* 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] Chinese Journal of Chemistry, 2014, vol. 32, # 2, p. 117 - 122
2
[ 202865-66-5 ]
[ 94569-84-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
With manganese(IV) oxide In dichloromethane at 20℃; for 48 h;
To the solution of (2-bromo-5-fluoro-phenyl)methanol (0.852 g, 4.156 mmol) in DCM (15 ml) was added MnO2 (4.254 g, 85percent, 41.56 mmol). The mixture was stirred at room temperature for two days, and then filtered and washed with DCM. The filtrate was concentrated to afford 777 mg 2-bromo-5-fluoro-benzaldehyde (92percent yield). The newly made aldehyde (0.777 g, 3.828 mmol) was then dissolved in anhydrous THF (10 ml) and cooled to 0° C. Trifluoromethyl trimethylsilane (1.13 ml, 7.656 mmol) was added, and followed by tetrabutyl ammonium fluoride (0.020 g, 0.076 mmol). The temperature was then allowed to warm to room temperature. The mixture was stirred for 5 h at room temperature, then diluted with ethyl acetate, washed with water, brine and dried by MgSO4. The solvent was removed under reduced pressure to give 2-bromo-5-fluoro-phenyl)2,2,2-trifluoro-ethanol, 1.1 g (90percent purity) as a crude product, which was used for the next step without further purification.
76%
at 55℃; for 1 h; Microwave irradiation
General procedure: The benzyl alcohols substrates (1a–1p) (0.2mmol), FeCl3·6H2O (0.002mmol, 5.4mg) and triphenylmethanol 2 (0.2mmol, 52mg) were mixed in a dried vessel. Then the reaction was irradiated under the microwave at 55°C for 1h. The crude mixture was purified by a flash column chromatography to afford the benzaldehydes (4a–4p).
76%
With triphenylmethyl alcohol; [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I) In toluene at 140℃; for 1 h; Microwave irradiation
2-bromo-5-fluorophenyl methanol (0.5mmol, 102.0mg),Triphenylmethanol(0.5 mmol, 130.2 mg)And Ph3PAuNTf2(0.015 mmol, 11 mg)Dissolved inOf the 0.5 mL toluene solvent,The reaction mixture was heated to 140 deg.] C with a microwave reactor,The reaction was stirred for 60 minutes,After completion of the reaction,The target product IV was isolated by flash column chromatography,Yield 76percent.
777 mg
With manganese(IV) oxide In dichloromethane at 20℃; for 48 h;
To a solution of (2-bromo-5-fluoro-phenyl) methanol (0.852 g, 4.156 mmol) in DCM (15 ml) was added MnO2 (4.254 g, 85percent, 41.56 mmol). The mixture was stirred at room temperature for two days, then filtered and washed with DCM. The filtrate was concentrated to give 777 mg of 2-bromo-5-fluoro-Benzaldehyde (92percent yield).The newly prepared aldehyde (0.777 g, 3.828 mmol) was then dissolved in anhydrous formTHF (10 ml) and cooled to 0 ° C. Trifluoromethyltrimethylsilane (1.13 ml, 7.656 mmol) was added followed by tetrabutylAmmonium fluoride (0.020 g, 0.076 mmol). Let the temperature warm to room temperature. The mixture was stirred at room temperature for 5 hours and then with acetic acidDiluted with ethyl acetate, washed with water, brine and dried over MgSO4. The solvent was removed under reduced pressure to give the crude product (2-bromo-5-fluoro-benzene)Yl) 2,2,2-trifluoro-ethanol, 1.1 g (90percent purity) for the next step without further purification.
Reference：
[1] New Journal of Chemistry, 2017, vol. 41, # 22, p. 13377 - 13381
[2] Patent: US2008/153852, 2008, A1, . Location in patent: Page/Page column 23
[3] RSC Advances, 2014, vol. 4, # 25, p. 12834 - 12839
[4] Tetrahedron, 2015, vol. 71, # 38, p. 6744 - 6748
[5] Patent: CN104817441, 2017, B, . Location in patent: Paragraph 0050-00053
[6] Journal of the American Chemical Society, 2006, vol. 128, # 29, p. 9340 - 9341
[7] Patent: CN104045626, 2017, B, . Location in patent: Paragraph 0271
[8] Patent: US2007/286822, 2007, A1, . Location in patent: Page/Page column 56-57
3
[ 112399-50-5 ]
[ 94569-84-3 ]
[ 202865-66-5 ]
Reference：
[1] Journal of the American Chemical Society, 2006, vol. 128, # 29, p. 9340 - 9341
4
[ 202865-66-5 ]
[ 394-28-5 ]
[ 94569-84-3 ]
Reference：
[1] Chinese Journal of Chemistry, 2014, vol. 32, # 2, p. 117 - 122
5
[ 94569-84-3 ]
[ 202865-66-5 ]
Yield
Reaction Conditions
Operation in experiment
99.8%
With sodium tetrahydroborate In ethanol; water at 0 - 20℃; for 1 h;
To a solution of compound A2-1 (75.0 g, 369 mmol) in EtOH (375 rnL) was added a solution OfNaBH4 (4.47 g, 118 mmol) in water (9 mL) at 0°C, and the mixture was stirred at rt for 1 h. The mixture was treated with water and EtOAc, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4. The solvent was concentrated in vacuo to give 75.6 g of compound A2-2 (yield = 99.8 percent) as a colorless solid. 1H NMR (CDCl3) δ 7.5O-7.46(1H, m), 7.29-7.25(1H, m), 6.92-6.85(1H, m), 4.72(2H, s).
92%
at 5 - 20℃; for 0.5 h;
(1) 200 g of Compound I was dissolved in 1400 ml of methanol, cooled to 5 ° C or less, and slowly added 18.1 g of sodium borohydride, and the temperature was raised to 20 ° C, and the reaction plate was sampled for 0.5 h. After the reaction is completed, the mixture is evaporated to a paddle shape under reduced pressure, and then added dropwise to 3000 ml of deionized water for crystallization, and stirred and filtered. Drying under reduced pressure gave Compound II in a yield of 92percent.
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 2, p. 756 - 759
[2] Patent: WO2007/19098, 2007, A2, . Location in patent: Page/Page column 44
[3] Tetrahedron, 2007, vol. 63, # 38, p. 9401 - 9405
[4] Patent: CN108358961, 2018, A, . Location in patent: Paragraph 0016; 0057; 0058-0060; 0062; 0069; 0071; 0078
[5] CrystEngComm, 2014, vol. 16, # 23, p. 4999 - 5011
[6] Journal of Medicinal Chemistry, 2006, vol. 49, # 15, p. 4447 - 4450
[7] Patent: US2007/265226, 2007, A1, . Location in patent: Page/Page column 55
[8] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7317 - 7322
[9] Advanced Synthesis and Catalysis, 2014, vol. 356, # 16, p. 3415 - 3421
[10] Tetrahedron Letters, 2015, vol. 56, # 50, p. 7005 - 7007
[11] Tetrahedron, 2015, vol. 71, # 42, p. 8172 - 8177
[12] Angewandte Chemie - International Edition, 2016, vol. 55, # 5, p. 1777 - 1781[13] Angew. Chem., 2016, vol. 128, # 5, p. 1809 - 1813
[14] Tetrahedron Letters, 2016, vol. 57, # 48, p. 5395 - 5398
[15] Chemical Communications, 2017, vol. 53, # 57, p. 8042 - 8045
6
[ 6942-39-8 ]
[ 202865-66-5 ]
Yield
Reaction Conditions
Operation in experiment
96.8%
Stage #1: With sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol at 20℃; Stage #2: With hydrogenchloride; water In tetrahydrofuran; ethanol for 0.166667 h;
6.24. Synthesis of (S)-2-amino-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-propionic acid The mixture of 2-bromo-5-fluoro-benzoic acid methyl ester (1 g, 4.292 mmol), NaBH4 (0.423 g, 11.159 mmol) and LiCl (0.474 g, 11.159 mmol) in THF/EtOH (20 ml/10 ml) was stirred at room temperature overnight. Aqueous HCl (10 ml, 2N) was added and stirred for about 10 min. Then the organic solvent was removed under low vacuum. The residue was diluted with water and extracted by ethyl acetate. The organic layer was washed with aqueous NaHCO3 (10percent), water and brine, and then dried (MgSO4) and concentrated to afford 852 mg (96.8percent crude yield) crude product, (2-bromo-5-fluoro-phenyl)methanol, as a white solid, which was used without further purification.
96.8%
With hydrogenchloride; sodium tetrahydroborate; lithium chloride In tetrahydrofuran; ethanol
6.56. Synthesis of (S)-2-amino-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[5-fluoro-2-(3-methyl-pyrazol-1-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-propionic acid The mixture of 2-bromo-5-fluoro-benzoic acid methyl ester (1 g, 4.292 mmol), NaBH4 (0.423 g, 11.159 mmol) and LiCl (0.474 g, 11.159 mmol) in THF/EtOH (20 ml/10 ml) was stirred at room temperature overnight. Aqueous HCl (10 ml, 2N) was added and stirred for about 10 min. Then the organic solvent was removed under low vacuum. The residue was diluted with water and extracted by ethyl acetate. The organic layer was washed with aqueous NaHCO3 (10percent), water and brine, and then dried (MgSO4) and concentrated to afford 852 mg (96.8percent crude yield) crude product, (2-bromo-5-fluoro-phenyl)methanol, as a white solid, which was used without further purification.
Reference：
[1] Journal of the American Chemical Society, 2006, vol. 128, # 29, p. 9340 - 9341
[2] Collection of Czechoslovak Chemical Communications, 1999, vol. 64, # 4, p. 649 - 672
10
[ 112399-50-5 ]
[ 94569-84-3 ]
[ 202865-66-5 ]
Reference：
[1] Journal of the American Chemical Society, 2006, vol. 128, # 29, p. 9340 - 9341
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 9, p. 2985 - 2988
14
[ 13675-18-8 ]
[ 202865-66-5 ]
[ 1061223-45-7 ]
Yield
Reaction Conditions
Operation in experiment
62%
With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); N-ethyl-N,N-diisopropylamine; triphenylphosphine In ethanol for 4 h; Inert atmosphere; Reflux
To a solution of (2-bromo-5-fluorophenyl) methanol (10.05 g, 0.049 mol) in Ethanol 100 mL), NiCI2(dppp) (2.67 g, 0.0049 mol), (HO)2B-B(OH)2 (6.62g, 0.074 mol), PPh3 (0.01 mol), (DIPEA (25.7 mL, 0.148 mol) are added. The resulting mixture is degassed using a stream of nitrogen. The reaction mixture is stirred at reflux for 4 hrs, then cooled to room temperature, diluted with H20 and extracted with EtOAc. The organic layer is dried over Na2S04 and evaporated in vacuo to yield (4-fluoro-2-(hydroxymethyl)phenyl)boronic acid (6) that is used in the next reaction step without further purification (Yield: 62percent).
With manganese(IV) oxide; In dichloromethane; at 20℃; for 48h;
To the solution of <strong>[202865-66-5](2-bromo-5-fluoro-phenyl)methanol</strong> (0.852 g, 4.156 mmol) in DCM (15 ml) was added MnO2 (4.254 g, 85percent, 41.56 mmol). The mixture was stirred at room temperature for two days, and then filtered and washed with DCM. The filtrate was concentrated to afford 777 mg 2-bromo-5-fluoro-benzaldehyde (92percent yield). The newly made aldehyde (0.777 g, 3.828 mmol) was then dissolved in anhydrous THF (10 ml) and cooled to 0° C. Trifluoromethyl trimethylsilane (1.13 ml, 7.656 mmol) was added, and followed by tetrabutyl ammonium fluoride (0.020 g, 0.076 mmol). The temperature was then allowed to warm to room temperature. The mixture was stirred for 5 h at room temperature, then diluted with ethyl acetate, washed with water, brine and dried by MgSO4. The solvent was removed under reduced pressure to give 2-bromo-5-fluoro-phenyl)2,2,2-trifluoro-ethanol, 1.1 g (90percent purity) as a crude product, which was used for the next step without further purification.
76%
With triphenylmethyl alcohol; iron(III) chloride hexahydrate; at 55℃; for 1h;Microwave irradiation;
General procedure: The benzyl alcohols substrates (1a?1p) (0.2mmol), FeCl3·6H2O (0.002mmol, 5.4mg) and triphenylmethanol 2 (0.2mmol, 52mg) were mixed in a dried vessel. Then the reaction was irradiated under the microwave at 55°C for 1h. The crude mixture was purified by a flash column chromatography to afford the benzaldehydes (4a?4p).
76%
With triphenylmethyl alcohol; [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I); In toluene; at 140℃; for 1h;Microwave irradiation;
2-bromo-5-fluorophenyl methanol (0.5mmol, 102.0mg),Triphenylmethanol(0.5 mmol, 130.2 mg)And Ph3PAuNTf2(0.015 mmol, 11 mg)Dissolved inOf the 0.5 mL toluene solvent,The reaction mixture was heated to 140 deg.] C with a microwave reactor,The reaction was stirred for 60 minutes,After completion of the reaction,The target product IV was isolated by flash column chromatography,Yield 76percent.
777 mg
With manganese(IV) oxide; In dichloromethane; at 20℃; for 48h;
To a solution of (2-bromo-5-fluoro-phenyl) methanol (0.852 g, 4.156 mmol) in DCM (15 ml) was added MnO2 (4.254 g, 85percent, 41.56 mmol). The mixture was stirred at room temperature for two days, then filtered and washed with DCM. The filtrate was concentrated to give 777 mg of 2-bromo-5-fluoro-Benzaldehyde (92percent yield).The newly prepared aldehyde (0.777 g, 3.828 mmol) was then dissolved in anhydrous formTHF (10 ml) and cooled to 0 ° C. Trifluoromethyltrimethylsilane (1.13 ml, 7.656 mmol) was added followed by tetrabutylAmmonium fluoride (0.020 g, 0.076 mmol). Let the temperature warm to room temperature. The mixture was stirred at room temperature for 5 hours and then with acetic acidDiluted with ethyl acetate, washed with water, brine and dried over MgSO4. The solvent was removed under reduced pressure to give the crude product (2-bromo-5-fluoro-benzene)Yl) 2,2,2-trifluoro-ethanol, 1.1 g (90percent purity) for the next step without further purification.
To a solution of 3 (62.0 g, 293 mmol) in MeOH (400 mL) was added NaBH4 (5.57 g, 147 mmol) portionwise at 0° C., and the mixture was stirred at room temperature for 1 h. Water was added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford 4b, which was used for the next step without purification. To a solution of 4b (60.8 g, 293 mmol) and i-Pr2NEt (61 mL, 0.35 mol) in CH2Cl2 was added chloromethyl methyl ether (27 mL, 0.35 mmol) at 0° C., and the mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with CHCl3. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford 5b (73.2 g, quant). 1H NMR (300 MHz, CDCl3) delta (ppm) 3.43 (s, 3H), 4.62 (s, 2H), 4.78 (s, 2H), 6.88 (td, J=8.5, 3.2 Hz, 1H), 7.25 (dd, J=9.6, 3.1 Hz, 1H), 7.48 (dd, J=8.8, 5.3 Hz, 1H).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
To a solution of 3 (62.0 g, 293 mmol) in MeOH (400 mL) was added NaBH4 (5.57 g, 147 mmol) portionwise at 0° C., and the mixture was stirred at room temperature for 1 h. Water was added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford 4b, which was used for the next step without purification. To a solution of 4b (60.8 g, 293 mmol) and i-Pr2NEt (61 mL, 0.35 mol) in CH2Cl2 was added chloromethyl methyl ether (27 mL, 0.35 mmol) at 0° C., and the mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with CHCl3. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford 5b (73.2 g, quant). 1H NMR (300 MHz, CDCl3) delta (ppm) 3.43 (s, 3H), 4.62 (s, 2H), 4.78 (s, 2H), 6.88 (td, J=8.5, 3.2 Hz, 1H), 7.25 (dd, J=9.6, 3.1 Hz, 1H), 7.48 (dd, J=8.8, 5.3 Hz, 1H).
With 2-(Dimethylamino)pyridine; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate;
2,2-Dimethyl-propionic Acid 2-bromo-5-fluoro-benzyl Ester (26B): <strong>[202865-66-5](2-Bromo-5-fluoro-phenyl)-methanol</strong> (0.79 g, 3.8 mmol) was dissolved in methylene chloride with DIEA (1 mL, 5.7 mmol), treated with about 5 mg of dimethylaminopyridine, and the solution was cooled to 0° C. and pivaloyl chloride (0.7 mL, 5.7 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The solvent was removed; the residue was dissolved in ethyl acetate and the organic layer was washed with 1N HCl, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, filtered and concentrated to an oil. The product was purified by silica chromatography (5percent ethyl acetate/hexanes as eluent) to give 2,2-dimethyl-propionic acid 2-bromo-5-fluoro-benzyl ester as a colorless oil, 0.88 g, 3.0 mmol, 80percent yield. 1H NMR (500 MHz, CDCl3) 7.46 ppm (1H, m), 7.00 ppm (1H, m), 6.83 ppm (1H, m), 5.03 ppm (2H, s), 1.19 ppm (9H, s).
(2-Bromo-5-fluoro-phenyl)-methanol (25B): 2-Bromo-5-fluoro-benzoic acid (2.8 g, 12. 8 mmol) was dissolved in THF at 0° C. and 25 ml of a 1M solution of borane in THF was added. The reaction mixture was heated to reflux for 16 hours, cooled to room temperature, and poured into ethyl acetate and 1N HCl. The organic layer was washed with 1N NaOH, brine, dried over magnesium sulfate, filtered, and concentrated to give (2-bromo-5-fluoro-phenyl)-methanol as a white solid, 1.7 g, 8.3 mmol, 65percent. 1H NMR (500 MHz, CDCl3) 7.47 ppm (1H, m), 7.27 ppm (1H, m), 6.85 ppm (1H, m), 4.69 ppm (2H, s).
4-(5-fluoro-α-hydroxy-2-tolyl)-4-hydroxy-1-methylpiperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
a. Reaction of <strong>[202865-66-5]2-bromo-5-fluorobenzyl alcohol</strong> and 1-methyl-4-piperidone by the method described in Example 16a provides 4-(5-fluoro-alpha-hydroxy-2-tolyl)-4-hydroxy-1-methylpiperidine.
With diisopropylamine; In dichloromethane; water; at 0 - 20℃; for 0.916667h;
To a solution of compound A2-2 (75.6 g, 369 mmol) and diisopropylamine (57.7 g, 446 mmol) in CH2Cl2 (770 mL) was added SEMCl (73.8 g, 443 mmol) under N2 atmosphere at 0°C. After stirring at rt for 45 min, the mixture was treated with cold- water, and stirred for lOmin. The resulting mixture was extracted with n-Hexane, and washed with water and brine. After dried over Na2SO4, the solvent was concentrated in vacuo to give 131.O g of compound A2-3 (quant). EPO <DP n="46"/>1H NMR (CDCl3) delta 7.48-7.43(1H, m), 7.24-7.20(1H5 m), 6.88-6.82(1H, m), 4.79(2H, s), 4.60(2H, s), 3.69-3.63(2H5 m)5 0.97-0.91(2H, m)5 0.00(9H, s).
With phosphorus tribromide; In 1,2-dimethoxyethane; at 0 - 20℃; for 3h;
To a solution of <strong>[202865-66-5](2-bromo-5-fluorophenyl)methanol</strong> (11, 4.10 g, 20.0 mmol) in dry DME (40 mL) at 0° C. was added a solution of PBr3 (3.25 g, 12.0 mmol) in dry DME (40 mL) dropwise. The mixture was then slowly warmed up to RT and stirred at for another 3 h. The mixture was diluted with water (100 mL), and extracted with 1:1 petroleum-ether-EtOAc (100 mL.x.2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated to give 1-bromo-2-(bromomethyl)-4-fluorobenzene (12).
Example 1; (3'R,4'S,5S,5'S,6'R)-3-[(4-ethylphenyl)methyl]-6'-(hydroxymethyl)-3',4',5',6'-tetrahydrospiro[thieno[2,3,f]isobenzofuran-5(7H),2'-[2H]pyran]-3',4',5'-triol; 1) Synthesis of 5-bromo-2-fluoro-4-hydroxymethylbenzaldehyde; [Show Image] Tetramethylpiperidine (0.68 g, 4.87 mmol) was dissolved in tetrahydrofuran (4.5 mL). To the resultant solution was added n-butyllithium (1.0 M n-hexane solution, 4.88 mL) at 0°C, and the solution was then stirred for 15 minutes. The solution was cooled to -78°C, and a solution of <strong>[202865-66-5](2-bromo-5-fluorophenyl)-methanol</strong> (0.50 g, 2.43 mmol) in tetrahydrofuran (2.5 mL) was added dropwise. The temperature of the solution was raised over 2 hours to -40°C. The solution was again cooled to -78°C, and N,N-dimethylformamide (0.47 mL, 6.07 mmol)was added thereto. The temperature of the solution was raised to room temperature, and the solution was then stirred for 30 minutes. Saturated aqueous ammonium chloride was added, and the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, to thereby obtain the titled compound (604.3 mg, quantitative). 1H-NMR (CDCl3) delta: 4.78 (2H, s), 7.46 (1H, d, J = 10.6 Hz), 8.01 (1H, d, J = 6.2 Hz), 10.29 (1H, s).
100%
Example 16 (1S,3'R,4'S,5'S,6'R)-6-[(4-ethylphenyl)methyl]-5-fluoro-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2'-[2H]pyran]-3',4',5'-triol [Show Image] [Show Image] 1) Synthesis of 5-bromo-2-fluoro-4-(hydroxymethyl)benzaldehyde; Tetramethylpiperidine (0.68 g, 4.87 mmol) was dissolved in tetrahydofuran (4.5 mL). To the resultant solution was added n-butyllithium (1.0 M n-hexane solution, 4.88 mL) at 0°C, and this solution was stirred for 15 minutes. The resultant mixture was cooled to -78°C and a solution of (2-promo-5-fluorophenyl)methanol (0.50 g, 2.43 mmol) in tetrahydrofuran (2.5 mL) was added dropwise thereto. The temperature of the solution was raised over 2 hours to -40°C. The solution was again cooled to -78°C, and then dimethylformamide (0.47 mL, 6.07 mmol) was added thereto. The temperature of the solution was raised to room temperature, and the solution was stirred for 30 minutes. Saturated aqueous ammonium chloride was then added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, to thereby obtain the titled compound (604.3 mg, quantitative). 1H-NMR (CDCl3) delta: 4.78 (2H, s), 7.46 (1H, d, J=10.6 Hz), 8.01 (1H, d, J=6.2 Hz), 10.29 (1H, s).
