(2R)-1-[(2-甲基丙烷-2-基)氧羰基]吡咯烷-2-羧酸

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 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

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Prepared as described in Example 83 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (37 mg, 0.17 mmol). Yield 31 mg (41%). Prepared

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4.82 g (19.5 mmol) of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ) are added to a suspension of 2.80 g (13.0 mmol) of N-Boc-D-proline and 1.66 g (13.0 mmol) of 4-chloroaniline in 50 ml of toluene, and the mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered, and petroleum ether is added to the filtrate. The precipitate formed is filtered off and dried, giving tert-butyl (R)-2-(4-chlorophenyl-carbamoyl)pyrrolidine-1-carboxylate as colourless crystals; ESI 325. The reaction mixture is filtered petroleum ether is added to the filtrate The precipitate formed is filtered off dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Triethylamine (0.2 g, 2 mmoles) was slowly added to a solution of (D-proline (0.23 g, 2 mmoles) and t-BOC-ON (0.5 g, 2 mmoles) in DMF (3 mL) at room temperature and the mixture stirred for 36 h. The DMF was coevaporated with toluene under vacuum. Aqueous hydrochloric acid (1×10-4M) (20 mL) and ethyl acetate (20 mL) were added to the flask to dissolve the residue. The organic layer was washed with water (3×20 mL) and brine (2×20 mL); dried (5 g of MgSO4) and evaporated under reduced pressure. The residue, containing the product, was chromatographed on 5 g of silica gel column (1×25 cm). Upon evaporation under reduced pressure a transparent oil was obtained. The oil was crystallized from ethyl acetate/diethyl ether to give 0.4 g (2 mmoles) (99% yield) of a crystalline powder, mp 133°-134° C. (lit.91 mp 132°-133° C.). 1H-NMR (CDCl3) δ 1.46(9Ha,s); 1.86-2.40(4Hb,m); 3.43-3.80(2Hc,m); 4.26-4.66(1Hd,m); 11.43(1He,s). IR (Nujol) 1740, 1635 cm-1. to dissolve the residue The organic layer was washed with water (3×20 mL) and brine (2×20 mL) dried (5 g of MgSO4) evaporated under reduced pressure The residue, containing the product was chromatographed on 5 g of silica gel column (1×25 cm) Upon evaporation under reduced pressure a transparent oil was obtained The oil was crystallized from ethyl acetate/diethyl ether

反应条件: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (R)-1-(tert-Butyloxycarbonyl)pyrrolidin-2-yl-carboxylic acid (9.7 g, 48 mmol) is dissolved in THF (250 mL) cooled to −30° C. and treated with NMM (5.75 mL, 52 mmol), isobutyl chloroformate (6.79 mL, 52 mmol) and stirred for 20 min. The reaction mixture is filtered and the filtrate is added to a solution of diazomethane (˜71 mmol) in ether (200 mL) at 0° C. The reaction mixture is stirred for 20 min. then quenched with acetic acid dropwise. The solvent is removed under vacuo and the residue is dissolved in methanol (100 mL) and treated with a solution of silver benzoate (2.18 g, 9.5 mmol) in triethylamine (21.4 mL) for 35 min. The reaction mixture is concentrated, diluted with ethyl acetate (600 mL) and washed with saturated sodium bicarbonate (3×150 mL), water (3×150 mL), potasium sulfite (3×150 mL) and brine. The organic layer is dried (MgSO4) and concentrated; flash chromatography gives the title compound as a clear oil (5.3 g, 21.8 mmol). 1H NMR (CDCl3, 300 MHz) □ 4.1(br.s., 1H), 3.66(s, 3H), 3.38-3.28(m, 2H), 2.92-2.80(m, 1H), 2.30(dd, 1H), 2.10-1.98(m, 1H), 1.90-1.65(m, 3H), 1.43(s, 9H). The reaction mixture is filtered The reaction mixture is stirred for 20 min. then quenched with acetic acid dropwise The solvent is removed under vacuo the residue is dissolved in methanol (100 mL) The reaction mixture is concentrated diluted with ethyl acetate (600 mL) washed with saturated sodium bicarbonate (3×150 mL), water (3×150 mL), potasium sulfite (3×150 mL) and brine The organic layer is dried (MgSO4) concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from 1-(tert-butoxycarbonyl)-D-proline (49 mg, 0.23 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 70 mg, 0.23 mmol, 1.0 equiv), EDC (66 mg, 0.34 mmol, 1.5 equiv) and HOAt (16 mg, 0.11 mmol, 0.5 equiv) in DMF (500 μl) essentially according to the procedure described in Example 26, Step C. Preparative reverse phase HPLC [gradient elution with 95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1 H), 8.11 (br s, 1 H), 7.54 (d, J=2.0 Hz, 1 H), 7.40 (dd, J=2.0, 8.4 Hz, 1 H), 7.23 (d, J=8.4 Hz, 1 H), 4.69–4.66 (m, 1 H), 4.43–4.39 (m, 1 H), 4.18–4.16 (m, 2 H), 4.04–3.99 (m, 1 H), 3.55–3.48 (m, 3 H), 2.27–1.88 (m, 8 H), 1.30 (s, 9 H). LCMS (M+H): 504.3. Preparative reverse phase HPLC [gradient elution with 95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN (+0.1% TFA)]

