* 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 Example 1 5-chloro-2-hydroxybenzonitrile 5-chloro-2-hydroxybenzaldehyde (300 g, 1.92 mol) and hydroxylamine-O-sulfonic acid (260 g, 2.30 mol) were suspended in water (4.5 L) at room temperature, which was then stirred at 60° C. for 7 hours. Water (3 L) was added to the reaction mixture, which was then cooled with ice, followed by filtering a crystal before further washing with water (1.5 L). The precipitated crystal was suspended in water (1.5 L), filtered, washed with water, and subjected to tray drying at 50° C. for 22 hours to obtain 272 g of the title compound (white crystal, yield: 93percent). 1H-NMR(CDCl3)δ:6.94(1H, d, J=8.8 Hz), 7.42(1H, dd, J=8.8, 2.9 Hz), 7.47(1H, d, J=2.9 Hz)
Reference：
[1] Patent: WO2006/115130, 2006, A1, . Location in patent: Page/Page column 53-54
[2] Patent: US2007/117866, 2007, A1,
[3] Gazzetta Chimica Italiana, 1959, vol. 89, p. 1009,1013
[4] Journal of Molecular Recognition, 2012, vol. 25, # 6, p. 352 - 360
[5] Journal of Organic Chemistry, 2015, vol. 80, # 2, p. 1229 - 1234
[6] Patent: CN107286076, 2017, A,
2
[ 71643-66-8 ]
[ 13589-72-5 ]
Reference：
[1] Patent: US6046212, 2000, A,
[2] Patent: US6136848, 2000, A,
Step S5A: Synthesis of 5-chloro-2-hydroxy-benzonitrile (5A) To a solution of 2-hydroxy-benzonitrile (5g, 42mmol) in chloroform (50mL) was added 15mL of a solution of NCS (N-chlorosuccinimide, 5.558g, 44.1mmol) in chloroform. The reaction mixture was refluxed overnight. TLC monitored the reaction. After the reaction completed, the mixture was poured into ice-water. The organic layer was washed with water, then stayed overnight. The precipitated solids were collected by filtration. The filtrate was concentrated, recrystallized from chloroform and filtered to give a solid. The two batches of product were combined to give 4g of 5-chloro-2-hydroxy-benzonitrile (5A). 1H-NMR (DMSO-d6) : δ (ppm): 11.44 (s, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.55 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H). MS (ESI): M++1=154.6.
4 g
With N-chloro-succinimide In chloroformReflux
Step S5A: Synthesis of 5-chloro-2-hydroxy-benzonitrile (5A) To a solution of 2-hydroxy-benzonitrile (5 g, 42 mmol) in chloroform (50 mL) was added 15 mL of a solution of NCS(N-chlorosuccinimide, 5.558 g, 44.1 mmol) in chloroform. The reaction mixture was refluxed overnight. TLC monitored the reaction. After the reaction completed, the mixture was poured into ice-water. The organic layer was washed with water, then stayed overnight. The precipitated solids were collected by filtration. The filtrate was concentrated, recrystallized from chloroform and filtered to give a solid. The two batches of product were combined to give 4 g of 5-chloro-2-hydroxy-benzonitrile (5A). 1H-NMR (DMSO-d6): δ (ppm): 11.44 (s, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.55 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.02 (d, J=9.2 Hz, 1H). MS (ESI):
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 2, p. 1229 - 1234
6
[ 87974-49-0 ]
[ 13589-72-5 ]
Yield
Reaction Conditions
Operation in experiment
16 g
for 2 h; Reflux
23 g of 5-chloro-2-hydroxybenzaldehyde oxime was added to 190 mlAcetic anhydride, heated to reflux for 2 hours, concentrated, the residue was poured into ice water, ethyl acetate extraction and liquid separation, the organic phase was collected, dried, concentrated, and the column was separated to give 16g5-chloro-2-hydroxybenzonitrile.
Reference：
[1] Journal of Molecular Recognition, 2012, vol. 25, # 6, p. 352 - 360
[2] Patent: CN107286076, 2017, A, . Location in patent: Paragraph 0023; 0024
7
[ 14221-01-3 ]
[ 695-96-5 ]
[ 144-55-8 ]
[ 13589-72-5 ]
Reference：
[1] Patent: EP1323713, 2003, A1,
8
[ 635-93-8 ]
[ 39900-62-4 ]
[ 13589-72-5 ]
Reference：
[1] Journal of Organic Chemistry, 2015, vol. 80, # 17, p. 8657 - 8667
9
[ 95-85-2 ]
[ 13589-72-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 7, p. 1075 - 1089
10
[ 17200-29-2 ]
[ 13589-72-5 ]
Reference：
[1] Journal of the American Chemical Society, 2004, vol. 126, # 26, p. 8197 - 8205
11
[ 71643-66-8 ]
[ 544-92-3 ]
[ 13589-72-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 7, p. 1075 - 1089
12
[ 39900-62-4 ]
[ 13589-72-5 ]
Reference：
[1] Gazzetta Chimica Italiana, 1959, vol. 89, p. 1009,1013
[2] Journal of Organic Chemistry, 2001, vol. 66, # 17, p. 5866 - 5874
[3] Journal of Molecular Recognition, 2012, vol. 25, # 6, p. 352 - 360
13
[ 198902-28-2 ]
[ 13589-72-5 ]
Reference：
[1] Chemische Berichte, 1904, vol. 37, p. 4027
Sodium hydride (96 mg, 4.1 mmol) was added to a solution of 2-cyano-4-chloro phenol (0.5 g, 3.26 mmol) in anhydrous DMF (6 mL) at -10 C. After 15 minutes the mixture became homogeneous and t-butyl bromo acetate was added dropwise. After 2 hours, the mixture was quenched with water and extracted with ethyl acetate (2×). The combined organic layers were washed with water (2×) brine (1×), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexanes) to afford 850 mg of the title compound as a colorless syrup (97%). 1H NMR (400 MHz, CDCl3) delta 7.53 (d, 1H, J=2.7 Hz); 7.46 (dd, 1H, J=9.1, 2.7 Hz); 6.78 (d, 1H, J=9.1 Hz); 4.63 (s, 3H); 1.46 (s, 9H).
(2S,3S,4R,5R)3-amino-5-{6-[5-chloro-2-(2-morpholin-4-yl-2-oxo-ethoxy)-benzylamino]-purin-9-yl}-4-hydroxy-tetrahydro-furan-2-carboxylic acid methylamide[ No CAS ]
(2S,3S,4R,5R)-3-azido-5-(6-{5-chloro-2-[oxo-2-(morpholin-1-yl)-ethoxy]-benzylamino}-purin-9-yl)-4-hydroxytetrahydrofuran-2-carboxylic acid methylamide[ No CAS ]
(2S,3S,4R,5R)3-azido-5-{6-[5-chloro-2-(2-oxo-2-piperidin-1-yl-ethoxy)-benzylamino]-purin-9-yl}-4-hydroxy-tetrahydro-furan-2-carboxylic acid methylamide[ No CAS ]
(2S,3S,4R,5R)3-amino-5-{6-[5-chloro-2-(2-oxo-2-piperazin-1-yl-ethoxy)-benzylamino]-purin-9-yl}-4-hydroxy-tetrahydro-furan-2-carboxylic acid methylamide[ No CAS ]
(2S,3S,4R,5R)3-amino-5-{6-[5-chloro-2-(2-oxo-2-piperidin-1-yl-ethoxy)-benzylamino]-purin-9-yl}-4-hydroxy-tetrahydro-furan-2-carboxylic acid methylamide[ No CAS ]
(2S,3S,4R,5R)3-amino-5-(6-{5-chloro-2-[2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethoxy]-benzylamino}-purin-9-yl)-4-hydroxy-tetrahydro-furan-2-carboxylic acid methylamide[ No CAS ]
(2S,3S,4R,5R)3-azido-5-(6-{5-chloro-2-[2-(4-dimethylamino-piperidin-1-yl)-2-oxo-ethoxy]-benzylamino}-purin-9-yl)-4-hydroxy-tetrahydro-furan-2-carboxylic acid methylamide[ No CAS ]
Reference Example 1 5-chloro-2-hydroxybenzonitrile 5-chloro-2-hydroxybenzaldehyde (300 g, 1.92 mol) and hydroxylamine-O-sulfonic acid (260 g, 2.30 mol) were suspended in water (4.5 L) at room temperature, which was then stirred at 60 C. for 7 hours. Water (3 L) was added to the reaction mixture, which was then cooled with ice, followed by filtering a crystal before further washing with water (1.5 L). The precipitated crystal was suspended in water (1.5 L), filtered, washed with water, and subjected to tray drying at 50 C. for 22 hours to obtain 272 g of the title compound (white crystal, yield: 93%). 1H-NMR(CDCl3)delta:6.94(1H, d, J=8.8 Hz), 7.42(1H, dd, J=8.8, 2.9 Hz), 7.47(1H, d, J=2.9 Hz)
ω-(2-cyano-4-chlorophenoxy)-2-benzyloxy-acetophenone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 20h;
Example 1 a : co (2-Cvano-4-chlorophenoxv)-2-benzvloxy-acetophenone; A suspension of potassium carbonate (0. 56 g, 4.0 mmol), <strong>[13589-72-5]4-chloro-2-cyanophenol</strong> (0.25 g, 1.6 mmol) and bromo-2-benzyloxy-acetophenone (0.49 g, 1.6 mmol) in dry DMF (10 ml) is stirred at room temperature for 20 h. After evaporating the solvent under reduced pressure the residue is taken up in ethyl acetate. The solution is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by silical gel column chromatography to yield the title compound.
3-amino-5-chloro-2-(2-ethoxy-5-nitrobenzoyl)-benzofuran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 80℃; for 5h;
Example 3 : 3-Amino-5-chloro-2- (2-ethoxv-5-nitrobezovl)-benzofuran; A suspension of potassium carbonate (0.27 g, 1.95 mmol), <strong>[13589-72-5]4-chloro-2-cyanophenol</strong> (0.12 g, 0.78 mmol) and eebromo-2-ethoxy-5-nitroacetophenone (0.24 g, 8.5 mmol) in dry DMF (5 ml) is stirred at 80C for 5 h. After evaporating the solvent under reduced pressure the residue is taken up in ethyl acetate. The solution is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by silicagel column chromatography to yield the title compound of m. p. 175-176C.
ω-(4-chloro-2-cyanophenoxy)-2-ethoxy-5-fluoroacetophenone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 5h;
Example 143: (o- (4-Chloro-2-cvanophenoxy)-2-ethoxy-5-fluoroacetophenone; A suspension of potassium carbonate (0.66 g, 4.8 mmol), bromo-2-ethoxy-5- fluoroacetophenone (0.85 g, 3.2 mmol) and <strong>[13589-72-5]4-chloro-2-cyanophenol</strong> in dry DMF (10 ml) is stirred at room temperature for 5 h. The solid is filtered, the filtrate diluted with ethyl acetate and washed with brine. The resulting solution is dried, evaporated under reduced pressure and the residue is purified using chromatography.'H-NMR (CDC13, 400 MHz): 7.62-7. 54 (m, 2H); 7.39 (d, 1 H); 7.26-7. 24 (m, 1 H); 6.98-6-94 (m, 1 H); 6.65 (d, 1 H); 5.39 (s, 2H); 4.19 (q, 2H); 1.53 (t, 3H); m. p. 117-119C.
With triphenylphosphine; In tetrahydrofuran; dichloromethane;
Preparation O 5-Chloro-2-isopropoxy-benzonitrile (Compound O1) <strong>[13589-72-5]5-Chloro-2-hydroxy-benzonitrile</strong> (1.0 g, 6.51 mmol), anhydrous THF (100 mL), 2-propanol (0.50 mL, 6.53 mmol), and triphenylphosphine (2.57 g, 9.80 mmol) were combined together. To this solution diethylazodicarboxylate (1.54 mL, 9.78 mmol) was added by syringe and the reaction was stirred at room temperature overnight. The solvent was stripped off and the product was purified via a Flash 40, 90 g column, eluted with a 2:1 ratio of hexanes:CH2Cl2 (1 L). 1H NMR (400 MHz, DMSO) delta7.83 (d, 1H, J=2.7 Hz); 7.63 (dd, 1H, J=9.1, 2.7 Hz); 7.25 (d, 1H, J=9.1 Hz); 4.74 (sept, 1H, J=6.0 Hz); 1.25 (d, 1H, J=6.2 Hz).
