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Chemical Structure| 625-92-3
Chemical Structure| 625-92-3
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Product Details of [ 625-92-3 ]

CAS No. :625-92-3 MDL No. :MFCD00014634
Formula : C5H3Br2N Boiling Point : -
Linear Structure Formula :- InChI Key :SOSPMXMEOFGPIM-UHFFFAOYSA-N
M.W : 236.89 Pubchem ID :69369
Synonyms :

Calculated chemistry of [ 625-92-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 0.0
Molar Refractivity : 39.64
TPSA : 12.89 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) : -6.16 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.99
Log Po/w (XLOGP3) : 2.23
Log Po/w (WLOGP) : 2.61
Log Po/w (MLOGP) : 2.01
Log Po/w (SILICOS-IT) : 2.8
Consensus Log Po/w : 2.33

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.27
Solubility : 0.128 mg/ml ; 0.000539 mol/l
Class : Soluble
Log S (Ali) : -2.14
Solubility : 1.73 mg/ml ; 0.00731 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.74
Solubility : 0.0435 mg/ml ; 0.000184 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.39

Safety of [ 625-92-3 ]

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 [ 625-92-3 ]

* 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 [ 625-92-3 ]
  • Downstream synthetic route of [ 625-92-3 ]

[ 625-92-3 ] Synthesis Path-Upstream   1~76

  • 1
  • [ 625-92-3 ]
  • [ 191104-26-4 ]
Reference: [1] Patent: US2002/193596, 2002, A1,
  • 2
  • [ 625-92-3 ]
  • [ 407-20-5 ]
Reference: [1] Synthesis, 2010, # 14, p. 2490 - 2494
[2] Angewandte Chemie - International Edition, 2010, vol. 49, # 12, p. 2215 - 2218
[3] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1062,1068
  • 3
  • [ 625-92-3 ]
  • [ 233770-01-9 ]
YieldReaction ConditionsOperation in experiment
98% With iodine; isopropylmagnesium chloride In tetrahydrofuran at -10 - -5℃; for 0.0833333 h; Sequentially slowly add a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (0. 25 g, 2. 41 mmol) and a solution of iodine (0. 62 g, 2. 41 mmol) in anhydrous tetrahydrofuran to a solution of 3, 5-dibromopyridine (0. 52 g, 2. 19 mmol) in anhydrous tetrahydrofuran (4 mL) at-10 °C with the internal temperature below-5 °C. Stir approximately 5 min and dilute the reaction with ethyl acetate and an aqueous saturated solution of sodium hydrogen sulfite solution. Separate the organic layer and dry (magnesium sulfate), filter and concentrate to give the title compound (4. 85 g, 98percent), which is used directly with out further purification. 1H NMR (400 MHz, CDCl3) 6 7. 54-7. 51 (m, 1H), 8. 26 (s, 1H), 8. 42 (s, 1H) ; MS (ES) : m/z=284 [M+H] +.
58% With iodine; isopropylmagnesium chloride In tetrahydrofuran at -78 - 20℃; for 2 h; To a solution of 3,5-dibromopyridine (48 g, 200 mmol) in THF (200 mL) was added a 2 M solution of isopropylmagnesium chloride in THF (80 mL).
After being stirred at room temperature for 2 h, the solution was cooled to -78° C.
To it was added a precooled solution of iodine (51 g, 200 mmol) in THF (100 mL).
The mixture was diluted with ether and washed with a saturated solution of ammonium chloride, a 2 M solution of sodium thiosulfate, and brine.
The resulting organic layer was dried over MgSO4, filtered and concentrated.
Crystalization from ethanol gave 33.5 g (58percent) of desired product. 1H NMR (CDCl3) δ 8.75 (1H, s), 8.60 (1H, s), 8.20 (1H, s).
Reference: [1] Patent: WO2005/94822, 2005, A1, . Location in patent: Page/Page column 35
[2] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
[3] European Journal of Organic Chemistry, 2002, # 2, p. 327 - 330
[4] Patent: US2006/4018, 2006, A1, . Location in patent: Page/Page column 12; 27
[5] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1062,1068
  • 4
  • [ 625-92-3 ]
  • [ 233770-01-9 ]
  • [ 53710-18-2 ]
Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 41, p. 12425 - 12433
  • 5
  • [ 625-92-3 ]
  • [ 3543-02-0 ]
Reference: [1] Monatshefte fuer Chemie, 1885, vol. 6, p. 664
[2] Monatshefte fuer Chemie, 1885, vol. 6, p. 664
  • 6
  • [ 625-92-3 ]
  • [ 74115-13-2 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1171,1174
[2] Tetrahedron Letters, 2004, vol. 45, # 18, p. 3607 - 3610
[3] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 15, p. 1989 - 1992
[4] Roczniki Chemii, 1936, vol. 16, p. 136,137[5] Chem. Zentralbl., 1936, vol. 107, # II, p. 1167
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6784 - 6788
[7] Patent: WO2004/108663, 2004, A1,
  • 7
  • [ 625-92-3 ]
  • [ 4318-78-9 ]
Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 15, p. 6653 - 6656
[2] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1062,1068
[3] Chemische Berichte, 1936, vol. 69, p. 1534,1536
[4] Recueil des Travaux Chimiques des Pays-Bas, 1936, vol. 55, p. 122,126
[5] Patent: CH174873, 1933, ,
[6] Chemistry - A European Journal, 2000, vol. 6, # 15, p. 2830 - 2846
  • 8
  • [ 625-92-3 ]
  • [ 7758-99-8 ]
  • [ 4318-78-9 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1936, vol. 55, p. 122,126
[2] Chemische Berichte, 1936, vol. 69, p. 1534,1536
  • 9
  • [ 625-92-3 ]
  • [ 13535-01-8 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1062,1068
[2] Roczniki Chemii, 1936, vol. 16, p. 136,137[3] Chem. Zentralbl., 1936, vol. 107, # II, p. 1167
  • 10
  • [ 625-92-3 ]
  • [ 13535-01-8 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1936, vol. 55, p. 122,126
  • 11
  • [ 625-92-3 ]
  • [ 68-12-2 ]
  • [ 113118-81-3 ]
YieldReaction ConditionsOperation in experiment
67.3%
Stage #1: With N,N,N,N,-tetramethylethylenediamine; isopropylmagnesium chloride In tetrahydrofuran at 10 - 25℃;
Stage #2: at 5 - 15℃; for 0.5 h;
Take 3,5-dibromopyridine 250g, tetrahydrofuran 1000ml, tetramethylethylenediamine 150g, into a 5L reaction flask,Turn on stirring. The system ice water bath was cooled to 10-15°C. Take isopropylmagnesium chloride (2.6M, THF) 750ml,Drip into the reaction solution and keep it below 15°C (slightly warming). After dropping, remove the ice bath.Maintain 1-2h at 20-25°C. The reaction solution was cooled in an ice water bath to 5-10°C.DMF 130g was taken and dissolved in 100 ml THF. The DMF-THF mixture was slowly added dropwise into the reaction solution.Keep the internal temperature below 15°C (exotherm should be added slowly).After the completion of the drop, maintain the reaction at 10-15°C for 30 minutes.The reaction solution was poured into 2L ice water, stirred for 10 minutes, and allowed to stand and separate, collecting the aqueous phase and the organic phase, respectively.The aqueous phase was extracted once with 1 L of ethyl acetate and the organic phases were combined. The organic phase was washed successively with 1 L of water, 1 L of saturated saline, and dried over anhydrous sodium sulfate.Distillation under reduced pressure at 50-55°C yields a greyish brown crude product. To the crude product was added PE:EA=6:1 (W:W) mixed solvent 200 ml and beaten at 20-25°C for 1 h. Filter and filter cake to rinse once with 50ml PE. The infrared lamp was dried to give an off-white solid to white solid, 112 g, yield 67.3percent.
40%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃; for 3 h;
In   diethyl ether (42.0 mL) was dissolved   3,5-dibromopyridine (1.00 g, 4.22 mmol).   n-Butyllithium (2.76 mol/L solution in   n-hexane, 1.61 mL, 4.43 mmol) was added dropwise at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Further,   DMF (0.98 mL, 12.7 mmol) was added and the mixture was stirred for 3 hours allowing the temperature to rise slowly to room temperature. A saturated   aqueous ammonium chloride solution and   water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 7/3) to give   5-bromonicotinaldehyde (314 mg, 40percent).
Reference: [1] European Journal of Medicinal Chemistry, 2006, vol. 41, # 7, p. 847 - 861
[2] Tetrahedron Letters, 2001, vol. 42, # 29, p. 4841 - 4844
[3] Patent: CN107628990, 2018, A, . Location in patent: Paragraph 0020; 0021; 0038; 0039; 0040; 0041; 0042-0046
[4] Patent: US2013/65905, 2013, A1, . Location in patent: Paragraph 0189
[5] Patent: WO2004/814, 2003, A1, . Location in patent: Page 77
  • 12
  • [ 625-92-3 ]
  • [ 126726-62-3 ]
  • [ 118775-69-2 ]
YieldReaction ConditionsOperation in experiment
52% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate decahydrate; potassium acetate In acetonitrile at 120℃; for 0.05 h; Microwave irradiation A mixture of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct; 98.0 mass percent, potassium acetate hydrate (7.4997 mmol; 3.7 mL), sodium carbonate decahydrate(7.4997 mmol; 3.7 mL), Acetonitrile (15 mL) and 3,5-dibromopyridine (4.9998 mmol; 1184.4 mg) in 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.9998 mmol; 840.0 mg; 0.940 mL) in a pressure tube was heated under microwave at 120 °C for 3 min. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was concentrated. The residue was purified on silica eluted with 0 to 10percent MeOH in DCM to afford 3-bromo-5-isopropenyl-pyridine as a dark tan solid (512.6mg, 52percent>).
Reference: [1] Patent: WO2014/1377, 2014, A1, . Location in patent: Page/Page column 87
  • 13
  • [ 625-92-3 ]
  • [ 35590-37-5 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at -15℃; for 0.25 h;
Stage #2: With N,N-dimethyl-formamide In tetrahydrofuran at 0℃; for 2 h;
Stage #3: With ammonia; iodine In tetrahydrofuran; water at 20℃; for 2 h;
General procedure: To a flask containing dried LiCl (0.35 g, 8.24 mmol) was added iPrMgCl (2 M in THF, 4.1 mL) and THF (5 mL) at 15° C. After beingstirred for 15 min, 3-bromo-1-benzonitrile (1.46 g, 8.03 mmol) inTHF (1 mL) was added to the reaction mixture and the obtainedmixture was stirred for 15 min. Then, DMF (1.3 mL, 12 mmol) wasadded at 0° C and the mixture was stirred for 2 h. Then, aq NH3 (7 mL, 28-30percent) and I2 (4.06 g, 16 mmol) were added to the reaction mixture. After being stirred for 2 h at room temperature, the reactionmixture was poured into satd aq Na2SO3 solution and was extracted with CHCl3 (3∗30 mL). The organic layer was dried over Na2SO4 and filtered. After removal of the solvent, the residue waspurified by short column chromatography on silica gel (eluent:hexane/ethyl acetate=9:1, v/v) to provide pure 1,3-dicyanobenzene (0.73 g) in 71percent yield. Most nitriles mentioned in this work are commercially availableand were identified by comparison with the authentic samples.
Reference: [1] Tetrahedron, 2013, vol. 69, # 5, p. 1462 - 1469
  • 14
  • [ 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,
  • 15
  • [ 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
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  • [ 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).

Reference: [1] Patent: US2005/234236, 2005, A1, . Location in patent: Page/Page column 13
[2] Patent: US2004/198736, 2004, A1, . Location in patent: Page/Page column 86
[3] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 1, p. 197 - 209
[4] Journal of Medicinal Chemistry, 2009, vol. 52, # 23, p. 7446 - 7457
[5] Journal of Organic Chemistry, 1990, vol. 55, # 1, p. 69 - 73
[6] Tetrahedron, 2010, vol. 66, # 25, p. 4490 - 4494
[7] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6784 - 6788
[8] Patent: US2006/84665, 2006, A1, . Location in patent: Page/Page column 69
[9] Tetrahedron Letters, 2004, vol. 45, # 18, p. 3607 - 3610
[10] Biochemistry, 2010, vol. 49, # 49, p. 10421 - 10439
[11] Chemical Communications, 2011, vol. 47, # 30, p. 8605 - 8607
[12] Tetrahedron Letters, 1998, vol. 39, # 32, p. 5875 - 5876
[13] Tetrahedron, 2001, vol. 57, # 20, p. 4447 - 4454
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[15] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 3, p. 351 - 354
[16] Patent: US2007/167497, 2007, A1, . Location in patent: Page/Page column 26
[17] Journal of Medicinal Chemistry, 2006, vol. 49, # 11, p. 3159 - 3171
[18] Patent: WO2009/23844, 2009, A2, . Location in patent: Page/Page column 98
[19] Patent: WO2010/21797, 2010, A1, . Location in patent: Page/Page column 60
[20] Patent: WO2010/24980, 2010, A1, . Location in patent: Page/Page column 79
[21] Patent: WO2005/94822, 2005, A1, . Location in patent: Page/Page column 28-29
[22] Journal of Medicinal Chemistry, 2000, vol. 43, # 11, p. 2217 - 2226
[23] Patent: US2015/329556, 2015, A1, . Location in patent: Paragraph 1793-1795
[24] Acta Chemica Scandinavica, 1993, vol. 47, # 8, p. 805 - 812
[25] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 15, p. 2573 - 2576
[26] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 21, p. 4745 - 4751
[27] Patent: WO2006/86068, 2006, A1, . Location in patent: Page/Page column 25
[28] Patent: WO2003/99776, 2003, A1, . Location in patent: Page 112-113
[29] Tetrahedron Letters, 2010, vol. 51, # 33, p. 4350 - 4353
[30] Patent: WO2008/124083, 2008, A2, . Location in patent: Page/Page column 48-49
[31] Patent: WO2004/108663, 2004, A1, . Location in patent: Page 81-82
  • 17
  • [ 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
  • 18
  • [ 625-92-3 ]
  • [ 12775-96-1 ]
  • [ 50720-12-2 ]
Reference: [1] Patent: US2003/125345, 2003, A1,
  • 19
  • [ 625-92-3 ]
  • [ 20826-04-4 ]
Reference: [1] Journal of Organic Chemistry, 1951, vol. 16, p. 1485,1491
  • 20
  • [ 625-92-3 ]
  • [ 64-17-5 ]
  • [ 17117-17-8 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: at 0 - 20℃; for 18 h;
Stage #2: at 70℃; for 48 h;
Under a nitrogen atmosphere, sodium (4.60 g, 200 mmol) was added to absolute ethanol (100 mL) at 0-5 °C, and the stirring mixture was allowed to warm to ambient temperature over 18 h. To the resulting solution was added 3,5-dibromopyridine (31.5 g, 133 mmol), followed by DMF (100 mL). The mixture was heated at 70°C for 48 h. The brown mixture was cooled, poured into water (600 mL), and extracted with ether (3 x 500 mL). The combined ether extracts were dried (Na2S04), filtered, and concentrated by rotary evaporation. Purification by vacuum distillation afforded 22.85 g (85.0percent) of an oil, bp 89-90°C at 2.8 mm Hg (lit. bp 111°C at 5 mm Hg, see K. Clarke, et al., J. Chem. Soc. 1885 (I960))
42%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃;
Stage #2: at 60℃; for 4 h;
Example 2. Preparation of 3-ethoxy-2-methoxy-5-bromopyridine (Compound 1004) [0091] As shown in step 2-i of Scheme 2, to 4.0 g (0.1 mol, 60percent in mineral oil) NaH in a 100 mL DMF suspension was added 10 mL of an absolute ethyl alcohol (4.6 g, 0.1 mol)/DMF solution at RT. After the evolution of hydrogen gas, the reaction mixture was stirred at RT for 30 minutes and the resulting ethoxide solution transferred to a solution of 3,5- dibromopyridine (11.84g, 0.05 mol, obtained from Aldrich Chemical Co.) in 100 mL DMF at 60 0C. The reaction was stirred at 60 0C for 4 hours and the mixture was allowed to come to RT. Brine and ethyl acetate were added and the organics were partitioned, dried over MgSO4, filtered, and the volatiles removed under reduced pressure. The resulting crude material was purified by silica chromatography, with the desired product eluting with 20percent ethyl acetate/hexanes. 3-Bromo-5-ethoxypyridine (Compound 1001, 4.25 g) was obtained as the pure product (42 percent yield): 1H NMR (CDCl3) δ 8.3(dd, 2H), 7.4(d, IH), 4.12(q, 2H), 1.45(t, 3H).
42%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃;
Stage #2: at 60℃; for 4 h;
As shown in step 2-i of Scheme 2, to 4.0 g (0.1 mol, 60percent in mineral oil) NaH in a 100 mL DMF suspension was added 10 mL of an absolute ethyl alcohol (4.6 g, 0.1 mol)/DMF solution at RT. After the evolution of hydrogen gas, the reaction mixture was stirred at RT for 30 minutes and the resulting ethoxide solution transferred to a solution of 3,5- dibromopyridine (11.84g, 0.05 mol, obtained from Aldrich Chemical Co.) in 100 mL DMF at 60 0C. The reaction was stirred at 60 0C for 4 hours and the mixture was allowed to come to RT. Brine and ethyl acetate were added and the organics were partitioned, dried over MgSO4, filtered, and the volatiles removed under reduced pressure. The resulting crude material was purified by silica chromatography, with the desired product eluting with 20percent ethyl acetate/hexanes. 3-Bromo-5-ethoxypyridine (Compound 1001, 4.25 g) was obtained as the pure product (42 percent yield): 1H NMR (CDCl3) δ 8.3(dd, 2H), 7.4(d, IH), 4.12(q, 2H), 1.45(t, 3H). 3-Benzyloxy-5-bromopyridine was prepared by an analogous procedure: 1H NMR (CDCl3) δ 8.33(d, 2H), 7.5-7.35(m, 6H), 5.15(s, 2H).
42%
Stage #1: at 20 - 25℃; for 0.5 h;
Stage #2: at 60℃; for 4 h;
As shown in step 2-i of Scheme 2, to NaH (4.0 g, 60percent in mineral oil, 0.1 mol) in a 100 mL DMF suspension was added 10 mL of an absolute ethyl alcohol (4.6 g, 0.1 mol)/DMF solution at RT. After the evolution of hydrogen gas, the reaction mixture was stirred at RT for 30 minutes and the resulting ethoxide solution transferred to a solution of 3,5- dibromopyridine (11.84 g, 0.05 mol, obtained from Aldrich Chemical Co.) in 100 mL DMF at 60°C. The reaction was stirred at 60°C for 4 hours and then allowed to come to RT. Brine and ethyl acetate were added and the organics were partitioned, dried over MgS04, filtered, and the volatiles removed under reduced pressure. The resulting crude material was purified by silica gel chromatography, with the desired product eluting with 20percent ethyl acetate/hexanes to give 3-bromo-5-ethoxypyridine (Compound 2001, 4.25 g, 42percent yield): 1H NMR (CDC13) δ 8.3(dd, 2H), 7.4(d, 1H), 4.12(q, 2H), 1.45(t, 3H).

Reference: [1] Patent: WO2006/23630, 2006, A2, . Location in patent: Page/Page column 60
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 14, p. 4126 - 4141
[3] Patent: WO2010/96389, 2010, A1, . Location in patent: Page/Page column 37; 39
[4] Patent: WO2010/135014, 2010, A1, . Location in patent: Page/Page column 45-47
[5] Patent: WO2011/87776, 2011, A1, . Location in patent: Page/Page column 48; 51
[6] Recueil des Travaux Chimiques des Pays-Bas, 1948, vol. 67, p. 377
[7] Patent: WO2007/113548, 2007, A1, . Location in patent: Page/Page column 158-159
  • 21
  • [ 625-92-3 ]
  • [ 17117-17-8 ]
YieldReaction ConditionsOperation in experiment
85% With sodium ethanolate In DMF (N,N-dimethyl-formamide); ethanol at 70℃; for 48 h; Under a nitrogen atmosphere, sodium (4.60 g, 200 mmol) was added to absolute ethanol (100 mL) at 0-5° C, and the stirring mixture was allowed to warm to ambient temperature over 18 h. To the resulting solution was added 3,5-dibromopyridine (31.5 g, 133 mmol), followed by DMF (100 mL). The mixture was heated at 70° C for 48 h. The brown mixture was cooled, poured into water (600 mL), and extracted with ether (3 x 500 mL). The combined ether extracts were dried (Na2SO4),] filtered, and concentrated by rotary evaporation. Purification by vacuum distillation afforded 22.85 g (85.0 percent) of an oil, bp 89-90° C at 2.8 mm Hg (lit. bp 111° C at 5 mm Hg, see K. Clarke, et al., J. Chem. Soc. 1885 (1960)).
85.0% With sodium In ethanol; N,N-dimethyl-formamide 5-Ethoxy-3-bromopyridine
Under a nitrogen atmosphere, sodium (4.60 g, 200.0 mmol) was added to absolute ethanol (100 mL) at 0-5° C., and the stirring mixture was allowed to warm to ambient temperature over 18 h.
To the resulting solution was added 3,5-dibromopyridine (31.50 g, 133.0 mmol), followed by DMF (100 mL).
The mixture was heated at 70° C. for 48 h.
The brown mixture was cooled, poured into water (600 mL), and extracted with ether (3*500 mL).
The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation, producing 46.70 g of an oil.
Purification by vacuum distillation afforded 22.85 g (85.0percent) of an oil, bp 89-90° C. at 2.8 mm Hg, (lit. bp 111° C. at 5 mm Hg, see K.
Clarke et al., J. Chem. Soc. 1885 (1960)).
Reference: [1] Patent: WO2004/5293, 2004, A2, . Location in patent: Page 63-64
[2] Patent: US2002/169200, 2002, A1,
[3] Patent: US2003/125345, 2003, A1,
  • 22
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  • [ 141-52-6 ]
  • [ 17117-17-8 ]
Reference: [1] European Journal of Pharmacology, 2000, vol. 409, # 1, p. 45 - 55
  • 23
  • [ 625-92-3 ]
  • [ 51468-00-9 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1948, vol. 67, p. 377
[2] Patent: WO2007/113548, 2007, A1,
  • 24
  • [ 625-92-3 ]
  • [ 124-41-4 ]
  • [ 18677-48-0 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1171,1174
  • 25
  • [ 625-92-3 ]
  • [ 84539-34-4 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1953, vol. 72, p. 296,298
  • 26
  • [ 625-92-3 ]
  • [ 42409-58-5 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1171,1174
  • 27
  • [ 625-92-3 ]
  • [ 15862-46-1 ]
Reference: [1] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1062,1068
  • 28
  • [ 625-92-3 ]
  • [ 77-78-1 ]
  • [ 14529-54-5 ]
Reference: [1] Journal fuer Praktische Chemie (Leipzig), 1911, vol. &lt;2&gt; 84, p. 447
  • 29
  • [ 625-92-3 ]
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 20986-40-7 ]
Reference: [1] Tetrahedron Letters, 1984, vol. 25, # 51, p. 5939 - 5942
  • 30
  • [ 625-92-3 ]
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 20986-40-7 ]
  • [ 4591-56-4 ]
Reference: [1] Tetrahedron Letters, 1984, vol. 25, # 51, p. 5939 - 5942
  • 31
  • [ 625-92-3 ]
  • [ 152684-26-9 ]
Reference: [1] Acta Chemica Scandinavica, 1993, vol. 47, # 8, p. 805 - 812
[2] Recueil des Travaux Chimiques des Pays-Bas, 1955, vol. 74, p. 1171,1174
  • 32
  • [ 625-92-3 ]
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 4591-56-4 ]
Reference: [1] Tetrahedron Letters, 1984, vol. 25, # 51, p. 5939 - 5942
  • 33
  • [ 625-92-3 ]
  • [ 64-17-5 ]
  • [ 201230-82-2 ]
  • [ 20986-40-7 ]
  • [ 4591-56-4 ]
Reference: [1] Tetrahedron Letters, 1984, vol. 25, # 51, p. 5939 - 5942
  • 34
  • [ 625-92-3 ]
  • [ 124-38-9 ]
  • [ 13958-91-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 4, p. 709 - 712
  • 35
  • [ 625-92-3 ]
  • [ 124-38-9 ]
  • [ 13958-91-3 ]
Reference: [1] Tetrahedron Letters, 1996, vol. 37, # 15, p. 2565 - 2568
  • 36
  • [ 625-92-3 ]
  • [ 65001-21-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 23, p. 8150 - 8157
[2] Synlett, 2011, # 8, p. 1117 - 1120
  • 37
  • [ 625-92-3 ]
  • [ 56-35-9 ]
  • [ 1448262-75-6 ]
  • [ 59020-10-9 ]
YieldReaction ConditionsOperation in experiment
65% With magnesium; ethylene dibromide In tetrahydrofuran at 35℃; for 1 h; Sonication; Inert atmosphere General procedure: A mixture of magnesium turnings (0.027g, 1.1mmol), bromobenzene (0.15g, 1mmol), bis(tri-n-butyltin) oxide (0.60g, 1mmol) and 1,2-dibromoethane (0.094g, 0.5mmol) as initiator in dry THF (5mL) was sonicated for 1h in an ultrasonic cleaning bath at around 35°C, with monitoring of the reaction by TLC. Once the reaction finished, aqueous saturated NH4Cl solution (40mL) was added and extracted with ethyl acetate (3×20mL). The combined extracts were washed with brine (60mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by column chromatography with silica gel doped with 10percent of KF to retain the tri-n-butyltin bromide formed during the reaction.
Reference: [1] Journal of Organometallic Chemistry, 2013, vol. 741-742, # 1, p. 24 - 32
  • 38
  • [ 625-92-3 ]
  • [ 1461-22-9 ]
  • [ 1448262-75-6 ]
  • [ 59020-10-9 ]
YieldReaction ConditionsOperation in experiment
55% With magnesium; ethylene dibromide In tetrahydrofuran at 35℃; for 1 h; Sonication; Inert atmosphere General procedure: A mixture of magnesium turnings (0.036g, 1.5mmol), bromobenzene (0.15g, 1mmol), tri-n-butyltin chloride (0.49g, 1.5mmol) and 1,2-dibromoethane (0.094g, 0.5mmol) as initiator in dry THF (5mL) was sonicated for 1h in an ultrasonic cleaning bath at around 35°C, with monitoring of the reaction by TLC. Once the reaction finished, aqueous saturated NH4Cl solution (40mL) was added and extracted with ethyl acetate (3×20mL). The combined extracts were washed with brine (60mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the product was isolated by column chromatography with silica gel doped with 10percent of KF to retain tri-n-butyltin halides formed during the reaction. 4 (0.286, 0.78mmol, 78percent) eluted with 98:2 (hexane/diethyl ether).
Reference: [1] Journal of Organometallic Chemistry, 2013, vol. 741-742, # 1, p. 24 - 32
  • 39
  • [ 625-92-3 ]
  • [ 64436-92-6 ]
Reference: [1] Patent: US2014/336182, 2014, A1,
[2] Patent: WO2008/124083, 2008, A2,
  • 40
  • [ 625-92-3 ]
  • [ 74-88-4 ]
  • [ 3430-23-7 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 3009 - 3013
[2] Patent: US2007/185187, 2007, A1, . Location in patent: Page/Page column 9
  • 41
  • [ 625-92-3 ]
  • [ 74-88-4 ]
  • [ 3430-23-7 ]
  • [ 125419-80-9 ]
Reference: [1] Tetrahedron Letters, 1996, vol. 37, # 15, p. 2565 - 2568
  • 42
  • [ 625-92-3 ]
  • [ 74-88-4 ]
  • [ 3430-23-7 ]
Reference: [1] Tetrahedron Letters, 1996, vol. 37, # 15, p. 2565 - 2568
  • 43
  • [ 625-92-3 ]
  • [ 823-96-1 ]
  • [ 3430-16-8 ]
YieldReaction ConditionsOperation in experiment
90% With caesium carbonate In 1,4-dioxane; water at 100 - 110℃; for 32 h; Add cesium carbonate (1. 38 g, 4. 22 mmol), trimethylboroxine (0. 2 mL, 1. 47 mmol) and tetrakis (triphenylphosphine) palladium (0) (0. 488 g, 0. 42 mmol) to a solution of 3, 5-dibromopyridine (1. 0 g, 4. 22 mmol) in 9 : 1 dioxane : water (10 mL) and stir under nitrogen at 110 °C for 16 h. Add more trimethylboroxine (0. 2 mL, 1. 47 mmol) and stir at 100 °C for an additional 16 h. Cool the reaction mixture to room temperature, filter through diatomaceous earth, and wash with ethyl acetate. Concentrate the filtrate and purify the residue by silica gel chromatography, eluting with 80 : 20 hexane : ethyl acetate, to give the title compound as a colorless oil (0. 654 g, 90percent). 1H NMR (300 MHz, Cd13) 8 2. 34 (s, 3 H), 7. 66 (s, 1 H), 8. 36 (s, 1 H), 8. 49 (s, 1 H). GC-MS (EI) : m/z= 171. 0, 173. 0 [M].
Reference: [1] Patent: WO2005/94822, 2005, A1, . Location in patent: Page/Page column 25
  • 44
  • [ 625-92-3 ]
  • [ 107-31-3 ]
  • [ 70201-42-2 ]
YieldReaction ConditionsOperation in experiment
75%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1 h; Inert atmosphere
Stage #2: at 20℃; for 0.5 h; Inert atmosphere
Step 1: (0420) Diisopropylamine (2.4 g, 24.0 mmol) was dissolved in dry tetrahydrofuran (20 ml) under a nitrogen atmosphere, n-butyllithium in n-hexane (9.6 ml, 24.0 mmol) was added dropwise thereto at 0° C. followed by stirring at this temperature for 30 minutes, dry tetrahydrofuran (30 ml) was added and the mixture was cooled to −78° C., 3,5-dibromo-pyridine 26-a (4.7 g, 20 mml) in dry tetrahydrofuran (50 ml) was added dropwise thereto followed by stirring for 30 minutes. Methyl formate (2.4 g, 40 mml) was added followed by stirring for 30 minutes, The mixture was warmed to room temperature, extracted with saturated sodium bicarbonate (100 ml) and ethyl acetate (50 ml×3). The combined organic phase was dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give 26-b as a pale yellow solid (4.0 g, yield: 75percent). 1HNMR (300 MHz, DMSO-d6): δ ppm 10.06 (s, 1H), 8.87 (s, 2H).
Reference: [1] Patent: US2017/158680, 2017, A1, . Location in patent: Paragraph 0418; 0419; 0420
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 10, p. 2789 - 2794
[3] Journal of Fluorine Chemistry, 2006, vol. 127, # 6, p. 755 - 759
[4] Patent: US6232320, 2001, B1,
  • 45
  • [ 625-92-3 ]
  • [ 109-94-4 ]
  • [ 70201-42-2 ]
YieldReaction ConditionsOperation in experiment
63%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1.5 h; Inert atmosphere
Stage #2: at -78℃; for 0.5 h; Inert atmosphere
Lithium diisopropylamide (507 mmol, 1 .2 eq.) was added to 200 mL of dry THF at -78 "C under N2. A solution of 3,5-dibromopyridine ( 100 g, 424 mmol) in 537 mL of dry THF was then added drop- wise over 30 min. The reaction mixture was stirred at -78 "C for 1 h. Ethyl formate (34.4 g, 465 mmol) was added drop-wise and stirred at -78 °C for 30 min, then the reaction mixture was poured into ice-cold saturated aqueous NaHCO3, solution. The mixture was extracted with 3 x 500 mL of EtOAc. The organic layer was concentrated to provide a brown solid, which was filtered through a pad of silica gel (clutcd with dichloromethane) to give the title compound as a yellow powder (70 g, 63percent).
63%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1.5 h; Inert atmosphere
Stage #2: at -78℃; for 0.5 h; Inert atmosphere
Lithium diisopropylamide (507 mmol, 1 .2 eq.) was added to 200 mL of dry THF at -78 "C under N2. A solution of 3,5-dibromopyridine ( 100 g, 424 mmol) in 537 mL of dry THF was then added drop- wise over 30 min. The reaction mixture was stirred at -78 "C for 1 h. Ethyl formate (34.4 g, 465 mmol) was added drop-wise and stirred at -78 °C for 30 min, then the reaction mixture was poured into ice-cold saturated aqueous NaHCOr, solution. The mixture was extracted with 3 x 500 mL of EtOAc. The organic layer was concentrated to provide a brown solid, which was filtered through a pad of silica gel (clutcd with dichloromethane) to give the title compound as a yellow powder (70 g, 63percent).
63%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere
Stage #2: at -78℃; for 0.5 h;
Step 1 . 3.5-Dibromoisonicotinaldehvde Lithium di isopropylamide (507 mmol, 1 .2 eq. ) was added to 200 mL of dry THF at -78 "C under N2. A solution of 3,5-dibromopyridine ( 1 00 g, 424 mmol ) in 537 mL of dry THF was then added drop- wise over 30 m in The reaction mixture was stirred at -78 °C for 1 h. Ethyl formate (34.4 g, 465 mmol) was added drop-wise and stirred at -78 °C for 30 mm, then the reaction mixture was poured into ice-cold saturated aqueous NaHCO;, solution. The mixture was extracted with 3 x 500 mL of ethyl acetate. The organic layer was concentrated to provide a brown solid, which was filtered through a pad of silica gel (el uted with dichloromethane) to give the title compound as a yellow powder (70 g, 63percent).
63%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1.5 h; Inert atmosphere
Stage #2: at -78℃; for 0.5 h; Inert atmosphere
Lithium diisopropylamide (507 mmol, 1 .2 eq.) was added to 200 mL of dry THF at -78 "C under N2. A solution of 3,5-dibromopyridine ( 100 g, 424 mmol) in 537 mL of dry THF was then added drop- wise over 30 min. The reaction mixture was stirred at -78 "C for 1 h. Ethyl formate (34.4 g, 465 mmol) was added drop-wise and stirred at -78 °C for 30 min, then the reaction mixture was poured into ice-cold saturated aqueous NaHCO3, solution. The mixture was extracted with 3 x 500 mL of EtOAc. The organic layer was concentrated to provide a brown solid, which was filtered through a pad of silica gel (clutcd with dichloromethane) to give the title compound as a yellow powder (70 g, 63percent).
63%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1.5 h; Inert atmosphere
Stage #2: at -78℃; for 0.5 h;
[0187] Step 1. 3,5-Dibromoisonicotinaldehyde. Lithium diisopropylamide (507 mmol, 1.2 eq.) was added to 200 mL of dry THF at -78 °C under N2. A solution of 3,5-dibromopyridine (100 g, 424 mmol) in 537 mL of dry THF was then added drop-wise over 30 mm. The reaction mixture was stirred at -78 °C for 1 h. Ethyl formate (34.4 g, 465 mmol) was added drop-wise and stirred at -78 °C for 30 mm, then the reaction mixture was poured into ice-cold saturated aqueous NaHCO3 solution. The mixture was extracted with 3 x 500 mL of EtOAc. The organic layer was concentrated to provide a brown solid, which was filtered through a pad of silica gel (eluted with dichloromethane) to give the title compound as a yellow powder (70 g, 63percent).

Reference: [1] Patent: WO2013/127266, 2013, A1, . Location in patent: Page/Page column 135
[2] Patent: WO2013/127267, 2013, A1, . Location in patent: Page/Page column 86
[3] Patent: WO2013/127269, 2013, A1, . Location in patent: Page/Page column 148
[4] Patent: WO2013/127268, 2013, A1, . Location in patent: Page/Page column 64; 65
[5] Patent: WO2013/130935, 2013, A1, . Location in patent: Paragraph 0187
  • 46
  • [ 625-92-3 ]
  • [ 68-12-2 ]
  • [ 70201-42-2 ]
YieldReaction ConditionsOperation in experiment
45%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -70 - 0℃; for 2 h; Inert atmosphere
Stage #2: at -70℃; for 2 h;
Under nitrogen protection, 150 mL anhydrous THF and 49.1 g diisopropylamine were added into a 2 L three-necked flask, and the solution was cooled to −5° C. 194 mL 2.5M n-BuLi solution was dropwise added in, and meanwhile the temperature was kept at or below 0° C., and after dropwise adding finished, the system was kept at the temperature and reacted for 1 hour, and then the solution was cooled to −70° C. 100 g 3,5-dibromopyridine dissolved in 500 mL THF was dropwise added with keeping temperature ≦−70° C., and after the dropwise adding finished, the system was kept at the temperature and stirred for 2 hours. 61.6 g DMF dissolved in 250 mL THF was dropwise added into the resulted system with keeping temperature ≦−70° C., and stirred for 2 hours. The reaction had completed by checking by TLC. The reaction liquid was added into 2.5 L saturated sodium bicarbonate solution, extracted by ethyl acetate (800 mL×3). The organic phases were merged, washed by saturated salt water, dried by anhydrous sodiumsulfate, concentrated and recrystallized with petroleum ether to give a yellow solid, i.e. compound A2, 50 g, 45percent yield. 1H-NMR (400 MHz, DMDO-d6) (ppm) 8.91 (s, 2H), 10.09 (s, 1H).
Reference: [1] Patent: US2016/207916, 2016, A1, . Location in patent: Paragraph 0038-0040
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Reference: [1] Patent: WO2013/127266, 2013, A1,
[2] Patent: WO2013/127267, 2013, A1,
[3] Patent: WO2013/127268, 2013, A1,
[4] Patent: WO2013/130935, 2013, A1,
[5] Patent: WO2013/130943, 2013, A1,
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  • 52
  • [ 625-92-3 ]
  • [ 100-51-6 ]
  • [ 130722-95-1 ]
YieldReaction ConditionsOperation in experiment
73%
Stage #1: With sodium hydride In hexane; N,N-dimethyl-formamide at 20℃; for 2.08333 h; Inert atmosphere; Cooling with ice
Stage #2: at 20℃; for 15 h; Inert atmosphere
3-(Benzyloxy)-5-bromopyridine [1099] (Zhu. G.-D. et al., Bioorg. Med. Chem. Lett. 2006, 16, 3150-3155) [1100] A 500 mL three-necked flask was charged with sodium hydride (60percent dispersion in oil; 9.6 g, 240 mmol, 2.0 equiv.) and fitted out with stir bar, dropping funnel, N2 balloon, and septa. The sodium hydride was washed with hexane (2×150 mL), then anhydrous DMF (110 mL) was added. With stifling and intermittent ice cooling, benzyl alcohol (25 mL, 240 mmol, 2.0 equiv.) was added dropwise within 105 min. The temperature was kept high enough to permit efficient stifling and prevent excessive frothing. After the addition was finished, the dropping funnel was rinsed with anhydrous DMF. Stirring was continued at room temperature for 20 min. The flask was briefly opened to add 3,5-dibromopyridine (28.4 g, 120 mmol) all at once. The atmosphere was again replaced with N2, and the reaction mixture was stirred at room temperature