tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a sealed tube was added 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (507 mg, 1.07 mmol), tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (0.2, mL, 1.1 mmol), piperidine (0.05 mL, 0.54 mmol) and ethanol (3 mL). The tube was capped and heated to 100° C. for 16 hrs. The reaction was not complete so an additional amount of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (732 mg, 3 eq) was added and heating was continued for 4 hrs at 110° C. The reaction was cooled and concentrated then dissolved in DCM (50 mL) and washed with water (50 mL) and brine. The organic layer was dried (MgSO4), filtered and concentrated. The resulting material was purified by Isolera (250 g column; 2%-3% MeOH/DCM) to provide 403 mg (57%) of tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate as a solid. The tube was capped was added heating The reaction was cooled concentrated then dissolved in DCM (50 mL) washed with water (50 mL) and brine The organic layer was dried (MgSO4) filtered concentrated The resulting material was purified by Isolera (250 g column; 2%-3% MeOH/DCM)

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

Procedure: (S)-N-Boc-2-Ethynyl-pyrrolidine was prepared according to Method X above by the treatment of (S)-N-Boc-2-formyl-pyrrolidine (470 mg, 2.36 mmol) (Example 87A above) with potassium tert-butoxide (340 mg, 3.07 mmol) and diazomethyl-phosphonic-acid-diethylester (550 mg, 3.07 mmol) (also prepared according to Method X). The product was obtained after silica gel column chromatography with 10% Et2O in hexanes. (Yield 200 mg, 43%). also prepared

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

Procedure: (S)-N-Boc-2-Formyl-pyrrolidine was prepared by Swern oxidation of (S)-N-Boc prolinol (Fluka) according to the conditions described by M. G. B. Drew et al., J. Chem. Soc. Perkin 1, 1998, 1627, for the oxidation of CBZ-prolinol.

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

Procedure: (S)-N-Boc-2-Ethynyl-pyrrolidine was prepared according to Method X above by the treatment of (S)-N-Boc-2-formyl-pyrrolidine (470 mg, 2.36 mmol) (Example 87A above) with potassium tert-butoxide (340 mg, 3.07 mmol) and diazomethyl-phosphonic-acid-diethylester (550 mg, 3.07 mmol) (also prepared according to Method X). The product was obtained after silica gel coloumn chromatography with 10% Et2O in hexanes. (Yield 200 mg, 43%). also prepared

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

Procedure: (S)-N-Boc-2-Formyl-pyrrolidine was prepared by Swern oxidation of (S)-N-Boc prolinol (Fluka) according to the conditions described by M. G. B. Drew et al., J. Chem. Soc. Perkin 1, 1998, 1627, for the oxidation of CBZ-prolinol.

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

Procedure: Following the procedure of Example 3, 6.8 g of (S)-2-formyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester in 20 ml of methylene chloride is reacted with 40 g of triphenylphosphine, 26 g of carbon tetrabromide in 700 ml of methylene chloride to give 5.8 g of the desired product as a colorless solid, mp 58°-59° C., [α]D26° =+24°±1 (C=1.048%, methylene chloride).

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

Procedure: Following the procedure of Example 2, 16.0 g of pyridinium chlorochromate, 10.0 g of (S)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, 36.0 g of crushed 4Å molecular sieves and 4.5 ml of glacial acetic acid in 250 ml of methylene chloride gives 6.8 g of the product as a yellow oil.

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

Procedure: To a stirred cold (minus 50° C.) solution of N-boc-prolinal (5.98 g, 30 mmol) and PPh3 (62.95 g, 240 mmol) in CH2Cl2 (200 mL) was slowly added a solution of CBr4 (39.80 g, 120 mmol) in CH2Cl2 (50 mL), and the stirring was continued for 1 hr at 0° C. To this mixture was added sat. NaHCO3 and the mixture was extracted with CHCl3. The extract was washed with H2O, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with CHCl3 and n-hexane-AcOEt (4:1, v/v) as eluent to give 7.84 g (74%) 1-(tert-butoxycarbonyl)-2-(2,2-dibromoethenyl)pyrrolidine as colorless plates. mp 61-63; IR (KBr) 1693 cm−1; 1H-NMR (CDCl3) δ1.46 (9 H, s), 1.72-2.19 (4H, m), 3.35-3.45 (2H, m),4.35 (1H, br s), 6.36 (1H, br s); MS (FAB) m/z 352, 354, 356, 358; Anal. Calcd. for C11H17NO2Br2: C, 37.21; H 4.83; N, 3.94. Found: C, 37.14; H, 4.83; N, 4.00. the mixture was extracted with CHCl3 The extract was washed with H2O dried over MgSO4 evaporated The residue was chromatographed on silica-gel with CHCl3 and n-hexane-AcOEt (4:1