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from 1-(tert-butoxycarbonyl)-D-proline (49 mg, 0.23 mmol), N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 70 mg, 0.23 mmol, 1.0 equiv), EDC (66 mg, 0.34 mmol, 1.5 equiv) and HOAt (16 mg, 0.11 mmol, 0.5 equiv) in DMF (500 μl) essentially according to the procedure described in Example 26, Step C. Preparative reverse phase HPLC [gradient elution with 95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN (+0.1% TFA)] afforded the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1 H), 8.11 (br s, 1 H), 7.54 (d, J=2.0 Hz, 1 H), 7.40 (dd, J=2.0, 8.4 Hz, 1 H), 7.23 (d, J=8.4 Hz, 1 H), 4.69–4.66 (m, 1 H), 4.43–4.39 (m, 1 H), 4.18–4.16 (m, 2 H), 4.04–3.99 (m, 1 H), 3.55–3.48 (m, 3 H), 2.27–1.88 (m, 8 H), 1.30 (s, 9 H). LCMS (M+H): 504.3. Preparative reverse phase HPLC [gradient elution with 95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 5:95 water (+0.1% TFA)/CH3CN (+0.1% TFA)]

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 25.0 g of N-α-t-BOC-D-proline in 250 ml of tetrahydrofuran which is cooled to 0° C. is added dropwise 15 ml of 10M borane-methyl sulfide complex. The reaction is kept at around -20° C. during the addition followed by warming to room temperature and then is gently refluxed for one hour. The mixture is cooled to 0° C., 250 ml of methanol is added carefully and the reaction is evaporated in vacuo to give 23.3 g of a colorless oil which crystallizes on standing to a colorless solid, mp 50°-53° C., [α]D26° =+47°±1 (C=1.162%, methylene chloride). is added dropwise 15 ml of 10M borane-methyl sulfide complex The reaction is kept at around -20° C. during the addition is gently refluxed for one hour The mixture is cooled to 0° C. the reaction is evaporated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 25.0 g of N-α-t-BOC-D-proline in 250 ml of tetrahydrofuran which is cooled to 0° C. is added dropwise 15 ml of 10M borane-methyl sulfide complex. The reaction is kept at around -20° C. during the addition followed by warming to room temperature and then is gently refluxed for one hour. The mixture is cooled to 0° C., 250 ml of methanol is added carefully and the reaction is evaporated in vacuo to give 23.3 g of a colorless oil which crystallizes on standing to a colorless solid, mp 50°-53° C., [α]D26° =+47°±1 (C=1.162%, methylene chloride). is added dropwise 15 ml of 10M borane-methyl sulfide complex The reaction is kept at around -20° C. during the addition is gently refluxed for one hour The mixture is cooled to 0° C. the reaction is evaporated in vacuo

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 500 mL flask, N-Boc-D-Proline (300 mg, 1.39 mmol) was dissolved in dichloromethane (35 mL) and cooled to 0° C. under nitrogen. N-Methylmorpholine (153 μL, 1.39 mmol) was added followed by dropwise addition of iso-butyl chloroformate (180 μL, 1.39 mmol) and the reaction mixture stirred at 0° C. for 1 h. 2-Bromoaniline (1.31 mL, 1.39 mmol) was dissolved in dichloromethane (5 mL) then added quickly to the activated acid at 0° C. The mixture was stirred overnight from 0° C. to room temperature. The reaction mixture was diluted with dichloromethane, washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified on column chromatography (eluent: Pentane/EtOAc, 50/50 to 0/100 then EtOAc/MeOH 80/20) to give the product (394 mg, 77%) as a yellow oil. This product was used in the next step without further purification. then added quickly to the activated acid at 0° C The mixture was stirred overnight from 0° C. to room temperature washed with water dried over Na2SO4 concentrated under reduced pressure The crude mixture was purified on column chromatography (eluent

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a 500 mL flask, N-Boc-D-Proline (300 mg, 1.39 mmol) was dissolved in dichloromethane (35 mL) and cooled to 0° C. under nitrogen. N-Methylmorpholine (153 μL, 1.39 mmol) was added followed by dropwise addition of iso-butyl chloroformate (180 μL, 1.39 mmol) and the reaction mixture stirred at 0° C. for 1 h. 2-Bromoaniline (1.31 mL, 1.39 mmol) was dissolved in dichloromethane (5 mL) then added quickly to the activated acid at 0° C. The mixture was stirred overnight from 0° C. to room temperature. The reaction mixture was diluted with dichloromethane, washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was purified on column chromatography (eluent: Pentane/EtOAc, 50/50 to 0/100 then EtOAc/MeOH 80/20) to give the product (394 mg, 77%) as a yellow oil. This product was used in the next step without further purification. then added quickly to the activated acid at 0° C The mixture was stirred overnight from 0° C. to room temperature washed with water dried over Na2SO4 concentrated under reduced pressure The crude mixture was purified on column chromatography (eluent

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was prepared from N-BOC-(R)-proline according to the procedures of Examples 1a-c above. [α]D≤ +113.0 (c 0.94, MeOH).