.8percentInto a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and reflux condenser were charged 5-formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (IV) (0.6 Kg; 3.09 mole), methanol (2.0 L) and aqueous KOH solution (prepared by dissolving 450 g KOH in 1.8 L of water), stirred well and raised the reaction mass temperature to 60-7024, 4-dimethyl-5-formyl -1H- pyrrole-3-carboxylate (0.9g, 4.6mmol) in methanol (5ml) was added sodium hydroxide (1.0g) in water (8ml) solution of was heated at reflux for 4h, cooled to room temperature, poured into ice water (16ml) was added methylene chloride (10ml), standing layer was collected and the aqueous layer was adjusted with 10percent hydrochloric acid, pH3, and the filter cake was washed with cold water, and dried to give a pale yellow solid 11 (0.71g, 92percent).To a three-necked flask equipped with a thermometer, ethyl 5-formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylate (9, 1.17 g, 6.0 mmol) and methanol (6.0 mL) were added with stirring, to which was added solution of sodium hydroxide (1.20 g) in water (10 mL). The reaction mixture was kept under reflux at 82-83 °C for 4.5 h under nitrogen atmosphere. The mixture was then cooled down to r.t. before being added into ice-water (20 mL). The obtained mixture was extracted with dichloromethane (12 mL). The organic layer was then washed with water (15 mL 9 3) until there was no absorption under ultraviolet (UV) light. The aqueous layers were combined before being acidified with hydrochloride (2.0 mol/L) to pH 2 until many precipitates appeared from the mixture. The yellowish solids were obtained via filtrating under vacuum, washing with water, and drying under vacuum to provide 3 (0.91 g, 91 percent), m.p. >250 °C (sublimes and decomposes) (lit. 275-277° C [13]), yield 90.0 percent (lit. [13]). RStep If. 5-Formyl-2, 4-dimethyl-lH-pyrrole-3-carboxylic acid (compound 108) A solution of KOH (6.2 g, 11 lmmol) in water (400 mL) was added to a solution of compound 507 (7.2 g, 37mmol) in ethanol (60 mL). The mixture was refluxed until the reaction was completed. The mixture was cooled to room temperature and the aqueous layer was extracted with dichloromethane. The aqueous layer was acidified to pH=2 with IN HCl. The precipitate was collected by filtration, washed with water and dried to give yellow solid product 108 (5.5 g, 89percent). LCMS: m/z 168(M+1), 2-formyl-3, 5-dimethylpyrrole-4-carboxylic acid4-ethoxycarbonyl-3, 5-dimethylpyrrole-2-carboxylic acid tert-Bu-ester 16.35g was dissolved in neat trifluoroacetic acid 85 mL and the solution was stirred at room temperature for 30 min (the mix turned Burgundy red with gas evolution), then cooled to +5 °C on ice/water bath. Neat triethyl orthoformate 16.5 mL (1.6 eq.) was added and the mix was stirred at +5 °C for 35 min, then concentrated on rotovap from ambient water bath to a small volume. The residue was diluted gradually with water addition, 300mL, the resulting slurry was shaken for 5 min and the precipitated ethyl ester intermediate was collected by filtration, washed thoroughly with water and dried by suction.This ethyl ester intermediate was suspended in ethanol 150 mL, placed on a120 °C oil bath and stirred to complete dissolution. A solution of KOH 20g (pellets, 85percent) in water 200mL was then added to the mix, the flask was equipped with a short- path distillation adaptor and the reaction mixture was distilled under a stream of nitrogen gas on a 120 °C oil bath for 90 min. (Only water distilled at this point and the ethyl ester hydrolysis was complete by HPLC). The reaction mixture was cooled, charcoal (5 spoons) was added and the reaction mix was then stirred on ambient water bath for 30 min, and filtered (the charcoal was thoroughly washed with water). The combined filtrates were acidified with addition of 6M HC1, the precipitated product was collected by filtration on a large Buchner funnel, washed with water and semi- dried by suction. The crude product was dissolved in EtOH (900mL) at reflux, the solution was allowed to crystallize at ambient temperature overnight (14 hours). The product was collected by filtration, washed with EtOH, dried by suction and on highvac. Concentrating the supernatants to a small volume, diluting the slurry with ethanol lOOmL and refluxing the mix for 30 min, then letting the mix to crystallize at RT overnight provided a second crop of a pure product. The combined yield was 8.32g (81percent overall) of a light-tan crystalline solid. 1H-NMR (dStep 3 5-Formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (2 g, 10 mmol) was added to a solution of potassium hydroxide (3 g, 53 mmol) dissolved in methanol (3 mL) and water (10 mL). Step 2 Step 2 Step 2

Molecular Weight:167.16
XLogP3:0.8
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:167.058243149
Monoisotopic Mass:167.058243149
Topological Polar Surface Area:70.2
Heavy Atom Count:12
Complexity:205
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes