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[ CAS No. 13472-85-0 ] {[proInfo.proName]}

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Chemical Structure| 13472-85-0
Chemical Structure| 13472-85-0
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Product Details of [ 13472-85-0 ]

CAS No. :13472-85-0 MDL No. :MFCD01318952
Formula : C6H6BrNO Boiling Point : -
Linear Structure Formula :- InChI Key :XADICJHFELMBGX-UHFFFAOYSA-N
M.W :188.02 Pubchem ID :2734895
Synonyms :

Calculated chemistry of [ 13472-85-0 ]

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.17
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 38.43
TPSA : 22.12 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.74 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.16
Log Po/w (XLOGP3) : 2.41
Log Po/w (WLOGP) : 1.85
Log Po/w (MLOGP) : 1.33
Log Po/w (SILICOS-IT) : 2.04
Consensus Log Po/w : 1.96

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.95
Solubility : 0.21 mg/ml ; 0.00112 mol/l
Class : Soluble
Log S (Ali) : -2.52
Solubility : 0.572 mg/ml ; 0.00304 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.01
Solubility : 0.185 mg/ml ; 0.000986 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.74

Safety of [ 13472-85-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 13472-85-0 ]

* 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.

  • Upstream synthesis route of [ 13472-85-0 ]
  • Downstream synthetic route of [ 13472-85-0 ]

[ 13472-85-0 ] Synthesis Path-Upstream   1~67

  • 1
  • [ 13472-85-0 ]
  • [ 13466-38-1 ]
Reference: [1] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
  • 2
  • [ 13472-85-0 ]
  • [ 53939-30-3 ]
YieldReaction ConditionsOperation in experiment
76% With trichlorophosphate In N,N-dimethyl-formamide a
5-Bromo-2-chloro-pyridine
To a solution of 15.0 g (75.8 mmol) 5-bromo-2-methoxypyridine in 90 ml dry N,N-dimethylformamide 21.2 ml (227 mol) phosphorus oxychloride were slowly added at 0° C.
After completed addition the reaction mixture was heated to 110° C. over a period of 30 min.
At this temperature the reaction started to be exothermic.
The heating bath was partly removed such that the internal temperature did not exceed 120° C.
When the internal temperature started to drop heating was resumed, and the reaction mixture was kept at an internal temperature of 100-110° C. for 18 h.
After cooling to room temperature the reflux condenser was exchanged by a claisen condenser, and the title compound was gained as a mixture with N,N-dimethylformamide by vacuum distillation at 40-50° C. (1-10 mbar).
The distillate was diluted with cyclohexane and washed with two portions of water.
The combined aqueous layers were extracted with cyclohexane.
The combined organic extracts were dried with sodium sulfate and concentrated to give 11.0 g (76percent) of the title compound as a white solid.
MS m/e, isotope cluster (percent): 191 (M+, 75), 193 (100), 195 (24).
Reference: [1] Tetrahedron Letters, 1998, vol. 39, # 15, p. 2059 - 2062
[2] Synthetic Communications, 1990, vol. 20, # 19, p. 2971 - 2977
[3] Patent: US2002/19531, 2002, A1,
[4] Patent: US2002/40040, 2002, A1,
  • 3
  • [ 13472-85-0 ]
  • [ 74-88-4 ]
  • [ 81971-39-3 ]
Reference: [1] Patent: WO2014/81617, 2014, A1, . Location in patent: Page/Page column 42-43
  • 4
  • [ 13472-85-0 ]
  • [ 81971-39-3 ]
Reference: [1] Patent: WO2013/49565, 2013, A1,
[2] Patent: WO2013/49559, 2013, A1,
[3] Patent: WO2005/44195, 2005, A2,
  • 5
  • [ 13472-85-0 ]
  • [ 13473-01-3 ]
Reference: [1] Synthesis, 2012, vol. 44, # 5, p. 735 - 746
[2] Synlett, 2009, # 15, p. 2508 - 2512
  • 6
  • [ 13472-85-0 ]
  • [ 51834-97-0 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With n-butyllithium; Trimethyl borate In tetrahydrofuran at -78℃; for 2.75 h;
Stage #2: for 1.5 h; Heating / reflux
To a stirred solution of 5-bromo-2-methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78 °C was added an n-butyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was allowed to stir at -78 °C for 45 min. Trimethyl borate (7.06 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h. The bright orange reaction mixture was warmed to 0 °C and was treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution (30percent; approx. 50 mL). The resulting yellow and slightly turbid reaction mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h. The reaction mixture was then allowed to cool to room temp. The aqueous layer was neutralized with a 1N HCl solution then extracted with Et2O (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 60percent).
60%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.75 h;
Stage #2: With Trimethyl borate In tetrahydrofuran; hexane at -78℃; for 2 h;
Stage #3: With sodium hydroxide; water; dihydrogen peroxide In tetrahydrofuran; hexane at 0 - 20℃; for 1.5 h; Heating / reflux
Step 2. 5-Hydroxy-2-methoxypyridine; To a stirred solution of 5-bromo-2-methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78 °C was added an n-butyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was allowed to stir at -78 °C for 45 min. Trimethyl borate (7.06 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h. The bright orange reaction mixture was warmed to 0 °C and was treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution (30percent; approx. 50 mL). The resulting yellow and slightly turbid reaction mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h. The reaction mixture was then allowed to cool to room temp. The aqueous layer was neutralized with a 1N HCl solution then extracted with Et2O (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 60percent).
60%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.75 h;
Stage #2: With Trimethyl borate In tetrahydrofuran; hexane for 2 h;
Stage #3: With sodium hydroxide; dihydrogen peroxide In tetrahydrofuran; hexane; water at 0 - 20℃; for 1.5 h; Heating / reflux
Step 2.
5-Hydroxy-2-methoxypyridine

To a stirred solution of 5-bromo-2-methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78° C. was added an n-butyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was allowed to stir at -78° C. for 45 min.
Trimethyl borate (7.06 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h.
The bright orange reaction mixture was warmed to 0° C. and was treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution (30percent; approx. 50 mL).
The resulting yellow and slightly turbid reaction mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h.
The reaction mixture was then allowed to cool to room temp.
The squares layer was neutralized with a 1N HCl solution then extracted with Et2O (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a viscous yellow oil (3.5 g, 60percent).
60%
Stage #1: With n-butyllithium; dihydrogen peroxide In tetrahydrofuran; hexane at -78℃; for 0.75 h;
Stage #2: With Trimethyl borate In tetrahydrofuran; hexane at -78 - 0℃;
Stage #3: With dihydrogen peroxide; sodium hydroxide In tetrahydrofuran; hexane at 0℃; Reflux
Step 2.
5-Hydroxy-2-methoxypyridine
To a stirred solution of 5-bromo-2-methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78° C. was added an n-butyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was allowed to stir at -78° C. for 45 min.
Trimethyl borate (7.06 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h.
The bright orange reaction mixture was warmed to 0° C. and was treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution (30percent; approx. 50 mL).
The resulting yellow and slightly turbid reaction mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h.
The reaction mixture was then allowed to cool to room temp.
The aqueous layer was neutralized with a 1N HCl solution then extracted with Et2O (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a viscous yellow oil (3.5 g, 60percent).
60%
Stage #1: With n-butyllithium; dihydrogen peroxide In tetrahydrofuran; hexane at -78℃; for 0.75 h;
Stage #2: With Trimethyl borate In tetrahydrofuran; hexane at -78℃; for 2 h;
Stage #3: With sodium hydroxide; dihydrogen peroxide In tetrahydrofuran; hexane; water at 0 - 20℃; for 1.5 h; Heating / reflux
To a stirred solution of 5-bromo-2-methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78 °C was added an n-butyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was allowed to stir at -78 °C for 45 min.
Trimethyl borate (7.06 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h.
The bright orange reaction mixture was warmed to 0 °C and was treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution (30percent; approx. 50 mL).
The resulting yellow and slightly turbid reaction mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h.
The reaction mixture was then allowed to cool to room temp.
The aqueous layer was neutralized with a 1N HCl solution then extracted with Et2O (2 x 100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 60percent).

Reference: [1] Medicinal Chemistry Research, 2013, vol. 22, # 4, p. 1825 - 1836
[2] Heterocycles, 2002, vol. 57, # 1, p. 55 - 71
[3] Patent: EP1449834, 2004, A2, . Location in patent: Page 27
[4] Patent: EP1042305, 2005, B1, . Location in patent: Page/Page column 33
[5] Patent: US2003/207914, 2003, A1, . Location in patent: Page/Page column 12
[6] Patent: US2012/46290, 2012, A1, . Location in patent: Page/Page column 20
[7] Patent: EP1047418, 2005, B1, . Location in patent: Page/Page column 33-34
[8] Patent: US2006/89370, 2006, A1, . Location in patent: Page/Page column 34
[9] Patent: WO2014/186035, 2014, A1,
[10] European Journal of Medicinal Chemistry, 2016, vol. 109, p. 268 - 275
  • 7
  • [ 13472-85-0 ]
  • [ 121-43-7 ]
  • [ 51834-97-0 ]
YieldReaction ConditionsOperation in experiment
60% With sodium hydroxide; n-butyllithium; dihydrogen peroxide In tetrahydrofuran; hexane Step 2.
5-Hydroxy-2-methoxypyridine

To a stirred solution of 5-bromo-2-methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78° C. was added an n-butyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was allowed to stir at -78° C. for 45 min.
Trimethyl borate (7.06 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h.
The bright orange reaction mixture was warmed to 0° C. and was treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution (30percent; approx. 50 mL).
The resulting yellow and slightly turbid reaction mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h.
The reaction mixture was then allowed to cool to room temp.
The aqueous layer was neutralized with a 1N HCl solution then extracted with Et2O (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 60percent).
60% With sodium hydroxide; n-butyllithium; dihydrogen peroxide In tetrahydrofuran; hexane Step 2.
5-Hydroxy-2-methoxypyridine
To a stirred solution of 5-bromo-2-methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78° C. was added an n-butyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was allowed to stir at -78° C. for 45 min.
Trimethyl borate (7.06 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h.
The bright orange reaction mixture was warmed to 0 ° C. and was treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution (30percent; approx. 50 mL).
The resulting yellow and slightly turbid reaction mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h.
The reaction mixture was then allowed to cool to room temp.
The aqueous layer was neutralized with a 1 N HCl solution then extracted with Et2O (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 60percent).
60%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.75 h;
Stage #2: for 2 h;
Stage #3: With sodium hydroxide; dihydrogen peroxide In tetrahydrofuran; hexane; water at 0 - 20℃; for 1.5 h; Heating / reflux
Step 2. 5-Hydroxy-2-methoxypyridine; To a stirred solution of 5-bromo-2-methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at -78° C. was added an n-butyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was allowed to stir at -78° C. for 45 min. Trimethyl borate (7.06 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h. The bright orange reaction mixture was warmed to 0° C. and was treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution (30percent; approx. 50 mL). The resulting yellow and slightly turbid reaction mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h. The reaction mixture was then allowed to cool to room temp. The aqueous layer was neutralized with a 1N HCl solution then extracted with Et2O (2.x.100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a viscous yellow oil (3.5 g, 60percent).
Reference: [1] Patent: US2002/65296, 2002, A1,
[2] Patent: US2004/102636, 2004, A1,
[3] Patent: US2007/244120, 2007, A1, . Location in patent: Page/Page column 20-21
  • 8
  • [ 624-28-2 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
95% With sodium methylate In methanol; water Step 1.
5-Bromo-2-methoxypyridine

A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 rmol) in MeOH (60 mL) was heated at 70° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc/90percent hexane) Rf0.57.
95% With sodium methylate In methanol; water Step 1.
5-Bromo-2-methoxypyridine
A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70 ° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2*100 mmL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc /90percent hexane) R.f.0.57.
95% With sodium methylate In methanol at 70℃; for 42 h; A13k. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction ; [] Step 1. 5-Bromo-2-methoxypyridine: A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95percent yield): TLC (10percent EtOAc / 90percent hexane) Rf 0.57.
83% With ammonium chloride; sodium In methanol Reference Example 10
5-Bromo-2-methoxypyridine
After sodium (10 g, 0.435 mol) was dissolved in methanol (500 ml), 2,5-dibromopyridine (50 g, 0.211 mol) was added thereto and the mixture was heated for 2 days under reflux.
The reaction solution was cooled as it was, and then concentrated.
Then, the residue was diluted with ethyl acetate and an aqueous saturated solution of ammonium chloride.
The organic layer was washed with an aqueous saturated solution of ammonium chloride and brine, and then dried over anhydrous sodium sulfate and concentrated, to give the title compound (33 g, 83percent) as a pale brown oil.
1H NMR (400 MHz, DMSO-d6) δ ppm; 3. 84 (3H, s), 6. 72(1H, dd, J= 0. 8, 8. Hz), 7. 89 (1H, dd, J= 2. 4, 8. 8 Hz), 8. 29 (1H, dd, J= 0. 8, 2.4 Hz).
83%
Stage #2: for 48 h; Heating / reflux
Reference Example 10
5-Bromo-2-methoxypyridine
After sodium (10 g, 0.435 mol) was dissolved in methanol (500 ml), 2,5-dibromopyridine (50 g, 0.211 mol) was added thereto and the mixture was heated for 2 days under reflux.
The reaction solution was cooled as it was, and then concentrated.
Then, the residue was diluted with ethyl acetate and an aqueous saturated solution of ammonium chloride.
The organic layer was washed with an aqueous saturated solution of ammonium chloride and brine, and then dried over anhydrous sodium sulfate and concentrated, to give the title compound (33 g, 83percent) as a pale brown oil.
1H NMR (400 MHz, DMSO-d6) δ ppm; 3.84 (3H, s), 6.72 (1H, dd, J=0.8, 8.8 Hz), 7.89 (1H, dd, J=2.4, 8.8 Hz), 8.29 (1H, dd, J=0.8, 2.4 Hz).

Reference: [1] Patent: US2002/65296, 2002, A1,
[2] Patent: US2004/102636, 2004, A1,
[3] Patent: EP1042305, 2005, B1, . Location in patent: Page/Page column 32-33
[4] Tetrahedron, 1985, vol. 41, # 7, p. 1373 - 1384
[5] Patent: EP1308441, 2003, A1,
[6] Patent: US2004/6082, 2004, A1, . Location in patent: Page/Page column 23
[7] Patent: US5512575, 1996, A,
[8] Patent: US2002/137770, 2002, A1,
[9] Patent: US5922742, 1999, A,
[10] Patent: US5714496, 1998, A,
  • 9
  • [ 624-28-2 ]
  • [ 124-41-4 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
95% at 70℃; for 42 h; A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95percent yield): TLC (10percent EtOAc / 90percent hexane) Rf 0.57
95% at 70℃; for 42 h; B3k. General Method for Substituted Aniline Formation Via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction; Step 1. 5-Bromo-2-methoxypyridine; A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2.x.100 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc/90percent hexane) Rf 0.57.
95% at 70℃; for 42 h; Step 1.
5-Bromo-2-methoxypyridine

A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc/90percent hexane) Rf 0.57.
95% at 70℃; for 42 h; Sealed tube Step 1.
5-Bromo-2-methoxypyridine
A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc/90percent hexane) Rf 0.57.
95% at 70℃; for 42 h; A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95percent yield): TLC (10percent EtOAc / 90percent hexane) Rf 0.57.
78.6% for 17 h; Heating / reflux 1)
5-Bromo-2-methoxypyridine
Sodium methoxide (55.2 g) was added to 2,5-dibromopyridine (50.0 g) in methanol (100 mL).
The resultant mixture was refluxed for 17 hours, followed by cooling in air.
The formed salt was separated by filtration, and the filtrate solvent was evaporated under reduced pressure.
5percent Aqueous sodium hydrogencarbonate and diethyl ether were added thereto for partitioning the residue.
The organic layer was washed with saturated brine, followed by drying over magnesium sulfate anhydrate.
After a filtration step, the solvent was evaporated under reduced pressure, to thereby give 5-bromo-2-methoxypyridine as an oily product (31.2 g, 78.6percent).
1H-NMR (300MHz, CDCl3) δ:3.91 (3H, s), 6.66 (1H, d, J=8.81Hz), 7.63 (1H, dd, J=8.81, 2.39Hz), 8.20 (1H, d, J=2.39Hz).
58% at 20 - 70℃; for 1 h; Step 1: 5-Bro -2-methoxypyridine A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70°C for 1 hour and then allowed to cool to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over Na2S04 and concentrated under reduced pressure to give a pale yellow volatile oil (2.5 g, 58percent yield). 1H NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 7.87 (dd, 1H), 6.81 (d, 1H), 3.82 (s, 3H).

Reference: [1] Patent: EP1449834, 2004, A2, . Location in patent: Page 27
[2] Patent: US2007/244120, 2007, A1, . Location in patent: Page/Page column 20
[3] Patent: US2003/207914, 2003, A1, . Location in patent: Page/Page column 12
[4] Patent: US2012/46290, 2012, A1, . Location in patent: Page/Page column 20
[5] Patent: EP1047418, 2005, B1, . Location in patent: Page/Page column 33
[6] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
[7] Bulletin des Societes Chimiques Belges, 1986, vol. 95, # 11, p. 1009 - 1020
[8] Journal of Medicinal Chemistry, 2000, vol. 43, # 11, p. 2217 - 2226
[9] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1583 - 1592
[10] Journal of the American Chemical Society, 1997, vol. 119, # 33, p. 7694 - 7701
[11] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 26-27
[12] Patent: WO2013/49559, 2013, A1, . Location in patent: Page/Page column 67
[13] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 8, p. 1077 - 1080
[14] Patent: WO2013/49565, 2013, A1, . Location in patent: Page/Page column 72
  • 10
  • [ 1628-89-3 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
86% With bromine; sodium acetate In ethyl acetate at 10 - 50℃; for 16.5 h; Ethyl acetate (325 kg), sodium acetate (58 kg, 707 mol) and 2-methoxypyridine (68.7 kg, 630 mol) were mixed in a reactor vessel (inner volume 1000 L).
To this solution was added dropwise bromine (122.3 kg, 765 mol) over 6.5 hr while keeping the inside temperature from exceeding 10°C.
After the dropwise addition, the inside temperature was raised to 20°C and the mixture was stirred for 5 hr.
The ratio of reaction progress at this time point was 73percent.
Thereafter, the inside temperature was raised to 50°C and the reaction was continued more for 5 hr.
The ratio of reaction progress at this time point was 98percent.
The reaction mixture was cooled and water (70 kg) was added to the reaction mixture.
While keeping the inside temperature from exceeding 5°C, the solution obtained by dissolving sodium hydroxide (46.1 kg) and sodium sulfite (17 kg) in water (200 kg) was added dropwise.
The reaction mixture was stood still to allow partitioning.
After confirming that the pH of the aqueous layer was not less than 8 and peroxide was absent, the organic layer was separated.
The aqueous layer was extracted with ethyl acetate (40 kg), and the extract and the above-mentioned organic layers were combined.
The mixture was concentrated under reduced pressure to give crude 5-bromo-2-methoxypyridine (gross: 121.8 kg, net: 110.7 kg, yield 93percent).
The crude product was purified by distillation under reduced pressure to give 5-bromo-2-methoxypyridine (101.8 kg, yield 86percent) having the following analytical data at a purity of not less than 99percent.
1H-NMR spectrum (CDCl3) 8: 3.90(s,3H), 6.65(d,1H,J=8.8Hz), 7.62(dd,1H,J=2.4Hz,8.8Hz), 8.20(d,1H,J=2.4Hz)
86% With bromine; sodium acetate In dichloromethane at 0 - 20℃; Large scale To a suspension of 2-methoxypyridine (1-9) (3.96 kg; 36.3 mol), NaOAc (3.57 kg; 39.9 mol), and dichloromethane (22 L) was added a solution of bromine (2.06 L; 39.9 mol) in dichloromethane (2 L), maintaining the reaction temperature below 7°C over 2-3 hours. The mixture was aged for 1 hour at 0°C — 7°C and stirred at room temperature overnight. The reaction mixture was filtered and rinsed with dichloromethane (about 5 L) (the filtration stepmay be omitted without negatively impacting the yield). The filtrate and washings were combined, washed with cold 2 M NaOH (22 L; pH is maintained between 9 and 10) maintaining the temperature below 10°C, and with cold water (11 L). The organic layer was separated and concentrated under reduced pressure to give crude product 1-10 (6.65 kg). The crude product j 10 was purified by vacuum distillation to give pure 1-10 (5.90 kg, 86 percent). (Reference: G. Butoraet al., J. Amer. Chem. Soc. 1997, 119, 7694-7701).‘H NIVIR (250 MHz; CDC13): ö 8.18 (d, J= 2.5 Hz, 1H), 7.61 (dd, J= 8.8 and 2.5 Hz, 1H), 6.64 (d, J= 8.8 Hz, 1H), and 3.89 (s, 3H).‘3CNMR(62.9 MHz; CDC13): ö 162.9, 147.5, 141.0, 112.6, 111.7, and 53.7.
84% With N-Bromosuccinimide In acetonitrile for 21 h; Reflux Step h:
5-Bromo-2-methoxypyridine (Compound 303)
A solution of 2-methoxy-pyridine (100 g, 0.92 mole), NBS (180 g, 1.0 mole) in acetonitrile (1.0 L) was stirred at reflux for 21 h. TLC showed that the reaction was complete.
The reaction mixture was cooled to room temperature and concentrated. ˜900 ml solvent was collected.
The resulting suspension was filtered and washed with n-hexane (˜400 mL).
The filtrate was concentrated again to afford crude product.
The crude product was distilled at reduced pressure (30° C./˜0.3 mmHg) to afford the title compound as a clear oil (146 g, 84percent). LCMS (m/z): 190.0 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 3.90 (s, 3H), 6.65 (d, J=8.8 Hz, 1H), 7.62 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.19 (s, 1H).
84% With N-Bromosuccinimide In acetonitrile for 21 h; Reflux A solution of 2-methoxy-pyridine (100 g, 0.92 mole), NBS (180 g, 1.0 mole) inacetonitrile (1. OL) was stirred at reflux for 21 h. TLC showed that the reaction wascomplete. The reaction mixture was cooled to room temperature and concentrated. 900ml solvent was collected. The resulting suspension was filtered and washed with n-hexane (400mL). The filtrate was concentrated again to afford crude product. The cmde product was distilled at reduced pressure (30°C[-0.3mmHg) to afford the title compound as a clearoil (146 g, 84percent). LCMS (m/z): 190.0 [M+1f ‘H NMR (400 MHz, CDC13): ö 3.90 (s,3H), 6.65 (d, J= 8.8 Hz, 1H), 7.62 (dd, J= 8.8 Hz, 2.4Hz, 1H), 8.19 (s, 1H).
66%
Stage #1: With bromine In acetic acid at 10 - 20℃;
Stage #2: With sodium hydroxide In acetic acid at 0℃;
A solution of bromine (13.1mL, 256.6 mMol) in glacial acetic acid (45 mL) was added drop wise into a mechanically stirred suspension of 2-Methoxy-pyridine (19 mL, 183 mMol) in glacial acetic acid (88 mL) with the temperature kept at ten degrees.
After complete addition the solution was allowed to stir overnight while gradually warming to room temperature.
Upon arrival the reaction mixture was poured over ice and the pH adjusted to eight with solid sodium hydroxide.
The material was then diluted with diethyl ether (150 mL) and filtered thru Celite.
The aqueous layer was extracted with diethyl ether (2*100 mL) and ethyl acetate (2*100 mL) and all the organics combined.
The solution was dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator to a dark brown oil.
The oil was eluted thru a plug of silica gel with hexanes and concentrated to yield 22.6 g (66percent yield) of 5-Bromo-2-methoxy-pyridine as a clear oil. 1H NMR (DMSO-d6): δ=8.29 (dd,1H,J=2.6,0.5 Hz), 7.89 (dd, 1H, J=8.8, 2,6 Hz), 6.84 (dd, 1H, J=8.8, 0.5 Hz), 3.84 (s, 3H). LC/MS (Method A), rt=1.35 mins., purity=76.5percent, calculated mass=187,[M+H]+=188/190, [M-H]- 187/189. HPLC (Method C): rt=8.1 mins., purity=88.0percent at; 210-370 nm and 88.3percent at; 286 nm.
51.3% With bromine; sodium acetate In hexane; water; acetic acid; ethyl acetate a.
5-Bromo-2-methoxy-pyridine
To a suspension of 2-methoxypyridine (10.00 g, 0.09 mol) and sodium acetate (8.27 g, 0.10 mmol) in 30 mL of glacial acetic acid was added a solution of bromine in 20 mL glacial acetic acid while maintaining the reaction temperature below 50° C.
After 3 hours, 100 mL of H2O was added and the resulting solution neutralized with cold 2.5 M NaOH.
The suspension was extracted with ether (2*200 mL), the combined organics were dried over MgSO4, filtered and evaporated.
The crude material was purified on silica gel (eluent: hexane to hexane:ethyl acetate 97:3) and distilled (34-36.5° C./0.05 mm Hg) to give 8.84 g (51.3percent) of 5-bromo-2-methoxypyridine as a clear colorless liquid.
51.3% With bromine; sodium acetate In hexane; acetic acid; ethyl acetate a.
5-Bromo-2-methoxy-pyridine.
To a suspension of 2-methoxypyridine (10.00 g, 0.09 mol) and sodium acetate (8.27 g, 0.10 mmol) in 30 mL of glacial acetic acid was added a solution of bromine in 20 mL glacial acetic acid while maintaining the reaction temperature below 50° C.
After 3 hours, 100 mL of H20 was added and the resulting solution neutralized with cold 2.5M NaOH.
The suspension was extracted with ether (2*200 mL), the combined organics were dried over MgSO4, filtered and evaporated.
The crude material was purified on silica gel (eluent:hexane to hexane:ethyl acetate 97:3) and distilled (34-36.5° C./0.05 mm Hg) to give 8.84 g (51.3percent) of 5-bromo-2-methoxypyridine as a clear colorless liquid.
51.3% With bromine; sodium acetate In hexane; water; acetic acid; ethyl acetate a.
5-Bromo-2-methoxy-pyridine
To a suspension of 2-methoxypyridine (10.00 g, 0.09 mol) and sodium acetate (8.27 g, 0.10 mmol) in 30 mL of glacial acetic acid was added a solution of bromine in 20 mL glacial acetic acid while maintaining the reaction temperature below 50° C.
After 3 hours, 100 mL of H2O was added and the resulting solution neutralized with cold 2.5 M NaOH.
The suspension was extracted with ether (2*200 mL), the combined organics were dried over MgSO4, filtered and evaporated.
The crude material was purified on silica gel (eluent: hexane to hexane:ethyl acetate 97:3) and distilled (34-36.5° C./0.05 mm Hg) to give 8.84 g (51.3percent) of 5-bromo-2-methoxy-pyridine as a clear colorless liquid.

