* 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.
Reference：
[1] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 8
[2] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9-10
[3] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
[4] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
[5] Patent: JP2005/112761, 2005, A, . Location in patent: Page/Page column 9
2
[ 117811-78-6 ]
[ 13504-86-4 ]
Yield
Reaction Conditions
Operation in experiment
90.2%
at 80℃; for 3 h;
708 g of water and 337 g of 48percent sodium hydroxide were added to 928 g of the crude product obtained in Reference Example 3, and the temperature was raised to 80 ° C., followed by reaction ripening for 3 hours. After completion of the aging, 146 g was distilled out under reduced pressure to 13 kPa under the same temperature condition. After concentration, the temperature was cooled to 20 ° C., 180 g of 48percent caustic soda was added, and aging was carried out at 25 ° C. for 12 hours. The content of cis-benzyloxycarbonyl-4-hydroxy-L-proline in the reaction solution was 2.19 mol (the yield based on trans-4-hydroxy-L-proline was 81.0percent). 35 g of toluene was added to the hydrolysis reaction solution, and the mixture was concentrated under reduced pressure at 7 kPa at 40 ° C. to distill off 332 g. To the concentrated solution, 161 g of concentrated sulfuric acid was added dropwise to adjust the pH to 1.3. After adjusting to acidity, 710 g of tetrahydrofuran and 354 g of water were added and the layers were separated. To the separated aqueous layer side, 356 g of tetrahydrofuran was added and the layers were separated. The separated tetrahydrofuran layer side was mixed and concentrated at 40 ° C. under 26 kPa reduced pressure to obtain 896 g of a concentrate (cis-benzyloxycarbonyl-4-hydroxy-L-proline 2.12 mol (yield 90. 2percent), cis / trans = 98.3 / 1.7)
Reference：
[1] Tetrahedron Letters, 1994, vol. 35, # 3, p. 451 - 454
[2] Archives of Biochemistry, 1955, vol. 57, p. 301,303
[3] Tetrahedron Letters, 1993, vol. 34, # 23, p. 3671 - 3674
[4] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, p. S234 - S237
[5] Patent: US5962660, 1999, A,
4
[ 170159-62-3 ]
[ 13504-86-4 ]
Reference：
[1] Bioscience, Biotechnology, and Biochemistry, 1995, vol. 59, # 6, p. 1161 - 1162
5
[ 13504-85-3 ]
[ 13504-86-4 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1999, vol. 72, # 12, p. 2737 - 2754
[2] Bioscience, Biotechnology, and Biochemistry, 1995, vol. 59, # 6, p. 1161 - 1162
[3] Tetrahedron Letters, 1994, vol. 35, # 3, p. 451 - 454
[4] Journal of Fluorine Chemistry, 1991, vol. 54, # 1-3, p. 195
[5] Journal of Medicinal Chemistry, 1991, vol. 34, # 2, p. 717 - 725
[6] Journal of the American Chemical Society, 1957, vol. 79, p. 185,190
6
[ 64187-47-9 ]
[ 13504-86-4 ]
Reference：
[1] Journal of the American Chemical Society, 1957, vol. 79, p. 185,190
[2] Journal of Medicinal Chemistry, 1991, vol. 34, # 2, p. 717 - 725
[3] Journal of Fluorine Chemistry, 1991, vol. 54, # 1-3, p. 195
7
[ 51-35-4 ]
[ 13504-86-4 ]
Reference：
[1] Bioscience, Biotechnology, and Biochemistry, 1995, vol. 59, # 6, p. 1161 - 1162
[2] Tetrahedron Letters, 1994, vol. 35, # 3, p. 451 - 454
[3] Journal of Fluorine Chemistry, 1991, vol. 54, # 1-3, p. 195
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 2, p. 717 - 725
[5] Journal of the American Chemical Society, 1957, vol. 79, p. 185,190
[6] Patent: JP5703654, 2015, B2,
8
[ 501-53-1 ]
[ 13504-86-4 ]
Reference：
[1] Bioscience, Biotechnology, and Biochemistry, 1995, vol. 59, # 6, p. 1161 - 1162
[2] Journal of Fluorine Chemistry, 1991, vol. 54, # 1-3, p. 195
[3] Journal of Medicinal Chemistry, 1991, vol. 34, # 2, p. 717 - 725
[4] Journal of the American Chemical Society, 1957, vol. 79, p. 185,190
[5] Synthetic Communications, 2012, vol. 42, # 9, p. 1278 - 1287
Example 1 Preparation of compound 59 4-Hydroxy-pyrrolidine-1, 2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester (3) [0155] Commercially available (Bachem) Z-Hydroxy- proline (l) (10g, 42.51mmols) was dissolved 90mls of THF (tetrahydrofuran) and was cooled to 0 C with an ice water bath. To this was added previously prepared tert- butyl N, N'-diisopropyl-imidocarbamate (2) (27ml, 135mmol) via a dropping funnel over 30 minutes. After addition the cooling bath was removed and the reaction stirred at ambient temperature for 24 hours. The volume of the reaction was reduced and then diethyl ether was added prior to washing with saturated sodium bicarbonate, then 0.5M hydrochloric acid, then water, and finally with brine. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 15g of crude material. Material was run through a plug of Si02 and eluted with 45% EtOAc-Hexanes to give 4-Hydroxy-pyrrolidine-1, 2- dicarboxylic acid 1-benzyl ester 2-tert-butyl ester 3 as a colorless oil 11. Og (81%)
(1) 56.34g of (2S,4S)-N-benzyloxycarbonyl-2-carboxy-4-hydroxy pyrrolidine obtained by the method stated in J. A. C. S. 79, 185 (1957) and 1280 ml of 6N-HCl were heat-refluxed for 30 minutes. The rection mixture was concentrated and added with acetone to precipitate crystals. The crystals were separated. Yield 35.19 g.
