* 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 Organic Chemistry, 1954, vol. 19, p. 1633,1636[2] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
2
[ 6602-54-6 ]
[ 24517-64-4 ]
Reference：
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[2] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
[3] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[4] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
[5] Patent: WO2003/76442, 2003, A1, . Location in patent: Page/Page column 69
[6] Tetrahedron Letters, 2013, vol. 54, # 25, p. 3233 - 3237
3
[ 6602-54-6 ]
[ 7664-41-7 ]
[ 24517-64-4 ]
Reference：
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 421,425
[2] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[3] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
4
[ 6602-54-6 ]
[ 64-17-5 ]
[ 7664-41-7 ]
[ 24517-64-4 ]
Reference：
[1] Journal of the American Chemical Society, 1958, vol. 80, p. 421,425
[2] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[3] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
5
[ 6602-54-6 ]
[ 20577-27-9 ]
Yield
Reaction Conditions
Operation in experiment
95%
for 48 h; Reflux
Acetic acid (826 mL) was added to 2-chloronicotinonitrile (250 g) and mixture was refluxed for 48 h. The reaction mass was poured in ice-water mixture. The precipitate obtained was filtered washed with water and dried to obtain 2-hydroxy-nicotinonitrile. Yield: 95 percent; *H NMR (300 MHz, DMSO-d6): δ 12.57 (s, 1H), 8.16 (dd, J=3, 6Hz, 1H), 7.80 (dd, J=3, 6Hz, 1H), 6.37 (t, 1H); MS (ES): m/z 121.
68%
at 120℃; for 8 h;
Acetic acid (20 mL) was added in three portions to 2-chloronicotinonitrile (1.38 g, 10 mmol) under stirring at room temperature. Then, the temperature raised to 120 °C, and kept for 8 h. After cooled to room temperature, the resulting precipitation was filtered. 2-hydroxynicotinonitrile was obtained as white needle crystal. Yield: 68percent, 1H NMR (400 MHz, CDCl3): δ: 10.12 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 6.34 (m, 1H).TOF MS (EI+): C6H4N2O, found 121.03. Mp: 224-225 °C.
Reference：
[1] Tetrahedron Letters, 2004, vol. 45, # 35, p. 6633 - 6636
[2] Patent: WO2014/207508, 2014, A1, . Location in patent: Page/Page column 55
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 18, p. 7624 - 7643
[4] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 21, p. 5738 - 5746
[5] Synthetic Communications, 2011, vol. 41, # 19, p. 2859 - 2869
[6] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 14, p. 4273 - 4278
[7] European Journal of Medicinal Chemistry, 2013, vol. 60, p. 410 - 420
6
[ 6602-54-6 ]
[ 10366-35-5 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: at 90℃; for 2 h; Stage #2: for 1 h; Cooling with ice
To 1000ml three-necked flask was added concentrated sulfuric acid 400ml, 2-chloronicotinonitrile (138g, 1mol), completely dissolved, warmingTo 90 ° C, stirred for 2 hours,The reaction mixture was poured into a mixture of 1000 ml of ammonia water and 1 kg of ice and stirred for 1 hour. After filtration, the crude solid was obtained by filtration. The crude product was added to 1000 ml of ethyl acetate, stirred for 1 hour and separated by filtration to obtain a white solid. The white solid was further dried by blowing at 50 ° C to afford 153 g of the intermediate 2-chloronicotinamide as a white solid in 98percent yield.
96%
With Acetaldehyde oxime; copper(II) oxide In water for 10 h; Reflux
General procedure: To a 25 mL round-bottom flask equipped with magnetic stirrer were added nitrile (2.5 mmol), acetaldoxime (3.75 mmol), copper oxide (0.25 mmol) and H2O (10 mL). The mixture was heated to reflux for 2-14 h. After cooling to room temperature, the solution was directly evaporated to dryness and the residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give the corresponding amides. The commercially available amides were characterised by melting points, 2-amino-5-bromobenzamide (Table 2, entry 6) and 3,4-dichloropicolinamide (Table 2, entry 13) were characterised by NMR spectra and LC-MS.
71%
With copper(l) iodide; caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene In nitromethane; water at 20 - 100℃; for 3 h;
To a nitromethane (0.1 mL) solution of 2-chloroisophthalonitrile (4i) (30 mg, 0.217 mmol) were addedH2O (1.0 mL), DBU (66 mg, 0.433 mmol), copper (I) iodide (8 mg, 0.0433 mmol), cesium (I)carbonate (35 mg, 0.108 mmol) at room temperature. The reaction mixture was heated at 100 °C for3 h and then poured into water (50 mL). The organic layer was separated and the aqueous layer wasextracted with AcOEt. The combined organic layer was dried over MgSO4. The solvent wasremoved under reduced pressure. The residue was purified by preparative TLC on silica gel elutingwith AcOEt-n-hexane (1:1) to give 2-chloronicotinamide (5i)S12 (24 mg, 71percent) as pale yellow powders.mp 161-163 °C,
Reference：
[1] Patent: CN105367571, 2017, B, . Location in patent: Paragraph 0014; 0037; 0038
[2] Tetrahedron Letters, 2012, vol. 53, # 4, p. 449 - 452
[3] Journal of Chemical Research, 2011, vol. 35, # 8, p. 480 - 483
[4] Synlett, 2018, vol. 29, # 15, p. 2061 - 2065
[5] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[6] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
[7] Synthetic Communications, 1993, vol. 23, # 22, p. 3149 - 3155
7
[ 6602-54-6 ]
[ 5345-47-1 ]
Reference：
[1] Journal of Organic Chemistry, 1954, vol. 19, p. 1633,1636[2] Org. Synth. Coll., 1963, vol. Vol. IV, p. 166
8
[ 6602-54-6 ]
[ 36404-88-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 1988, vol. 31, # 3, p. 618 - 624
[2] Chemical and Pharmaceutical Bulletin, 2002, vol. 50, # 8, p. 1066 - 1072
[3] Patent: US5624935, 1997, A,
[4] Patent: US4619930, 1986, A,
[5] Patent: US4757073, 1988, A,
[6] Journal of Medicinal Chemistry, 2008, vol. 51, # 13, p. 4021 - 4029
[7] Patent: EP1726590, 2006, A1, . Location in patent: Page/Page column 47
9
[ 6602-54-6 ]
[ 3939-13-7 ]
Yield
Reaction Conditions
Operation in experiment
69%
With cesium fluoride In dimethyl sulfoxide at 90℃; for 2 h;
General procedure: To a solution of 2,3-dichloropyridine(1.00 g, 6.76 mmol) in DMSO (33.8 ml) was added CsF (2.053 g, 13.51mmol) at room temperature. The mixture was stirred at 110 °C under air for 20h. The mixture was quenched with water at room temperature and extracted withEtOAc. The organic layer was separated, washed with water and brine, dried overNa2SO4 and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with EtOAc in hexane) togive 3-chloro-2-fluoropyridine (0.639 g, 4.86 mmol, 71.9 percent) as colorlessoil. Thecompound 3B'-8B' were prepared in amanner similar to that described for 2B'.
Reference：
[1] European Journal of Inorganic Chemistry, 2017, vol. 2017, # 2, p. 330 - 339
[2] Tetrahedron Letters, 2015, vol. 56, # 44, p. 6043 - 6046
[3] Heterocycles, 1992, vol. 34, # 8, p. 1507 - 1510
[4] Organic Letters, 2015, vol. 17, # 8, p. 1866 - 1869
[5] Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12137 - 12145
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, p. 2244 - 2247
12
[ 1986-81-8 ]
[ 33252-28-7 ]
[ 6602-54-6 ]
[ 89284-61-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1988, vol. 36, p. 2244 - 2247
13
[ 6602-54-6 ]
[ 20577-26-8 ]
Reference：
[1] Tetrahedron, 2012, vol. 68, # 34, p. 6941 - 6947
[2] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 13, p. 3013 - 3032
14
[ 6602-54-6 ]
[ 6752-16-5 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrazine In ethanol at 170℃; for 0.166667 h; Microwave irradiation
Example 8; [00146] Compound 7 (1.4 mmol) was dissolved in EtOH (10 mL) in a microwave tube, to which 5 equivalent of NH2NH2 was added, and the reaction mixture was heated by microwave irradiation for 10 min at 170aC. Evaporated the solvent to obtain the compound 8 in quantitative yield.
47%
With hydrazine hydrate; caesium carbonate In N,N-dimethyl-formamide at 60℃;
2-Chloronicotinonitrile (0.75 g, 5.30 mmol), cupper iodide (I) (50 mg, 0.05 mmol), cesium carbonate (2.59 g, 7.96 mmol) and 1,10-phenanthroline (96 mg, 0.53 mmol) were suspended in 20 mL of dimethylformamide. Hydrazine hydrate (1.6 mL, 31.83 mmol) was added and the mixture was stirred at 60°C overnight. The mixture was cooled to room temperature, water was added and the aqueous phase was extracted with dichloromethane (x3). The combined organic layers were dried with magnesium sulphate, filtered and evaporated. The crude was purified by column chromatography using the SP1 Purification system (methanol-dichloromethane gradient) to yield 0.34 g (2.51 mmol, 47percent) of the title compound as a yellow solid. Purity:100percent. 1H NMR (200 MHz, DMSO-d6) δ ppm 11.91 (1 H, br. s.), 8.33 (1 H, dd, J=4.3, 1.6 Hz), 8.10 (1 H, dd, J=7.8, 1.6 Hz), 6.94 (1 H, dd, J=7.8, 4.7 Hz), 5.55 (2 H, s). LRMS: m/z 135 (M+1).
Reference：
[1] Patent: WO2007/59219, 2007, A1, . Location in patent: Page/Page column 56
[2] Chemical Communications, 2014, vol. 50, # 85, p. 12911 - 12914
[3] Canadian Journal of Chemistry, 1988, vol. 66, # 3, p. 420-428
[4] Journal of Heterocyclic Chemistry, 2012, vol. 49, # 4, p. 763 - 767
[5] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 361 - 371
[6] Tetrahedron Letters, 2004, vol. 45, # 11, p. 2389 - 2392
[7] Tetrahedron, 2015, vol. 71, # 34, p. 5597 - 5601
[8] Patent: EP2380890, 2011, A1, . Location in patent: Page/Page column 36
[9] Journal of Medicinal Chemistry, 2018, vol. 61, # 6, p. 2472 - 2489
[10] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4763 - 4772
15
[ 6602-54-6 ]
[ 60-34-4 ]
[ 72583-83-6 ]
Reference：
[1] Tetrahedron Letters, 2004, vol. 45, # 11, p. 2389 - 2392
[2] Farmaco, 2005, vol. 60, # 6-7, p. 513 - 517
[3] Canadian Journal of Chemistry, 1988, vol. 66, # 3, p. 420-428
16
[ 6602-54-6 ]
[ 271-73-8 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2013, vol. 68, p. 361 - 371
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2438 - 2442
33
[ 6602-54-6 ]
[ 623-50-7 ]
[ 371945-06-1 ]
Yield
Reaction Conditions
Operation in experiment
70%
at 70℃; for 4 h;
To a stirred mixture of the pyridine 51a (2.00 g, 1.0 eq), the alcohol 51b (1.43 mL, 1.05 eq), CuI (0.05 g, 0.02 eq) is added Cs2CO3 (10.3 g, 2.2 eq) and heated at 70° C. during4 h. The reaction mixture is cooled down to RT, poured into H2O (300 mL) and allowed to stand for 1 h until precipitation. The suspension is filtered, triturated with Et2O/Hex (1:1), dried with toluene azeotrope to give 51c (2.0 g, 70percent).
50%
With caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 80℃; for 24 h; Inert atmosphere
2- Chloro 3-pyridine carbonitrile (1, 2.0 g, 1 equiv.), Cs2C03 (14.2 g, 3 equiv.) and ethyl glycolate (1.5 mL, 1.2 equiv.) were placed in a flask under inert atmosphere. Dry toluene and DBU (4.3 mL, 2 equiv) were added and the suspension was heated at 80 °C for 24 h with vigorous stirring. The reaction mixture was cooled to RT, and then water and EtOAc were added. The organic layer was seperated and was washed with water before being dried over anhydrous Na2S04 and concentrated in vacuo. Purification was done by column chromatography on silica gel using 10-40percent EtOAC: hexane as a mobile phase to get product 2 (1.5 g, 50percent) as a white solid. *H NMR (CDC13, 400 MHz): δ 8.51 (dd, / = 5.0, 2.0 Hz, 1H), 7.96 (dd, / = 8.0, 2.0 Hz, 1H), 7.23-7.28 (m,1H), 4.44 (q, / = 7.0 Hz, 2H), 4.01 (br, s, 2H), 1.44 (t, / = 7.0 Hz, 3H); ESI-MS: nt/z 229.05 [M+Na]+
40%
With caesium carbonate In 1-methyl-pyrrolidin-2-one at 75℃; for 20 h; Inert atmosphere
2-Chloro-3-pyridinecarbonitrile, 1 , (4.0Og, 28.9mmol), Cs2CO3 (28.2g, 86.6mmol) and ethyl glycolate (3mL, 31.7mmol) were placed in a flask under Ar(g). Dry NMP was added, and the suspension was heated at 75°C for 2Oh with vigorous stirring. The reaction mixture was cooled to rt, whereupon water (200 mL) and Et2ψ (3 x 10OmL) were added. The organic layers were combined, washed with water (3 x 15mL) before being dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 15-40percent EtOAc/Hex) gave 2 (2.41 g, 1 1 Jmmol, 40percent) as a white solid.1H NMR (400MHz, CDCI3) δH: 8.51 (dd, J=5.0, 2.0Hz, 1 H), 7.96 (dd, J=8.0, 2.0Hz, 1 H), 7.23-7.28 (m, 1 H), 4.44 (q, J=7.0Hz, 2H), 4.01 (br. s., 2H), 1.44 (t, J=7.0Hz, 3H).MS (ES+) 229 (100percent, [M+Na]+).
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - -30℃; for 1 h; Inert atmosphere Stage #2: With iodine In tetrahydrofuran; hexane at -78℃; for 0.5 h;
Step 1: Synthesis of 2-chloro-4-iodonicotinonitrile In an atmosphere of argon gas, at -30° C., n-butyl lithium (2.4M hexane solution, 3.0 mL, 7.2 mmol) was added dropwise to a solution of diisopropylamine (0.728 g, 7.2 mmol) in anhydrous tetrahydrofuran (20 mL) to get a reaction mixture. The reaction mixture was stirred at -30° C. for 30 minutes, and then cooled to -78° C. A solution of 2-chloro-nicotinonitrile (1.0 g, 7.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the reaction mixture was then stirred at -78° C. for 60 minutes. A solution of iodine (1.8 g, 7.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the reaction mixture was then stirred at -78° C. for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), diluted with water (50 mL), and extracted with ethyl acetate (100 mL*3). The organic phases were combined. The combined organic phases were washed with saline solution (100 mL*3), dried with anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=80:1) to get product as yellow solid (0.357 g, yield: 19percent). 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J=5.2 Hz, 1H), 8.15 (d, J=5.2 Hz, 1H) MS (ESI+): m/z 264.9 [M+H]+
To 1000ml three-necked flask was added concentrated sulfuric acid 400ml, 2-chloronicotinonitrile (138g, 1mol), completely dissolved, warmingTo 90 C, stirred for 2 hours,The reaction mixture was poured into a mixture of 1000 ml of ammonia water and 1 kg of ice and stirred for 1 hour. After filtration, the crude solid was obtained by filtration. The crude product was added to 1000 ml of ethyl acetate, stirred for 1 hour and separated by filtration to obtain a white solid. The white solid was further dried by blowing at 50 C to afford 153 g of the intermediate 2-chloronicotinamide as a white solid in 98% yield.
96%
With Acetaldehyde oxime; copper(II) oxide; In water; for 10h;Reflux;
General procedure: To a 25 mL round-bottom flask equipped with magnetic stirrer were added nitrile (2.5 mmol), acetaldoxime (3.75 mmol), copper oxide (0.25 mmol) and H2O (10 mL). The mixture was heated to reflux for 2-14 h. After cooling to room temperature, the solution was directly evaporated to dryness and the residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give the corresponding amides. The commercially available amides were characterised by melting points, 2-amino-5-bromobenzamide (Table 2, entry 6) and 3,4-dichloropicolinamide (Table 2, entry 13) were characterised by NMR spectra and LC-MS.
71%
With copper(l) iodide; caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In nitromethane; water; at 20 - 100℃; for 3h;
To a nitromethane (0.1 mL) solution of 2-chloroisophthalonitrile (4i) (30 mg, 0.217 mmol) were addedH2O (1.0 mL), DBU (66 mg, 0.433 mmol), copper (I) iodide (8 mg, 0.0433 mmol), cesium (I)carbonate (35 mg, 0.108 mmol) at room temperature. The reaction mixture was heated at 100 C for3 h and then poured into water (50 mL). The organic layer was separated and the aqueous layer wasextracted with AcOEt. The combined organic layer was dried over MgSO4. The solvent wasremoved under reduced pressure. The residue was purified by preparative TLC on silica gel elutingwith AcOEt-n-hexane (1:1) to give 2-chloronicotinamide (5i)S12 (24 mg, 71%) as pale yellow powders.mp 161-163 C,
Stage #1: ethyl 2-sulfanylacetate With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 0.25h;
Stage #2: 2-chloro-3-pyridinecarbonitrile In dimethyl sulfoxide; mineral oil at 20℃; for 3h;
2 4.2.2 Synthesis of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate (9)
According to the literature procedure [19], ethyl thioglycolate (1.2 mL, 11 mmol) was added to a stirred mixture of NaH 60% dispersion in mineral oil (0.36 g, 15 mmol) and dry dimethylsulfoxide (DMSO) (10 mL). After stirring at room temperature for 15 min, a solution of 2-chloro-3-cyanopyridine (1.40 g, 10 mmol) in dry DMSO (20 mL) was added dropwise. The reaction was stirred at room temperature for further 3 h and then was poured onto stirred water/ice. The light yellow precipitate was collected by filtration and dried to give 9, 2.22 g. Yield 100%. Mp 183-184 °C. IR: 3487, 3395, (NH2), 1689 (CO) cm-1. 1H NMR δ: 1.29 (t, J = 7.1 Hz, 3H), 4.30 (q, J = 7.1 Hz, 2H), 7.31 (br s, 2H), 7.46 (dd, J = 4.6, 8.2 Hz, 1H), 8.54 (dd, J = 1.6, 8.2 Hz, 1H), 8.68 (dd, J = 1.6, 4.6 Hz, 1H). 13C NMR δ: 14.4 (q), 59.9 (t), 93.3 (s), 119.3 (d), 125.5 (s), 131.4 (d), 147.7 (s), 150.7 (d), 159.6 (s), 164.3 (s).
94%
With sodium carbonate In ethanol at 90℃; for 2.5h;
1 ester 237
To a solution of 236 (3() g, 218 mrnol) in EtOH 300 mL) is added sodiumcarbonaie (25 g, 237 mmol) and ethyl 2-mercaptoacetale (31 mL, 283 mmoi). After stirring at90 °C for 2.5 hours, the mixture is cooled to room temperature and water (500 mL) is added.The solid is collected by filtration, washed with water, and dred to give 237 as a yellow solid(45 g, 94% yield). (MS:[M+Hi 2233)
93.2%
With sodium carbonate In ethanol for 4.5h; Heating / reflux;
1 Intermediate 1; [ETHVL 3-AMINOTHIENOR2, 3-BLPVRIDINE-2-CARBOXVLATE]
A mixture of 2-chloro-3-cyanopyridine (330g), ethyl 2-mercaptoacetate (361. [2G),] sodium carbonate (265g) and EtOH (1.2L) was heated to reflux for 4.5 hours. It was then cooled to ambient temperature, added to water [(10L)] and the addition was washed in with water (5L). The resulting slurry was stirred for 30 minutes and then it was filtered. The filter cake was washed with two portions of water (2 x 2.5L) and dried at the pump. The solids were then dried to constant weight under vacuum at [45°C] to yield the title compound as a brown solid (493.1 g, 93.2%). 8H (CDCI3) 8. 68 (1 H, dd, [J 4.] 7, 1.2Hz), 7.93 (1 H, dd, J 8.5, 1.2Hz), 7.29 (1 H, dd, J 8.5, 4.7Hz), 5.90 (2H, b), 4.38 (2H, q, J 7. [0HZ),] 1.40 (3H, t, J 7. [0HZ).] LCMS RT 2.9 minutes, 223 [(M+H)] +
93.2%
With sodium carbonate In ethanol for 4.5h; Heating / reflux;
1 INTERMEDIATE [1]; Ethyl [3-AMINOTHIENOF23-B3PVRIDINE-2-CARBOXYLATE]
A mixture [OF 2-CHLORO-3-CYANOPYRIDINE] (330 g), ethyl 2-mercaptoacetate (361.2 g), sodium carbonate (265 [G)] and [ETOH] (1. [2 1)] was heated to reflux for 4.5 hours. It was then cooled to ambient temperature, added to water [(10 1)] and the addition was washed with water [(5] 1). The resulting slurry was stirred for 30 minutes and then it was filtered. The filter cake was washed with two portions of water (2 x 2. [5 1)] and dried at the pump. The solids were then dried to constant weight under vacuum at [45°C] to yield the title compound as a brown solid (493.1 g, 93. [2%).] [6H] [(CDC13)] 8. [68] [(1H,] dd, [J4.] 7,1. 2 Hz), 7.93 [(1H,] dd, [J8.] 5,1. 2 Hz), 7.29 [(1H,] dd, J 8.5, 4.7 Hz), 5.90 (2H, b), 4. [38] (2H, q, J7. 0 Hz), 1.40 (3H, t, J7.0 Hz). LCMS RT 2.9 minutes, 223 [(M+H) +.]
93%
With sodium carbonate In ethanol for 4.5h; Heating / reflux;
1
A mixture of 2-chloro-3-cyanopyridine (330 g, 2.38 mol), ethyl 2-mercaptoacetate (361.2 g, 3.01 mol), sodium carbonate (265 g, 2.5 mol) and EtOH (1. 2 1) was heated to reflux for 4.5 h. The reaction mixture was then cooled to ambient temperature and added to water (15 1). The resulting slurry was stirred for 0.5 h then filtered. The filter cake was washed with two portions of water (2 x 2.5 1). The solids were then dried to constant weight under vacuum at 45°C to yield the title compound as a brown solid (493 g, 93%). aH (CDC13) 8.68 (1H, dd, J4. 7,1. 2 Hz), 7.93 (1H, dd, J8. 5,1. 2 Hz), 7.29 (1H, dd, J8. 5, 4.7 Hz), 5.90 (2H, br), 4. 38 (2H, q, J7. 0 Hz), 1.40 (3H, t, J7. 0 Hz). LCMS RT 2.9 minutes, 223 (M+H) +.
93.2%
With sodium carbonate In ethanol for 4.5h; Heating / reflux;
1 Intermediate 1; Ethyl 3-AMINOTHIENO2, 3-BLPVRIDINE-2-CARBOXVLATE
Intermediate 1 Ethyl 3-AMINOTHIENO2, 3-BLPVRIDINE-2-CARBOXVLATE A mixture of 2-chloro-3-cyanopyridine (330g, 2. 3MOL), ethyl 2- mercaptoacetate (361.2g, 3. 0MOL), sodium carbonate (265g, 2. 5mol) and EtOH (1.2L) was heated to reflux for 4.5 hours. The reaction mixture was cooled to ambient temperature and added to water (15L). The resultant precipitate was stirred for 30 minutes and then filtered. The filter cake was washed with two portions of water (2 x 2.5L) and dried to constant weight under vacuum at 45°C to yield the title compound as a brown solid (493. 1G, 93.2%). 5H (CDCI3) 8.68 (1H, dd, J 4. 7,1. 2Hz), 7.93 (1H, dd, J 8. 5,1. 2Hz), 7.29 (1 H, dd, J 8.5, 4.7Hz), 5.90 (2H, b), 4.38 (2H, Q, J 7. 0Hz), 1.40 (3H, t, J 7. 0HZ). LCMS RT 2.9 minutes, 223 (M+H) +.
93.2%
With sodium carbonate In ethanol for 4.5h; Heating / reflux;
1 Intermediate 1; Ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate
A mixture of2-chloro-3-cyanopyridine (330g, 2.3mol), ethyl 2- mercaptoacetate (361.2g, 3.0mol), sodium carbonate (265g, 2. 5mol) and EtOH (1.2L) was heated to reflux for 4.5 hours. The reaction mixture was cooled to ambient temperature and added to water (15L). The resultant precipitate was stirred for 30 minutes and then filtered. The filter cake was washed with two portions of water (2 x 2.5L) and dried to constant weight under vacuum at45 C to yield the title compound as a brown solid (493.1g, 93.2%). 8H(CDCI3) 8. 68 (1 H, dd, J 4.7, 1.2Hz), 7.93 (1 H, dd, J 8.5, 1.2Hz), 7.29 (1H, dd, J 8.5, 4.7Hz), 5.90 (2H, b), 4.38 (2H, q,J 7.0Hz), 1.40 (3H, t, J 7.0Hz). LCMS RT 2.9 minutes, 223 (M+H) +.
92%
With sodium carbonate In ethanol for 4.58333h; Inert atmosphere; Reflux;
A.i; C.i
Under Ar(g), 2-chloro-3-pyridinecarbonitrile, 1 , (3.026g, 21.8mmol) and sodium carbonate (2.51 "Ig, 23.7mmol) were dissolved in dry ethanol (11.5mL). Ethyl-2-meracaptacetate (3.1mL, 28.3mmol) was then added, and the reaction mixture was heated at reflux for 4h 35 min. The reaction was then cooled to rt; water (14OmL) was then added, at which point a precipitate formed, and the resulting reaction mixture was subsequently stirred for a further 30min. The precipitate was filtered, washed with water (2 x 15mL) and the resulting residue collected and dried under vacuum to furnish 2 (4.435g, 20mrnol, 92%) as an orange solid.1H NMR (400MHz, CDCI3) δH: 8.70 (dd, J=4.6, 1.44Hz, 1 H), 7.96 (dd, J=8.1 ,1.57Hz, 1 H), 7.33 (dd, J=8.2, 4.6Hz, 1 H), 5.92 (br. s, 2H), 4.38 (q, J=7.1 Hz, 2H),1.41 (t, J=7.2Hz, 3H).MS (ES+) 223.0 (100%, [M+H]+).
89%
Stage #1: ethyl 2-sulfanylacetate With sodium hydride In dimethyl sulfoxide at 25℃;
Stage #2: 2-chloro-3-pyridinecarbonitrile In dimethyl sulfoxide at 25℃; for 3h;
83%
With sodium carbonate In ethanol for 3h; Reflux;
1
Reference Example 1 ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate [Show Image] A suspension of 2-chloronicotinonitrile (25.7 g, 185 mmol), ethyl mercaptoacetate (27.0 g, 225 mmol) and sodium carbonate (19.9 g, 187 mmol) in ethanol (70 mL) was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, water was added, and the resulting solid was collected by filtration. This was suspended in methanol, collected by filtration, and dried to give the title compound (32.3 g, yield 83%). 1H NMR (CDCl3) δ1.40 (3H, t, J = 7.2 Hz), 4.38 (2H, q, J = 7.2 Hz), 5.92 (2H, br s), 7.31 (1H, dd, J = 4.7 Hz, 8.0 Hz), 7.93 (1H, dd, J = 1.7 Hz, 8.0 Hz), 8.69 (1H, dd, J = 1.7 Hz, 4.7 Hz).
68%
With water; potassium hydroxide In 1,2-dimethoxyethane at -5 - 0℃; for 1h; Inert atmosphere;
37%
With potassium carbonate In ethanol for 48h; Inert atmosphere;
ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate (3) (Scheme 13)
[00491] A mixture of 2-chloronicotinonitrile (1) (6.93 g, 50 mmol, 1 equiv), ethyl 2-mercaptoacetate (2) (6 g, 50 mmol, 1 equiv) and K2CO3 (11.1 g, 50 mmol, 1 equiv) was refluxed in 50 mL of EtOH under Ar for 48h. Reaction mixture was hot-filtered from K2CO3 and put to a fridge (-18 °C) for overnight. The precipitate formed was filtered, washed with water and recrystallized from EtOH to afford the target product (3) as a yellow solid (4.15 g, 37%).
With sodium carbonate In ethanol
With sodium ethanolate In N,N-dimethyl-formamide at 70℃;
With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) for 15h;
2
EXAMPLE 2: SYNTHESIS OF COMPOUND A57 To a solution of 0.1 g (0.53 mmol) of compound 3 in DCM (5 mL) was added 0.078 g (0.53 mmol) of phenethylisocyanate 2 (commercially available from Sigma- Aldrich, St. Louis, MO (www. sigma-aldrich. com) ) and the resulting reaction mixture was stirred for about 4 h. at about 25°C. The solvent was removed under reduced pressure to provide a residue that was purified using a silica gel column eluted with a gradient of 20: 80 ethyl acetate: hexane to 50: 50 ethyl acetate: hexane to provide 3- substituted Pyridyl Compound A57 as a white solid (150 mg, 84% yield). Compound 3 was obtained by dissolving 5 g of 2-chloro-3-cyano-pyridine (commercially available from Sigma-Aldrich, St. Louis, MO (www. sigma-aldrich. com)), 6.21 g of piperazine (72.16 mmol) (commercially available from Sigma-Aldrich, St. Louis, MO (www. sigma-aldrich. com) ), and 1.25 ML (72.16 mmol) OF DEA in DMF and allowing the resulting reaction mixture to stir for about 15 h. Water and ethyl acetate were then added to the reaction mixture, the aqueous and organic phases separated, and the aqueous phase was extracted twice with ethyl acetate. The combined ethyl acetate layers were then washed with water, washed with brine, dried (NA2SO4), and the solvent was removed under reduced pressure to provide a residue. The residue was purified using a silica gel column to provide compound 3 (5.5 g, 81 %).
72.5%
With sodium hydroxide In ethanol
VI.a Step (a):
Step (a): Preparation of 1-(3-cyano-2-pyridinyl)piperazine A mixture of piperazine (0.5 mol) and 2-chloro-3-cyanopyridine (0.1 mol) in absolute ethanol (225 ml) was heated at reflux for 16 hours. The cooled mixture was filtered to remove precipitated piperazine hydrochloride and the filtrate evaporated in vacuo. The residue was diluted with water (200 ml), made basic (pH>10) with 5N sodium hydroxide and extracted with ether (5*300 ml). The combined extracts were dried (MgSO4) and evaporated in vacuo affording 13.6 g of a white solid (72.5% yield); mp 99°-103° C. Spectral data are consistent with the assigned structure. This material was used without further purification.
46%
With potassium carbonate In 1,4-dioxane at 100 - 110℃;
To prepare 2-(piperazin-1-yl)nicotinonitrile (C), a solution ofPiperazine (3 g), and K2CO3 (4.8 g, 1 equiv) in dioxane (15 mL)was added 2-chloro-3-cyanopyridine (4.8 g, 1 equiv) and wasstirred to reflux at 100-110 °C for 4-5 h (Scheme 2). The resultingprecipitate was filtered off and concentrated at reduced pressure toobtain the crude product which was purified was silica gel columnchromatography MeOH/CHCl3 (5:95 v/v) to give compound C asyellow solid (3 g, 46%).27
In butan-1-ol for 18h; Heating;
In dimethyl sulfoxide at 100℃; for 6h;
In ethanol; water monomer
2.a 2-[4-[4-(7,9-Dioxo-6-thia-8-azaspiro[4.4]nonan-8-yl)butyl]-1-piperazinyl]pyridine-3-carbonitrile Hydrochloride (Ib, Z=3-cyano-2-pyridinyl)
(a) 1-(3-Cyano-2-pyridinyl)piperazine. A mixture of 2-chloro-3-cyanopyridine (13.86 g., 0.1 mole) and piperazine (43.25 g., 0.5 mole) in ethanol is stirred for a period of 16 hr. at room temperature. The solvent is removed under reduced pressure and residual material dissolved in water and made basic with sodium hydroxide. The basified solution is extracted with ether and the ethereal extract dried and concentrated in vacuo to afford a cream colored solid.
In water monomer
209.1 Synthesis of 3-{(2S,4S)-4-[4-(3-cyano-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride
(1) Piperazine (125 g) was melted by heating at 150°C and 2-chloro-3-cyanopyridine (20.0 g) was added thereto. The mixture was stirred at 110°C for 2 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with brine, dried and concentrated under reduced pressure to give 1-(3-cyano-2-pyridyl)piperazine (24.2 g) as a brown solid.
at 120℃;
With potassium carbonate In 1,4-dioxane Reflux;
With potassium carbonate In 1,4-dioxane at 100℃;
4.1.7. General methods of preparation of compound 12
A mixture of 2-Chloro-3-cyano pyridine (10 mmol), piperazine (10 mmol) and K2CO3 (12 mmol) in 1,4-dioxane was reflux at 100 °C for 8-9 h. The reaction mixture was cooled down to room temperature. The reaction mixture was filter and washed with 1,4-dioxane. The filtrate was concentrated and purified by column chromatography using 8% MeOH/CHCl3.
In methanol at 60 - 70℃;
4.1.5 General procedure for synthesis of compound 6a, 6b
General procedure: The ethyl 4-(piperazin-1-yl)quinoline-3-carboxylates were prepared by mixing compound 5a/5b with excess amount of piperazine (7 eq.) in anhydrous methanol and refluxing overnight at 60-70°C. The reaction was monitored via TLC. On completion of reaction the organic solvent was concentrated on rota-evaporator and the crude product left was extracted using ethyl acetate (3×100 ml) and then with brine solution. The combined ethyl acetate layers were concentrated and the acquired crude products were purified via recrystallization from MeOH solvent.
With potassium carbonate In 1,4-dioxane at 100℃;
1. General methods of preparation of compound 9
To a solution of 6 (1mmol) in DCM (20ml) was added piperazine 7 (3mmol). The resulting mixture was stirred at room temperature for 4 h and then dried under vacuum. The mixture was diluted with DCM and water (100 mL × 3). The organic layer was dried anhydrous sodium sulphate concentrated the crude from was purified by column chromatography (eluting with 5% CHCl3/ MeOH) as a yellow solid 8. The solution of compound 8 (1mmol) in DMSO (10ml) was compound 5 (1mmol), in presence of TEA (3mmol), HOBt (3mmol), EDC, at room temperature 8h, the reaction mixture after 8h, diluted with ethyl acetate (50ml) and water (100 mL × 2) followed by brine. The organic layer dried over sodium sulphate, concentrated and purified by silica gel column chromatography 80% EtOHHexane light yellow solid 60 % yield.
In ethanol for 16h; Reflux;
1.6 Procedure for the synthesis of 8
A mixture of 6 (1.10 g, 8 mmol) and 7 (3.42 g, 40 mmol) in absolute ethanol (20 mL) was reflux for 16 hoursThe cooled mixture was diluted with redistilled water (100 mL) and CHCl3 (300 mL). The resulting solution was vigorously stirred at room temperature for about 1 hour. The organic phase was then separated, dried over Na2SO4, filtered and evaporated to dryness on RVO. The crude residue of 26 was purified by silica gel chromatography using gradient mobile phase CHCl3:MeOH (100:0 -> 90:10 v/v). Proper pure fractions were identified by TLC and evaporated to dryness. Yellowish powder. Yield: 90 % (1.35 g); 1H NMR (500 MHz, CDCl3) δ 8.32 (dd, J = 4.8, 2.0 Hz, 1H), 7.74 (dd, J = 7.6, 2.0 Hz, 1H), 6.72 (dd, J = 7.6, 4.8 Hz, 1H), 3.69 - 3.64 (m, 4H), 3.02 - 2.97 (m, 4H), 1.78 (s, 1H). 1H NMR of 8 agrees with literature reported spectra
In ethanol for 16h; Reflux;
1.6 Procedure for the synthesis of 8
A mixture of 6 (1.10 g, 8 mmol) and 7 (3.42 g, 40 mmol) in absolute ethanol (20 mL) was reflux for 16 hoursThe cooled mixture was diluted with redistilled water (100 mL) and CHCl3 (300 mL). The resulting solution was vigorously stirred at room temperature for about 1 hour. The organic phase was then separated, dried over Na2SO4, filtered and evaporated to dryness on RVO. The crude residue of 26 was purified by silica gel chromatography using gradient mobile phase CHCl3:MeOH (100:0 -> 90:10 v/v). Proper pure fractions were identified by TLC and evaporated to dryness. Yellowish powder. Yield: 90 % (1.35 g); 1H NMR (500 MHz, CDCl3) δ 8.32 (dd, J = 4.8, 2.0 Hz, 1H), 7.74 (dd, J = 7.6, 2.0 Hz, 1H), 6.72 (dd, J = 7.6, 4.8 Hz, 1H), 3.69 - 3.64 (m, 4H), 3.02 - 2.97 (m, 4H), 1.78 (s, 1H). 1H NMR of 8 agrees with literature reported spectra
With triethylamine; trichlorophosphate at 20 - 90℃;
1 Embodiment 1
Embodiment 1 3-cyanopyridine N-oxide, phosphorus oxychloride and triethylamine in a weight ratio of 1: 5: 08 was continuously fed in the reactor No. 1 by controlling the feed rate to maintain the temperature inside the reactor at 20°C-25°C; the reaction liquid from the No. 1 reactor turn into the No. 2 and No. 3 reactor. Reactor No. 2's temperature was controlled at 40-50°C, whilst reactor No. 3's temperature was controlled at 80-90°C. The solution's average residence time in the control vessel was kept for 1 to 2 hours. The reaction liquid within the vessel 3 is continuously fed into a subsequent distillation recovery system. Recovered in the reaction solution was distilled under reduced pressure to phosphorus oxychloride, recovered at the end of the degree of vacuum with a pressure of 0. 06 ~ -0. 09MPa, temperature at 85 ~ 105 ° C, and no apparent phosphorus oxychloride was distilled off. Concentrate recovered phosphorus oxychloride after 10 times slowly into water to precipitate the 2-chloro-3-cyanopyridine, control the discharge temperature no higher than 50 ° C, the discharge is completed the following cooling to 40 ° C and kept stirred for 1 ~ 1.5 hours, suction filtered, washed with water to give 2-fold after 2X 2-chloro-3-cyanopyridine, purity 99%, yield 96% by weight of pure off, 6-chloro-3-cyanopyridine content 0.5% .
91.41%
With bis(trichloromethyl) carbonate; N-benzyl-N,N,N-triethylammonium chloride; triethylamine; sodium chloride In 1,2-dichloro-ethane at -10 - 0℃; for 2h;
1-21
Take a dry four-necked flask,Set up the exhaust gas absorption device,Add 6g (50mmol) of 3-cyanopyridine N-oxide,12.65 g (125 mmol) of triethylamine and 50 mL of 1,2-dichloroethane,When the temperature drops to 0 ° C,0.63 g (2 mmol) of benzyltriethylammonium chloride and 2.93 g (50 mmol) of sodium chloride were added.And add 50 mL containing 14.84 g (50 mmol) at -10 °C.a solution of bis(trichloromethyl) carbonate in 1,2-dichloroethane,The addition is completed, and the reaction is kept at this temperature for 2 hours.The reaction was completed, quenched by adding 40 mL of deionized water, and layered.The organic phase was washed sequentially with 20 mL of 10% sodium hydroxide solution.Wash with 20 mL of deionized water.The layers were separated, the organic phase was collected, and the aqueous phase was extracted with (25 mL*2) 1,2-dichloroethane.The organic phases were combined, and activated carbon was added to reflux at 60 ° C for one hour.After decolorization, filtration, drying with anhydrous magnesium sulfate,Remove the solvent,6.33 g of wine red product was obtained with a yield of 91.41%.
90.3%
With oxalyl dichloride; triethylamine In dichloromethane at -70℃; for 0.5h; Inert atmosphere; regioselective reaction;
With POCl2 for 6h; Heating;
With oxalyl dichloride; triethylamine In dichloromethane regioselective reaction;
With potassium hydroxide; 18-crown-6 ether In toluene at 60℃; for 16h;
31
Example 31 N4-[(trans-4-aminocyclohexyl)methyl]-N2-[(2-isopropoxypyridin-3-yl)methyl]-5-nitropyrimidine-2,4-diamine A mixture of 2-chloronicotinonitrile (1.0 g, 7.2 mmol), 2-propanol (0.87 g, 14.4 mmol), KOH (0.81 g, 14.4 mmol) and 18-crown-6 (1.8 g, 2.89 mmol) in toluene (30 mL) was stirred at 60° C. for 16 h. The reaction mixture was quenched with water and the organic phase was separated and then washed with water (*5). The organic phase was dried over Na2SO4 and concentrated to yield crude 2-isopropoxy-nicotinonitrile (1.1 g, 94%) which was used without further purification.
67%
With potassium hydroxide In toluene at 20 - 25℃; for 18h;
84.1 2-(Methylamino)nicotinonitrile
2-Chloro-3-cyanopyridine (30.0 g, 216 mmol) was added to 40% aqueous methylamine solution (300 mL) and stirred for 2 hours after heating to 80°C. The reaction solution was concentrated under reduced pressure and filtered. The resulting solid was washed with water (30 mL * 3) and dried to give 2-(methylamino)nicotinamide (22.3 g, as a pale yellow solid) with a yield of 76%. 1H NMR: (400 MHz, Methanol-d4) δ 8.25-8.22(m, 1H), 7.79-7.74(m, 1H), 6.65-6.59(m, 1H), 2.96(s, 3H).
76%
In water at 80℃; for 2h;
39.1 2-(Methylamino)nicotinonitrile
2-Chloro-3-cyanopyridine (30.0 g, 216 mmol) was added into 40% methylamine aqueous solution (300 mL), which was heated to 80° C. and then stirred for 2 hours. The reaction solution was concentrated by reduced pressure distillation. The solid obtained by filtration was washed with water (30 mL*3) and then dried to give 2-(methylamino)nicotinonitrile (22.3 g, pale yellow solid) with a yield of 76%. 1H NMR: (400 MHz, Methonal-d4) δ8.25-8.22 (m, 1H), 7.79-7.74 (m, 1H), 6.65-6.59 (m, 1H), 2.96 (s, 3H).
With 18-crown-6 ether; potassium hydroxide In toluene at 110℃; for 5h; Dean-Stark;
85%
With potassium hydroxide In toluene at 25℃; for 2h;
69%
With sodium hydride In N,N-dimethyl-formamide at 0 - 30℃; for 72h;
128 Reference Example 128
To a mixture of benzyl alcohol (32.0 g), 2-chloro-3-cyanopyridine (37.3 g) and N,N-dimethylformamide (200 mL) was added sodium hydride (60%, oil, 12.92 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(benzyloxy)nicotinonitrile as an oil (39.13 g, 69%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).<1>H-NMR (CDCl3) delta : 5.52 (2H, s), 6.99 (1H, dd, J=7.6, 5.2 Hz), 7.31-7.52 (5H, m), 7.89 (1H, dd, J=7.6, 2.0 Hz), 8.36 (1H, dd, J=5.2, 2.0 Hz). [0580] To a mixture of 2-(benzyloxy)nicotinonitrile (47.50 g) and anhydrous toluene (100 mL) was dropwise added a solution (1 M, 500mL) of diisobutylaluminum hydride in hexane at -78 DEG C. The reaction mixture was allowed to warm to room temperature with stirring for 1.5 hrs. A saturated aqueous ammonium chloride solution was dropwise added to the mixture and the mixture was stirred at room temperature for 30 min. Ethyl acetate was added to the mixture, and the mixture was further stirred at room temperature for 30 min. Insoluble materials were filtered off. The filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(benzyloxy)nicotinaldehyde as an oil (19.71 g, 41%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).<1>H-NMR (CDCl3) delta : 5.54 (2H, s), 7.04 (1H, dd, J=7.4, 5.2 Hz), 7.26-7.50 (5H, m), 8.14 (1H, dd, J=7.4, 2.0 Hz), 8.40 (1H, dd, J=5.2, 2.0 Hz), 10.45 (1H, s). [0581] To a mixture of potassium t-butoxide (4.52 g) and dimethoxyethane (20 mL) was added a solution (20 mL) of toluenesulfonylmethylisocyanide (4.12 g) in dimethoxyethane at -78 DEG C. Further, a solution (20 mL) of 2-(benzyloxy)nicotinaldehyde (4.12 g) in dimethoxyethane was added to the reaction mixture. The reaction mixture was stirred at -78 DEG C for 1 hr. Methanol (20 mL) was added to the reaction mixture at room temperature and the mixture was heated under reflux for 30 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-(2-benzyloxy-3-pyridyl)acetonitrile as an oil from a fraction eluted with ethyl acetate-hexane (1:8, v/v).<1>H-NMR (CDCl3) delta : 3.70 (2H, s), 5.44 (2H, s), 6.95 (1H, dd, J=7.4, 5.0 Hz), 7.32-7.49 (5H, m), 7.71 (1H, dd, J=7.4, 1.8 Hz), 8.17 (1H, dd, J=5.0, 1.8 Hz). [0582] A mixture of 2-(2-benzyloxy-3-pyridyl)acetonitrile (1.0 g) and 10% hydrogen chloride-methanol (30 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated, and saturated aqueous sodium hydrogencarbonate was added to basify the residue. The mixture was concentrated and a mixed solvent of ethyl acetate and tetrahydrofuran (3:1, v/v) was added to the residue. Insoluble materials were removed by filtration. The filtrate was dried over anhydrous magnesium sulfate and concentrated to give crystals (0.42 g, 56%) of methyl 2-(2-oxo-1,2-dihydro-3-pyridyl)acetate. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 183-184 DEG C.
With copper(l) iodide; triethylamine at 100℃; for 20h;
75%
Stage #1: 2-chloro-3-pyridinecarbonitrile With triethylamine; triphenylphosphine at 20℃; for 0.0833333h;
Stage #2: trimethylsilylacetylene at 80℃; for 18.5h;
36.36a
In a suitably sized pressure vessel, commercially available 2-chloro-nictinonitrile (1.5 g, 10.8 mmol) was combined with triphenylphosphine (0.228 g, 8 mole %) and palladium (II) acetate (0.083 g, 3.5 mol %) in triethylamine (2OmL). Nitrogen was bubbled through the resulting suspension at room temperature for five minutes then trimethylsilylacetylene (8.5mL, 60.1 mmol) was added, the vessel sealed and immersed in an 80 0C oil bath. After 18.5 h the pressure tube was cooled to room temperature and the contents were filtered. The filtrate was concentrated under vacuum and the crude product purified by flash chromatography on silica gel eluting with EtOAc/ hexanes to give the title compound (1.62 g, 75 %) as a tan solid.
62%
With copper(l) iodide In triethylamine at 100℃; for 20h;
61%
With triethylamine In toluene at 70℃; for 5h; Inert atmosphere;
13.M.a
a. 2-((Trimethylsilyl)ethynyl)nicotinonitrile To a solution of 2-chloronicotinonitrile (21.6 g, 156 mmol) in toluene (200 mL) was added Pd(dppf)Cl2 (2.3 g, 3.12 mmol), copper (I) iodide (594 mg, 3.12 mmol), triethylamine (32 mL, 312 mmol) and ethynyltrimethylsilane (23 g, 234 mmol). The reaction mixture was stirred at 70° C. under N2 for 5 h. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give a residue. 40 mL of water was added to the residue, and the mixture was extracted with EtOAc (3*100 mL). The combined organic layers were washed with brine (1*100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (eluting with a gradient of PE/EtOAc v/v 40:1, 20:1, 10:1, 5:1) to yield 2-((trimethylsilyl)ethynyl)nicotinonitrile as a yellow solid (19.14 g, yield 61%). ESI MS: m/z 201 [M+H]+.
With hydrogenchloride; sodium chloride; diisobutylaluminium hydride; sodium carbonate; In tetrahydrofuran; hexane;
PREPARATION 75 2-Chloro-3-formylpyridine 200 ml of a 1.02M hexane solution of diisobutylaluminum hydride were added to a solution of 16.7 g of 2-chloro-3-cyanopyridine in 200 ml of tetrahydrofuran at a temperature of -30 to 20 C. over a period of 30 minutes, after which the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, hydrochloric acid was added to the reaction mixture at 0 C, and then the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium carbonate and with a saturated aqueous solution of sodium chloride, in that order, and then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 6:1 to 5:1 by volume as the eluent, to give 7.0 g of the title compound having Rf=0.50 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
With hydrogenchloride; sodium hydroxide; In dichloromethane;
EXAMPLE 3 2-(1-Piperazinyl)pyridine-3-carboxaldehyde A solution of 2-chloro-3-cyanopyridine (VII; 2.0 g, 0.01 mole) in methylene chloride was treated dropwise with a 1M solution of DABAL-H in methylene chloride (0.03 mole, 33 mL) at -78. The solution turned from a colorless to a bright yellow-orange color during the addition, and the stirring was continued for 3 hr at -78. The mixture was treated with 3N HCl (75 mL) which rapidly warmed the reaction to -10. The rate of addition was regulated so as to maintain the reaction temperature below 0. The solution was treated dropwise with 10% sodium hydroxide solution which formed a bright yellow emulsion which was filtered through sintered glass. The collected aluminum salts were exhaustively washed with methylene chloride, filtered, and the filtrate dried (MgSO4). Concentration of the organic solution in vacuo gave a yellow solid which was purified by Kugelrohr distillation (60/0.4 Torr.) affording 0.46 g (33%) of 2-chloro-3-pyridinecarboxaldehyde (VI) as a white solid, m.p. 48.
In a nitrogen atmosphere, 121 mL of 1.01 M diisobutylaluminium hydride-hexane solution was dropwise added to toluene (280 mL) solution of 13.9 g of 2-chloronicotinonitrile at 0C, and stirred at 0C for 1 hour. Ice and 420 mL of 2 N hydrochloric acid were added in that order at 0C to the reaction liquid, and stirred at room temperature for 1 hour. The reaction liquid was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure to obtain 10.4 g of crude 2-chloropyridine-3-carbaldehyde. In a nitrogen atmosphere, 1.54 g of 60 % sodium hydride (oily) was added to tetrahydrofuran (80 mL) solution of 7.7 mL of triethyl phosphonoacetate at 0C, and stirred at 0C for 20 minutes. Tetrahydrofuran (80 mL) solution of 5.48 g of the compound obtained was added to the reaction liquid at 0C, and stirred at 0C for 1 hour. Aqueous saturated ammonium chloride solution was added to the reaction liquid, heated up to room temperature, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was crystallized (hexane/ethyl acetate), separated and purified to obtain 7.14 g of the entitled compound as a pale yellow solid.
With cesium fluoride; In dimethyl sulfoxide; at 90℃; for 2h;
General procedure: To a solution of 2,3-dichloropyridine(1.00 g, 6.76 mmol) in DMSO (33.8 ml) was added CsF (2.053 g, 13.51mmol) at room temperature. The mixture was stirred at 110 C under air for 20h. The mixture was quenched with water at room temperature and extracted withEtOAc. The organic layer was separated, washed with water and brine, dried overNa2SO4 and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, eluted with EtOAc in hexane) togive 3-chloro-2-fluoropyridine (0.639 g, 4.86 mmol, 71.9 %) as colorlessoil. Thecompound 3B'-8B' were prepared in amanner similar to that described for 2B'.
With hydrazine; In ethanol; at 170℃; for 0.166667h;Microwave irradiation;
Example 8; [00146] Compound 7 (1.4 mmol) was dissolved in EtOH (10 mL) in a microwave tube, to which 5 equivalent of NH2NH2 was added, and the reaction mixture was heated by microwave irradiation for 10 min at 170aC. Evaporated the solvent to obtain the compound 8 in quantitative yield.
47%
With hydrazine hydrate; caesium carbonate;copper(l) iodide; 1,10-Phenanthroline; In N,N-dimethyl-formamide; at 60℃;
2-Chloronicotinonitrile (0.75 g, 5.30 mmol), cupper iodide (I) (50 mg, 0.05 mmol), cesium carbonate (2.59 g, 7.96 mmol) and 1,10-phenanthroline (96 mg, 0.53 mmol) were suspended in 20 mL of dimethylformamide. Hydrazine hydrate (1.6 mL, 31.83 mmol) was added and the mixture was stirred at 60C overnight. The mixture was cooled to room temperature, water was added and the aqueous phase was extracted with dichloromethane (x3). The combined organic layers were dried with magnesium sulphate, filtered and evaporated. The crude was purified by column chromatography using the SP1 Purification system (methanol-dichloromethane gradient) to yield 0.34 g (2.51 mmol, 47%) of the title compound as a yellow solid. Purity:100%. 1H NMR (200 MHz, DMSO-d6) delta ppm 11.91 (1 H, br. s.), 8.33 (1 H, dd, J=4.3, 1.6 Hz), 8.10 (1 H, dd, J=7.8, 1.6 Hz), 6.94 (1 H, dd, J=7.8, 4.7 Hz), 5.55 (2 H, s). LRMS: m/z 135 (M+1).
With hydrazine hydrate; In ethanol; at 60℃;
In a round bottom flask 5g (36mmol) of 2-chloronicotinonitrile and 6ml (38.25mmol) hydrazine hydrate were mixed in ethanol. Reaction mixture was refluxed for 3-4h and the reaction completion as well as formation of desired product was confirmed by TLC. After completion of reaction ethanol was eliminated under reduced pressure with the help of rota-evaporator. Thus obtained yellow solid was washed with ice cold water [53].
Acetic acid (826 mL) was added to 2-chloronicotinonitrile (250 g) and mixture was refluxed for 48 h. The reaction mass was poured in ice-water mixture. The precipitate obtained was filtered washed with water and dried to obtain 2-hydroxy-nicotinonitrile. Yield: 95 %; *H NMR (300 MHz, DMSO-d6): delta 12.57 (s, 1H), 8.16 (dd, J=3, 6Hz, 1H), 7.80 (dd, J=3, 6Hz, 1H), 6.37 (t, 1H); MS (ES): m/z 121.
68%
With acetic acid; at 120℃; for 8h;
Acetic acid (20 mL) was added in three portions to 2-chloronicotinonitrile (1.38 g, 10 mmol) under stirring at room temperature. Then, the temperature raised to 120 C, and kept for 8 h. After cooled to room temperature, the resulting precipitation was filtered. 2-hydroxynicotinonitrile was obtained as white needle crystal. Yield: 68%, 1H NMR (400 MHz, CDCl3): delta: 10.12 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 6.34 (m, 1H).TOF MS (EI+): C6H4N2O, found 121.03. Mp: 224-225 C.
With acetic acid; at 125℃; for 8h;
A mixture of 2-chloronicotinonitrile (1.38 g,10 mmol) and acetic acid (20 mL) was heated to 125 C and kept for 8 h, the mixture was used in the next step without further disposal.
With caesium carbonate In toluene at 90℃; for 16h;
27.A
An oven dried round bottom flask was purged with argon then charged with 2- chloronicotinonitrile (277 mg, 2.0 mmol), azetidin-2-one (142 mg, 2.0 mmol), Palladium dibenzylideneacetone (115 mg, 0.1 mmol), Xantphos (174 mg, 0.3 mmol) and cesium carbonate (1.3g, 4.0 mmol) followed by toluene (10 mL). The suspension was heated at 90 0C for 16 hours (overnight). After cooling, the yellow suspension was filtered through a pad of celite and the filter cake was rinsed with CH2Cl2. The filtrate was concentrated and subjected to flash chromatography on silica gel using 5% MeOH:95% CH2Cl2 to give a yellow solid. Yield: 100 mg (28.9%) 1H-NMR (400 MHz, DMSO-d6) δ 8.65 (dd, IH, J = 1.6 Hz, 3.2 Hz), 8.30 (dd, IH, J = 6.0 Hz, 2.0 Hz), 7.35 (m, IH), 3.88 (t, 2H, J = 5.2 Hz), 3.18 (t, 2H, J = 5.2 Hz).
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 90℃;
With copper(l) iodide; caesium carbonate; at 70℃; for 4h;
To a stirred mixture of the pyridine 51a (2.00 g, 1.0 eq), the alcohol 51b (1.43 mL, 1.05 eq), CuI (0.05 g, 0.02 eq) is added Cs2CO3 (10.3 g, 2.2 eq) and heated at 70 C. during4 h. The reaction mixture is cooled down to RT, poured into H2O (300 mL) and allowed to stand for 1 h until precipitation. The suspension is filtered, triturated with Et2O/Hex (1:1), dried with toluene azeotrope to give 51c (2.0 g, 70%).
50%
With caesium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In toluene; at 80℃; for 24h;Inert atmosphere;
2- Chloro 3-pyridine carbonitrile (1, 2.0 g, 1 equiv.), Cs2C03 (14.2 g, 3 equiv.) and <strong>[623-50-7]ethyl glycolate</strong> (1.5 mL, 1.2 equiv.) were placed in a flask under inert atmosphere. Dry toluene and DBU (4.3 mL, 2 equiv) were added and the suspension was heated at 80 C for 24 h with vigorous stirring. The reaction mixture was cooled to RT, and then water and EtOAc were added. The organic layer was seperated and was washed with water before being dried over anhydrous Na2S04 and concentrated in vacuo. Purification was done by column chromatography on silica gel using 10-40% EtOAC: hexane as a mobile phase to get product 2 (1.5 g, 50%) as a white solid. *H NMR (CDC13, 400 MHz): delta 8.51 (dd, / = 5.0, 2.0 Hz, 1H), 7.96 (dd, / = 8.0, 2.0 Hz, 1H), 7.23-7.28 (m,1H), 4.44 (q, / = 7.0 Hz, 2H), 4.01 (br, s, 2H), 1.44 (t, / = 7.0 Hz, 3H); ESI-MS: nt/z 229.05 [M+Na]+
40%
With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 75℃; for 20h;Inert atmosphere;
2-Chloro-3-pyridinecarbonitrile, 1 , (4.0Og, 28.9mmol), Cs2CO3 (28.2g, 86.6mmol) and <strong>[623-50-7]ethyl glycolate</strong> (3mL, 31.7mmol) were placed in a flask under Ar(g). Dry NMP was added, and the suspension was heated at 75C for 2Oh with vigorous stirring. The reaction mixture was cooled to rt, whereupon water (200 mL) and Et2theta (3 x 10OmL) were added. The organic layers were combined, washed with water (3 x 15mL) before being dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 15-40% EtOAc/Hex) gave 2 (2.41 g, 1 1 Jmmol, 40%) as a white solid.1H NMR (400MHz, CDCI3) deltaH: 8.51 (dd, J=5.0, 2.0Hz, 1 H), 7.96 (dd, J=8.0, 2.0Hz, 1 H), 7.23-7.28 (m, 1 H), 4.44 (q, J=7.0Hz, 2H), 4.01 (br. s., 2H), 1.44 (t, J=7.0Hz, 3H).MS (ES+) 229 (100%, [M+Na]+).
In N,N-dimethyl-formamide; at 120 - 125℃; for 18h;Product distribution / selectivity;
Comparative Example 2 In 86.2 g of dimethylformamide solution containing 32.1 g of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 36.3 g of 2-chloro-3-cyanopyridine was added, the mixture was reacted at 120 to 125 C for 18 hours under a nitrogen atmosphere. The reaction solution was concentrated under a reduced pressure. The solution was subjected to after-treatments in the same manner as in Example 3, and then measured with the HPLC. 2-(4-Methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine was generated in 40.9 % yield based on <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>.
With sodium hydroxide; potassium iodide; triethylamine; In N-methyl-acetamide; nitrogen; water; ethyl acetate;
Example 7 Preparation of Piperazine Derivative To 11 ml of dimethylformamide were added 5.51 g (31.3 mmol) of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> obtained in Example 6, 4.47 g (31.3 mmol) of 2-chloro-3-cyanopyridine, 4.1 g (31.3 mmol) of triethylamine and 5.20 g (31.3 mmol) of potassium iodide, and the resulting mixture was reacted at 125 to 130 C. for 24 hours in nitrogen gas atmosphere. Next, triethylamine and dimethylformamide were distilled off from the reaction mixture under reduced pressure, and thereafter 20 ml of water and 25 ml of ethyl acetate were added to the resulting mixture. The pH of the reaction mixture was adjusted to 8 to 9 with a 10% aqueous sodium hydroxide. The mixture was allowed to separate into two layers. Thereafter, the aqueous layer was extracted twice with 30 ml of ethyl acetate, and the organic layers were combined together. The combined organic layer was washed with 5% aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was crystallized from petroleum ether, to give 3.14 g of pale yellow 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine (yield based on <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>: 36%, melting point: 65.7 to 66.8 C.). Its HPLC purity was 97.1%.
With potassium fluoride; In dimethyl sulfoxide; at 150℃; for 2h;Inert atmosphere; Large scale;
To a 300 L reactor was added 2-chloronicotinonitrile (13.86 kg, 100 mol), <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> (18.51 kg, 105 mol), potassium fluoride (17.42 kg, 300mol), dimethyl sulfoxide (DMSO) (100L), replaced with nitrogen three times, heated to 150 C, stirred for 2 hours. The reaction was completed by TLC, and direct distillation was carried out, and ethyl acetate 60 L was added to the residue. After centrifugation, 20 L of methanol, oxalic acid (12.6 kg, 100 mol) was added to the filtrate, and the mixture was stirred at 15-25 C for 6 hours, and filtered to give a pale yellow solid, 36.5 kg, yield 99%.
benzyl 3-cyano-3',6'-dihydro-2,4'-bipyridine-1'(2'H)-carboxylate 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ol complex[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); at 80℃; for 16.0h;
[1247] The product from Example 58B (200 mg, 0.58 mmol), potassium carbonate (241 mg, 1.75 mmol), PdCl2dppf (29 mg, 0.035 mmol), and 2-chloro-3-cyanopyridine (85 mg, 0.61 mmol) were combined in degassed N,N-dimethylformamide (4 mL). The reaction mixture was heated at 80 C. for 16 hours, allowed to cool to 23 C., diluted with water, dichloromethane, and the layers separated. The aqueous phase was extracted with dichloromethane (2×). All the dichloromethane phases were combined, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (50% ethyl acetate:hexanes) to provide the title compound sufficiently pure to carry on in further reactions (323 mg, 78% yield). 1H NMR (300 MHz, CDCl3) delta1.13 (s, 12H), 2.74 (br s, 2H), 3.75 (dd, 2H, J=6 Hz), 4.26 (m, 2H), 5.19 (s, 2H), 6.57 (br m, 1H), 7.32 (m, 6H), 7.98 (dd, 1H, J=1.8, 7.8 Hz), 8.76 (dd, 1H, J=1.8, 4.5 Hz); MS (ESI) m/e 320 (M+H)+.
78%
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In DMF (N,N-dimethyl-formamide); at 80℃; for 16.0h;
The product from Example 58B (200 mg, 0.58 mmol), potassium carbonate (241 mg, 1.75 mmol), PdCl2dppf (29 mg, 0.035 mmol), and 2-chloro-3-cyanopyridine (85 mg, 0.61 mmol) were combined in degassed N,N-dimethylformamide (4 mL). The reaction mixture was heated at 80 C. for 16 hours, allowed to cool to 23 C., diluted with water, dichloromethane, and the layers separated. The aqueous phase was extracted with dichloromethane (2). All the dichloromethane phases were combined, dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on flash silica gel (50% ethyl acetate:hexanes) to provide the title compound sufficiently pure to carry on in further reactions (323 mg, 78% yield). 1H NMR (300 MHz, CDCl3) ? 1.13 (s, 12H), 2.74 (br s, 2H), 3.75 (dd, 2H, J=6 Hz), 4.26 (m, 2H), 5.19 (s, 2H), 6.57 (br m, 1H), 7.32 (m, 6H), 7.98 (dd, 1H, J=1.8, 7.8 Hz), 8.76 (dd, 1H, J=1.8, 4.5 Hz); MS (ESI) m/e 320 (M+H)+.
A one liter 4NRB flask with stirrer, condenser, temperature controller thermocouple and addition funnel was charged with 2-chloro-3-pyridinecarbonitrile (27.70 g, 0.20 mol) followed by 120 ml of 1-propanol and 80 ml of water. Triethylamine (20.2 g, 0.20 mol) was added in one portion followed by addition of cyclopropylamine (17.10 g, 0.30 mol) over a period of 2 minutes. The reaction mixture was heated at reflux (86-87 C.) and after 2.5 hours, a tlc analysis (silica gel, MTBE mobile phase) showed some product formation. After stirring at reflux for 16 hours, tlc analysis showed a little starting material remaining. HPLC analysis showed 22% starting material-75% 2-(cyclopropylamino)-3-pyridinecarbonitrile. An additional 0.1 mol (10.1 g) of triethylamine (total of 30.3 g, 0.30 mol of triethylamine) and 0.03 mol of cyclopropylamine (1.70 g) were added and the mixture continued to be heated at reflux for another 3 hours. HPLC analysis showed 15% starting material remaining. An additional 4.0 g of cyclopropylamine (total 0.40 mol) was added and the mixture heated at reflux for another 18 hours. At the end of that time HPLC analysis showed 2.9% starting material. Potassium hydroxide (33.6 g, 0.60 mol) was added and the mixture heated to about 40 C. under vacuum for about 15 minutes to remove any volatile amines. The mixture was then heated at reflux for 5 hours under atmospheric pressure to hydrolyze the nitrile to the carboxylic acid. Water (80 ml) was added and n-propanol was distilled off as an azeotrope with water (azeotrope boiling point is 87.7 C., 28.3% water, 71.7% n-propanol). When the distilling head temperature increased to 92 C. the distillation was stopped and the reaction mixture allowed to cool. The reaction mixture was chilled to about 10 C. with an ice-methanol bath and 50 ml (59.2 g) of 37% HCl solution was added dropwise, maintaining the reaction mixture at no more than 25 C. All of the HCl was added and after stirring about 2 minutes longer crystallization of the 2-(cyclopropylamino)-3-pyridine carboxylic acid began and the product set up to a cake. Water (100 ml) was added to break up the solid mass and make the mixture stirrable. After about 30 minutes, the solid was collected by filtration. Additional solid was obtained by concentrating the filtrate. After drying by air aspiration for about 2 hours, the wet-cake solid weighed 23.02 g. HPLC showed 97% 2-(cyclopropylamino)-3-pyridine carboxylic acid and two small unknown impurity peaks of 1.8% and 1.3% concentrations. The solid was dried in a vacuum oven at 50 C. for 65 hours to yield 18.19 g.
With sodium hydroxide In ethanol; water at 20℃; for 17h;
13.i
Example 13: 2-1 F (S)- (2S)-MORPHOLIN-2-YL (phenyl) METHYL] THIO} PVRIDINE-3-CARBONITRILE fumarate o H S CF1 ;, 11 Ph) : N S N N Ph Ph Ph C P, Ph N N I Ph H Ph" Fumarate salt i) To a degassed solution of S- (6)-PHENYL [(2S)-4-(PHENYLMETHYL) morpholin-2- yl] methyl} ethanethioate (5) (0.050 g, 0.147 mmole) and 2-CHLORO-3-CYANOPYRIDINE (0.020 g, 0.146 mmol) in ethanol (1.5 ml) is added a solution of sodium hydroxide in water (2 M, 0.146 ML, 0.293 mmole). The resulting solution is stirred at room temperature FOR-17 hours. The reaction mixture is diluted with methanol and loaded onto an SC10-2 column preconditioned with MeOH. The column is washed with MeOH then basic material is eluted with 2 N NH3/methanol. This ammonia solution is concentrated in vacuo to give 2-([(S)-PHENYL [(2S)-4- (phenylmethyl) morpholin-2-yl] METHYL} THIO) PYRIDINE-3-CARBONITRILE as an off white solid (0.055 g, 93%). LCMS 6 min gradient method, Rt = 2. 8 min, (M+H+) = 402
93%
With sodium hydroxide In ethanol; water at 20℃; for 17h;
13G.i
To a degassed solution of S-{(S)-PHENYL [(2S)-4-(PHENYLMETHYL) morpholin-2-yl] methyl} ethanethioate (5) (0.050 g, 0.147 mmole) and 2-chloro-3-cyanopyridine (0.020 g, 0.146 mmol) in ethanol (1.5 ml) is added a solution of sodium hydroxide in water (2 M, 0.146 ml, 0.293 mmole). The resulting solution is stirred at room temperature FOR-17 hours. The reaction mixture is diluted with methanol and loaded onto an SC10-2 column preconditioned with MeOH. The column is washed with MeOH then basic material is eluted with 2 N NH3/METHANOL. This ammonia solution is concentrated in vacuo to give 2- ( { [ (S)-PHENYL [ (2S)-4- (PHENYLMETHYL) morpholin-2-yl] methyl} thio) PYRIDINE-3-CARBONITRILE as an off white solid (0.055 g, 93%). LCMS 6 min gradient method, Rt = 2.8 min, (M+H+) = 402
93%
With sodium hydroxide In ethanol; water at 20℃; for 17h;
13G.i
To a degassed solution of S-{(S)-phenyl [(2S)-4-(phenylmethyl) morpholin-2-yl] methyl} ethanethioate (5) (0.050 g, 0.147 mmole) and 2-chloro-3-cyanopyridine (0.020 g, 0.146 mmol) in ethanol (1.5 ml) is added a solution of sodium hydroxide in water (2 M, 0.146 ml, 0.293 mmole). The resulting solution is stirred at room temperature for-17 hours. The reaction mixture is diluted with methanol and loaded onto an SC10-2 column preconditioned with MeOH. The column is washed with MeOH then basic material is eluted with 2 N NH3/methanol. This ammonia solution is concentrated in vacuo to give 2- (I [ (S)-phenyl [ (2S)-4- (phenylmethyl) morpholin-2-yl] methyl} thio) pyridine-3-carbonitrile as an off white solid (0.055 g, 93%). LCMS 6 min gradient method, Rt = 2.8 min, (M+H+) = 402
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 17h;
To a solution of 2-chloronicotinonitrile (3.0 g, 21.7 mmol) and <strong>[74879-18-8](S)-2-methylpiperazine</strong> (2.17 g, 21.7 mmol) in DMF (10 mL) was added K2C03 (9.0 g, 65.1 mmol). The mixture was stirred at 120 C for 17 h. The solution was diluted with water (20 mL) and extracted with DCM (50 mL x 3). The organic phases were dried (Na2504), filtered, and concentrated in vacuo to afford (S)-2-(3-methylpiperazin-1-yl)nicotinonitrile (3.03 g, 80%) as yellow oil. ESI-MS (EI+, m/z: 203 [M+H].
64%
With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane; In toluene; at 100℃;
Example 41 GENERAL PROCEDURE: PALLADIUM CATALYZED COUPLING TO HETEROARYL CHLORIDE; 2-Chloro-nicotinonitrile (1.0 mmol), (S) -2-methyl piperazine (1.5 mmol), sodium tert- butoxide (1.5 mmol) and tris (dibenzylideneacetone)-dipalladium (0) (0.04 mmol) were added to a screw cap vial. 2, 8, 9-Triisobutyl-2,5, 8, 9-tetraaza-1-phospha-bicyclo [3.3. 3] undecane (0. 08 mmol) was dissolved in toluene (5 mL) and this solution was added to the other reagents. The reaction mixture was stirred at 100 C overnight. The solution was diluted with dichloromethane and washed with water. The organic phase was dried, filtered and concentrated, then purified by flash chromatography in 10% (2M ammonia in methanol) in dichloromethane to yield the desired product.
64%
With sodium t-butanolate; 2,8,9-tris(2-methylpropyl)-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane;tris-(dibenzylideneacetone)dipalladium(0); In dichloromethane; toluene; at 100℃;
EXAMPLE 9 General Procedure: Palladium Catalyzed Coupling to Heteroaryl Chloride 2-Chloro-nicotinonitrile (1.0 mmol), (S)-2-methyl piperazine (1.5 mmol), sodium tert-butoxide (1.5 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (0.04 mmol) were added to a screw cap vial. 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (0.08 mmol) was dissolved in toluene (5 mL) and this solution was added to the other reagents. The reaction mixture was stirred at 100 C. overnight. The solution was diluted with dichloromethane and washed with water. The organic phase was dried, filtered and concentrated, then purified by flash chromatography in 10% (2M ammonia in methanol) in dichloromethane to yield the desired product. In this manner the following compounds were synthesized: Example Structure Name Yield 9.1 2-[(3S)-3-methylpiperazin-1-yl]nicotinonitrile 64%1H 1.03(d, J=6.3 Hz, 3H); 1.73(s, broad, 1H); 2.59(dd, J=12.9, 10.2 Hz, 1H); 2.94(m, NMR 4H); 4.16(m, 2H); 6.64(dd, J=7.8, 4.8 Hz, 1H); 7.66(dd, J=7.8, 2.1 Hz, 1H); 8.23(dd, J=4.8, 2.1 Hz, 1H).
With sodium carbonate In isopropyl alcohol at 80 - 90℃; for 8h;
153A
To a 250-mL, round-bottomed flask containing a large magnetic stir bar were added 2- chloro-3-cyanopyridine (1.39 g, 10.0 mmol), 2-methoxyphenylboronic acid (1.82 g, 12.0 mmol), and dichlorobis(triphenylphosphine)palladium(II) (351 mg, 0.50 mmol). Isopropyl alcohol (50 mL) and 2M sodium carbonate solution (50 mL) were added. The flask was stoppered and immersed in an oil bath heated to 80-90 C. The biphasic mixture was stirred vigorously and heated for 8 hours. After cooling to room temperature, ethyl acetate (50 mL) was added and the black mixture was transferred to a separatory funnel. The aqueous layer was removed and subsequently extracted with ethyl acetate (3 x 20 mL). The combined ethyl acetate layers were dried over magnesium sulfate, filtered, and concentrated by rotary evaporator to give a brown oil. The product was crystallized from ethyl acetate/hexanes to give 1.38 g (66%) of the title compound as a tan powder.
With potassium fluoride In 1,4-dioxane at 90℃; for 18h;
96.A 2-thiophen-3-ylnicotinonitrile
EXAMPLE 96A 2-thiophen-3-ylnicotinonitrile To an oven-dried, N2-purged, 50 mL, round-bottomed flask containing a magnetic stir bar were added potassium fluoride (767 mg, 13.2 mmol), bis(tri-t-butylphosphine)palladium (51.0 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 2-chloro-3-cyanopyridine (559 mg, 4.00 mmol), and 3-thiopheneboronic acid (819 mg, 6.4 mmol). The flask was sealed with a septum and purged with dry N2 atmosphere. Anhydrous dioxane (4 mL) was added via syringe. The reaction mixture was heated to ~90° C. in an oil bath for 18 hours. After cooling to room temperature, ethyl acetate (15 mL) was added and the mixture was filtered through a pad of silica. The filtrate was concentrated by rotary evaporation to give a brown oil. The product was purified by recrystallization from ethyl acetate/hexanes to give 417 mg (56%) of the title compound. MS (ESI-) m/z 186.9 (M+H)+; 1H NMR (CDCl3) δ 7.30 (7.8, 4.7 Hz, 1H), 7.44 (dd, J=5.3, 2.9 Hz, 1H), 7.88 (dd, J=5.1, 1.4 Hz, 1H), 8.03 (dd, J=8.0, 1.9 Hz, 1H), 8.29 (dd, J=3.0, 1.4 Hz, 1H), 8.82 (dd, J=4.7, 1.7 Hz, 1H).
56%
With potassium fluoride In 1,4-dioxane at 90℃; for 18h;
165A
To an oven-dried, N2-purged , 50 mL, round-bottomed flask containing a magnetic stir bar were added potassium fluoride (767 mg, 13.2 mmol), bis(tri-t-butylphosphine)palladium (51.0 mg, 0.10 mmol), tris (dibenzylideneacetone)dipalladium mg, 0.05 mmol), 2-chloro-3- cyanopyridine (559 mg, 4.00 mmol), and 3-thiopheneboronic acid (819 mg, 6.4 mmol). The flask was sealed with a septum and purged with dry N2 atmosphere. Anhydrous dioxane (4 mL) was added via syringe. The reaction mixture was heated to - 90 C in an oil bath for 18 hours. After cooling to room temperature, ethyl acetate (15 mL) was added and the mixture was filtered through a pad of silica. The filtrate was concentrated by rotary evaporator to give a brown oil. The product was purified by recrystallization from ethyl acetate/hexanes to give 417 mg (56%) of the title compound as a beige solid. MS (ESI-) m/z 186.9 (M+H)
EXAMPLE-5 Preparation of 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1-a] pyrido{2,3-c} [2]Benzazepine of Formula 17: 1-Methyl-3-phenylpiperazine (50.0 g, 0.284 mol) was heated with 2-chloro-3-cyanopyridine (39.35 g, 0.284 mol) in the presence of potassium fluoride (49.51 g, 0.852 mol) and N,N-dimethylformamide (750.0 ml) as a solvent for 30.0 hrs at 148-154° C., followed by quenching with water and extraction with ethyl acetate gave 1-(3-cyanopyridyl-2-)-<strong>[5271-27-2]4-methyl-2-phenylpiperazine</strong> (70.0 g). 1-(3-Cyanopyridyl-2)-<strong>[5271-27-2]4-methyl-2-phenylpiperazine</strong> on hydrolysis with saturated alcoholic potassium hydroxide solution (850.0 ml) at 80-85° C. followed by extraction with chloroform gave 1-(3-carboxypyridyl-2)-<strong>[5271-27-2]4-methyl-2-phenylpiperazine</strong> (20.0 g).
2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-pyridin-3-yl]methoxy]nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With sodium hydride In N,N-dimethyl-formamide at 0 - 30℃; for 3h;
79 Reference Example 79
To a mixture of [6-(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridylmethanol (4.01 g), 2-chloro-3-cyanopyridine (1.79 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60%, oil, 0.62 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.72 g, 92%) of 2-[[6-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118 DEG C.
[4-[[2-(furan-2-yl)-5-methyl-4-oxazolyl]methoxy]phenyl]methanol[ No CAS ]
[ 6602-54-6 ]
2-[4-[[2-(furan-2-yl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With sodium hydride In N,N-dimethyl-formamide at 0 - 30℃; for 3h;
89 Reference Example 89
To a mixture of [4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methanol (4.14 g), 2-chloro-3-cyanopyridine (1.91 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60%, oil, 0.66 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.65 g, 87%) of 2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzyloxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals.melting point: 135-136 DEG C.
2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium hydride In N,N-dimethyl-formamide at 0 - 30℃; for 1.5h;
137 Reference Example 137
To a mixture of [3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolyl]methanol (2.00 g), 2-chloro-3-cyanopyridine (1.16 g) and N,N-dimethylformamide (60 mL) was gradually added sodium hydride (60%, oil, 335 mg) under ice-cooling. After stirring the reaction mixture at room temperature for 90 min., water was added to the reaction mixture. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (2.61 g, 96%) of 2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 139-140 DEG C.
2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With sodium hydride In N,N-dimethyl-formamide at 0 - 30℃; for 15h;
85 Reference Example 85
To a mixture of 3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl alcohol (4.00 g), 2-chloro-3-cyanopyridine (1.62 g) and N,N-dimethylformamide (40 mL) was added sodium hydride (60%, oil, 515 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained crystals were recrystallized from ethyl acetate-hexane to give 2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinonitrile as pale-yellow crystals (4.50 g, 90%). melting point: 117-118 DEG C.
2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With sodium hydride In N,N-dimethyl-formamide at 0 - 30℃; for 5h;
113 Reference Example 113
To a mixture of [3-(5-methyl-2-phenyl-4-thiazolylmethoxy)-5-isoxazolyl]methanol (1.80 g), 2-chloro-3-cyanopyridine (0.83 g) and N,N-dimethylformamide (80mL) was added sodium hydride (60%, oil, 0.26 g) under ice-cooling. The reaction mixture was stirred at room temperature for 5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (2.08 g, 86%) of 2-[[3-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinonitrile from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 135-136 DEG C.
2-[4-[[3-methyl-1-(pyridin-2-yl)-1H-pyrazol-4-yl]methoxy]benzyloxy]nicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With sodium hydride In N,N-dimethyl-formamide at 0 - 30℃; for 3h;
132 Reference Example 132
To a mixture of [4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]phenyl]methanol (2.00 g), 2-chloro-3-cyanopyridine (1.00 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.30 g) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (2.48 g, 92%) of 2-[4-[[3-methyl-1-(2-pyridyl)-1H-pyrazol-4-yl]methoxy]benzyloxy]nicotinonitrile. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 108-109 DEG C.
3-cyano-2-[4-[[2-(furan-2-yl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With sodium hydride In N,N-dimethyl-formamide at 1 - 30℃; for 15h;
146 Reference Example 146
To a mixture of [4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxyphenyl]methanol (5.00 g), 2-chloro-3-cyanopyridine (2.65 g) and N,N-dimethylformamide (150 mL) was added sodium hydride (60%, oil, 0.70 g) at room temperature and the mixture was stirred for 15 hrs. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give crystals (6.60 g, yield 99%) of 3-cyano-2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]pyridine. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 137-138 DEG C.
2-(4'-methyl-1'-piperazinyl)-3-cyano-pyridine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
In toluene;
EXAMPLE 1 Preparation of 2-(4'-methyl-1'-piperazinyl)-3-cyanopyridine hydrochloride The following mixture is placed into a 100 ml flask: 10 g of 2-chloro-3-cyanopyridine, 30 to 40 ml of toluene and 10 ml of 2-methylpiperazine. Said mixture is refluxed for 4 hours. The reaction mixture is evaporated under reduced pressure. The residue is taken up with water, rendered strongly alkaline with NaOH and extracted with CHCl3. The extract is dehydrated and evaporated under reduced pressure to remove the excess of 1-methylpiperazine. The residue is then extracted with acetone and the product is precipitated as a dihydrochloride by passage of gaseous HCl through the acetone solution. Yield: 60%; m.p. 221-222,5C. Elementary analysis: % Calculated: C; 55,46; H; 6,30; N; 23,48. % Found: C; 55,30; H; 6,53; N; 23,31.
With potassium fluoride; In water; N,N-dimethyl-formamide;
1. 1-(3-cyanopyridyl-2)-<strong>[5271-27-2]2-phenyl-4-methylpiperazine</strong>. 17.43 g (0.3 mol) dry potassium fluoride is added to a solution of 13.85 g (0.1 mol) 2-chloro-nicotinonitrile and 17.62 g (0.1 mol) <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> in 250 ml dry DMF and the suspension is heated at 140° C under a nitrogen atmosphere for 20 hours. After cooling, the reaction mixture is poured out into 1,250 ml water. The aqueous phase is extracted four times with 300 ml ethyl acetate, after which the combined organic extracts are washed with 100 ml water. After drying, the ethyl acetate extracts are evaporated. The crude oil may be used as such for the following step. The nitrile obtained may however also be purified by column chromatography on SiO2, with hexane-acetone (95:5). In this way, 21.9 g (79percent) pure 1-(3-cyanopyridyl-2)-<strong>[5271-27-2]4-methyl-2-phenylpiperazine</strong> is obtained; the substance crystallizes from petroleum ether 40/60; melting point 66.5°-67.5° C. Rf in toluene: ethanol (6:4) = 0.74 (SiO2) Rf in toluene: acetone (6:4) = 0.27 (SiO2).
With caesium carbonate In dimethyl sulfoxide at 50℃; for 0.5h;
10.A
A mixture of 2-chloro-nicotinonitrile (10.30 g, 74.4 mmol), 1H-[1,2,4]Triazole (5.36 g, 77.6 mmol), and Cs2CO3 (25.28 g, 77.6 mmol) in DMSO (30 mL) was stirred at 50° C. for C for 30 min. The resulting off-white semisolid was partitioned with water (600 mL) and DCM (600 mL), and the aq layer was extracted with DCM (2×200 mL). The combined organic layers were dried (Na2SO4), concentrated, and put under vacuum at 90° C. to remove the bulk of DMSO. The resulting white solid was briefly triturated with refluxing diethyl ether (100 mL), allowed to cool to rt, and filtered. The filter cake was washed with ether (3×50 mL) and dried to yield the title compound as white fluffy needles (11.37 g, 89%).
Step A: 2-(1-Methyl-1H-indazol-5-yloxy)-nicotinonitrile (3n): <strong>[756839-14-2]1-Methyl-1H-indazol-5-ol</strong> (1n) (synthesised as described in Example 94) (0.10 g, 0.68 mmol) and 2-chloro-nicotinonitrile (2n) (0.11 g, 0.81 mmol) were suspended in DMSO (2 mL). The reaction mixture was heated to 110 C. for 18 hours. The reaction mixture was diluted with water and extracted into EtOAc. The combined organics were dried, Na2SO4 and concentrated under reduced pressure to afford the crude product.
With trifluorormethanesulfonic acid; In dichloromethane; at -10℃; for 0.5h;
10,8 g of trifluoromethane sulfonic acid was added dropwise to a mixture of 2 g (10 mmol) 2-chloropyridine-3-carbonitrile and 2,17 g (10 mmol) 2-methyl-1-phenyl-propan-2-ol in 40 ml dichloromethane at -10C. After 30 minutes the reaction mixture was poured onto sodium hydrogencarbonate solution, the organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were evaporated and the residue was purified via silica gel chromatography with heptane/ethyl acetate mixtures to yield 1,42 g (36 %) of the title compound as a colorless solid. 1H-NMR(CDCI3, delta in ppm): 8,5 (s, broad, 1 H); 7,75 (d, 1 H); 7,4 (m, 2H); 7,2 (m, 2H); 6,85 (d, 1 H); 2,9 (s, very broad, 2H); 1 ,4 (s, very broad, 3H); 1 ,3 (s, very broad, 3H).
With caesium carbonate; In dimethyl sulfoxide; at 95℃; for 18h;
Example 4Synthesis of 5-(3-(lH-tetrazol-5-yl)pyridin-2-yloxy)-lambdar-(3-chlorobenzyl)-2- fluorobenzamide Step 1 : To 2-chloronicotinonitrile (900 mg, 6.50 mmol), <strong>[51446-30-1]2-fluoro-5-hydroxybenzoic acid</strong> (1.0 g, 6.4 mmol) and cesium carbonate (4.2 g, 13 mmol) was added DMSO (7 mL). The mixture was heated to 95 0C for 18 hours in a sealed tube. The mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with 6 N HCl (pH ~ 2) and then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 5-(3-cyanopyridin-2-yloxy)-2-fluorobenzoic acid. MS m/z 257 = [M+H]+. Calc'd for C3H7FN2O3: 258.21.
Example 43.1: 2-((R)-3-Methyl-piperazin-l -yl)-nicotinonitrile. A mixture of (R)-2-methyl piperazine (507 mg, 5.06 mmol), 2-chloro-nicotinonitrile (1.05 g, 7.6 mmol), triethylaniine (2 mL, 14.3 mmol) and tetrahydrofuran (8 mL) was heated at 80° C overnight. The reaction mixture was cooled to room temperature and aqueous saturated sodium bicarbonate (75 mL) was added. The mixture was extracted with dichloromethane (3x200 mL) and the combined organic layer washed with water (75 mL), washed with brine (75 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel using dichloromethane: 2M ammonia in methanol (95:5) to give 2- ((R)-3-methyl-piperazin-l-yl)-nicotinonitrile (964 mg, 94 percent). 1H NMR (300 MHz, CDCl3): delta(ppm) 8.34 (dd, IH), 7.77 (dd, IH), 6.74 (m, IH), 4.27 (m, 2H), 3.08 (m, 4H), 2.70 (m, IH), 1.15 (d, 3H).
With caesium carbonate In acetonitrile at 80℃; for 3h;
230 Preparation 230N-(3-Cyanopyridin-2-yl)-N-methylmethanesulfonamide
Preparation 230N-(3-Cyanopyridin-2-yl)-N-methylmethanesulfonamide10723] To a solution of 2-chloronicotinonitrile (10 g, 71.9 mmol) in MeCN (200 mE) was added cesium carbonate (32.5 g, 99 mmol) followed by N-methylmethanesulfonamide (9.42 g, 86 mmol) and the reaction was heated to 80° C. for 3hours. The reaction was cooled, concentrated in vacuo and partitioned between EtOAc and water. The organic layer was collected, dried over sodium sulfate and concentrated in vacuo. The residue was purified using silica gel colunm chromatography eluting with 50% EtOAc in hexanes to afford the title compound (12.9 g, 85%). ‘H NMR (400 MHz, DMSOd 5): ö ppm 3.21 (s, 3H), 3.28 (s, 3H), 7.62 (m, 1H), 8.45 (d, 1H), 8.77 (d, 1H). MS mlz 212 [M+H]
72%
With 1-methyl-2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine In dichlorobenzene, 1,2- at 100℃; for 1h;
57
Example 57; N-Methyl-./V-(3-((2-(2-oxoindolin-5-ylamino)-5-(trifluoromethyl)pyridin-4- ylamino)methyl)pyridin-2-yl)methanesulfonamide; iV-(3-Cyanopyridin-2-yl)-iV-methylmethanesulfonamide; PdjKdbab XantPhos MTBD To a 50 mL round bottom flask charged with 2-chloronicotinonitrile (1 g, 7.2 mmol), Pd2(dba)3 (662 mg, 0.72 mmol), XantPhos (418 mg, 0.72 mmol) were added 1,2- dichlorobenzene (10 mL) and MTBD (3.11 mL, 21.7 mmol). The resulting mixture was purged with argon, followed by heating to 100°C for 1 h. The reaction mixture was poured into 40 mL of buffer (pH 4) and the layers were separated. The organic layer was washed one additional time with the same volume of buffer. The volatiles were dried over Na2SO4 and concentrated. The crude was further purified by flash column chromatography [SiO2, CHCl3/MeOH (95:5)] to afford 1. Ig (5.2 mmol, 72%) ofN-(3-cyanopyridin-2-yl)-N-methylmethanesulfonamide.1H νMR (400 MHz, CDCl3) δ 8.66 (dd, J= 1.9, 4.9 Hz, 1H), 8.06 (dd, J= 1.9, 7.8 Hz, 1H), 7.39 (dd, J= 4.9, 7.8 Hz, 1H)), 3.41 (s, 1H), 3.20 (s, 1H).
53.8%
With caesium carbonate In acetonitrile at 80℃; for 8h;
A.2 Step 2: N-(3-cyanopyridin-2-yl)-N-methylmethanesulfonamide
To a stirred solution of 2-chloronicotinonitrile (Aldrich, 100.0 g, 1.0 eq) in ACN (1.0 L) was added cesium carbonate (704 g, 3.0 eq) followed by N- methylmethanesulfonamide (118 g, 1.5 eq). The contents were heated at 80°C for 8 h while monitoring by TLC. After completion, the solution was cooled to rt and filtered. The filtrate was concentrated and the resulting residue was diluted with DCM (1.0 L) and water (500 mL). The layers were separated and the organic layer was washed with brine (250 mL), dried over anhydrous sodium sulphate, filtered and concentrated to obtain the crude product. The crude product was triturated with mixture of diethyl ether (150 mL), DCM (10 mL) and methanol (10 mL) and filtered to obtain N-(3-cyanopyridin-2-yl)-N- methylmethanesulfonamide as a brown solid (82 g, 53.8%).
46%
With caesium carbonate In acetonitrile at 25 - 80℃; for 8h;
1 Preparation of N-(3-Aminomethyl-pyridin-2-yl)-N-methyl-methanesulfonamide acetate (B5)
Step 1. Preparation of N-(3-cyano-pyridin-2-yl)-N-methyl-methanesulfonamide (B5-1): A solution of 2-chloro-3-cyano-pyridine (10 g, 72.4 mmol) in acetonitrile (200 mL) at 25° C. was treated with N-methyl-methanesulfonamide (14 g, 128.2 mmol) and Cs2CO3 (33 g, 101.2 mmol). The reaction mixture was slowly heated to 80° C. and maintained at 80° C. for 8 hours. The reaction mixture was then cooled to 25 C, filtered through a Celite bed, and concentrated. The resultant residue was treated with water (300 mL) and extracted with EtOAc (3*200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, treated with carbon, and filtered. The filtrate was then concentrated, and the resultant residue was triturated with ether (100 mL). The resultant solids were collected and dried to provide B5-1 as an off-white solid. Yield: 7 g, 46%. 1H NMR (CDCl3) δ: 8.6-8.72 (m, 1H), 8.02-8.12 (d, 1H), 7.3-7.45 (m, 1H), 3.4 (s, 3H) and 3.2 (s, 3H). Mass: (M+1) 212 calculated for C8H9N3O2S. HPLC purity: 99.9%.
Stage #1: H-Gly-NH2 With sodium carbonate In dimethyl sulfoxide at 20℃; for 16h;
Stage #2: 2-chloro-3-pyridinecarbonitrile With potassium fluoride In dimethyl sulfoxide at 120℃; for 4h;
2-(3-Cyano-pyridin-2-ylamino)-acetamide
Glycinamide (8.8 g, 79.4 mmol)and sodium carbonate (4.6 g, 43.3mmol) were suspended in DMSO (200 ml) and stirred atambient temperature for 16 h. The solid was removed by filtration through Celite, the filtrate treated with 2-chloronicotinonitrile (10.0 g, 72.2 mmol) and potassium fluoride (10.0 g, 173.3 mmol) and heated at 120 uC for 4 h. The mixture was allowed to cool to ambient temperature then diluted with water (800 ml). The precipitated solid was collected by filtration, washed with dichloromethane (50 ml) and water (50 ml), then triturated with diethyl ether (100 ml), filtered and left to air dry which afforded the title compound as an off-white solid (6.7 g, 53%).
53%
Stage #1: H-Gly-NH2 With sodium carbonate In dimethyl sulfoxide at 20℃; for 16h;
Stage #2: 2-chloro-3-pyridinecarbonitrile With potassium fluoride In dimethyl sulfoxide at 120℃; for 4h;
1 Step 1: 2-(3-Cyano-pyridin-2-ylamino)-acetamide
Following the procedure of Kaspersen, Frans M. et al, Journal of Labelled Compounds and Radiopharmaceuticals (1989), 27(9), 1055-68, glycinamide (8.8 g, 79.4 mmol) and sodium carbonate (4.6 g, 43.3 mmol) were suspended in DMSO (200 ml) and stirred at ambient temperature for 16 h. The solid was removed by filtration through celite, the filtrate treated with 2-chloronicotinonitrile (10.0 g, 72.2 mmol) and potassium fluoride (10.0 g, 173.3 mmol) and heated at 120° C. for 4 h. The mixture was allowed to cool to ambient temperature then diluted with water (800 ml). The precipitated solid was collected by filtration, washed with dichloromethane (50 ml) and water (50 ml), then triturated with diethyl ether (100 ml), filtered and left to air dry which afforded the title compound as an off white solid (6.7 g, 53%). 1H NMR (DMSO-D6, 400 MHz) 8.26 (dd, J=4.9 Hz, 1.8 Hz, 1H), 7.93 (dd, J=7.6 Hz, 1.8 Hz, 1H), 7.40 (s, 1H), 7.12 (t, J=4.9 Hz, 1H), 7.00 (s, 1H), 6.69 (dd, J=7.6 Hz, 4.9 Hz, 1H), 3.34 (s, 2H).
53%
Stage #1: H-Gly-NH2 With sodium carbonate In dimethyl sulfoxide at 20℃; for 16h;
Stage #2: 2-chloro-3-pyridinecarbonitrile With potassium fluoride In dimethyl sulfoxide at 120℃; for 4h;
1
Step 1 : 2-(3-Cvano-pyridin-2-ylamino)-acetamide [00194] Following the procedure of Kaspersen, Frans M. et al, Journal of LabelledCompounds and Radiopharmaceuticals (1989), 27(9), 1055-68, glycinamide (8.8 g, 79.4 mmol) and sodium carbonate (4.6 g, 43.3 mmol) were suspended in DMSO (200 ml) and stirred at ambient temperature for 16 h. The solid was removed by filtration through celite, the filtrate treated with 2-chloronicotinonitrile (10.0 g, 72.2 mmol) and potassium fluoride (10.0 g, 173.3 mmol) and heated at 1200C for 4 h. The mixture was allowed to cool to ambient temperature then diluted with water (800 ml). The precipitated solid was collected by filtration, washed with dichloromethane (50 ml) and water (50 ml), then triturated with diethyl ether (100 ml), filtered and left to air dry which afforded the title compound as an off white solid (6.7 g, 53%). 1H NMR (DMSO-D6, 400MHz) 8.26 (dd, J = 4.9Hz, 1.8Hz, IH), 7.93 (dd, J = 7.6Hz, 1.8Hz, IH), 7.40 (s, IH), 7.12 (t, J = 4.9Hz, IH), 7.00 (s, IH), 6.69 (dd, J = 7.6Hz, 4.9Hz, IH), 3.34 (s, 2H).
With ammonium peroxydisulfate; sulfuric acid; silver nitrate In water at 20℃;
1.1 Step 1: 6-tert-butyl-2-chloro-pyridine-3-carbonitrile
2,2-Dimethylpropanoic acid (50. mL, 870 mmol), 2-chloropyridine-3-carbonitrile (30 g, 220 mmol) and AgNO3 (9.2 g, 54 mmol) were suspended in 10% aq. H2SO4 (300 mL). A solution of ammonium peroxydisulfate (91 g, 430 mmol) and water (480 mL) was added to the mixture dropwise through an addition funnel. The mixture was stirred at room temperature overnight. The pH of reaction mixture was adjusted to 8-9 with 30% NH4OH (250 mL) and the mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (0-25% ethyl acetate/hexanes) to give 6-tert-butyl-2-chloro-pyridine-3-carbonitrile (37 g, 83%) as a clear oil which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 1.29 (s, 9H). ESI-MS m/z calc. 194.1. found 195.0 (M+1)+. Retention time: 1.66 min (3 min run).
83%
With ammonium hydrogen peroxysulfate; sulfuric acid; silver nitrate In water at 20℃;
1.1 Step 1: 6-tert-butyl-2-chloro-pyridine-3-carbonitrile
Suspend 2,2-Dimethylpropionic acid (50.mL, 870mmol), 2-chloropyridine-3-carbonitrile (30g, 220mmol) and AgNO3 (9.2g, 54mmol) in 10% H2SO4 aqueous solution (300mL) in. A solution of ammonium hydrogen peroxysulfate (91 g, 430 mmol) and water (480 mL) was added dropwise to the mixture via an addition funnel. The mixture was stirred at room temperature overnight.The pH of the reaction mixture was adjusted to about 8-9 with 30% NH 4 OH (about 250 mL) and the mixture was extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (0-25% ethyl acetate/hexane),6-tert-butyl-2-chloro-pyridine-3-carbonitrile (37g, 83%) was obtained as a clear oil,It solidified after standing.
38%
Stage #1: 2-chloro-3-pyridinecarbonitrile; Trimethylacetic acid With ammonium peroxydisulfate; sulfuric acid; silver nitrate In water at 20℃; for 36h;
Stage #2: With ammonium hydroxide In water
38
2-Chloronicotinonitrile (2.1 g, 15.2 mmol), pivalic acid (7.7 g, 75.8 mmol) and silver nitrate (0.5 g, 3.0 mmol) were suspended in 10% aqueous H2SO4 (20 ml). Ammonium persulfate (6.9 g, 30.3 mmol) in H2O (40 ml) was added to the mixture. The mixture was stirred at r.t. for 36 h. NH4OH was added until pH=9. The product was extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (Pet. Ether/EtOAc 9:1) to give the title substance in 38% yield.1H NMR (CDCl3) δ 7.91 (d, IH), 7.38 (d, IH), 1.37 (s, 9H).
38%
With ammonium peroxydisulfate; sulfuric acid; silver nitrate In water at 20℃; for 36h;
121
6-tert-Butyl-2-chloronicotinonitrile 2-Chloronicotinonitrile (2.1 g, 15.2 mmol), pivalic acid (7.7 g, 75.8 mmol) and silver nitrate (0.5 g, 3.0 mmol) were suspended in 10% aqueous H2SO4 (20 ml). Ammonium persulfate (6.9 g, 30.3 mmol) in H2O (40 ml) was added to the mixture. The mixture was stirred at r.t. for 36 h. NH4OH was added until pH=9. The product was extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (Pet. Ether/EtOAc 9:1) to give the title substance in 38% yield. 1H NMR (CDCl3) δ 7.91 (d, 1H), 7.38 (d, 1H), 1.37 (s, 9H).
With ammonium peroxydisulfate; silver(I) nitrite; sulfuric acid In water at 18℃; for 1h; Inert atmosphere;
1 Step 1: 6-(tert-butyl)-2-chloronicotinonitrile
To a solution of 2-chloronicotinonitrile (0.20 g, 1.4 mmol) in water (2 mL) was added pivalic acid (0.59 g, 5.8 mmol), sulfuric acid (2.0 mL, 1.4 mmol) and (nitrooxy)silver (59 mg, 0.35 mmol). The mixture was flushed with nitrogen, then a solution of (NH4)2S2O8 (0.66 g, 2.9 mmol) in water (3 mL) was added portionwise. The mixture was stirred at 18°C for 1 hour, then diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give a residue that was purified by silica gel chromatography (petroleum ether / EtOAc = 5:1) to give the title compound.
2-(4-methyl-2-phenylpiperazin-1-yl)pyridine-3-carbonitrile oxalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.7 - 66.8%
Example 1 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate After adding 21.1 g (119.7 mmol) of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 20.0 g (144.4 mmol) of 2-chloro-3-cyanopyridine, and 16.6 g (164.1 mmol) of triethylamine to 42 g of dimethylformamide, the mixture was reacted at 125 to 130 °C for 24 hours under a nitrogen atmosphere. After distilling out triethylamine and dimethylformamide from the reactant solution under a reduced pressure, the residue was added with 32 ml of water and 87 g of ethyl acetate, and then a pH value thereof was adjusted to 8 to 9 with 10 percent aqueous sodium hydroxide solution. After phase-separating the solution, an organic layer was added with 24 g of methanol, and then 15.2 g of oxalic acid. This solution was filtrated to collect crystals, and then the crystals collected were dried to obtain 31.6 g of an objective compound (HPLC content: 86.1 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 61.7 percent). IR (KBr) gamma=3039, 2223, 1733, 1636, 1578, 1567, 1436, 758, 701 cm-11H-NMR (CDC13, 400 MHz) delta ppm: 8.29, 7.77, 6.76 (dd, each 1H); 7.1-7.44 (m, 5H); 5.46 (t, 1H, CHPh); 3.83, 3.59 (m, each H); 2.95 (dd, 1H); 2.65-2.80 (m, 4H); 2.25 (m, 1H); 2.33 (s, 3H, NCH3). Example 2 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate After adding 21.1 g (119.7 mmol) of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 24.0 g (173.2 mmol) of 2-chloro-3-cyanopyridine, and 16.6 g (164.1 mmol) of triethylamine to 42 g of dimethylformamide, the mixture was reacted at 125 to 130 °C for 24 hours under a nitrogen atmosphere. After distilling out triethylamine and dimethylformamide from the reactant solution under a reduced pressure, the solution was added with 32 ml of water and 87 g of ethyl acetate, and then a pH value thereof was adjusted to 8 to 9 with 10 percent aqueous sodium hydroxide solution. After phase-separating the solution, an organic layer was added with 24 g of methanol, and then 15.2 g of oxalic acid. This solution was filtrated to collect crystals, and then the crystals collected were dried to obtain 31.9 g of an objective compound (HPLC content: 92.4 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 66.8 percent). Example 3 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate In 57.3 kg of dimethylformamide solution containing 21.3 kg of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 22.2 kg of 2-chloro-3-cyanopyridine and 15.3 kg of triethylamine were added, the mixture was reacted at 114 to 125 °C for 17 hours under a nitrogen atmosphere. The reaction solution was concentrated under a reduced pressure. The distillated amount was 36 kg. The residue was added with 29.3 kg of water and then a pH value thereof was adjusted to 8.45 with 25 percent aqueous sodium hydroxide solution. This solution was added with 79.2 kg of ethyl acetate, washed with 20 kg of 5 percent sodium chloride solution, and then subjected to a phase separation. An organic layer was added with 23.1 kg of methanol, and then added with 13.9 kg of oxalic acid dihydrate at a temperature of 45 to 48 °C for about 1 hour. The solution was stirred at the temperature for 1 hour, filtrated at around 35 °C to collect crystals, and then the crystals collected were washed with a mixture of 42.2 kg of ethyl acetate and 12.4 kg of methanol. The crystals were dried at around 50 °C under a reduced pressure to obtain 32.65 kg of an objective compound (HPLC content: 90.2 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 66.2 percent).
56.6%
Comparative Example 1 After adding 21.1 g (119.7 mmol) of <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong>, 20.0 g (144.4 mmol) of 2-chloro-3-cyanopyridine, 12.8 g (126.3 mmol) of triethylamine, and 2.0 g (12.0 mmol) of potassium iodide to 42 g of dimethylformamide, the mixture was reacted at 125 to 130 °C for 24 hours under a nitrogen atmosphere. After distilling out triethylamine and dimethylformamide from the reactant solution under a reduced pressure, the residue was added with 32 ml of water and 87 g of ethyl acetate, and then a pH value thereof was adjusted to 8 to 9 with 10 percent aqueous sodium hydroxide solution. After phase-separating the solution, an organic layer was added with 24 g of methanol, and then 15.2 g of oxalic acid. This solution was filtrated to collect crystals, and then the crystals collected were dried to obtain 26.6 g of 2-(4-methyl-2-phenylpiperazin-1-yl)-3-cyanopyridine oxalate (HPLC content: 93.8 percent, the yield from <strong>[5271-27-2]1-methyl-3-phenylpiperazine</strong> was 56.6 percent).
Stage #1: sodium selenide; 2-chloro-3-pyridinecarbonitrile In N,N-dimethyl-formamide at 20 - 70℃; for 2.08333h;
Stage #2: chloroacetonitrile In N,N-dimethyl-formamide at 60 - 70℃; for 2h;
Stage #3: With sodium methylate In methanol; N,N-dimethyl-formamide at 60 - 70℃; for 1h;
15.a
Step a:3-Aminoselenophenor2.3-b1pyridine-2-carbonitrile: To a suspension of sodium selenide (0.9 g, 7.2 mmol, prepared from 0.75 g of selenium as described above) in DMF (7 mL) was added a solution of 2-chloropyridine-3-carbonitrile (1 g, 7.2 mmol) in DMF (3 mL) at rt for 5 min and stirred the mixture at 60-700C for 2 h. Then chloroacetonitrile (0.46 mL, 7.22 mmol) was added dropwise to the reaction mixture and again stirred at 60-700C for 2 h. Then, a solution of sodium methoxide (0.39 g, 7.2 mmol) in methanol (7 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to room temperature (rt) and poured into cold water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried to give the product as a yellow color solid (1.3 g, 81%), mp 208-2100C. 1H NMR (400 MHz, DMSO-d6): δ 8.68 (IH, d, J=4.4 Hz, H-6), 8.47 (IH, d, J=8.4 Hz, H-4), 7.55 (IH, dd, J=8.0, 4.8 Hz, H-5), 7.24 (2H, s, -NH2).
75%
Stage #1: sodium selenide; 2-chloro-3-pyridinecarbonitrile In N,N-dimethyl-formamide at 20 - 70℃; for 2.08333h;
Stage #2: chloroacetonitrile In N,N-dimethyl-formamide at 60 - 70℃; for 2h;
Stage #3: With sodium methylate In methanol; N,N-dimethyl-formamide at 60 - 70℃; for 1h;
31.a
Example 31; Synthesis of (3-chloro-4-fluorophenyl)pyrimidino[4',5'-5,4 selenopheno[2,3-b1pyridin-4- ylamine (compd. No. 31)Step a:3-Aminoselenophenof2,3-b]pyridine-2-carbonitrile: To a suspension of sodium selenide (0.9 g, 7.2 mmol) in DMF (7 mL) was added a solution of 2-chloropyridine-3-carbonitrile (1 g, 7.2 mmol) in DMF (3 mL) at rt for 5 min and stirred the mixture at 60-70°C for 2 h. Then chloroacetonitrile (0.46 mL, 7.22 mmol) was added dropwise to the reaction mixture and again stirred at 60-70°C for 2 h. Then, a solution of sodium methoxide (0.39 g, 7.2 mmol) in methanol (7 mL) was added dropwise and stirring was continued for 1 h at the same temperature. The mixture was allowed to rt and poured into cold water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried to give the product as a yellow color solid (1.2 g, 75%), mp 208-210°C.