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

Procedure: To a stirred cold (minus 50°) solution of N-boc-prolinal (5.98 g, 30 mmol) and PPh3 (62.95 g, 240 mmol) in CH2Cl2 (200 mL) was slowly added a solution of CBr4 (39.80 g, 120 mmol) in CH2Cl2 (50 mL), and the stirring was continued for 1 hr at 0° C. To this mixture was added sat. NaHCO3 and the mixture was extracted with CHCl3. The extract was washed with H2O, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with CHCl3 and n-hexane-AcOEt (4:1, v/v) as eluent to give 7.84 g (74%) 1-(tert-butoxycarbonyl)-2-(2,2-dibromoethenyl) pyrrolidine as colorless plates. mp 61–63; IR (KBr) 1693 cm−1; 1H-NMR (CDCl3) δ 1.46 (9 H, s), 1.72–2.19 (4H, m), 3.35–3.45 (2H, m), 4.35 (1H, br s), 6.36 (1H, br s); MS (FAB) m/z 352, 354, 356, 358; Anal. Calcd for C11H17NO2Br2: C, 37.21; H, 4.83; N, 3.94. Found: C, 37.14; H, 4.83; N, 4.00. the mixture was extracted with CHCl3 The extract was washed with H2O dried over MgSO4 evaporated The residue was chromatographed on silica-gel with CHCl3 and n-hexane-AcOEt (4:1

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

Procedure: The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol (0.8 ml). Then, the solution was added with trimethyl orthoformate (50 μl), acetic acid (50 μl), N-Boc-L-prolinal (manufactured by Aldrich Corporation) (25.7 mg) and stirred at room temperature for 10 minutes. Subsequently, sodium cyanoborohydride (24.4 mg) was added, followed by stirring overnight at room temperature. The solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by washing with 1 mol/l sodium hydroxide and saturated saline solution and drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol). Then, the purified product was dissolved in methanol (500 μl) and added with a 4 mol/l hydrogen chloride/dioxane solution, followed by stirring at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining hydrochloride (20.5 mg) of the subject compound as a pale brown solid. by stirring overnight at room temperature The solvent was distilled off under reduced pressure the residue was then dissolved in chloroform by washing with 1 mol/l sodium hydroxide and saturated saline solution drying with anhydrous sodium sulfate After filtration the solvent was distilled off under reduced pressure the residue was then purified through silica gel column chromatography (chloroform/methanol) Then, the purified product was dissolved in methanol (500 μl) added with a 4 mol/l hydrogen chloride/dioxane solution by stirring at room temperature for 2 hours After completion of the reaction the solvent was distilled off under reduced pressure the residue was then purified through silica gel column chromatography (chloroform/methanol)

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

Procedure: 30.1 ml (60.2 mmol) 2 M isopropylmagnesium chloride (diethyl ether) and 4.0 g (20.1 mmol) BOC-L-prolinal were allowed to react at −80° C. for 30 min according to procedure F. Yield of the crude product 4.31 g. The product was purified with a silica column using 16% ethyl acetate in petroleum ether as eluent. Yield 1.84 g (7.6 mmol, 38%). The product was oxidized to the corresponding ketone according to procedure G. Yield of crude product 1.59 g. The product was purified with a silica column using 16% ethyl acetate in petroleum ether as eluent. Yield 1.15 g (4.8 mmol, 63%). to react at −80° C. for 30 min The product was purified with a silica column The product was purified with a silica column

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

Procedure: 25 ml (75 mmol) 3 M methylmagnesium chloride (diethyl ether) and 8.25 g (41.4 mmol) BOC-L-prolinal were allowed to react at −80° C. for 30 min according to procedure F. Yield of the crude product 9.19 g. The product was purified with a silica column using 33% ethyl acetate in petroleum ether as eluent. Yield 7.54 g (35.0 mmol 85%). The product was oxidized to the corresponding ketone according to procedure G. Yield of crude product 6.91 g. The product was purified with a silica column using 20–25% ethyl acetate in petroleum ether as eluent. Yield 5.61 g (26.3 mmol, 75%). to react at −80° C. for 30 min The product was purified with a silica column The product was purified with a silica column