tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 1 L, 2-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 g, 38.31 mmol, 1.00 equiv), tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (15.4 g, 76.52 mmol, 2.00 equiv), PPh3 (20.1 g, 76.63 mmol, 2.00 equiv), and N,N-dimethylformamide (400 mL). DIAD (15.5 g, 76.65 mmol, 2.00 equiv) was added dropwise over 30 min. The resulting solution was stirred for 12 h at 25° C. and then diluted with 1 L of water. The resulting solution was extracted with ethyl acetate and the organic layers combined and washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum and the residue was placed on a silica gel column and eluted with chloroform/methanol (100/1) to give 1.2 g (6%) of tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a off-white solid. Into a 1 L, 2-necked round-bottom flask purged maintained under an inert atmosphere of nitrogen The resulting solution was extracted with ethyl acetate washed with brine The mixture was dried over anhydrous sodium sulfate concentrated under vacuum eluted with chloroform/methanol (100/1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 100-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), prepared as described in Example 1 except in the Mitsunobu reaction using (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate instead of (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (254 mg, 0.81 mmol, 1.20 equiv), tetrakis(triphenylphosphane)palladium (47 mg, 0.04 mmol, 0.06 equiv), ethylene glycol dimethyl ether (50 mL), sodium carbonate (180 mg, 1.70 mmol, 2.50 equiv), and water (10 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum and extracted with dichloromethane. The organic layers were combined, dried and concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane/methanol (50/1) to give 0.27 g (79%) of tert-butyl (2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a brown solid. Into a 100-mL 3-necked round-bottom flask purged maintained under an inert atmosphere of nitrogen prepared as described in Example 1 except in the Mitsunobu reaction The resulting mixture was concentrated under vacuum extracted with dichloromethane dried concentrated under vacuum eluted with dichloromethane/methanol (50/1)

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

Procedure: (R)-N-Boc-2-Formyl-pyrrolidine was prepared by Swern oxidation of (R)-N-Boc prolinol (Fluka) using the procedure for the oxidation of CBZ-prolinol described by of M. G. B. Drew et al. supra.

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

Procedure: (R)-N-Boc-2-Formyl-pyrrolidine was prepared by Swern oxidation of (R)-N-Boc prolinol (Fluka) using the procedure for the oxidation of CBZ-prolinol described by of M. G. B. Drew et al. supra.

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a water cooled (25° C.) solution of 10.0 g of (R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester in 250 ml of dry methylene chloride is added in one portion 16.0 g of pyridinium chlorochromate, 36.0 g of dried, crushed 4Å molecular sieves and 4.5 ml of glacial acetic acid. The resulting mixture is stirred at 25° C. for one hour. Twenty-five grams of diatomaceous earth and 500 ml of diethyl ether is added, the suspension is filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo. The residue is dissolved in diethyl ether and is passed through a short column of silica gel using diethyl ether as the eluant. The first two 500 ml fractions contain the desired aldehyde. The solvent is concentrated in vacuo to give 10.1 g of desired product. 36.0 g of dried crushed 4Å molecular sieves and 4.5 ml of glacial acetic acid Twenty-five grams of diatomaceous earth and 500 ml of diethyl ether is added the suspension is filtered through a pad of diatomaceous earth the filtrate concentrated in vacuo The residue is dissolved in diethyl ether The solvent is concentrated in vacuo

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

Procedure: In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a.

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

Procedure: In accordance with Scheme I, N-α-t-BOC-D-proline 2a is reacted in an ether solvent such as tetrahydrofuran at a temperature ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex to produce (R)-2-(hydroxymethyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 3a. Compound 3a in a chlorinated hydrocarbon solvent such as methylene chloride is treated with an oxidizing agent such as pyridinium chlorochromate, 4Å molecular sieves and glacial acetic acid to give (R)-2-formyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester 4a. Compound 4a in methylene chloride is treated with a methylene chloride solution of triphenylphosphine and carbon tetrabromide to produce (R)-2-(2,2-dibromoethenyl)-1pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 5a. The dibromo compound 5a in an ether solvent such as tetrahydrofuran is reacted at -78° C. with an alkyl lithium reagent such as sec-butyllithium to give (R)-2-ethynyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester 6a. ranging from -2° C. to the reflux temperature of the solvent with 10M borane-methyl sulfide complex