With N2; LiOH; In ethanol; dichloromethane; water;
1g: Preparation of Compound 7 A 3-neck 300 mL round-bottomed flask equipped with a reflux condenser, magnetic stir bar and an N2 inlet was charged with 5 g (1 equivalent) of <strong>[13589-72-5]2-hydroxy-5-chlorobenzonitrile</strong>, absolute ethanol 125 mL, and 12.16 mL (1 equivalent) of sodium ethoxide. This mixture was stirred at 25 C. for 15 minutes. Ethyl 5-bromovalerate (5.2 mL, 1 equivalent) was then added dropwise over 10 minutes. The resulting mixture was heated to reflux (75 C.) for 72 hours. The reaction mixture was cooled and the solids filtered off. The solvent was removed on a rotary evaporator. The crude residue was dissolved in methylene chloride (200 mL) and washed with saturated NaHCO3 (2*75 mL), H2O (1*100 mL) and brine (1*100 mL). The crude material was then dissolved in ethanol (120 mL) and water (10 mL). LiOH (4 g) was added and the resulting mixture was heated to reflux (75 C.) for 1 hours then stirred at ambient temperature overnight. The solvent was evaporated and 75 mL of H2O was added. The aqueous solution was acidified to a pH of about 3 with concentrated HCl and the flask cooled to 4 C. Tan colored solids precipitated. This material was collected by vacuum filtration and dried on the high vacuum overnight to give the crude acid. These solids were further purified by recrystallization from ethyl acetate/hexanes (95/5) (three times) to give 2.88 g of the product, 5-(4-chloro-2-cyanophenoxy)pentanoic acid (35% yield). Melting point: 87-90 C. Molecular Formula: C12H12ClNO3. Combustion analysis: %C: 56.82(calc'd), 57.03(found); %H: 4.77(calc'd), 4.71(found); %N: 5.52(calc'd), 5.45(found); Cl 13.98(calc'd), 13.93(found).
With hydrogenchloride; sodium chloride; sulfuric acid;aluminium trichloride; In water; acetic anhydride;
Further, 39.25 g (0.25 mol) of the <strong>[13589-72-5]5-chloro-2-hydroxybenzonitrile</strong> were dissolved in 40 ml of acetic anhydride, followed by the addition of 0.5 ml of concentrated sulfuric acid. After the reaction mixture was heated at 60 C. for 10 minutes, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with 1N NaOH and a saturated aqueous solution of sodium chloride and was then dried over Na2 SO4. The solvent was distilled off under reduced pressure, whereby 45 g of 2-acetoxy-5-chlorobenzonitrile (yield: 92%). A mixture of 44 g of the 2-acetoxy-5-chlorobenzonitrile and 99 g (0.75 mol) of aluminum chloride was then heated at 160 C. for 3 hours. The reaction mixture was allowed to cool down to room temperature, and was then poured into ice water which contained 100 ml of concentrated hydrochloric acid. The slurry was extracted with ethyl acetate (3*350 ml). The extract was washed with 1N hydrochloric acid (3*200 ml) and a saturated aqueous solution of sodium chloride (400 ml) and was then dried over Na2 SO4. The solvent was distilled off under reduced pressure. The residue was washed with dichloromethane to remove byproducts, and was then collected by filtration, whereby 16.5 g of the title compound were obtained as brown powder (yield: 38%). Melting point: 137.9-139.8 C. 1 H-NMR(CDCl3)delta(ppm): 2.72(3H,s,COCH3), 8.21(1H,d,J=2.5 Hz,H4/6), 8.32(1H,d,J=2.5 Hz,H4/6), 12.77(1H,brs,ArOH).
