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Structure of 39891-09-3 * 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] Catalysis Science and Technology, 2017, vol. 7, # 17, p. 3747 - 3757
2
[ 773837-37-9 ]
[ 70258-18-3 ]
[ 39891-09-3 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 20℃; for 20 h; Reflux
Example 46 (1 R)-1-(6-amιno-Pyrιdιn-3-yl-acetyl amιno)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1- boronic acid formateStep 1. Synthesis of (6-chloropyridin-3-yl) acetonitrite. To a solution of 2-chloro-5-(chloromethyl)pyrιdιne (25 g, 0 154 mol) in ethanol (40 mL) stirring at 0 °C was added a solution of sodium cyanide (8 17 g 0 167 mol) in water (18 mL) The reaction mixture was refluxed for 2 hours then stirred at ambient temperature for a further 18 hours The solvent was evaporated in vacuo and the residue extracted from water into DCM (500 mL), washed with brine dned over sodium sulfate, filtered and evaporated in vacuo The crude material was purified by column chromatography over silica gel eluting with 70/30 DCM/hexanes to afford 20 g (85percent) of product as brown oil which solidified on standing ESI-MS m/z 153 (MH)*
63%
at 0 - 100℃; for 3 h;
To a stirred solution of 2-chloro-5-(chloromethyl)pyridine (1 g, 6.17 mmol, 1.0 equiv.) in ethanol (10 ml_) was added the solution of NaCN (325 mg, 6.79 mmol, 1.1eq) in H20 (10 mL) dropwise at 0°C and stirred for 3h at 100 °C. The reaction mixture was diluted with water (50ml), extracted with ethyl acetate (70ml_x2) washed with brine (20mL), dried over anhydrous Na2S04 and evaporated under vacuum. The crude was purified by using silica gel chromatography (100-200 mesh) using ethyl acetate /petrol ether (3:7) to get 2-(6- chloropyridin-3-yl)acetonitrile (400 mg, 63 percent) as a yellow solid.
63%
at 0 - 100℃; for 3 h;
To a stirred solution of 2-chloro-5-(chloromethyl)pyridine (1 g, 6.17 mmol, 1.0 eq) in ethanol (10 mL) was added the solution of NaCN (325 mg, 6.79 mmol, 1.1 eq) in water (10 mL) dropwise at 0 °C and then stirred for 3 h at 100 °C. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (2 x 70 mL) washed with brine (20 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under vacuum. The crude was purified by using silica gel chromatography (100-200 mesh) using ethyl acetate /petrol ether (3:7) to get 2-(6-chloropyridin-3-yl)acetonitrile (400 mg, 63 percent) as a yellow solid.
63%
at 0 - 100℃; for 3 h;
Step 1: To a stirred solution of 2-chloro-5-(chloromethyl)pyridine (1 g, 6.17 mmol, 1.0 equiv.) in ethanol (10 mL) was added the solution of NaCN (325 mg, 6.79 mmol, 1.1 eq) in H2O (10 mL) dropwise at 0° C. and stirred for 3 h at 100° C. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (70 mL*2) washed with brine (20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude was purified by using silica gel chromatography (100-200 mesh) using ethyl acetate/petrol ether (3:7) to get 2-(6-chloropyridin-3-yl)acetonitrile (400 mg, 63percent) as a yellow solid.
63%
at 0 - 100℃; for 3 h;
Step 1 To a stirred solution of 2-chloro-5-(chloromethyl)pyridine (1 g, 6.17 mmol, 1.0 eq) in ethanol (10 mL) was added the solution of NaCN (325 mg, 6.79 mmol, 1.1 eq) in water (10 mL) dropwise at 0° C. and then stirred for 3 h at 100° C. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (2*70 mL) washed with brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum. The crude was purified by using silica gel chromatography (100-200 mesh) using ethyl acetate/petrol ether (3:7) to get 2-(6-chloropyridin-3-yl)acetonitrile (400 mg, 63percent) as a yellow solid.
