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Chemical Structure| 1692-25-7
Chemical Structure| 1692-25-7
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Product Details of [ 1692-25-7 ]

CAS No. :1692-25-7 MDL No. :MFCD00674177
Formula : C5H6BNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :ABMYEXAYWZJVOV-UHFFFAOYSA-N
M.W : 122.92 Pubchem ID :2734378
Synonyms :

Calculated chemistry of [ 1692-25-7 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 34.06
TPSA : 53.35 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.22 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : -0.24
Log Po/w (WLOGP) : -1.24
Log Po/w (MLOGP) : -1.39
Log Po/w (SILICOS-IT) : -1.15
Consensus Log Po/w : -0.81

Druglikeness

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

Water Solubility

Log S (ESOL) : -0.88
Solubility : 16.3 mg/ml ; 0.132 mol/l
Class : Very soluble
Log S (Ali) : -0.42
Solubility : 46.5 mg/ml ; 0.378 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.87
Solubility : 16.6 mg/ml ; 0.135 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.85

Safety of [ 1692-25-7 ]

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:

Applications of [ 1692-25-7 ]

Pyridin-3-ylboronic acid (CAS: 1692-25-7) can be used in the preparation of Nilotinib (AMN-107) (CAS: 641571-10-0). Nilotinib, also known as AMN107, is a tyrosine kinase inhibitor.

Application In Synthesis of [ 1692-25-7 ]

* 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 [ 1692-25-7 ]
  • Downstream synthetic route of [ 1692-25-7 ]

[ 1692-25-7 ] Synthesis Path-Upstream   1~48

  • 1
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YieldReaction ConditionsOperation in experiment
52% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; N,N-dimethyl-formamide at 110℃; for 2 h; Microwave irradiation; Inert atmosphere General procedure: Method B: In a20 mL microwave Biotage tube, a 1M Na2CO3 aqueous solution(5 mL) purged with argon were introduced into a mixture purged with argon of 4-iodo-1H-imidazole (1a) (0.194 g, 1.0 mmol), a boronicacid 2 (1.6 mmol) and Pd(PPh3)4 (0.80 g, 0.05 mmol) in DMF (15 mL). The mixture washeated under microwaveirradiation. When the reaction was complete, the mixture was cooled toroom temperature and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel to provide compounds 3j and 3p-3u in yields ranging from 30 to 95percent. Time and temperaturereactions were collected in Table 1.
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 46, p. 6347 - 6350
  • 2
  • [ 2302-25-2 ]
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  • [ 51746-85-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 224 - 239
  • 3
  • [ 1692-25-7 ]
  • [ 1120-90-7 ]
YieldReaction ConditionsOperation in experiment
53% With 1,10-Phenanthroline; oxygen; potassium iodide; copper(ll) bromide In N,N-dimethyl-formamide at 80℃; for 20 h; General procedure: under oxygen, a sealed reaction tube was charged with KX (X = I, Br) (0.2 mmol), arylboronic acid (0.3 mmol), CuBr2 (4.5 mg, 10 mol percent), 1,10-phen (7.2 mg, 20 mol percent) and DMF (2 mL). The mixture was stirred at 80 or 130 °C. After the completion of the reaction, the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel to give the product.
Reference: [1] Tetrahedron Letters, 2011, vol. 52, # 16, p. 1993 - 1995
  • 4
  • [ 1692-25-7 ]
  • [ 6630-33-7 ]
  • [ 176690-44-1 ]
YieldReaction ConditionsOperation in experiment
64% With sodium carbonate In water; N,N-dimethyl-formamide at 110℃; Inert atmosphere Example 380 : Synthesis of (1E,6E)-1-(4-hydroxyphenyl)-7-[2-(pyridin-3-yl)phenyl]hepta-1,6-diene-3,5-dione (CU513); (1) Synthesis of 2-(pyridin-3-yl)benzaldehyde; To a suspension of 1-bromobenzaldehyde (250 μL, 2.14 mmol), sodium carbonate (270 mg, 2.55 mmol), and 3-pyridineboronic acid (289 mg, 2.35 mmol) in 4.2 mL of N,N-dimethylformamide/water (2:1) were added palladium acetate (24 mg, 0.11 mmol) and triphenylphosphine (115 mg, 0.44 mmol) under nitrogen. After being stirred at 110°C overnight, the reaction mixture was filtered. The filtrate was diluted with chloroform, and the solution was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol = 99/1 to 95/5) to obtain the title compound as a white powder (250 mg, 64percent).
Reference: [1] Patent: EP2123637, 2009, A1, . Location in patent: Page/Page column 106
  • 5
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Reference: [1] Dalton Transactions, 2014, vol. 43, # 26, p. 10235 - 10247
  • 6
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  • [ 2176-45-6 ]
YieldReaction ConditionsOperation in experiment
88% With Eosin Y; sodium t-butanolate In N,N-dimethyl-formamide at 20℃; for 2 h; Irradiation; Green chemistry General procedure: A solution of the appropriate arylboronic acid (1.0 mmol), the diphenyliodonium trifluoromethanesulfonate (1.2 mmol), eosin Y (34.5 mg, 0.02 mmol) and t-BuONa (1.1 mmol, 25 mg) in DMF (2.0 mL) in a borosilicate flask was subjected to constant irradiation with an LED 18-watt visible light, and the reaction was stirred at room temperature for 1–2 h. After completion of the reaction (TLC), the reaction mixture was poured into H2O (50 mL) and stirred for another 2 h. The aqueous phase was extracted with CH2Cl2(2 × 20 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The residues was purified by silica gel column chromatography [ethyl acetate – petroleum ether (60–90 °C) = 1:10–1:4] to afford the pure product. 3-Phenoxypyridine (3h): slightly yellow oil; 1H NMR (CDCl3, 400 MHz) δ 8.21–8.20 (m, 1H), 7.70–7.66 (m, 1H), 7.42–7.38 (m, 2H), 7.16–7.14 (m, 2H), 7.01–6.97 (m, 1H), 6.91–6.89 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 163.8, 154.2, 147.8, 139.4, 129.7, 124.6, 121.2, 118.4, 111.5.
Reference: [1] Journal of Chemical Research, 2016, vol. 40, # 5, p. 261 - 264
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YieldReaction ConditionsOperation in experiment
68% With sodium carbonate In ethanol; water; toluene at 80℃; for 16 h; Preparation of 3-(pyridin-3-yl)benzenamine (6); To 3-bromoaniline (513.1 mg, 2.983 mmol) was added ethanol/toluene (1:1, 20 mL), 3-pyridinylboronic acid (397.3 mg, 3.232 mmol), sodium carbonate (1.85 g, 17.45 mmol) in 9 mL water, and tetrakis(triphenylphosphine)palladium (504.3 mg, 0.439 mmol). The resulting mixture is heated to 80° C. and stirred for 16 h. The reaction mixture is cooled, diluted with 10 mL of water and extracted with EtOAc (3.x.25 ml). The organics were combined and, washed with 10 mL of water and saturated aqueous NaCl (2.x.10 mL), then dried over magnesium sulfate and concentrated in vacuo to a brown oil. The oil is purified over silica (0-5percent MeOH in CH2Cl2) to afford 345 mg (68percent yield) of the desired compound. MS (ESI, pos. ion) m/z: 171 (M+1).
Reference: [1] Patent: US2007/293494, 2007, A1, . Location in patent: Page/Page column 17-18
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 17, p. 7410 - 7424
[3] ACS Medicinal Chemistry Letters, 2012, vol. 3, # 5, p. 373 - 377
  • 8
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Reference: [1] Patent: WO2009/125923, 2009, A2,
  • 9
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  • [ 134363-45-4 ]
Reference: [1] Tetrahedron, 2003, vol. 59, # 27, p. 4973 - 4977
[2] Organic Letters, 2018, vol. 20, # 5, p. 1316 - 1319
[3] Patent: WO2008/10964, 2008, A1,
  • 10
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  • [ 134363-45-4 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 18, p. 4550 - 4553
  • 11
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  • [ 5094-12-2 ]
Reference: [1] Organic Letters, 2011, vol. 13, # 10, p. 2726 - 2729
  • 12
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  • [ 19733-56-3 ]
Reference: [1] Organic Process Research and Development, 2011, vol. 15, # 4, p. 831 - 840
  • 13
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  • [ 5419-55-6 ]
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YieldReaction ConditionsOperation in experiment
73%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes; toluene at -60 - -50℃; for 0.75 h;
Stage #2: With hydrogenchloride In tetrahydrofuran; hexanes; water; toluene at -50 - -15℃;
General Procedure for the Preparation of Pyridin-3-yl-Boronic Acids (1-6).; [0275] Compounds 1-6 were prepared by the esterification of the appropriate lithiopyridine followed by hydrolysis as previously reported (Cai et al., Tetrahedron Lett. 43: 4285-4287 (2002) ). The synthesis of pyridin-3-yl-3-boronic acid (1) is representative of compounds 2-6. [0276]/Pyridin-3-yl-3-boronic acid (1). A 500 mL 3-neck flask was charged with toluene (85 mL), cooled to below-60 °C and a solution of n-BuLi (1.6 M in hexanes, 48.6 mL, 77.8 mmol) was added dropwise over 10 min. After the internal temperature reached-60 °C a solution of 3-bromopyridine (6.8 mL, 70.7 mmol) in toluene (30 mL) was added drop wise to keep the internal temperature below-50 °C. A brownish-black solid precipitated and the resultant slurry was stirred for 20 min. THF (30 mL) was added drop-wise to keep the internal temperature below-50 °C and the resultant slurry was stirred for 15 min. To the slurry was added triisopropyl borate (19.6 mL, 84.9 mmol) in one portion via syringe. The solution was warmed to-15 °C, quenched with HCl (aq) (2.7 N, 70.0 mL) and transferred to a separatory funnel. The aqueous layer was collected and the organic layer was washed with water (10 mL), the combined aqueous layers were neutralized to pH 7 with NaOH (aq) (10 N) and extracted with THF (200 mL x 1,125 mL x 2). The combined organics were concentrated in vacuo and the residue was dissolved in THF/CH30H (1: 1, 140 mL), filtered and diluted to 300 mL with CH3CN. The solvent was switched to CH3CN by distillation and concentrated to 100 mL. The solids were collected by filtration to afford the title compound 1 (6.4 g, 73percent yield) as an off white solid : 1H NMR (CD30D) 6 8.64 (br s, 1H), 8.50 (m, 1H), 8.38 (br s, 1H), 7.65 (br s, 1H). This material was used directly in Suzuki cross coupling reactions.
Reference: [1] Patent: WO2005/66162, 2005, A1, . Location in patent: Page/Page column 92
[2] Organic Syntheses, 2005, vol. 81, p. 89 - 97
  • 14
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Reference: [1] Synthetic Communications, 2003, vol. 33, # 5, p. 795 - 800
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 224 - 239
[3] Journal of Organic Chemistry, 2017, vol. 82, # 17, p. 9258 - 9262
[4] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 15, p. 5661 - 5674
[5] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 283 - 287
[6] Journal of Organic Chemistry, 2002, vol. 67, # 15, p. 5394 - 5397
[7] Patent: US2009/170790, 2009, A1, . Location in patent: Page/Page column 23
[8] Journal of the American Chemical Society, 2011, vol. 133, # 30, p. 11438 - 11441
[9] European Journal of Medicinal Chemistry, 2014, vol. 73, p. 167 - 176
[10] New Journal of Chemistry, 2014, vol. 38, # 8, p. 3522 - 3528
[11] Patent: CN108440587, 2018, A,
[12] Patent: US2008/318878, 2008, A1, . Location in patent: Page/Page column 17
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  • [ 121-43-7 ]
  • [ 1692-25-7 ]
Reference: [1] Patent: US5981550, 1999, A,
[2] Patent: US6004984, 1999, A,
[3] Patent: US5985901, 1999, A,
[4] Patent: US6156772, 2000, A,
  • 16
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  • [ 109-72-8 ]
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Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 23, p. 4285 - 4287
  • 17
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  • [ 121-43-7 ]
  • [ 64-17-5 ]
  • [ 1692-25-7 ]
Reference: [1] Patent: US5908840, 1999, A,
[2] Patent: EP944628, 2002, B1,
  • 18
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  • [ 121-43-7 ]
  • [ 594-19-4 ]
  • [ 1692-25-7 ]
Reference: [1] Patent: US5347013, 1994, A,
[2] Patent: US5364856, 1994, A,
  • 19
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 945 - 949
  • 20
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Reference: [1] New Journal of Chemistry, 2014, vol. 38, # 8, p. 3522 - 3528
  • 21
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  • [ 1692-25-7 ]
Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 21, p. 10568 - 10580
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  • [ 201733-56-4 ]
  • [ 128143-86-2 ]
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  • [ 381218-94-6 ]
Reference: [1] Journal of the Chemical Society. Perkin Transactions 2, 2002, # 10, p. 1669 - 1681
  • 23
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Reference: [1] Chemical Science, 2016, vol. 7, # 6, p. 3676 - 3680
  • 24
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Reference: [1] Dalton Transactions, 2008, # 44, p. 6311 - 6318
  • 25
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YieldReaction ConditionsOperation in experiment
>= 99 %Chromat. With potassium carbonate In water at 45 - 100℃; for 22 h; (ii) Suzuki reaction of aryl halides (in water) Preparation of the catalyst-stock-solution: The catalyst stock solution was prepared as described for the aqueous Sonogshira reaction using 9-Et-2-SO3HFlu-PCy2-HBF4 (13a). Cross-coupling reaction: Aryl halide (1 mmol), boronic acid (1.2 mmol) and K2CO3 (3.2 mmol) were first added to water (4 ml), then the catalyst stock solution and two drops of Labrasol.(R). (caprylocaproyl macrogol-8 glyceride blend, saturated polyglycolized glycerides consisting of mono-, di-and triglycerides of mono- and di-fatty acids of polyethylene glycol (PEG)) were added. The reaction mixture was stirred at the respective temperatures (see Table 8) for 0.5-20 h (see Table 8). After cooling to room temperature the reaction mixture was diluted with ether (15 ml), washed with water (10 ml), the organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product was isolated by column chromatography (silica, cyclohexane / ethylacetate (100:2). Alternatively the yield was determined via gas chromatography with hexadecane or diethylene glycol di-n-butylether as an internal standard.
Reference: [1] Chemistry - A European Journal, 2008, vol. 14, # 14, p. 4267 - 4279
[2] Chemistry - A European Journal, 2007, vol. 13, # 9, p. 2701 - 2716
[3] Patent: EP1894938, 2008, A1, . Location in patent: Page/Page column 53; 58; 59
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Reference: [1] Applied Organometallic Chemistry, 2013, vol. 27, # 4, p. 232 - 238
  • 27
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  • [ 1692-25-7 ]
  • [ 66521-66-2 ]
YieldReaction ConditionsOperation in experiment
72% With 1-(2,6-diisopropylphenyl)-3-(2-oxo-2-(2,4,6-tri-tert-butylphenylamino)ethyl)-1H-imidazol-3-ium bromide; palladium diacetate; sodium hydroxide In water; dimethyl sulfoxide at 100℃; for 10 h;          Pd(OAc)(35.00 mg, 0.15 mmol) and 1-(2,6-diisopropylphenyl)-3-(2-oxo-2-(2,4,6-tri-tert-butylphenylamino)ethyl)-1H-imidazol-3-iumbromide (96.00 mg, 0.15 mmol) was dissolved in 10 ml of DMSO : H2O,and 4-chloropyrimidin-2-amine (2.00 g, 15.43 mmol), NaOH (0.93 g, 23.15 mmol),pyridin-3-ylboronic acid (2.28 g, 18.5 mmol)  were added. The mixture was heated to 100 oCand stirred for 10h. After cooling, the mixturewas poured into EtOAc (40.0 mL and washed with water (2 ×10.0 mL), brine (2 × 25.0 mL), then dried over MgSO4, evaporation ofthe solvent under reduced pressure provided the crude product, which waspurified by column chromatography (hexane : EtOAc = 1:1) afford product as off white solid 1.92 g, 11.15 mmol) in 72percent yield. 1HNMR (300 MHz, DMSO): δ 9.23(dd, J =1.5 Hz, 1H), 8.68 (dd, J1= 3.0 Hz, J2 = 1.8 Hz,1H), 8.41-8.35 (m, 2H), 7.55-7.50 (m, 1H), 7.20 (d, J1 = 5.1 Hz, 1H), 6.78 (bs, 2H);   13C NMR (75 MHz, CDCl3): δ 163.8, 161.6, 159.4, 151.1, 148.0, 134.1,123.7, 106.0. HRMS(ESI) calcd. for C9H9N4 [M+H]+173.0827, found 173.0825.
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 49, p. 6657 - 6661
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  • [ 31970-30-6 ]
Reference: [1] Angewandte Chemie - International Edition, 2006, vol. 45, # 21, p. 3484 - 3488
[2] Journal of the American Chemical Society, 2007, vol. 129, # 11, p. 3358 - 3366
  • 29
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  • [ 31970-30-6 ]
Reference: [1] Applied Organometallic Chemistry, 2013, vol. 27, # 4, p. 232 - 238
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6403 - 6418
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 894 - 899
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  • [ 1970-81-6 ]
Reference: [1] Patent: EP2222686, 2015, B1,
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  • [ 30235-27-9 ]
YieldReaction ConditionsOperation in experiment
2.5 mg With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In 1,4-dioxane; water for 4 h; Inert atmosphere; Reflux 3-pyridyl boronic acid (20mmole), 2-Amino-4-bromo - thiazole (20 mmol) dissolved in Dioxane – water(1:1,70),then added Potassium carbonate (50 mmol) and replaced three times with argongas . the again add Bis (triphenylphosphine) palladium (II)  dichloride (1mmol) and the reaction was heatedat reflux for 5h. Cooling, the solvent was distilled off under reducedpressure, the residue was dissolved with methylene chloridethen it was driedover anhydrous sodium sulfate and by column chromatography to give 4-(3-pyridyl) -2-aminothiazole 2.5g.
Reference: [1] Patent: CN103130792, 2016, B, . Location in patent: Paragraph 0733
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YieldReaction ConditionsOperation in experiment
56% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In tetrahydrofuran; water for 5 h; Inert atmosphere; Heating In the three-necked flask, Join p-Bromoiodobenzene (28g, 0.1mol),3-pyridyl boronic acid (12.3g, 0.1mol),Potassium carbonate (27.2g, 200mmol),Tetrakistriphenylphosphine palladium (0.8g),Tetrahydrofuran (200ml) and water (50ml),Heated under a nitrogen atmosphere for 5 hours.cool down,filter,The crude product was purified by column chromatography to give the product 13g,Yield 56percent.