for 15 h. A thin layer chromatogram (small aliquot quenched into EtOAc/H2O; silica gel, EtOAc/hexane 15:85) taken shortly before the end of this period demonstrated the near-absence of starting material (Rf 0.6) and the formation of a product (Rf 0.25); benzyl alcohol was detected at Rf 0.15. The bulk of DMF was distilled in an oil pump vacuum at a bath temperature of 40° C. into a receiver cooled with acetone/dry ice. Initial foaming was due to the evaporation of residual hexane. The receiver was subsequently changed to maintain a high vacuum. The residue was taken up in diethyl ether (300 mL) and the resulting suspension poured into ice water (300 mL). The phases were separated, and the aqueous phase was twice extracted with ether (100 mL each). The combined organic phases were washed with brine (100 mL) and dried over MgSO4 (15 g). Evaporation furnished an orange-colored liquid together with a colorless solid. After transfer into a 200 mL flask, benzyl alcohol was distilled off in an oil pump vacuum into a −78° C. receiver. The product began to crystallize after partial cooling, whereon methanol (60 mL) was added. Crystallization was initially allowed to proceed at room temperature, then in the freezer overnight. [1101] The product was isolated by suction filtration, washed with two portions of freezer-chilled methanol (20 mL each), and dried (40° C./oil pump) to obtain 23.2 g (73percent) of light-tan crystals (mp 67-68.5° C.). The mother liquor was concentrated to a few mL, diluted with methanol (15 mL), seeded, and placed in the freezer. Isolation as above gave 1.7 g of a solid which upon TLC examination revealed contamination with polar material. The second mother liquor still contained substantial amounts of benzyl alcohol, which was removed by evaporation into a 50 mL flask and bulb-to-bulb distillation at 80° C. in an oil pump vacuum until by visual appearance no further distillate was formed. The dark residue (2.7 g) together with the impure second crystal fraction was taken up in CH2Cl2 (3 mL) and chromatographed on silica gel (25×3.8 cm, EtOAc/hexane 1:9) to yield, after evaporation and drying, another 2.4 g (8percent) of the product 2. 1H NMR (CDCl3, 300 MHz) δ 8.33 (narrow m, 2H), 7.50-7.32 (m, 6H), 5.11 (s, 2H).
63%
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oilInert atmosphere
Stage #2: at 180℃; for 2 h; Inert atmosphere
Benzylalcohol (10 mL, 96 mmol) was dissolved in dry DMF (30 mL) and sodium hydride (60percent suspension in mineral oil) (2.5 g, 62.50 mmol) was slowly added. When no more gas evolved, 3,5-dibromopyridine (10 g, 42.21 mmol) was added and the reaction mixture was stirred at 180 °C for 2 h. After addition of water, the aqueous phase was extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered, and evaporated to dryness. The resulting oil was purified by column chromatography eluting with an 8/2 mixture of petroleum ether and diethyl ether and then a second column chromatography eluting with a 9/1 mixture of CH2Cl2 and ethyl acetate to afford 2 (7.02 g, 63percent) as a beige needle. Mp 67-68 °C (lit.:14 64-65 °C); IR (KBr): 1553, 1425, 1259, 990 cm-1; 1H NMR (400 MHz): 5.25 (s, 2H, -OCH2Ph), 7.37-7.51 (m, 5H, Ph-H), 7.84 (dd, J=J'=2.0 Hz, 1H, pyridine-H), 8.33 (d, J=2.0 Hz, 1H, pyridine-H), 8.40 (d, J=2.0 Hz, 1H, pyridine-H); 13C NMR (100 MHz): 70.2, 120.2, 124.3, 128.2, 128.4, 128.7, 136.2, 137.4, 142.5, 155.3; the data are in conformity with the literature.14 MS (ESI) m/z (percent): 265.9 [(M+H)+, 100], 267.9 [(M+H)+2, 100]. Anal. Calcd for C12H10BrNO: C, 54.57; H, 3.82; N, 5.30. Found: C, 54.63; H, 3.83; N, 5.31.
43%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 60℃; for 1 h;
Stage #2: at 80℃; for 2 h;
Benzyl alcohol (4.60 g, 42.6 mmol) was slowly added to a stirred solution of NaH (60percent disp., 1.70 g, 42.5 mmol) in DMF (50 mL). The reaction was heated to 60 0C for 1 hours. 3,5-Dibromopyridine (10.0 g, 42.2 mmol) in DMF (20 mL) was added and the mixture was heated at 80 0C for 2 hours. The reaction <n="172"/>mixture was 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- Benzyloxy-5-bromopyridine (4.75 g, 43percent). MS m/z calculated for (M + H)+ 265, found 265.
26%
Stage #1: With sodium hydride In N,N-dimethyl-formamide for 1.5 h; Reflux
Stage #2: at 20℃; for 12 h; Reflux
To a solution of benzyl alcohol (1.04g, 9.66mmol) in anhydrous DMF (80mL) was slowly added 60percent NaH (0.58g, 14.49mmol). The mixture was allowed to react at room temperature for 30min then it was heated to reflux for 1h. 3,5-dibromopyridine (2.41g, 10.17mmol) was added and the reaction was continued for 12h. After cooling down to room temperature, the mixture was poured in water and extracted with ethyl acetate. The organic phase was washed with brine, dried on MgSO4, filtered and evaporated. The crude product was purified by silica gel chromatography (cyclohexane/AcOEt 95:5) affording 10 as a white solid. Yield 26percent. Mp 66–68°C. 1H NMR (400MHz, CDCl3): δ 5.06 (2H, s, OCH2), 7.36–7.44 (6H, m, H-4, H-Ph), 8.30 (1H, d, J=2.3Hz, H-6), 8.31 (1H, d, J=2.3Hz, H-2). 13C NMR (100MHz, CDCl3): δ 155.5, 143.5, 137.0, 135.7, 129.1, 128.8, 127.9, 124.7, 120.7, 71.0.

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  • 55
  • [ 625-92-3 ]
  • [ 98-80-6 ]
  • [ 142137-17-5 ]
YieldReaction ConditionsOperation in experiment
68% With potassium carbonate In 1,2-dimethoxyethane; waterHeating / reflux A mixture of 3,5-dibromopyridine (10.0 g, 42.2 mmol), phenylboronic acid (4.6 g, 38.0 mmol), tetrakis(triphenylphosphine)palladium(0) (1.45 g, 1.25 mmol), potassium carbonate (17.5 g, 127 mmol), water (63 ml) and 1,2-dimethoxyethane (126 ml) was stirred at reflux overnight.
Aqueous sodium hydroxide (1 M, 60 ml) was added followed by extraction twice with diethyl ether (100 ml).
Chromatography on silica gel with dichloromethane as solvent gave the title compound.
Yield 6.1 g, 68percent, Mp 42-44° C.