100%
1)Synthesis of 5-bromo-2-fluoro-4-(hydroxymethyl)benzaldehydeTetramethylpiperidine (0.68 g, 4.87 mmol) was dissolved in tetrahydrofuran (4.5 mL).To the resultant solution was added n-butyllithium (1.0 M n-hexane solution, 4.88 mL) at 0° C., and this solution was stirred for 15 minutes.The resultant mixture was cooled to -78° C. and a solution of <strong>[202865-66-5](2-bromo-5-fluorophenyl)methanol</strong> (0.50 g, 2.43 mmol) in tetrahydrofuran (2.5 mL) was added dropwise thereto.The temperature of the solution was raised over 2 hours to -40° C.The solution was again cooled to -78° C., and then dimethylformamide (0.47 mL, 6.07 mmol) was added thereto.The temperature of the solution was raised to room temperature, and the solution was stirred for 30 minutes.Saturated aqueous ammonium chloride was then added thereto, and the resultant mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, to thereby obtain the titled compound (604.3 mg, quantitative).1H-NMR (CDCl3) delta: 4.78 (2H, s), 7.46 (1H, d, J=10.6 Hz), 8.01 (1H, d, J=6.2 Hz), 10.29 (1H, s).
(1S,3'R,4'S,5'S,6'R)-3',4',5'-tris(benzyloxy)-6'-(benzyloxymethyl)-5-fluoro-3',4',5',5'-tetrahydro-6-(hydroxymethyl)-spiro[isobenzofuran-1(3H),2'-[2H]pyran][ No CAS ]
(1S,3'R,4'S,5'S,6'R)-3',4',5'-tris(benzyloxy)-6'-(benzyloxymethyl)-6-(chloromethyl)-5-fluoro-3',4',5',6'-tetrahydro-spiro[isobenzofuran-1(3H),2'-[2H]pyran][ No CAS ]
(1S,3'R,4'S,5'S,6'R)-3',4',5'-tris(benzyloxy)-6'-(benzyloxymethyl)-6-[(4-ethylphenyl)methyl]-5-fluoro-3',4',5',6'-tetrahydro-spiro[isobenzofuran-1(3H),2'-[2H]pyran][ No CAS ]
With 1H-imidazole; dmap; In N,N-dimethyl-formamide; at 23℃; for 48h;Inert atmosphere;
Intermediate example 299c; -bromo-5-fluorobenzyl)oxy](triisopropyl)silane; To a solution of 5.00 g (24.4 mmol) <strong>[202865-66-5](2-bromo-5-fluorophenyl)methanol</strong> in 100 mL Nu,Nu-dimethylformamide were added 2.49 g imidazole, 6.20 mLchloro(triisopropyl)silane, 1.49 g N,N-dimethylpyridin-4-amine and the mixture was stirred at 23 C for 2 days. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of the solvent the residue was purified by chromatography to give 8.17 g (93%) of the title compound.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In ethanol; water; at 120℃;Inert atmosphere;
[2-Amino-6-[4-fluoro-2-(hydroxymethyl)phenyl]quinazolin-4-yl]isoindolin-2-ylmethanone (?A4?) [0341] 74 mg of <strong>[202865-66-5](2-bromo-5-fluorophenyl)methanol</strong>, 100 mg of potassium carbonate, 1 ml of water and 15 mg of [1,1?-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added to a solution of 150 mg of [2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone in 3 ml of ethanol under argon. The mixture is heated at 120° C. for min; the hot mixture is filtered through kieselguhr, and the filtrate is evaporated in vacuo. The residue is purified by reverse-phase column chromatography. [0342] Yield: 8 mg (5percent) of [2-amino-6-[4-fluoro-2-(hydroxymethyl)phenyl]quinazolin-4-yl]isoindolin-2-ylmethanone; HPLC retention time: 1.51 min; [0343] 1H NMR (400 MHz, DMSO-d6/TFA-d1) delta [ppm] 8.08-8.02 (m, 2H), 7.81 (d, J=8.7, 1H), 7.42 (d, J=7.2, 1H), 7.39-7.25 (m, 4H), 7.24 (d, J=6.9, 1H), 7.16 (td, J=8.5, 2.8, 1H), 4.99 (s, 2H), 4.82 (s, 2H), 4.36 (s, 2H).
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