(2,5-dioxopyrrolidin-1-yl) (4-methylphenyl)methyl carbonate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Disuccinimidyl carbonate (5.03 g, 19.65 mmol) in 30 mL MeCN and 30 mL DCM was treated with 4-methylbenzyl alcohol (2.4 g, 19.6 mmol) followed by DMAP (1.20 g, 9.82 mmol). The resulting cloudy reaction mixture was stirred overnight at rt, poured into 100 mL water, and partitioned. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated. The solid thus obtained was stirred with approx. 25 mL ether, filtered, and the resulting product was washed with a small volume of ether and dried. The resulting cloudy reaction mixture partitioned The organic layer was dried over anhydrous sodium sulfate the solvent evaporated The solid thus obtained filtered the resulting product was washed with a small volume of ether dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Disuccinimidyl carbonate (5.03 g, 19.65 mmol) in 30 mL MeCN and 30 mL DCM was treated with 4-methylbenzyl alcohol (2.4 g, 19.6 mmol) followed by DMAP (1.20 g, 9.82 mmol). The resulting cloudy reaction mixture was stirred overnight at rt, poured into 100 mL water, and partitioned. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated. The solid thus obtained was stirred with approx. 25 mL ether, filtered, and the resulting product was washed with a small volume of ether and dried. The resulting cloudy reaction mixture partitioned The organic layer was dried over anhydrous sodium sulfate the solvent evaporated The solid thus obtained filtered the resulting product was washed with a small volume of ether dried

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The above compound was prepared in a similar manner as described in EXAMPLE 130 from 4-[(3-methoxy-5-methyl-pyrazin-2-ylamino)-methyl]-piperidine (EXAMPLE 130, STEP 2) using N-(4-methylbenzyloxycarbonyloxy)succinimide (INTERMEDIATE 1A). M.S.(M+1): 385. The above compound was prepared in a similar manner

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-[(3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine (EXAMPLE 127, STEP 3) (0.093 g, 0.00042 mol) and N-(4-methylbenzyloxycarbonyloxy)succinimide (INTERMEDIATE 1A)(118 mg) in DMF (2 mL) was stirred at rt for 18 h. The reaction was diluted with ethyl acetate (30 mL), washed with 10% aqueous sodium bicarbonate (20 mL) followed by brine (10 mL), concentrated in vacuo and chromatographed on silica using a gradient elution of 5–15% acetone/dichloromethane. Concentration in vacuo followed by crystallization from ether/hexane gave the title compound. M.S.(M+1): 371. washed with 10% aqueous sodium bicarbonate (20 mL) concentrated in vacuo chromatographed on silica using a gradient elution of 5–15% acetone/dichloromethane Concentration in vacuo followed by crystallization from ether/hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from (4-cyclopropyl-phenyl)-methanol as described for similar compounds previously (Chem. Pharm. Bull., 38(1):110–115(1990) and INTERMEDIATE 1A).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of the 4-(pyridin-4-ylaminomethyl)-piperidin-3-ol from Step 2 above (0.076 g, 0.367 mmol) in DMF (1.5 mL) was treated with carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-methyl-benzyl ester (0.097 g, 0.37 mmol) (INTERMEDIATE 1A) and the resulting reaction mixture stirred at rt for 5 min. The mixture was then partitioned between dilute sodium carbonate solution and EtOAc. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a crude product. Purification by flash column chromatography (DCM to 80/20/2 DCM MeOH NH4OH) afforded the cis 3-hydroxy-4-(pyridin-4-ylaminomethyl)-piperidine-1-carboxylic acid 4-methyl-benzyl ester compound. M.S (M+1): 356. the resulting reaction mixture The mixture was then partitioned between dilute sodium carbonate solution and EtOAc The organic layer was washed with saturated sodium bicarbonate solution and brine dried over anhydrous sodium sulfate the solvent evaporated to give a crude product Purification by flash column chromatography (DCM to 80/20/2 DCM MeOH NH4OH)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Disuccinimidyl carbonate (5.03 g, 19.65 mmol) in 30 mL MeCN and 30 mL DCM was treated with 4-methylbenzyl alcohol (2.4 g, 19.6 mmol) followed by DMAP (1.20 g, 9.82 mmol). The resulting cloudy reaction mixture cleared over 2 min, stirred overnight at rt, then poured into 100 mL water and partitioned. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated. The solid thus obtained was stirred with approx. 25 mL ether, filtered, washed with a small volume of ether and dried to yield carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-methyl-benzyl ester as a white solid. Ref: Chem. Pharm. Bull., 38(1):110–115 (1990). The resulting cloudy reaction mixture partitioned The organic layer was dried over anhydrous sodium sulfate the solvent evaporated The solid thus obtained filtered washed with a small volume of ether dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The above compound was prepared in a similar manner as described in EXAMPLE 130 from 4-[(3-methoxy-5-methyl-pyrazin-2-ylamino)-methyl]-piperidine (EXAMPLE 130, STEP 2) using N-(4-methylbenzyloxycarbonyloxy)succinimide (INTERMEDIATE 1A). M.S. (m+1): 385. The above compound was prepared in a similar manner

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-[(3-methoxy-pyrazin-2-ylamino)-methyl]-piperidine (EXAMPLE 127, STEP 3) (0.093 g, 0.00042 mol) and N-(4-methylbenzyloxycarbonyloxy)succinimide (INTERMEDIATE 1A) (118 mg) in DMF (2 mL) was stirred at rt for 18 h. The reaction was diluted with ethyl acetate (30 mL), washed with 10% aqueous sodium bicarbonate (20 mL) followed by brine (10 mL), concentrated in vacuo and chromatographed on silica using a gradient elution of 5–15% acetone/dichloromethane. Concentration in vacuo followed by crystallization from ether/hexane gave the title compound. M.S. (M+1): 371. washed with 10% aqueous sodium bicarbonate (20 mL) concentrated in vacuo chromatographed on silica using a gradient elution of 5–15% acetone/dichloromethane Concentration in vacuo followed by crystallization from ether/hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from (4-cyclopropyl-phenyl)-methanol as described for similar compounds previously (Chem. Pharm. Bull., 38(1):110–115(1990) and INTERMEDIATE 1A).