1-tert-Butyl 2-methyl (2R)-4-oxopyrrolidine-1,2-dicarboxylate

Preparation 6 4-chloro-6-fluoropyrrolo[l, 2-b]pyridazine-3-carboxamideStep 1 : (R)- 1 -tert-butyl 2-methyl 4-oxopyrrolidine-l, 2-dicarboxylate[00179] To slurry of pyridinium dichromate (9.97 g, 26.5 mmol) indichloromethane (60 mL) at rt was added (2R, 4R)-1 -tert-butyl 2-methyl 4- hydroxypyrrolidine-l, 2-dicarboxylate (5.00 g, 20.39 mmol) in several portions. The resulting mixture was stirred overnight at rt. Celite (5g) was added and the mixture stirred for 40 min, filtered and the filter cake was rinsed with additionaldichloromethane (50 mL x 3). The resulting filtrate was concentrated and toluene (40 mL) was added followed by concentration again under vacuum to give ~ 6.5 g of a brown syrup as the crude product. Purification by flash silica gel chromatography (120g column, EtOAc in hexane, 0 to 100percent gradiant, 85 mL/min) afforded 4.18 g (84percent>) of the title compound as a white solid. LCMS (condition A): m/z 144 (M-Boc) -ve. To slurry of pyridinium dichromate (9.97 g, 26.5 mmol) indichloromethane (60 mL) at rt was added (2R, 4R)- 1 -tert-butyl 2-methyl 4- hydroxypyrrolidine-l, 2-dicarboxylate (5.00 g, 20.39 mmol) in several portions. The resulting mixture was stirred overnight at rt. Celite (5g) was added and the mixture stirred for 40 min, filtered and the filter cake was rinsed with additionaldichloromethane (50 mL x 3). The resulting filtrate was concentrated and toluene (40 mL) was added followed by concentration again under vacuum to give ~ 6.5 g of a brown syrup as the crude product. Purification by flash silica gel chromatography (120g column, EtOAc in Hexane, 0 to 100percent gradiant, 85 mL/min) afforded 4.18 g (84percent>) of the title compound as a white solid. LCMS (condition A): m/z 144 (M-Boc) -ve. Scheme 4. Step A: Stir a mixture of N-te^butyl-czAt room temperature, 3C (14.92 g, 60.87 mmol) was dissolved in dichloromethane (100 mL)Add to Martin in batches(51.63 mg, 121.73 mmol), The reaction was stirred at room temperature for 4 hours.After cooling to 0 ° C, the sodium bicarbonate solution was added dropwise to the reaction solution until no more bubbles were generated, and a white solid was precipitated.The reaction solution was filtered and the filter cake was washed with methyl tertiary butyl ether (50 mL x 3) and the filtrate was extracted with methyl tertiary butyl ether (30 mL x 2).The organic phase was washed with saturated sodium chloride solution (50 mL x 2), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give pale yellow liquid 3D (10.3 g, yield 59.8percent).Preparation of [1- (3, 4-DIMETHOXY-5-TRIFLUOROMETHYLTHIOBENZOYL)-4-ETHYNYL-2, 5-DIHYDRO-LH-] [PYRROLE-2R-CARBOXYLIC] acid hydroxyamide [100570]] Step 1: To a stirred solution of 4R-hydroxypyrrolidine-1, 2R-dicarboxylic acid 1- [TERT-BUTYL] ester 2-methyl ester [(30.] 4 g, 0.124 mol, 1.0 eq.; product from Step 2 of Example 90) in [CH2C12] [(800] mL) at [23°C, ] was added NaHCO3 (103 g, 1.23 mol, 10.0 eq. ), followed by Dess- Martin periodinane (61 g, 0.144 mol, 1. 16 eq. ). After being stirred at [23 °C] for 1 h, another batch of Dess-Martin periodinane (14 g, 0.033 mol, 0.27 eq. ) was added. After 3 h, the reaction mixture was quenched by addition of aqueous solution [OF NA2S203] and extracted with [CH2CL2] (3 x 300 mL). The combined organic layer was washed with brine, dried [(NA2S04)] and concentrated in [VACUUM.] The residue was chromatographed on silica gel (EtOAc/Hexane : [0percent-40percent)] to afford 4-oxopyrrolidine-1, 2R-dicarboxylic acid [1-TERT-BUTYL] ester 2-methyl ester (14.3 g, 48percent).(2S, 4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1 , 2-dicarboxylate (10 g, 40.8 mmol, 1.0 equiv) was suspended in DCM (Volume: 408 ml) and Dess-Martin periodinane (20.75 g, 48.9 mmol) was added in one portion. The reaction mixture was stirred at room temperature overnight and then diluted with water and DCM and filtered. The organic layer was separated and washed with water twice and dried (MgS04), filtered and concentrated in vacuo to afford the crude product which was purified by silica gel chromatography (0-20percent EtOAc/heptanes) to afford 9.92g of the desired product (R)-1- tert-butyl 2-methyl 4-oxopyrrolidine-1 , 2-dicarboxylate 32 which solidified upon standing. [M-C4H9+] = 188.1 , Rt = 0.65.

N-Boc-4-oxo-D-Proline methyl ester is a useful chemical reagent.

Molecular Weight:243.26
XLogP3:0.6
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:243.11067264
Monoisotopic Mass:243.11067264
Topological Polar Surface Area:72.9
Heavy Atom Count:17
Complexity:344
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes