* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
2
[ 101012-32-2 ]
[ 7758-99-8 ]
[ 100960-03-0 ]
[ 101860-97-3 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
3
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2697 - 2706
4
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
[ 142892-30-6 ]
Reference：
[1] Synthesis, 1992, # 6, p. 528 - 530
5
[ 6635-88-7 ]
[ 10025-87-3 ]
[ 99310-62-0 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
6
[ 6635-88-7 ]
[ 101012-32-2 ]
Yield
Reaction Conditions
Operation in experiment
42.9%
at 80℃; for 4.5 h; Heating / reflux
(1-oxypyridin-3-yl)acetonitrile (7.5 g, 35.9 mmol) is carefully added to vigorously stirred phosphorous oxychloride (100 mL). The mixture is slowly heated to 80° C. (in 5° C. increments) over 1.5 hr. (CAUTION. If heating is too quick, violent decomposition occurs at ca 70° C.) All the solids dissolved. The reaction is heated at reflux for 3 hr. The excess phosphorous oxychloride is removed and the residue is cautiously treated with cold water. Saturated sodium bicarbonate is added to make the mixture basic, then it is extracted with ethyl acetate (3.x.). The combined extract is washed with brine, dried, filtered and concentrated. The residue is purified by chromatography eluting with pentane-10 to 100percent ether. The second compound off the column is the desired (2-chloropyridin-3-yl)acetonitrile (2.35 g, 42.9percent yield) a light brown solid.
20%
for 3 h; Reflux
(1-Oxypyridin-3-yl)acetonitrile (1115) (4.00 g, 29.8 mmol) was added slowly to a stirred solution of POCI3 (50 mL). The mixture was heated to 80 °C in 5 - 7 °C increments every 10 -15 minutes. The reaction was then heated at reflux for 3 hours. Excess POCI3 was removed by distillation and the brown residue carefully poured on to cold water (200 mL). A saturated solution NaHC03 (300 mL) was then added carefully. Solid NaHC03 was added in portions to the aqueous mixture until the evolution of gas ceased. The aqueous layer was separated in to two portions (250 mL each) and each portion was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (200 mL) and dried over Na2S04. The solvent was removed and the residue purified by column chromatography on silica gel (0- 100percent EtOAc in petroleum benzine) to afford a mixture of two isomeric compounds. The mixture was re-purified by column chromatography on silica gel (0-40percent diethyl ether in petroleum benzine 40-80 °C) to afford the title compound (1116) (0.932 g, 20percent) as a white solid; 1 H NMR (400 MHz, CDCI3) 6 8.41 (dd, J = 4.8, 1.8 Hz, 1 H), 7.90 (ddt, J = 7,6, 1.7, 0.7 Hz, 1 H), 7.34 (dd, J = 7,6, 4.8 Hz, 1 H), 3.87 (s, 2H), LCMS Method C: rt 4,50 min; m/z 153 [M+H]+.
Reference：
[1] Patent: US2005/54631, 2005, A1, . Location in patent: Page/Page column 23-24
[2] Patent: WO2014/27199, 2014, A1, . Location in patent: Page/Page column 141
[3] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
[4] Patent: WO2012/110773, 2012, A1, . Location in patent: Page/Page column 138; 139
7
[ 89581-84-0 ]
[ 143-33-9 ]
[ 101012-32-2 ]
Yield
Reaction Conditions
Operation in experiment
61%
at 50℃; for 4 h;
(Step 3) To a solution of the compound (20.5 g) obtained in step 2 in DMSO (100 mL) was added sodium cyanide (12.4 g), and the mixture was stirred at 50°C for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was poured into a mixture of water and ethyl acetate. The organic layer was washed with brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10-->25percent ethyl acetate/hexane) to give (2-chloropyridin-3-yl)acetonitrile (11.7 g, 61percent) as a white powder. 1H-NMR(CDCl3): δ 3.87(2H,s), 7.34(1H,dd,J=7.6,4.8Hz), 7.88-7.93(1H,ddd like), 8.41(1H,dd,J=4.8,1.8Hz)
INTERMEDIATE 2(2-Chloropyridin-3-yl)acetonitrileIn a 3 L reactor, set for reflux under positive nitrogen pressure and using a bleach scrubber, was prepared a solution of potassium cyanide (68.32 g, 1.04M) in EtOH (136 <n="37"/>mL) and water (255 mL). The mixture was heated to reflux, at which point a solution of 2-chloro-3-(chloromethyl)pyridine {Intermediate 1; 170.0 g, 1.04M) in EtOH (170 mL) was added dropwise over 30 minutes. The whole mixture was maintained at reflux for a further 150 minutes. The mixture was then allowed to cool just below boiling point and the equipment set for distillation. A total of 8.5 volumes of EtOH were removed. On cooling, half a volume of water was added. At a temperature of 4O0C, the solution was seeded and crystallised instantaneously. The thick beige slurry was allowed to cool to ambient temperature and then to 00C. This mixture was filtered, rinsed with cold water (2 vo Is) and dried at 450C in a vacuum oven overnight. The title compound was afforded as a beige solid in excellent yield and purity (126.9 g, 80percent). δH (d6-DMSO, 300 MHz) 8.45 (IH, dd), 8.00 (IH, dd), 7.50 (IH, dd), 4.15 (2H, s). LCMS (ES)+ RT 2.15 min, m/e 153.01 155.01 (M+l M+3, Product).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 14, p. 3189 - 3193
[2] Patent: WO2009/153554, 2009, A1, . Location in patent: Page/Page column 35-36
9
[ 89581-84-0 ]
[ 151-50-8 ]
[ 101012-32-2 ]
Yield
Reaction Conditions
Operation in experiment
80%
for 3 h; Heating / reflux
INTERMEDIATE 2(2-Chloro?yridin-3 - vDacetonitrileIn a 3 L reactor, set for reflux under positive nitrogen pressure and using a bleach scrubber, was prepared a solution of potassium cyanide (68.32 g, 1.04M) in EtOH (136 mL) and water (255 mL). The mixture was heated to reflux, at which point a solution of 2-chloro-3-(chloromethyl)pyridine {Intermediate 1; 170.0 g, 1.04M) in EtOH (170 mL) was added drop wise over 30 minutes. The whole mixture was maintained at reflux for a further 150 minutes. The mixture was then allowed to cool just below boiling point and the equipment set for distillation. A total of 8.5 volumes of EtOH were removed. On cooling, half a volume of water was added. At a temperature of 4O0C, the solution was seeded and crystallised instantaneously. The thick beige slurry was allowed to cool to ambient temperature and then to O0C. This mixture was filtered, rinsed with cold water (2 vols) and dried at 450C in a vacuum oven overnight. The title compound was afforded as a beige solid in excellent yield and purity (126.9 g, 80percent). ?H (d6-DMSO, 300 MHz) 8.45 (IH, dd), 8.00 (IH, dd), 7.50 (IH, dd), 4.15 (2H, s). LCMS (ES)+ RT 2.15 min, m/e 153.01 155.01 (M+l M+3, Product).
In a 3 L reactor, set for reflux under positive nitrogen pressure and using a bleach scrubber, was prepared a solution of potassium cyanide (68.32 g, 1.04M) in EtOH (136 mL) and water (255 niL). The mixture was heated to reflux, at which point a solution of 2-chloro-3-(chloromethyl)pyridine {Intermediate 1; 170.0 g, 1.04M) in EtOH (170 mL) was added dropwise over 30 minutes. The whole mixture was maintained at reflux for a further 150 minutes. The mixture was then allowed to cool just below boiling point and the equipment set for distillation. A total of 8.5 volumes of EtOH were removed. On cooling, half a volume of water was added. At a temperature of 4O0C, the solution was seeded and crystallised instantaneously. The thick beige slurry was allowed to cool to ambient temperature and then to 00C. This mixture was filtered, rinsed with cold water (2 vols) and dried at 450C in a vacuum oven overnight. The title compound was afforded as a beige solid in excellent yield and purity (126.9 g, 80percent). δH (d6-DMSO, 300 MHz) 8.45 (IH, dd), 8.00 (IH, dd), 7.50 (IH, dd), 4.15 (2H, s). LCMS (ES)+ RT 2.15 min, m/e 153.01 155.01 (M+l M+3, Product).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 7, p. 2168 - 2173
