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Structure of 222978-03-2 * Storage: {[proInfo.prStorage]}
* 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 N-Bromosuccinimide; dibenzoyl peroxide In chloroform for 12 h; Reflux
3-fluoro-4-nitrile toluene 1 (10 g, 74.07 mmol)Dissolved in chloroform 200mL,Add BPO 1g, stirring dissolved,NBS (19.77 g, 11.11 mmol) was added portionwise,Reflux 12h,Cooling, the reaction solution with saturated aqueous solution of sodium bicarbonate 3 times wash,Wash the amount of water 3 times, the amount of saturated salt water washed 3 times, evaporation of the solvent under reduced pressure, column chromatography was pale yellow liquid 14.00g, yield88.79percent.
88%
With N-Bromosuccinimide; dibenzoyl peroxide In chloroform for 12 h; Reflux
To the solution of 83 2-fluoro-4-methylbenzonitrile 16 (10g, 74.07mmol) in 73 CHCl3 (200mL), 84 dibenzoyl peroxide (1g, 4.13mmol) and 85 N-Bromosuccinimide (19.77g, 11.11mmol) were added. The reaction was stirred at refluxing for 12h. The mixture was treated with saturated 86 sodium bicarbonate solution, washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the corresponding product 17. It was obtained as a yellow 87 oil in 88percent yield. HRMS (ESI): m/z, calculated for C8H5BrFN 213.9678 (M+H)+, found 213.9667.
Reference：
[1] Patent: CN106810552, 2017, A, . Location in patent: Paragraph 0068; 0070; 0071
[2] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1325 - 1344
[3] Organic and Biomolecular Chemistry, 2004, vol. 2, # 9, p. 1339 - 1352
[4] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2925 - 2930
[5] Journal of the American Chemical Society, 2001, vol. 123, # 9, p. 2107 - 2108
[6] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 17, p. 2483 - 2486
[7] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 11, p. 1411 - 1415
[8] Journal of Medicinal Chemistry, 2003, vol. 46, # 17, p. 3612 - 3622
[9] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 16, p. 4568 - 4574
[10] Patent: US6506738, 2003, B1,
[11] Patent: WO2011/94890, 2011, A1, . Location in patent: Page/Page column 118
[12] Patent: US2012/4198, 2012, A1, . Location in patent: Page/Page column 32
[13] Patent: WO2014/144545, 2014, A2, . Location in patent: Page/Page column 51
2
[ 452-74-4 ]
[ 222978-03-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2004, vol. 2, # 9, p. 1339 - 1352
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 14, p. 2973 - 2984
[3] Journal of Medicinal Chemistry, 2003, vol. 46, # 17, p. 3612 - 3622
[4] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2925 - 2930
[5] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 10, p. 1257 - 1260
[6] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 11, p. 1411 - 1415
[7] Journal of the American Chemical Society, 2001, vol. 123, # 9, p. 2107 - 2108
[8] Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 17, p. 2483 - 2486
3
[ 2094-98-6 ]
[ 85070-67-3 ]
[ 222978-03-2 ]
Yield
Reaction Conditions
Operation in experiment
65%
With N-Bromosuccinimide; sodium thiosulfate In tetrachloromethane; water
To a solution of 2-fluoro-4-methyl-benzonitrile (1.45 g, 10.7 mmol) in CCl4 (100 mL) was added 1,1'-azobis(cyclohexanecarbonitrile) (0.240 g, 0.982 mmol) and NBS (2.19 g, 12.3 mmol). The mixture was stirred and heated at reflux overnight, and then cooled to room temperature. A solution of Na2S2O3 (5 g) in H2O (100 mL) was added, and the organic layer was collected. The aqueous layer was extracted with CH2Cl2 (3*50 mL), and the extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on silica gel column (1:10 EtOAc/hexanes), affording 4-bromomethyl-2-fluoro-benzonitrile as a pale yellow oil (1.49 g, 65percent). 1H NMR (CDCl3) δ 4.45 (s, 2H), 7.24-7.30 (m, 2H), 7.60 (dd, 1H, J=6.3, 8.1 Hz).
