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Chemical Structure| 50720-12-2
Chemical Structure| 50720-12-2
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Product Details of [ 50720-12-2 ]

CAS No. :50720-12-2 MDL No. :MFCD00234169
Formula : C6H6BrNO Boiling Point : -
Linear Structure Formula :- InChI Key :FZWUIWQMJFAWJW-UHFFFAOYSA-N
M.W :188.02 Pubchem ID :817163
Synonyms :

Calculated chemistry of [ 50720-12-2 ]

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) : -6.37 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.98
Log Po/w (XLOGP3) : 1.51
Log Po/w (WLOGP) : 1.85
Log Po/w (MLOGP) : 0.92
Log Po/w (SILICOS-IT) : 2.04
Consensus Log Po/w : 1.66

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.38
Solubility : 0.776 mg/ml ; 0.00413 mol/l
Class : Soluble
Log S (Ali) : -1.58
Solubility : 4.92 mg/ml ; 0.0261 mol/l
Class : Very 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 : 1.76

Safety of [ 50720-12-2 ]

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 [ 50720-12-2 ]

* 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 [ 50720-12-2 ]
  • Downstream synthetic route of [ 50720-12-2 ]

[ 50720-12-2 ] Synthesis Path-Upstream   1~26

  • 1
  • [ 50720-12-2 ]
  • [ 74115-13-2 ]
YieldReaction ConditionsOperation in experiment
87.4% With hydrogen bromide; acetic acid In water at 120℃; A solution of 3-bromo-5-methoxy-pyridine (33 18.8 g, 0.1 mol), HBr (80 mL, 48percent) and glacial HOAc (60 mL) was stirred overnight at 120° C. Hydrobromic acid (60 mL, 48percent) was added slowly to replace evaporated solvents and stirred at 120° C. for overnight. The reaction mixture was cooled to RT and then poured into the ice. The pH was adjusted to about 6 by adding 6N NaOH and then extracted with EtOAc (2.x.200 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was stirred in CH2Cl2 (150 mL) and the resulting precipitate was filtered. The product was washed with CH2Cl2 to afford 3-bromo-5-hydoxypyridine (34; 15.2 g, 87.4percent theory) as a white solid.
87.4% With water; hydrogen bromide In acetic acid at 120℃; Step 2
A solution of 3-bromo-5-methoxy-pyridine (134b 18.8 g, 0.1 mol), HBr (80 ML, 48percent) and glacial HOAc (60 ML) was stirred overnight at 120° C.
The reaction mixture was cooled to RT and then poured into the ice.The PH was adjusted to about 6 by adding 6N NaOH and then extracted with EtOAc (2*200 ML).The organic layer was dried over Na2SO4 and concentrated in vacuo.The crude product was stirred in CH2Cl2 (150 ML) and the resulting precipitate was filtered.The product was washed with CH2Cl2 to afford 3-bromo-5-hydoxypyridine (134c 15.2 g, 87.4percent theory) as a white solid.
82% With hydrogen bromide In water for 24 h; Heating / reflux Using reported procedures, 3,5-dibromopyridine 1 (5 g, 21 mmol) was dissolved in 100 mL anhydrous methanol (Figure 2). The solution was cooled to O0C and 16 g of sodium hydride (60percent [w/w]) mineral oil suspension) were added in portions. This mixture was stirred for 1 h at room temperature and refluxed at 80°C for 4 h. The solvent was removed by rotary evaporation. The residue was taken in 100 mL of water. EPO <DP n="19"/>The mixture was extracted with dichloromethane (3 x 100 mL). The organic portions were combined, dried (anhydrous magnesium sulfate), filtered, and evaporated, and the residue (3.5 g) was characterized as 5-bromo-3-methoxypyridine 2. The 5-bromo-3-methoxypyridine 2 was refluxed with 20 mL concentrated (57percent) hydrogen bromide for 24 h. The reaction was quenched with saturated NaHCO3 solution, and the basic mixture was extracted with dichloromethane (3 x 50 mL). The organic portions were pooled together, dried (magnesium sulfate), filtered, evaporated to provide the 5-bromo-3-hydroxypyridine 3 (3 g, 82percent) in >95percent purity as ascertained by thin-layer chromatography (TLC) (Rf = 0.5, ethyl acetate/hexane,l :1). NMR (CDC13, 500 MHz) -ppm: 8.28 (d, IH, J = 1.8 Hz), 8.24 (d, IH, J - 2.7 Hz), 7.38 (dd, IH, J = 1.8, 2.7 Hz). MS, m/z, 173, 175 (25percent, [M+H]+).
61% With hydrogenchloride; sodium hydroxide; hydrogen bromide In acetic acid Reference Example 35
Production of 5-bromopyridine-3-ol
To a solution of 3-bromo-5-methoxypyridine (5.0 g, 27 mmol) in acetic acid (15 mL) was added 48percent hydrobromic acid (23 mL), and the reaction mixture was heated under reflux for 16 hr.
The mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure.
The residue was adjusted to pH9-10 by adding 8N aqueous sodium hydroxide solution.
The obtained aqueous solution was washed with diethyl ether, and the pH was adjusted to 5-6 by adding 6N hydrochloric acid.
The obtained precipitate was collected by filtration, and washed with diisopropyl ether to give the title compound (2.8 g, 61percent) as a pale-yellow powder.
1H-NMR (DMSO-d6, 300 MHz) δ 7.40 (1H, t, J=2.1 Hz), 8.12-8.15 (2H, m), 10.47 (1H, br. s).

Reference: [1] Patent: US2005/234236, 2005, A1, . Location in patent: Page/Page column 13-14
[2] Patent: US2004/198736, 2004, A1, . Location in patent: Page/Page column 86
[3] Tetrahedron Letters, 2004, vol. 45, # 18, p. 3607 - 3610
[4] Tetrahedron, 2009, vol. 65, # 4, p. 757 - 764
[5] Patent: WO2006/86068, 2006, A1, . Location in patent: Page/Page column 18; 1/6
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6784 - 6788
[7] Tetrahedron, 2010, vol. 66, # 25, p. 4490 - 4494
[8] Patent: US2009/137595, 2009, A1,
[9] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2307 - 2319
[10] Patent: WO2004/108663, 2004, A1, . Location in patent: Page 82
  • 2
  • [ 625-92-3 ]
  • [ 50720-12-2 ]
YieldReaction ConditionsOperation in experiment
62% With sodium methylate; sodium In methanol; water; N,N-dimethyl-formamide EXAMPLE 7A
3-bromo-5-methoxypyridine
A solution of methanol (180 mL) was treated with sodium spheres (4.7 g, 0.20 mol) portionwise, evaporated to dryness, azeotroped with toluene (100 mL), and then concentrated under reduced pressure.
The sodium methoxide in dry DMF (130 mL) was treated with 3,5-dibromopyridine (32 g, 135 mmol), from Avocado Chemicals.
After heating at 70° C. for 4 hours, the mixture was poured onto ice/water (300 g) and filtered.
The filter cake was dried under reduced pressure to provide the title compound (15.6 g, 62percent yield). MS (DCI/NH3) m/z 188/190 (M+H)+.
Reference: [1] Patent: US2002/19388, 2002, A1,
[2] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1171,1174
[3] Patent: US6392045, 2002, B1,
[4] Patent: US5948793, 1999, A,
[5] Patent: US6127386, 2000, A,
[6] Patent: US5629325, 1997, A,
[7] Patent: US2007/60618, 2007, A1, . Location in patent: Page/Page column 10
[8] Patent: US6437138, 2002, B1,
  • 3
  • [ 625-92-3 ]
  • [ 67-56-1 ]
  • [ 50720-12-2 ]
YieldReaction ConditionsOperation in experiment
73% With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20 - 90℃; for 1 h; 1006441 A suspension of 60percent sodium hydride (11.4 g, 285 mmol) in DMF (450 mL) was charged with methanol (11.5 mL, 285 mmol) at room temperature and heated to 60°C. The resulting solution was charged with 3,5-dibromopyridine (45 g, 190 mmol) and heated to 90°Cfor 1 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with diethyl ether (3 X 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2504, filtered and concentrated in vacuo resulting in crude compound which was purified by chromatography on silica gel, eluting with 5-10percent ethyl acetate in hexane to give 26.1 g, 73percent yield of the title compound as an off white solid. ‘H NMR (400 MHz, CDC13): ö = 8.27 (d, J= 17.20 Hz, 2 H), 7.36 (s, 1 H), 3.86 (br. s, 3 H); MS (E5): m/z = 187.85 [M-Hf; LCMS: tR = 1.81 mm.
70%
Stage #1: With sodium hydride In N,N-dimethyl-formamide for 0.5 h;
Example 43A
3-bromo-5-methoxypyridine
A suspension of NaH (0.47 g, 19.6 mmol) in DMF (20 mL) was cautiously treated with methanol (0.59 g, 18.4 mmol).
After 30 minutes, the mixture was treated with a solution of 3,5-dibromopyridine (4.0 g, 16.9 mmol) in DMF (5.0 mL).
After stirring overnight, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with diethyl ether (200 mL).
The organic phase was dried (MgSO4) and concentrated under reduced pressure.
The residue was purified by chromatography on SiO2 (CH2Cl2) to provide the title compound (2.24 g, 70percent yield) as a yellow solid.
70% With sodium hydride In DMF (N,N-dimethyl-formamide) A suspension of NaH (0.47 g, 19.6 mmol) in DMF (20 mL) was cautiously treated with methanol (0.59 g, 18.4 mmol). After 30 minutes, the mixture was treated with a solution of 3,5-dibromopyridine (4.0 g, 16.9 mmol) in DMF (5.0 mL). After stirring overnight, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with diethyl ether (200 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 (CH2Cl2) to provide the title compound (2.24 g, 70percent yield) as a yellow solid.
67%
Stage #1: at 90℃; for 2 h;
Stage #2: at 90℃; for 2 h;
Sodium (2.33 g, 101.3 mmol) was added to methanol (50 ml) and was allowed to react, the mixture was evaporated. 3.5-Dibromopyridine (20.0 g, 84.4 mmol) and dimethyl sulfoxide (100 ml) were added.
The mixture was stirred at 90° C. for 2 h.
Sodium hydroxide (400 ml, 1 M) was added and the mixture was extracted twice with diethyl ether (200 ml).
Chromatography on silica gel with dichloromethane and 3percent ethanol as solvent gave the title compound.
Yield 10.6 g, 67percent.
Mp 30-32° C.
60% at 0 - 80℃; for 5 h; Using reported procedures, 3,5-dibromopyridine 1 (5 g, 21 mmol) was dissolved in 100 mL anhydrous methanol (Figure 2). The solution was cooled to O0C and 16 g of sodium hydride (60percent [w/w]) mineral oil suspension) were added in portions. This mixture was stirred for 1 h at room temperature and refluxed at 80°C for 4 h. The solvent was removed by rotary evaporation. The residue was taken in 100 mL of water. EPO <DP n="19"/>The mixture was extracted with dichloromethane (3 x 100 mL). The organic portions were combined, dried (anhydrous magnesium sulfate), filtered, and evaporated, and the residue (3.5 g) was characterized as 5-bromo-3-methoxypyridine 2. The 5-bromo-3-methoxypyridine 2 was refluxed with 20 mL concentrated (57percent) hydrogen bromide for 24 h. The reaction was quenched with saturated NaHCO3 solution, and the basic mixture was extracted with dichloromethane (3 x 50 mL). The organic portions were pooled together, dried (magnesium sulfate), filtered, evaporated to provide the 5-bromo-3-hydroxypyridine 3 (3 g, 82percent) in >95percent purity as ascertained by thin-layer chromatography (TLC) (Rf = 0.5, ethyl acetate/hexane,l :1). NMR (CDC13, 500 MHz) -ppm: 8.28 (d, IH, J = 1.8 Hz), 8.24 (d, IH, J - 2.7 Hz), 7.38 (dd, IH, J = 1.8, 2.7 Hz). MS, m/z, 173, 175 (25percent, [M+H]+).; The synthesis route to prepare nifrolidine 9 is shown in Figure 2. Starting with 3,5- dibromopyridine 1, 3-bromo-5-methoxypyridine 2 was prepared in approximately 60percent-89percent yield by treatment with sodium hydride in methanol. Using an alternate procedure of sodium methoxide in N,N-dimethylformamide, more reproducible results were obtained in this reaction. Demethylation of 2 with refluxing hydrogen bromide provided 3-bromo-5-pyridinol 3 in 82percent yield. The mixture generally had to be refluxed for longer times than reported (36 h rather than 16 h) for the high yields. Protection of (S)-pyrrolidinemethanol 4 was performed EPO <DP n="27"/>with di-tert-butyldicarbonate to provide l-BOC-2-(S)-ρyrrolidinemethanol 5 in 88percent yield (alternatively, 5 is also available from Aldrich Chemical Co.). Mitsonobu reaction coupling of 3 and 5 was performed by diethyl azodicarboxylate in the presence of triphenylphosphine to provide the bromopyridyl ether 6 in 44percent yield, which is somewhat lower than reported. To introduce a 3'-propanolic group at the 5-position, an allyl group was introduced. Using reported procedures, allylation of this bromo derivative 6 was first performed by allyltributyl tin in the presence of catalytic amounts of tetrakis(triphenylphosphine)palladium to provide the 5-allylpyridyl ether derivative 7 in 57percent yield. Hydroboration of the allyl group followed by alkaline hydrogen peroxide treatment using previously described conditions led to the important alcohol intermediate, 8 in 26percent yield. The low yield in this step was probably a result of the formation of a BH3 complex of the alcohol 8. Some preliminary efforts to neutralize this BH3 complex were not successful. Similar BH3-complex formation has recently been reported for other amines. The substituted alcohol 8 was treated with DAST to convert the alcohol to the corresponding fluoride using methods that we have previously used. Removal of the N-BOC group was achieved by treating with TFA to provide 9 in 25percent yield. Final product 9, nifrolidine, was used as a p-toluenesulfonate salt for in vitro binding assays. For radiolabeling with 18F, the tosylate 10 was prepared from the BOC-protected key alcohol intermediate 8 by reacting with toluenesulfonyl chloride in yields of 40percent-50percent. The tosylate 10 was found to be stable and suitable for 18F radiolabeling and was stored at 0°C to 200C.

Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 11, p. 1867 - 1871
[2] Patent: WO2015/106292, 2015, A1, . Location in patent: Paragraph 00634; 00643; 00644
[3] Patent: EP1147112, 2003, B1, . Location in patent: Page/Page column 31
[4] Patent: US2003/225268, 2003, A1, . Location in patent: Page 29
[5] Patent: US2004/72823, 2004, A1, . Location in patent: Page/Page column 20
[6] Patent: WO2006/86068, 2006, A1, . Location in patent: Page/Page column 17-18; 25-26; 1/6
[7] Patent: US2014/336182, 2014, A1, . Location in patent: Paragraph 0314
  • 4
  • [ 625-92-3 ]
  • [ 124-41-4 ]
  • [ 50720-12-2 ]
YieldReaction ConditionsOperation in experiment
93% at 20 - 70℃; A solution of 3,5-dibromopyridine (32, 20 g, 84.4 mmol) in DMF (200 mL) was stirred at RT under nitrogen atmosphere and 21.3 mL of sodium methoxide (25percent by wt. in methanol, 92.8 mmol) was added slowly. The reaction mixture was stirred overnight at 70° C. under N2. The reaction was cooled to RT and quenched with water (200 mL) and extracted with Et2O (2.x.200 mL). The combined organic extracts was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude 3-bromo-5-methoxypyridine (33, 14.8 g, 93percent theory) afforded a colorless oil after flash chromatography on silica gel (EtOAc:hexane 1:10).
93% at 70℃; A solution of 3,5-dibromopyridine (134a, 20 g, 84.4 mmol) in DMF (200 mL) was stirred at RT under nitrogen atmosphere and then 21.3 mL of sodium methoxide (25percent by wt. in methanol (92.8 mmol) was added slowly. The reaction mixture was stirred overnight at 70° C. under N2. The reaction was cooled to RT and quenched with water (200 mL) and extracted with Et2O (2.x.200 mL). The combined organic extracts was washed with brine, dried (MgSO4) and concentrated in vacuo. The crude 3-bromo-5-methoxypyridine (134b 14.8 g, 93percent theory) afforded a colorless oil after purification by flash chromatography on silica gel (EtOAc:hexane 1:10).
87% at 20 - 40℃; for 18 h; 3,5-Dibromopyridine (29.41 g, 0.12 mol) was dissolved in dimethylformamide (300 ml), 28percent sodium methoxide (40.00 ml, 0.19 mol) was added, and the mixture was stirred with heating at 40° C. for 1 hr, and the mixture was stirred at room temperature for 17 hr. Water (500 ml) was added to the reaction mixture, and the mixture was extracted three times with diethyl ether. The organic layer was washed with saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1 to 4:1) to give the object product as a white solid (20.28 g, yield 87percent). 1H NMR(CDCl3 400 MHz) (δ) ppm: 3.87 (3H, s), 7.38 (1H, dd, J=2.6, 1.9 Hz), 8.26 (1H, d, J=2.6 Hz), 8.30 (1H, d, J=1.9 Hz)
66% at 100℃; for 3 h; To a solution of 3,5-dibromopyridine (10.0 g, 42.2 mmol) in DMF (10 mL) in a flask with a distillation head was added NaOMe solution 25percent wt/wt (10 mL) and the mixture was heated to 100° C. for 3 hours. At the end of 3 hours 8 mL of MeOH was collected. The DMF solution was cooled to room temperature and diluted with H2O (25 mL) and extracted with MTBE (2.x.25 mL). The combined organic layers were washed with H2O (2.x.25 mL), dried over Na2SO4, filtered and concentrated. The residue was then dried under high vacuum for 10 hours to give the title compound (5.2 g, 66percent). 1H NMR (400 MHz, DMSO-D6) δ 8.26-8.31 (m, 2H) 7.69-7.72 (m, 1H) 3.84 (s, 3H).
59% at 40℃; for 24 h; Sodium methoxide (255 mmol) was added to a solution of 3,5-dibromopyridine (124 mmol) inN,N-dimethylformamide (200 mL) and the reaction mixture was heated at 40 °C for 24 h. The resulting mixture was diluted with water (200 mL) and was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by Flash chromatography (40/1 petroleum ether/ethyl acetate) to provide 3-bromo-5-methoxypyridine in 59percent yield as a white solid
59% at 40℃; for 24 h; Intermediate 12: Synthesis of 5-methoxypyridine-3-sulfonyl chloride.1. Synthesis ofSodium methoxide (255 mmol) was added to a solution of 3,5-dibromopyridine (124 mmol) in N,7V-dimethylformamide (200 mL) and the reaction mixture was heated at 40 0C for 24 h. The resulting mixture was diluted with water (200 mL) and was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by Flash chromatography (40/1 petroleum ether/ethyl acetate) to provide 3-bromo-5-methoxypyridine in 59percent yield as a white solid.
59% at 40℃; for 24 h; Intermediate 12: Synthesis of 5-methoxypyridine-3-sulfonyl chloride.B 1. Synthesis ofSodium methoxide (255 mmol) was added to a solution of 3,5-dibromopyridine (124 mmol) in N,N-dimethylformamide (200 mL) and the reaction mixture was heated at 40 0C for 24 h. The resulting mixture was diluted with water (200 mL) and was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated. The residue was purified by Flash chromatography (40/1 petroleum ether/ethyl acetate) to provide 3-bromo-5-methoxypyridine in 59percent yield as a white solid
57% at 70℃; for 4 h; Add sodium (0. 583 g, 25 mmol) to methanol (10 mL) at 0 °C. Stir the mixture at 0 °C until obtain a solution and concentrate. Add N, N-dimethylformamide (25 mL) and add 3, 5-dibromopyridine (3. 0 g, 12. 66 mmol). Stir at 70 °C for 4 h. Cool to room temperature and add water. Extract twice with diethyl ether. Combine the organic phases, wash once with water, dry over sodium sulfate and concentrate. Purify the residue by silica gel chromatography, eluting with a gradient of 100 : 0 to 50 : 50 hexanes : ethyl acetate, to give the title compound as a solid (1. 37 g, 57percent). LC-MS (ES) : =187. 9, 190. 0 [M+H) +.
53% at 10 - 35℃; for 15 h; Reference Example 104 5-(methyloxy)pyridine-3-carbonitrile (1793) (1794) A suspension of 3,5-dibromopyridine (3.0 g, 12.6 mmol) and sodium methoxide (3.4 g, 62.9 mmol) in DMF (20 mL) was stirred at room temperature for 15 hrs and the solvent was evaporated under reduced pressure. The concentrated residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2percent-20percent ethyl acetate/hexane) to give 3-bromo-5-(methyloxy)pyridine as a white powder (1.25 g, 53percent). A suspension of the obtained 3-bromo-5-(methyloxy)pyridine (500 mg, 2.659 mmol), zinc cyanide (187 mg, 1.59 mmol) and tetrakistriphenylphosphine palladium (154 mg, 0.133 mmol) in DMF was reacted in a microwave reaction apparatus at 80° C. for 10 min. and then at 120° C. for 10 min. The mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The concentrated residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2percent-30percent ethyl acetate/hexane) to give the title compound as a colorless oil (300 mg, 84percent). (1795) 1H-NMR (300 MHz, CDCl3) δ: 3.91 (3H, s), 7.40 (1H, dd, J=2.8, 1.7 Hz), 8.49 (1H, d, J=1.5 Hz), 8.51 (1H, d, J=3.0 Hz).

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  • 5
  • [ 625-92-3 ]
  • [ 67-56-1 ]
  • [ 124-41-4 ]
  • [ 50720-12-2 ]
YieldReaction ConditionsOperation in experiment
79.4% at 80℃; for 1.5 h; Sodium methoxide (124 g, 2.30 mol), 3,5-dibromopyridine (300 g, 1.26 mol) and a mixture of DMF and methanol (1200 ml_, 4:1) were added to a 2-L 3-neck flask fitted with a reflux condenser and under a nitrogen atmosphere. The resulting suspension was heated (8O0C external temperature) for 1.5 h. The dark solution was cooled to ambient temperature, and the resulting suspension was poured into water (600 ml_) and extracted with di-isopropyl ether (4 x 600 ml_). The combined organic phases were washed with saturated aqueous sodium chloride (500 ml_), dried (anhydrous sodium sulfate), filtered, and concentrated by rotary evaporation to give 3-bromo-5-methoxoxypyridine (187 g, 79.4percent yield) of suitable purity for use in the synthesis of (2S)-(4E)-N-methyl-5-[3-(5-methoxypyridin)yl]-4-penten-2-amine hemi-galactarate.
Reference: [1] Patent: WO2009/18367, 2009, A2, . Location in patent: Page/Page column 39
  • 6
  • [ 624-28-2 ]
  • [ 50720-12-2 ]
Reference: [1] Patent: US2003/65018, 2003, A1,
  • 7
  • [ 625-92-3 ]
  • [ 12775-96-1 ]
  • [ 50720-12-2 ]
Reference: [1] Patent: US2003/125345, 2003, A1,
  • 8
  • [ 50720-12-2 ]
  • [ 17117-17-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2307 - 2319
  • 9
  • [ 50720-12-2 ]
  • [ 42409-58-5 ]
  • [ 1379325-16-2 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 1, p. 168 - 171
  • 10
  • [ 50720-12-2 ]
  • [ 42409-58-5 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1171,1174
  • 11
  • [ 50720-12-2 ]
  • [ 152684-26-9 ]
YieldReaction ConditionsOperation in experiment
85% With sulfuric acid; nitric acid In water at 0℃; for 20 h; The compound (20.91 g, 0.11 mol) obtained in Step 1 was dissolved in concentrated sulfuric acid (63 ml), nitric acid (5.2 ml, 0.12 mol) was added under ice-cooling, and the mixture was stirred for 20 hr. The reaction mixture was gently poured into ice water and the mixture was stirred. The precipitated solid was filtered and washed with water. The obtained solid was dissolved in ethyl acetate, and the solution was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the object product as a pale-yellow solid (21.97 g, yield 85percent). 1H NMR(CDCl3 400 MHz) (δ) ppm: 4.01 (3H, s), 7.68 (1H, d, J=1.6 Hz), 8.16 (1H, d, J=1.9 Hz)
76%
Stage #1: at 20℃;
Stage #2: at 0 - 20℃;
Stage #3: With sodium carbonate In water; ethyl acetate
To a cooled flask containing 3-methoxy-5-bromopyridine I (39,8 g, 0.21 mol) was slowly added concentrated H2SO4 (120 ml) with the reaction mixture temperature maintained below 20 °C. The resulting mixture was stirred unitl homogeneity. The reaction mixture was cooled to 0-5 ftC and 90percent I INO3 (16>;5 g, 0.24 moi) was added dropwise while maintaining constant temperature. The resulting reaction mixture was stirred for 24 h, at ambient temperature. The reaction was deemed complete (<;5percent of 1 by HPLC) and the reaction mixture was poured onto ice (400 g), then partitioned with EtOAc (400 ml). The layers were separated and (he organic phase was sequentially washed with saturated aqueous Na2CO3 solution (400 ml), water (400 ml) and brine (400 ml), dried overNa2SO-i) Tillered, and concentrated under reduced pressure to furnish a pale yellow solid (45.8 g) as crude product. The material was recrystallized from MTBE (175 mL) and the crystals were harvested, washed with cold MTBK (80 mL-), and dried under high vacuum to give 22.7 g of yellow soiM as product. The mother liquor and filtraie were combined, concentrated, and recrystoellized from MTBE (35 mL) gave 6.3 g of pure product, The remaining mother liquor and filtrates were combined and concentrated. The resulting residue was purified by silica gel chromatography, eluting with a slow gradient of hexanes-EtOAc (hexanes, 4:1 hexancs-EtOAc) to give 8.5 g of product, Λ combined total of 37.5 g (0.16 mol, 76percent yield) of a yellow crystalline solid was obtained as 2-nitro-3 -methoxy-5 -bromopyridine:1H NMR (30Q MHz, CDCl3) 6 8.16 (d, J.(TM). 1.9 Hz, 1 H), 7.68 (d, J = 1.6 Hz, 1 H), 4.01 (s, 3 H); IXMS m/z (MH') 232.9, /R 0.73 min.