[2] Chinese Chemical Letters, 2011, vol. 22, # 9, p. 1009 - 1012
12
[ 6443-85-2 ]
[ 101012-32-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2697 - 2706
[2] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
[3] Patent: WO2012/110773, 2012, A1,
[4] Patent: WO2014/27199, 2014, A1,
13
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2697 - 2706
14
[ 6959-48-4 ]
[ 101012-32-2 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
15
[ 59-67-6 ]
[ 101012-32-2 ]
Reference：
[1] Chinese Chemical Letters, 2011, vol. 22, # 9, p. 1009 - 1012
16
[ 49609-84-9 ]
[ 101012-32-2 ]
Reference：
[1] Chinese Chemical Letters, 2011, vol. 22, # 9, p. 1009 - 1012
17
[ 2942-59-8 ]
[ 101012-32-2 ]
Reference：
[1] Chinese Chemical Letters, 2011, vol. 22, # 9, p. 1009 - 1012
18
[ 6635-88-7 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
[ 142892-30-6 ]
Reference：
[1] Synthesis, 1992, # 6, p. 528 - 530
19
[ 42330-59-6 ]
[ 101012-32-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 14, p. 3189 - 3193
20
[ 6635-88-7 ]
[ 10025-87-3 ]
[ 99310-62-0 ]
[ 39891-09-3 ]
[ 101012-32-2 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
21
[ 101012-32-2 ]
[ 61494-55-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: for 0.583333 h; Reflux Stage #2: With hydrogenchloride In water at 0℃; for 1 h;
A solution of 15percent w/w NaOH (15 mL) was added to (2-chloropyridin-3-yl)acetonitrile (1116) (0.932 g, 6.1 mmol). The mixture was heated at reflux for 35 minutes then cooled to room temperature. The mixture was further cooled to 0 °C and then acidified with cone. HCI (ca 5 mL) to pH 1. The suspension was left to stand for 1 hour in an ice bath. The precipitate was filtered and washed with cold propan-2-ol (3x15 mL) to yield the title compound (1117) (1 .05 g, 100percent) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 12.63 (s, 1 H), 8.32 (dd, J = 4.8, 1.9 Hz, 1 H), 7.86 (dd, J = 7.5, 1.9 Hz, 1 H), 7.41 (dd, J = 7.5, 4.8 Hz, 1 H), 3.75 (s, 2H). LCMS Method C: rt 4.06 min; m/z 172 [M+Hf.
100%
for 0.583333 h; Reflux
A solution of 15percent w/w NaOH (15 mL) was added to (2-chioropyridin-3-yl)acetonitrile (1116) (0.932 g, 6.11 mmol). The mixture was heated at reflux for 35 minutes then cooled to room temperature. The mixture was further cooled to 0 °C and then acidified with cone. HCi (ca 5 mL) to pH 1. The suspension was left to stand for 1 hour in an ice bath. The precipitate was filtered and washed with cold propan-2~ol (3x15 mL) to yield the title compound (1117) (1.05 g, 100percent) as an off-white solid; 1H NMR (400 MHz, cfe-DMSO) δ 12.63 (s, 1 H), 8.32 (dd, J = 4.8, 1.9 Hz, 1 H), 7.86 (dd, J = 7.5, 1.9 Hz, 1 H), 7.41 (dd, J = 7.5, 4.8 Hz, 1 H), 3.75 (s, 2H). LCMS Method C: rt 4.06 min; m/z 172 [M+H]+.
90%
Stage #1: With sodium hydroxide In water for 0.5 h; Heating / reflux Stage #2: With hydrogenchloride In water at 0 - 10℃;
(2-Chloropyridin-3-yl)acetic acidTo a 2 L reactor, set for reflux, was stirred a pre-prepared 15percent w/w solution of sodium hydroxide (5 vols) to which was added (2-chloropyridin-3-yl)acetonitrile (Intermediate 2\\ 276.4 g, 1.81M). The beige suspension was heated to reflux for 30 minutes, at which point the reaction was deemed complete by HPLC. The brown solution was then cooled to 0-50C and acidified to pH 1 with cone. HCl while keeping the temperature below 1O C, using concentrated hydrochloric acid (1.8 vols). An off-white solid precipitated and was left to mature for another hour before filtration. Once dried, the material was recrystallised from propan-2-ol (4 vols) to afford the title compound as an off-white material in excellent yield and purity (280.3 g, 90percent). ?H (d?-DMSO, 300 MHz) 12.70 (IH, s), 8.35 (IH, dd), 7.85 (IH, dd), 7.40 (IH, dd), 4.25 (2H, s). LCMS (ES)+ RT 1.75 min, m/e 171.99 (M+l, Product).
90%
Stage #1: With sodium hydroxide In water for 0.5 h; Reflux Stage #2: With hydrogenchloride In water at 0 - 10℃;
(2-Chloropyridin-3-yl)acetic acid To a 2 L reactor, set for reflux, was stirred a pre-prepared 15percent w/w solution of sodium hydroxide (5 vols) to which was added (2-chloropyridin-3-yl)acetonitrile (Intermediate 2; 276.4 g, 1.81M). The beige suspension was heated to reflux for 30 minutes, at which point the reaction was deemed complete by HPLC. The brown solution was then cooled to 0-50C and acidified to pH 1 with cone. HCl while keeping the temperature below 1O0C, using concentrated hydrochloric acid (1.8 vols). An off-white solid precipitated and was left to mature for another hour before filtration. Once dried, the material was recrystallised from propan-2-ol (4 vols) to afford the title compound as an off-white material in excellent yield and purity (280.3 g, 90percent). δH (d6-DMSO, 300 <n="27"/>MHz) 12.70 (IH, s), 8.35 (IH, dd), 7.85 (IH, dd), 7.40 (IH, dd), 4.25 (2H, s). LCMS (ES)+ RT 1.75 min, m/e 171.99 (M+l, Product).
90%
Stage #1: for 0.5 h; Reflux Stage #2: With hydrogenchloride In water at 0 - 10℃;
INTERMEDIATE 3(2-Chloropyridin-3-yl)acetic acidTo a 2 L reactor, set for reflux, was stirred a pre-prepared 15percent w/w solution of sodium hydroxide (5 vols) to which was added (2-chloropyridin-3-yl)acetonitrile {Intermediate 2; 216 A g, 1.81M). The beige suspension was heated to reflux for 30 minutes, at which point the reaction was deemed complete by HPLC. The brown solution was then cooled to 0-50C and acidified to pH 1 with cone. HCl while keeping the temperature below 1O0C, using concentrated hydrochloric acid (1.8 vols). An off-white solid precipitated and was left to mature for another hour before filtration. Once dried, the material was recrystallised from propan-2-ol (4 vols) to afford the title compound as an off-white material in excellent yield and purity (280.3 g, 90percent). δH (d6-DMSO, 300 MHz) 12.70 (IH, s), 8.35 (IH, dd), 7.85 (IH, dd), 7.40 (IH, dd), 4.25 (2H, s). LCMS (ES)+ RT 1.75 min, m/e 171.99 (M+l, Product).
80%
at 0 - 90℃; for 4 h;
(Step 4) To a solution of the compound (11.7 g) obtained in step 3 in water (66 mL) was added concentrated sulfuric acid (55.6 mL) at 0°C, and the mixture was stirred at 90°C for 4 hr. The reaction mixture was poured into ice-cold water, and the precipitate was filtered off. The filtrate was extracted three times with ethyl acetate. The organic layer was washed with brine, and concentrated to give (2-chloropyridin-3-yl)acetic acid (10.5 g, 80percent) as a white powder. 1H-NMR(CDCl3+DMSO-d6): δ 3.75(2H,s), 7.25(1H,dd,J=7.4,4.8Hz), 7.69(1H,dd,J=7.4,1.8Hz), 8.31(1H,dd,J=4.8,1.8Hz)
39%
at 100℃; for 2 h;
(2-Chloropyridin-3-yl)acetonitrile (1.0 g, 6.55 mmol) in conc. hydrochloric acid (15 mL) is stirred at 100° C. for 2 hr. After cooling to room temperature the reaction mixture is diluted with water and the solution is concentrated to dryness. The residue is dissolved in water, made basic with ammonium hydroxide, re-acidified with acetic acid and extracted with ethyl acetate. The combined extract is washed with brine, dried, filtered and concentrated to give (2-chloropyridin-3-yl)acetic acid (442 mg, 39percent) as a white solid.
Reference：
[1] Patent: WO2012/110773, 2012, A1, . Location in patent: Page/Page column 138; 139
[2] Patent: WO2014/27199, 2014, A1, . Location in patent: Page/Page column 141
[3] Patent: WO2009/13462, 2009, A1, . Location in patent: Page/Page column 26
[4] Patent: WO2009/93008, 2009, A1, . Location in patent: Page/Page column 25-26
[5] Patent: WO2009/153554, 2009, A1, . Location in patent: Page/Page column 36
[6] Patent: EP2018863, 2009, A1, . Location in patent: Page/Page column 74
[7] Patent: US2005/54631, 2005, A1, . Location in patent: Page/Page column 24
[8] Journal of the American Chemical Society, 1959, vol. 81, p. 740,742
[9] Journal of Medicinal Chemistry, 1990, vol. 33, # 10, p. 2697 - 2706
[10] Patent: WO2007/88345, 2007, A1, . Location in patent: Page/Page column 23
22
[ 101012-32-2 ]
[ 884049-52-9 ]
Reference：
[1] Chinese Chemical Letters, 2011, vol. 22, # 9, p. 1009 - 1012
With sodium hydroxide; cetyltributylphosphonium bromide; In water; at 100℃; for 1h;
Example 17 3- [ (L -METHYL-1 , 2 -DIHYDRO-LH-SPIRO [PIPERIDINE-4, 3'-pyrrolo [2, 3-B] PYRIDIN]-1- yl) methyl]-1, 2,3, 4-TETRAHYDROISOQUINOLIN-8-OL (A) 1-BENZYL-1 , 2'-dihydrospiro [piperidine-4, 3'-pyrrol [2, 3-B] PYRIDINE] A mixture of (2-chloropyridin-3-yl) acetonitrile (830 mg, 5.44 mmol, reported by Bremner, H. D. et AL., Synthesis, 1992,528), N BENZYL-N, N BIS (2-chloroethyl) amine (1389 mg, 5.98 mmol), and hexadecyltributylphosphonium bromide (138.1 mg, 0.272 mmol) in 50 % NaOH solution (8.3 mL) was stirred at 100 C for lh (J. Heterocycle Chem, 1986,23, 73). The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The extracts combined were dried (NA2S04), filtered, and concentrated to give 2.293 g of crude product, which was purified by silica gel column chromatography (hexane/ethyl acetate: 1/1) to give 1026.6 mg (60 %) of BENZYL-4- (2-CHLOROPYRIDIN-3-YL) piperidine-4-carbonitrile as a brown solid. 1H NMR (270MHz, CDC13) 8 8. 40 (1H, dd, J = 1. 8, 4.6 Hz), 7.75 (1H, dd, J = 1.8, 7.9 Hz), 7.36-7. 23 (6H, m), 3.62 (2H, s), 3.90-3. 00 (2H, m), 2.67-2. 46 (4H, m), 2.16- 2.04 (2H, m). To a stirred suspension OF LIALH4 (478.2 mg, 12.6 mmo) in THF (30 mL) was added a solution of BENZYL-4- (2-CHLOROPYRIDIN-3-YL) piperidine-4-carbonitrile (983. 6 mg, 3.15 mmol) in THF (20 mL) at 0 C and the reaction mixture was refluxed for 15 h. After cooled down to 0 C, the reaction mixture was quenched with aqueous NA2S04 solution (3.6 mL). The reaction mixture was diluted with CH2C12 (20 mL) and dried (NA2S04). After Celite filtration, the filtrate was concentrated to give 1.0677 g of the amine derivative, which was dissolved in acetonitrile (20 mL) and refluxed in the presence of K2CO3 (1.306 g, 9.45 mmol) for 21 h. After Celite filtration, the filtrate was concentrated to give 1.0483 g of crude product as the title compound. 1H NMR (270MHz, CDC13) 8 7. 82 (1H, dd, J = 1.5, 5.3 Hz), 7.35-7. 20 (6H, m), 6.53 (1H, dd, J = 4.8, 6.4 Hz), 4.45 (2H, br. s), 3.55 (2H, s), 3.45 (2H, s), 3.90-3. 00 (2H, m), 2.88-2. 79 (2H, m), 2. 18-2. 07 (2H, m), 1.96-1. 84 (2H, m), 1.80-1. 65 (2H, m). MS (ESI positive) m/z: 280 (M+H) +.
2-[(4-iodo-2-methylphenyl)amino]thieno[2,3-b]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With sodium hydride; In dimethyl sulfoxide; at 80℃; for 3h;
EXAMPLE 18; 2-['('4-Iodo-2-methylphenyl)ainino]thienor2,3-61pyridine-3-carbonitrile; To a stirred solution of Intermediate 8 (429 mg, 3.28 mmol) and (2-chloropyridin- 3-yl)acetonitrile (D. H. Bremner et al, Synthesis, 1997, 949) (500 mg, 3.28 mmol) in DMSO (20 mL)was added sodium hydride (164 mg, 4.1 mmol). When evolution of gases had finished the reaction mixture was heated for 3 hours at 8O0C. After this time the reaction mixture was poured onto ice and extracted into DCM (2 x 50 mL). The organics were dried (Na2SO4) and then evaporated in vacuo to give a brown residue. Column chromatography (SiO2, 5:1 hexane:EtOAc) gave the title compound as a yellow powder (198 mg, 15%). deltaH (DMSO-d6) 10.11 (IH, s), 8.29 (IH, dd, J 1.5, 4.7 Hz), 7.75 (2H, m), 7.63 (IH, dd, J 1.7, 8.1 Hz), 7.39 (IH, dd, J8.1, 4.8 Hz), 7.19 (IH, d, J8.3 Hz), 2.24 (3H, s). LCMS (ES+) RT 3.68 minutes, 392 (M+H)+.
2-[(2-chloro-4-iodophenyl)amino]thieno[2,3-b]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With sodium hydride; In dimethyl sulfoxide; at 80℃; for 4h;
EXAMPLE 20; 2-r(2-Chloro-4-iodophenvDaminolthienor2,3-blpyridine-3-carbonitrile; Intermediate 9 (300 mg, 1.01 mmol) and <strong>[101012-32-2](2-chloropyridin-3-yl)acetonitrile</strong> (D. H. Bremner et al, Synthesis, 1997, 949) (165 mg, 1.01 mmol) were stirred together in DMSO (20 mL) and sodium hydride (48 mg, 1.21 mmol) was added portionwise. After <n="34"/>evolution of gases was complete the reaction mixture was heated for 4 h at 8O0C. After this time the reaction mixture was added to ice (50 mL) and then extracted into DCM (2 x 50 mL), which was dried (Na2SO4) and evaporated in vacuo to give a yellow residue. This residue was subjected to column chromatography (SiO2, 1 :4 EtOAc :hexane) to afford the title compound as a yellow powder (118 mg, 28%). deltaH (DMSO-d6) 10.38 (IH, s), 8.35 (IH, dd, J 1.5, 4.8 Hz), 8.00 (IH, d, J 1.9 Hz), 7.80 (2H, m), 7.42 (IH, dd, J 8.0, 4.8 Hz), 7.35 (IH, d, J 8.3 Hz). LCMS (ES+) RT 3.70 minutes, 412 (M+H)+.
With sodium hydride; In dimethyl sulfoxide; at 20 - 90℃; for 4.25h;
EXAMPLE 10; <n="30"/>2-[(2-Fluoro-4-iodophenyl')aminolthienor2,3-&lpyridine-3-carbonitrile; To a solution of <strong>[101012-32-2](2-chloropyridin-3-yl)acetonitrile</strong> (D. H. Bremner et al, Synthesis, 1997, 949) (700 mg, 4.59 mmol) and Intermediate 1 (1.28 g, 4.60 mmol) in dry DMSO (15 mL) was added sodium hydride (202 mg, 60% in mineral oil, 5.06 mmol). The mixture was stirred at room temperature for 15 minutes before heating to 9O0C for four hours. The reaction mixture was poured into water (80 mL) and the solid precipitate filtered and washed with water/ethanol (2:1 mixture, 50 mL) followed by diethyl ether/ hexane (1:1 mixture, 20 mL). The solid was dried in a vacuum oven and recrystallised from ethanol/water to give the title compound as a pale brown solid (800 mg, 45%). delta? (DMSO-d6) 10.40 (IH, s), 8.37 (IH, dd, J 1.3, 4.6 Hz), 7.83-7.81 (2H, m), 7.64 (IH, d, J 8.3 Hz), 7.44 (IH, dd, J4.7, 8.0 Hz), 7.33 (IH, dd, J8.3, 8.3 Hz). LCMS RT 3.08 minutes, (ES") 394 (M-H)", (ES+) 396 (M+H)+.
45%
With sodium hydride; In dimethyl sulfoxide; mineral oil; at 20 - 90℃; for 4.25h;
INTERMEDIATE 14 2-[(2-Fluoro-4-iodophenyl)amino1thieno[2,3-?]pyridme-3-carbonitrileTo a solution of <strong>[101012-32-2](2-chloropyridin-3-yl)acetonitrile</strong> {Intermediate 2; 700 mg, 4.59 mmol) and Intermediate 4 (1.28 g, 4.60 mmol) in dry DMSO (15 mL) was added sodium hydride (202 mg, 60% in mineral oil, 5.06 mmol). The mixture was stirred at room temperature for 15 minutes before heating to 9O0C for four hours. The reaction mixture was poured into water (80 mL) and the solid precipitate filtered and washed with water/ ethanol (2:1 mixture, 50 mL) followed by diethyl ether/hexane (1:1 mixture, 20 mL). The solid was dried in a vacuum oven and recrystallised from ethanol/water to give the title compound as a pale brown solid (800 mg, 45%). ?H (DMSOd6) 10.40 (IH, s), 8.37 (IH, dd, J 1.3, 4.6 Hz), 7.83-7.81 (2H, m), 7.64 (IH, d, J 8.3 Hz), 7.44 (IH, dd, J 4.7, 8.0 Hz), 7.33 (IH, dd, J 8.3, 8.3 Hz). LCMS RT 3.08 minutes, (ES") 394 (M-H)", (ES+) 396 (M+H)+.
(Step 3) To a solution of the compound (20.5 g) obtained in step 2 in DMSO (100 mL) was added sodium cyanide (12.4 g), and the mixture was stirred at 50C for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was poured into a mixture of water and ethyl acetate. The organic layer was washed with brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10?25% ethyl acetate/hexane) to give (2-chloropyridin-3-yl)acetonitrile (11.7 g, 61%) as a white powder. 1H-NMR(CDCl3): delta 3.87(2H,s), 7.34(1H,dd,J=7.6,4.8Hz), 7.88-7.93(1H,ddd like), 8.41(1H,dd,J=4.8,1.8Hz)
INTERMEDIATE 2(2-Chloro?yridin-3 - vDacetonitrileIn a 3 L reactor, set for reflux under positive nitrogen pressure and using a bleach scrubber, was prepared a solution of potassium cyanide (68.32 g, 1.04M) in EtOH (136 mL) and water (255 mL). The mixture was heated to reflux, at which point a solution of 2-chloro-3-(chloromethyl)pyridine {Intermediate 1; 170.0 g, 1.04M) in EtOH (170 mL) was added drop wise over 30 minutes. The whole mixture was maintained at reflux for a further 150 minutes. The mixture was then allowed to cool just below boiling point and the equipment set for distillation. A total of 8.5 volumes of EtOH were removed. On cooling, half a volume of water was added. At a temperature of 4O0C, the solution was seeded and crystallised instantaneously. The thick beige slurry was allowed to cool to ambient temperature and then to O0C. This mixture was filtered, rinsed with cold water (2 vols) and dried at 450C in a vacuum oven overnight. The title compound was afforded as a beige solid in excellent yield and purity (126.9 g, 80%). ?H (d6-DMSO, 300 MHz) 8.45 (IH, dd), 8.00 (IH, dd), 7.50 (IH, dd), 4.15 (2H, s). LCMS (ES)+ RT 2.15 min, m/e 153.01 & 155.01 (M+l & M+3, Product).
In ethanol; water; for 3h;Reflux; Inert atmosphere;
In a 3 L reactor, set for reflux under positive nitrogen pressure and using a bleach scrubber, was prepared a solution of potassium cyanide (68.32 g, 1.04M) in EtOH (136 mL) and water (255 niL). The mixture was heated to reflux, at which point a solution of 2-chloro-3-(chloromethyl)pyridine {Intermediate 1; 170.0 g, 1.04M) in EtOH (170 mL) was added dropwise over 30 minutes. The whole mixture was maintained at reflux for a further 150 minutes. The mixture was then allowed to cool just below boiling point and the equipment set for distillation. A total of 8.5 volumes of EtOH were removed. On cooling, half a volume of water was added. At a temperature of 4O0C, the solution was seeded and crystallised instantaneously. The thick beige slurry was allowed to cool to ambient temperature and then to 00C. This mixture was filtered, rinsed with cold water (2 vols) and dried at 450C in a vacuum oven overnight. The title compound was afforded as a beige solid in excellent yield and purity (126.9 g, 80%). deltaH (d6-DMSO, 300 MHz) 8.45 (IH, dd), 8.00 (IH, dd), 7.50 (IH, dd), 4.15 (2H, s). LCMS (ES)+ RT 2.15 min, m/e 153.01 & 155.01 (M+l & M+3, Product).
NaH (4.25 g) was slowly added to a solution of 3-chloro-2-pyridylacetonitrile (10 g) in DMSO (140 ml) under nitrogen. The mixture was stirred at room temperature for lh. A solution of bis- (2-chloro-ethyl)-carbamic acid tert-butyl ester (15.87 g) in DMSO (140 ml) was added and the resulting mixture was stirred at 70C for 2 hrs. After cooling, the reaction mixture was partitioned between ethyl acetate and water, the combined organic layers were washed with saturated sodium bicarbonate and brine, dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography [sio2 ; ethyl acetate-hexane (3: 7) ] to give 12.96 g (61%) of 2-chloro-4'-cyano-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-carboxylic acid tert-butyl ester as a white solide ; MS (ES+) 322/324 (M+H+).
