METHYL3-OXOCYCLOBUTANECARBOXYLATE

Concentrated sulfuric acid (0.2 mL) was added dropwise to a solution of 3-oxocyclobutanecarboxylic acid (1 g, 8.77 mmol) in methanol, and the mixture was refluxed at 75°C. A mixture of 3-oxocyclobutanecarboxylic acid (50 g, 438 mmol), methanol (17.75 mL; 438 mmol), 4-ΛTo a solution of 3-oxocyclobutanecarboxylic acid (20.1 g, 176 mmol) in MeOH (500mL) was added H2S04 aqueous solution (9.5 mL, 17.48 mmol, 1.84 M). The mixture was stirredat 75 oc overnight and concentrated in vacuo. The residue was adjusted to pH= 10 withsaturated NaHC03 aqueous solution, the resulting solution was extracted with DCM (200 mL x3). The combined organic layers were washed with brine (100 mL) and dried over anhydrousNa2S04, filtered and then concentrated in vacuo to give the title compound as yellow oil (20.8 g, yield 92.2percent).1HNMR (400 MHz, CDCh) 8 (ppm): 3.76(s, 3H), 3.46-3.36 (m, 2H), 3.33-3.20 (m, 3H).Steps 3: synthesis of methyl 3-oxocyclobutylcarboxylate 0C and stirring, SOCl2 (3.1mL, 0.045mol, 0.5eq.) Was slowly added dropwise to 3-oxo-cyclobutane carboxylic acid (10.0g, 0.09mol) inCH3OH (50mL) solution and the reaction mixture was refluxed for 4.0h. After the reaction, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel chromatography (eluent:PE / EtOAc (V / V) = 10/1) to give the title compound as a colorless oil (10.0g, 90percent).0° C and, SOCl 2 (3.1ml, 0.045mol) was slowly added dropwise 3-oxo-cyclobutane-carboxylic acid (1-1) (10.0g, 0.088mol) in CH 3 OH (50ml) , , Solution addition was complete, the reaction was refluxed of 4.0h, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent: PE: EtOAc (V: V) = 10: 1) to give colorless, oily liquid (10.0g, 90percent).The 3-oxo-cyclobutane carboxylic acid (25.0g, 0.220mmol), methanol (14mL) and N, N- dimethyl-4-aminopyridine (3.00g, 353mmol) was dissolved in methylene chloride (a 500 mL) , at 25 °C with stirring, slowly added dropwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (64.0g, 340mmol), stirred overnight. The reaction was washed with aqueous hydrochloric acid (1.5N, 72mL), water (150mLx2) and saturated brine (75mLx2) and washed. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the product 3-oxo-cyclobutanoic acid methyl ester (25g, yellow liquid). Yield: 89percentIn a 100 mL round bottom flask was added 3-oxocaproic acid (10.0 g, 0.088 mol, 1. Oeq)Of methanol(50 mL)0 & gt; C, thionyl chloride (3. lmL, 0.045mOl, 0.5 eq) was slowly added dropwise with stirring at 0 &. After the addition was complete, the reaction solution was refluxed for 4.0 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:? /? 89percent.47A. Methyl 3-oxocyclobutanecarboxylate [00209] To a mixture of 3-oxocyclobutanecarboxylic acid (2.5 g, 21.9 mmol), EDC (6.3 g, 32.9 mmol) and DMAP (0.27 g, 2.19 mmol) in DCM (100 mL) was added MeOH (0.98 mL, 24.1 mmol). The mixture was stirred at rt overnight, then was concentrated in vacuo to give a crude oil, which was chromatographed (SiC^; 80 g; continuous gradient from 0 to 25percent Solvent B over 30 min, hold at 25percent Solvent B for 10 min, where Solvent A = Hexanes and Solvent B = 10percent EtOAc) to give the title compound (2.41 g, 18.81 mmol, 86percent yield) as a colorless oil. To a stirring solution of29.4 (65g, 0.57 mol) inCH30H (650 ml)at 0°C was added dropwiseSOCb (65 ml)and the reactionwas stirred with warming to rt for15 hr. The solvent was removed under reduced pressure, and the residue was dilutedwith water (200 ml), and extractedwith DCM (3 x 200 ml). The combinedorganic layers were dried, filtered and concentrated under reduced pressure to give a crude, which was purified by flash15 chromatography (silicagel/ PE/EA 20: 1 to 50:1) to yield compound29.5 (50 g, 83percent) as a yellow oil.A solution of N, N'-dicyclohexylcarbodiimide (7.17 g, 0.0347 mol) in methylene chloride (8 mL, 0.1 mol) was added dropwise to a stirred mixture of 3-oxocyclobutanecarboxylic acid (3.6 g, 0.032 mol), methanol (2.6 mL, 0.063 mol) and 4-dimethylaminopyridine (3.08 g, 0.0252 mol) in methylene chloride (20 mL, 0.2 mol). To a stirring solution of 3-oxocycobutanecarboxyiio acid {27 ) (15 gA mixture of 3-oxocyclobutanecarboxylic acid (10.0 g), MeOH (3.6 mL), DMAP (1.1 g) and EDO (25.2 g) in DCM (100 mL) was stirred at 25°C for 18 hours. The mixture was washed with water (8x200 mL). The combined aqueous phases were extracted with DCM (3x300 mL).The combined organ ics were dried, filtered and concentrated to methyl 3- oxocyclobutanecarboxylate (10.0 g).To a solution of 3-oxocyclobutanecarboxylic acid (10.0 g, 0.088 mol) in methanol (50 mL) at 0 ° C was slowly added dropwise a solution of SOClTo a solution of oxalyl chloride (5.25 mL, 60.0 mmol) in DCM (200 ml) at -78° C. was added DMSO (7.10 mL, 100 mmol). To a solution of 3-oxocyclobutanecarboxylic acid (20.1 g, 176 mmol) in methanol (500 mL) was added aqueous H2SO4 (9.5 mL, 17.48 mmol, 1.84 M).The reaction system was heated to 75 ° C, Stir overnight, After the reaction, Concentrated under reduced pressure.The resulting residue was adjusted to pH = 10 with saturated aqueous sodium bicarbonate solution, The mixture was extracted with DCM (200 mL x 3).The combined organic phases were washed with saturated brine (100 mL)Then dried over anhydrous sodium sulfate, filter, Concentration under reduced pressure gave the title compound as a yellow oil (20.8 g, yield 92.2percent).Step A - Synthesis of Intermediate Compound 4b To a solution of compound 4a (4.0 g, 35.1 mmol) in DCM (50 ml) and MeOH (5 mL) was added TMSCH

Molecular Weight:128.13
XLogP3:-0.5
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:128.047344113
Monoisotopic Mass:128.047344113
Topological Polar Surface Area:43.4
Heavy Atom Count:9
Complexity:142
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes