* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With triethylamine In ethanol; dichloromethane at 0 - 20℃;
Example 214. Synthesis of 3-fluoro-2-(4-(3-((2S,4R)-4-hydroxy-2- (hydroxymethyl)pyro-lidin-l-yl)-lH-pyrazol-l-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-2-yl)benzonitrile, 1-214 Synthesis of compound 214.2. To a solution of 214.1 (5.0 g, 25.6mmol, l.Oeq) in DCM (50 niL) and ethanol (10 niL) was added Et3N (5.2 niL, 0.038 mmol, 1.5 eq) di-tert.butyl dicarbonate (032mmol, 1.2eq) at 0 °C. Reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction, mixture was transferred into water and extracted with DCM, combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure to obtained crude which was purified by column chromatography to furnish 214.2 . (6.1 g, 74.9 percent). MS(ES): m/z 260.12 [M+H]+.
Reference:
[1] Patent: WO2017/40757, 2017, A1, . Location in patent: Paragraph 00954-00955
[2] Tetrahedron Asymmetry, 2002, vol. 13, # 2, p. 167 - 172
[3] Angewandte Chemie - International Edition, 2009, vol. 48, # 10, p. 1784 - 1787
2
[ 41840-28-2 ]
[ 61478-25-9 ]
[ 37813-30-2 ]
Reference:
[1] Journal of Organic Chemistry, 1980, vol. 45, # 23, p. 4728 - 4739
3
[ 61478-25-9 ]
[ 61478-26-0 ]
Reference:
[1] Journal of Organic Chemistry, 1980, vol. 45, # 23, p. 4728 - 4739
With hydrogenchloride In water for 16h; Inert atmosphere; Reflux;
98%
With thionyl chloride for 5h; Heating;
98%
With thionyl chloride at 0℃; for 16.0833h; Heating / reflux;
1
Step 1: (2S, 4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid ethyl ester (2); Thionyl chloride (22.2 mL, 0.304 mol) was added dropwise to ethanol (92 mL) at 0°C. 4-Hydroxy-proline 1 or (10 g, 0.076 mol) was added portionwise to that solution at 0°C. The mixture was stirred at 0°C for 5 min and then refluxed for 16 hrs. After completion of the reaction, the solvent was evaporated. The obtained white solid was washed with ether and filtered to yield the titled compound as a white solid (14.70 g, 98 %). Used in the next step without further purification.
98%
With thionyl chloride
95%
With thionyl chloride at 0 - 80℃; for 8.25h;
Synthesis of (2S,4R)-ethyl 4-hydroxypyrrolidine-2-carboxylate (2)
To a suspension of trans-4-Hydroxy-L-proline (2.0 g, 1.0 mmol) in ethanol (20 V) was added dropwise thionyl chloride (0.438 Ml, 0.4 mmol). The resulting solution was stirred at 80 °C for 8 h. Reaction was monitored by TLC. Upon completion, reaction mixture was evaporated under reduced pressure at 40 °C to obtain the (2S,4R)-ethyl 4-hydroxypyrrolidine-2-carboxylate (2.3 g, Yield: 95%) [17, 18].
87%
Stage #1: ethanol With thionyl chloride at 10℃; for 0.25h;
Stage #2: 4R-4-hydroxyproline at 60℃; for 4h;
4.3.1. Esterification of amino-acids
General procedure: Thionyl chloride (7.71 mL, 76.2 mmol) was added droplet in cold (10 °C) ethanol (100mL), the solution was left at 10 °C for 15 min. The acid (38.1mmol) was added to the medium and the mixture was refluxed at 60 °C for 4 h. The reaction was followed with TLC and the plates revealed with ninhydrin. The medium was concentrated and the white crystals were dissolved in DCM, washed with NH4OH aq. The aqueous layer was extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated.
With hydrogenchloride
With hydrogenchloride for 8h; Ambient temperature; Yield given;
With triethylamine; In ethanol; dichloromethane; at 0 - 20℃;
Example 214. Synthesis of 3-fluoro-2-(4-(3-((2S,4R)-4-hydroxy-2- (hydroxymethyl)pyro-lidin-l-yl)-lH-pyrazol-l-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-2-yl)benzonitrile, 1-214 Synthesis of compound 214.2. To a solution of 214.1 (5.0 g, 25.6mmol, l.Oeq) in DCM (50 niL) and ethanol (10 niL) was added Et3N (5.2 niL, 0.038 mmol, 1.5 eq) di-tert.butyl dicarbonate (032mmol, 1.2eq) at 0 C. Reaction mixture was stirred at room temperature for 16 h. Upon completion of the reaction, mixture was transferred into water and extracted with DCM, combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure to obtained crude which was purified by column chromatography to furnish 214.2 . (6.1 g, 74.9 %). MS(ES): m/z 260.12 [M+H]+.
With triethylamine In dichloromethane at 25 - 30℃; for 4h;
General procedure for the synthesis of (2S,4R)-ethyl 1-benzyl-4-hydroxypyrrolidine-2-carboxylate (3a-c)
General procedure: To a stirred solution of (2S,4R)-ethyl 4-hydroxypyrrolidine-2-carboxylate (1.0 mmol) and substituted benzyl bromide (1.0 mmol) in DCM (20 V) was added triethylamine (2.0 mmol). After complete addition, the reaction mixture is stirred at room temperature for 4 h. Reaction was monitored by TLC. Upon complete conversion, reaction mixture was diluted with dichloromethane (10 V) and water (10 V). Organic layer was separated, the organic layer with brine was washed, dried over sodium sulfate, filtered and distilled off completely under reduced pressure to get the (2S,4R)-ethyl 1-benzyl-4-hydroxypyrrolidine-2-carboxylate (yield: 60-66%)