Reference: [1] Patent: US2006/84665, 2006, A1, . Location in patent: Page/Page column 70
[2] Patent: WO2010/100127, 2010, A1, . Location in patent: Page/Page column 69-70
[3] Acta Chemica Scandinavica, 1993, vol. 47, # 8, p. 805 - 812
[4] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1171,1174
  • 12
  • [ 50720-12-2 ]
  • [ 64436-92-6 ]
YieldReaction ConditionsOperation in experiment
25% at 140℃; for 20 h; Microwave irradiation; Sealed tube 3-Bromo-5-methoxypyridine (9f5) (500 mg, 2.66 mmol), ammonium hydroxide (15 mL) and coppersulfate pentahydrate (33 mg, 0.13 mmol) were heated at 140 °C in the microwave in a closed tube for 20 h. The reaction mixture was cooled to room temperature and the crude material separated between ethyl acetate and water. The organic layer was washed with water (3 times) and brine, dried over MgSO4, filtered and concentrated in vacuo to give 84 mg, yield 25percent of the desired product as solids. 1H NMR (400 MHz, CDCl3): δ 7.72 (d, J = 5.4 Hz, 2H), 6.51 (t, J = 2.4 Hz, 1H), 3.79 (s, 3H) ppm; HPLC-MS: m/z 125.0
Reference: [1] Organic Process Research and Development, 2012, vol. 16, # 5, p. 788 - 797
[2] Advanced Synthesis and Catalysis, 2013, vol. 355, # 4, p. 627 - 631
[3] European Journal of Medicinal Chemistry, 2015, vol. 106, p. 50 - 59
[4] Patent: US2007/167497, 2007, A1, . Location in patent: Page/Page column 26
[5] Patent: US2014/336182, 2014, A1, . Location in patent: Paragraph 0315
[6] Patent: WO2008/124083, 2008, A2, . Location in patent: Page/Page column 49
[7] Patent: WO2007/113548, 2007, A1, . Location in patent: Page/Page column 154
  • 13
  • [ 50720-12-2 ]
  • [ 1445972-34-8 ]
  • [ 64436-92-6 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 14, p. 3734 - 3737
  • 14
  • [ 1336-21-6 ]
  • [ 50720-12-2 ]
  • [ 64436-92-6 ]
Reference: [1] Patent: US2001/31771, 2001, A1,
[2] Patent: US6441006, 2002, B2,
  • 15
  • [ 1336-21-6 ]
  • [ 50720-12-2 ]
  • [ 64436-92-6 ]
Reference: [1] Patent: US2001/14691, 2001, A1,
  • 16
  • [ 50720-12-2 ]
  • [ 68-12-2 ]
  • [ 113118-83-5 ]
YieldReaction ConditionsOperation in experiment
63%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 2 h;
Stage #2: for 1 h;
The bromo compound T (100 mg, 0.53 mmol) was taken in an oven-dried RB equipped with magnetic stir-bar and dissolved in anhydrous THF (1 mL). Then, iPrMgCl (0.3 mL) was added at 0° C. and the resulting mixture was stirred at room temperature for 2 h (the solution turned into light brown beer color). Next, DMF (0.1 mL) in anhydrous THF (0.1 mL) was added slowly. Initially formed solid was slowly dissolved and the solution color turned from light brown to light yellow. After 1 h, the reaction was cooled to 0° C. and quenched with water (2 mL). The organic layer was separated and the aqueous layer was washed with additional amount of CH2Cl2 (3×3 mL). The organic layers were combined, dried over Na2SO4 and concentrated under vacuo on a rotary evaporator. The crude product was purified via gradient silica gel column chromatography using a mixture of hexanes and ethyl acetate (20:1 to 1:1) to obtain the desired product U as a colorless syrup (45 mg, 63percent). 1H NMR (500 MHz, CDCl3): δ 10.09 (s, 1H), 8.65 (d, J=0.9 Hz, 1 H), 8.54 (d, J=3.1 Hz, 1H), 7.60 (dd, J=5.1, 1.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 190.6, 156.2, 145.1, 144.8, 132.0, 116.3, 55.7.
56%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 2 h;
Stage #2: for 1 h;
Stage #3: With hydrogenchloride In tetrahydrofuran; water
Isopropylmagnesiumchloride (31 mL, 2.0 M in THF) was syringed in and the reaction mixture was stirred for 2 hours at room temperature. N,N-dimethylformamide (8.5 mL) in tetrahydrofuran (12 mL) was added and stirring was continued for an additional hour. The solution was quenched with 2 N HCl to pH of 3 then partitioned between ethyl acetate and water. The organic layer was separated and concentrated to give a residue which was purified using flash chromatography to give 3-methoxy-5-formylpyridine (4.30 g, 56percent) as an oil. 1H NMR (DMSO-40: δ 10.1 (s, IH), 8.71 (d, IH), 8.59 (d, IH), 7.74 (m, IH), 3.92 (s, 3H).
49%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.25 h; Inert atmosphere
Stage #2: for 0.5 h;
To a stirred solution of 3-bromo-5-methoxypyridine (1.00 g, 5.32 mmol) in a mixed solvent (THF/hexane=1:1, 20 mL) was added n-BuLi (2.5 M, 2.4 mL) at -78°C under N2. After stirring at -78 °C for 15 min DMF (0.54 mL, 6.92 mmol) was added slowly. The mixture was stirred for another 30 min and warmed to 0 °C. The mixture was quenched with 20 mL of aq. NaHCO3, extracted with EA (50 mL x 2). The combined organics was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated. The resulted residue was purified by column chromatography eluted with PE/EA (5:1) to give the title product (360 mg, 49percent) as a light yellow solid.