21 g
With sodium carbonate In ethanol for 4 h; Reflux
16.2 g 2-chloropyridine benzyl chlorine, 5.1 g of sodium cyanide are added to a 250 ml four-mouthed flask. Add 150 ml ethanol, 11 g sodium carbonate. Heat to reflux. Reflux reaction for 4 hours. After the reaction, prolapsed ethanol, add 100 g water and stirred, filtered to obtain 21 g 2-chloropyridine acetonitrile.
Reference：
[1] Patent: WO2010/130708, 2010, A1, . Location in patent: Page/Page column 105
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 7, p. 2168 - 2173
[3] Patent: WO2013/13817, 2013, A1, . Location in patent: Page/Page column 111
[4] Patent: WO2013/13815, 2013, A1, . Location in patent: Page/Page column 221
[5] Patent: US2013/29961, 2013, A1, . Location in patent: Paragraph 0705
[6] Patent: US2013/29962, 2013, A1, . Location in patent: Paragraph 1077; 1085
[7] Journal of the American Chemical Society, 2013, vol. 135, # 16, p. 6289 - 6299
[8] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 1079 - 1089
[9] Patent: CN105669584, 2016, A, . Location in patent: Paragraph 0079; 0080; 0081
3
[ 70258-18-3 ]
[ 143-33-9 ]
[ 39891-09-3 ]
Yield
Reaction Conditions
Operation in experiment
96%
at 0 - 100℃; for 20 h;
To a solution of 2-chloro-5-(chlofomethyl)pyridine (75g, 0.46mol) in ethanol (120ml) stirring at O0C, was added a solution of sodium cyanide (24.5Og, 0.50mol) in water (40ml). The reaction mixture heated at 10O0C for 2 hours then stirred at room temperature for a further 18 hours. The solvent was evaporated in vacuo and the residue extracted from water into dichloromethane (500ml), washed with brine, dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was purified by column chromatography over silica gel eluting with dichloromethane. The title compound was obtained as a brown oil which solidified on standing (67g, 0.44mol, 96percent). 1H-NMR (CDCl3, 400MHz); δ 3.7 (s, 2H), 7.4 (d, 1H), 7.65 (d, 1H), 8.4 (s, 1H).
45.6%
With potassium iodide In ethanol; water at 85℃; for 5 h;
1.17.a (6-chloro-pyridin-3-yl)-acetonitrile A solution of 7.5 g (41.66 mmol) of 2-chloro-5-chloromethyl-pyridine, dissolved in 100 ml of ethanol, is added dropwise to a solution of 6.91 g (41.66 mmol) of potassium iodide and 2.24 g (49.01 mmol) of sodium cyanide in 400 ml of an ethanol/water mixture (9:1). Then the reaction mixture is heated to 85° C. for five hours. The solvent is substantially distilled off in vacuo and the residue is extracted with water and ethyl acetate. The organic phase is washed with water three times and dried over sodium sulphate. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol). Yield: 2.9 g (45.6percent of theory); C7H5ClN2 (M=152.58); calc.: molar peak (M+H)+: 151/153 fnd.: molar peak (M+H)+: 151/153.
Reference：
[1] Patent: WO2007/45989, 2007, A1, . Location in patent: Page/Page column 9; 24
[2] Patent: US2004/242572, 2004, A1, . Location in patent: Page/Page column 44
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 4, p. 864 - 868
4
[ 70258-18-3 ]
[ 151-50-8 ]
[ 39891-09-3 ]
Yield
Reaction Conditions
Operation in experiment
89%
at 20 - 50℃;
To a solution of 2-chloro-5-(chloromethyl)pyridine (5.0 g, 0.031 mol) in ethanol (38 mL) and water (19 mL) was added potassium cyanide (2.41 g, 0.0370 mol) at RT under nitrogen atmosphere. The reaction mixture was stirred at 50° C. overnight. The reaction was diluted with water and extracted with DCM. The organic layer was washed with brine and dried over sodium sulfate. The solution was filtered and the filtrate was concentrated to afford the desired compound (4.2 g, 89percent). Analytical LCMS: (M+H)+=153.1.
A solution of 5.2 g (32 MMOL) of 2-chloro-5-chloromethylpyridine dissolved in 40 mL of ethanol was treated with 20 mL of water and 2.4 g (37 MMOL) of potassium cyanide. The mixture was stirred and heated at 50 °C for 20 hours. The dark mixture was then partitioned between DICHLOROMETHANE and water and the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 4.54 g (92percent) of Preparatory Compound E, (6-chloro-3- pyridinyl) acetonitrile, as a dark brown liquid :'H NMR (CDCI3) 8 8.38 (d, J = 3.0 Hz, 1H), 7.71 (dd, J = 3.0 and 7.6 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 3.80 (s, 2H) ppm. GCMS: (EI) m/z 152 (M+).
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2697 - 2706
[2] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
9
[ 6635-88-7 ]
[ 39891-09-3 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
10
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2697 - 2706
11
[ 6959-48-4 ]
[ 39891-09-3 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
12
[ 133457-49-5 ]
[ 39891-09-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 887 - 892
13
[ 21543-49-7 ]
[ 39891-09-3 ]
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 16, p. 6289 - 6299
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 1079 - 1089
14
[ 73781-91-6 ]
[ 39891-09-3 ]
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 16, p. 6289 - 6299
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 3, p. 1079 - 1089
15
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
[ 142892-30-6 ]
Reference：
[1] Synthesis, 1992, # 6, p. 528 - 530
16
[ 6635-88-7 ]
[ 10025-87-3 ]
[ 99310-62-0 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
17
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2697 - 2706
18
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
[ 142892-30-6 ]
Reference：
[1] Synthesis, 1992, # 6, p. 528 - 530
19
[ 6635-88-7 ]
[ 10025-87-3 ]
[ 99310-62-0 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
20
[ 39891-09-3 ]
[ 54127-64-9 ]
Reference：
[1] Patent: US4115575, 1978, A,
[2] Patent: US4410530, 1983, A,
[3] Patent: CN105985288, 2016, A, . Location in patent: Paragraph 0103; 0104; 0105
21
[ 39891-09-3 ]
[ 39891-13-9 ]
Yield
Reaction Conditions
Operation in experiment
78%
at 80℃; for 24 h;
A 4.45 g (29.3 MMOL) portion of Preparatory Compound E was treated with 5 mL of concentrated hydrochloric acid. The mixture was stirred and heated at 80 °C for 24 hours. The solution was poured in to ice and the resulting precipitate filtered. Residual water was removed from the sample by treatment with toluene and removal of the azeotrope under reduced pressure. This procedure yielded 3.93 g (78percent) of Preparatory Compound F, (6-chloro-3-pyridinyl) acetic acid, as a fine yellow powder: mp 170-171 °C ;'H NMR (CDCI3) 8 8.34 (d, J = 3. 0 Hz, 1H), 7.66 (dd, J = 3.0 and 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 3.70 (s, 2H) ppm. MS: (ES+) m/z 172 (M+). Anal. CALCD for C7H6CINO2 : C, 49.0 ; H, 3.52 ; N, 8.16. Found: C, 49.3 ; H, 3.53 ; N, 8.11.
Reference：
[1] Patent: WO2004/57960, 2004, A2, . Location in patent: Page 16-17
[2] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2004, vol. 43, # 4, p. 864 - 868
22
[ 39891-09-3 ]
[ 64-17-5 ]
[ 197376-47-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
at 100℃; for 3 h;
To a solution of EtOH (27 mL), concentrated H2SO4 (10 mL) was added dropwise and 2-chloropyridine-5-acetonitrile (2.00 g, 13.1 mmol) was added portionwise. The solution was stirred at 100° C. for three hours. The mixture was added dropwise to a solution of NaHCO3 (30.00 g) in H2O (100 mL) and it was extracted twice with DCM. The organic layer were collected, dried and evaporated to give the title compound (2.60 g, quant.) (0395) C9H10ClNO2 Mass (calculated) [199]; (found) [M+H]+=200.
75%
Stage #1: for 5 h; Reflux Stage #2: With sodium hydrogencarbonate In water at 20℃;
Step 2. Synthesis of (6-chloropyridin-3-yl) acetic acid ethyl ester. 10 g (65 5 mmol) (6-chloropyrιdιn-3-yl)acetonιtrιle were added to a mixture of 122 mL ethanol and 46 mL cone sulfuric acid and the mixture stirred under reflux for 5 h After cooling to ambient temperature, the reaction mixture was slowly added dropwise. while stirring, to a mixture of 161 g sodium bicarbonate and 450 mL water The aqueous phase was extracted with DCM (three times with 300 mL each time) The combined organic phases were dried over sodium sulfate, filtered and concentrated on a rotary evaporator The crude oil was purified by silica gei chromatography, eluted using a gradient of 2/98(v/v) EtOAc/hexanes to 9/91 (v/v) EtOAc/hexanes to afford 9 8 g (75percent) of product as clear oil ESI-MS m/z 200 (MH)f
13 g
for 4 h; Reflux
15.2 g 2-chloropyridin-5-ylacetonitrile was added to a 250 ml four-mouthed flask. Add 150 ml ethanol. 10ml 98percent concentrated sulfuric acid. Heat to reflux. Reflux reaction for 4 hours, reaction finishes, prolapsed ethanol, add 100 g water to stir, is neutral pH the sodium carbonate is used to regulate, filter, to obtain 2-chloro pyridine ethyl acetate 13 g.
A 4.45 g (29.3 MMOL) portion of Preparatory Compound E was treated with 5 mL of concentrated hydrochloric acid. The mixture was stirred and heated at 80 C for 24 hours. The solution was poured in to ice and the resulting precipitate filtered. Residual water was removed from the sample by treatment with toluene and removal of the azeotrope under reduced pressure. This procedure yielded 3.93 g (78%) of Preparatory Compound F, (6-chloro-3-pyridinyl) acetic acid, as a fine yellow powder: mp 170-171 C ;'H NMR (CDCI3) 8 8.34 (d, J = 3. 0 Hz, 1H), 7.66 (dd, J = 3.0 and 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 3.70 (s, 2H) ppm. MS: (ES+) m/z 172 (M+). Anal. CALCD for C7H6CINO2 : C, 49.0 ; H, 3.52 ; N, 8.16. Found: C, 49.3 ; H, 3.53 ; N, 8.11.
To a solution of 2-chloro-5-(chlofomethyl)pyridine (75g, 0.46mol) in ethanol (120ml) stirring at O0C, was added a solution of sodium cyanide (24.5Og, 0.50mol) in water (40ml). The reaction mixture heated at 10O0C for 2 hours then stirred at room temperature for a further 18 hours. The solvent was evaporated in vacuo and the residue extracted from water into dichloromethane (500ml), washed with brine, dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was purified by column chromatography over silica gel eluting with dichloromethane. The title compound was obtained as a brown oil which solidified on standing (67g, 0.44mol, 96%). 1H-NMR (CDCl3, 400MHz); delta 3.7 (s, 2H), 7.4 (d, 1H), 7.65 (d, 1H), 8.4 (s, 1H).
45.6%
With potassium iodide; In ethanol; water; at 85℃; for 5h;
1.17.a (6-chloro-pyridin-3-yl)-acetonitrile A solution of 7.5 g (41.66 mmol) of 2-chloro-5-chloromethyl-pyridine, dissolved in 100 ml of ethanol, is added dropwise to a solution of 6.91 g (41.66 mmol) of potassium iodide and 2.24 g (49.01 mmol) of sodium cyanide in 400 ml of an ethanol/water mixture (9:1). Then the reaction mixture is heated to 85 C. for five hours. The solvent is substantially distilled off in vacuo and the residue is extracted with water and ethyl acetate. The organic phase is washed with water three times and dried over sodium sulphate. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol). Yield: 2.9 g (45.6% of theory); C7H5ClN2 (M=152.58); calc.: molar peak (M+H)+: 151/153 fnd.: molar peak (M+H)+: 151/153.