68% With potassium carbonate In 1,2-dimethoxyethane; water A mixture of 3,5-dibromopyridine (10.0 g, 42.2 mmol), phenylboronic acid (4.6 g, 38.0 mmol), tetrakis(triphenylphosphine)palladium(0) (1.45 g, 1.25 mmol), potassium carbonate (17.5 g, 127 mmol), water (63 ml) and 1,2-dimethoxyethane (126 ml) was stirred at reflux overnight. Aqueous sodium hydroxide (1 M, 60 ml) was added followed by extraction twice with diethyl ether (100 ml). Chromatography on silica gel with dichloromethane as solvent gave the title compound. Yield 6.1 g, 68percent, Mp 42-44 C.
68% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water for 4 h; Reflux (Triphenylphosphine)palladium tetrakis (125 mg, 0.08 mmol, 2 mol percent) was added to a solution of3,5-dibromopyridine (1.00 g, 4.22 mmol) in dimethoxyethane (13 mL) and themixture was stirred for 10 min. Asolution of potassium carbonate (1.75 g, 12.7 mmol) in water (6.5 mL) wasadded, followed by phenyl boronic acid (463 mg, 3.79 mmol), and the mixture washeated at reflux for 4 h. A solution of1M NaOH (6 mL) was added to the cooled mixture, the mixture was extracted withdiethyl ether, the organic extracts were combined, dried over MgSO4, filtered, and the solvents were evaporated. The crude was purified by columnchromatography using dichloromethane as an eluent to give 608 mg of the product(68 percent yield) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 8.76(d, 1H, 2.0 Hz); 8.66 (d, 1H, 2.2 Hz); 8.03 (t, 1H, 2.2 Hz, 2.0 Hz); 7.43-7.59(m, 5H). 13CNMR(CDCl3, 75 MHz): δ 149.3,146.3, 138.2, 136.8, 136.2, 129.1, 128.6, 127.1, 120.8,
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[2] Patent: US2004/72823, 2004, A1, . Location in patent: Page/Page column 20
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[9] Patent: US5811442, 1998, A,
[10] Patent: WO2008/91681, 2008, A2, . Location in patent: Page/Page column 240-241
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[12] Patent: US2010/16298, 2010, A1, . Location in patent: Page/Page column 203
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  • [ 73183-34-3 ]
  • [ 452972-13-3 ]
YieldReaction ConditionsOperation in experiment
86% With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In 1,4-dioxane at 120℃; for 2 h; Preparation of compound 4-1[221]After introducing 3,5-dibromopyridine (25 g, 105.5 mmol), diborane (28 g, 110.8 mmol), PdCl2(PPh3)2(3.7 g, 5.27 mmol), KOAc (20.7 g, 211 mmol), and 1,4-dioxane 527 mL into a flask, the mixture was stirred under reflux at 120°C for 2 hours. After the reaction is completed, an organic layer was extracted with ethyl acetate, and remaining moisture was removed with magnesium sulfate and dried. The remaining product was then separated with column chromatography to obtain compound 4-1 (25 g, 86percent).
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  • [ 76-09-5 ]
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  • [ 452972-13-3 ]
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  • [ 4248-19-5 ]
  • [ 361550-43-8 ]
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  • [ 286946-77-8 ]
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  • [ 870234-98-3 ]
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Reference: [1] Patent: WO2013/127266, 2013, A1,
[2] Patent: WO2013/127267, 2013, A1,
[3] Patent: WO2013/127268, 2013, A1,
[4] Patent: WO2013/130935, 2013, A1,
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  • [ 625-92-3 ]
  • [ 1126-09-6 ]
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YieldReaction ConditionsOperation in experiment
60% at 150℃; for 72 h; To a 250 mL salable tube was added 3,5- DI. BROMO PYRIDINE (5.00 G, 21. 1 MMOL), ethyl iso- NEPICOTATE (16.0 G, 106 mmol) and cesium carbonate (7.22 g, 22.2 mmol). THE-. tube was vented with N2 and sealed. The mixture was heated to 150°C for 72 h then cooled to ambient temperature. The crude prod- uct was dissolved in toluene and filtered. The or- ganic layer was concentrated in vacuo and the resi- due was purified by flash chromatography on silica gel eluting with 1: 1 EtOAc/Hexane to provide the title compound (3.95g, 60percent) as a light yellow oil. 1H NMR (CDCl3, 400 MHz) 5 8.21 (d, J=2.73 Hz, 1H), 8.1 (d, J=1.95 Hz, 1H), 7.3 (t, J=2.34 Hz, 1H), 4.18 (q, J=7.03, 14. 43HZ, 2H), 3.66 (m, 2H), 2.89 (m, 2H), 2.48 (m, 1H), 2.04 (m, 2H), 1.87 (m, 2H), 1.28 (t, J=7.21 Hz, 3H).
12% at 150℃; for 1 h; Microwave irradiation A stirred mixture of 3,5-dibromopyridine (0.500 g, 2.11 mmol), ethyl piperidine-4- carboxylate (1.60 g, 10.2 mmol) and cesium carbonate (0.729 g, 2.24 mmol) was heated in a microwave reactor at 150 °C for 1 hour. The reaction was cooled and concentrated. The residue was purified by flash chromatography over silica using a hexane/ethyl acetate eluant to afford ethyl l-(5-bromopyridin-3-yl)piperidine-4-carboxylate as a yellow oil (0.078 g, 12percent)). Using the final three steps described in Example 106, this intermediate was used to prepare the title compound. H NMR (500 MHz, CDC13) δ 8.30 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 7.55-7.52 (m, 2H), 7.30 (s, 1H), 7.16 (t, J = 8.5 Hz, 2H), 5.43 (s, 1H), 3.85-3.82 (m, 2H), 3.06-2.85 (m, 8H), 2.40-2.23 (m, 2H), 1.99-1.54 (m, 13H) ppm. 13C NMR (125 MHz, CDCI3) δ 173.8, 163.8, 161.8, 146.9, 139.0, 137.6, 135.8, 134.5, 128.9, 121.1, 116.0, 115.8, 59.5, 53.1, 48.6, 47.6, 46.1, 43.7, 39.2, 36.1, 28.8, 28.5, 25.1, 24.3, 24.2 ppm. Purity: > 99percent LCMS (214 nm & 254 nm); retention time 1.19 min; (M+H+) 437.3.
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  • [ 73183-34-3 ]
  • [ 1012085-50-5 ]
Reference: [1] Journal of Natural Products, 2017, vol. 80, # 4, p. 1205 - 1209
[2] Patent: US2010/174086, 2010, A1, . Location in patent: Page/Page column 10-11
[3] Patent: WO2010/80471, 2010, A1, . Location in patent: Page/Page column 19
[4] Patent: WO2010/80471, 2010, A1, . Location in patent: Page/Page column 23-24
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