With thiourea In ethanol at 120℃; for 0.75h; Sealed tube; Irradiation;
1 5.1.1.2.1. 2-Mercaptonicotinonitrile (9)
To a mixture of 2-chloro-3-cyanopyridine (1.0 g, 7.25 mmol) in ethanol (15 mL) was added thiourea (0.551 g, 7.25 mmol) in a sealed tube. The solution was irradiated at 120 °C (800 W) for 45 min. The solution was cooled to room temperature and the mixture was filtered off and washed with ethanol. The crude solid was purified by column chromatography over silica gel using dichloromethane/petroleum ether (5:5, v/v) as the eluent to give 2-mercaptonicotinonitrile (9) as a yellow powder (0.552 g, 58%); mp 249-250 °C (lit. [10] : 248-250 °C); IR (KBr) νmax (cm-1): 2871, 2226 (CN), 1584, 1489, 1440, 1318, 1236, 1173, 1159, 1079, 1059, 1033, 982, 968, 854, 813, 775, 712; 1H NMR (300 MHz, DMSO-d6): δ 8.13 (dd, 1H, J1 = 2 Hz, J2 = 7 Hz, H-4), 7.95 (dd, 1H, J1 = 2 Hz, J2 = 8 Hz, H-6), 6.67 (dd, 1H, J1 = 7 Hz, J2 = 8 Hz, H-5); 13C NMR (75 MHz, DMSO-d6): δ 171.2 (C-2), 145.5 (C-6), 142.7 (C-4), 116.8 (CN), 116.6 (C-3), 112.4 (C-5); HRMS calcd for C6H5N2S [M + H]+ 137.0173 found 137.0171.
With sodium sulfide In <i>tert</i>-butyl alcohol at 150℃; for 0.333333h; Microwave irradiation;
Multi-step reaction with 2 steps
1: sodium methylate / N,N-dimethyl-formamide / 24 h / 20 °C
2: sodium hydride / tetrahydrofuran; mineral oil / 5 h / Reflux
With thioacetamide; 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran for 5h; Reflux;
With thiourea In butan-1-ol for 4h; Reflux;
11.30 2-benzylisothiazolo[5,4-b]pyridin-3(2H)-one (5e)
General procedure: A mixture of 2-chloronicotinonitrile 6 (1.0g, 7.2mmol) and thiourea (1.81g, 23.8mmol) in n-butanol (40mL) was heated to reflux. Four hours later, the precipitate was filtered, rinsed with n-butanol, and dried in vacuo to afford the 2-mercaptonicotinonitrile 7 (0.91g, 6.7mmol). Then, the compound was dissolved in concentrated H2SO4 (8mL) and heated for 4h. The solution was then cooled to room temperature and adjusted to pH 6 by the addition of KOH to yield a white solid (0.62, 4.1mmol). Without further purification, the solid was dissolved in DCM and reacted with benzyl bromide (0.77g, 4.5mmol) in the presence of K2CO3 (0.62g, 4.5mmol), Et3N (2.1g, 20.4mmol), and a catalytic amount of KI at room temperature for overnight. The organic solvent was removed under reduced pressure. The crude residue was extracted with DCM and washed with water. The organic phase was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a crude residue, which was subjected to purification by flash column chromatography on silica gel to obtain the desired compound 5e (0.54g, 2.23mmol). Yield 55%; 1H NMR (400MHz, CDCl3) δ 8.72-8.78 (m, 1H), 8.32 (d, J=7.82Hz, 1H), 7.35-7.41 (m, 6H), 5.10 (s, 2H); 13C NMR (101MHz, CDCl3) δ 163.7, 162.4, 153.6, 135.8, 134.9, 129.2, 129.0, 128.5, 128.5, 128.0, 120.7, 119.3, 77.4, 77.1, 76.7, 47.5; HRMS m/z calcd for [C13H10N2OS+H]+ 243.0592, found 243.0588
38.1
2-Chloro-3-cyanopyridine (10.0 g) was dissolved in methanol (200 ml), a 28% solution of sodium methoxide in methanol (27.8 g) was added to the solution, and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, and then concentrated under reduced pressure, and the deposited crystals were collected by filtration to obtain a methoxy compound (4.15 g). (2) By using the compound obtained in (1) mentioned above (4.15 g) as a starting material, a dimethyl compound (350 mg) was obtained in the same manner as that of Reference Example 17, (1). (3) By using the compound obtained in (2) mentioned above (350 mg) as a starting material, the title compound (301 mg) was obtained in the same manners as those of Reference Example 3, (3) and (4). MS (ESI) m/z = 210.0 [M+H]+ 1H-NMR (200 MHz, CDCl3) δ (ppm): 1.48 (s, 6H), 2.19-2.28 (m, 2H), 2.67-2.76 (m, 2H), 4.00 (s, 3H), 6.80-6.90 (m, 1H), 7.45-7.57 (m, 1H), 8.01-8.07 (m, 1H)
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 150℃; for 1.5h;Microwave irradiation;
General procedure: To a solution of aryl halide 4a (48 mg, 0.35 mmol) in 2 mL dimethylformamide were added boronic ester 5 (106 mg, 0.385 mmol), Pd(PPh3)4 (20 mg, 5 mol %), and K3PO4 (242 mg, 1.11 mmol). The mixture was irradiated at 150 C for 90 min using a microwave reactor. The reaction mixture was then diluted with EtOAc, filtrated on a small pad of Celite, and concentrated under vacuum. The crude mixture was then purified by column chromatography (DCM/CyHex 7/3) to afford 63 mg of the corresponding phenanthrene 7a (72% yield).
4.1.1. General procedure for the preparation of the 2-methoxy substituted pyridines (2a, b)
General procedure: Sodium (1.5 g, 65.2 mmol) was added to dried methanol (40 mL). After the dissolvation of the sodium the 2-chloro-pyridine 1 (59 mmol) was added and the solution was heated under reflux for 6 h. Then water (50 mL) and ethyl acetate (50 mL) were added. The organic phase was separated and the water phase was additionally extracted with three portions of ethyl acetate (each 50 mL). The organic layers were unified and dried over sodium sulfate. After filtration the solvent was evaporated to dryness and the remaining oil was purified using column chromatography over silica gel and a mixture of chloroform/ethyl acetate (75/25) as eluent solvent.
90%
Stage #1: methanol With sodium at 20℃; for 0.5h;
Stage #2: 2-chloro-3-pyridinecarbonitrile for 5h;
1.1 Preparation of 2-methoxy-nicotinonitrile
Sodium (2.50 g, 109 mmol)Was dissolved in methanol (40 mL)And the mixture was stirred at room temperature for 30 minutes. Then,2-chloronicotinonitrile(5.0 g, 36.1 mmol)And the mixture was stirred for 5 hours. The reaction was terminated using water and the resulting solid was separated, washed with water and dried to give 2-methoxy-nicotinonitrile (4.35 g, 90%)
90%
Stage #1: methanol With sodium at 20℃; for 0.5h;
Stage #2: 2-chloro-3-pyridinecarbonitrile for 5h;
1.1 Step 1: Preparation of 2-methoxy-nicotinonitrile
Sodium (2.50 g, 109 mmol) was added to methanol (40 mL),It was stirred at room temperature for 30 minutes.2-chlorocyanopyridine (5.0 g, 36.1 mmol) was added and stirred for 5 hours.After adding water to terminate the reaction, separate the solid and wash it with water,After drying, 2-methoxy-nicotinonitrile (4.35 g, 90%) was obtained.
81%
Stage #1: methanol With sodium at 20℃; for 0.166667h;
Stage #2: 2-chloro-3-pyridinecarbonitrile at 0 - 25℃;
Stage #3: With water at 0℃;
2a
4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction medium is stirred at room temperature for 10 minutes and then 10 g (72.2 mmol) of 2- chloronicotinonitrile is added at 0°C. The reaction medium is stirred at 25°C for 16 hours. The reaction is hydrolyzed by slowly adding water at 0°C. After returning to room temperature, the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 7.85 g (81%) of 2-methoxy-nicotinonitrile in the form of a yellow solid. LCMS (EI, m/z): (M+l) 135.041H NMR: 6H ppm (400 MHz, DMSO): 8.46-8.48 (1H, dd, CHarom), 8.25-8.27 (1H, dd, CHarom), 7.17-7.20 (1H, dd, CHarom), 3.99 (3H, s, CH3).
81%
Stage #1: methanol With sodium at 20℃; for 0.166667h;
Stage #2: 2-chloro-3-pyridinecarbonitrile at 0 - 25℃; for 16h;
2a Example 2a 2-methoxy-nicotinonitrile
Example 2a 2-methoxy-nicotinonitrile 4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction medium is stirred at room temperature for 10 minutes and then 10 g (72.2 mmol) of 2-chloronicotinonitrile is added at 0° C. The reaction medium is stirred at 25° C. for 16 hours. The reaction is hydrolyzed by slowly adding water at 0° C. After returning to room temperature, the precipitate obtained is filtered, rinsed with water and then dried at 50° C. to yield 7.85 g (81%) of 2-methoxy-nicotinonitrile in the form of a yellow solid. LCMS (EI, m/z): (M+1) 135.04 1H NMR: δH ppm (400 MHz, DMSO): 8.46-8.48 (1H, dd, CHarom), 8.25-8.27 (1H, dd, CHarom), 7.17-7.20 (1H, dd, CHarom), 3.99 (3H, s, CH3).
81%
With sodium at 0 - 25℃; for 16h;
2a Example 2a: 2-methoxy-nicotinonitrile
4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction medium is stirred at room temperature for 10 minutes and then 10 g (72.2 mmol) of 2-chloronicotinonitrile is added at 0°C. The reaction medium is stirred at 25°C for 16 hours. The reaction is hydrolyzed by slowly adding water at 0°C. After returning to room temperature, the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 7.85 g (81 %) of 2-methoxy-nicotinonitrile in the form of a yellow solid. LCMS (EI, m/z): (M+1) 135.04 1H NMR: δH ppm (400 MHz, DMSO): 8.46-8.48 (1H, dd, CHarom), 8.25-8.27 (1H, dd, CHarom), 7.17-7.20 (1H, dd, CHarom), 3.99 (3H, s, CH3)
81%
With sodium at 0 - 25℃;
2.2a Example 2a: 2-methoxy-nicotinonitrile
Example 2a: 2-methoxy-nicotinonitrile 4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction medium is stirred at room temperature for 10 minutes and then 10 g (72.2 mmol) of 2- chloronicotinonitrile is added at 0°C. The reaction medium is stirred at 25 °C for 16 hours. The reaction is hydrolyzed by slowly adding water at 0°C. After returning to room temperature, the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 7.85 g (81%) of 2-methoxy-nicotinonitrile in the form of a yellow solid. LCMS (EI, m/z): (M+l) 135.04 1H NMR: δΗ ppm (400 MHz, DMSO): 8.46-8.48 (1H, dd, CHarom), 8.25-8.27 (1H, dd, 7.17-7.20 (1H, dd, CHarom), 3.99 (3H, s, CH3).
81%
With sodium at 0 - 25℃; for 16h;
2a Example 2a: 2-methoxy-nicotinonitrile
Example 2a: 2-methoxy-nicotinonitrile 4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction medium is stirred at room temperature for 10 minutes and then 10 g (72.2 mmol) of 2- chloronicotinonitrile is added at 0°C. The reaction medium is stirred at 25 °C for 16 hours. The reaction is hydrolyzed by slowly adding water at 0°C. After returning to room temperature, the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 7.85 g (81%) of 2-methoxy-nicotinonitrile in the form of a yellow solid. LCMS (EI, m/z): (M+l) 135.04 1H NMR: δΗ ppm (400 MHz, DMSO): 8.46-8.48 (1H, dd, CHarom), 8.25-8.27 (1H, dd, CHarom), 7.17-7.20 (1H, dd, CHarom), 3.99 (3H, s, CH3).
81%
With sodium at 0 - 25℃; for 16h;
2a Example 2a: 2-methoxy-nicotinonitrile
4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction medium is stirred at room temperature for 10 minutes and then 10 g (72.2 mmol) of 2-chloronicotinonitrile is added at 0°C. The reaction medium is stirred at 25°C for 16 hours. The reaction is hydrolyzed by slowly adding water at 0°C. After returning to room temperature, the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 7.85 g (81 %) of 2-methoxy-nicotinonitrile in the form of a yellow solid. LCMS (EI, m/z): (M+1) 135.04 1H NMR: δH ppm (400 MHz, DMSO): 8.46-8.48 (1H, dd, CHarom), 8.25-8.27 (1H, dd, CHarom), 7.17-7.20 (1H, dd, CHarom), 3.99 (3H, s, CH3)
58%
With palladium diacetate; caesium carbonate; tert-butyl XPhos In toluene at 80℃; for 12h;
4 Example 4
Example 2 (or Example 3) The obtained product 69g (2-chloro-3-cyanopyridine, 0.5mol) was added to 300ml of water, 25g of sodium hydroxide was added, and the hydrolysis reaction was heated at reflux for 3 hours. , then 3.0g of activated carbon was added to continue stirring for 0.5 hours, hot filtration, and filtrate to cool to room temperature, adjust the pH to 5 with concentrated hydrochloric acid, filter, wash the filter cake, 71 g of 2-chloronicotinic acid. was obtained, HPLC purity was 99.1%, and yield was 90%.
88%
With sulfuric acid at 100℃; for 10h;
5.1.9 2-chloronicotinic acid (7)
A solution of the 2-chloronicotinonitrile (4.14 g, 30 mmol) in 30 mL of 50% sulfuric acid was heated for at 100 °C for 10 h and then the reaction mixture was poured into the crushed ice. The resultant precipitate was filtered, washed with water and dried. The solid was recrystallized from 90% ethanol. Yield: 4.16 g, 88%.
With water; sodium chloride; sodium hydroxide at 90℃;
1-3; 1-2 The process for preparing carboxylic acid by hydrolyzing a nitrile compound in this embodiment includes the following steps:
1) Add 300g (0.27mol) 2-chloro-3-cyanopyridine and 30g NaOH (0.75mol) to a 300mL saturated aqueous sodium chloride solution,The molar ratio of 2-chloro-3-cyanopyridine to NaOH is 1: 2.78; stir and heat to 90 ° C,Insulation and hydrolysis reaction, after a period of time, take a sample for liquid chromatography analysis,When the content of 2-chloro-3-cyanopyridine in the chromatographic data is less than or equal to 1%, the reaction is stopped,The reaction solution was prepared.2) Inject hydrogen chloride gas into the reaction solution obtained in step 1) to adjust the pH to 2 to 3.After 1h of reaction, a large number of crystals were precipitated and filtered once.One filtrate recovery can continue to be used as a solvent for the hydrolysis of nitrile compounds to prepare carboxylic acids,The solid mixture obtained by one-time filtration is the generated 2-chloronicotinic acid solid and sodium chloride solid.3) Add anhydrous ethanol to the solid mixture obtained in step 2) and stir,The 2-chloronicotinic acid in the solid mixture is dissolved, filtered twice, and washed with a small amount of absolute ethanol.The solid obtained by filtration is dried to obtain sodium chloride,The ethanol obtained by distillation of the filtrate obtained by the secondary filtration is recycled, and then concentrated,After drying, 2-chloronicotinic acid is obtained, and the concentration of sodium chloride in the concentrate is 0.05%.
With C19H14N4NiO2; potassium <i>tert</i>-butylate In 1,4-dioxane at 90℃; for 4h; Inert atmosphere; Schlenk technique;
General procedure for the Buchwald-Hartwig reaction
General procedure: Under an N2atmosphere, KOtBu (1.3 mmol), complex 1 (1 mol%),dioxane (2 ml), amines (1.3 mmol) and aryl chlorides (1.0 mmol)were successively added into a Schlenk tube. The mixture wasstirred vigorously at 90C for 4 h. Then the solvent was removedunder reduced pressure and the residue was purified by columnchromatography on silica gel (eluent:PE/EA = 15:1) to give the pureproducts. The reported yields are the average of two runs.The catalytic reactions have been given in Tables 4-7. The result-ing amines were identified by comparison of the1H and13C NMRdata with those previously reported (ESI).
76%
With (2,2′-bis(biphenylphosphino)-1,1′-binaphthalene)Ni(η2-NC-Ph); sodium t-butanolate In toluene at 80℃; for 24h; Inert atmosphere; Glovebox;
With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 16h;
General procedure: 4.3.1. Ethyl 5-amino-2-methylpyrazolo[1,5-a]quinoline-3-carboxylate (7a). Condition C: A mixture of 2-fluorobenzonitrile6a (121 mg, 1.00 mmol), 1H-pyrazole 4 (202 mg, 1.20 mmol) andCs2CO3 (980 mg, 3.00 mmol) in DMF (5.0 mL) was stirred at 120 Cfor 16 h. After monitoring the end of the reaction on TLC, themixture was cooled to room temperature and diluted with water.The resulting mixture was extracted with ethyl acetate twice. Thecombined organic layers werewashed with water twice, dried overMgSO4 and the solvent was removed in vacuo to afford a residue.The residue was purified by flash column chromatography(hexane:EtOAc1:1) on silica gel to afford 7a (124 mg, 46% yield).Condition D: The reaction was carried out in DMSO instead of DMFunder the same conditions as that of condition C to afford 7a (175 mg, 65% yield).