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 11, p. 1867 - 1871
[2] Tetrahedron, 2001, vol. 57, # 20, p. 4447 - 4454
[3] Biochemistry, 2010, vol. 49, # 49, p. 10421 - 10439
[4] Patent: US2014/309427, 2014, A1, . Location in patent: Paragraph 0157; 0158
[5] Patent: WO2007/84560, 2007, A2, . Location in patent: Page/Page column 164
[6] Patent: WO2017/88755, 2017, A1, . Location in patent: Paragraph 000128; 000129; 000130
[7] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
[8] Tetrahedron Letters, 1998, vol. 39, # 32, p. 5875 - 5876
[9] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4745 - 4751
[10] Patent: WO2007/47207, 2007, A2, . Location in patent: Page/Page column 69
  • 17
  • [ 50720-12-2 ]
  • [ 113118-83-5 ]
YieldReaction ConditionsOperation in experiment
0.26% With n-butyllithium In tetrahydrofuran; ethyl acetate; N,N-dimethyl-formamide b)
5-Methoxypyridine-3-carboxaldehyde.
To a stirred solution of 5-bromo-3-methoxypyridine (0.815 g, 4.35 mmol) in THF (15 mL) at -78° C. was added n-BuLi (4.6 mmol).
After 1 h, DMF (0.64 g, 8.20 mmol) was added and stirred continuously for 30 min at -78° C.
The cold mixture was poured into a stirred aqueous solution of 5percent NaHCO3 (25 mL) and extracted with ether (3*15 mL).
The extract was evaporated and the crude was purified by chromatography on silica gel with hexane: EtOAc (4:1~2:1) as eluant, yielding 155 mg (0.26percent) of the title compound. 1H NMR (CD3OD): 9.88 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 3.70 (s, 3H).
Reference: [1] Patent: US2003/65018, 2003, A1,
  • 18
  • [ 50720-12-2 ]
  • [ 109345-94-0 ]
Reference: [1] Patent: WO2014/186035, 2014, A1,
  • 19
  • [ 50720-12-2 ]
  • [ 286946-77-8 ]
Reference: [1] Patent: WO2016/37578, 2016, A1,
  • 20
  • [ 50720-12-2 ]
  • [ 286947-03-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6435 - 6446
[2] Patent: WO2016/37578, 2016, A1,
[3] Patent: WO2014/43252, 2014, A2,
  • 21
  • [ 50720-12-2 ]
  • [ 73183-34-3 ]
  • [ 445264-60-8 ]
YieldReaction ConditionsOperation in experiment
2.6 g With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In toluene for 2 h; Inert atmosphere; Reflux 3 -Bromo-5 -methoxypyridine (2g, 10.63 mmol), bis(pinacolato)diborane (4.05 g, 15.98 mmol) and potassium acetate (4.78 g, 42.55 mmol) were taken in dry toluene (25 mL) and degassed with nitrogen for 20 mi Pd(dppf)C12.DCM (0.87 g, 0.10 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 reaction mixture was cooled to 25°C and filtered through a Celite® reagent pad. The filtrate was diluted with ethyl acetate (100 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 2.6 g of 3-methoxy-5-(4,4,5,5- tetramethyl- [1,3,2] dioxaborolan-2-yl)-pyridine LCMS: 236 (M+H).
Reference: [1] Patent: WO2009/74812, 2009, A1, . Location in patent: Page/Page column 68
[2] Patent: WO2014/186035, 2014, A1, . Location in patent: Page/Page column 156
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 23, p. 10479 - 10497
[4] Patent: CN106674200, 2017, A, . Location in patent: Paragraph 0112; 0113
  • 22
  • [ 50720-12-2 ]
  • [ 76-09-5 ]
  • [ 445264-60-8 ]
Reference: [1] Chemical Communications, 2011, vol. 47, # 30, p. 8605 - 8607
  • 23
  • [ 50720-12-2 ]
  • [ 952059-69-7 ]
Reference: [1] Patent: US2014/336182, 2014, A1,
[2] Patent: WO2008/124083, 2008, A2,
[3] Patent: WO2007/113548, 2007, A1,
  • 24
  • [ 50720-12-2 ]
  • [ 1241752-31-7 ]
Reference: [1] Patent: WO2014/43252, 2014, A2,
  • 25
  • [ 50720-12-2 ]
  • [ 1207557-36-5 ]
Reference: [1] Patent: WO2017/11776, 2017, A1,
  • 26
  • [ 50720-12-2 ]
  • [ 1207557-35-4 ]
Reference: [1] Patent: WO2017/11776, 2017, A1,
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