Next, 85 g (0.33 mol) of the 4-chloro-2-iodophenol and 32.5 g (0.36 mol) of copper cyanide were dissolved in 150 ml of DMF. After the resultant solution was heated under reflux for 2 hours, the DMF was distilled off under reduced pressure. The residue was extracted with ethyl acetate and the extract was then washed with water. An insoluble matter was filtered off. The solvent was then distilled off under reduced pressure, whereby 40.4 g of 5-chloro-2-hydroxybenzonitrile were obtained (yield: 80%) (melting point: 150.3-152.6 C.).
80%
In ethyl acetate; N,N-dimethyl-formamide;
2) 4-Chloro-2-iodophenol (85 g, 0.33 mol) was dissolved in 150 ml of DMF, followed by the addition of 32.5 g (0.36 mol) of copper cyanide. The resulting mixture was refluxed for 2 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the thus-prepared solution was washed with water. Subsequent to elimination of an undissolved salt, the solution was concentrated under reduced pressure, whereby 40.4 g of 5-chloro-2-hydroxybenzonitrile were obtained (yield: 80%). Without purification, it was provided for use in the next step.
With sodium hydroxide; sodium chloride; sulfuric acid; acetic anhydride; In water;
3) 5-Chloro-2-hydroxybenzonitrile (39.25 g, 0.25 mol) and acetic anhydride (40 ml) were combined, to which 0.5 ml of concentrated sulfuric acid was added. The reaction mixture was stirred at 60 C. for 10 minutes, followed by the addition of water. Subsequent to extraction with ethyl acetate, the organic layer was washed with 1 N aqueous solution of sodium hydroxide and a saturated aquous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, whereby 45 g of 2-acetoxy-5-chlorobenzonitrile were obtained as a brown solid (yield: 92%). It was provided for immediate use in the next step.
(iii) Anhydrous potassium carbonate (2.76 g) was added to a stirred solution of <strong>[13589-72-5]4-chloro-2-cyanophenol</strong> (1.53 g) and 2-bromo-2-methyl propanal (2.26 g) in THF (50 ml) and the mixture heated at reflux for 5 hours. The mixture was then cooled to 4 C., the suspended solid removed by filtration and the filtrate evaporated to give a yellow oil which crystallized on standing. The solid was triturated with hexane and collected by filtration to give 2-(4-chloro-2-cyanophenoxy)-2-methylpropanal (2.11 g), m.p. 85-88 C.; NMR: 1.52(6H,s), 6.79(1H,d,J=8 Hz), 7.42(1H,dd,J=8,2.5 Hz), 7.57(1H,d,J=2.5 Hz), 9.80(1H,s).
With sodium hydroxide; In methanol; ice-water; acetic anhydride;
(ii) A solution of 5-chloro-2-hydroxybenzaldoxime (4.2 g) in acetic anhydride (15 ml) was heated for 4 hours at reflux, then allowed to stand for 16 hours at ambient temperature. The mixture was added to a vigorously stirred ice-water mixture and after one hour the resulting solid was collected by filtration. 2M Sodium hydroxide solution (120 ml) was added to a stirred solution of this solid in methanol (50 ml) and the mixture stirred for 20 minutes. The pH of the mixture was then adjusted to 4.0 with 2M hydrochloric acid solution. The mixture was cooled to 4 C. and the white precipitate collected by filtration to give 4-chloro-2-cyanophenol (2.6 g), m.p. 166-168 C.; NMR (CDCl3 /d6 -DMSO): 6.69(1H,d,J=8 Hz), 7.04(1H,dd,J=8,2.5 Hz), 7.11(1H,d,J=2.5 Hz), 10.33(1H,s).