With palladium 10% on activated carbon; hydrogen; sodium hydrogencarbonate In methanol at 20℃; for 2h; Sealed tube; chemoselective reaction;
General procedure forhydrodechlorination of 2-chloropyridine derivatives
General procedure: To a solution of the 2-chloropyridine derivative (1 equiv.) in MeOH (10 mL) was added 10% Pd/C (1 mol%) and NaHCO3 (1 equiv. per pyridine chlorine).The reaction vessel was sealed and flushed with hydrogen gas three times. The black suspension was stirred at room temperature under an atmosphere of hydrogen (1 atm.) for two hours. The mixture was filtered through celite washing with methanol and concentrated in vacuo. Purification by column chromatography was performed as required to yield the hydrodechlorinated pyridine product.
2-(3-cyanopyridin-2-yloxy)-N-phenylacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With sodium carbonate In ethanol Inert atmosphere; Reflux;
4.3.1. General procedure A: synthesis of the thienopyridine-2-carboxamides 4 and cyanopyridines 13 from pyridines 7
General procedure: A mixture of 2-mercaptoacetamides 6a-c or 2-hydroxyacetamides 11a-c (1.05 mmol), pyridine 7a-c (1 mmol)and anhydrous sodium carbonate (1.05 mmol) in absolute ethanol(1 mL) was stirred at reflux for 15 h. The mixture was then cooled to room temperature and the solvent removed in vacuo. The resultant crude solid was washed with small amounts of water and the remaining solid was recrystallized, using methanol to give the thienopyridine-2-carboxamide 4 or cyanopyridine 13.
With tetraphosphorus decasulfide; ammonia In methanol at 20℃; for 12h;
2-Chloro-3-carbothioamide (2c)
General procedure: a. Ground phosphoruspentasulfide (115 g, 0.5 mol) was added to asolution of 4-cyanopyridine (52 g, 0.5 mol) in 250 mLof 20% ammonium in methanol under vigorous stirringmaintaining the reaction mixture temperature below35-40°C. The reaction mixture was kept at roomtemperature for 12 h, and then 150 mL of water wasadded that caused dissolution of the solid and intensiveexothermic gas liberation. After cooling of the reactionmixture to room temperature the precipitate wasfiltered off, washed with water, and dried.Yield 78%, Rf 0.55,mp 165° (decomp.).
With diammonium sulfide In water at 20℃; for 12h; Green chemistry;
With triethylamine; trichlorophosphate; at 0 - 5℃; for 8.5h;Reflux;
The product obtained in Example 1 (containing <strong>[20577-27-9]2-hydroxy-3-cyanopyridine</strong>, 0.88 mol) was added to 250 ml of POCl3 (about 2.7 mol) and dissolved under stirring, the system was cooled to 0 C, and triethylamine was. slowly added dropwise 101g (1.0mol), control the system temperature between 0-5;, after the dropwise addition, stirring was continued at this temperature for half an hour; After that, the temperature was slowly raised to the reflux of the system, and the reflux was maintained for 8 hours to complete the reaction. Recover excess phosphorus oxychloride (POCl3) under reduced pressure, add 200ml ice water to the system,The pH was adjusted to 11 with a small amount of NaOH, and a brown precipitate 117g (product containing 2-chloro-3-cyanopyridine) was precipitated in a yield of 96.6%. The triethylamine in the mother liquor can be recovered by distillation.
94.6%
With P,P-dichlorophenylphosphine oxide; phosphorus pentachloride; at 160℃; for 5h;
General procedure: A mixture of phenols (100.0 mmol) phenylphosphonic dichloride (11.0 mmol) and phosphorus pentachloride (110.0 mmol) was slowly heated to 160 C while distilled the byproduct POCl3. And the mixture was stirred at the same temperature for 5 hours. TLC analysis showed the reaction had been finished. The POCl3 was evaporated in vacuum and the residue was poured into ice water, and it was neutralized with saturated aqueous sodium carbonate solution, and extracted with acetic ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, the obtained crude product was distilled or purified with silica gel chromatography, the target compound was obtained. The structures of compounds were confirmed by MS and 1H NMR data which were listed as follows.
Step 1: Synthesis of 2-chloro-4-iodonicotinonitrile In an atmosphere of argon gas, at -30 C., n-butyl lithium (2.4M hexane solution, 3.0 mL, 7.2 mmol) was added dropwise to a solution of diisopropylamine (0.728 g, 7.2 mmol) in anhydrous tetrahydrofuran (20 mL) to get a reaction mixture. The reaction mixture was stirred at -30 C. for 30 minutes, and then cooled to -78 C. A solution of 2-chloro-nicotinonitrile (1.0 g, 7.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the reaction mixture was then stirred at -78 C. for 60 minutes. A solution of iodine (1.8 g, 7.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise, and the reaction mixture was then stirred at -78 C. for 30 minutes. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), diluted with water (50 mL), and extracted with ethyl acetate (100 mL*3). The organic phases were combined. The combined organic phases were washed with saline solution (100 mL*3), dried with anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=80:1) to get product as yellow solid (0.357 g, yield: 19%). 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J=5.2 Hz, 1H), 8.15 (d, J=5.2 Hz, 1H) MS (ESI+): m/z 264.9 [M+H]+
With dmap; 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; zinc In acetonitrile at 80℃; for 6h; Schlenk technique; Inert atmosphere; Sealed tube;
90%
With dmap; 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; zinc In acetonitrile at 80℃; for 6h; Inert atmosphere; Sealed tube;
44 Example 1 Compound (1a)
General procedure: Under argon protection, NiCl2·6H2O (0.05mmo 1,11.9mg), dppf (0.06mmol, 33.3mg), Zn (0·2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn(CN)2 (0.8mmol) , 93.9mg), p-Chloroanisole (1.0 mmol, 140.6 mg) and acetonitrile (5.0 mL) were sequentially added in a 25.0 mL sealed tube, then directly put it into the oil bath at 60 °C, and heating was stopped after 6h, and cooled to room temperature, the reaction solution was directly filtered through a short silica gel column, washed with dichloromethane, concentrated and purified by silica gel column chromatography( given that the product is most easily pulled out, in order to avoid loss of sample mix, unless otherwise noted, both are wet method). Eluent: petroleum ether / ethyl acetate = 20:1, the product was 117.2 mg as a white solid, yield 88%, and 1H NMR purity was greater than 98%.
With sodium hydrogencarbonate In ethanol at 90℃; for 12h;
1 Pyridine-hydrosothiazole carboxylic acid synthesis reaction of the general formula
Weigh 2-chloro-3-cyano-pyridine (lOmmol, 1.04 g), L-cysteine hydrochloride (25 mmol), sodium bicarbonate(60 mmol) was added to a 100 mL round bottom flask and 30 mL of absolute ethanol was added and heated at 90 ° C for 12 hours until the reaction was completed.Cooled to room temperature, spin to anhydrous ethanol to milky white solid. Dissolved in water, in the ice bath conditions, slowly add hydrochloric acid solution (thickDegree of 2mol / L), to the determination of solution ρH- = 3-4, the reaction system precipitated a large number of white solid, filter, and then washed with ice water2-3 times, after drying to give the compound pyridine dihydrolthiazole carboxylic acid A3, light orange powder as a solid, the yield of 88%.
In aq. phosphate buffer; isopropyl alcohol at 50℃; for 16h; Inert atmosphere;
2-(2-Chloropyridin-3-yl)thiazole-4-carboxylic Acid (11)
2-Chloronicotinonitrile (10; 50 g, 361 mmol, 1 equiv) was dissolved in 1.5:1 i-PrOH/pH 7 phosphate buffer (722 mL, 0.5 M) and solid L-cysteine hydrochloride (65.6 g, 542 mmol, 1.5 equiv) was added in one portion. The reaction mixture was heated to 50 °C and stirred for 16 h. The reaction was then terminated by removing i-PrOH under reduced pressure and diluting with EtOAc (500 mL) and aq 2 M HCl until the solution was acidic (pH >2). The mixture was extracted with EtOAc (3 × 400 mL), the combined extracts were dried (Na2SO4), and concentrated to give the intermediate thiazoline as a yellow solid (76.9 g, 317 mmol, 88%); mp 156-158 °C. The crude material was of sufficient purity to be used directly in the next reaction without further purification. 1H NMR (600 MHz, MeOD): δ = 8.49 (dd, J = 4.9, 1.8 Hz, 1 H), 8.10 (dd, J = 7.7, 1.8 Hz, 1 H), 7.49 (dd, J = 7.7, 4.9 Hz, 1 H), 5.36 (t, J = 9.2 Hz, 1H), 3.87-3.80 (m, 2 H). Crude thiazoline (76.9 g, 317 mmol, 1 equiv) and BrCCl3 (46.9 mL, 476 mmol, 1.5 equiv) were dissolved in DMF (317 mL, 1 M) in a flask and the flask was immersed in an ice bath. DBU (99 mL, 666 mmol, 2.1 equiv) was added dropwise via an addition funnel over 20 min. On large scale this addition was significantly exothermic. After addition, the reaction mixture was then brought to 50 °C and stirred for 3 h. After completion, the mixture was slowly introduced dropwise into a vigorously stirring aq 1 M HCl (2 L) at 0 °C to ensure a uniform precipitate. The mixture was stirred for 10 min and the fine brown precipitate was filtered and dried under vacuum at 50 °C for 18 h to give 76.0 g (99%, 87% over 2 steps) of crude thiazole product 11 as a grey-brown solid; mp > 200 °C. The crude material was of sufficient purity to be used directly in the next reaction without further purification. 1H NMR (600 MHz, MeOD): δ = 8.76 (dd, J = 7.9, 1.8 Hz, 1 H), 8.58 (s, 1H), 8.50 (dd, J = 4.7, 1.9 Hz, 1 H), 7.58 (dd, J = 7.9, 4.7 Hz, 1 H). 13C NMR (150 MHz, DMSO-d6): δ = 162.4, 161.6, 151.3, 148.0, 147.6, 140.2, 131.1, 128.3, 124.4. HRMS (ESI): m/z calcd for C9H5ClN2O2S [M - H]-: 238.9687; found: 238.9689.
benzyl (6-hydroxyspiro[3.3]heptane-2-yl)carbamate[ No CAS ]
benzyl (6-((3-cyanopyridin-2-yl)oxy)spiro[3.3]heptan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: benzyl (6-hydroxyspiro[3.3]heptane-2-yl)carbamate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h;
Stage #2: 2-chloro-3-pyridinecarbonitrile In tetrahydrofuran; mineral oil for 16h;
78%
Stage #1: benzyl (6-hydroxyspiro[3.3]heptane-2-yl)carbamate With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h;
Stage #2: 2-chloro-3-pyridinecarbonitrile In tetrahydrofuran for 16h;
Example 1-3. Preparation of benzyl (6-((3-cyanopyridin-2-yl)oxy)spiro[3.3]heptan-2-yl)carbamate
To a solution of Intermediate 1-2 (0.48 g, 1 ,8 mmol) in anhydrous THF (14 mL) at 0 °C, was added 60% NaH (0, 162 g, 4.04 mmol). The reaction mixture was stirred at rt until becoming mostly homogeneous (-30 min), then, 2-chloronicotinonitrile (0.5 g, 4 mmol) was added in one portion, and the reaction mixture was allowed to stir for 16 h. The reaction mixture was quenched by the addition of sat, NITiCl and evaporated. The residue was partitioned between water (20 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with sat, NaHCC and brine, dried (MgSC ) and concentrated under reduced pressure. The residue was purified via flash chromatography to afford benzyl (6-((3~cyanopyridin-2-yl)oxy)spiro[3.3]heptan-2-yl)carbamate (0.52 g, 78 % yield), as a clear oil. MS (ESI) m/z: 364.1 ( +H)+; 1H NMR (400MHz, CDCl3) δ 8.31 (dd, ./ 5. 1. 2,0 Hz, i l l ), 7,86 (dd, ./ 7.5. 2.0 Hz, i l l ). 7.42 - 7.29 (ra, 51 1 ). 6,95 (dd, ./ 7.6. 5.0 Hz, i l l ). 5.23 (quin, ,7=7,2 Hz, 1H), 5,09 (s, 2H), 4,83 (br. s. , IH), 2.74 - 2.61 (m, 1H), 2.59 - 2,38 (m, 3H), 2,27 (dt, J=l 1.8, 7.3 Hz, 2H), 2,02 - 1.91 (m, 2H).
With pyridine; ammonium peroxydisulfate In acetonitrile at 50℃; for 24h;
74%
With pyridine; ammonium peroxydisulfate; tris(2,2-bipyridine)ruthenium(II) hexafluorophosphate; 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinoxy In acetonitrile at 0.5℃; for 24h; Molecular sieve; Sealed tube; Irradiation;
Representative Procedure - Preparation of 4-Methoxybenzonitrile(4a)
General procedure: To an oven-dried 2 ml reaction vial equipped with a stir bar wasadded the aldehyde 3a (0.136 g, 1 mmol, 1 equiv) and pyridine(0.474 g, 6.0 mmol, 6 equiv), followed by acetonitrile (2 ml, 0.5M in 3a). The vial was then charged with Ru(bpy)3(PF6)2 (0.017g, 0.02 mmol, 0.02 equiv), 2 (0.043 g, 0.20 mmol, 0.20 equiv),(NH4)2S2O8(0.501 g, 2.2 mmol, 2.2 equiv), and activated 3 Åmolecular sieves (ca. 0.2 g), sealed with a cap, and irradiated inblue LED reactor for 24 h. In the absence of fan cooling, the temperatureof the reaction mixture plateaued at approximately 50°C . After the irradiation was complete, the reaction mixturewas quenched with EtOAc and transferred to a separatoryfunnel. Further EtOAc (30 ml) was added, followed by 0.5 MHCl(aq) (30 ml). The layers were separated, and the aqueous layerwas extracted with EtOAc (3 × 20 ml). The organic layers werethen combined and washed with 0.5 M 0.5 M HCl(aq) (2 × 20 ml),saturated aqueous sodium bicarbonate (2 × 20 ml), and finallybrine (20 ml). The organic layer was then dried over sodiumsulfate and the solvent removed in vacuo to afford the crudeproduct. The resulting crude mixture was adhered to silica gelusing 1.5 weight equivalents of SiO2(relative to the theoreticalyield). The dry-packed material was gently added on top of asilica gel plug. The plug was washed with an excess of hexanes(ca. 5 column volumes). The desired product was eluted off theplug via a 90:10 by volume mixture of hexanes/EtOAc (3-4column volumes). The solvent was removed in vacuo by rotaryevaporation affording the pure nitrile 3c (0.066 g, 50%) as awhite solid.
2-(4-((3-cyanopyridin-2-yl)oxy)-3-fluorophenyl)acetic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate; In dimethyl sulfoxide; at 60℃; for 14h;
To 2-chloronicotinonitrile (0.489 g, 3.53 mmol) in DMSO (5 mL) was added 2-(3- fluoro-4-hydroxyphenyl)acetic acid (0.6 g, 4 mmol) and K2C03 (1.072 g, 7.760 mmol) and the reaction mixture was heated to 60 C for 14h. The reaction mixture was allowed to cool to room temperature, quenched by the addition of IN HCl and the resultant solid was filtered and dried under vacuum to afford (0.9 g, 90 % yield) of Intermediate 1 as a tan solid. MR (400MHz, CD3OD) delta 8.32 (dd, J=5.0, 1.9 Hz, 1H), 8.25 (dd, 7=7.7, 2.0 Hz, 1H), 7.35 - 7.23 (m, 3H), 7.23 - 7.10 (m, 1H), 3.70 (s, 2H). LCMS m/z = 273.0 (M+H).+
With N-butylamine; triethylamine; trichlorophosphate In 1,2-dichloro-ethane at 10 - 100℃; for 10.3333h;
1-3 Example 3:
Weigh 100g of dichloroethane into a 250ml three-necked flask,Weigh 10g of N-oxo-nicotinamide into a three-necked flask.Cool down to 15 ± 5 ° C,Weigh 40g of phosphorus oxychloride to control the dropping time to 2.5h and add it to the three-necked flask.After the addition is completed, the temperature is lowered to 10 ± 5 ° C, and 7 g of triethylamine and 8 g of n-butylamine are mixed uniformly.The dropping time was controlled to be added to the three-necked flask at 1.5 h, and the addition was completed.Stirring was continued for 40 min at a temperature of 15 ° C, and the temperature was raised to 45 ° C, and the mixture was stirred for 1.5 h.Raise the temperature to 60 ° C, stir for 1.5 h, then warm to 100 ° C, and stir for 5 h.After the heat preservation, the chloride reaction liquid is obtained, and the chloride reaction liquid is transferred to the rotary steaming bottle.The temperature is controlled at 70 ° C and the pressure is 8 Kpa for rotary evaporation.To the absence of significant liquid outflow, measure 50 ml of water into a rotary flask and warm to 70 ° C.The solution in the rotary flask was transferred to a 250 ml three-necked flask and stirred for 2.5 h.The mixture was cooled to 25 ° C, stirred for 40 min, and suction filtered to give 2-chloro-3-cyanopyridine wet product.
With copper(l) iodide; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 20h; Inert atmosphere;
19.1 19.1 Preparation of Compound (QR16022-SM-002)
5 g (QR16022-SM-001) was dissolved in DMF (50 mL) under nitrogen protection, added with 2 eq. potassium carbonate, stirred at room temperature for 5-10 min, added successively with 0.1 molar eq. CuI, 1.2 eq. methylamine hydrochloride, and then heated to 100° C. for 20 h. The end of the reaction was confirmed by TLC. The reaction mixture was filtered, concentrated, and purified by column chromatography to give 1.71 g Compound (QR16022-SM-002).
1.71 g
With copper(l) iodide; potassium carbonate In N,N-dimethyl-formamide at 20 - 100℃; for 20h; Inert atmosphere;
32.1 32.1 Preparation of Compound (ST0032-SM-002)
5 g of ST0032-SM-001 was dissolved in DMF (50 mL) under nitrogen protection, 2 molar equivalents of potassium carbonate was added, stirred at room temperature for 5 to 10 minutes. 0.1 molar equivalents of CuI and 1.2 molar equivalents of methylamine hydrochloride were added, and the mixture was heated to 100°C. for 20 hours. The endpoint of the reaction was determined by TLC. The mixture was filtered, concentrated, and purified by column chromatography to give 1.71 g of the compound (ST0032-SM-002).
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