The ketone was dissolved in methanol (50 mL) and the reaction flask was cooled to 0 C. in an ice bath. A solution of NaBH4 (1.44 g, 38.0 mmol) in water (5 mL) was added dropwise. The reaction was allowed to sit in the refrigerator (-5 C.) for 20 h. Volatiles were removed in vacuo. The residue was diluted with H2 O (10 mL) and acidified to pH 2-3 with concentrated HCl, then extracted with ethyl acetate (2*10 mL). The aqueous layer was saturated with NaCl and again extracted with ethyl acetate (2*10 mL). Now the aqueous layer was concentrated to a white solid, which was diluted with 2:1 ethyl acetate-THF (30 mL) and heated at mild reflux for 0.5 h. Salts were removed by filtration through celite. This filtrate and the organic layers from the previous extractions were combined, dried (MgSO4) and concentrated to yield the crude N-CBZ-cis-4-hydroxy-L-proline as a yellow oil.
66
[ 288-32-4 ]
[ 13504-86-4 ]
[ 74-88-4 ]
(1-benzyloxycarbonyl-(4S)-tert-butyldimethylsilyloxy-(2S)-pyrrolidinyl)-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate; In water; N,N-dimethyl-formamide;
Example 34 (1-Benzyloxycarbonyl-(4S)-tert-butyldimethylsilyloxy-(2S)-pyrrolidinyl)carboxylic acid methyl ester (1-Benzyloxycarbonyl-(4S)-hydroxy-(2S)-pyrrolidinyl) carboxylic acid (5.3 g, 20 mmol) was dissolved in DMF (50 ml), potassium carbonate (5.5 g, 40 mmol) and methyl iodide (1.86 ml, 30 mmol) were added, and the mixture was stirred at 70C for 1 hour. To the reaction solution was added water, followed by extraction with ethyl acetate two times. The combined extracts were dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in DMF (50 ml), TBDMS-Cl (4.5 g, 30 mmol) and imidazole (4.0 g, 60 mmol) were added, and the mixture was stirred at 50C overnight. To the reaction solution was added water, this was extracted with ethyl acetate two times, and combined extracts were dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to obtain the title compound (7.1 g, 90%) as a colorless oily substance from a hexane: ethyl acetate (9:1-4:1)-eluted part. MS (LC-ESI) m/z: 394 (M++1).
1 -Benzyl 2-methyl (2S, 4R)-4-hydroxypyrrolidine-1 ,2-dicarboxylate was prepared from commercially available frans-4-hydroxy-L-proline based on literature references (e.g., Bridges et al. J. Med. Chem. 1991, 34, 717; Gregson et al. J. Med. Chem. 2004, 47, 1161). A solution of 1 -benzyl 2-methyl (2S, 4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (frans-4-hydroxy-N-Cbz-L-proline methyl ester, 15 g, 53.7 mmol), chloroacetic acid (8.4 g, 88.6 mmol), and triphenyl phosphine (23.2 g, 88.6 mmol) in toluene (100 ml_) was cooled to 0-100C, with mechanical stirring. To this stirred solution was slowly charged DIAD (17.9 g, 88.6 mmol) while maintaining the temperature of the reaction mixture 0-100C. The reaction mixture was warmed to room temperature and was stirred at room temperature for 16 h.[0211] The stirred the reaction mixture was cooled to 0-100C and was charged with methanol (40 ml_). To the stirred reaction mixture was charged 5 N NaOH (40 ml_) while maintaining the reaction temperature 0-100C. The reaction mixture is stirred at 0- 100C for 2 h. Phases were separated. The aqueous phase was extracted with toluene (4 x 30 ml_). The aqueous phase was cooled to 0-100C and was acidified with concentrated HCI (18 ml_) to pH 2. The acidified aqueous solution was extracted with ethyl acetate (3 x 40 ml_). The combined ethyl acetate solution was concentrated under vacuum to give 23 g of an oil.[0212] The oil was dissolved in methanol (150 ml_). The stirred solution was charged with concentrated sulfuric acid (1 ml_). The mixture was heated at reflux for 6 h. The mixture was concentrated to about 75 mL An aqueous solution of sodium bicarbonate (75 mL, prepared from 10 mL of saturated sodium bicarbonate and 65 mL <n="72"/>of water) was charged dropwise, followed by the addition of water (150 ml_). The slurry was stirred at room temperature for 0.5 h. The slurry was filtered and the wet cake was dried under vacuum (400C ) for 16 h to afford 9.0 g of the title compound (60% yield). 1H NMR (CDCI3, delta, ppm): 7.61-7.09 (m, 5 H), 5.42-5.04 (m, 2H), 4.47-4.38 (m, 2 H), 3.81-3.57 (m, 5 H), 3.37-3.20 (m, 1 H), 2.39-2.11 (m, 2 H). MS (m/z, positive ESI1 for M+H): 280.