(1) In 60 ml of N,N-dimethylformamide were dissolved 6.2 g of 2-bromo-4-chlorophenol, 7.2 g of zinc cyanide and 3.5 g of tetrakis(triphenylphosphine) palladium, and the solution was stirred at 120ØC for 2 hours. The reaction mixture was cooled to room temperature, and the formed black precipitate was removed by filtration. After concentrating the filtrate, a saturated aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (chloroform/ethyl acetate =10/1), and crystallized from n-hexane to give 2.7 g of 2-cyano-4-chlorophenol. m.p.=166-168ØC
With sodium hydroxide; potassium tert-butylate; In diethylene glycol dimethyl ether; water; toluene;
Example 1-(9) 5-Chloro-2-[[(2S)-2-hydroxy-3-(trityloxy)propyl]oxy]benzonitrile To a diglyme (1.1 L) solution of <strong>[13589-72-5]5-chloro-2-hydroxybenzonitrile</strong> (the compound of Reference Example 1; 270 g, 1.8 mol) and (2S)-2-[(trityloxy)methyl]oxirane (465 g, 1.47 mol) was added potassium tert-butoxide (33 g, 0.29 mol) at room temperature, followed by stirring the reaction mixture at 105 C. for 23 hours. The reaction mixture was cooled with ice, to which toluene (2 L) and a 1N sodium hydroxide aqueous solution (1.35 L) were then added to separate an organic layer. The organic layer was washed 3 times each sequentially with the 1N sodium hydroxide aqueous solution (1.35 L) and warm water (3 L), followed by vacuum concentration. Toluene (3 L) was added to the concentrate, to dissolved it, followed by cooling and filtering the precipitated crystal to obtain 590 g of the title compound (yield: 85%). 1H-NMR (CDCl3)delta: 2.50 (1H, d, J=6.1 Hz), 3.35~3.45 (2H, m), 4.05~4.20 (3H, m), 6.91 (1H, d, J=9.0 Hz), 7.22~7.33 (8H, m), 7.38~7.53 (9H, m).
Microwave experiments were carried out using a Personal Chemistry Smith Synthesizer, which uses a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperatures from 40-250C can be achieved, and pressures of up to 20bar can be reached. Intermediate 1: 5-Chloro-2-cyanomethoxybenzonitrile A solution of <strong>[13589-72-5]4-chloro-2-cyanophenol</strong> (2.5g) in acetone was treated with potassium carbonate (2.3g), followed by bromoacetonitrile (1.2mL) and the resulting mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was evaporated to dryness to give 5-chloro-2-cyanomethoxybenzonitrile (3.3g) as a pale yellow solid. 1H NMR (DMSO-d6): delta 5.40 (s, 2H), 7.45 (d, 1H), 7.85 (dd, 1H), 8.05 (d, 1H).
With potassium carbonate; In acetone; at 20℃;
Intermediate A: 5-Chloro-2-cyanomethoxybenzonitrile [Show Image] A solution of <strong>[13589-72-5]4-chloro-2-cyanophenol</strong> (2.5g) in acetone is treated with potassium carbonate (2.3g), followed by bromoacetonitrile (1.2mL) and the resulting mixture is stirred at room temperature overnight. The mixture is filtered and the filtrate is evaporated to dryness to give 5-chloro-2-cyanomethoxybenzonitrile (3.3g) as a pale yellow solid. 1H NMR (DMSO-d6): delta 5.40 (s, 2H), 7.45 (d, 1H), 7.85 (dd, 1H), 8.05 (d, 1H).
With hydrogenchloride; In ethyl acetate; N,N-dimethyl-formamide;
Intermediate 2: Ethyl (4-chloro-2-cyanophenoxy)acetate A solution of <strong>[13589-72-5]4-chloro-2-cyanophenol</strong> (5.0g) in N,N-dimethylformamide (20mL) was added dropwise to an ice-cooled suspension of sodium hydride (60% oil dispersion, 1.4g) in N,N-dimethylformamide (165mL). The resultant mixture was stirred at 0-5C for 40 minutes, then ethyl bromoacetate (3.9mL) was added and stirring was continued for 1.5 hours. Ethyl acetate and hydrochloric acid (1M) were added and the layers were separated. The organic layer was washed with water, aqueous sodium bicarbonate solution and brine, then dried over sodium sulphate and filtered. The filtrate was evaporated to give crude ethyl (4-chloro-2-cyanophenoxy)acetate (7.8g) as a yellow oil which was used without further purification.
