* 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 4-methyl-morpholine In dichloromethane at 20℃; for 17 h;
A reaction vessel was charged with 2-fluoroethanol (1.00 mL, 16.9 mmol), p-toluenesulfonylchloride (3.85 g, 20.2 mmol), N-methylmorpholine (9.30 mL, 84.5 mmol), and CH2Cl2 (50 mL), and reaction was effected at room temperature for 17 hours. After the reaction, water was added to the reaction system, and the product was extracted three times with ethyl acetate into the organic layer. The resulting organic layer was washed with saturated saline and dried with MgSO4. After concentration under reduced pressure, the concentrate was purified by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=19:81→40:60) to yield a product (3.79 g (17.2 mmol), >100percent yield, light yellow liquid). 114-NMR (600 MHz, CDCl3): δ7.81 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 4.63-4.60 (m, 1H), 4.55-4.52 (m, 1H), 4.31-4.27 (m, 1H), 4.26-4.23 (m, 1H), 2.46 (s, 3H); LRMS (EI) calculated for C9Hi1F03S (Mt): 218.0, found: 218.0.
98%
at 0 - 5℃; for 3.5 h; Inert atmosphere
Example 2(a) Fluoroethyl tosylate (12) 2-Fluoroethanol (640 mg, 10 mmol, 0.6 mL) was dissolved in pyridine (10 mL) under nitrogen. The solution was stirred at 0° C. and tosyl chloride (4.2 g, 21.8 mmol) added portionwise to the solution over a period of 30 min, keeping the temperature below 5° C. The reaction was stirred at 0° C. for 3 h. Ice was slowly added followed by water (20 mL). The reaction mixture was extracted into ethyl acetate and washed with water. Excess pyridine was removed by washing with 1 N HCl solution until, the aqueous layer became acidic. Excess tosyl chloride was removed by washing with 1 M aqueous sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 2.1 g (98percent) of fluoroethyl tosylate (12) as a colourless oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 21.6 (CCH3), 68.5 (d, JCF=173 Hz, OCH2CH2F), 80.6 (d, JCF=173 Hz, OCH2CH2F), 128.0, 129.9, 132.6, and 145.1.
98%
at 0 - 5℃; for 3.5 h; Inert atmosphere
2-Fluoroethanol (640 mg, 10 mmol, 0.6 mL) was dissolved in pyridine (10 mL) under nitrogen. The solution was stirred at 0° C. and tosyl chloride (4.2 g, 21.8 mmol) added portionwise to the solution over a period of 30 min, keeping the temperature below 5° C. The reaction was stirred at 0° C. for 3 h. Ice was slowly added followed by water (20 mL). The reaction mixture was extracted into ethyl acetate and washed with water. Excess pyridine was removed by washing with 1 N HCl solution until, the aqueous layer became acidic. Excess tosyl chloride was removed by washing with 1 M aqueous sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 2.1 g (98percent) of fluoroethyl tosylate (12) as a colourless oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 21.6 (CCH3), 68.5 (d, JCF=173 Hz, OCH2CH2F), 80.6 (d, JCF=173 Hz, OCH2CH2F), 128.0, 129.9, 132.6, and 145.1.
98%
at 0 - 5℃; for 3.5 h; Inert atmosphere
Example 2(a) Fluoroethyl Tosylate (12) (0173) 2-Fluoroethanol (640 mg, 10 mmol, 0.6 mL) was dissolved in pyridine (10 mL) under nitrogen. The solution was stirred at 0° C. and tosyl chloride (4.2 g, 21.8 mmol) added portionwise to the solution over a period of 30 min, keeping the temperature below 5° C. The reaction was stirred at 0° C. for 3 h. Ice was slowly added followed by water (20 mL). The reaction mixture was extracted into ethyl acetate and washed with water. Excess pyridine was removed by washing with 1 N HCl solution until the aqueous layer became acidic. Excess tosyl chloride was removed by washing with 1 M aqueous sodium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 2.1 g (98percent) of fluoroethyl tosylate (12) as a colourless oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 21.6 (CCH3), 68.5 (d, JCF=173 Hz, OCH2CH2F), 80.6 (d, JCF=173 Hz, OCH2CH2F), 128.0, 129.9, 132.6, and 145.1.
95%
at 0℃; for 4.5 h;
To a 0° C. solution of 2-fluoroethanol (1.0 g, 15.6 mmol) in pyridine (15 mL) was added tosyl chloride (6.5 g, 34.1 mmol) over 30 min. The reaction mixture was stirred at 0° C. for 4 h and quenched by adding ice-cold water and EtOAc. The layers separated and the organic layer was washed successively with water, 1M HCl (5.x.), saturated Na2CO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (12 g) using 5percent to 40percent EtOAc in hexane as the eluant to obtain fluorotosylate 20 (3.2 g, 95percent) as a slightly yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=10.0 Hz, 1H), 7.38 (d, J=10.0 Hz, 2H), 4.59 (dt, J=50.0 5.0 Hz, 2H), 4.28 (dt, J=30.0 5.0 Hz, 2H), 2.47 (s, 3H).
95%
at 0℃; for 4.5 h;
To a 0° C. solution of 2-fluoroethanol (1.0 g, 15.6 mmol) in pyridine (15 mL) was added tosyl chloride (6.5 g, 34.1 mmol) over 30 min. The reaction mixture was stirred at 0° C. for 4 h and quenched by adding ice-cold water and EtOAc. The layers separated and the organic layer was washed successively with water, 1M HCl (5.x.), saturated Na2CO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (12 g) using 5percent to 40percent EtOAc in hexane as the eluant to obtain fluorotosylate 20 (3.2 g, 95percent) as a slightly yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=10.0 Hz, 1H), 7.38 (d, J=10.0 Hz, 2H), 4.59 (dt, J=50.0 5.0 Hz, 2H), 4.28 (dt, J=30.0 5.0 Hz, 2H), 2.47 (s, 3H).
92%
at 20℃; for 24 h;
Synthesis of 2-fluoroethyl tosylate was performed by making a solution of 2- fluoroethanol (2 mmol) and p-toluenesulfonyl chloride (1.1 mmol) in 5 M NaOH (1.6 mmol), which was stirred at room temperature for 24 hours. The reaction mixture wasdiluted with CH2CI2 and the organic phase was washed with 10 percent NaOH. The organic layer was dried (Na2504) and concentrated in vacuo. The crude product was purified by chromatography on a silica gel column with CH2CI2 to give a colorless oil that was stored in the freezer (yield 92 percent). ESI/MS m/z: 241 [M+Na], ESI/MS/MS m/z: 241 (74), 97(100). 1H NMR (CDCI3) O: 2.45 (5, 3H, CH3), 4.21 (t, 1H, J= 4 Hz, CH2), 4.30 (t,1 H, J = 4 Hz, CH2), 4.49 (t, 1 H, J = 4 Hz, CH2), 4.64 (t, 1 H, J = 4 Hz, CH2), 7.34 (d, 2H, J= 8 Hz), 7.80 (d, 2H, J= 8 Hz).
85%
at 0℃; for 4 h; Inert atmosphere
To a cold (0 oC) solution2-fluoroethanol (2.0 g, 31.2 mmol) in pyridine (30 mL) was added 4-toluenesulfonyl chloride (13.0 g, 68.2 mmol) portion-wise over 30 min. The reaction mixture was maintained at 0 oC for 4 h and then quenched withice (30 g) and H2O (40 mL).The product was extracted into EtOAc (100 mL), subsequently washed withaq. HCl (1 M) until the washes were acidic, and then washed with saturated aq. sodium bicarbonate (3 × 25mL). The organic layer was collected,dried (MgSO4), filtered, and concentrated under reduced pressure toafford S6 as a colorless oil (85percent). All characterization data agreed with previous literature.
83%
at 0 - 20℃; for 4 h;
The synthesis of 7 was similarly performed as previously described by Block et al4. Inbrief, to a solution of 2-fluoroethanol (250 mg, 3.90 mmol) in anhydrous pyridine (5mL) at 0 °C was added tosyl chloride (149 mg, 7.80 mmol) portionwise. The reaction mixture was stirred at room temperature for 4 h, quenched with ethyl acetate (30 mL),washed with water (2x), 1 N HCl, saturated NaHCO3 solution and brine and was dried (MgSO4). After removal of the solvent the crude product was purified by short flash chromatography (n-hexane/ethyl acetate 50:1 to 1:2) to give 7 (710 mg, 83percent)as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.77 (m, 2H); 7.41 – 7.29(m, 2H), 4.69 – 4.45 (m, 2H), 4.33 – 4.18 (m, 2H), 2.46 (s, 3H); 13C NMR (101 MHz,CDCl3) δ 145.1, 132.7, 129.9, 128.0, 80.5 (d, JCF = 173.8 Hz), 68.4 (d, JCF = 21.0 Hz),21.7; ESI-MS m/z 240.9 [M+Na]+.
78%
at 0 - 20℃; for 16 h; Inert atmosphere
Under argon atmosphere, 0 ° C in dry pyridine (15 ml) solution of 2-fluoro-ethanol (1.92g, 29.97mmol) To a stirred solution of, by keeping lower than 5 temperature, p- toluenesulfonyl chloride It was added over a period of 15 minutes. Then four hours the reaction mixture at 0°C , then the mixture was stirred for 12 hours at room temperature. The reaction mixture was cooled to 0 ° C., ice (15 g), followed by addition of water (40 ml) and EtOAc (50ml). The organic extracts were water (30 ml), washed with 1M HCl (until aqueous extract is acidic), 10percent sodium carbonate (2 × 30 ml), brine (40 ml), dried (Na2SO4). The solvent was removed under reduced pressure to give the title compound (5.10g, 78percent) as a colorless oil.
77%
With triethylamine In dichloromethane at 0 - 25℃; for 5 h;
Add toluenesulfonyl chloride (1.8 g, 9.4 mmol) to the mixture of 2-fluoroethanol (500 mg, 7.8 mmol) and triethylamine (1.6 g, 15.6 mmol) in dichloromethane (30 mL) at 0-5° C. Stir the reaction at ambient temperature for 5 hrs. Remove the volatiles under reduced pressure to yield the crude product. Purify by flash chromatography (silica gel, PE:EtOAc=2:1) to afford a white solid as the title compound (1.3 g, 77percent).
73%
at 20℃; for 24 h; Cooling with ice
To an anhydrous pyridine (180 mL) solution of 2-fluoroethanol (11 mL, 187 mmol), tosyl chloride (40.9 g, 215 mmol) was added portionwise over 30 minutes or more under ice cooling. The reaction mixture was slowly heated to room temperature and then stirred for one day. The reaction was suppressed by addition of cold purified water (200 mL) and stirring was continued for 1 hour. After the whole mixture was extracted with ethyl acetate twice, the extract was washed with purified water (100 mL) and subsequently with 1 M hydrochloric acid (250 mL) 4 times. The organic layer was washed with a saturated sodium hydrogen carbonate solution and subsequently with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered, and the solvent in the filtrate was evaporated off in vacuo. The resulting oily crude product was purified by silica gel column chromatography (heptanes/AcOEt = 8/2 to 5/5) to give 2-fluoroethyl tosylate as a colorless liquid (yield: 29.6 g, 73percent).
71.8%
for 4.5 h; Cooling with ice; Inert atmosphere
A solution of 22.9 mL (25 g, 391 mmol) 2-fluoroethanol in 300 mL pyridine was cooled in an ice bath, and 163 g (850 mmol) tosyl chloride was added thereto in portions over a period of 30 min, under argon. Stirring was performed for an additional 4 hours on the ice bath, and 300 g ice and 500 mL water were then added. After adding 1000 mL ethyl acetate the phases were separated, and the organic phase was washed with 500 mL of a 5percent sodium carbonate solution and 200 mL water. After drying over sodium sulfate and stripping the solvent, the crude product was obtained as an oil, which was purified by distillation in an oil pump vacuum (approximately 100° C. at 1-2 mbar). 61.27 g (280.7 mmol, 71.8percent yield) of a colorless liquid was obtained.
67%
With pyridine In toluene at 0℃;
To a solution of 2-fluoroethanol (0.32 mL, 5 mmol) in pyridine and toluene (5 mL, 1:1) mixture was added p-toluenesulfonyl chloride at 0° C. The reaction mixture was stirred overnight. The reaction mixture was dissolved in EtOAc (150 mL) and washed with water and brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified on a silica gel column using Biotage Isolera One purification system employing EtOAc/n-heptane (5/95=>30/70) to give the title compound as a colorless liquid (1.54 g, 67percent).1H NMR (400 MHz, CDCl3) δ=7.85 (m, 2H), 7.40 (m, 2H), 4.65 (m, 1H), 4.55 (m, 1H), 4.35 (m, 1H), 4.25 (m, 1H), 2.48 (s, 3H).
60%
With dmap; triethylamine In dichloromethane at 20℃; for 48 h; Inert atmosphere; Cooling with ice
p-toluenesulfonyl chloride (13.3 g, 70 mmol), triethylamine (35 mL, 0.25 mol) and dimethylamino pyridine (0.4 g, 3.3 mmol) were added to CH2Cl2 (80 mL) on an ice bath. Then a solution of 2-fluoroethanol (4.6 mL, 80 mmol) in CH2Cl2 (30 mL) was added dropwise to the reaction mixture under N2 atmosphere. The ice bath was removed, and the mixture was shaken at room temperature for 48 h. Then the reaction mixture was concentrated by vacuum distillation and purified by column chromatography with ethyl acetate and petroleum ether. Compound 3 was obtained as colorless oil (9.15 g, 60percent yield). 1H NMR (400 MHz, CDCl3) δ 7.81 (m, J=8.3Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.57 (m, 2H), 4.26 (m, 2H), 2.46 (s, 3H)
42%
at 0 - 5℃; for 4.5 h;
2-Fluoroethanol (50.7 g, 792 mmol) was dissolved in pyridine (350 mL) and the solution cooled in an ice-salt bath. Tosyl chloride (151 g, 792 mmol) was added in portions over approximately 30 mm keeping the temperature below 5°C. The mixture was stirred for 4 h at 0 °C, quenched with ice cooled water (600 mL) and extracted with ethyl acetate (3 x 250 mL). The combined organic extracts werewashed with hydrochloric acid (1 M) until the aqueous phase remained acidic, followed by washing with potassium carbonate (10percent, 2 x 200 mL) and brine. The organic phase was dried (magnesium sulphate), filtered and concentrated, giving an almost colourless oil (72.6 g, 42percent). ‘H NMR (300 MHz,CDCI3): 6 2.45 (3H, s, CH3), 4.33 (2H, dt, J = 13.5 Hz, 4.0 Hz, OCH2), 4.57 (2H, dt, J = 47.0 Hz, 4.0 Hz, CH2F), 7.35(2H, d, J = 8.0 Hz, Ar), 7.80 (2H, d,J = 8.0 Hz, Ar). ‘3C NMR (75 MHz, CDCI3): 6 21.6 (CH3), 68.7 (d, J = 19.0 Hz, OCH2), 80.5 (d, J = 172.0 Hz, CH2F), 128.0 (Ar), 129.9 (Ar), 132.6 (CMe), 145.1 (C-S). ‘9F NMR (CDCI3): 6 -224.5.
38%
at 0 - 20℃; for 15 h;
Preparation of 2-fluoroethyl-4-methylbenzenesulfonate; A solution of pyridine (17 ml_, 0.21 moles), p-toluenesulfonyl chloride (3.57 g, 18.73 mmol) and fluoroethanol (1 ml_, 17.03 mmol) was stirred at 00C for 1 h and at room temperature for a further 14 h under an argon atmosphere. The pale transparent mixture was quenched with ice-water (-30 ml_) and shaken for 5 min to hydrolyse any unreacted tosyl chloride. The suspension was extracted with ethyl acetate (-15 ml_) and the excess pyridine was neutralised by adding dilute sulphuric acid (containing crushed ice) to the organic layer. The organic layer was then washed with more dilute sulphuric acid (containing crushed ice), ice-water, dilute potassium hydroxide (containing crushed ice) and again with ice-water. Following this, the ether solution was dried over anhydrous sodium sulphate and the solvent was removed in vacuo to afford 2- fluoroethyl-4-methylbenzenesulfonate (1.40 g, 6.41 mmol) in 38percent yield as a clear oil. 1H NMR (CDCI3, 300 MHz) δ: 3.58 (s, 3H), 4.19-4.31 (m, 2H), 4.47-4.66 (m, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H).
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2
[ 1207989-43-2 ]
[ 383-50-6 ]
Yield
Reaction Conditions
Operation in experiment
88%
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 3 h;
A typical procedure: 3-chloroperbenzoic acid (77percent) (829 mg, 3.7 mmol) was added to a stirred solution of 684 mg (3.64 mmol) of 4 in 10 mL of CH2Cl2. The mixture was stirred at room temperature for 3 h. During the reaction, insoluble 3-chlorobenzoic acid was formed. After that, 5 mL of CH2Cl2 was added to the reaction mixture to dissolve the acid and then a satd Na2CO3 solution was added. After the mixture was stirred for 20 min, the organic layer was separated, washed with water, dried over anhydrous MgSO4, and filtered. Removal of solvent under reduced pressure gave 2-fluoroethyl benzenesulfonate[31] in 87percent yield.
Reference：
[1] Journal of Fluorine Chemistry, 2012, vol. 140, p. 17 - 27
3
[ 371-62-0 ]
[ 104-15-4 ]
[ 383-50-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
at 0℃; for 3.5 h;
p-Toluenesulfonic acid 2-fluoroethyl ester; [Show Image] 1 g (15.6 mmol) of 2-fluoroethanol was dissolved in pyridine (15 mL), and 6.5 g (34.1 mmol) of p-toluenesulfonic acid was added thereto over a period of 30 minutes while stirring on ice. The mixture was stirred at 0°C under nitrogen atmosphere for 3 hours, and after adding 35 mL of ice water to the reaction mixture, extraction was performed with 30 mL of ethyl acetate. The obtained organic layer was washed three times with 30 mL of 1N hydrochloric acid, and then further washed with sodium carbonate solution and saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure to yield the title compound (3.19 g, 94percent) as a colorless oil. 1H-NMR (270 MHz, CDCl3) δ (ppm): 2.46 (3H, s), 4.14-4.25 (1H, m), 4.25-4.36 (1H, m), 4.43-4.36 (1H, m), 4.61-4.71 (1H, m), 7.36 (2H, d, J = 8.1 Hz), 7.81 (2H, d, J = 8.1 Hz).
94%
at 0℃; for 3.5 h; Inert atmosphere
2-fluoroethanol was dissolved 1g (15.6mmol) in pyridine (15) and, with stirring on an ice bath was added p- toluene sulfonic acid 6.5g (34.1mmol) over 30 minutes and a stream of nitrogen for 3 hours at 0 ° It was stirred. 35 ice water was added to the reaction solution, which was extracted with ethyl acetate 30. The obtained organic layer was washed with 1N hydrochloric acid 30 3 times and washed with sodium carbonate solution and saturated brine in addition. Drying the obtained organic layer over anhydrous sodium sulfate and under reduced pressure to remove the solvent, to give the title compound as 3.19g (94percent) a colorless oily substance
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5
[ 371-62-0 ]
[ 4124-41-8 ]
[ 383-50-6 ]
Reference：
[1] Synthesis, 2004, # 6, p. 885 - 888
6
[ 42772-85-0 ]
[ 383-50-6 ]
Reference：
[1] Angewandte Chemie - International Edition, 2014, vol. 53, # 25, p. 6473 - 6476[2] Angew. Chem., 2014, vol. 126, # 25, p. 6591 - 6594,4
[3] European Journal of Medicinal Chemistry, 2014, vol. 90, p. 742 - 750
[4] European Journal of Medicinal Chemistry, 2014, vol. 90, p. 742 - 750
7
[ 657-83-0 ]
[ 383-50-6 ]
Reference：
[1] Journal of Fluorine Chemistry, 2012, vol. 140, p. 17 - 27
8
[ 98-59-9 ]
[ 383-50-6 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2014, vol. 90, p. 742 - 750
[2] European Journal of Medicinal Chemistry, 2014, vol. 90, p. 742 - 750
With sodium iodide; In methanol; ice-water; N,N-dimethyl-formamide;
Example 1 ethyl 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate. To a mixture of <strong>[79660-46-1]ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate</strong> (5.36 kg) and sodium iodide (2.94 kg) in dimethylformamide (20.5 liters), was added anhydrous potassium carbonate (2.97 kg) at 100o under stirring. After the addition was completed, the mixture was stirred at 95 to 100o for 15 min. 2-Fluoroethyl tosylate (2.98 kg) was added during a period of 2 hours and the mixture was heated at 95 to 100o for 1.5 hours. Further, 2.73 kg of 2-fluoroethyl tosylate were added during a period of 2 hours. After being heated for 4 hours, an additional 0.82 kg of the tosylate was added during a period of 1.5 hours and the reaction mixture was heated for 6 hours at the same temperature. After cooling, the mixture was added to ice-water (64 liters). The resultant precipitate was filtered, washed with water and suspended in methanol (32 liters) under stirring for 30 min. The crystals were collected by filtration and dried to give 5.02 kg (80.0 %) of the objective compound, mp 188 - 190o. Anal. Calcd. (%) for C1sub;4HFNO⊃: C, 53.00; H, 3.50; N, 4.42. Found (%): C, 52.99; H, 3.40; N, 4.47.
With tetraethylammonium chloride; potassium carbonate In N,N-dimethyl-formamide at 70℃; for 18h;
118.b
Step b); 1-(2-Fluoro-ethyl)-4-iodo-1H-pyrrole-2-carboxylic acid methyl ester; To a solution of 2.87 gm (0.013 mol) of toluene-4-sulfonic acid 2-fluoro-ethyl ester in 50 mL of DMF was added 1.81 gm (0.013 mol) of potassium carbonate, 0.2 gm (1.2 mmol) of tetraethylammonium chloride and 3.0 gm (0.012 mol) of 4-iodo-1H-pyrrole-2-carboxylic acid methyl ester. The reaction mixture was heated to 70° C. for 18 h. The reaction mixture was cooled and added to 350 mL of EtOAc. The organic layer was washed 3 times (100 mL) with H2O, once with saturated brine, dried (Na2SO4) and the solvents removed at reduced pressure. Chromatography on silica gel using a gradient of hexanes to 2%-3% EtOAc-hexanes yielded 3.2 gm (90% yield) of a white solid (m.p. 49-50.5° C.). 1H NMR (400 MHz, CDCl3) δ: 3.80 (s, 3H), 4.58 (m, 2H), 4.63 (m, 1H), 4.76 (m, 1H,), 6.93 (s, 1H), 7.06 (s, 1H).
With calcium carbonate; In acetone; at 20 - 70℃; for 85h;
(2) Production of 2-bromo-5-(2-fluoroethoxy)benzoic acid; [Show Image] Calcium carbonate (12.0 g) and 2-fluoroethyl 4-methylbenzenesulfonate (9.45 g) were added to a solution of <strong>[154607-00-8]methyl 2-bromo-5-hydroxybenzoate</strong> (10.0 g) produced in the above (1) in acetone (100 mL), stirred at room temperature for 13 hours and then stirred at 70C for three days. Water was added to the reaction solution followed by extracting with ethyl acetate. The resulting organic layer was washed with a saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was dissolved in methanol (200 mL), a 4N aqueous solution of sodium hydroxide (15.0 mL) was added thereto, the mixture was stirred at room temperature for 13 hours, a 4N aqueous solution of sodium hydroxide (10.0 mL) was further added thereto and the mixture was stirred at room temperature for 9 hours. To the reaction solution was added 6N hydrochloric acid (20 mL) and the solid separated out therefrom was filtered to give the aimed compound (8.89 g, 78%) as a colorless solid. 1HNMR (400MHz, DMSO-d6, delta): 4.20-4.46 (2H, m), 4.64-4.82 (2H, m), 7.05 (1H, dd, J=9.0Hz,3.1Hz), 7.28 (1H, d, J=3.1Hz), 7.76 (1H, d, J=9.0Hz,), 13.41 (1H, brs)
With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 16h; Inert atmosphere;
4-(2-Fluoroethoxy)benzaldehyde (46)
To a suspension of 4-hydroxybenzaldehyde 45 (0.98 g, 8.0 mmol, 1.0 equiv.) and potassium carbonate (1.66 g, 12.0 mmol, 1.5 equiv.) in N,N-dimethylformamide (6 mL) at RT was added a solution of 2-fluoroethyl 4-methylbenzenesulfonate (3.48 g, 16.0 mmol, 2 equiv.) in N,N-dimethylformamide (2 mL) followed by stirring at 40 °C for 16 h. Upon cooling to ambient temperature the reaction mixture was partitioned between water (100 mL) and diethyl ether (100 mL), the aqueous layer was isolated and further extracted with diethyl ether (2 × 100 mL). The combined organic fractions were washed with aqueous sodium hydroxide (1 M, 100 mL), brine, dried (Na2SO4) and concentrated under reduced pressure to give a crude residue. Purification by gradient column chromatography on silica gel (65:35 60:40 v/v hexanes:Et2O) to afford the title compound 46 as an opaque oil (1.34 g, quantitative); Rf 0.27 (60:40 v/v hexanes:Et2O); IR (ZnSe) 2962, 1687 (C=O), 1601, 1509, 1256, 1162, 1073, 833, 731, 518; 1H NMR (500 MHz, CDCl3) δ 9.90 (1H, s, CHO), 7.84 (2H, d, J = 8.3 Hz, ArH), 7.04 (2H, d, J = 8.3 Hz, ArH), 4.84-4.75 (2H, dt, 2JH-F = 47 Hz, JH-H = 4.0 Hz, CH2F), 4.33-4.28 (2H, dt, 3JH-F = 28 Hz, JH-H = 4.0 Hz, OCH2); 13C NMR (125.8 MHz, CDCl3) δ 190.9 (CHO), 163.5 (C), 132.2 (aryl), 129.5 (C), 115.0 (aryl), 81.7 (d, 1JC-F = 176 Hz, CH2F), 67.4 (d, 2JC-F = 25 Hz, OCH2); m/z (GC-MS) 161.10 ([M]+, C9H9FO2, 60%), 121.06 ([M-(CH2)2F]+, 100%), 93.01 ([C7H8]+, 30%), 65.08 ([C5H5]+, 26%).
95%
With potassium carbonate In acetonitrile at 70℃; for 17h;
88%
With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 60℃; for 20h;
Intermediate 28: [4-(2-fluoroethoxy)phenyl]methanol
2-fluoroethanol (1.0 g, 95 %, 14.8 mmol) was dissolved in dichloromethane (5.0 ml) and diisopropylethylamine (14.8 mmol, 2.59 ml) followed by p-toluenesulphonyl chloride (14.8 mmol, 2.85 g) were added. 4-dimethylaminopyridine (1.5 mmol, 187 mg) was added, the mixture was stirred 20 hours and then partitioned between 0.5 M HC1 and diethyl ether, the organic phase was collected, dried, evaporated, and the crude was purified by column chromatography using silicon dioxide gel, eluting with 0-30 % ethyl acetate in petroleum ether to afford the desired tosylated fluoroethanol (1.73 g, 54 % yield). This material (700 mg, 3 ? mmnl), (3 mmnlj 436 mg), tetrabutylammonium iodide (0.5 mmol, 190 mg), potassium carbonate (7.0 mmol, 967 mg) and DMF (4.0 ml) were stirred at 60 °C for 20 hours, then partitioned between water and diethyl ether, the organic phase was collected, dried, evaporated, and gave the intermediate 4- O-alkylated benzaldehyde (2.84 mmol, 479 mg, 88 % yield). This aldehyde (374 mg, 2.22 mmol) was reduced with sodium borohydride (2.0 mmol, 76 mg) in ethanol (2.0 ml). The reaction was quenched with 1 M NaOH, partitioned between ether and NaOH (0.5 M), the organic phase was collected, dried, evaporated, and the crude was purified by column chromatography using silicon dioxide gel, eluting with 30-50 % ethyl acetate in petroleum ether to afford the title compound (327 mg, 1.92 mmol, 86 % yield).
77%
Stage #1: 4-hydroxy-benzaldehyde With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.166667h;
Stage #2: 2-fluoroethyl tosylate In N,N-dimethyl-formamide at 130℃; for 15h;
3.4. General Procedure for Fluoroethoxylation of Hydroxyacetophenones and benzaldehydes
General procedure: A round bottom flask was charged with sodium hydride (1.2 eq.). The appropriate hydroxyacetophenone or hydroxybenzaldehyde (1 eq.) in DMF (100 mL) was added dropwise over 10 min at rt. Then 2,2,2-trifluoroethyl-4-methylbenzenesulphonate (1.2 eq.) in DMF (50 mL) was added dropwise. The reaction mixture was then allowed to reflux at 130°C for 15 h. After completion of reaction, monitored by TLC, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, brine solution and finally dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by column chromatography (silica gel 60-200 mesh) to afford desired compounds.
With N(Bu4)OH In N,N-dimethyl-formamide at 20℃; for 24h;
Stage #1: (1,4-dioxaspiro[4.5]dec-8-yl)methanol With sodium hydride In dimethyl sulfoxide at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: 2-fluoroethyl tosylate In dimethyl sulfoxide at 75℃; for 2h; Inert atmosphere;
11.A
Step A: Preparation of 8-((2-fluoroethoxy)methyl)-1,4-dioxaspiro[4.5]decane Sodium hydride (60% in mineral oil) (0.087 g, 2.18 mmol) was washed with pentane and then suspended in dry DMSO (2 mL) under a nitrogen atmosphere. A solution of 1,4-dioxaspiro[4.5]decan-8-ylmethanol (0.3407 g, 1.98 mmol) in dry DMSO (3 mL) was added, and the resulting mixture was stirred for 10 minutes at room temperature. 2-Fluoroethyl 4-methylbenzenesulfonate (0.432 g, 1.98 mmol) was then added, and the reaction mixture was stirred at 75° C. for 2 hours. Water (5 mL) was cautiously added, followed by Et2O (50 mL). The layers were separated, and the organic layer was washed with brine (3×10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/heptane mixture) to provide the title compound (0.137 g, 31.7%). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.18-1.36 (m, 2 H), 1.47-1.87 (m, 7 H), 3.35 (d, J=6.6 Hz, 2 H), 3.59-3.77 (m, 2 H), 3.88-400 (m, 4 H), 4.46-4.65 (m, 2 H).
Sodium hydride (55% oiliness,140 mg, 3.2 mmols) was added to DMF (5 mL) solution oftert-butyl (3R)-3-hydroxypyrrolidine-1- carboxylate (501.2 mg, 2.7 mmols) and stirred at room temperature for 30 minutes, followed by addition of 2-fluoroethyl p-toluenesulfonate (1.17 g, 5.4 mmols) and further 24 hours' stirring at the same temperature. Ethyl acetate was added to the reaction liquid which then was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was purified on silica gel column chromatography (KP-Sil FLASH 25 + M, ethyl acetate : hexane =1:10 → 2:8) to provide the title compound (253 mg, 41 %).
NaH 60% dispersion in mineral oil (3.3mmol) was slowly added to a stirring solution of hydroxyl amine (5a-f) (3.0mmol) in 6mL of DMF at room temp, and stirred for 30min. Compound 6 was then slowly added to reaction mixture, followed by an additional hour of stirring. A saturated NaHCO3 (aq) solution (40mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The subsequent residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with a 2:5 EtOAc/hexanes gradient, to afford the desired Boc-protected O-alkylated fluoroethoxy compounds, identified by LCMS. The intermediate was then dissolved in CH2Cl2 (2mL), followed by dropwise addition of CF3COOH (2mL), and stirred at room temperature for 3h. Volatiles were then removed under reduced pressure and the crude product was neutralized with a saturated NaHCO3 (aq) solution (10mL). The reaction mixture was extracted with CH2Cl2 (3×20mL), and the organic layers were combined, dried, and concentrated to afford the free-amine intermediates (7a-f) as oils used in the next step without any further purification.
With potassium carbonate In N,N-dimethyl-formamide at 60℃;
2.1 Step 1: 2-Bromo-6-(2-fluoroethoxy)naphthalene
A solution of 2.37 g (10.6 mmol) 2-Bromo-6-naphthol, 3.42 g (24.4 mmol) K2CO3and 4.16 g (19.1 mmol) 2-Fluoroethyltosylate in 25 mL DMF was heated overnight at 60° C. The solution was poured into 300 mL water and extracted with chloroform (3×100 mL). The organic phases were washed with 100 mL 1 N NaOH and 100 ml water and dried over Na2SO4. After stripping the solvent the crude product was purified by column chromatography (Hexane/EtOAc 80/20). Appearance: Yellow solidMelting point: 83-85° C.Yield: 2.70 g (10.0 mmol, 94.3%)
32%
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h;
1.1 Step 1: Preparation of compound 5-1
2-Fluoroethyl tosylate (238 μL, 1.4 mmol) in a DMF (3 mL) suspension of compound 4-1 (310 mg, 1.4 mmol) and potassium carbonate (228 mg, 1.65 mmol). In addition, the mixture was stirred at 70 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. After washing with water, the extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, elution solvent: ethyl acetate / n-hexane 1/4), and the solvent was distilled off under reduced pressure to obtain compound 5-1 (121 mg, 0) as a white solid. .45 mmol, 32%) was obtained.
With potassium carbonate In N,N-dimethyl-formamide
S.2.1 Step 1:
Step 1: 2-Bromo-6-(2-fluoroethoxy)naphthalene A solution of 2.37 g (10.6 mmol) 2-Bromo-6-naphthol, 3.42 g (24.4 mmol) K2CO3 and 4.16 g (19.1 mmol) 2-Fluoroethyltosylate in 25 mL DMF was heated overnight at 60°C. The solution was poured into 300 mL water and extracted with chloroform (3 x 100 mL). The organic phases were washed with 100 mL 1 N NaOH and 100 ml water and dried over Na2SO4. After stripping the solvent the crude product was purified by column chromatography (Hexane/EtOAc 80/20). Product characteristics: Appearance: Yellow solid Melting point: 83-85°C Yield: 2.70 g (10.0 mmol, 94.3%) Thin-layer chromatography (silica gel): Rf 2-Bromo-6-naphthol (Hexane/EtOAc 80/20) = 0.45 Rf 2-Bromo-6-(2-fluoroethoxy)naphthalene (Hexane/EtOAc 80/20) = 0.65 1H-NMR (CDl3): δ = 7.80-7.10 (m, 6H), 4.90 (t, 1H), 4.75 (t, 1H), 4.30 (t, 1H), 7.15 (t, 1H).
Stage #1: 3,6,9,12-tetraoxapentadec-14-yn-1-ol With sodium hydride In tetrahydrofuran at 0℃; for 0.166667h;
Stage #2: 2-fluoroethyl tosylate In tetrahydrofuran at 20℃; for 16h;
Stage #1: N-(tert-butoxycarbonyl)-L-prolinol With sodium hydride In N,N-dimethyl-formamide at -10℃; for 0.166667h; Inert atmosphere;
Stage #2: 2-fluoroethyl tosylate In N,N-dimethyl-formamide at -10 - 20℃; for 26h; Inert atmosphere;
4.5.12 (S)-N-tert-Butyloxycarbonyl-2-(2-fluoroethoxymethyl)pyrrolidine (21)
Under argon atmosphere, a stirred solution of (S)-N-tert-butyloxycarbonyl-2-hydroxymethylpyrrolidine (4) (1.50 g, 7.45 mmol, 1.50 equiv) in dry DMF (35 mL) was cooled to -10 °C and treated with 60% NaH (397 mg, 9.94 mmol, 2.00 equiv). After stirring for 10 min, 1-fluoro-2-tosyloxyethane (1.08 g, 4.97 mmol, 1.00 equiv) was added to the mixture. It was stirred below -5 °C for 4 h, at 0 °C for 4 h and room temperature for 18 h. Then, it was quenched by dropwise addition of water until no H2 evolved anymore and concentrated in vacuo. The residue was taken up in water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic phase was dried over MgSO4 and concentrated in vacuo. Subsequently, the crude product was purified by flash column chromatography (silica gel, 20% EtOAc in cyclohexane) to obtain a colorless oil (845 mg, 3.42 mmol, 69%). 1H NMR (400 MHz, CDCl3): δ = 4.53 (dt, 2JH,F = 47.8 Hz, 3JH,H = 4.2 Hz, 2H, 13-CH2), 4.05-3.83 (m, 1H, 2-CH), 3.80-3.60 (m, 2H, 12-CH2), 3.69-3.57 (m, 1H, 10-CHa), 3.51-3.31 (m, 1H, 10-CHb), 3.43-3.21 (m, 2H, 5-CH2), 2.00-1.75 (m, 4H, 3-CH2, 4-CH2), 1.47 (s, 9H, 9-CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.6 (6-CO, rotamer B), 154.5 (6-CO, rotamer A), 83.1 (d, 1JC,F = 169.3 Hz, 13-CH2), 79.3 (8-CO, rotamer B), 79.2 (8-CO, rotamer A), 72.3 (10-CH2, rotamer B), 71.5 (10-CH2, rotamer A), 70.3 (d, 2JC,F = 19.6 Hz, 12-CH2), 56.4 (2-CH), 46.9 (5-CH2, rotamer B), 46.4 (5-CH2, rotamer A), 28.7 (3-CH2, rotamer A), 28.5 (3C, 9-CH3), 28.0 (3-CH2, rotamer B), 23.7 (4-CH2, rotamer B), 22.9 (4-CH2, rotamer A) ppm. 19F NMR (282 MHz, CDCl3): δ = -223.6 (s, 13-CH2F, rotamer A), -223.9 (s, 13-CH2F, rotamer B) ppm. HRMS (ESI+, MeOH): m/z = 270.1479 [M+Na]+; calcd 270.1476 for C12H22FNO3+Na.
[0146] Potassium carbonate (297.2 mg, 2.15 mmol) was added to an N,N-dimethylformamide (18 mL) solution of 55 <strong>[55687-04-2]2-chloroquinoxalin-6-ol</strong> (194.2 mg, 1.08 mmol) synthesized in the step 9-1, which was then stirred at 80 C. for 0.5 hour. Then, 48 2-fluoroethyl-4-methylbenzenesulfonate (460 μL) was added thereto, which was then stirred at 80 C. for 1.5 hours. This suspension was cooled down to room temperature and extracted with ethyl acetate (60 mL×2). The total organic layer was dried with magnesium sulfate. The solvent was evaporated and the residue was then purified by silica-gel chromatography (ethyl acetate/hexane=1/3 (volume ratio) and further chloroform) to provide (127 32) shown in the scheme 8 (yield: 133.0 mg (54.3%)). [0147] 1H-NMR (400 MHz, deuterated chloroform) δ 8.72 (s, 1H), 7.93 (d, J=9.2 Hz, 1H), 7.51 (dd, J=9.2, 2.8 Hz, 1H), 7.39 (d, J=2.8 Hz, 1H), 4.92-4.78 (m, 2H), 4.43-4.34 (m, 2H); MS (APCI) m/z 227[MH+].
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 100℃; for 6h;Inert atmosphere;
Dry DMF (15 ml) solution of <strong>[2460-58-4]2-hydroxy-4-nitrobenzaldehyde</strong> (0.50 g, 2.99 mmol) to a stirred solution of, under argon atmosphere, was added K2CO3 (1.24g, 8.98mmol) at room temperature . To this stirred suspension, 2-fluoroethyl - was added dropwise (4-methylbenzene) sulfonate (0.78 g, 3.59 mmol). The reaction mixture was heated for 6 hours to 0.89 ° C.. The cooled reaction mixture was added to water (250ml), and extracted with EtOAc (3 × 75ml). The combined organic layers were washed with brine (50ml), dried (Na2SO4), the solvent was removed under reduced pressure to give a brown solid, by flash chromatography was purified by (3 1 DCM / hexanes), the title compound (0.493g, 77percent) as a yellow solid.
With caesium carbonate; In dimethyl sulfoxide; at 20℃; for 18h;
Example 28: 1,1,1,3,3,3-Hexafluoropropan-2-yl 1-(4-chloro-3-(2-fluoroethoxy)benzyl)-1,8- diazaspiro[4.5]decane-8-carboxylate Step 1: Preparation of 4-chloro-3-(2-fluoroethoxy)benzaldehyde A vial was charged with cesium carbonate (211 mg, 0.650 mmol) and DMSO (2mL), and the reaction was stirred for 5 min at rt prior to addition of 2-fluoroethyl 4-methylbenzenesulfonate (71 mg, 0.330 mmol). The reaction mixtured was stirred at rt for 18 h. The resulting solution was poured into EtOAc (150 mL) and washed with sat sodium carbonate (3 x 50 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was chromatographed on a silica column to afford [2,2,2-trifluoro-1- (trifluoromethyl)ethyl] 1-[[4-chloro-3-(2-fluoroethoxy)phenyl]methyl]-1,8-diazaspiro[4.5]decane- 8-carboxylate (10 mg, 0.017 mmol, 22 % yield).1H NMR (400 MHz, Chloroform-d) delta 9.95 (s, 1H), 7.62- 7.54 (m, 1H), 7.49- 7.41 (m, 2H), 4.95- 4.87 (m, 1H), 4.83- 4.75 (m, 1H), 4.45- 4.31 (m, 2H).
With caesium carbonate; In N,N-dimethyl-formamide; at 85℃; for 5h;Inert atmosphere;
2-Chloro-5-hydroxypyridine (0.300 g 2.316 mmol) and 2-fluoroethyl-4- methylbenzenesulfonate (0.505 g, 2.316 mmol, CAS 383-50-6) were dissolved in DMF (7 mL). CS2CO3 (1.132 g, 3.474 mmol) was added under nitrogen atmosphere. The mixture was heated to 85 C for 5 h. After cooling to ambient temperature, the dark brown suspension was diluted with water and extracted with EtOAc. The org layers were washed with brine, dried over MgS04, filtered and concentrated. The product was purified by flash column chromatography (silica; EtOAc in heptane 0/100 to 35/65). The desired fractions were collected and concentrated in vacuo providing intermediate 15 (0.374 g, 92%).
[2-(2-fluoroethoxy)phenyl]diphenylphosphine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 20h;
Synthesis Example 12 [2-(2-Fluoroethoxy)phenyl]-diphenylphosphine The same synthesis procedure as in Synthesis Example 10 was performed using 2-diphenylphosphanyl phenol as a starting material. Separation was done by Hi-flash silica column chromatography (developing solvent, ethyl acetate:hexane=3:97→21:79) to yield a product (76% yield, white solid). 1H-NMR (600 MHz, CDCl3): δ7.36-7.29 (m, 11H), 6.91-6.87 (m, 2H), 6.74-6.70 (m, 1H), 4.40 (dt, J=47.4, 4.8 Hz, 2H), 4.11 (dt, J=25.8, 4.8 Hz, 2H); LRMS (EI) calculated for C20H18FOP (M1): 324.1, found: 324.1.
NaH 60% dispersion in mineral oil (3.3mmol) was slowly added to a stirring solution of hydroxyl amine (5a-f) (3.0mmol) in 6mL of DMF at room temp, and stirred for 30min. Compound 6 was then slowly added to reaction mixture, followed by an additional hour of stirring. A saturated NaHCO3 (aq) solution (40mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The subsequent residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with a 2:5 EtOAc/hexanes gradient, to afford the desired Boc-protected O-alkylated fluoroethoxy compounds, identified by LCMS. The intermediate was then dissolved in CH2Cl2 (2mL), followed by dropwise addition of CF3COOH (2mL), and stirred at room temperature for 3h. Volatiles were then removed under reduced pressure and the crude product was neutralized with a saturated NaHCO3 (aq) solution (10mL). The reaction mixture was extracted with CH2Cl2 (3×20mL), and the organic layers were combined, dried, and concentrated to afford the free-amine intermediates (7a-f) as oils used in the next step without any further purification.
NaH 60percent dispersion in mineral oil (3.3mmol) was slowly added to a stirring solution of hydroxyl amine (5a-f) (3.0mmol) in 6mL of DMF at room temp, and stirred for 30min. Compound 6 was then slowly added to reaction mixture, followed by an additional hour of stirring. A saturated NaHCO3 (aq) solution (40mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The subsequent residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with a 2:5 EtOAc/hexanes gradient, to afford the desired Boc-protected O-alkylated fluoroethoxy compounds, identified by LCMS. The intermediate was then dissolved in CH2Cl2 (2mL), followed by dropwise addition of CF3COOH (2mL), and stirred at room temperature for 3h. Volatiles were then removed under reduced pressure and the crude product was neutralized with a saturated NaHCO3 (aq) solution (10mL). The reaction mixture was extracted with CH2Cl2 (3×20mL), and the organic layers were combined, dried, and concentrated to afford the free-amine intermediates (7a-f) as oils used in the next step without any further purification.
Stage #1: tert-butyl 3-hydroxyazetidine-1-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃;
Stage #2: 2-fluoroethyl tosylate In N,N-dimethyl-formamide; mineral oil
4.1.2 General synthetic procedure for compounds 7a-f
NaH 60% dispersion in mineral oil (3.3mmol) was slowly added to a stirring solution of hydroxyl amine (5a-f) (3.0mmol) in 6mL of DMF at room temp, and stirred for 30min. Compound 6 was then slowly added to reaction mixture, followed by an additional hour of stirring. A saturated NaHCO3 (aq) solution (40mL) was then added to the crude reaction mixture and stirred at room temp for 1h. The reaction mixture was extracted with CH2Cl2 (3×20mL) to afford the crude product. The subsequent residue was loaded onto a Biotage SNAP flash purification cartridge, eluting with a 2:5 EtOAc/hexanes gradient, to afford the desired Boc-protected O-alkylated fluoroethoxy compounds, identified by LCMS. The intermediate was then dissolved in CH2Cl2 (2mL), followed by dropwise addition of CF3COOH (2mL), and stirred at room temperature for 3h. Volatiles were then removed under reduced pressure and the crude product was neutralized with a saturated NaHCO3 (aq) solution (10mL). The reaction mixture was extracted with CH2Cl2 (3×20mL), and the organic layers were combined, dried, and concentrated to afford the free-amine intermediates (7a-f) as oils used in the next step without any further purification.
tert-butyl N-[(1S,2S)-2-(2-fluoroethylamino)cyclopentyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium iodide; In N,N-dimethyl-formamide; at 100℃; for 1h;
To a solution of <strong>[586961-34-4]tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate</strong> (0.2 g, 998.62 umol, 1 eq) in DMF (2 mL) was added KI (182.35 mg, 1.10 mmol, 1.1 eq) and 2-fluoroethyl 4-methylbenzenesulfonate (239.74 mg, .10 mmol, 1.1 eq). The mixture was stirred at l00C for 1 h then poured into aqueous LiCl (3%, 50 mL), extracted with EtOAc (30 mLx2), and the combined organic layers were washed with brine (50 mL), dried over Na SCL, filtered and concentrated under reduced pressure to afford the title compound (250 mg, crude) as brown solid
Stage #1: (3S)-N-[5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidi n-3-yl]-3-hydroxypyrrolidine-1-carboxamide With potassium carbonate In ethanol at 20℃; for 0.25h;
Stage #2: 2-fluoroethyl tosylate In ethanol at 70℃; for 18h;
12 The synthesis of reference substance 2-fluoroethyl-O-Larotrectinib (2-fluoroethoxy Larotrectinib)
Add (R,S)-Larotrectinib (100mg, 0.5mmol), dry ethanol (10mL), potassium carbonate (97mg, 0.7mmol) to the reactor, stir at room temperature for 15 minutes, add 2-fluoroethyl-p-toluenesulfonate A dry ethanol solution (5 mL) of the acid ester (87.2 mg, 0.5 mmol), the reaction mixture was heated to 70° C. and reacted for 18 hours. TLC detected the complete conversion of the raw materials, the ethanol was evaporated, the crude product was subjected to silica gel column chromatography, and the eluent was a mixed solvent (DCM: MeCH3: TEA = 10:1: 0.002) to obtain 56 mg (0.23 mmol, 46%) of light Yellow solid.
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 13h;
2-Fluoropropyl tosylate (300 mg, 1.3 mmol) in a DMF (3 mL) suspension of compound 3-1 (233 mg, 1.3 mmol) and potassium carbonate (684 mg, 4.9 mmol). In addition, the mixture was stirred at 70 C. for 13 hours. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. After washing with water, the extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, elution solvent: ethyl acetate / n-hexane 1/4), and the solvent was distilled off under reduced pressure to obtain a white solid compound 4-2 (184 mg 0.77). mmol) was obtained.
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