1-(4-cyano-3-fluorobenzyl)-5-(acetoxymethyl)-imidazole hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; ethyl acetate;
Step E: Preparation of 1-(4-cyano-3-fluorobenzyl)-5-(acetoxymethyl)-imidazole hydrobromide A solution of the product from Step B (36.72 g, 96.14 mmol) and the product from Step D (20.67 g, 96.14 mmol) in 250 mL of EtOAc was stirred at 60 C. for 20 hours, during which a white precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume 100 mL, reheated at 60 C. for two hours, cooled to room temperature, and filtered again. The filtrate was concentrated in vacuo to a volume 40 mL, reheated at 60 C. for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 300 mL of methanol, and warmed to 60 C. After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further purification.
In methanol; ethyl acetate;
Step E Preparation of 1-(4-cyano-3-fluorobenzyl)-5-(acetoxymethyl)-imidazole hydrobromide A solution of the product from Step B (36.72 g, 96.14 mmol) and the product from Step D (20.67 g, 96.14 mmol) in 250 mL of EtOAc was stirred at 60 C. for 20 hours, during which a white precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume of 100 mL, reheated at 60 C. for two hours, cooled to room temperature, and filtered again. The filtrate was concentrated in vacuo to a volume 40 mL, reheated at 60 C. for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 300 mL of methanol, and warmed to 60 C. After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further purification.
In methanol; ethyl acetate;
Step E Preparation of 1-(4-Cyano-3-fluorobenzyl)-5-(acetoxymethyl)-imidazole Hydrobromide A solution of the product from Step B (36.72 g, 96.14 mmol) and the product from Step D (20.67 g, 96.14 mmol) in 250 mL of EtOAc was stirred at 60 C. for 20 hours, during which a white precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume of 100 mL, reheated at 60 C. for two hours, cooled to room temperature, and filtered again. The filtrate was concentrated in vacuo to a volume 40 mL, reheated at 60 C. for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 300 mL of methanol, and warmed to 60 C. After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further purification.
In methanol; ethyl acetate;
Step C Preparation of 1-(4-Cyano-3-fluorobenzyl)-5-(acetoxymethyl)-imidazole Hydrobromide A solution of 1-triphenylmethyl-4-(acetoxymethyl)imidazole (36.72 g, 96.14 mmol) and <strong>[222978-03-2]4-bromomethyl-2-fluoro-benzonitrile</strong>, as described in Example 9, Step D), (20.67 g, 96.14 mmol) in 250 mL of EtOAc was stirred at 60 C. for 20 hours, during which a white precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume of 100 mL, reheated at 60 C. for two hours, cooled to room temperature, and filtered again. The filtrate was concentrated in vacuo to a volume 40 mL, reheated at 60 C. for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 300 mL of methanol, and warmed to 60 C. After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the title product hydrobromide as a white solid.
In methanol; ethyl acetate;
Step E Preparation of 1-(4-cyano-3-fluorobenzyl)-5-(acetoxymethyl)-imidazole hydrobromide A solution of the product from Step B (36.72 g, 96.14 mmol) and the product from Step D (20.67 g, 96.14 mmol) in 250 mL of EtOAc was stirred at 60 C. for 20 hours, during which a white precipitate formed. The reaction was cooled to room temperature and filtered to provide the solid imidazolium bromide salt. The filtrate was concentrated in vacuo to a volume of 100 mL, reheated at 60 C. for two hours, cooled to room temperature, and filtered again. The filtrate was concentrated in vacuo to a volume 40 mL, reheated at 60 C. for another two hours, cooled to room temperature, and concentrated in vacuo to provide a pale yellow solid. All of the solid material was combined, dissolved in 300 mL of methanol, and warmed to 60 C. After two hours, the solution was reconcentrated in vacuo to provide a white solid which was triturated with hexane to remove soluble materials. Removal of residual solvents in vacuo provided the titled product hydrobromide as a white solid which was used in the next step without further purification.
With N-Bromosuccinimide; sodium thiosulfate; In tetrachloromethane; water;
To a solution of 2-fluoro-4-methyl-benzonitrile (1.45 g, 10.7 mmol) in CCl4 (100 mL) was added 1,1'-azobis(cyclohexanecarbonitrile) (0.240 g, 0.982 mmol) and NBS (2.19 g, 12.3 mmol). The mixture was stirred and heated at reflux overnight, and then cooled to room temperature. A solution of Na2S2O3 (5 g) in H2O (100 mL) was added, and the organic layer was collected. The aqueous layer was extracted with CH2Cl2 (3*50 mL), and the extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified on silica gel column (1:10 EtOAc/hexanes), affording 4-bromomethyl-2-fluoro-benzonitrile as a pale yellow oil (1.49 g, 65%). 1H NMR (CDCl3) delta 4.45 (s, 2H), 7.24-7.30 (m, 2H), 7.60 (dd, 1H, J=6.3, 8.1 Hz).