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Oxalyl chloride (9.0 mL, 100 mmol) was added to a solution of DMSO (10.5 mL, 150 mmol) in 80 mL of CH2Cl2 at −78° C., under a nitrogen atmosphere. The solution was stirred for 20 min at −78° C., tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (9.9 g, 49 mmol) was added, and the resultant solution stirred at −78° C. for 20 min. Triethylamine (28 mL, 200 mmol) was added to the reaction solution, the dry ice-acetone bath was removed, and the resultant solution was allowed to stir for two hours, slowly warming to ambient temperature. The reaction solution was quenched with brine, the phases were separated, and the organic phase was washed with 1 M KH2PO4 and saturated NaHCO3. The organic solution was then dried over Na2SO4, filtered, and concentrated to an orange oil. This oil was then dissolved in heptane, filtered through a plug of silica gel eluting with heptane, and the filtrate was concentrated to yield tert-butyl (2R)-2-formylpyrrolidine-1-carboxylate (7.87 g). the dry ice-acetone bath was removed to stir for two hours slowly warming to ambient temperature The reaction solution was quenched with brine the phases were separated the organic phase was washed with 1 M KH2PO4 and saturated NaHCO3 The organic solution was then dried over Na2SO4 filtered concentrated to an orange oil This oil was then dissolved in heptane filtered through a plug of silica gel eluting with heptane the filtrate was concentrated

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of Boc-D-prolinol (201 mg, 1.0 mmol), p-toluenesulfonyl chloride (400 mg, 2.1 mmol), triethylamine (420 μL, 3.0 mmol), and 4-(dimethylamino)pyridine (12 mg, 0.1 mmol) in dichloromethane (10 mL) was heated at 40° C. for 48 hours, cooled to room temperature, concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel to provide 160 mg (45%) of the desired product. cooled to room temperature concentrated under vacuum diluted with ethyl acetate washed with water and brine dried (MgSO4) filtered concentrated The residue was purified by column chromatography on silica gel

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of Boc-D-prolinol (201 mg, 1.0 mmol), p-toluenesulfonyl chloride (400 mg, 2.1 mmol), triethylamine (420 μL, 3.0 mmol), and 4-(dimethylamino)pyridine (12 mg, 0.1 mmol) in dichloromethane (10 mL) was heated at 40° C. for 48 hours, cooled to room temperature, concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel to provide 160 mg (45%) of the desired product. cooled to room temperature concentrated under vacuum diluted with ethyl acetate washed with water and brine dried (MgSO4) filtered concentrated The residue was purified by column chromatography on silica gel

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

Procedure: (R)-N-Boc-2-Formyl-pyrrolidine was prepared by Swern oxidation of (R)-N-Boc prolinol (Fluka) using the procedure for the oxidation of CBZ-prolinol described by of M. G. B. Drew et al. supra.

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

Procedure: Methanesulfonyl chloride (0.06 mL, 0.77 mmol) was added to a solution of (R)-N-Boc-pyrrolidine-2-methanol (125.3 mg, 0.62 mmol) and triethylamine (0.22 mL, 1.6 mmol) in dichloromethane at 0° C. under argon. After stirring for 1 h, the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL). The organic layer was sequentially washed with water (15 mL) and brine (15 mL), dried over anhydrous sodium sulfate and the solvent was removed in vacuo to yield (R)-N-Boc-pyrrolidine-2-methanol methanesulfonate, which was used crude. the reaction mixture was partitioned between dichloromethane (50 mL) and sodium hydrogen sulfate (15 mL) The organic layer was sequentially washed with water (15 mL) and brine (15 mL) dried over anhydrous sodium sulfate the solvent was removed in vacuo