In ethanol; water; for 3h;Inert atmosphere; Reflux;
INTERMEDIATE 2(2-Chloropyridin-3-yl)acetonitrileIn a 3 L reactor, set for reflux under positive nitrogen pressure and using a bleach scrubber, was prepared a solution of potassium cyanide (68.32 g, 1.04M) in EtOH (136 <n="37"/>mL) and water (255 mL). The mixture was heated to reflux, at which point a solution of 2-chloro-3-(chloromethyl)pyridine {Intermediate 1; 170.0 g, 1.04M) in EtOH (170 mL) was added dropwise over 30 minutes. The whole mixture was maintained at reflux for a further 150 minutes. The mixture was then allowed to cool just below boiling point and the equipment set for distillation. A total of 8.5 volumes of EtOH were removed. On cooling, half a volume of water was added. At a temperature of 4O0C, the solution was seeded and crystallised instantaneously. The thick beige slurry was allowed to cool to ambient temperature and then to 00C. This mixture was filtered, rinsed with cold water (2 vo Is) and dried at 450C in a vacuum oven overnight. The title compound was afforded as a beige solid in excellent yield and purity (126.9 g, 80%). deltaH (d6-DMSO, 300 MHz) 8.45 (IH, dd), 8.00 (IH, dd), 7.50 (IH, dd), 4.15 (2H, s). LCMS (ES)+ RT 2.15 min, m/e 153.01 & 155.01 (M+l & M+3, Product).
Example 6AEthyl 2-(2-chloropyridin-3-yl)acetimidateThrough a cooled solution of <strong>[101012-32-2]2-<strong>[101012-32-2](2-chloropyridin-3-yl)acetonitrile</strong></strong> (Synthesis (6), 528-30, 1992) (1.7 g, 11.1 mmol), ethanol (1.0 mL, 16.7 mmol), and dichloromethane (25 mL) was bubbled HCl gas at 0 C. for 30 minutes. After standing at 4 C. for 24 hours, the reaction mixture was concentrated, and the residue was triturated with diethyl ether. The precipitate was collected and dried to obtain the titled compound. MS (ESI+) m/z 199 (M+H)+.
With sodium hexamethyldisilazane; In tetrahydrofuran; for 0.333333h;Cooling with ice; Inert atmosphere;
2-(2-Chloropyridin-3-yl)acetonitrile (0.280 g, 1.835 mmol) was dissolved in dry tetrahydrofuran (1.5 mL) under nitrogen and cooled in an ice bath. 1,4-Dibromobutane (0.220 ml, 1.842 mmol) was added followed by dropwise addition of sodium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 4.5 ml, 4.50 mmol). The mixture was stirred for 20 minutes then quenched by addition of saturated ammonium chloride (10 mL). Water (100 mL) and ethyl acetate (200 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired 1-(2-chloropyridin-3-yl)cyclopentanecarbonitrile (0.252 g, 1.219 mmol, 66.4% yield).
methyl 5-(2-chloropyridin-3-yl)-5-cyano-2-oxocyclohexane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With potassium tert-butylate; In tetrahydrofuran; at 0 - 25℃; for 3h;
To a solution of 2-(2-methylpyridin-3-yl)acetoni- trile (1.0 g, 6.6 mmol) and methyl acrylate (1.8 mE, 19.9 mmol) in THF (10 mE) at 0 C. was added potassiumtert-butoxide (8.6 mE, 8.6 mmol, 1 M in THF) and the resulting reaction mixture stirred at 25 C. for 3 h. The mixture was partitioned between H20 (100 mE) and EtOAc (80 mE), the aqueous layer further extracted with EtOAc (2x80 mE), combined organics dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by colunm chromatography (normal silica, mesh size: 60-120, 0% to 0.5% MeOH in DCM) to give methyl 5-(2-chloro- pyridin-3-yl)-5-cyano-2-oxocyclohexane- 1 -carboxylate (1.2 g, 63%) as a yellow liquid.ECMS (Method F): mlz 293 (M+H) (ESj, at 1.97 mm UV active.
Chemistry
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Material Science
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110K+ Compounds
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