(6-Chloro-pyridin-3-yl)-acetic acid ethyl ester To a solution of EtOH (27 mL), concentrated H2SO4 (10 mL) was added dropwise and 2-chloropyridine-5-acetonitrile (2.00 g, 13.1 mmol) was added portionwise. The solution was stirred at 100C for three hours. The mixture was added dropwise to a solution of NaHCO3 (30.00 g) in H2O (100 mL) and it was extracted twice with DCM. The organic layer were collected, dried and evaporated to give the title compound (2.60 g, quant.) C9H10ClNO2 Mass (calculated) [199]; (found) [M+H]+ = 200.
To a solution of EtOH (27 mL), concentrated H2SO4 (10 mL) was added dropwise and 2-chloropyridine-5-acetonitrile (2.00 g, 13.1 mmol) was added portionwise. The solution was stirred at 100 C. for three hours. The mixture was added dropwise to a solution of NaHCO3 (30.00 g) in H2O (100 mL) and it was extracted twice with DCM. The organic layer were collected, dried and evaporated to give the title compound (2.60 g, quant.) (0395) C9H10ClNO2 Mass (calculated) [199]; (found) [M+H]+=200.
75%
Step 2. Synthesis of (6-chloropyridin-3-yl) acetic acid ethyl ester. 10 g (65 5 mmol) (6-chloropyriotadiotan-3-yl)acetoniotatriotale were added to a mixture of 122 mL ethanol and 46 mL cone sulfuric acid and the mixture stirred under reflux for 5 h After cooling to ambient temperature, the reaction mixture was slowly added dropwise. while stirring, to a mixture of 161 g sodium bicarbonate and 450 mL water The aqueous phase was extracted with DCM (three times with 300 mL each time) The combined organic phases were dried over sodium sulfate, filtered and concentrated on a rotary evaporator The crude oil was purified by silica gei chromatography, eluted using a gradient of 2/98(v/v) EtOAc/hexanes to 9/91 (v/v) EtOAc/hexanes to afford 9 8 g (75%) of product as clear oil ESI-MS m/z 200 (MH)f
To a solution at-5 C of 44 mL of absolute ethanol in 155 mL of chloroform under nitrogen was added dropwise 45 mL of acetyl chloride. After 0.5 hours a solution of 8.46 g (55.4 MMOL) of Preparatory Compound E in 71 mL of chloroform was added dropwise keeping the temperature at 0 C or below. The mixture was then kept at 0 C for 4 hours and was then allowed to warm to room temperature overnight (about 22 C). Ethyl ether was added (350 mL) with cooling and the mixture was stirred for several minutes and was then filtered through a medium porosity sintered glass funnel always careful to keep a layer of ether over the white solid. After washing with an ample amount of ether, the solid/ether mixture was washed into a 1 L three-neck round-bottomed flask fitted with a mechanical stirrer and was then diluted with 400 mL of ether and was treated dropwise with 12.34 g (122 mmol, 2.2 equiv. ) of triethylamine in ether while cooling. The contents were stirred overnight under nitrogen. The mixture was filtered, the filtrate was dried over sodium sulfate and was concentrated to give 9.91 g (90%) of Preparatory Compound K, ethyl 2- (6-CHLORO-3-PYRIDINYL) ethanimidoate, as an oil.
22.0 g (144 mmol) of (6-chloropyridin-3-yl)acetonitrile are added to a mixture of 270 ml of ethanol and 101 ml conc. sulfuric acid, and the mixture is stirred under reflux for 24 h. With stirring, the reaction mixture is then slowly added dropwise to a mixture of 350 g of sodium bicarbonate and 1 liter of water. The aqueous phase is extracted with dichloromethane (five times 400 ml each). The combined organic phases are dried over sodium sulfate, filtered and freed from the solvent using a rotary evaporator. This gives 23.1 g (80% of theory) of the title compound, which is reacted without further purification.1H-NMR (400 MHz, DMSO-d6): delta=8.32 (d, 1H), 7.78 (dd, 1H), 7.49 (d, 1H), 4.10 (q, 2H), 3.77 (s, 2H), 1.19 (t, 3H).LC-MS (Method 3): Rt=1.91 min; MS (ESIpos): m/z=200 [M+H]+.
13 g
With sulfuric acid; for 4h;Reflux;
15.2 g 2-chloropyridin-5-ylacetonitrile was added to a 250 ml four-mouthed flask. Add 150 ml ethanol. 10ml 98% concentrated sulfuric acid. Heat to reflux. Reflux reaction for 4 hours, reaction finishes, prolapsed ethanol, add 100 g water to stir, is neutral pH the sodium carbonate is used to regulate, filter, to obtain 2-chloro pyridine ethyl acetate 13 g.
Example 46 (1 R)-1-(6-amiotano-Pyriotadiotan-3-yl-acetyl amiotano)-2-(2-hvdroxy-3-carboxyphenyl)ethyl-1- boronic acid formateStep 1. Synthesis of (6-chloropyridin-3-yl) acetonitrite. To a solution of 2-chloro-5-(chloromethyl)pyriotadiotane (25 g, 0 154 mol) in ethanol (40 mL) stirring at 0 C was added a solution of sodium cyanide (8 17 g 0 167 mol) in water (18 mL) The reaction mixture was refluxed for 2 hours then stirred at ambient temperature for a further 18 hours The solvent was evaporated in vacuo and the residue extracted from water into DCM (500 mL), washed with brine dned over sodium sulfate, filtered and evaporated in vacuo The crude material was purified by column chromatography over silica gel eluting with 70/30 DCM/hexanes to afford 20 g (85%) of product as brown oil which solidified on standing ESI-MS m/z 153 (MH)*
63%
In ethanol; water; at 0 - 100℃; for 3h;
To a stirred solution of <strong>[70258-18-3]2-chloro-5-(chloromethyl)pyridine</strong> (1 g, 6.17 mmol, 1.0 equiv.) in ethanol (10 ml_) was added the solution of NaCN (325 mg, 6.79 mmol, 1.1eq) in H20 (10 mL) dropwise at 0C and stirred for 3h at 100 C. The reaction mixture was diluted with water (50ml), extracted with ethyl acetate (70ml_x2) washed with brine (20mL), dried over anhydrous Na2S04 and evaporated under vacuum. The crude was purified by using silica gel chromatography (100-200 mesh) using ethyl acetate /petrol ether (3:7) to get 2-(6- chloropyridin-3-yl)acetonitrile (400 mg, 63 %) as a yellow solid.
63%
In ethanol; water; at 0 - 100℃; for 3h;
To a stirred solution of <strong>[70258-18-3]2-chloro-5-(chloromethyl)pyridine</strong> (1 g, 6.17 mmol, 1.0 eq) in ethanol (10 mL) was added the solution of NaCN (325 mg, 6.79 mmol, 1.1 eq) in water (10 mL) dropwise at 0 C and then stirred for 3 h at 100 C. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (2 x 70 mL) washed with brine (20 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under vacuum. The crude was purified by using silica gel chromatography (100-200 mesh) using ethyl acetate /petrol ether (3:7) to get 2-(6-chloropyridin-3-yl)acetonitrile (400 mg, 63 %) as a yellow solid.
63%
In ethanol; water; at 0 - 100℃; for 3h;
Step 1: To a stirred solution of <strong>[70258-18-3]2-chloro-5-(chloromethyl)pyridine</strong> (1 g, 6.17 mmol, 1.0 equiv.) in ethanol (10 mL) was added the solution of NaCN (325 mg, 6.79 mmol, 1.1 eq) in H2O (10 mL) dropwise at 0 C. and stirred for 3 h at 100 C. The reaction mixture was diluted with water (50 ml), extracted with ethyl acetate (70 mL*2) washed with brine (20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. The crude was purified by using silica gel chromatography (100-200 mesh) using ethyl acetate/petrol ether (3:7) to get 2-(6-chloropyridin-3-yl)acetonitrile (400 mg, 63%) as a yellow solid.