Reference: [1] Synthesis, 1994, # 1, p. 87 - 92
[2] Patent: EP1553086, 2005, A1, . Location in patent: Page/Page column 7-8
[3] Patent: WO2016/154369, 2016, A1, . Location in patent: Page/Page column 21
[4] Synthesis, 2012, vol. 44, # 5, p. 735 - 746
[5] Patent: US9249156, 2016, B2, . Location in patent: Page/Page column 35
[6] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 26; 29
[7] Organic and Biomolecular Chemistry, 2008, vol. 6, # 8, p. 1364 - 1376
[8] Synthesis, 2001, # 14, p. 2175 - 2179
[9] Journal of the American Chemical Society, 1997, vol. 119, # 33, p. 7694 - 7701
[10] Chemistry - A European Journal, 2017, vol. 23, # 35, p. 8450 - 8456
[11] Patent: US2006/19965, 2006, A1, . Location in patent: Page/Page column 27
[12] Journal of the American Chemical Society, 1982, vol. 104, # 15, p. 4142 - 4146
[13] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 22, p. 3689 - 3697
[14] Tetrahedron Letters, 1998, vol. 39, # 15, p. 2059 - 2062
[15] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 8, p. 2714 - 2718
[16] Journal of the American Chemical Society, 1999, vol. 121, # 19, p. 4722 - 4723
[17] Patent: US2003/144329, 2003, A1,
[18] Patent: US2003/83357, 2003, A1,
[19] Patent: US2002/37889, 2002, A1,
[20] Patent: US6515003, 2003, B1,
[21] Patent: WO2014/186035, 2014, A1, . Location in patent: Page/Page column 150; 151
  • 11
  • [ 624-28-2 ]
  • [ 67-56-1 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
98% for 5 h; Reflux (1) In a 500 ml reaction flask, 47 g of 2,5-dibromopyridine,8 g of solid sodium hydroxide and 200 ml of methanol,Stirring began to heat up to reflux, the reaction time was 5 hours,Stop the reaction, steamed most of the methanol, cooled, add 100 ml of water,Extract once with dichloromethane, remove methylene chloride to give the crude product,The crude product was distilled under reduced pressure to give 2-methoxy-5-bromopyridine,The yield is 98percent.
Reference: [1] Patent: CN106905229, 2017, A, . Location in patent: Paragraph 0026; 0027
[2] Journal of Organic Chemistry, 1999, vol. 64, # 3, p. 836 - 842
[3] Patent: US2004/102472, 2004, A1, . Location in patent: Page 37
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
  • 12
  • [ 13466-38-1 ]
  • [ 74-88-4 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
12g With silver carbonate In benzene at 50℃; for 16 h; Silver carbonate (16.0 g, 57.8 mmol) and methyl iodide (6.5 mL, 103 mmol) were sequentially added to a solution of 5-bromopyridin-2(1H)-one (15.0 g, 86.2 mmol) in benzene (225 mL). The mixture was stirred for 16 h at 50° C. After cooling to room temperature, the mixture was filtered through celite and concentrated. Purification by chromatography using 1-5percent ethyl acetate in pet ether provided 12 g of the desired compound: 1H NMR (300 MHz, CDCl3) 8.15-8.25 (narrow m, 1H), 7.63 (dd, J=9, 3 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 3.92 (s, 3H).
12 g With silver carbonate In benzene at 50℃; for 16 h; Silver carbonate (16.0 g, 57.8 mmol) and methyl iodide (6.5 mL, 103 mmol) were sequentially added to a solution of 5-bromopyridin-2(1H)-one (15.0 g, 86.2 mmol) in benzene (225 mL).
The mixture was stirred for 16 h at 50° C.
After cooling to room temperature, the mixture was filtered through celite and concentrated.
Purification by chromatography using 1-5percent ethyl acetate in pet ether provided 12 g of the desired compound: 1H NMR (300 MHz, CDCl3) 8.15-8.25 (narrow m, 1H), 7.63 (dd, J=9, 3 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 3.92 (s, 3H).
Reference: [1] Heterocycles, 1990, vol. 31, # 5, p. 819 - 824
[2] Patent: US2015/210671, 2015, A1, . Location in patent: Paragraph 0173; 0179; 0180
[3] Patent: US9145393, 2015, B2, . Location in patent: Page/Page column 29; 30; 37
  • 13
  • [ 1628-89-3 ]
  • [ 13472-85-0 ]
  • [ 13472-59-8 ]
Reference: [1] The Journal of organic chemistry, 2004, vol. 69, # 6, p. 1959 - 1966
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4790 - 4798
  • 14
  • [ 1628-89-3 ]
  • [ 13472-85-0 ]
  • [ 65873-72-5 ]
YieldReaction ConditionsOperation in experiment
51% With bromine; sodium acetate In hexane; acetic acid a)
The 5-(2-methoxypyridine)carboxaldehyde was prepared as follows:
Bromine (0.99 ml) was added dropwise to a stirred suspension of sodium acetate (1.59 g) and 2-methoxypyridine (1.93 ml) in acetic acid (10 ml).
The reaction mixture was stirred at room temperature for 25 minutes, then at 80° C. for 2.5 h.
The mixture was then allowed to cool and poured into ice-water, neutralised with 2M sodium hydroxide and extracted with ether.
The combined extracts were dried (MgSO4), filtered and evaporated.
The crude product was purified by column chromatography on silica gel eluding with 5percent ethyl acetate in hexane to give 5-bromo-2-methoxypyridine as a colourless oil (1.75 g, 51percent).
MS (ES) 190, 188 (M+H)+.
1H NMR (CDCl3) 8.20 (1H, d), 7.63 (1H, dd), 6.65 (1H, d), 3.90 (3H, s).
Reference: [1] Patent: US2002/107252, 2002, A1,
  • 15
  • [ 624-28-2 ]
  • [ 67-56-1 ]
  • [ 124-41-4 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
95% at 70℃; for 42 h; Step 1.
5-Bromo-2-methoxypyridine
A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76 g, 69.6 mmol) in MeOH (60 mL) was heated at 70° C. in a sealed reaction vessel for 42 h, then allowed to cool to room temp.
The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2*100 mL).
The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1 g, 95percent yield): TLC (10percent EtOAc/90percent hexane) 190.57.
Reference: [1] Patent: US2008/269265, 2008, A1, . Location in patent: Page/Page column 17
[2] Synthesis, 2012, vol. 44, # 1, p. 57 - 62
  • 16
  • [ 67-56-1 ]
  • [ 39856-50-3 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
54% at 75℃; for 2 h; A solution of 5-bromo-2-nitropyridine (5.0 g, 24.63 mmol), in methanol (100 mL) was added sodium methoxide (2.67 g, 49.44 mmol) and stirred at 75 00 for 2 h. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (2 x 200 mL). The combined extracts were washed with water (200 mL), brine (200 mL), dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient mixture of 5percent ethyl acetate in pet-ether as eluant to afford 2.5 g (54percent) of 5-bromo-2-methoxypyridine 122-1 as a colorless liquid. 1H NMR (400 MHz, CDCI3): c5 8.19 (d, J= 2.2 Hz, 1 H), 7.63 (dd, J= 1.8, 8.8 Hz, 1H), 6.66 (d, J= 8.7 Hz, 1H), 3.90 (5, 3H). ESI-LC/MS: m/z190.13 [(M+2)H+]; R = 3.13 mm [Agilent [C with Ion trap Detector; Waters Symmetry 018, 3.5 pm, 4.6 X 75 mm column; gradient of 50:50 H20 (0.1percent H000H): CH3CN (0.1percent H000H) to 10:90 H20 (0.1percent H000H): CH3CN (0.1percent H000H) in 4mm and hold for 3mm with flow rate of 1.0 mL/min].
Reference: [1] Patent: WO2014/78802, 2014, A1, . Location in patent: Page/Page column 199
  • 17
  • [ 53939-30-3 ]
  • [ 124-41-4 ]
  • [ 13472-85-0 ]
YieldReaction ConditionsOperation in experiment
33% at 90℃; for 24 h; A 0.5 M sodium methoxide methanol solution (NaOMe in MeOH, 10.4 mL, 5.19 mmol) was added to 5-bromo-2-chloropyridine (96, 500 mg, 2.59 mmol) dissolved in methanol (10 mL) at room temperature, stirred at 90° C. for 24 hours, followed by adding water. Organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-methoxy-5-bromopyridine (97a, 160 mg, 33percent).1H NMR (400 MHz, CDCl3) δ 3.98 (s, 3H), 6.39 (d, J=2.4 Hz, 1H), 7.47 (dd, J=8.8, 2.4 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 53.5, 60.3, 111.6, 112.5, 140.9, 147.4, 162.9.
Reference: [1] Patent: US2010/261727, 2010, A1, . Location in patent: Page/Page column 23
  • 18
  • [ 6628-77-9 ]
  • [ 13472-85-0 ]
Reference: [1] Heterocycles, 2002, vol. 57, # 1, p. 55 - 71
  • 19
  • [ 624-28-2 ]
  • [ 13472-85-0 ]
Reference: [1] Patent: US2003/96829, 2003, A1,
  • 20
  • [ 39856-50-3 ]
  • [ 34851-41-7 ]
  • [ 13472-85-0 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 4, p. 577 - 579
  • 21
  • [ 1628-89-3 ]
  • [ 13472-85-0 ]
  • [ 13472-60-1 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1583 - 1592
  • 22
  • [ 53939-30-3 ]
  • [ 67-56-1 ]
  • [ 13472-85-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 77 - 105
  • 23
  • [ 1072-97-5 ]
  • [ 13472-85-0 ]
Reference: [1] Yakugaku Zasshi, 1952, vol. 72, p. 381[2] Chem.Abstr., 1953, p. 6403
  • 24
  • [ 39856-50-3 ]
  • [ 124-41-4 ]
  • [ 13472-85-0 ]
Reference: [1] Yakugaku Zasshi, 1952, vol. 72, p. 381[2] Chem.Abstr., 1953, p. 6403
  • 25
  • [ 13472-85-0 ]
  • [ 6628-77-9 ]
Reference: [1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 24, p. 8224 - 8227
[2] Advanced Synthesis and Catalysis, 2009, vol. 351, # 11-12, p. 1722 - 1726
[3] Journal of Organic Chemistry, 2012, vol. 77, # 16, p. 6908 - 6916
  • 26
  • [ 13472-85-0 ]
  • [ 13472-61-2 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: With n-butyllithium; isopropylmagnesium chloride In tetrahydrofuran; hexane at 0℃; for 0.75 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran; hexane at 0 - 20℃; for 1.5 h; Inert atmosphere
To an ice-cooled solution of isopropylmagnesium chloride (1.61 M inTHF, 4.64 mL, 7.47 mmol) in THF (20 mL) was slowly added n-BuLi(1.5 M in hexane, 4.98 mL, 7.47 mmol). The mixture was then stirred for 5 min to give a yellow solution, then 5-bromo-2-methoxypyridine (1.405 g, 0.98 mL, 7.10 mmol, 95percent) was added and the resulting solution was stirred for 45 min at 0 °C. Molecular iodine (3.79 g, 14.94 mmol) was added and the mixture was stirred for 30 min at 0 °C then for 1 h at r.t. Sat. aq NH4Cl (5 mL) was then added, and the phases were separated. The aqueous phase was extracted with EtOAc (2 × 75mL) and the combined organic layers were dried over MgSO4, filtered,and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (EtOAc–heptanes, 5–80percent) to afford 4.
Reference: [1] Synthesis, 2012, vol. 44, # 5, p. 735 - 746
[2] Synthesis (Germany), 2015, vol. 47, # 20, p. 3231 - 3240
[3] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10480 - 10483
  • 27
  • [ 13472-85-0 ]
  • [ 544-92-3 ]
  • [ 15871-85-9 ]
YieldReaction ConditionsOperation in experiment
56.5% at 120 - 140℃; for 41 h; 2)
6-Methoxynicotinonitrile
Copper cyanide (24.6 g) was added to the above-obtained 5-bromo-2-methoxypyridine (31.0 g) in N,N-dimethylformamide (600 mL).
The resultant mixture was stirred at 120°C for 19 hours, and at 140°C for 22 hours, followed by cooling in air.
The reaction mixture was subjected to filtration, and then the filtrate was partitioned between water and methylene chloride.
The organic layer was washed with saturated brine, followed by drying over magnesium sulfate anhydrate.
After a filtration step, the solvent was removed under reduced pressure.
The residue still contained N,N-dimethylformamide, therefore water and ethyl acetate were added thereto for partitioning the residue again.
The organic layer was dried over magnesium sulfate anhydrate.
After a filtration step, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane - ethyl acetate), to thereby give 6-methoxynicotinonitrile as a solid product (12.5 g, 56.5percent).
1H-NMR(300MHz,CDCl3)δ:4.00(3H,s), 6.82(1H,d,J=8.81Hz), 7.77(1H,dd,J=8.81,2.39Hz), 8.49(1H,d,J=2.39Hz).
Reference: [1] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 27
[2] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3168 - 3185
  • 28
  • [ 13472-85-0 ]
  • [ 15871-85-9 ]
Reference: [1] Synlett, 2008, # 1, p. 69 - 72
  • 29
  • [ 13472-85-0 ]
  • [ 13061-96-6 ]
  • [ 13472-56-5 ]
Reference: [1] Green Chemistry, 2017, vol. 19, # 21, p. 5046 - 5053
  • 30
  • [ 1628-89-3 ]
  • [ 13472-85-0 ]
  • [ 13472-59-8 ]
Reference: [1] The Journal of organic chemistry, 2004, vol. 69, # 6, p. 1959 - 1966
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 22, p. 4790 - 4798
  • 31
  • [ 13472-85-0 ]
  • [ 13472-60-1 ]
YieldReaction ConditionsOperation in experiment
10.6 g at 20 - 80℃; for 16 h; Bromine (17.8 g, 111 mmol) was added to a solution of 5-bromo-2-methoxypyridine (12.0 g, 63.8 mmol), sodium acetate (5.23 g, 63.8 mmol), and acetic acid (65 mL). The mixture was stirred at 80° C. for 4 h and then at room temperature for 12 h. The mixture was diluted with ether and washed with water, sodium bicarbonate and hypo solution. The organic layer was dried over sodium sulphate, filtered and concentrated. Purification by chromatography using 1-5percent ethyl acetate in pet ether provided 10.6 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) 8.20-8.40 (m, 2H), 3.92 (s, 3H).
10.6 g at 20 - 80℃; for 16 h; Bromine (17.8 g, 111 mmol) was added to a solution of 5-bromo-2-methoxypyridine (12.0 g, 63.8 mmol), sodium acetate (5.23 g, 63.8 mmol), and acetic acid (65 mL).
The mixture was stirred at 80° C. for 4 h and then at room temperature for 12 h.
The mixture was diluted with ether and washed with water, sodium bicarbonate and hypo solution.
The organic layer was dried over sodium sulphate, filtered and concentrated.
Purification by chromatography using 1-5percent ethyl acetate in pet ether provided 10.6 g of the desired compound: 1H NMR (300 MHz, DMSO-d6) 8.20-8.40 (m, 2H), 3.92 (s, 3H).
Reference: [1] Patent: US2010/81673, 2010, A1, . Location in patent: Page/Page column 14
[2] Patent: US2015/210671, 2015, A1, . Location in patent: Paragraph 0173; 0181; 0182
[3] Patent: US9145393, 2015, B2, . Location in patent: Page/Page column 37; 38
  • 32
  • [ 1628-89-3 ]
  • [ 13472-85-0 ]
  • [ 13472-60-1 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 1583 - 1592
  • 33
  • [ 13472-85-0 ]
  • [ 68-12-2 ]
  • [ 65873-72-5 ]
YieldReaction ConditionsOperation in experiment
94%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1.5 h;
Stage #2: at -78 - 20℃; for 1.5 h;
N-Butyl lithium (50 mL, 2.5M in hexane) was added drop wise to a solution of 5-Bromo-2-methoxy-pyridine (22.4 g, 119.1 mMol) in dry tetrahydrofuran (240 mL) at -78 degrees.
After complete addition the solution was stirred at -78 for an additional ninety minutes at which time dimethylformamide (18.5 mL, 238.3 mMol) was added drop wise and the solution stirred for ninety more minutes at -78 and then allowed to warm to room temperature.
The mixture was then poured into saturated sodium bicarbonate solution (1000 mL) and extracted with diethyl ether (3*250mL).
The combined organics were dried with magnesium sulfate, filtered, and concentrated to dryness to yield 15.4 g (94percent yield) of 6-Methoxy-pyridine-3-carbaldehyde as a pale yellow solid. 1H NMR (DMSO-d6): δ=9.97 (s,1H), 8.77 (m, 1H), 8.12 (dd, 1H, J=8.6, 2.3 Hz), 6.99 (d, 1H, J=8.7 Hz), 3.97 (s, 3H). LC/MS (Method A), rt=0.25 mins., purity=92.8percent, calculated mass=137, [M+H]+=138. HPLC (Method C): rt=4.9 mins., purity=95.9percent at; 210-370 nm and 98.7percent at; 256 nm.
20%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at -78℃; for 2 h;
A solution of 5-bromo-2-methoxypyridine SM 1(1.04 g, 5.5 mmol) in THF (20 mL) was added n-BuLi (5.5 mL, 5.5 mmol) at -78 °C under N2, stirred at -78 °C for 0.5 h. Then DMF (1.5mL) was added and stirred at -78 °C for 2 h. The reaction was quenched with water and extracted with EtOAc, dried and evaporated, purified by combiflash (petroleum ether: ethyl acetate = 1:1) to give compound 1 (150 mg, 20percent).
66.7 g
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78℃; for 1 h;
To a solution of 5-bromo-2-methoxy-pyridine (95.0 g, 0.51 mol) in THF (2.0 L) was addedn-BuLi (212 ml, 0.53 mol) at -78 °C slowly. After the mixture was stuffed at -78 °C for 0.5 hr, tothe reaction mixture was added anhydrous DMF (44.3 g, 0.61 mmol) slowly. The reaction mixture was stirred at -78 °C for another lhr and then the reaction was quenched with sat. aqueous solution of NH4C1. The resulting mixture was extracted with EA. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue waspurified by flash column to give 6-methoxypyridine-3-carbaldehyde (66.7 g) as a light yellow solid.
Reference: [1] Synthesis, 2012, vol. 44, # 5, p. 735 - 746
[2] Journal of medicinal chemistry, 2004, vol. 47, # 20, p. 4829 - 4837
[3] Patent: US2006/19965, 2006, A1, . Location in patent: Page/Page column 27
[4] Synthesis, 1994, # 1, p. 87 - 92
[5] Synlett, 2009, # 15, p. 2508 - 2512
[6] Chemistry - A European Journal, 2017, vol. 23, # 35, p. 8450 - 8456
[7] Patent: WO2016/44770, 2016, A1, . Location in patent: Page/Page column 741
[8] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
[9] Journal of the American Chemical Society, 1997, vol. 119, # 33, p. 7694 - 7701
[10] Journal of the American Chemical Society, 1999, vol. 121, # 19, p. 4722 - 4723
[11] Patent: WO2016/107832, 2016, A1, . Location in patent: Page/Page column 157
  • 34
  • [ 13472-85-0 ]
  • [ 65873-72-5 ]
YieldReaction ConditionsOperation in experiment
81% With n-butyllithium In tetrahydrofuran; <i>N</i>-methyl-acetamide b)
5-Bromo-2-methoxypyridine (1.53 g) was stirred in dry tetrahydrofuran (35 ml) under argon at -78° C. Butyl lithium (6.6 ml, 1.6M solution) was added dropwise to the solution and stirring continued at -78° C. for 1.5 h.
Dimethylformamide (1.3 ml) was then added dropwise and stirring continued at -78° C. for a further 30 minutes before allowing to warm to room temperature.
The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and the aqueous phase was extracted with ether.
The combined extracts were dried (MgSO4), filtered and evaporated.
The residue was purified by column chromatography on silica gel to give 5-(2-methoxypyridine)carboxaldehyde as a white solid (0.91 g, 81percent).
1H NMR (CDCl3) 9.95 (1H, s), 8.63 (1H, d), 8.06 (1H, dd), 6.85 (1H, d), 4.04 (3H, s).
Reference: [1] Patent: US2002/107252, 2002, A1,
  • 35
  • [ 13472-85-0 ]
  • [ 65873-72-5 ]
Reference: [1] Patent: US2003/144329, 2003, A1,
[2] Patent: US2003/83357, 2003, A1,
[3] Patent: US6515003, 2003, B1,
[4] Patent: US5618821, 1997, A,
  • 36
  • [ 1628-89-3 ]
  • [ 13472-85-0 ]
  • [ 65873-72-5 ]
YieldReaction ConditionsOperation in experiment
51% With bromine; sodium acetate In hexane; acetic acid a)
The 5-(2-methoxypyridine)carboxaldehyde was prepared as follows:
Bromine (0.99 ml) was added dropwise to a stirred suspension of sodium acetate (1.59 g) and 2-methoxypyridine (1.93 ml) in acetic acid (10 ml).
The reaction mixture was stirred at room temperature for 25 minutes, then at 80° C. for 2.5 h.
The mixture was then allowed to cool and poured into ice-water, neutralised with 2M sodium hydroxide and extracted with ether.
The combined extracts were dried (MgSO4), filtered and evaporated.
The crude product was purified by column chromatography on silica gel eluding with 5percent ethyl acetate in hexane to give 5-bromo-2-methoxypyridine as a colourless oil (1.75 g, 51percent).
MS (ES) 190, 188 (M+H)+.
1H NMR (CDCl3) 8.20 (1H, d), 7.63 (1H, dd), 6.65 (1H, d), 3.90 (3H, s).
Reference: [1] Patent: US2002/107252, 2002, A1,
  • 37
  • [ 13472-85-0 ]
  • [ 107-31-3 ]
  • [ 65873-72-5 ]
Reference: [1] Organic Letters, 2014, vol. 16, # 19, p. 4972 - 4975
  • 38
  • [ 13472-85-0 ]
  • [ 20461-86-3 ]
  • [ 65873-72-5 ]
Reference: [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 6, p. 1500 - 1505[2] Angew. Chem., 2017, vol. 129, # 6, p. 1522 - 1527,6
  • 39
  • [ 13472-85-0 ]
  • [ 123506-66-1 ]
Reference: [1] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
  • 40
  • [ 13472-85-0 ]
  • [ 76053-45-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
  • 41
  • [ 13472-85-0 ]
  • [ 138469-76-8 ]
Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 3, p. 1217 - 1232
  • 42
  • [ 13472-85-0 ]
  • [ 152684-30-5 ]
Reference: [1] Acta Chemica Scandinavica, 1993, vol. 47, # 8, p. 805 - 812
  • 43
  • [ 13472-85-0 ]
  • [ 78191-00-1 ]
  • [ 213193-32-9 ]
YieldReaction ConditionsOperation in experiment
62%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.333333 h;
Stage #2: at -70 - 20℃;
[0559] To a solution of III-1 (30 g, 0.162 mol, 1 eq.) in 300 mL of anhydrous THF was added dropwise a solution of n-BuLi (2.5M in hexane, 77.5 mL, 0.19 mol, 1.2 eq.) at −70° C. After completion of addition, the mixture was stirred at −70° C. for 20 min, followed by addition of a solution of N-methoxy-N-methylacetamide (33 g, 0.322 mol, 2 eq.) in 100 mL of anhydrous THF by drop wise, the solution was allowed to warm to rt and stirred for 2 hrs. The reaction was quenched with saturated aq. NH4Cl (100 mL), extracted with EtOAc (300 mL×3), the organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with petroleum ether/EtOAc (100:1) to yield III-2 (14.8 g, 62percent yield) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.81 (d, J=2.0 Hz, 1H), 8.16 (dd, J=2.4, 8.4 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 3.93 (s, 3H), 2.55 (s, 3H). MS (ESI) m/z [M+H]+ 151.6.
62%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 0.333333 h;
Stage #2: at 20℃; for 2 h;
To a solution of Ill-i (30 g, 0.162 mol, 1 eq.) in 300 mL of anhydrous THF was added dropwise a solution of n-BuLi (2.5M in hexane, 77.5 mL, 0.19 mol, 1.2 eq.) at -70°C. After completion of addition, the mixture was stuffed at -70°C for 20 mm, followed by addition of a solution of N-methoxy-N-methylacetamide (33 g, 0.322 mol, 2 eq.) in 100 mL of anhydrous THF by drop wise, the solution was allowed to warm to rt and stirred for 2 hrs. The reaction was quenched with saturated aq. NH4C1 (100 mL), extracted with EtOAc (300 mLx3), the organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with petroleum ether/EtOAc (100:1) to yield 111-2 (14.8 g, 62percent yield) as a white solid. ‘H NMR (DMSO-d6, 400 MHz) (58.81 (d, J= 2.0 Hz, 1H), 8.16 (dd, J= 2.4, 8.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 3.93 (s, 3H), 2.55 (s, 3H). MS (ES) m/z [M+H] 15 1.6.
Reference: [1] Patent: US2014/94456, 2014, A1, . Location in patent: Paragraph 0558-0559
[2] Patent: WO2015/153683, 2015, A1, . Location in patent: Paragraph 0313
  • 44
  • [ 13472-85-0 ]
  • [ 111-34-2 ]
  • [ 213193-32-9 ]
Reference: [1] Patent: WO2005/40151, 2005, A1, . Location in patent: Page/Page column 45-46
  • 45
  • [ 13472-85-0 ]
  • [ 97674-02-7 ]
  • [ 213193-32-9 ]
Reference: [1] Patent: WO2017/214505, 2017, A1, . Location in patent: Paragraph 000494; 000495
  • 46
  • [ 13472-85-0 ]
  • [ 75-07-0 ]
  • [ 213193-32-9 ]
Reference: [1] Patent: WO2013/155341, 2013, A1, . Location in patent: Paragraph 0144
[2] Patent: WO2015/61229, 2015, A1, . Location in patent: Paragraph 0177
  • 47
  • [ 13472-85-0 ]
  • [ 213193-32-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 24, p. 10290 - 10303
  • 48
  • [ 13472-85-0 ]
  • [ 111-34-2 ]
  • [ 213193-32-9 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1998, vol. 35, # 3, p. 717 - 723
  • 49
  • [ 13472-85-0 ]
  • [ 1124-29-4 ]
Reference: [1] Patent: US2014/94456, 2014, A1,
[2] Patent: WO2015/153683, 2015, A1,
  • 50
  • [ 13472-85-0 ]
  • [ 163105-89-3 ]
YieldReaction ConditionsOperation in experiment
75%
Stage #1: With n-butyllithium; Triisopropyl borate In tetrahydrofuran; hexanes at -78 - 20℃; for 12.0333 h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran; hexanes for 0.5 h;
Stage #3: With sodium hydroxide; water In tetrahydrofuran; hexanes
Intermediate 25a : [6-(methyloxy)-3-pyridinyl]boronic acidTo a stirred solution of 17.0 ml_ (0.131 mol) of 5-bromo- 2methoxypyridine in 130 ml_ THF at -780C was added 79 ml_ (0.197 mol) 2.5 M nBuLi (in hexanes) and the solution stirred for 2 min at -780C. To this solution was added 45 ml_ (0.197 mol) of B(OiPr)3 and the reaction allowed to warm to room temperature over 12 hr. The solution was then poured into 300 ml_ 1.0 N HCI (aq) and stirred vigorously for 30 min. The pH of the solution was raised to 7.0 with 3.0 N NaOH (aq) then the solution was extracted with three 150 ml_ portions of EtOAc. The combined organics were washed with 200 ml_ brine, dried over Na2SO4 and concentrated. This residue was then dissolved in 350 ml_ 2.0 M NaOH, washed with two 200 ml_ portions of EtOAc then the pH of the aqueous layer was lowered to 7.0 with cone. HCI (aq.) The resulting solids were filtered, washed with H2O and dried to yield 15.01 g (75percent) of [6-(methyloxy)-3-pyridinyl]boronic acid as a white powder: 1 H NMR (400 MHz, DMSO-c/6). δ 8.51 (s, 1 H), 8.12 (bs, 2H), 7.95 (d, 1 H, J = 7.8 Hz), 6.73 (d, 1 H, J = 7.8 Hz), 3.83 (s, 3H)
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 224 - 239
[2] Patent: WO2008/28118, 2008, A1, . Location in patent: Page/Page column 77
[3] Journal of Organic Chemistry, 2005, vol. 70, # 1, p. 388 - 390
[4] Journal of Organic Chemistry, 2002, vol. 67, # 21, p. 7541 - 7543
[5] Patent: US2006/111394, 2006, A1, . Location in patent: Page/Page column 17
[6] Journal of Medicinal Chemistry, 2010, vol. 53, # 1, p. 77 - 105
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
[8] Patent: US2008/207902, 2008, A1, . Location in patent: Page/Page column 65
  • 51
  • [ 13472-85-0 ]
  • [ 5419-55-6 ]
  • [ 163105-89-3 ]
YieldReaction ConditionsOperation in experiment
67%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78 - 20℃;
Stage #3: With hydrogenchloride; water In tetrahydrofuran
Step i: 6-Methoxypyridin-3-ylboronic acid (R-3-1) (0154) To a solution of compound 303 (20 g, 0.11 mole) in anhydrous THF (180 ml) was added dropwise n-BuLi (59 mL, 2M in THF) at −78° C., the resulting mixture was stirred for 1 h. Triisopropyl borate (37 mL) was added at −78° C. and the reaction mixture was warmed to room temperature and continued to stir overnight. TLC (hexanes/ethyl acetate=5:1) showed reaction complete. The mixture was adjusted pH to 3-4 with 4N HCl (90 ml). The precipitate was collected by filtration to afford crude compound R-3-1 (21 g, 128percent). The crude compound R-3-1 (21 g) was dissolved in water (200 ml) and the solution was adjusted pH to 8-9 with concentrated ammonia solution, the precipitate was collected by filtration to afford the pure title compound R-3-1 as a white solid. (11 g, 67percent). LCMS (m/z): 154.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6): δ 3.86 (s, 3H), 6.76 (d, J=8.4 Hz, 1H), 7.99 (dd, J=8.4 Hz, 2.0 Hz, 1H), 8.05 (br, 2H), 8.52 (d, J=2.0 Hz, 1H).
67%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h;
Stage #2: at -78 - 20℃;
To a solution of compound 303 (20 g, 0.11 mole) in anhydrous THF (180 ml) was added dropwise n-BuLi (59 mL, 2M in THF) at -78 °C, the resulting mixture was stirredfor 1 h. Triisopropyl borate (37mL) was added at -78 °C and the reaction mixture was warmed to room temperature and continued to stir overnight. TLC (hexanes/ethyl acetate =5:1) showed reaction complete. The mixture was adjusted pH to 3-4 with 4N HC1 (90 ml). The precipitate was collected by filtration to afford cmde compound R-3-1 (21 g, 128percent). The cmde compound R-3-1 (21g) was dissolved in water (200 ml) and the solutionwas adjusted pH to 8-9 with concentrated ammonia solution, the precipitate was collected by filtration to afford the pure title compound R-3-1 as a white solid. (11 g, 67percent). LCMS (m/z): 154.1 [M+1f ‘HNMR(400MF{z,DMSO-d6): ö3.86(s, 3H), 6.76 (d,J= 8.4 Hz, 1H), 7.99 (dd, J= 8.4 Hz, 2.0 Hz, 1H), 8.05 (br, 2H), 8.52 (d, J 2.0 Hz, 1H).
Reference: [1] Patent: US9249156, 2016, B2, . Location in patent: Page/Page column 36
[2] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 26; 29
[3] Patent: WO2005/68436, 2005, A1, . Location in patent: Page/Page column 26
  • 52
  • [ 13472-85-0 ]
  • [ 121-43-7 ]
  • [ 163105-89-3 ]
YieldReaction ConditionsOperation in experiment
88% With hydrogenchloride; n-butyllithium In tetrahydrofuran anhydride; ethyl acetate 6-Methoxy-3-pyridylboronic acid
5-Bromo-2-methoxypyridine (152g) was dissolved in tetrahydrofuran anhydride (1520mL) under stirring in nitrogen atmosphere, followed by cooling to -75.1°C as bulk temperature.
Under cooling and stirring, 380mL of a 2.46mol/L butyl lithium solution was added dropwise thereinto, followed by the dropwise addition of 192mL of trimethoxyborane.
The cooling bath was removed 30 minutes after completion of the dropwise addition, and the mixture was stirred at room temperature overnight.
On the next day, 1.5L of a 2mol/L aqueous solution of hydrochloric acid was added thereto, followed by stirring for 1.5 hours.of sodium hydroxide.
It was then extracted with 1L of ethyl acetate, and the resulting aqueous layer was extracted again with 1L of ethyl acetate.
The combined organic layer was washed twice with 1L of 10percent saline water, dried over anhydrous magnesium sulfate, and then evaporated, to give 105g (88percent) of the title compound as a slightly yellowish white solid.
1H-NMR(CDCl3,400MHz):3.83(3H,s), 6.74(1H,d), 7.98 (1H, dd), 8.10 (2H, s), 8.50 (1H, s).
Reference: [1] Patent: EP1300396, 2003, A1,
  • 53
  • [ 13472-85-0 ]
  • [ 380917-97-5 ]
Reference: [1] Synthesis, 2012, vol. 44, # 1, p. 57 - 62
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
[3] Patent: US2016/39759, 2016, A1,
  • 54
  • [ 13472-85-0 ]
  • [ 73183-34-3 ]
  • [ 445264-61-9 ]
YieldReaction ConditionsOperation in experiment
84% With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In 1,4-dioxane at 108℃; Inert atmosphere Step j:
2-methoxy-5-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound R-3-2)