With potassium carbonate; In acetone; for 10h;Heating / reflux;
To a solution of <strong>[13589-72-5]5-chloro-2-hydroxy-benzonitrile</strong> (10 g, 65.0 mmol) in acetone (100 mL) was added ethylbromoacetate (11 g, 71.4 mmol) followed by K2CO3 (19.7 g, 143 mmol). After heating at reflux for 10 h, the mixture was filtered and the filtrate was concentrated to afford the desired product (15.3 g), which was used in the next step without further purification. 1H NMR (CDCl3): 7.57 (d, J=2.5 Hz, 1H), 7.48 (dd, J=9.0, 2.5 Hz, 1 H), 6.81 (d, J=9.0 Hz 1H), 4.78 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).
Intermediate E: Ethyl (4-chloro-2-cyanophenoxy)acetate [Show Image] A solution of <strong>[13589-72-5]4-chloro-2-cyanophenol</strong> (5,0g) in N,N-dimethylformamide (20mL) is added dropwise to an ice-cooled suspension of sodium hydride (60% oil dispersion, 1.4g) in N,N-dimethylformamide (165mL). The resultant mixture is stirred at 0-5C for 40 minutes, then ethyl bromoacetate (3.9mL) is added and stirring is continued for 1.5 hours. Ethyl acetate and hydrochloric acid (1M) are added and the layers were separated. The organic layer is washed with water, aqueous sodium bicarbonate solution and brine, then dried over sodium sulphate and filtered. The filtrate is evaporated to give crude ethyl (4-chloro-2-cyanophenoxy)acetate (7.8g) as a yellow oil which is used without further purification.
With potassium carbonate; In N,N-dimethyl-formamide; at 160℃; for 0.166667h;Microwave irradiation;
Example 514-[4-(4-Chloro-2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester; A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.178 mmol), <strong>[13589-72-5]5-chloro-2-hydroxybenzonitrile</strong> (Maybridge, Tintagel, Cornwall, UK; 28 mg, 0.178 mmol), and potassium carbonate (54 mg, 0.392 mmol) in dimethylformamide (1 mL) was heated in the microwave oven at 160 C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture and the resulting precipitate was filtered through a silica gel plug, eluting with methanol. The solvent was removed and the residue was purified by HPLC to give 4-[4-(4-chloro-2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (19 mg, 24%) as a white solid. Mass spectrum MH+=455. 1H NMR (300 MHz, DMSO-d6) delta 1.41 (s, 9H), 1.96-2.04 (m, 4H), 2.96-3.08 (m, 2H), 4.02-4.12 (m, 2H), 4.96-5.06 (m, 1H), 7.69 (d, 1H, J=8.7 Hz), 7.94 (dd, 1H, J=2.6, 8.9 Hz), 8.25 (d, 1H, J=2.4 Hz), 8.50 (s, 1H), 8.57 (s, 1H).
With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 55℃; for 0.666667h;
General procedure: To a solution of 7a-c or 16 (4 mmol) and methyl 2-(chloromethyl)benzoate6 (9) (0.74 g, 4 mmol) in DMF (4 ml) was added dry K2CO3 (1.1 g, 8 mmol). The mixture was stirred at 50-55 for 40 min, poured into H2O (30 ml), and extracted with CHCl3 (15 ml × 3). The extract was washed with H2O (20 ml × 2) and dried over Na2SO4. The solvent was evaporated in vacuo and the product crystallized from an appropriate solvent.
With potassium carbonate; In N,N-dimethyl-formamide; at 50 - 55℃; for 0.666667h;
General procedure: To a stirred solution of 7a-c or 16 (4 mmol) and 2-(chloromethyl)benzonitrile9 (11) (0.6 g, 4 mmol) in DMF (4 ml) was added dry K2CO3 (1.1 g, 8 mmol). The mixture was stirred at 50-55 for 40 min, poured into H2O (30 ml), and extracted with CHCl3 (15 ml × 3). The extract was washed with H2O (20 ml × 2) and dried over Na2SO4. The solvent was evaporated in vacuo and the product crystallized from an appropriate solvent.
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