N-[(S)-1H-2-oxoperhydroazepin-3-yl]-(E)-(2R,3R,4S,5R)-3,4,5-triacetoxy-2-methoxy-8-methyldec-6-enamide[ No CAS ]
[ 222978-03-2 ]
N-[(S)-2-oxo-1-(4-cyano-3-fluorobenzyl)perhydroazepin-3-yl]-(E)-(2R,3R,4S,5R,8R)-3,4,5-triacetoxy-2-methoxy-8-methyldec-6-enamide[ No CAS ]
N-[(S)-2-oxo-1-(4-cyano-3-fluorobenzyl)perhydroazepin-3-yl]-(E)-(2R,3R,4S,5R,8S)-3,4,5-triacetoxy-2-methoxy-8-methyldec-6-enamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In 4-methyl-2-pentanone; at 50℃; for 24h;
EXAMPLE 22; N-[(S)-2-oxo-1-(4-cyano-3-fluorobenzyl)perhydroazepin-3-yl]-(E)-(2R,3R,4S,5R)-3,4,5-triacetoxy-2-methoxy-8-methyldec-6-enamide; 15 mL of 3-methyl-2-butanone and 800 mg (1.6 mmol) of compound 1, 1.72 g (8.0 mmol) of 4-cyano-3-fluorobenzyl and 2.61 g (8.0 mmol) of anhydrous cesium carbonate are successively introduced into a 50 ml round-bottomed flask equipped with a magnetic stirrer, and under an argon atmosphere. The reaction medium is heated for 24 hours at 50 C. Ethyl acetate (100 ml) and water (70 ml) are poured into the suspension. After separation of the phases by settling, the organic phase is washed with 70 ml of water and dried over magnesium sulfate. After filtering and evaporating to dryness, the crude product (2.4 g) is purified by preparative chromatography (SiO2 60, 20 g 40-60 mum RS cartridge, eluent: EtOAc/heptane gradient. 227 mg (22%) of the expected product 22 are obtained. ES: 654(+)=(M+Na)(+) 1H NMR spectrum (400 MHz)-delta in ppm-DMSO-d6, mixture of isomers (80%-20%): 0.74 (t, J=7.5 Hz, 0.6H); 0.75 (t, J=7.5 Hz, 2.4H); 0.86 (d, J=7.0 Hz, 2.4H); 0.87 (d, J=7.0 Hz, 0.6H); from 1.12 to 1.29 (m, 3H); 1.42 (m, 1H); from 1.57 to 1.76 (m, 2H); from 1.79 to 1.88 (m, 2H); from 1.90 to 2.00 (m, 1H); 1.96 (s, 2.4H); 1.97 (s, 0.6H); 2.01 (s, 2.4H); 2.02 (s, 0.6H); 2.03 (s, 0.6H); 2.04 (s, 2.4H); from 3.22 to 3.35 (partially masked m, 1H); 3.31 (s, 0.6H); 3.32 (s, 2.4H); 3.66 (m, 1H); 3.84 (d, J=4.5 Hz, 0.2H); 3.85 (d, J=4.5 Hz, 0.8H); 4.49 (d, J=16.0 Hz, 1H); 4.61 (m, 1H); 4.85 (d, J=16.0 Hz, 1H); from 5.20 to 5.38 (m, 4H); 5.52 (dd, J=8.0 and 15.5 Hz, 0.8H); 5.54 (dd, J=8.0 and 15.0 Hz, 0.2H); 7.32 (dd, J=1.5 and 8.0 Hz, 1H); 7.41 (dd, J=1.5 and 10.5 Hz, 1H); 7.88 (dd, J=7.0 and 8.0 Hz, 1H); 7.97 (d, J=6.5 Hz, 1H).
2-Fluoro-4-[(3aS,4R,8aS,8bR)-2-(4-fluoro-benzyl)-1,3-dioxo-decahydro-pyrrolo[3,4-a]pyrrolizin-4-yl]-benzimidic acid methyl ester; hydrochloride[ No CAS ]
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