1 -Benzyl 2-methyl (2S, 4R)-4-hydroxypyrrolidine-1 ,2-dicarboxylate was prepared from commercially available frans-4-hydroxy-L-proline based on literature references (e.g., Bridges et al. J. Med. Chem. 1991, 34, 717; Gregson et al. J. Med. Chem. 2004, 47, 1161). A solution of 1 -benzyl 2-methyl (2S, 4R)-4-hydroxypyrrolidine- 1 ,2-dicarboxylate (frans-4-hydroxy-N-Cbz-L-proline methyl ester, 15 g, 53.7 mmol), chloroacetic acid (8.4 g, 88.6 mmol), and triphenyl phosphine (23.2 g, 88.6 mmol) in toluene (100 ml_) was cooled to 0-100C, with mechanical stirring. To this stirred solution was slowly charged DIAD (17.9 g, 88.6 mmol) while maintaining the temperature of the reaction mixture 0-100C. The reaction mixture was warmed to room temperature and was stirred at room temperature for 16 h.[0211] The stirred the reaction mixture was cooled to 0-100C and was charged with methanol (40 ml_). To the stirred reaction mixture was charged 5 N NaOH (40 ml_) while maintaining the reaction temperature 0-100C. The reaction mixture is stirred at 0- 100C for 2 h. Phases were separated. The aqueous phase was extracted with toluene (4 x 30 ml_). The aqueous phase was cooled to 0-100C and was acidified with concentrated HCI (18 ml_) to pH 2. The acidified aqueous solution was extracted with ethyl acetate (3 x 40 ml_). The combined ethyl acetate solution was concentrated under vacuum to give 23 g of an oil.[0212] The oil was dissolved in methanol (150 ml_). The stirred solution was charged with concentrated sulfuric acid (1 ml_). The mixture was heated at reflux for 6 h. The mixture was concentrated to about 75 mL An aqueous solution of sodium bicarbonate (75 mL, prepared from 10 mL of saturated sodium bicarbonate and 65 mL <n="72"/>of water) was charged dropwise, followed by the addition of water (150 ml_). The slurry was stirred at room temperature for 0.5 h. The slurry was filtered and the wet cake was dried under vacuum (400C ) for 16 h to afford 9.0 g of the title compound (60% yield). 1H NMR (CDCI3, delta, ppm): 7.61-7.09 (m, 5 H), 5.42-5.04 (m, 2H), 4.47-4.38 (m, 2 H), 3.81-3.57 (m, 5 H), 3.37-3.20 (m, 1 H), 2.39-2.11 (m, 2 H). MS (m/z, positive ESI1 for M+H): 280.
To an ice-cooled solution of N-(benzyloxycarbonyl)-cis-41'-hydroxyproline (290 mg, 1.09 mmol; Aldrich) in anhydrous DMF (2 mL) under argon was added NaH (60% disp. in mineral oil) (96 mg, 2.40 mmol, 2.2 eq.). The mixture was allowed to stir for 20 min., and then benzyl bromide (0.14 mL, 1.20 mmol, 1.1 eq.) was added. The mixture was allowed to stir for 1 hr at 0 C. and then quenched with a few drops of water. Saturated NaHCO3 solution was added (10 mL) and the aqueous layer was washed with ethyl ether. The aqueous layer was then acidified to pH 2 with 1N HCl, extracted with ethyl acetate (3×20 mL), dried over MgSO4, and concentrated to afford a yellow oil. (205 mg, 53%) The crude material was carried on without purification.
To a solution of (2S,4S)-1-(benzyloxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.0 g, 18.85 mmol) in THF (100 mL) was added NaH (1.583 g, 39.6 mmol) at 0 C. under N2. The resulting suspension was stirred at RT for 30 min. A solution of 1,1-difluoro-2-(trifluoromethylsulfonyl)ethane (4.11 g, 20.73 mmol) in THF (5 ml) was added to the suspension. The reaction mixture was stirred at RT for 3 h. The reaction mixture was quenched with water and concentrated. The residue was extracted with EtOAc; the aqueous layers was acidified to ph 3 with 1N HCl and extracted with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4, and filtered. The crude product was used in the next step without purification. LC/MS [M-H]+: 328; Ret time (Method F): 0.93 min (Phenomenex-Luna s10 4.6×50 mm column, 4 min gradient, 4 mL/min).
(2S,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)-4-methoxy-N-(1,2,4-thiadiazol-5-yl)pyrrolidine-2-carboxamide[ No CAS ]
(2S,4S)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrrolo[1,2-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-4-methoxypyrrolidine-2-carboxamide[ No CAS ]
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