3-(Carbamoylmethyl)-5-methylhexanoic acid

70 g of 3-isobutylglutaric acid dry product and 70 g of acetic anhydride at 120 temperature reaction 2h, To give 3-isobutylglutaric anhydride.The solution of 3-isobutylglutaric anhydride (75 g) was then slowly added dropwise to 180 g of aqueous ammonia, The control temperature is 10 ° C.3-isobutyl glutaric anhydride added, continue to react 2h.Finally, the pH of the solution was adjusted to 2 to 3 with hydrochloric acid and filtered to obtain a white powder solid, That is, the final product 3-isobutyl glutaric acid monoamide, liquid content of 99.8percentThe yield was 95percent, the overall yield was 77.5percentFigure 4 is a liquid phase detection of 3-isobutylglutaric acid monoamide.Example: 5(+/-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid IIII An aqueous solution of ammonia (1.486 litre) was added to a solution of the anhydride VIII (667 g, 3.919 mole) in ferf-butyl methyl ether (901 ml) at 0 °C. The reaction mixture was allowed to warm to room temperature, and stirred at this temperature until the reaction was complete as indicated by TLC.The aqueous layer was washed with terf-butyl methyl ether (3 To a four-necked flask was added 100 g of 3-isobutylglutaric acid, 400 mL of xylene and 40 g of urea, and the mixture was heated to 130 ° C with stirring. The mixture was heated at reflux for 3 hours and cooled to 80 ° C. , Continue to cool to 40 ° C, the pH of the ion-exchange membrane pH = 12, keep the lh, keep the organic layer, add water to the aqueous solution ρH- = 1.0, ethyl acetate (350mL + 150mL) extraction 2 The ethyl acetate layer was combined and 280 mL of ethyl acetate was distilled off under reduced pressure. The crystals were cooled to 5 ° C and incubated for 1 h. The mixture was filtered and dried to give 3-isobutylglutaric acid monoamide, weighing: 93.0 g Rate: 93.5percent, purity 98.8percent.Example: 6(+/-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid II IITriethylamine (20 ml) was added to a solution of the acid XII (41 g, 119.73 mmole) in acetone (205Step 1: Chloroform (43.12 mL) and ethanol (0.358 mL) were added to 3-Isobutyl glutarimide (3.58 g-21.16 mmol) was dissolved in 18.4 mL of 2 M sodium hydroxide (NaOH) solution in the temperature of 65 C for 35 min. The reaction mixture was cooled to 0-5 C and then it was acidified with concentrated HCl until adjusting pH 1-2; the white solid was obtained which was filtered and washed with cold water and dried at 55 C. The solid was dried at 55 C to give a white solid 3.13 g (yield: 79%). m.p 106-108 C (reference:106-108 C) [20]. FT-IR (KBr): 3366, 3223 (N-H), 2961, 2923, 2880, 2797 (C-H), 1704 (C=O), 1668, 1585.2(C=O), 1461.8 (C-N), 1294.0, 1278.6 (C-O), 1241.9, 1214.9, 1133.9, 1010.5, 700.0, 655.7, 592.0, cm-1. 1H NMR (DMSO-d6, 400 MHz) delta ppm: 0.82 (d, J = 7.8 Hz, 6H), 1.09(t, J = 6.6 Hz 2H), 1.56-1.63 (m, 1H), 1.96-2.5 (m, 5H), 6.76 (s, 1H), 7.30 (s, 1H), 12.03(s, 1H).Under ice-water bath, 1.560g (-) - menthol, 1.928g EDC, 60ml of dichloromethane, 1.870g (±)-3-carbamoylmethyl -5-methylhexanoic acid and 1.222g DMAP were added to 250 ml eggplant-shaped flask, stirred at room temperature overnight. Workup: 140ml of dichloromethane was added to the reaction system, and then washed with 3 * 20ml water, the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. Testing chromatography of the crude product liquid see Figure 1. Using preparative liquid chromatography on the crude esterification reaction product obtained in was separated and purified, respectively, to give 1.436g (4a) and 1.416g (4b), total 87.8% yield.Racemic Example: 6(+/-)-3-(Carbamoylmethyl)-5-methylhexanoic Acid II IITriethylamine (20 ml) was added to a solution of the acid XII (41 g, 119.73 mmole) in acetone (205' ml) at - 20 C under an atmosphere of nitrogen. A solution of ethyl chloroformate (12.4 ml) in acetone (164 ml) was then added and the reaction mixture was maintained for 0.5 h to 1 h at this temperature. A solution of aqueous ammonia (120 ml) was added to the reaction mixture at - 20 C and the reaction mixture was stirred for 2 h at this temperature when the reaction was complete as indicated from TLC. The reaction mixture was allowed to warm to room temperature and concentrated to furnish an oily residue. The crude residue was cooled to 0 C, and an aqueous solution of sodium hydroxide was added at this temperature. The reaction mixture was stirred until the reaction was complete as indicated from the TLC.The reaction mixture was washed with terf-butyl methyl ether (3 chi 50 ml). The aqueous layer was acidified with concentrated hydrochloric acid until the pH attained 1 , and extracted with ethyl acetate (5 * 50 ml). The organic layer was concentrated under reduced pressure to give the amide II; yield 13 g, 58%.

Used as an intermediate for pregabalin synthesis.

Molecular Weight:187.24
XLogP3:0.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:6
Exact Mass:187.12084340
Monoisotopic Mass:187.12084340
Topological Polar Surface Area:80.4
Heavy Atom Count:13
Complexity:189
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes