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HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
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Structure of 456-42-8 * 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.
Reference：
[1] Journal of the American Chemical Society, 1980, vol. 102, # 4, p. 1367 - 1371
[2] Nippon Kagaku Zasshi, 1958, vol. 79, p. 1428,1430[3] Chem.Abstr., 1960, p. 5518
2
[ 352-70-5 ]
[ 456-42-8 ]
Reference：
[1] Journal of the Chemical Society, 1949, p. 1089,1096
[2] Zeitschrift fuer Physikalische Chemie (Leipzig), 1931, vol. <A> 156, p. 397,398
[3] Journal of the Indian Chemical Society, 1944, vol. 21, p. 112,114
[4] Tetrahedron, 1971, vol. 27, p. 945 - 951
[5] Bulletin des Societes Chimiques Belges, 1960, vol. 69, p. 312 - 322
[6] Journal of the American Chemical Society, 1960, vol. 82, p. 99 - 104
[7] Journal of the American Chemical Society, 1963, vol. 85, p. 709 - 724
[8] Journal of Organic Chemistry USSR (English Translation), 1987, vol. 23, # 4, p. 711 - 719[9] Zhurnal Organicheskoi Khimii, 1987, vol. 23, # 4, p. 788 - 797
[10] Journal of Organic Chemistry USSR (English Translation), 1982, vol. 18, p. 317 - 324[11] Zhurnal Organicheskoi Khimii, 1982, vol. 18, # 2, p. 365 - 373
[12] Journal of Organic Chemistry USSR (English Translation), 1981, vol. 17, # 4, p. 693 - 699[13] Zhurnal Organicheskoi Khimii, 1981, vol. 17, # 4, p. 793 - 799
3
[ 65108-06-7 ]
[ 456-42-8 ]
Reference：
[1] Journal of the American Chemical Society, 1985, vol. 107, # 13, p. 3747 - 3757
4
[ 28490-56-4 ]
[ 456-42-8 ]
Reference：
[1] Journal of the American Chemical Society, 1980, vol. 102, # 4, p. 1367 - 1371
5
[ 456-41-7 ]
[ 456-42-8 ]
Reference：
[1] Journal of the American Chemical Society, 1980, vol. 102, # 4, p. 1367 - 1371
6
[ 100-11-8 ]
[ 456-42-8 ]
Reference：
[1] Journal of the American Chemical Society, 1980, vol. 102, # 4, p. 1367 - 1371
7
[ 456-47-3 ]
[ 456-42-8 ]
Reference：
[1] Journal of the Chemical Society, 1935, p. 1815,1818
8
[ 394-54-7 ]
[ 65108-06-7 ]
[ 128408-33-3 ]
[ 456-42-8 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1997, vol. 70, # 5, p. 1163 - 1169
9
[ 191402-55-8 ]
[ 65108-06-7 ]
[ 128408-28-6 ]
[ 456-42-8 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1997, vol. 70, # 5, p. 1163 - 1169
10
[ 81577-13-1 ]
[ 65108-06-7 ]
[ 128408-32-2 ]
[ 456-42-8 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1997, vol. 70, # 5, p. 1163 - 1169
11
[ 65108-06-7 ]
[ 128408-27-5 ]
[ 456-42-8 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1997, vol. 70, # 5, p. 1163 - 1169
12
[ 352-70-5 ]
[ 402-64-2 ]
[ 456-42-8 ]
Reference：
[1] Journal fuer Praktische Chemie (Leipzig), 1932, vol. <2> 135, p. 101,113
[2] Zeitschrift fuer Physikalische Chemie (Leipzig), 1931, vol. <A> 156, p. 397,398
[3] Journal of the Chemical Society, 1949, p. 1089,1096
13
[ 201230-82-2 ]
[ 456-42-8 ]
[ 331-25-9 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With C28H22CoN4O6 In butan-1-ol at 60℃; for 2 h; Glovebox; High pressure; Green chemistry Stage #2: With tetra-(n-butyl)ammonium iodide; sodium hydroxide In butan-1-ol at 60℃; for 22 h; Glovebox; High pressure; Green chemistry
General procedure: A 100 mL reactor equipped with Teflon-coated magnetic stir bars was charged with n-Butyl alcohol (20 mL) and the catalyst (0.5 mmol). The reactor was then taken out of the glove box and pressured with carbon monoxide (1 atm). The mixture was stirred 2 h at 60 °C, cooled to ambient temperature and slowly vented. After benzyl chloride (10 mmol), NaOH (15 mL, 15percent), and TBAI (0.25 mmol) were added, the reactor was sealed and the reaction mixtures were stirred for 22 h at 60 °C under carbon monoxide (1 atm). After the reaction, the water phase was detached and washing the organic phase three times with H2O (3×5 mL), the combined water layer was washed with Et2O, then the resulting solution was cooled to 0 °C and adjusted to pH=1–2 with HCl (6 mol/L). The product was filtered, dried in RT, and then recrystallized.
Reference：
[1] Bulletin des Societes Chimiques Belges, 1960, vol. 69, p. 312 - 322
[2] Journal of the American Chemical Society, 1963, vol. 85, p. 709 - 724
18
[ 456-42-8 ]
[ 458-45-7 ]
Reference：
[1] Journal of Physical Organic Chemistry, 1999, vol. 12, # 10, p. 751 - 757
19
[ 123-08-0 ]
[ 456-42-8 ]
[ 66742-57-2 ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate In ethanol for 5.41667 h; Heating / reflux
Accordingly, a mixture of 3-fluorobenzyl chloride (2.86 g, 19.80 mmol) 4- hydroxybenzaldehyde (3.03 g, 24.80 mmol), K2CO3 (10.30 g, 74.50 mmol),NaI (137.1 mg, 0.91 mmol), and ethanol, (40 mL) is heated to reflux in 70 min and kept at reflux temperature for 4 hours and 15 min.After working up the reaction mixture, 4-(3-fluorobenzyloxy)benzaldehyde, <n="82"/>is isolated as a yellow oil in 95percent yield.The product has GC purity of 97.6 (area percent, see Example 25A) and a content of 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde (Via) of 0.14percent by weight determined by GC (see Example 25B)
95%
With sodium hydroxide In ethanol for 6.75 h; Heating / reflux
Accordingly, 3-fluorobenzyl chloride (14.5g, 100 mmol) is added under stirring and under nitrogen atmosphere to a solution of 4- hydroxybenzaldehyde (12.2g, 100 mmol) and of NaOH (4.0g, 100 mmol) in ethanol (100 mL).The mixture is gradually heated in 25 min to reflux and stirred at reflux temperature for 6 hours and 20 min. The reaction mixture is filtrated and then concentrated at reduced pressure to obtain 4-(3-fluoro- benzyloxy)benzaldehyde (23.43 g) as a yellow solid residue.Dichloromethane (25OmL) is added to the residue, the insoluble is filtered and the resulting solution is concentrated under reduced pressure to provide 4-(3-fluorobenzyloxy)benzaldehyde as a yellow solid, in 80.4percent yield. The product has GC purity of 91.6 (area percent, see Example 24A) and a content of 3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy)benzaldehyde (Via) of 0.13percent by weight determined by GC(see Example 25B)
95%
With potassium carbonate; sodium iodide In ethanol for 5.41667 h; Heating / reflux
EXAMPLE 14 <n="46"/>Preparation of (S)-2-[4-(3-fluorobenzyloxy)benzylamino1propanamide (safinamide, Ia) methanesulfonate (Ic) according to the methods described in the prior art14.1 Preparation of 4-(3-fluorobenzyloxy)benzaldehyde (IVa) 14.1. a) Procedure of Example Ia of US 6,335,354 B24-(3-Fluorobenzyloxy)benzaldehyde (IVa) is prepared by the procedure described in Example Ia of US 6,335,354 B2.Accordingly, a mixture of 3-fluorobenzyl chloride (2.86 g, 19.80 mmol) 4- hydroxybenzaldehyde (3.03 g, 24.80 mmol), K2CO3 (10.30 g, 74.50 mmol ),NaI (137.1 mg, 0.91 mmol), and ethanol, (40 mL) is heated to reflux in 70 minutes and kept at reflux temperature for 4 hours and 15 minutes.After working up the reaction mixture, 4-(3-fluorobenzyloxy)benzaldehyde, is isolated as a yellow oil in 95percent yield. The product has GC purity of 97.6 (area percent, see Example 16A) and a content of 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde (Va) of 0.14percent by weight determined by GC (see Example 16B)
92%
With potassium carbonate In ethanol for 6 h; Heating / reflux
To a mixture of 4-hydroxybenzaldehyde (2.28 kg, 18.68 mol), potassium carbonate, (2.84 kg, 20.54 mol), potassium iodide (0.33 kg, 1.98 mol) in ethanol (21.0 kg), 3-fluorobenzyl chloride (2.70 kg, 18.68 mol) is added under stirring, at room temperature.The mixture is gradually heated to reflux and then kept at that temperature for 6 hours. The reaction mixture is then allowed to cool to 25 °C, the suspension is filtered and the solid is washed with ethanol (1.5 kg); the ethanol solutions are combined and then concentrated at reduced pressure until a residue of approximately 6.0 kg is obtained.To this residue, toluene (10 kg) and water (2.5 kg) are added, the solvent mixture is stirred vigorously for 30 min and, after separation of the aqueous phase, the organic layer is evaporated to dryness under reduced pressure to provide crude 4-(3-fluorobenzyloxy)benzaldehyde.To this product dissolved in toluene (3 kg) a seed of 4- (3- fluorobenzyloxy)benzaldehyde is added under stirring at 20-25 °C, then n- hexane (6.0 kg) is added in 45 min and the mixture is cooled to 0 °C under stirring.After 3 hours the solid is filtered and washed with n-hexane (2.0 kg). After drying, 3.95 kg (92.0percent yield) of the desired product are obtained, with a gas-cromathographic purity of 99.8 (area percent, see Example 24A) and a 3-(3- <n="59"/>fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde content of 0.01percent by weight determined by G.C. (area percent, see Example 24B); m.p. 43.1 °C by DSC 5°C/min.
91%
Stage #1: With potassium carbonate; potassium iodide In ethanol for 0.25 h; Stage #2: for 6 h; Reflux
15.2 g (124.5 mmol) of p-hydroxybenzaldehyde, 17.2 g (124.5 mmol) of potassium carbonate and 2.0 g of potassium iodide (12 mmol) was added to 170 ml of absolute ethanol and stirred for 15 min,A solution of 3-fluorobenzyl chloride (17.3 ml, 141.7 mmol) was added dropwise and heated under reflux for 6 h. filter,The filter cake was washed with absolute ethanol (15 ml x 3), the filtrate and the washings were combined, concentrated under reduced pressure,The remaining pale yellow oil was added with 60 ml of toluene and 20 ml of water, stirred for 30 min,The toluene layer was separated and concentrated under reduced pressure. The residue was recrystallized from toluene-n-hexane (1: 1)A white solid of 4- (3-fluorobenzyloxy) benzaldehyde (26.1 g, 91percent), mp 43.8-4.99 .
90.2%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; sodium iodide In acetone at 20 - 25℃; for 24 h; Inert atmosphere
Into a dry reaction flask under nitrogen protection were added successively 3-fluorobenzyl chloride II-1 (X = 3-F, Y = -Cl) (50 g,0.34 mol), p-hydroxybenzaldehyde III-1 (44.3 g, 0.36 mol), acetone 500mL, DBU (57.6 g, 0.38 mol), sodium iodide (5.18 g, 0.034 mol), add at 20 ~ 25 deg. C, stirring 24h. The reaction solution was concentrated under reduced pressure, the residue was added to 500 mL of dichloromethane, the resulting mixture was washed with 1 M hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution, the organic phase is dried, concentrated, get crude, recrystallization from isopropyl ether gave 72 g of white solid I-1 (X = 3-F), yield 90.2percent, Mp: 42.5 to 43.9 ° C, the purity was 99.75percent by HPLC, no impurities IV-1 (X = 3-F) were detected.
90.7%
With potassium carbonate; potassium iodide In ethanol at 20℃; for 6 h; Heating / reflux
EXAMPLE 4Preparation of purified 4-(3-fluorobenzyloxy)benzaldehyde (IVaI in ethanol solutionTo a mixture of 4-hydroxybenzaldehyde (1.52 kg, 12.45 mol), potassium carbonate, (1.72 kg, 12.45 mol), potassium iodide (0.2 kg, 1.20 mol) in ethanol (13.0 kg), 1.8 kg, of 3-fluorobenzyl chloride (1.80 kg, 12.45 mol) are added under stirring, at room temperature.The mixture is gradually heated to reflux and then kept at that temperature for 6 hours.The reaction mixture is then allowed to cool to 25 0C, the suspension is filtered and the solid is washed with ethanol (1.0 kg); the ethanol solutions are combined and then concentrated at reduced pressure until a residue of approximately 3.5 kg is obtained.To this residue, toluene (5.0 kg) and water (1.7 kg) are added, the solvent mixture is stirred vigorously for 30 minutes and, after separation of the aqueous phase, the organic layer is evaporated to dryness under reduced pressure to provide crude 4-(3-fluorobenzyloxy)benzaldehyde.To this product dissolved in 2 kg of toluene a seed of 4-(3- fluorobenzyloxy)benzaldehyde is added under stirring at 20-25 0C, then n- hexane (3.8 kg) is added in 30 minutes and the mixture is cooled to 0 0C <n="30"/>under stirring.After 2 hours the solid is filtered and washed with n-hexane (1.3 kg). After drying, 2.6 kg (90.7percent yield) of the desired product are obtained, with a gas- cromathographic purity of 99.9 (area percent, see Example 16A) and a 3-(3- fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde content of 0.005percent by weight determined by G.C. (area percent, see Example 16B); m.p. 43.1 0C by DSC 5°/min.
88%
Stage #1: With potassium carbonate In isopropyl alcohol at 20 - 25℃; for 0.25 h; Stage #2: for 3.33333 h; Heating / reflux
In a 10 L reactor, 2-propanol (5.51 kg), potassium carbonate (793 g, 5.74 mol), potassium iodide (305 g, 1.84 mol) and 4-hydroxybenzaldehyde (700 g, 5.74 mol) are charged. The mixture is stirred at 20-25 °C for 15 min. 3-fluorobenzyl chloride (871 g, 6.03 mol) is charged in the reactor with the aid of a dropping funnel in about 20 min.The mixture is heated at reflux under stirring for 3 hours.After this time, the mixture is cooled to about 50 °C and sampled for in process control.The solvent is removed under vacuum until a volume of about 1.8 1 is reached.Cyclohexane (1.84 kg) and water (2.5 kg) are added, and then the mixture is heated to 65+/-3 °C and stirred at this temperature for 30 min. Stirring is stopped and the phases are allowed to separate for 20 min; the water phase is discharged. Water (1.31 kg) is added to the organic phase and the biphasic mixture stirred for 30 min at 65+/-3 °C. The phases are allowed to separate for 20 min. The water phase is discharged and the organic phase is concentrated under vacuum to a volume of about 3 1 at a temperature comprised between 40 and 55 °C. The mixture is cooled to about 30 °C, seeded and stirred at this temperature for 30 min.The mixture is cooled to 20+/-2 °C and stirred at this temperature for at least 3 hours. The product is filtered under suction and the solid is washed with cyclohexane (3 x 150 g).The wet solid (1.5 kg) is dried at 20-25 °C at a pressure below 100 mbar for 12 hours to provide 1.17 kg (5.09 mol); 88percent yield with a gas- cromathographic purity of 99.43 (area percent, see Example 24A) and a content of 0.063percent by weight determined by G.C. (area percent, see Example 24B) 3-(3- <n="60"/>fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde (Via). This product is further purified according to the procedure described in Example 1 1.1 to yield a product wherein the content of the impurity (Via) is 0.01 percent by weight determined by GC (see Example 24B) .
86.3%
With potassium carbonate In toluene for 7 h; Heating / reflux
A mixture of 3-fluorobenzyl chloride (10 kg, 69.16 mol), 4-hydroxy- benzaldehyde (7.8 kg, 63.88 mol), potassium carbonate (9.46 kg, 68.44 mol) and tetradecyl trimethylammonium bromide (1.03 kg, 3.72 mol) in toluene (30.0 kg) is slowly brought to reflux temperature under stirring and under nitrogen atmosphere, and then refluxed for 7 hours.The solution is concentrated at room pressure and then 6 kg of toluene are added and distilled off. This procedure is repeated once again. The heterogeneous mixture is then cooled to room temperature and the solid is eliminated by filtration. The residual solvent is eliminated under reduced pressure and then 2.6 kg of toluene are added to the oily residue. The mixture is stirred at 20-25 °C and seeded with a few grams of pure 4- (3-fluorobenzyloxy)benzaldehyde, and then n-hexane (18 kg) is added in 45 min to the stirred mixture kept at 20-25 °C After cooling to 3-6 °C and stirring for a further hour at this temperature the solid is collected by filtration and dried under reduced pressure to give 13.5 kg with a 86.3 percent yield, GC purity 99.8 (area percent, see Example 24A) and a 3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy)benzaldehyde content of 0.01percent by weight (see Example 24B).
86.2%
Stage #1: With potassium carbonate In ethanol at 20℃; for 0.5 h; Stage #2: With potassium iodide In ethanol for 4 h; Reflux
88. 70 g (0. 73mo 1) of p-hydroxybenzaldehyde was added to a 1000 ml reaction flask,Add ethanol 500ml,Plus K2C03105 · 10g (0.76mol),Stirred at room temperature for 30 min,Followed by addition of fluorobenzyl chloride 100.00 g (0.69 mol)KI 9 · 20g(0. 06 mol) and refluxed for 4 h.After completion of the reaction, the mixture was cooled to room temperature, stirred with 500 ml of water for 1 hour, and the filter cake was added1000ml water stirred lh, filter, room temperature drying cake 24h, white solid 4- (3-fluorobenzyloxy) benzaldehyde 137. 10g,Yield: 86.2percent. HPLC purity: 99.82percent.
85%
With cetyltrimethylammonium bromide; potassium carbonate In toluene for 6 h; Heating / reflux
EXAMPLE 5 Preparation of 4-(3-fluorobenzyloxy)benzaldehyde (IVa) by phase transfer catalysisA mixture of 3-fluoroben2yl chloride (5 kg, 34.58 mol), 4-hydroxy- benzaldehyde (3.9 kg, 31.94 mol), potassium carbonate (4.3 kg, 31.11 mol) and tetradecyl trimethylammonium bromide (0.41 kg, 1.22 mol) in toluene (13.5 kg) is slowly brought to reflux temperature under stirring and under nitrogen atmosphere, and then refluxed for 6 hours.The solution is concentrated at room pressure and then 3 kg of toluene are added and distilled off. This procedure is repeated once again. The heterogeneous mixture is then cooled to room temperature and the solid is eliminated by filtration. The residual solvent is eliminated under reduced pressure and then 1.2 kg of toluene are added to the oily residue. The mixture is stirred at 20-25 0C and seeded with a few grams of pure 4- (3-fluorobenzyloxy) benzaldehyde, and then additioned of n-hexane (9 kg) at this temperature, in 30 minutes. After cooling to 0-5 0C and stirring for a further hour at this temperature the solid is collected by filtration and dried under reduced pressure to give 6.5 kg (85percent yield, GC purity 99.9 (area percent, see Example 16A) and a 3-(3- fluorobenzyl) -4- (3 -fluorobenzyloxy) benzaldehyde content of 0.008percent by weight (see Example 16B).
80.4%
With sodium hydroxide In ethanol for 6.75 h; Heating / reflux
14.1.b) Procedure of J. Agric. Food Chem, 27, 4. 1979 4-(3-Fluorobenzyloxy)benzaldehyde (IVa) is prepared by the procedure reported in J. Agric. Food Chem, 27, 4, 1979.Accordingly, 3-fluorobenzyl chloride (14.5g, 100 mmol) is added under stirring and under nitrogen atmosphere to a solution of 4- hydroxybenzaldehyde (12.2g, 100 mmol) and of NaOH (4.Og, 100 mmol) in ethanol (100 mL).The mixture is gradually heated in 25 minutes to reflux and stirred at reflux temperature for 6 hours and 20 minutes. The reaction mixture is filtrated and then concentrated at reduced pressure to obtain 4-(3-fluoro- benzyloxy)benzaldehyde (23.43 g) as a yellow solid residue. Dichloromethane (25OmL) is added to the residue, the insoluble is filtered and the resulting solution is concentrated under reduced pressure to provide 4-(3-fluorobenzyloxy)benzaldehyde as a yellow solid, in 80.4percent yield. The product has GC purity of 91.6 (area percent, see Example 16A) and a content of 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde (Va) of 0.13percent by <n="47"/>weight determined by GC(see Example 16B)
Reference：
[1] Patent: WO2009/74478, 2009, A1, . Location in patent: Page/Page column 80-81
[2] Patent: WO2009/74478, 2009, A1, . Location in patent: Page/Page column 81
[3] Patent: WO2007/147491, 2007, A1, . Location in patent: Page/Page column 44-45
[4] Patent: WO2009/74478, 2009, A1, . Location in patent: Page/Page column 57-58
[5] Patent: CN106220525, 2016, A, . Location in patent: Paragraph 0013; 0014; 0019
[6] Patent: CN106365966, 2017, A, . Location in patent: Paragraph 0028; 0029; 0030; 0031; 0035; 0036; 0037; 0041
[7] Patent: WO2007/147491, 2007, A1, . Location in patent: Page/Page column 28-29
[8] Patent: WO2009/74478, 2009, A1, . Location in patent: Page/Page column 58-59
[9] Patent: WO2009/74478, 2009, A1, . Location in patent: Page/Page column 59
[10] Patent: CN106565520, 2017, A, . Location in patent: Paragraph 0015
[11] Patent: WO2007/147491, 2007, A1, . Location in patent: Page/Page column 29
[12] Patent: WO2007/147491, 2007, A1, . Location in patent: Page/Page column 45-46
[13] Letters in Drug Design and Discovery, 2014, vol. 11, # 6, p. 736 - 741
[14] Patent: US6335354, 2002, B2, . Location in patent: Example 1
[15] European Journal of Medicinal Chemistry, 2012, vol. 56, p. 203 - 209,7
[16] Letters in Drug Design and Discovery, 2015, vol. 12, # 5, p. 430 - 438
Reference：
[1] Nippon Kagaku Zasshi, 1958, vol. 79, p. 1428,1430[2] Chem.Abstr., 1960, p. 5518
[3] Journal of the American Chemical Society, 1963, vol. 85, p. 709 - 724
[4] Journal of the Chemical Society, 1935, p. 1815,1818
22
[ 456-42-8 ]
[ 75-65-0 ]
[ 456-47-3 ]
[ 351-22-4 ]
[ 72402-80-3 ]
Reference：
[1] Journal of Organic Chemistry, 1980, vol. 45, # 6, p. 951 - 957
23
[ 456-42-8 ]
[ 456-88-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2004, vol. 2, # 18, p. 2684 - 2691
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1990, vol. 39, # 7.2, p. 1479 - 1485[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1990, # 7, p. 1630 - 1636
27
[ 74-89-5 ]
[ 456-42-8 ]
[ 90389-84-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4693 - 4707
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 175 - 194
[2] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 330 - 348
[3] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 316 - 336
30
[ 619-08-9 ]
[ 456-42-8 ]
[ 443882-99-3 ]
Yield
Reaction Conditions
Operation in experiment
57%
With potassium carbonate In acetonitrileReflux
Step 1: 2-chloro-1-(3-fluorobenzyloxy)-4-nitrobenzene 2-chloro-4-nitrophenol (3.4 g, 20 mmol), 3-fluorobenzyl chloride (2.8 g, 20 mmol) and potassium carbonate (3.3 g, 24 mmol) was refluxed in acetonitrile (30 mL) overnight. The reaction mixture was poured into 100 mL of H2O, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated in vacuo to obtain the crude product. The crude product was washed with petroleum ether, filtered and dried, and the compound shown in the title (3.2 g, 57percent) was obtained. 1H NMR (CDCl3): δ 8.35 (1H, d, J=2.8 Hz), 8.17-8.14 (1H, m), 7.44-7.38 (1H, m), 7.25-7.19 (2H, m), 7.10-7.06 (1H, m), 7.03 (1H, d, J=9.2 Hz), 5.26 (2H, s).
53%
With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 23 h; Inert atmosphere
The synthesis was performed as described by Shiao et al. for similar compounds [60]. The work-up was performed as described by Fontana et al. [61]. 2-Chloro-4-nitrophenol (1.50 g, 8.64 mmol) was mixed with K2CO3 (3.58 g, 25.9 mmol), before DMF (90 mL) was added under nitrogen atmosphere. The mixture was heated to 75 °C, and 3-fluorobenzyl chloride (1.87 g, 13.0 mmol) dissolved in DMF (60 mL) was added slowly. The reaction mixture was stirred at 75 °C for 23 h, cooled to rt, quenched into cold water (150 mL, 5 °C) and filtered. The isolated solid was washed with an ACN/water mixture (1/1, 50 mL), and n-hexane (30 mL). The obtained white solid was dried under reduced pressure. This yielded 1.29 g (4.58 mmol, 53percent) of 2-chloro-1-((3-fluorobenzyl)oxy)-4-nitrobenzene as a white solid, mp. 90–96 °C; 1H NMR (400 MHz, DMSO-d6) δ: 8.35 (d, J=2.8, 1H), 8.25 (dd, J=8.8, 2.8, 1H), 7.52–7.44 (m, 2H), 7.35–7.30 (m, 2H), 7.24–7.17 (m, 1H), 5.42 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 162.2 (d, J=243.7), 158.6, 140.9, 138.4 (d, J=8.1), 130.7 (d, J=8.1), 125.4, 124.6, 123.5 (d, J=2.9), 122.0, 115.1 (d, J=20.6), 114.3 (d, J=22.0), 113.8, 70.1 (d, J=2.1); 19F NMR (564 MHz, DMSO-d6, C6F6) δ: −115.15 (s, dec.); 1H NMR findings are in accordance with literature [59].
Reference：
[1] Patent: US2016/214964, 2016, A1, . Location in patent: Paragraph 0124
[2] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 175 - 194
[3] Patent: EP3181553, 2017, A1, . Location in patent: Paragraph 0198; 0199
[4] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 330 - 348
[5] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 316 - 336
31
[ 456-42-8 ]
[ 5401-94-5 ]
[ 529508-58-5 ]
[ 202197-31-7 ]
Yield
Reaction Conditions
Operation in experiment
33%
With Ki; potassium carbonate In water; N,N-dimethyl-formamide
E. Preparation of 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine A mixture of 5-nitro-1H-indazole (8.15 gm, 50 mmole), m-fluoro-benzyl chloride (7.95 gm, 1.1 equiv), K2CO3 (7.59 gm, 1.1 equiv), and KI (8.47 gm, 1.02 equiv) in dry DMF (75 mL) was heated at 70° C. overnight. After cooling to RT, water (75 mL) was slowly added to give a precipitate that consisted of about a one to one mixture of isomers [HPLC Ret Time: 1.92 (1-substitued isomer vs. 2.03 (2-substituted isomer) YMC C18 S5 4.6*50 mm, 3 min gradient, 4 mL/min]. This was collected by filtration and washed with water. The solid was crystallized twice from acetone/water to afford the desired 1-(3-fluoro-benzyl)-5-nitro-1H-indazole (4.47 gm, 33percent). A suspension of this material (3.00 gm, 11.1) and 10percent Pd/C (3.00 gm) in EtOH (21 mL) was kept under an H2 atmosphere (balloon) for 24 hr. The catalyst was removed by filtration and the solvent was evaporated to leave the product as a solid (2.4 gm, 90percent). 1H NMR (CDCl3): δ 3.61 (br s, 2H), 5.52 (s, 2H), 6.81-7.85 (m, 7H), 7.85 (s, 1H); MS: 242 (M+H)+; HPLC Ret Time: 1.03 min (YMC Xterra ODS S7, 3.0*50 mm column, 2 min gradient, 5 mL/min).
Reference：
[1] Patent: US2003/186983, 2003, A1,
32
[ 456-42-8 ]
[ 5401-94-5 ]
[ 529508-58-5 ]
Reference：
[1] Chinese Chemical Letters, 2011, vol. 22, # 11, p. 1277 - 1280
With methanol; tetrachloromethane; iron(II) chloride tetrahydrate; formamide; at 180℃; for 6h;Inert atmosphere; Sealed tube; Autoclave;
General procedure: The reactions were carried out in a glass tube (V=10 mL) placed into a stainless steel autoclave (V=17 mL) at a controlled heating. The tube under argon was charged with FeCl2·4H2O (0.09 mmol, 0.018 g) and formamide (4.5 mmol, 0.20 g), the mixture was heated for 5 min, and then tetrachloromethane (18 mmol, 2.76 g), methanol (4.5 mmol, 0.14 g), and fluorotoluene 1-3 (9 mmol, 1.00 g) (or difluorotoluene 4-6 (9 mmol, 1.15 g)) were added. The sealed tube was placed into an autoclave, and the autoclave was sealed and heated for 6 h at 180 C. After completion of the reaction, the autoclave was cooled down to room temperature, the tube was opened, and the reaction mixture was filtered through a paper filter. The solvent was distilled off. The target product was separated from the initial mono- or difluorotoluenes by vacuum distillation.
With potassium carbonate; triethylamine; In DMF (N,N-dimethyl-formamide); at 65℃;
A mixture of 4-[(2-Diphenylmethoxy)ethyl]piperidine 4 (58 mg, 0.19 mmol), <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (51 mg, 0.35 mmol), Et3N (0.5 ml), and anhydrous K2CO3 (0.3 g) in DMF (10 ml) was stirred at 65 C. overnight. The reaction mixture was diluted with 30 ml water and extracted with Et2O. The combined organic phase was dried over Na2SO4 and evaporated to give a crude product, which was purified by chromatography (EtOAc/Hexane=1/3) to give 4-[2-(diphenylmethoxyethyl]-1-[(3-fluorophenyl)methyl]piperidine, a viscous liquid 62 mg (79% yield) (?Procedure A?). 1H NMR (CD3Cl) delta 7.34-7.20 (10H, m, 2Ph), 7.11-7.03 (3H, m, m-FPh), 6.95 (1H, m, m-FPh), 5.31 (1H, s, Ph2CH), 3.45-3.44 (2H, t, J=6.6Hz, OCH2), 3.44 (2H, s, m-FPhCH2), 2.84-2.80 (2H, bd, J=11.1Hz, N(CH)2), 1.97-1.89 (2H, t, J=11.4Hz, N(CH)2), 1.63-1.51 (4H, m), 1.49-1.44 (1H, m), 1.29-1.21 (2H, m). The free base was converted into its oxalate salt, m.p.=150-151 C. Anal. [C27H30NOF(COOH)2.0.3H2O] Calculated: C, 69.79; H, 6.58; N, 2.80; Found: C, 69.87; H, 6.80, N, 2.76.
5-amino-6-(2,3-dichlorophenyl)-2,3-dihydro-3-imino-2-(3-fluorophenyl)methyl-1,2,4-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium iodide; In acetone; for 5h;Heating / reflux;
3-Fluorobenzyl chloride (1.45 g, 10 mmol) was added to a stirred suspension of 3,5- diamino-6-(2,3-dichlorophenyl)-l,2,4-triazine (1.28 g, 5 mmol), NaI (0.1 g) and <n="19"/>acetone (50 ml). The mixture was stirred and heated at reflux for 5 h. After cooling, the solid was collected by filtration and then stirred with 0.88 aqueous ammonia- water (80 ml, 1:1) for 0.5 h. The resulting solid (ca.1.5 g) was removed by filtration and dried in vacuo. Recrystallisation from methanol gave the product (0.42 g) as a pale yellow solid, mp 189-190 0C. deltaH (500 MHz, dmso-de) 5.13 (2H, s, NCH2), 6-7 (2H, vbr peak, NH2), 7.14 (3H, m, aromatic H), 7.43 (3H, m, aromatic H), 7.72 (IH, dd, J= 7.5, 1.5 Hz). m/z 365 (M+ + 1).
With potassium carbonate;sodium iodide; In ethanol; for 5.41667h;Heating / reflux;Product distribution / selectivity;
Accordingly, a mixture of <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (2.86 g, 19.80 mmol) 4- hydroxybenzaldehyde (3.03 g, 24.80 mmol), K2CO3 (10.30 g, 74.50 mmol),NaI (137.1 mg, 0.91 mmol), and ethanol, (40 mL) is heated to reflux in 70 min and kept at reflux temperature for 4 hours and 15 min.After working up the reaction mixture, 4-(3-fluorobenzyloxy)benzaldehyde, <n="82"/>is isolated as a yellow oil in 95% yield.The product has GC purity of 97.6 (area %, see Example 25A) and a content of 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde (Via) of 0.14% by weight determined by GC (see Example 25B)
95%
With sodium hydroxide; In ethanol; for 6.75h;Heating / reflux;Product distribution / selectivity;
Accordingly, <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (14.5g, 100 mmol) is added under stirring and under nitrogen atmosphere to a solution of 4- hydroxybenzaldehyde (12.2g, 100 mmol) and of NaOH (4.0g, 100 mmol) in ethanol (100 mL).The mixture is gradually heated in 25 min to reflux and stirred at reflux temperature for 6 hours and 20 min. The reaction mixture is filtrated and then concentrated at reduced pressure to obtain 4-(3-fluoro- benzyloxy)benzaldehyde (23.43 g) as a yellow solid residue.Dichloromethane (25OmL) is added to the residue, the insoluble is filtered and the resulting solution is concentrated under reduced pressure to provide 4-(3-fluorobenzyloxy)benzaldehyde as a yellow solid, in 80.4% yield. The product has GC purity of 91.6 (area %, see Example 24A) and a content of 3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy)benzaldehyde (Via) of 0.13% by weight determined by GC(see Example 25B)
95%
With potassium carbonate; sodium iodide; In ethanol; for 5.41667h;Heating / reflux;Product distribution / selectivity;
EXAMPLE 14 <n="46"/>Preparation of (S)-2-[4-(3-fluorobenzyloxy)benzylamino1propanamide (safinamide, Ia) methanesulfonate (Ic) according to the methods described in the prior art14.1 Preparation of 4-(3-fluorobenzyloxy)benzaldehyde (IVa) 14.1. a) Procedure of Example Ia of US 6,335,354 B24-(3-Fluorobenzyloxy)benzaldehyde (IVa) is prepared by the procedure described in Example Ia of US 6,335,354 B2.Accordingly, a mixture of <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (2.86 g, 19.80 mmol) 4- hydroxybenzaldehyde (3.03 g, 24.80 mmol), K2CO3 (10.30 g, 74.50 mmol ),NaI (137.1 mg, 0.91 mmol), and ethanol, (40 mL) is heated to reflux in 70 minutes and kept at reflux temperature for 4 hours and 15 minutes.After working up the reaction mixture, 4-(3-fluorobenzyloxy)benzaldehyde, is isolated as a yellow oil in 95% yield. The product has GC purity of 97.6 (area %, see Example 16A) and a content of 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde (Va) of 0.14% by weight determined by GC (see Example 16B)
92%
With potassium carbonate;potassium iodide; In ethanol; for 6h;Heating / reflux;Product distribution / selectivity;
To a mixture of 4-hydroxybenzaldehyde (2.28 kg, 18.68 mol), potassium carbonate, (2.84 kg, 20.54 mol), potassium iodide (0.33 kg, 1.98 mol) in ethanol (21.0 kg), <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (2.70 kg, 18.68 mol) is added under stirring, at room temperature.The mixture is gradually heated to reflux and then kept at that temperature for 6 hours. The reaction mixture is then allowed to cool to 25 C, the suspension is filtered and the solid is washed with ethanol (1.5 kg); the ethanol solutions are combined and then concentrated at reduced pressure until a residue of approximately 6.0 kg is obtained.To this residue, toluene (10 kg) and water (2.5 kg) are added, the solvent mixture is stirred vigorously for 30 min and, after separation of the aqueous phase, the organic layer is evaporated to dryness under reduced pressure to provide crude 4-(3-fluorobenzyloxy)benzaldehyde.To this product dissolved in toluene (3 kg) a seed of 4- (3- fluorobenzyloxy)benzaldehyde is added under stirring at 20-25 C, then n- hexane (6.0 kg) is added in 45 min and the mixture is cooled to 0 C under stirring.After 3 hours the solid is filtered and washed with n-hexane (2.0 kg). After drying, 3.95 kg (92.0% yield) of the desired product are obtained, with a gas-cromathographic purity of 99.8 (area %, see Example 24A) and a 3-(3- <n="59"/>fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde content of 0.01% by weight determined by G.C. (area %, see Example 24B); m.p. 43.1 C by DSC 5C/min.
91%
15.2 g (124.5 mmol) of p-hydroxybenzaldehyde, 17.2 g (124.5 mmol) of potassium carbonate and 2.0 g of potassium iodide (12 mmol) was added to 170 ml of absolute ethanol and stirred for 15 min,A solution of <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (17.3 ml, 141.7 mmol) was added dropwise and heated under reflux for 6 h. filter,The filter cake was washed with absolute ethanol (15 ml x 3), the filtrate and the washings were combined, concentrated under reduced pressure,The remaining pale yellow oil was added with 60 ml of toluene and 20 ml of water, stirred for 30 min,The toluene layer was separated and concentrated under reduced pressure. The residue was recrystallized from toluene-n-hexane (1: 1)A white solid of 4- (3-fluorobenzyloxy) benzaldehyde (26.1 g, 91%), mp 43.8-4.99 .
90.2%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; sodium iodide; In acetone; at 20 - 25℃; for 24h;Inert atmosphere;
Into a dry reaction flask under nitrogen protection were added successively <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> II-1 (X = 3-F, Y = -Cl) (50 g,0.34 mol), p-hydroxybenzaldehyde III-1 (44.3 g, 0.36 mol), acetone 500mL, DBU (57.6 g, 0.38 mol), sodium iodide (5.18 g, 0.034 mol), add at 20 ~ 25 deg. C, stirring 24h. The reaction solution was concentrated under reduced pressure, the residue was added to 500 mL of dichloromethane, the resulting mixture was washed with 1 M hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution, the organic phase is dried, concentrated, get crude, recrystallization from isopropyl ether gave 72 g of white solid I-1 (X = 3-F), yield 90.2%, Mp: 42.5 to 43.9 C, the purity was 99.75% by HPLC, no impurities IV-1 (X = 3-F) were detected.
90.7%
With potassium carbonate; potassium iodide; In ethanol; at 20℃; for 6h;Heating / reflux;Product distribution / selectivity;
EXAMPLE 4Preparation of purified 4-(3-fluorobenzyloxy)benzaldehyde (IVaI in ethanol solutionTo a mixture of 4-hydroxybenzaldehyde (1.52 kg, 12.45 mol), potassium carbonate, (1.72 kg, 12.45 mol), potassium iodide (0.2 kg, 1.20 mol) in ethanol (13.0 kg), 1.8 kg, of <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (1.80 kg, 12.45 mol) are added under stirring, at room temperature.The mixture is gradually heated to reflux and then kept at that temperature for 6 hours.The reaction mixture is then allowed to cool to 25 0C, the suspension is filtered and the solid is washed with ethanol (1.0 kg); the ethanol solutions are combined and then concentrated at reduced pressure until a residue of approximately 3.5 kg is obtained.To this residue, toluene (5.0 kg) and water (1.7 kg) are added, the solvent mixture is stirred vigorously for 30 minutes and, after separation of the aqueous phase, the organic layer is evaporated to dryness under reduced pressure to provide crude 4-(3-fluorobenzyloxy)benzaldehyde.To this product dissolved in 2 kg of toluene a seed of 4-(3- fluorobenzyloxy)benzaldehyde is added under stirring at 20-25 0C, then n- hexane (3.8 kg) is added in 30 minutes and the mixture is cooled to 0 0C <n="30"/>under stirring.After 2 hours the solid is filtered and washed with n-hexane (1.3 kg). After drying, 2.6 kg (90.7% yield) of the desired product are obtained, with a gas- cromathographic purity of 99.9 (area %, see Example 16A) and a 3-(3- fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde content of 0.005% by weight determined by G.C. (area %, see Example 16B); m.p. 43.1 0C by DSC 5/min.
88%
In a 10 L reactor, 2-propanol (5.51 kg), potassium carbonate (793 g, 5.74 mol), potassium iodide (305 g, 1.84 mol) and 4-hydroxybenzaldehyde (700 g, 5.74 mol) are charged. The mixture is stirred at 20-25 C for 15 min. <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (871 g, 6.03 mol) is charged in the reactor with the aid of a dropping funnel in about 20 min.The mixture is heated at reflux under stirring for 3 hours.After this time, the mixture is cooled to about 50 C and sampled for in process control.The solvent is removed under vacuum until a volume of about 1.8 1 is reached.Cyclohexane (1.84 kg) and water (2.5 kg) are added, and then the mixture is heated to 65+/-3 C and stirred at this temperature for 30 min. Stirring is stopped and the phases are allowed to separate for 20 min; the water phase is discharged. Water (1.31 kg) is added to the organic phase and the biphasic mixture stirred for 30 min at 65+/-3 C. The phases are allowed to separate for 20 min. The water phase is discharged and the organic phase is concentrated under vacuum to a volume of about 3 1 at a temperature comprised between 40 and 55 C. The mixture is cooled to about 30 C, seeded and stirred at this temperature for 30 min.The mixture is cooled to 20+/-2 C and stirred at this temperature for at least 3 hours. The product is filtered under suction and the solid is washed with cyclohexane (3 x 150 g).The wet solid (1.5 kg) is dried at 20-25 C at a pressure below 100 mbar for 12 hours to provide 1.17 kg (5.09 mol); 88% yield with a gas- cromathographic purity of 99.43 (area %, see Example 24A) and a content of 0.063% by weight determined by G.C. (area %, see Example 24B) 3-(3- <n="60"/>fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde (Via). This product is further purified according to the procedure described in Example 1 1.1 to yield a product wherein the content of the impurity (Via) is 0.01 % by weight determined by GC (see Example 24B) .
86.3%
With potassium carbonate;cetyltrimethylammonium bromide; In toluene; for 7h;Heating / reflux;Product distribution / selectivity;
A mixture of <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (10 kg, 69.16 mol), 4-hydroxy- benzaldehyde (7.8 kg, 63.88 mol), potassium carbonate (9.46 kg, 68.44 mol) and tetradecyl trimethylammonium bromide (1.03 kg, 3.72 mol) in toluene (30.0 kg) is slowly brought to reflux temperature under stirring and under nitrogen atmosphere, and then refluxed for 7 hours.The solution is concentrated at room pressure and then 6 kg of toluene are added and distilled off. This procedure is repeated once again. The heterogeneous mixture is then cooled to room temperature and the solid is eliminated by filtration. The residual solvent is eliminated under reduced pressure and then 2.6 kg of toluene are added to the oily residue. The mixture is stirred at 20-25 C and seeded with a few grams of pure 4- (3-fluorobenzyloxy)benzaldehyde, and then n-hexane (18 kg) is added in 45 min to the stirred mixture kept at 20-25 C After cooling to 3-6 C and stirring for a further hour at this temperature the solid is collected by filtration and dried under reduced pressure to give 13.5 kg with a 86.3 % yield, GC purity 99.8 (area %, see Example 24A) and a 3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy)benzaldehyde content of 0.01% by weight (see Example 24B).
86.2%
88. 70 g (0. 73mo 1) of p-hydroxybenzaldehyde was added to a 1000 ml reaction flask,Add ethanol 500ml,Plus K2C03105 · 10g (0.76mol),Stirred at room temperature for 30 min,Followed by addition of <strong>[456-42-8]fluorobenzyl chloride</strong> 100.00 g (0.69 mol)KI 9 · 20g(0. 06 mol) and refluxed for 4 h.After completion of the reaction, the mixture was cooled to room temperature, stirred with 500 ml of water for 1 hour, and the filter cake was added1000ml water stirred lh, filter, room temperature drying cake 24h, white solid 4- (3-fluorobenzyloxy) benzaldehyde 137. 10g,Yield: 86.2%. HPLC purity: 99.82%.
85%
With cetyltrimethylammonium bromide; potassium carbonate; In toluene; for 6h;Heating / reflux;Product distribution / selectivity;
EXAMPLE 5 Preparation of 4-(3-fluorobenzyloxy)benzaldehyde (IVa) by phase transfer catalysisA mixture of 3-fluoroben2yl chloride (5 kg, 34.58 mol), 4-hydroxy- benzaldehyde (3.9 kg, 31.94 mol), potassium carbonate (4.3 kg, 31.11 mol) and tetradecyl trimethylammonium bromide (0.41 kg, 1.22 mol) in toluene (13.5 kg) is slowly brought to reflux temperature under stirring and under nitrogen atmosphere, and then refluxed for 6 hours.The solution is concentrated at room pressure and then 3 kg of toluene are added and distilled off. This procedure is repeated once again. The heterogeneous mixture is then cooled to room temperature and the solid is eliminated by filtration. The residual solvent is eliminated under reduced pressure and then 1.2 kg of toluene are added to the oily residue. The mixture is stirred at 20-25 0C and seeded with a few grams of pure 4- (3-fluorobenzyloxy) benzaldehyde, and then additioned of n-hexane (9 kg) at this temperature, in 30 minutes. After cooling to 0-5 0C and stirring for a further hour at this temperature the solid is collected by filtration and dried under reduced pressure to give 6.5 kg (85% yield, GC purity 99.9 (area %, see Example 16A) and a 3-(3- fluorobenzyl) -4- (3 -fluorobenzyloxy) benzaldehyde content of 0.008% by weight (see Example 16B).
80.4%
With sodium hydroxide; In ethanol; for 6.75h;Heating / reflux;Product distribution / selectivity;
14.1.b) Procedure of J. Agric. Food Chem, 27, 4. 1979 4-(3-Fluorobenzyloxy)benzaldehyde (IVa) is prepared by the procedure reported in J. Agric. Food Chem, 27, 4, 1979.Accordingly, <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (14.5g, 100 mmol) is added under stirring and under nitrogen atmosphere to a solution of 4- hydroxybenzaldehyde (12.2g, 100 mmol) and of NaOH (4.Og, 100 mmol) in ethanol (100 mL).The mixture is gradually heated in 25 minutes to reflux and stirred at reflux temperature for 6 hours and 20 minutes. The reaction mixture is filtrated and then concentrated at reduced pressure to obtain 4-(3-fluoro- benzyloxy)benzaldehyde (23.43 g) as a yellow solid residue. Dichloromethane (25OmL) is added to the residue, the insoluble is filtered and the resulting solution is concentrated under reduced pressure to provide 4-(3-fluorobenzyloxy)benzaldehyde as a yellow solid, in 80.4% yield. The product has GC purity of 91.6 (area %, see Example 16A) and a content of 3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)benzaldehyde (Va) of 0.13% by <n="47"/>weight determined by GC(see Example 16B)
With potassium carbonate; In acetonitrile; at 80℃;
General procedure: A mixture of 4-hydroxybenzaldehyde (1.0 g, 8.2 mmol), K2CO3 (2.2 g, 8.2 mmol), and alkyl bromide or benzyl chloride derivatives (8.2 mmol) were placed into a round bottomed flask containing 30 mL of acetonitrile. The mixture was then stirred and heated at 80 C for 12-24 h. After the completion of the reaction, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water (10 mL 3), and then dried over anhydrous MgSO4 to give compounds 6a-w.
60 g
With tetrabutyl ammonium fluoride; potassium carbonate; In toluene; at 25 - 110℃; for 8h;
Toluene (250 ml) was added to l-(chloromethyl)-3-fluorobenzene (50 gms) at 25- 30C. 4-Hydroxybenzaldehyde (38.8 gms), tetra butyl ammonium bromide (5.83 gms) and potassium carbonate (43.0 gms) was added to the reaction mixture at 25-30C. Heated the reaction mixture to 105-1 l0C and stirred for 8 hours at the same temperature. Cooled the reaction mixture to 25-30C. Filtered the reaction mixture and washed with toluene. Distilled off the solvent completely from the filtrate under reduced pressure. Methanol was added to the obtained compound at 25-30C and stirred for 15 minutes at the same temperature. The reaction mixture was slowly added to a pre-cooled aqueous potassium carbonate at 0-5 C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with water. N-heptane was added to the obtained wet compound at 25-30C and stirred for 2 hours at the same temperature. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 60.0 gms; M.R: 52-57C.
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
The starting material, <strong>[171178-47-5]6-chloro-3H-pyrido[3,4-d]pyrimidin-4one</strong> (710 mg, 3.92 mmol, prepared according to J. Chem. Soc., Perkin Trans. 1996, 1, 2221) is dissolved in DMF (20 ml). Cs2CO3 (1.66 g, 5.1 mmol) and 3-flurobenzylchloride (737 mg, 5.1 mmol) are added subsequently. The reaction is stirred at room temperature overnight, poured into water. After extraction with CH2Cl2, the organic layer is washed with H2O and brine, dried (Na2SO4) and filtered. After removal of the solvents, the residue is purified via a flash chromatography to give the product as a white solid. [00494] MS (APCI), M/z 290.0 (M+1). [00495] N.M.R (CDCl3) 1H delta(ppm) 8.92 (s, 1H), 8.10 (d, J=9.6 Hz, 2H), 7.0-7.4 (m, 5H). 5.17 (m, 2H).
N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[(1R)-2-(dimethylamino)-1-methylethoxy]quinazolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With potassium carbonate;18-crown-6 ether; In DMF (N,N-dimethyl-formamide); at 20℃;
2-Chloro-4-({5-[(1R)-2-(dimethylamino)-1-methylethoxy] quinazolin-4- YL} amino) phenol (obtained as described in Example 22, preparation of starting materials, 150 mg, 0.40 mmol), potassium carbonate (276 mg, 2.0 mmol), <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (64 mg, 0.44 mmol) and 18-crown-6 (10 mg) were stirred in DMF (5 ml) at ambient temperature overnight. Water (10 ml) was added and the mixture was extracted with ethyl acetate (3 x 15 ml). The combined organics were dried (MGS04), concentrated ICI VACUA and the residue was purified by chromatography using 10% methanol/ethyl acetate as the eluent to give the title compound as a gum (69 mg, 36%); NMR spectrum (CDCL3) ; 1.45 (d, 3H), 2.21 (s, 6H), 2.39 (dd, 1H), 2.84 (dd, 1H), 4.59-4. 72 (m, 1H), 5.08 (s, 2H), 6. 80-6. 99 (m, 3H), 7.10-7. 21 (m, 2H), 7.23-7. 39 (m, 2H), 7.53 (t, 1H), 7.61 (dd, 1H), 7.70 (d, 1H), 8.52 (s, 1H), 10.30 (s, 1H); Mass spectrum MH 481.
With Ki; potassium carbonate; In water; N,N-dimethyl-formamide;
E. Preparation of 1-(3-Fluoro-benzyl)-1H-indazol-5-ylamine A mixture of 5-nitro-1H-indazole (8.15 gm, 50 mmole), m-fluoro-benzyl chloride (7.95 gm, 1.1 equiv), K2CO3 (7.59 gm, 1.1 equiv), and KI (8.47 gm, 1.02 equiv) in dry DMF (75 mL) was heated at 70 C. overnight. After cooling to RT, water (75 mL) was slowly added to give a precipitate that consisted of about a one to one mixture of isomers [HPLC Ret Time: 1.92 (1-substitued isomer vs. 2.03 (2-substituted isomer) YMC C18 S5 4.6*50 mm, 3 min gradient, 4 mL/min]. This was collected by filtration and washed with water. The solid was crystallized twice from acetone/water to afford the desired 1-(3-fluoro-benzyl)-5-nitro-1H-indazole (4.47 gm, 33%). A suspension of this material (3.00 gm, 11.1) and 10% Pd/C (3.00 gm) in EtOH (21 mL) was kept under an H2 atmosphere (balloon) for 24 hr. The catalyst was removed by filtration and the solvent was evaporated to leave the product as a solid (2.4 gm, 90%). 1H NMR (CDCl3): delta 3.61 (br s, 2H), 5.52 (s, 2H), 6.81-7.85 (m, 7H), 7.85 (s, 1H); MS: 242 (M+H)+; HPLC Ret Time: 1.03 min (YMC Xterra ODS S7, 3.0*50 mm column, 2 min gradient, 5 mL/min).
N-[1-(3-Fluorobenzyl)-4-piperidyl]-N-(1H-5-indazolyl)amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60.0%
With potassium carbonate; acetic acid; In methanol; acetonitrile;
Example 117 N-[1-(3-Fluorobenzyl)-4-piperidyl]-N-(1H-5-indazolyl)amine Potassium carbonate (276 mg, 2.0 mmol, 2.0 eq) was added to a solution of <strong>[40064-34-4]4-piperidone monohydrate hydrochloride</strong> (154 mg, 1.0 mmol) and 3-fluorobenzyl chloride (145 mg, 1.0 mmol, 1.0 eq) in acetonitrile, and the mixture was stirred at room temperature for 17 hr. After the completion of the reaction, the reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine and was dried over sodium sulfate. The solvent was then removed by distillation under the reduced pressure. 5-Aminoindazole (106 mg, 0.80 mmol, 0.8 eq) was added to a solution of the resultant oil in methanol. Acetic acid (one drop) was added thereto, and the mixture was stirred at room temperature for 5 min. A borane-pyridine complex (112 mg, 1.20 mmol, 1.2 eq) was added thereto under ice cooling, and the mixture was stirred at room temperature for 15 hr. After the completion of the reaction, the reaction solution was poured into an aqueous sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over sodium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography [silica gel, chloroform/methanol] to give the title compound (195 mg, 60.0%). MS m/z: 324 1H-NMR delta: 1.34 - 1.45 (2H, m), 1.94 (2H, d, J = 11.22 Hz), 2.11 (2H, t, J = 10.73 Hz), 2.79 (2H, d, J =11.71 Hz), 3.15 - 3.27 (1H, m), 3.50 (2H, s), 5.10 (1H, d, J = 8.05 Hz), 6.66 (1H, s), 6.81 (1H, dd, J = 1.95, 9.03 Hz), 7.63 (1H, dt, J = 2.68, 8.78 Hz), 7.12 (1H, d, J = 8.78 Hz), 7.15 (1H, d, J = 7.56 Hz), 7.25 (1H, d, J = 8.78 Hz), 7.36 (1H, q, J = 7.34 Hz), 7.72 (1H, s), 12.55 (1H, s)
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20 - 50℃;
Step C [2-[3-(3-Fluoro-benzyloxy)-phenyl]-ethyl]-carbamic acid terr-butyl ester; 2.87 g (19.8 mmol) of l-chloromethyl-3-fluoro-benzene in 5 ml of dry dimethylformamide were added to a suspension of 4.66 g (19.6 mmol) of [2-(3-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester, 4 g of K2CO3 and 0.3 g of potassium iodide in 50 ml of dry dimethylformamide. The reaction was first stirred at room temperature overnight, then was heated up to 50 0C for 6 hours. After evaporation of the solvent, water was added to the residue and the product was extracted with ethyl acetate. 7 g of crude oil were obtained. Purification by flash chromatography using a mixture of ethyl acetate/hexane (1 :9 - * 2:8 gradient) gave 5.9 g (86% yield) of the title product as a colourless oil. 1H-NMR CDCl3: 7.40-6.68 (m, 8H); 5.05 (s, 2H); 4.53 (bs, IH); 3.44-3.30 (m, 2H); 2.77 (t, 2H); 1.44 (s, 9H).
With potassium carbonate; In 1,2-dimethoxyethane; at 60℃; for 24h;
A suspension of 0.207 g (1 mmol) of <strong>[348-36-7]ethyl 5-fluoro-1H-indole-2-carboxylate</strong>, 0.173 g (1.2 mmol) of 3-fluorobenzyl chloride and 0.276 g (2 mmol) of potassium carbonate in 10 ml of dimethylformamide is stirred at 60 C. for 24 hours. The reaction mixture is subsequently cooled and is poured into a mixture of ice-cold water and of ethyl acetate. After settling, the organic phase is separated and then it is washed with two times 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The solution is dried over magnesium sulfate and is filtered, and then the filtrate is concentrated under reduced pressure. 0.195 g of an oil is obtained, which oil is used as is in the following stage.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;
1.1. Ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylate A suspension of 0.207 g (1 mmol) of <strong>[348-36-7]ethyl 5-fluoro-1H-indole-2-carboxylate</strong>, 0.173 g (1.2 mmol) of 3-fluorobenzyl chloride and 0.276 g (2 mmol) of potassium carbonate in 10 ml of dimethylformamide is stirred for 24 hours at 60° C. The reaction mixture is then cooled and poured into a mixture of ice-water and ethyl acetate. After allowing the phases to separate by settling, the organic phase is separated out and then washed with twice 50 ml of water and then with 50 ml of saturated sodium chloride solution. The solution is dried over magnesium sulfate and filtered, and the filtrate is then concentrated under reduced pressure. 0.195 g of an oil is obtained, which is used without further purification in the following step.
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 24h;
2.1 ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate A suspension of 1.035 g (5 mmol) of <strong>[348-36-7]ethyl 5-fluoro-1H-indole-2-carboxylate</strong>, 0.865 g (6 mmol) of 3-fluorobenzyl chloride and 1.38 g (10 mmol) of potassium carbonate in 50 ml of dimethylformamide is stirred for 24 h at 60° C. The reaction mixture is subsequently cooled and poured into a mixture of ice-cold water and of ethyl acetate. After separation by settling out, the organic phase is separated and is then washed with twice 200 ml of water then with 200 ml of a saturated solution of sodium chloride. The solution is dried over magnesium sulphate and filtered and the filtrate is then concentrated under reduced pressure. 0.97 g of an oil is obtained, which oil is used as it is in the subsequent step.
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃;
Step B [2-[4-(3-Fluoro-benzyloxy)-3-methoxy-phenyl]-ethyl]-carbamic acid tert-butyl ester; 34.6 g (0.23 mol) of l-chloromethyl-3-fluoro-benzene in 50 ml of dry dimethylformamide were added to a suspension of 55.9 g (0.209 mol) of [2-(4-hydroxy-3-methoxy-phenyl)-ethyl]- carbamic acid tert-butyl ester, 43 g Of K2CO3 and 3.4 g of potassium iodide in 400 ml of dry dimethylformamide. The reaction was stirred at room temperature overnight. Solvent was removed, water was added to the residue and the product was extracted with ethyl acetate. The crude oil obtained was triturated with diethyl ether. The solid was filtered and 58.2 g (74% yield) of the title product were obtained.1H-NMR CDCl3: 7.40-6.60 (m, 7H); 5.10 (s, 2H); 4.50-4.60 (bs, IH); 3.90 (s, 3H); 3.30-3.40 (m, 2H); 3.75 (t, 2H, J=7.2 Hz); 1.44 (s, 9H).
With potassium carbonate In toluene for 120h; Heating / reflux;
18.a
In a 4 L round bottomed flask kept under nitrogen atmosphere, 4-hydroxy- benzaldehyde (400 g, 3.28 mol), potassium carbonate (453 g, 3.28 mol), toluene (2 L) and 3-fluorobenzyl chloride (1400 g, 9.68 mol) are added in sequence and the mixture is refluxed under stirring for 5 days. At this point a GC analysis reveals that the reaction mixture contains 4-(3- fluorobenzyloxy)benzaldehyde and 3- (3-fluorobenzyl) -4- (3- fluorobenzyloxy)benzaldehyde in a ratio of 91.4 : 8.6 (area/area, see Example 24A).The reaction mixture is cooled to room temperature and then 2 L of water are added under stirring. The organic phase is separated and the solvent is distilled under reduced pressure (20 mniHg) at 35 °C until no more solvent passes over. The pressure is then lowered to 3 mniHg and the external temperature is raised up to 300 °C and the fraction that distils between 255 °C and 265 °C, (40.6 g), is collected. A GC analysis shows an area/area ratio of C,O-dibenzylated derivative (Via) on the monoalkylated (IVa) of 99.6:0.4. (area, for GC conditions , see Example 24B).1H-NMR (CDCl3) (Bruker AV300) δ (ppm, with respect to TMS): 4.05 (2H, s, CH2); 5.13 (2H, s, OCH2); 6.85-7.40 (9H, m, aromatic H); 7.73-7.79 (2H, m, aromatic H ortho to C=O); 9.88 (s, CHO).13C-NMR (CDCl3) (Bruker AV300) δ (ppm): 36.1 (CH2); 69.4 (CH2O); 1 1 1.4 (aromatic CH ); 1 12.9 and 1 13.2 (d, Jc F = 20 Hz, aromatic CH ), 1 13.9 and 1 14.2 [d, Jc F = 22 Hz, aromatic CH ); 1 14.9 and 1 15.0 (d, Jc F = 21 Hz, aromatic CH ; 1 15.7 e 1 15.9 (d, Jc F = 25 Hz aromatic CH ); 122.6 (d, Jc F = 3 Hz, aromatic CH ); 124.4 (d, Jc F = 3 Hz, aromatic CH ); 129.6 and 129.8 [d, Jc F = 8 Hz, aromatic CH); [d, Jc F = 7 Hz, quaternary aromatic C); 129.9 (C quaternary aromatic C); 130.0 ( quaternary aromatic C); 130.1 and 130.2 (d, Jc F 7Hz, CH aromatic); 131.2 ( aromatic CH); 131.5 ( aromatic CH); 138.3 (d, Jc F = 7 Hz, quaternary aromatic C); 142.3 [d, Jc F = 7 Hz, quaternary aromatic C); 161.0, 161.2 and 164.4 [d, Jc F = 240, 2 C-F overlapping); 190.8 (CHO).
With cetyltrimethylammonium bromide; potassium carbonate In toluene for 6h; Reflux; Large scale; Overall yield = 93 percent;
1-2; 1
Under stirring conditions, make 2-fluorobenzyl chloride (6.0kg, 41.50moL), 4-hydroxy-benzaldehyde (4.7kg, 38.33moL), Potassium carbonate (5.2kg, 37.33moL) and tetradecyltrimethylammonium bromide (0.49kg, 1.46moL) in toluene (11.4kg) slowly reach the reflux level and reflux for 6h; After the reaction, the temperature is lowered to 20-40°C, filtered, the organic phase is washed with purified water, replaced with nitrogen, the organic phase is concentrated, toluene/cyclohexane (1/8, 9V) is added, and the temperature is increased to 40-45°C Heat the solution to clarify, stir for 10-20 minutes, and then cool down at a rate of 5°C/h, with a stirring rate of 100-120rpm; when the temperature drops to 30°C, add a mixture of seed crystals and cyclohexane, and control the stirring rate to Stir at 250-300rpm for 20-30 minutes, then continue to cool down to 25°C at a rate of 5°C/h, keep stirring for 3 hours; continue to cool to 20°C at a rate of 5°C/h, keep warm and stir for 3 hours; Cool down to 15°C at a rate of 5°C/h, keep warm and stir for 2 hours; then cool down to 5°C at a rate of 5°C/h, keep warm and stir for 3 hours; After filtering, the filter cake is rinsed with cyclohexane and dried to obtain the target product. The yield was 93%, the obtained product was detected by LC-MS, and the content of impurities in the product was calculated by the external standard method.
A mixture of 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol (0.20 g, 0.91 mmol), <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (0.11 mL, 0.91 mmol), 1 M aqueous sodium hydroxide solution (1.00 mL, 1.00 mmol) and water (4 mL) was stirred overnight at room temperature. The precipitate was collected by filtration and recrystallized from hexane/ethyl acetate to give the title compound (0.21 g, yield 74%) as colorless crystals.melting point 128-129 C. (recrystallized from hexane/ethyl acetate).1H NMR (CDCl3) delta 3.27 (2H, t, J=8.8Hz), 4.48 (2H, s), 4.66 (2H, t, J=8.8 Hz), 6.86 (1H, d, J=8.3 Hz), 6.95-7.03 (1H, m), 7.15-7.35 (3H, m), 7.72-7.78 (1H, m), 7.82-7.85 (1H, m).Elemental analysis (for C17H13FN2O2S)Calculated (%): C, 61.18; H, 3.99; N, 8.53.Found (%): C, 62.04; H, 3.96; N, 8.55.
With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4h;Inert atmosphere;
A mixture of <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (0.71 g; 4.91 mmol), 3-hydroxybenzaldehyde (0.6 g; 4.91 mmol) and Cs2CO3 (1.6 g; 4.91 mmol) in anhydrous DMF (5 ml) was stirred for 4h at -6O0C under N2, cooled to room temperature and poured onto H2O (15 ml). The precipitate formed was filtered off, washed with H2O and dried in vacuo to give the title compound (0.9 g; 80%), as creamy solid. 1H-NMR (CDCI3 ) 5.1 1 (s, 2H); 7.13 - 7.25 (m, 3H + CDCI3); 7.3 - 7.36 (m, 1 H); 7.44 - 7.48 (m, 3H); 9.96 (s, 1 H).
To a mixture of magnesium (1.75 g, 72.0 mmol) in diethylether (7.8 mL) at 0 C was added a portion (0.5 mL) of a solution of <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (3.25 g, 22.5 mmol) in diethyl ether (30 mL). The mixture was allowed to warm to room temperature to ensure that the reaction initiated, re-cooled to 0 C, and the remainder of 3-flurobenzyl chloride solution was added dropwise over 2 h. The reaction mixture was stirred at 0 C for 2 h and then added to a solution of Intermediate 1 (2.15 g, 9.56 mmol) in THF (20 mL) and diethyl ether (40 mL) at 0 C. The solution was stirred for 1 h at 0 C, quenched with sat'd ammonium chloride (5 mL) and allowed to warm to room temperature. The mixture was diluted with ethyl acetate (150 mL), washed (100 mL brine), dried over Na2S04, and concentrated under reduced pressure. The crude material was purified on a silica gel column to give l-(2,5-dimethoxyphenyl)-2-(3- fluorophenyl)ethanone (2.43 g, 93%) as a white solid. ¾ NMR (CDC13): delta 7.35 (m, IH), 7.11 (m, 6H), 4.31 (s, 2H), 3.86 (s, 3H), 3.73 (s, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;
3-Fluorobenzyl chloride (0.10 mol, 14.5 g) and 2,5-dihydroxybenzaldehyde (0.10 mol, 13.8 g) were dissolved in 30 mL of DMF, and K2CO3 (0.10 mol, 13.8 g) was added.[22] The mixture was stirred at 80 C for 8 h and the reaction was controlled by TLC in petroleum: acetic ether (3:1, v/v).At the end of the reaction, the mixture was diluted with waterand extracted 3 times with acetic ether, and the combinedorganic layers were dried (MgSO4). After removal of thesolvent, the residue was recrystallized from acetic ether to get compound 1.
With bis-triphenylphosphine-palladium(II) chloride; tetraethylammonium chloride; sodium hydroxide; In 5,5-dimethyl-1,3-cyclohexadiene; at 80℃; under 11251.1 Torr; for 20h;Autoclave;
General procedure: The carbonylation reaction was performed in a 150 mL polytetrafluoroethylene(PTFE)-lined autoclave equipped witha magnetic stir bar. In a typical experiment, the substituted benzyl chloride (0.01 mol), Pd(PPh3)2Cl2 (0.13 mmol),TEAC (0.18 mmol), NaOH (4 M, 8 mL) and DMB (10 mL)were placed in the autoclave. The autoclave was purged three times with N2 and three times with CO, and then heated to 80 C. During the reaction, the CO pressure was maintained at 1.5 MPa. When the reaction was complete,the autoclave was cooled to room temperature in ice water,and the CO was discharged to atmospheric pressure. The mixture was then adjusted to pH 2 with HCl (12 M), and the solid was collected via filtration and air-dried. The crude product was recrystallised in MeOH/H2O (1:1, v/v) to obtain 2,4-DCPA. The remaining commercially available catalysts were evaluated under the same conditions. The percent conversion and yield were quantified by the method reported by Lei et al.
80%
General procedure: A 100 mL reactor equipped with Teflon-coated magnetic stir bars was charged with n-Butyl alcohol (20 mL) and the catalyst (0.5 mmol). The reactor was then taken out of the glove box and pressured with carbon monoxide (1 atm). The mixture was stirred 2 h at 60 C, cooled to ambient temperature and slowly vented. After benzyl chloride (10 mmol), NaOH (15 mL, 15%), and TBAI (0.25 mmol) were added, the reactor was sealed and the reaction mixtures were stirred for 22 h at 60 C under carbon monoxide (1 atm). After the reaction, the water phase was detached and washing the organic phase three times with H2O (3×5 mL), the combined water layer was washed with Et2O, then the resulting solution was cooled to 0 C and adjusted to pH=1-2 with HCl (6 mol/L). The product was filtered, dried in RT, and then recrystallized.
N,N'-methylene-di(2-amino-5-mercapto-1,3,4-thiadiazole)[ No CAS ]
[ 1516888-52-0 ]
Yield
Reaction Conditions
Operation in experiment
64%
With potassium hydroxide; In ethanol; at 20 - 50℃; for 8h;
General procedure: To a stirred solution of intermediate 2 (0.28 g, 1 mmol) in 20 mL 0.1mol/L potassium hydroxide solution, substituted benzyl chloride (2 mmol) in ethanol (2 mL) was slowly added at room temperature. The mixture was stirred and heated at 50 C for 8 h. The solvent was removed and the residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether = v/v 1:1) to give the desired compound 3a to 3o.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; under 10343.2 Torr; for 0.25h;Microwave irradiation;
General procedure: A CEM-designed 10 mL pressure-rated vial was charged with DMF (15 mL), 6 (1.5 g, 5.1 mmol)and K2CO3 (0.2 g, 5.6 mmol). The mixture was irradiated in a CEM Discover Focused Synthesizer(150 w, 90 C, 200 psi, 15 minutes). The mixture was cooled to room temperature by passingcompressed air through the microwave cavity for 2 minutes. It was poured into cold ice (40 mL) andthe precipitate formed was filtered. The crude solid was recrystallized from EtOH to give the titlecompound 7a. All the other compounds are synthesized according to the same procedure. White crystals,yield 88%, m.p. 98-99 C; 1H-NMR (CDCl3, 400 MHz) delta: 3.06 (s, 3H, Het-Me), 4.52 (s, 2H, SCH2),6.97 (t, J = 8.25 Hz, 1H, ArH), 7.09-7.24 (m, 4H, ArH), 7.56 (t, J = 7.86 Hz, 2H, ArH), 7.63-7.69 (m,2H, ArH). MS (ESI), m/z: 384 (M+1)+. Elemental anal. (%), calculated: C, 56.38; H, 3.68; N, 18.26;found: C, 56.75; H, 3.63; N,18.49.
1-(but-2-ynyl)-6-chloro-3-(3-fluorobenzyl)pyrimidine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
General procedure: To a suspension of 5b (14.6 g, 73.5 mmol) and LiBr (5.6 g, 58.8 mmol) in DMF (150 mL) was added NaH (60%, 3.82 g, 95.5 mmol) in portions under nitrogen at 0 C. The mixture was stirred for 0.5 h. 2-Chloromethyl-4-methylquinazoline (15.6 g, 81 mmol) was added. The mixture was stirred overnight at 80 C. The mixture was evaporated and azeotroped with water in vacuo to remove most of the DMF. The crude product was suspended in the mixture of hot EtOAc (100 mL) and isopropyl ether (200 mL). The suspension was stirred for 30 min and allowed to stand at -20 C for 1 h. The formed precipitate was collected by filtration, washed with water, EtOH and isopropyl ether, and dried to give 6c as a yellow brown solid (21 g, 88%).
ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate[ No CAS ]
[ 456-42-8 ]
ethyl 7-((3-fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h;
Step A. Ethyl 7-((3-fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate. To a solution of ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate (Intermediate 4, 1.0 g, 4.59 mmol) in DMF (20 mL) was added Cs2CO3 (2.2 g, 6.75 mmol), followed by <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (0.6 mL, 5.02 mmol). The reaction was stirred at ambient temperature for 72 h. The crude reaction mixture was poured into EtOAc and water. The aqueous later was extracted with EtOAc and the combined organic fractions were washed with brine and concentrated under reduced pressure onto silica. Purification (FCC, SiO2, 0-60%, EtOAc/hexanes) afforded the title compound as a white solid (1.0 g, 69%). 1H NMR (400 MHz, CDCl3) delta 9.44 (t, J=2.0 Hz, 1H), 9.00-8.94 (m, 1H), 8.88 (t, J=2.3 Hz, 1H), 7.74-7.65 (m, 1H), 7.47-7.33 (m, 1H), 7.28-7.26 (m, 1H), 7.21 (d, J=9.4 Hz, 1H), 7.07 (t, J=8.6 Hz, 1H), 5.25 (s, 2H), 4.59-4.38 (m, 2H), 1.52-1.41 (m, 3H). [M+H]=327.2.
Catalyst CuSO4.5H2O (2.0 mg, 0.02 mmol), ligand bipyridine L1 (3.1 mg, 0.02 mmol), <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (1 mmol, 5 equiv.) and Na2S2O3·5H2O (248 mg, 1 mmol, 5 equiv.) After adding to the reaction tube, the reaction solvent water (1 mL) was added, and the mixture was stirred at a reaction temperature of 80 C for 2 hours. Then, the reaction system was cooled to 0 C in an ice bath, and triazene 5 (0.2 mmol, 1 equiv.) was added. After stirring at this temperature for 15 minutes, BF3·Et2O (0.2 mmol, 1 equiv.) was slowly added dropwise. Then, the mixture was stirred in an ice bath, and the reaction was allowed to naturally return to room temperature to continue the reaction for 12 hours. After the end of the reaction was monitored by thin layer chromatography, 5 mL of ethyl acetate was added to the reaction mixture, and anhydrous sodium sulfate and anhydrous magnesium sulfate were added thereto with stirring. After stirring for five minutes, it was filtered, and the filter cake was washed with ethyl acetate (5 mL x 3). Finally, the filtrate was removed under reduced pressure and the residue was purified by column chromatography to afford product 47 (eluent: petroleum ether/ethyl acetate 100:1). Yield: 83%.
Catalyst CuSO4.5H2O (2.0 mg, 0.02 mmol), ligand bipyridine L1 (3.1 mg, 0.02 mmol), <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (1 mmol, 5 equiv.) and Na2S2O3·5H2O (248 mg, 1 mmol, 5 equiv.) After adding to the reaction tube, the reaction solvent water (1 mL) was added, and the mixture was stirred at a reaction temperature of 80 C for 2 hours. Then, the reaction system was cooled to 0 C in an ice bath, and triazene 1 (0.2 mmol, 1 equiv.) was added. After stirring at this temperature for 15 minutes, BF3·Et2O (0.2 mmol, 1 equiv.) was slowly added dropwise. Then, the mixture was stirred in an ice bath, and the reaction was allowed to naturally return to room temperature to continue the reaction for 12 hours. After the end of the reaction was monitored by thin layer chromatography, 5 mL of ethyl acetate was added to the reaction mixture, and anhydrous sodium sulfate and anhydrous magnesium sulfate were added thereto with stirring. After stirring for five minutes, it was filtered, and the filter cake was washed with ethyl acetate (5 mL x 3). Finally, the filtrate was evaporated under reduced pressure to give a product (yield: EtOAc:EtOAc:EtOAc Yield: 90%.
With potassium carbonate; In N,N-dimethyl-formamide; for 12h;Reflux;
General procedure: A mixture of 2-methylpiperazine (5.00 mmol), substituted benzyl chlorides (5.00 mmol) and K2CO3 (7.50 mmol) in DMF(10.00 mL) was stirred at reflux for 12 h. The mixture was concentrated in vacuo, diluted with water (20.00 mL) and extracted withEtOAc (15.00 mL 3). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/PE 1:2 to 1:0) to affordcorresponding compounds 7a-f.
2-((3-fluorobenzyl)thio)-5-(pyridin-4-yl)-1,3,4-thiadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With sodium hydroxide; In N,N-dimethyl-formamide; under 10343.2 Torr; for 0.25h;Microwave irradiation; Heating;
General procedure: DMF (5 mL), 4 (0.25 g, 1mmol), RCH2Cl (1.1 mmol)and NaOH (0.05 g, 1.2mmol) were charged into a CEM designed10 mL pressure-rated vial. Then it was irradiated in aCEM Discover Focused Synthesizer (150 w, 90C, 200 psi,15 minutes). The mixture was cooled below 50 oC. The mixturewas poured into crushed ice and the 1,3,4-thiadiazolewas collected, recrystallized.
2-(3-fluorobenzylthio)-5-(pyridin-4-yl)-1,3,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium hydroxide; In N,N-dimethyl-formamide; under 10343.2 Torr; for 0.25h;Microwave irradiation; Heating;
General procedure: A CEM designed 10 mL pressure-rated vial was chargedwith DMF (5 mL), 3(0.25 g, 1 mmol), RCH2Cl(1.1 mmol)and NaOH (0.05 g, 1.2 mmol). The mixture was irradiated ina CEM Discover Focused Synthesizer (150 w, 90C, 200 psi,15 minutes). The mixture was cooled to room temperature bypassing compressed air through the microwave cavity for 2minutes. It was poured into ice (40 mL) and the formed precipitatewas filtered. The crude solid was recrystallized fromEtOH to give the title compounds
4-(3-fluorobenzyloxy)aniline hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89.8%
To a stirred solution of 4-aminophenol (4a) (32.7 g, 300 mmol, Aldrich) in dimethylformamide (400 ml) was added at 0C 168 g 20% potassium tert-butoxide in THF (168 g, 300 mmol, ACROS) over 0.5h. To the dark brown suspension was added at 0C <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (4) (28.9 g, 200 mmol, ABCR) over lh and stuffing at 0C was continued for 1.5h. The reaction mixture was added to tert-butylmethyether (1000 ml) and washed sequentially with water (1000 ml), 0.1M NaOH (1000 ml) and water (1000 ml). The organic layer was dried (Na2SO4), filtered and the solvent was removed by rotary evaporation (35- 45C/10 mbar) affording 41.3 g (95.1%) crude product as a dark-brown oil, which wasdissolved in ethyl acetate (800 ml). To the resulting dark-brown solution was added at roomtemperature 2 M HC1 in ethanol (100 ml, 200 mmol) over 0.5h and the resulting beige suspension was stilTed for 2h then filtered, washed with ethylacetate (3 x 50 ml) and dried (50C/b mbar/3 h) affording 45.6g(89.8%) hydrochloride (5)as a beige, crystalline powder. ?H NMR (400 MHz, DMSO-d6) 6.16, (s, 2H), 7.09-7.50 (m, 8H), 10.25 (br s, 3H). ESI-MS (mlz)218 [M+H]?. Anal.Calcd. for C,3H,2FNO HC1 (253.71). C, 61.55; H, 5.16; N, 5.52; 0, 6.31; Cl,13.97; F, 7.49. Found. C, 61.26; H, 5.09; N, 5.45; 0, 6.51; Cl, 13.92; F, 7.51.
Step 1: 2-chloro-1-(3-fluorobenzyloxy)-4-nitrobenzene 2-chloro-4-nitrophenol (3.4 g, 20 mmol), <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (2.8 g, 20 mmol) and potassium carbonate (3.3 g, 24 mmol) was refluxed in acetonitrile (30 mL) overnight. The reaction mixture was poured into 100 mL of H2O, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated in vacuo to obtain the crude product. The crude product was washed with petroleum ether, filtered and dried, and the compound shown in the title (3.2 g, 57%) was obtained. 1H NMR (CDCl3): delta 8.35 (1H, d, J=2.8 Hz), 8.17-8.14 (1H, m), 7.44-7.38 (1H, m), 7.25-7.19 (2H, m), 7.10-7.06 (1H, m), 7.03 (1H, d, J=9.2 Hz), 5.26 (2H, s).
53%
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 23h;Inert atmosphere;
The synthesis was performed as described by Shiao et al. for similar compounds [60]. The work-up was performed as described by Fontana et al. [61]. 2-Chloro-4-nitrophenol (1.50 g, 8.64 mmol) was mixed with K2CO3 (3.58 g, 25.9 mmol), before DMF (90 mL) was added under nitrogen atmosphere. The mixture was heated to 75 C, and <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (1.87 g, 13.0 mmol) dissolved in DMF (60 mL) was added slowly. The reaction mixture was stirred at 75 C for 23 h, cooled to rt, quenched into cold water (150 mL, 5 C) and filtered. The isolated solid was washed with an ACN/water mixture (1/1, 50 mL), and n-hexane (30 mL). The obtained white solid was dried under reduced pressure. This yielded 1.29 g (4.58 mmol, 53%) of 2-chloro-1-((3-fluorobenzyl)oxy)-4-nitrobenzene as a white solid, mp. 90-96 C; 1H NMR (400 MHz, DMSO-d6) delta: 8.35 (d, J=2.8, 1H), 8.25 (dd, J=8.8, 2.8, 1H), 7.52-7.44 (m, 2H), 7.35-7.30 (m, 2H), 7.24-7.17 (m, 1H), 5.42 (s, 2H); 13C NMR (100 MHz, DMSO-d6) delta: 162.2 (d, J=243.7), 158.6, 140.9, 138.4 (d, J=8.1), 130.7 (d, J=8.1), 125.4, 124.6, 123.5 (d, J=2.9), 122.0, 115.1 (d, J=20.6), 114.3 (d, J=22.0), 113.8, 70.1 (d, J=2.1); 19F NMR (564 MHz, DMSO-d6, C6F6) delta: -115.15 (s, dec.); 1H NMR findings are in accordance with literature [59].
a. synthesis of 3-chloro-4-(3-fluorobenzyloxy)aniline (0198) (0199) 1-(Chloromethyl)-3-fluorobenzene (4.9 g, 34.6 mmol) was added into DMF (48 mL) and stirred to dissolve completely, K2CO3 (9.6 g, 69 mmol) was added and stirred for 30 min. 2-Chloro-4-nitrophenol (6 g, 34.6 mmol), KI (0.29 g, 1.7 mmol) were added at 60C under an oil bath, then reacted for 3 h. The reaction solution was added into ice-water, a large amount of solid was precipitated after stirring, filtrated to deliver the product 2-chloro-1-(3-fluorobenzyloxy)-4-nitrobenzene, which was used in the next step directly. (0200) According to a method similar to the preparation of compound 4, taking 2-chloro-1-(3-fluorobenzyloxy)-4-nitrobenzene obtained in the previous step as the starting material, 3-chloro-4-(3-fluorobenzyloxy)aniline (81% yield) can be synthesized. ESI-MS (m/z): 252.1 [M+H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h;
General procedure: A mixture of 2-chloro-4-nitrophenol (1 equiv., 2.88 mmol, 0.5 g), the respective substituted benzyl chloride (viz; <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong>, 3-chlorobenzyl chloride, 3,4-dichlorobenzyl chloride) or 2-picolyl chloride HCl (1 equiv., 2.88 mmol) and anhydrous K2CO3 (1.66 equiv., 4.78 mmol, 0.66 g) in dry DMF (10 mL) was heated at 80 oC for 24 hours. After cooling, the reaction mixture was poured into ice/water (100 mL). The precipitated solid was filtered, washed with water, and then washed with cold n-hexane to afford the designated compounds (1a-d). [1,2]
methyl 5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate[ No CAS ]
[ 456-42-8 ]
methyl 4-((1-(3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium carbonate; sodium iodide; In acetonitrile; at 80℃; for 1h;
A mixture of methyl 5-cyclopropyl-2-fluoro-4- (piperidin-4-ylmethoxy) benzoate (100 mg, 0.33 mmol) , 1-(chloromethyl) -3-fluorobenzene (48 mg, 0.33 mmo) , sodium iodide (149 mg, 0.99 mmol) and potassium carbonate (137 mg, 0.99 mmol) in MeCN (10 mL) was stirred at 80 for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and brine (50 mL) . The organic layer was separated, washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with petroleum ether/EtOAc 5/1) to give the target compound (110 mg, 81) as a pale yellow oil. LCMS (ESI) m/z: 416.0 [M+H]+.
5-(1-benzyl-3-phenyl-1H-pyrazol-5-yl)-1,3,4-oxadiazole-2-thiol[ No CAS ]
[ 456-42-8 ]
2-(1-benzyl-3-phenyl-1H-pyrazol-5-yl)-5-(3-fluorobenzylthio)-1,3,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.6%
With potassium carbonate; In acetonitrile; for 3h;Reflux;
General procedure: A mixture of 2 (1.67 g, 5 mmol), 4-<strong>[456-42-8]fluorobenzyl chloride</strong> (1.67 g, 5 mmol) and potassium carbonate (g, 5.2 mmol) in acetonitrile (20 mL) was heated to reflux for 3 h. The resulting solution was concentrated by vacuum evaporation and the residue was poured onto crushed ice, then the solid precipitate was collected by filtration, washed with water and cold ethanol to afford pure precipitates of 3a in 86.8% yield, as white solid
With NHC-Pd(II)-Im; lithium tert-butoxide; In toluene; at 130℃; for 3h;Inert atmosphere; Sealed tube;
Under N2 atmosphere, LiOtBu (1.0 mmol), benzoxazole 2a (0.6 mmol), NHC-Pd(II)-Im complex 1 (2.0 mol %), dry toluene (2.0 mL) and benzyl chloride 3a (0.5 mmol) were successively added into a sealed tube. The mixture was stirred vigorously at 130 C for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel to afford pure product 4a.
With NHC-Pd(II)-Im; lithium tert-butoxide; In toluene; at 130℃; for 3h;Inert atmosphere; Sealed tube;
Under N2 atmosphere, LiOtBu (1.0 mmol), benzoxazole 2a (0.6 mmol), NHC-Pd(II)-Im complex 1 (2.0 mol %), dry toluene (2.0 mL) and benzyl chloride 3a (0.5 mmol) were successively added into a sealed tube. The mixture was stirred vigorously at 130 C for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel to afford pure product 4a.
General procedure: A solution of anhydrous diisopropylamide (2.30 mL, 16.37 mmol) in anhydrous THF (34 mL) was cooled to-10C. To the solution was added n-BuLi (2.5 M in hexane, 7.00 mL) dropwise over 20 min. The resulting mixture was stirred at -10C for 55 min. To the mixture was added isobutyronitrile (1.22 mL, 13.57 mmol)dropwise over 15 min. After the mixture was stirred at -10C for 75 min, a solution of 2-bromomethylnaphthalene (16d, 2 g, 9.05 mmol) in anhydrous THF (2 mL) was added dropwise over 10 min. The reaction mixture was stirred at -10C for 20 min, then allowed at 0C for additional 2.5 h. The reaction was carefully quenched by saturated NH4Cl aqueous solution. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (30 mL × 5). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give a brown oil, which was recrystallized from petroleum ether (10mL) to give 16c as a white solid (0.91 g, 48 %).
2-(3-fluorobenzylthio)-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
In N,N-dimethyl-formamide; at 90℃; under 10343.2 Torr; for 0.25h;Microwave irradiation; Alkaline conditions;
General procedure: A CEM designed 10 mL pressure-rated vial was charged with DMF (15 mL), 5 (1.5 g,5.1 mmol) and K2CO3 (0.2 g, 5.6 mmol) and 2,4-dichlorobenzyl chloride (5.1 mmol). Themixture was irradiated in a CEM Discover Focused Synthesizer (150 W, 90C, 200 psi,15 min). The mixture was cooled to room temperature by passing compressed air throughthe microwave cavity for 2 min. It was poured into cold ice (40 mL) and the precipitatethat formed with filtered. The crude solid was recrystallized from EtOH to give the title compounds 6a. All the other compounds were synthesized according the same procedure.
2-(3-fluorobenzyl)-6,7-dimethoxyisoquinolin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93.1%
With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere;
General procedure: The mixture of substituted isoquinolin-1(2H)-ones (1.0 mmol) and NaH (1.5 mmol) in DMF (20 ml) was stirred under N2 for 0.5 h at a. t.. Then the substituted benzyl chloride (1.5 mmol) was added. The mixture was stirred till the completion of the reaction monitored by TLC. The mixture was poured gently to acidified ice-water (200 ml) with stirring. A precipitate was formed and filtrated after being stood overnight. The solid was purified by flash column chromatography(silica gel: 150-200 mesh; eluent: DCM/CH3OH = 40/1 to 60/1, v/v) to yield the corresponding product as amorphous powder from off-white to yellow. If a precipitate did not form, the mixture was extracted with DCM (50 ml×3). The combined organic layers were washed with HCl solution (1M, 50 ml×3), saturated brine (50 ml), dried over Na2SO4, concentrated. The residue was purified by flash column chromatography (silicagel: 150-200 mesh; eluent: DCM/CH3OH =40/1 to 60/1, v/v) to yield the corresponding product
With magnesium; In tetrahydrofuran; at 0℃; for 0.5h;Inert atmosphere; Schlenk technique;
General procedure: A dry and argon-flushed Schlenk tube, equipped with a magnetic stirring bar and a rubber septum, was charged with Mg turnings (0.18 g, 7.20 mmol, 2.40 equiv), followed by freshly distilled THF (3.0 mL) or MTBE (1.9 mL) and a solution of MnCl2·2LiCl (3.80 mL, 3.80 mmol,1.25 equiv, 1.0 M in THF). The mixture was cooled to 0 C, the corresponding benzylic chloride (3.0 mmol, 1.00 equiv) was added at once and maintained at 0 C until a complete conversion of starting material was observed. The completion of the metalation was monitored by GC analysis of hydrolyzed and iodolyzed aliquots. When the oxidative insertion was complete, the solution of benzylic manganese chloride was separated from the resulting salts via a syringe equipped with a filter and transferred to another predried and argon-flushed Schlenk tube, before titrating with an iodine solution in THF.
With magnesium; In tetrahydrofuran; at 0℃; for 1h;Schlenk technique; Inert atmosphere;
General procedure: A dry and argon-flushed Schlenk-tube, equipped with a magnetic stirring bar and a rubberseptum, was charged with magnesium (0.18 g, 7.20 mmol, 2.40 equiv), followed by freshlydistilled THF (3.0 mL) or MTBE (1.9 mL) and a solution of MnCl2·2LiCl (3.80 mL, 3.80 mmol,1.25 equiv, 1.0 M in THF). The mixture was cooled to 0 C, the benzyl chloride (3.0 mmol, 1.0equiv) was added at once and maintained at 0 C until a complete conversion of starting materialwas observed. The completion of the metalation was monitored by GC-analysis of hydrolysedand iodolysed aliquots. When the oxidative insertion was complete, the solution of benzylicmanganese(II) chloride was separated from the resulting salts via a syringe equipped with afilter and transferred to another pre-dried and argon-flushed Schlenk-tube, before being titrated against iodine.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In acetone;Reflux;
General procedure: A mixture of compound 2 (2 g, 12 mmol), potassium carbonate (2 g, 14.4 mmol), appropriate alkylbromide or benzyl chloride derivatives (1.32 mmol), and a catalytic amount of benzyltriethylaminechloride (TEBA) in 50 mL acetone was heated under reflux for 18-24 h. After removing the solventunder reduced pressure, 80 mL of hot water was poured into the flask and the mixture was stirred for0.5 h to eliminate the excess of potassium carbonate. The remaining precipitate was filtered to yield arusset solid (3a-m), which was used without further purification.
In a 100 mL round bottom flask, Berberine I (0.5 g, 1.024 mmol), potassium carbonate (0.11 g, 0.081 mmol) andA suitable amount of dry DMF (2.5 mL) was stirred under nitrogen at 0 C. for 1 hour and <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (0.1778 g) was added dropwise.1.229 mmol). The reaction is allowed to warm up to 60C and the reaction is continued for about 7 hours. TLC follows until the end of the reaction. After cooling to room temperature (18-25 C.), the solid was filtered, washed with diethyl ether (10 mL), and dried. Column chromatography yielded 0.292 g of compound III-5.Yield 48%.
28%
General procedure: Compound 4a (500 mg. 1.0 mmol) and potassium carbonate(110 mg, 0.8 mmol) in DMF (2.5 mL) were stirred at 0?C for 1 h,then 1-bromoethane (140 mg, 1.3 mmol) was added and slowlyraised to room temperature and 60?C for 7 h maintained. After thereaction was completed (monitored by TLC, eluent, chloroform/methanol, 99/1, V/V), the mixture was cooled to room temperatureand diethylether (10 mL) was added and filtered. The solid wasfurther washed with diethylether (20 mL) and dried over undervacuum. The crude product was purified by alumina columnchromatography (chloroform/methanol, 99/1) to afford the compound5a (270 mg) as yellow solid.
8-chloro-3-((3-fluorobenzyl)thio)-[1,2,4]triazolo[4,3-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium hydroxide; In N,N-dimethyl-formamide; at 90℃; for 0.25h;Microwave irradiation;
DMF (5 ml), 8 - chloro - [1, 2, 4] triazolo [4, 3 -a ] Pyridine -3 (2H ) - Thione (1 mmol), 1 - chloro methyl -3 - fluorobenzene (1.1 mmol) and NaOH (0.05 g, 1.2 mmol) added to the CEM Discovery single mode microwave synthesis instrument 10 ml rated pressure tank. Then in (90 C, 15 minutes) the microwave radiation under the conditions of the reaction. After the reaction, the mixture is poured into the ice formed in the filter after precipitation, recrystallization collection, the crude product is purified by column chromatography. Namely 8 - chloro -3 - ((3 - fluorophenyl) thio) - [1, 2, 4] triazolo [4, 3 -a ] Pyridine, yield 93%.
81%
With sodium hydroxide; In N,N-dimethyl-formamide; at 90℃; for 0.25h;Microwave irradiation;
General procedure: Preparation of 2a: The 3-chloro-2-hydrazinylpyridine(143 mg, 1mmol) and thiourea (3 mmol) were exposed to CEM Discover Focused Synthesizer at 180 C for 30 min.Then the mixture was poured into water (40 mL), filtered and recrystallized to give the key intermediate 8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-thione. 1H NMR (CDCl3,400 MHz), : 6.22(s, 1H, SH), 6.66(t, J=5.0Hz, 1H, Py-H),7.48(d, J=7.6Hz, 1H, Py-H), 8.11(d, J=4.9Hz, 1H, Py-H). 8-Chloro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)- thione (1mmol),DMF (5 mL), RCH2Cl (1.1 mmol) and NaOH (0.05 g,1.2mmol) was irradiated at 90C for 15 min. After the reaction is completed, the mixture was poured into crushed ice and the target compound 2a was collected, recrystallized.The crude product was purified by column chromatography.The other compounds 2b~2k were synthesized using the same method.
1-(3-fluorobenzyl)-3-[2-(4H-1,2,4-triazol-4-yl)ethyl]-1H-indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 0.5h;
General procedure: To a solution of Compound 3 (2.1 g, 10 mmol) in DMF (30 ml) was added haloalkane (11 mmol) and NaH (1.66 g,12 mmol). After the reaction mixture was stirred at 0 C for 0.5 h, the mixture was added into 50 mL of ice-water and filtered to obtain a light white solid. Finally, they can be purified by chromatography on silica eluting with a gradient of methanol/dichloromethane (1:30) to give the compound 4a-t as solid.
5-((4,6-dimethylpyrimidin-2-yl)thiomethyl)-1,3,4-oxadiazole-2-thiol[ No CAS ]
[ 456-42-8 ]
C16H15FN4OS2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.2%
With potassium carbonate; In ethanol; at 20℃;
In 25 ml water is added in the flask 5 - ((4,6-dimethyl-pyrimidin-2 -) sulfur methyl) - 1, 3, 4-oxadiazol-2-thiol (5mmol) dissolved in K2CO3in aqueous solution, then adding dissolved in 5 ml of anhydrous ethanol fluorine phenmethyl chlorine in (5.25mmol) stirring reaction at room temperature, TLC detection reaction to the end. The reaction product is filtered, washing, drying, recrystallized with ethanol, to obtain white crystalline solid, that is, derivatives 5 m., the yield is 83.2%.
5-((4,6-dimethylpyrimidin-2-yl)thiomethyl)-1,3,4-thiadiazole-2-thiol[ No CAS ]
[ 456-42-8 ]
2-(((4,6-dimethylpyrimidin-2-yl)thio)methyl)-5-((3-fluorobenzyl)thio)-1,3,4-thiadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.3%
With potassium carbonate; In ethanol; water; at 20℃;
In 25 ml water is added in the flask 5 - ((4,6-dimethyl-pyrimidin-2 -) sulfur methyl) - 1, 3, 4-thiadiazole-2-thiol (5mmol) dissolved in K2CO3in aqueous solution, then adding dissolved in 5 ml of anhydrous ethanol fluorine phenmethyl chlorine in (5.25mmol) stirring reaction at room temperature, the final filtering, washing, drying, after crystallization ethanol to obtain white crystalline solid, that is, concentrate derived from 7o. Melting point 71-73C, the yield is 82.3%.
With sodium azide; triethylamine; In water; tert-butyl alcohol; at 20℃; for 1h;
General procedure: A solution of 2-formyl benzoic acid (1 mmol), propargyl amine (1 mmol), and cyclohexyl isocyanide (1 mmol) in ethyl alcohol (10 mL) was stirred for 24 h at room temperature andt hen concentrated under reduced pressure. A solution of an arylmethyl chloride or bromide (1.1 mmol), sodium azide (0.9 mmol), and triethylamine (1.3 mmol) in water (5 mL) and tert-butyl alcohol (5 mL) was stirred at room temperature for 1 h. This solution was added to the crude Ugi adduct along with 10 mol% CuI and the reaction was continued for another 24 h. Upon completion, the reaction was poured into ice water and the resultant solid was purified by recrystallization from ethyl acetate-petroleum ether.
With sodium azide; In ethanol; water; at 85℃; for 48h;
General procedure: To a solution of 2-methyl benzyl chloride (2.8 g, 20 mmol) in water/EtOH (40mL, 1:1) at room temperature was added NaN3 (3.9 g, 60 mmol). The resulting solution was allowed to stir at 85 C and reflux for 48 h. Afterward, Afterwards, the solution was concentrated in vacuum to remove EtOH, and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to obtain a colorless oil (2.4 g). Then the oil and propiolic amine (0.88 g, 16 mmol) were suspended in a solution of water/t-BuOH (40mL, 1:1), followed by the addition of sodium ascorbate (0.52 g, 3.2 mmol) and CuSO4·5H2O (0.40 g, 1.6 mmol). The resulting reaction was vigorously stirred for 12 h at rt. Afterwards, the solution was concentrated in vacuum to remove t-BuOH, and the aqueous layer was subsequently adjusted to pH = 12, extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give white solid A1 (2.2 g, 54%). According to the above procedure, corresponding aminomethyl triazoles A2-A15 were prepared in yields ranging from 36% to 62%.
With sodium azide; at 20℃;
General procedure: To a solution of sodium azide (3.60 g, 55 mmol) in dry dimethyl sulfoxide (120 mL) was added properly substituted benzyl chloride (50 mmol), and the reaction mixture was stirred at room temperature overnight monitored by TLC. Iice-water (100 mL) was carefully added to the reaction mixture and the aqueous layer was extracted with dichlormethane. The combined organic extracts were washed with water (50 mL) and the organic layer was dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated, leaving compound 1a-1k as a yellow oil (yield: 74%-83%).
With sodium azide; In ethanol;Reflux;
add 5.0 mmol of <strong>[456-42-8]m-<strong>[456-42-8]fluorobenzyl chloride</strong></strong>, 0.65 g of NaN3, 5 mL of absolute ethanol to a 50 mL round bottom flask, heat under reflux with stirring, and follow the reaction by TLC; after the reaction is complete, remove the ethanol by rotary evaporation. After extracting the reaction solution with EA 2-3 times, the organic layers were combined, and the organic layers were washed 3 times with saturated NaCl solution. After the EA was removed by rotary evaporation, the remaining materials were separated and purified by silica gel column chromatography using petroleum ether as the eluent.
5,6-dihydro[1,2,4]triazolo[3,4-a]isoquinolin-9-ol[ No CAS ]
[ 456-42-8 ]
9-(3-fluorobenzyloxy)-5,6-dihydro[1,2,4]triazolo[3,4-a]isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44.5%
With sodium hydride; In N,N-dimethyl-formamide; at 20℃;
General procedure: Compound 4b (0.2 g, 1.1 mmol) was dissolved in anhydrous DMF (2 mL), alkyl bromide, or benzylchloride derivatives (1.2 mmol) and NaH (0.15 g, 6.4 mmol) were added into this solution and stirredat a room temperature for 0.5-2 h. The mixture was poured into ice water, and then filtered, washedand dried. The compound (4c-t) was isolated and purified by silica gel column chromatography usingCH2Cl2/CH3OH (100:1) as the eluent.
With copper(II) acetate monohydrate; sodium carbonate; sulfur; In dimethyl sulfoxide; at 130℃; for 24h;Schlenk technique; Inert atmosphere;
General procedure: 2-Iodoaniline 1a (0.5 mmol), benzyl chloride 2a (1 mmol, 126 mg), sulfur powder (2 mmol, 64 mg), Cu(OAc)2·H2O (20 mg) and Na2CO3 (1 mmol, 106 mg) in DMSO (3 mL) were put into a Schlenk tube. The reaction mixture was stirred at 130 C for 24 h and cooled to room temperature, filtered and extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (300-400 mesh) to afford desired product 3aa as a light yellow solid; yield : 102 mg (97%);
3-(3-fluorobenzyl)benzo[d]oxazol-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
General procedure: One of 4a-d (1 equiv.) and K2CO3 (3 equiv.) in DMF was stirred at 90C for 1h, then the solution was allowed to cool to 60C and was added different substituted benzyl chlorides or phenyl ethyl chlorides (3 equiv.). The reaction mixture was stirred at 60C for another 7h and allowed to cool to room temperature. The saturated NH4Cl solution was added to quench the reaction. The mixture was diluted with water and extracted with ethyl acetate to afford the crude product that was purified by flash column chromatography on silica gel to yield the target products.
5-chloro-3-(3-fluorobenzyl)benzo[d]oxazol-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
General procedure: One of 4a-d (1 equiv.) and K2CO3 (3 equiv.) in DMF was stirred at 90C for 1h, then the solution was allowed to cool to 60C and was added different substituted benzyl chlorides or phenyl ethyl chlorides (3 equiv.). The reaction mixture was stirred at 60C for another 7h and allowed to cool to room temperature. The saturated NH4Cl solution was added to quench the reaction. The mixture was diluted with water and extracted with ethyl acetate to afford the crude product that was purified by flash column chromatography on silica gel to yield the target products.
5-fluoro-3-(3-fluorobenzyl)benzo[d]oxazol-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
General procedure: One of 4a-d (1 equiv.) and K2CO3 (3 equiv.) in DMF was stirred at 90C for 1h, then the solution was allowed to cool to 60C and was added different substituted benzyl chlorides or phenyl ethyl chlorides (3 equiv.). The reaction mixture was stirred at 60C for another 7h and allowed to cool to room temperature. The saturated NH4Cl solution was added to quench the reaction. The mixture was diluted with water and extracted with ethyl acetate to afford the crude product that was purified by flash column chromatography on silica gel to yield the target products.
3-(3-fluorobenzyl)-5-nitrobenzo[d]oxazol-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
General procedure: One of 4a-d (1 equiv.) and K2CO3 (3 equiv.) in DMF was stirred at 90C for 1h, then the solution was allowed to cool to 60C and was added different substituted benzyl chlorides or phenyl ethyl chlorides (3 equiv.). The reaction mixture was stirred at 60C for another 7h and allowed to cool to room temperature. The saturated NH4Cl solution was added to quench the reaction. The mixture was diluted with water and extracted with ethyl acetate to afford the crude product that was purified by flash column chromatography on silica gel to yield the target products.
[1,2,4]triazolo[3,4-a]phthalazin-6(5H)-one[ No CAS ]
[ 456-42-8 ]
5-(3-fluorobenzyl)-[1,2,4]triazolo[3,4-a]phthalazin-6(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.8%
General procedure: A mixture of compound 5 (0.5 g, 2.7 mmol) and NaH (0.2g, 8.1 mmol) was dissolved in N,N-dimethylformamide (20ml). The mixture was stirred and refluxed for 30 min. Thereaction was cooled to room temperature, and alkyl bromideor benzyl chloride was added dropwise to the mixture asappropriate before refluxing for 3 h. After the reaction wascompleted, the solvent was removed under reduced pressure.The residue was washed with water (10 ml × 3), filteredoff, and dried and purified using silica gel columnchromatography (CH2Cl2/CH3OH, 60:1) to yield compounds6a-y, a white powder.
7-(3-fluorobenzyl)-7H-[1,2,4]triazolo[4,3-a]perimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63.4%
With sodium hydride; In N,N-dimethyl-formamide; at 50℃;
General procedure: The intermediate 4 (0.4 g, 2.0 mmol) was dissolved in anhydrous DMF (5 mL), alkyl bromide, or benzyl chloride derivatives (2.4 mmol) and NaH (0.19 g, 8.0 mmol) were added into this solution and heated at 50 for 2-4 h. The mixture was poured into ice water, and then filtered, washed and dried. The compound (5a-s) was isolated and purified by silica gel column chromatography using CH2Cl2/CH3OH (100:1) as the eluent.
4,6-bis(4-bromophenyl)-2-((3-fluorobenzyl)thio)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: A mixture of 4 (1 mmol), different substituted benzyl chlorides or benzyl bromides 5 (1 mmol)and K2CO3 (1 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. After the completionof the reaction, the mixture was poured into ice-cold water and the precipitated solid was collectedby filtration, washed with water and dried in vacuo. The crude products were purified by columnchromatography (silica gel) using EtOAc/petroleum ether as eluent.
4-(3-bromophenyl)-2-((3-fluorobenzyl)thio)-6-(p-tolyl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: A mixture of 4 (1 mmol), different substituted benzyl chlorides or benzyl bromides 5 (1 mmol)and K2CO3 (1 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. After the completionof the reaction, the mixture was poured into ice-cold water and the precipitated solid was collectedby filtration, washed with water and dried in vacuo. The crude products were purified by columnchromatography (silica gel) using EtOAc/petroleum ether as eluent.
4-(4-bromophenyl)-2-((3-fluorobenzyl)thio)-6-(p-tolyl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: A mixture of 4 (1 mmol), different substituted benzyl chlorides or benzyl bromides 5 (1 mmol)and K2CO3 (1 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. After the completionof the reaction, the mixture was poured into ice-cold water and the precipitated solid was collectedby filtration, washed with water and dried in vacuo. The crude products were purified by columnchromatography (silica gel) using EtOAc/petroleum ether as eluent.
4-(3-bromophenyl)-6-(4-bromophenyl)-2-((3-fluorobenzyl)thio)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: A mixture of 4 (1 mmol), different substituted benzyl chlorides or benzyl bromides 5 (1 mmol)and K2CO3 (1 mmol) in DMF (10 mL) was stirred at room temperature for 12 h. After the completionof the reaction, the mixture was poured into ice-cold water and the precipitated solid was collectedby filtration, washed with water and dried in vacuo. The crude products were purified by columnchromatography (silica gel) using EtOAc/petroleum ether as eluent.
With sodium azide; In water; at 70℃; for 7h;Green chemistry;
General procedure: A mixture of sodium azide (1 mmol), benzyl or alkyl halide (1 mmol), and corresponding acetylene (1 mmolof phenyl acetylene or 2 mmol of alkyl acetylene) and catalyst (5 mg of catalyst equal to 0.1 mol % of copper)was taken in a round bottomed ask containing 1 mL of H 2 O and 0.2 mL of PEG 300 and heated at 70C for3 h under vigorous stirring. After completion of the reaction (monitored by TLC), the catalyst was removedby external magnet, washed with EtOH, and dried under vacuum. The collected solvent was concentratedunder vacuum and the product was allowed to crystalize, which did not require any further purication.The obtained products were conrmed and completely characterized by physical and spectral data (see theSupporting Information).
80%
With sodium azide; sodium L-ascorbate; In water; at 70℃; for 2h;
General procedure: A mixture of sodium azide (1.2 mmol), sodium ascorbate (0.1 mmol), alkyne (1.1 mmol), benzyl compound (1.0 mmol), PVC-EDA-Cu(II) (0.015 g, mol%), and water (3 mL) was vigorously stirred at 70 C under for specific time under aerobic condition. The reaction process was monitored by TLC. Upon completion of the reaction, the mixture was filtered to recover the catalyst. The catalyst was washed with water and ethanol, dried, and stored for subsequent runs. The filtrate was extracted with ethyl acetate (10 mL x 3) and washed with brine. After removing the organic solvent using a rotary evaporator, the crude product was further purified by recrystalization using ethanol as the solvent to afford the pure product.
With sodium azide; sodium L-ascorbate; In water; at 70℃; for 3.5h;
General procedure: A mixture of sodium azide (1.2 mmol), sodium ascorbate (0.1 mmol), alkyne (1.1 mmol), benzyl compound (1.0 mmol), PVC-EDA-Cu(II) (0.015 g, mol%), and water (3 mL) was vigorously stirred at 70 C under for specific time under aerobic condition. The reaction process was monitored by TLC. Upon completion of the reaction, the mixture was filtered to recover the catalyst. The catalyst was washed with water and ethanol, dried, and stored for subsequent runs. The filtrate was extracted with ethyl acetate (10 mL x 3) and washed with brine. After removing the organic solvent using a rotary evaporator, the crude product was further purified by recrystalization using ethanol as the solvent to afford the pure product.
2,3-bis-(3-fluoro-phenyl)-1-phenyl-propan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With tetra-(n-butyl)ammonium iodide; sodium carbonate; at 100℃; under 760.051 Torr; for 9h;
General procedure: A 25 mL flask equipped with a magnetic stir bar was charged with potassium arylfluoroborate (0.5mmol), TBAI (0.1 mmol, 37.6 mg), Na2CO3 (2.0 mmol, 213.0 mg), and PEG-400 (2 ml) before standardcycles of evacuation and back-filling with dry and pure carbon monoxide. Corresponding benzylchloride (1.0 mmol) was added successively. The mixture was then stirred at 100oC for the indicatedtime. After being allowed to cool to room temperature, the reaction mixture was diluted with 3 mL waterand extracted with diethyl ether (4 × 5 mL). The organic phases were combined, and the volatilecomponents were evaporated in a rotary evaporator. The residue was purified by columnchromatography on silica gel (petroleum ether: diethyl ether = 100 : 1 to 10 : 1).
5-((4,6-dimethylpyrimidin-2-ylthio)methyl)-4-phenyl-4H-1,2,4-triazole-3-thiol[ No CAS ]
[ 456-42-8 ]
2-((5-(3-fluorobenzylthio)-4-phenyl-4H-1,2,4-triazol-3-yl)methylthio)-4,6-dimethylpyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With potassium hydroxide; In N,N-dimethyl-formamide; at 40℃; for 0.25h;Microwave irradiation;
General procedure: Compound 6 (660 mg, 2 mmol), substituted benzyl chloride(2.10 mmol) and KOH (126 mg, 2.20 mmol) were dissolved in 10 mL anhydrous DMF. The resulting solution was exposed to CEM Discover Focused Synthesizer at 40 C for 15 min.The reaction mixture was then poured into cold water, and the precipitate formed was filtered, recrystallized from anhydrous ethanol and dried to give target compounds 7a~7m.
1-(2,4-difluorophenyl)-1-hydroxy-2-(1H-1,2,4-triazol-1-yl)ethane[ No CAS ]
[ 456-42-8 ]
C17H14F3N3O[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.6%
With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide; In toluene; at 100℃; for 2h;
Addition of intermediate 1-(2,4-difluorophenyl)-1-hydroxy-2-(1H-1,2,4-triazol-1-yl)-ethane to a 125 mL three-necked flask 1.58 g (0.007 mol), phase transfer catalyst TEBA 1.1 g, meta<strong>[456-42-8]fluorobenzyl chloride</strong> 1.16 g (0.008 mol), solvent toluene 30 mL, 50% NaOH 10 mL, reaction at temperature 100 C. for 2 hours. After the reaction was completed, the organic layer was separated, washed with water (50 mL×3), dried over anhydrous MgSO 4 , filtered, and spin-dried. The residue was purified by column chromatography (petroleum ether:ethyl acetate=6:1) to give 1.53 g of an oily substance. Compound 11, yield 65.6%.
ethyl 2-(1-(3-fluorobenzyl)-5,5-dimethyl-2,4-dioxoimidazolidin-3-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77.06%
General procedure: A mixture of alkyl 2-(5,5-dimethyl-2,4-dioxoimidazolidin-3-yl)acetate 29 (12 mmol, 29a: 2.40 gor 29b: 2.58 g), TEBA (1.20 mmol, 0.36 g), K2CO3 (12 mmol, 4.80 g) in acetone (60 mL) was heatedunder reflux for 30 min. The appropriate arylmethyl halide (12 mmol) in acetone (15 mL) was added.The mixture was heated under reflux for 5-7 h and stirred at room temperature for further 24-48 h. The inorganic precipitate was separated by filtration. The filtrate was collected, the solvent thenevaporated and the residue was dissolved in 30 mL of DCM and washed with 1% NaOH (2 x 30 mL)and H2O (2 x 30 mL). The organic phase was dried on anhydrous Na2SO4 overnight, separated fromthe drying agent and the solvent was evaporated. Then, Methods A or B were applied for purification.Method A: The residue was crystallized with EtOH and charcoal to give crystals of the intermediates.Method B: If Method A was applied, but no crystal appeared, the ethanolic solution was concentratedto give crude ester intermediates in glue form. No ester intermediate (30-40) was isolated in pureform (purity < 80%). The purity and identity of crude intermediates were evaluated using LC-MS.Taking into consideration the results of LC-MS a desirable ester was used for the synthesis of the finalproduct in the amount suitable to its concentration in the crude product obtained (40-80%).
4-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-carbaldehyde[ No CAS ]
[ 456-42-8 ]
4-(3-fluorobenzyloxy)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;
50 mg of intermediate XVII, 41 mul of <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong>,98 mg of potassium carbonate was added to 3 ml of N,N-dimethylformamide.The reaction was carried out at 90 C for 4 hours, and the system was cooled to room temperature.Water and ethyl acetate were added thereto, and the aqueous layer was extracted twice with ethyl acetate.The organic layer was collected, and the organic layer was washed twice with water and washed with saturated sodium chloride.Dry over anhydrous magnesium sulfate, filter, concentrate, and the residue was purified by column chromatography.Yield 60 mg of a yellow oil (intermediate XVIII-1),The yield was 64%.
7-(3-fluorobenzyloxy)-2,3-dihydro-1H-indene-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;
Will be 120 mg of intermediate IV, 107 mul of <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong>,255 mg of potassium carbonate was added to 3 ml of N,N-dimethylformamide.The reaction was carried out at 90 C for 4 hours, and the system was cooled to room temperature.Water and ethyl acetate were added thereto, and the aqueous layer was extracted twice with ethyl acetate.The organic layer was collected, and the organic layer was washed twice with water and washed with saturated sodium chloride.Dry over anhydrous magnesium sulfate, filter, concentrate, and the residue was purified by column chromatography.The title compound (Intermediate V-1), 120 mg of yellow solid.The yield was 65%.
4-(3-fluorobenzyloxy)-5,6,7,8-tetrahydronaphthalene-1-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;
50 mg of intermediate VII, 41 mul of <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong>,98 mg of potassium carbonate was added to 3 ml of N,N-dimethylformamide.The reaction was carried out at 90 C for 4 hours, and the system was cooled to room temperature.Water and ethyl acetate were added thereto, and the aqueous layer was extracted twice with ethyl acetate.The organic layer was collected, and the organic layer was washed twice with water and washed with saturated sodium chloride.Drying with anhydrous magnesium sulfate,Filtration, concentration, and the residue were purified by column chromatography73 mg of yellow solid,The yield was 90%.
1-(3-fluorophenethyl)-6,7-dimethoxy-2-methyl-3,4-dihydroisoquinolin-2-ium chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
Stage #1: 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline; m-fluorobenzyl chloride; methyl iodide With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1h;
Stage #2: With sodium iodide In acetonitrile at 20℃; for 4h; chemoselective reaction;
1-(3-Fluorophenethyl)-6,7-dimethoxy-2-methyl-3,4-dihydroisoquinolin-2-ium chloride (4f):
A solution of1d (50.0 mg, 0.244 mmol), methyl iodide (37.3 mg,0.268 mmol), 3-fluorobenzyl chloride (52.9 mg,0.366 mmol), and DIPEA (34.9 mg, 0.268 mmol) inCH3CN (1.0 mL) was stirred at rt. When 1d was completely consumed in 1 h based on the analysis of TLCand LC/MS, NaI (5.5 mg, 0.0367 mmol) was added to the reaction mixture and stirred at rt. for 4 h. The crude mixture was quenched with 0.5 N HCl (aq) and extracted with DCM (2 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was removed under vacuum. The crude mixture was purified on silica gel column chromatography using DCM/MeOH (9/1) as an eluent to afford 4f (60 mg, 0.13 mmol, 54%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.29-7.18 (m, 1H),7.08 (s, 1H), 6.98-6.95 (m, 1H), 6.94-6.84 (m, 3H), 4.08(t, J = 7.8 Hz, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 3.78 (s, 3H),3.63 (t, J = 7.2 Hz, 2H), 3.22 (t, J = 7.8 Hz, 2H), 3.12 (t,J = 7.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 176.1,162.8 (d,1JC-F = 245.8 Hz), 156.4, 148.7, 140.6, 140.5 (d,JC-F = 7.2 Hz), 133.3, 130.7 (d, JC-F = 8.3 Hz), 124.4 (d,JC-F = 2.7 Hz), 118.7, 115.4 (d, JC-F = 21.0 Hz), 114.2 (d,JC-F = 21.0 Hz), 112.2, 111.0, 56.9, 56.8, 53.5, 46.3, 33.7,33.4, 26.1; LC/MS m/z 328.2 [M - I-]; HRMS (FAB+) m/zcalcd for C20H23FNO2+ [M - I-] 328.1707, found328.1689.
Weighing 6.10g of <strong>[436-77-1]fangchinoline</strong>,0.33 g of sodium oxide was dissolved in 100 mL of tetrahydrofuran in a 500 mL three-necked flask.Then add 1.60g of m-fluorobenzyl chloride,Stir and mix together to heat to boiling,And the reaction was stirred for 4.0 h. TLC detects all reactions of <strong>[436-77-1]fangchinoline</strong>,The solvent was distilled off under reduced pressure and cooled to room temperature.10% hydrochloric acid neutralized to neutral,Treated with 500g of 5A molecular sieve adsorption resin,After washing with water, elute with absolute ethanol.The TLC tracks the separation and purification process of the reaction and the product, and collects the ethanol fraction.Ethanol was distilled off under reduced pressure to give a solid, and the solid was dried at 60 C for 4 h.That is, 6.50 g of a product as a pale yellow powder.
Ionic liquid method: weigh 6.10g of anti-ninoline base, 2.85g of <strong>[456-42-8]m-<strong>[456-42-8]fluorobenzyl chloride</strong></strong>,100 mL of N-ethylpyridine tetrafluoroborate, added to the reactor, mixed uniformly, and sonicated at 120 C for 1 h.The temperature was lowered to room temperature, extracted three times with acetone (200 mL×3), and the remaining phase ionic liquid was washed with 10 mL of deionized water.After vacuum drying, it was repeatedly used, and acetone was recovered, neutralized to neutral with 30% hydrochloric acid, treated with 500 g of 5A molecular sieve adsorption resin, washed with water and then eluted with absolute ethanol.The TLC traces the reaction and the separation and purification process of the product, collects the ethanol fraction, and distills off the ethanol to obtain a solid.The solid was dried at 60 C for 4 h.That is, the product was obtained as a pale yellow powder, 7.49 g, yield 94.77%.
With potassium iodide; In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere;
General procedure: The BTA derivatives were obtained by the following general procedure: A suspension of2-mercaptoBTA (1.0 eq) and K2CO3 (1.1 eq) in THF, where the corresponding benzyl chloride (1.1eq) was added dropwise and, thereafter, a catalytic amount of KI was added. The reaction mixturewas stirred at room temperature for 24 h. The course of the reaction was monitored by thin-layerchromatography. Over time, the reaction mixture was filtered and washed with CH2Cl2 (3 20 mL).The organic filtrate was washed with brine (20 mL), dried with anhydrous Na2SO4, and evaporated invacuo to give solids, in most of cases, which were purified by recrystallization from hexane: AcOEt 9:1to aord amorphous solids.
Take a 250 mL round bottom flask and <strong>[456-42-8]3-<strong>[456-42-8]fluorobenzyl chloride</strong></strong> (0.7229 g, 5 mmol),p-Toluenesulfonylmethylisocyanide (0.4881 g, 2.5 mmol) and tetrabutylammonium bromide (0.1612 g, 0.5 mmol) were dissolved in 30 mL of dichloromethane.After stirring until dissolved, 30 mL of 30% NaOH solution was slowly added dropwise using a constant pressure dropping funnel.After stirring for 5 h, HCl was added and the pH was adjusted to 7.The reaction solution was transferred to a sep. funnel and extracted three times with dichloromethane to give an orange-yellow organic phase.The obtained organic phase was concentrated, then 5 mL dichloromethane was added, and 1 mL of concentrated HCl was added, and the mixture was stirred for 1 hour and then quenched with saturated sodium hydrogen carbonate solution.The reaction solution was transferred to a sep. funnel and extracted three times with dichloromethane. Spin dry,Then, it was subjected to column chromatography (eluent: ethyl acetate: petroleum ether: = 1:5) to give the title compound. Characterized as follows:
2-(3-fluorophenyl)-4,6-diphenyl-1,3,5-triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With sulfur; potassium hydroxide; In dimethyl sulfoxide; at 120℃; for 24h;
Preparation method: adding 1.0 mmol of benzamidine hydrochloride into a 25 mL pressure tube,1.0 mmol of 3-fluorene fluoride, 0.75 mmol of sulfur powder, 1.5 mmol of KOH, and 2 mL of dimethyl sulfoxide were added thereto, and stirred at 120 C for 24 hours. The reaction was confirmed by TLC plate, and product was formed.The reaction solution was cooled, extracted, dried, evaporated under reduced pressure, and then filtered to afford white solid.
79%
With sulfur; potassium hydroxide; In dimethyl sulfoxide; at 130℃; for 24h;Sealed tube;
General procedure: A mixture of benzamidine hydrochloride (0.5 mmol), benzyl chloride (0.5 mmol), sulfur powder (0.375 mmol), KOH (1.5 mmol) and dimethyl sulfoxide (2.0 mL) was placed in a sealed pressure vessel (25 mL) containing a magnetic stirring bar. The tube was capped and stirred in a preheated oil bath at 130 C for 24 h. After the mixture was cooled to room temperature, the resulting solution was diluted with ethyl acetate (25 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered. The filtrate was concentrated, and the residue was purified by column chromatography on SiO2 (petroleum ether / dichloromethane, 30:1) to give 1,3,5-triazines (82% yield).
4-hydroxy-3-(1H-tetrazol-1-yl) benzonitrile[ No CAS ]
[ 456-42-8 ]
4-[(3-fluorobenzyl) oxy]-3-(1H-tetrazol-1-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 50℃; for 5h;Inert atmosphere;
General procedure: In a 100mL single-mouth bottle,4 g (21.4 mmol) of 4-hydroxy-3-(1H-tetrazol-1-yl)benzonitrile (Example 3), 3.16 g (25.7 mmol) of 2-bromopropane,5.9 g (42.7 mmol) of anhydrous potassium carbonate,710.48mg (4.28mmol)Potassium iodide and 32 mL of dried DMF,At 50 C, nitrogen protection reaction for 5 h,After the reaction,Pour the reaction solution into a beaker containing 200 mL of ice water.Stir for 30min, suction filtration,Wash the filter cake twice, dry to obtain crude product, crude petroleum ether:Ethyl acetate = 2:1 recrystallization, suction filtration at room temperature, washing the cake twice with a small amount of petroleum ether (5 mL × 2), and dried to give a white solid 3.26 g.Yield: 66.5%,
74.3%
General procedure: Add 4-hydroxy-3-(1H-tetrazol-1-yl)benzonitrile (3 g, 16.03 mmol), anhydrous potassium carbonate (6.65 g, 48.09 mmol), potassium iodide (27 mg, 0.16 mmol) to a 100 mL vial. And 24 mL of N,N-dimethylformamide (DMF), stirred at room temperature for 30 min,6 mL of a solution of bromoisobutane (3.07 g, 22.44 mmol) in DMF was added dropwise.After the completion of the dropwise addition, the reaction was carried out under nitrogen protection at 70 C for 10 hours.After the completion of the reaction, the mixture was filtered, and the filtrate was washed twice with DMF. The filtrate and washings were combined and concentrated to remove 3/4 of DMF. The residue was dissolved in ethyl acetate. The inorganic salt was removed by suction filtration, and ethyl acetate was evaporated under reduced pressure. The obtained crude product was recrystallized from petroleum ether: ethyl acetate (4:9) to afford white crystals.Yield: 72.2%. Mp 139.2 C -140.6 C.
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