A mixture of compound 303 (55 g, 0.29 mol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (90 g, 0.35 mol), potassium acetate (57 g, 0.58 mol) and bis(triphenylphosphine)palladium(II) chloride (2.2 g, 3 mmol) in anhydrous dioxane (500 mL) was heated at 108° C. under N2 atmosphere overnight.
The reaction mixture was concentrated and purified by column chromatography eluted with hexanes/ethyl acetate to afford title compound R-3-2 (58 g, 84percent).
84% With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In 1,4-dioxane at 108℃; Inert atmosphere A mixture of compound 303 (55 g, 0.29 mol), 4,4,4’,4’,5,5,5’,5’-octamethyl -2,2’- bi(1,3,2-dioxaborolane) (90 g, 0.35 mol), potassium acetate (57 g, 0.58 mol) and bis(triphenylphosphine)palladium(II) chloride (2.2 g, 3 mmol) in anhydrous dioxane (500 mL) was heated at 108°C under N2 atmosphere overnight. The reaction mixture wasconcentrated and purified by column chromatography eluted with hexanes/ethyl acetate to afford title compound R-3-2 (58 g, 84 percent). ‘H NMR (400 MHz, DMSO-d6): ö 1.30 (s, 12H), 3.88 (s, 3H), 6.81 (d, J= 8.0 Hz, 1H), 7.88 (dd, J 8.0 Hz, 2.0Hz, 1H), 8.41 (d, J2.0Hz, 1H).
3.6 g With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In toluene for 2 h; Inert atmosphere; Reflux 5-Bromo-2-methoxypyridine (5g, 26.59 mmol), bis(pinacolato)diborane (10.13 g, 39.89 mmol) and potassium acetate (10.44 g, 106 mmol) were taken in dry toluene (60 mL) and degassed with nitrogen for 20 mi Pd(dppf)C12.DCM (2.17 g, 2.66 mmol) was added to the reaction under nitrogen atmosphere and the resulting mixture was refluxed for 2 hr. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was cooled to 25°C and filtered through a Celite® reagent pad. Filtrate was diluted with ethyl acetate (200 mL), washed with water followed by brine, dried over Na2SO4 and concentrated under reduced pressure to provide the crude which was purified by silica gel (100-200 mesh) column chromatography using 10percent EtOAc in hexane as eluent to afford 3.6 g of 2-methoxy-5 -(4,4,5,5 -tetramethyl- [1,3 ,2]dioxaborolan-2-yl)- pyridine.
Reference: [1] Patent: US9249156, 2016, B2, . Location in patent: Page/Page column 36
[2] Patent: WO2018/85342, 2018, A1, . Location in patent: Page/Page column 26; 28
[3] Patent: WO2014/186035, 2014, A1, . Location in patent: Page/Page column 151
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 12, p. 2496 - 2500
[5] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 19, p. 6477 - 6485
[6] Patent: CN105906557, 2016, A, . Location in patent: Paragraph 0005; 0014
  • 55
  • [ 13472-85-0 ]
  • [ 61676-62-8 ]
  • [ 445264-61-9 ]
Reference: [1] Synthesis, 2012, vol. 44, # 5, p. 735 - 746
[2] Synlett, 2009, # 15, p. 2508 - 2512
  • 56
  • [ 13472-85-0 ]
  • [ 197958-29-5 ]
  • [ 381233-78-9 ]
Reference: [1] Patent: US2016/39759, 2016, A1, . Location in patent: Paragraph 0057-0058
  • 57
  • [ 13472-85-0 ]
  • [ 381233-78-9 ]
Reference: [1] Synthesis, 2012, vol. 44, # 1, p. 57 - 62
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
  • 58
  • [ 13472-85-0 ]
  • [ 381248-06-2 ]
Reference: [1] Synthesis, 2012, vol. 44, # 1, p. 57 - 62
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10584 - 10600
[3] Patent: US2016/39759, 2016, A1,
  • 59
  • [ 13472-85-0 ]
  • [ 68-12-2 ]
  • [ 936011-17-5 ]
YieldReaction ConditionsOperation in experiment
64.3%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -60℃; for 1 h;
Stage #2: at -60℃; for 1 h;
To a solution of diisopropylamine (22.7 g, 0.22 mol) in THF (0.5L) was cooled to -30°C, and then added n-BuLi (140 mL, 0.22 mol). After addition, the resulting solution was stirred for 0.5 h. The mixture was cooled to -60 °C, Example 60a (35.1 g,0.19 mol) dissolved in THF (200 mL) was added dropwise,maintained the temperature below -60 °C, the resulting solution was stirred for 1 h. DMF (20.4 g 0.28 mol) was added dropwise at -60 °C, the resulting solution was stirred for 1 h .The reaction mixture was quenched by saturated NH4C1 (200 mL) aqueous, and allowed warmed to room temperature .the residue was extracted with EtOAc (200 mL * 2). The combined organic phase was washed with brine, dried over Na2S04, filtrated and concentrated under reduced pressure to give the crude product which was further purified by silica gel chromatography to give the pure product (Example 60b, 26.4 g, yield 64.3percent) as a white solid. i NMR ^OO MHz, CDC13) δ 10.28 (s, 1H), 8.40 (s, 1H), 7.16 (s, 1H), 3.95 (s, 3H)
Reference: [1] Patent: WO2017/218960, 2017, A1, . Location in patent: Paragraph 00600
[2] Patent: WO2009/23964, 2009, A1, . Location in patent: Page/Page column 30
[3] Patent: WO2014/22528, 2014, A1, . Location in patent: Page/Page column 83; 86; 87
[4] Patent: WO2014/19186, 2014, A1, . Location in patent: Page/Page column 73
[5] Patent: US2014/94456, 2014, A1, . Location in patent: Paragraph 0925-026
[6] Patent: WO2017/147700, 2017, A1, . Location in patent: Paragraph 00511
[7] Patent: WO2018/83136, 2018, A1, . Location in patent: Page/Page column 37; .38
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  • [ 4637-24-5 ]
  • [ 936011-17-5 ]
Reference: [1] Patent: WO2015/153683, 2015, A1, . Location in patent: Paragraph 0717
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  • [ 1186637-43-3 ]
Reference: [1] Patent: WO2013/113669, 2013, A1,
[2] Patent: WO2017/139603, 2017, A1,
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  • [ 913836-17-6 ]
Reference: [1] Patent: US2014/94456, 2014, A1,
[2] Patent: WO2015/153683, 2015, A1,
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  • [ 1339928-25-4 ]
Reference: [1] Patent: US9249156, 2016, B2,
[2] Patent: US9249156, 2016, B2,
[3] Patent: US9249156, 2016, B2,
[4] Patent: WO2018/85342, 2018, A1,
[5] Patent: WO2018/85342, 2018, A1,
[6] Patent: WO2018/85342, 2018, A1,
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Reference: [1] Patent: US2014/94456, 2014, A1,
[2] Patent: WO2015/153683, 2015, A1,
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[2] Patent: WO2015/153683, 2015, A1,
[3] Patent: WO2018/83136, 2018, A1,
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  • [ 913836-16-5 ]
Reference: [1] Patent: US2014/94456, 2014, A1,
[2] Patent: WO2015/153683, 2015, A1,
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  • [ 13472-85-0 ]
  • [ 75-03-6 ]
  • [ 832735-58-7 ]
YieldReaction ConditionsOperation in experiment
46.5% With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4 h; 5-Bromo-1-ethylpyridin-2(1 H)-one
To a solution of 5-bromo-2-methoxypyridine (600 mg, 3.19 mmol) in DMF (10 mL), iodoethane (747 mg, 4.79 mmol) and K2C03(1323 mg, 9.57 mmol) were added. The reaction was stirred at 70 °C for 4 h. Then the solvent was evaporated. 20 mL of water was added to the residue, then it was adjusted to pH=8. EtOAc (3x30 mL) was extracted the water layer. The combined organic layer, dried with Mg2S04and cone, to get crude product. The crude product was then purified on a silica cartridge (40 g) with a Combiflash Companion, eluting at 40 mL/min with a gradient running from 100percent CH2CI2to 80percent MeOH/CH2CH2over 35 min) to give 300 mg (46.5percent) of the title compound. LC-MS m/z 202.1 (M+H)+, 0.61 (ret. time).
Reference: [1] Patent: WO2015/92713, 2015, A1, . Location in patent: Page/Page column 317
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