63%
In ethanol; water; at 0 - 100℃; for 3h;
Step 1 To a stirred solution of <strong>[70258-18-3]2-chloro-5-(chloromethyl)pyridine</strong> (1 g, 6.17 mmol, 1.0 eq) in ethanol (10 mL) was added the solution of NaCN (325 mg, 6.79 mmol, 1.1 eq) in water (10 mL) dropwise at 0 C. and then stirred for 3 h at 100 C. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (2*70 mL) washed with brine (20 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum. The crude was purified by using silica gel chromatography (100-200 mesh) using ethyl acetate/petrol ether (3:7) to get 2-(6-chloropyridin-3-yl)acetonitrile (400 mg, 63%) as a yellow solid.
21 g
With sodium carbonate; In ethanol; for 4h;Reflux;
16.2 g 2-chloropyridine benzyl chlorine, 5.1 g of sodium cyanide are added to a 250 ml four-mouthed flask. Add 150 ml ethanol, 11 g sodium carbonate. Heat to reflux. Reflux reaction for 4 hours. After the reaction, prolapsed ethanol, add 100 g water and stirred, filtered to obtain 21 g 2-chloropyridine acetonitrile.
With sodium hydride In mineral oil at 0 - 20℃; for 1h;
Synthesis of l-(6-chloro-pyridin-3-yl)-cvclobutanecarbonitrile (Intermediate 1-1.1) R1 R2 1-1 .1To a solution of compound Rl (65 g, 0.426 mol) in DMF (500 mL) at 0 °C is added NaH (60% in oil suspension, 37.5g, 0.937 mol) portion-wise over 20 minutes. The mixture is stirred for a further 20 minutes and R2 (44.1 mL, 0.435 mol) is added. The reaction mixture is warmed to room temperature and stirring is continued for 1 hour. The reaction is then quenched by the addition of water (200 mL) and concentrated in vacuo. The residue is partitioned between ethyl acetate (EtOAc) and saturated aqueous NaHC03 and the phases are separated. The organic phase is dried over Na2S04, filtered and concentrated in vacuo. The residue is purified by flash column chromatography (Si02, 20-60% ethyl acetate/heptane) to yield intermediate 1-1.1 (63 g); m/z 193 [M+l].
Stage #1: (6-chloro-pyridin-3-yl)-acetonitrile With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.666667h;
Stage #2: 1,3-dibromo-propane In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h;
52.1 Step 1. Synthesis of 83-1
To a solution of 2-chloro-5-pyridineacetonitrile (14.3 g, 94 mmol) in dimethylformamide (120 mL) at 0 °C, was added sodium hydride (8.6 g, 216 mmol, 60% in oil) portion-wise over 20 minutes. The mixture was stirred for a further 20 minutes and 1,3-dibromopropane (20 g, 98.7 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was quenched by water (50 mL). Ethyl acetate (200 mL) was added and the organic phase was washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on a silica gel column (petroleum ether to petroleum ether/ ethyl acetate = 3/1) to afford the desired product (9.4 g, 52% yield).
With lithium amide In tetrahydrofuran at 40 - 50℃; Large scale;
2
THF (8 L) and LiNH2(361 g, 15.72 mol) were charged to a reactor, and the system was heated to 40±3. 5-10%of total weight of a mixture of 2- (6-chloropyridin-3-yl) acetonitrile (800 g, 5.24 mol) and 1, 3-dibromopropane (2117 g, 10.49 mol) in THF (800 mL) was charged drop-wise to the reactor at 40-45, followed by addition of LiNH2(60 g, 2.61 mol) to the above reactor. The remaining of 2- (6-chloropyridin-3-yl) acetonitrile and 1, 2-dibromopropane solution was then charged drop-wise at 40-50. The reaction was stirred for 15-30 min, and then quenched with MeOH (2.4 L) under 25. Filtered through celite and the filtrate was concentrated. The residue was diluted with EA (4 L) , and the solution was washed with H2O (4 L) . The aqueous phase was re-extracted with EA (2.4 L) . The combined organic phase was washed with brine (2.4 L) and then concentrated. The residue was dissolved into THF and the solution was used for next step directly.
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