38% With sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 80℃; for 12 h; A synthetic scheme of 3- (4-broniophenyl)pyridine is shown in (C-1).
In a 100 mL three-necked flask were placed 2.4 g (20 mmol) of 3-pyridineboronic acid, 5.6 g (19 mmol) of para-bromoiodobenzene, and 4.5 g (42 mmol) of sodium carbonate.
The atmosphere in the flask was replaced with nitrogen, and to the flask were added 15 mL of water, 25 mL of DME, and 10 mL of ethanol.
The mixture was degassed by being stirred under reduced pressure, to which 0.22 g (0.19 mmol) of tetrakis(triphenylphosphine)palladium(0) was added.
The mixture was stirred under nitrogen stream at 80 °C for 12 hours.
After a predetermined time, water was added to the mixture, and an organic substance was extracted with chloroform from the aqueous layer.
The obtained extract was washed with a saturated aqueous sodium chloride solution together with the organic layer and then dried over magnesium sulfate.
The mixture was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and the filtrate was condensed to obtain an oily substance.
The obtained substance was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1); thus, 1.8 g of the target yellow oily substance was obtained with a yield of 38 percent.
Reference: [1] Patent: CN105753849, 2016, A, . Location in patent: Paragraph 0056; 0057
[2] Chemistry - A European Journal, 2017, vol. 23, # 60, p. 15089 - 15097
[3] Patent: EP2065378, 2009, A1, . Location in patent: Page/Page column 141
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Reference: [1] Journal of Organic Chemistry, 2015, vol. 80, # 9, p. 4430 - 4442
[2] Patent: CN105601613, 2016, A, . Location in patent: Paragraph 0093; 0094; 0095
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  • [ 78210-78-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 224 - 239
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YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere 1-bromo-3-iodobenzene (1.118 g, 3.95 mol) and 3-pyridine boronic acid (0.559 g, 4.54 mol) were added to a 100 mL three neck round bottom flask. To this flask, dioxane (20 mL) and aqueous K2CO3 (2 N, 20 mL) were added. The mixture was stirred and degassed with a steam of argon for 30 minutes. Then under argon atmosphere, 50 mg (0.04 mmol) of Pd(PPh3)4 (1percent) was added. The mixture was heated to 100° C. and stirred overnight. The next day, the solvent was removed by roto-evaporation and the residue was suspended into an equal amount of water (50 mL) and CH2Cl2 (50 mL). The organic layer was separated from aqueous layer and washed with brine (50 mL.x.3). After drying over Na2SO4, and removal of the drying agent, about 0.92 g of 3-(3-bromophenyl)pyridine product (100percent) was afforded. 1H NMR (400 MHz, CDCl3) 8.85 (s, 1H), 8.65 (d, 1H), 7.87 (d, 1H), 7.75 (s, 1H), 7.57-7.52 (m, 2H), 7.41-7.35 (m, 2H).
88% With palladium diacetate; sodium carbonate; triphenylphosphine In 1,2-dimethoxyethane; water for 18 h; Inert atmosphere; Reflux A mixture of 3-bromoiodobenzene (19.8 g, 70.0 mmol, pyridine-3- borononic acid (8.6 g, 70.0 mmol) in 1 ,2-dimethoxyethane (315 mL) and 2.0 M aqueous sodium carbonate (105 mL) was sparged with nitrogen for 30 minutes, then palladium acetate (393 mg, 1 .75 mmol) and triphenylphosphine (918 mg, 3.50 mmol) were added and the mixture was heated at reflux for 18 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 x 150 ml_). The combined organic layer was washed with water and brine (2 x 150 ml_ each), then dried over magnesium sulfate, filtered and concentrated to a dark brown oil. The crude product was purified by silica gel MPLC (0 - 90percent ethyl acetate in hexanes as eluent). The product fractions eluting when the gradient had reached 55 - 85percent ethyl acetate in hexanes were combined and concentrated by rotary evaporation to give 3-(3-bromophenyl)pyridine as a dark yellow oil (14.5 g, 88percent yield) having a purity of 97percent based on UPLC analysis. This material was taken directly to Step 2.
77% With sodium carbonate In 1,4-dioxane; water at 95℃; for 24 h; Inert atmosphere Example 14; Synthesis of Compound 31; A 100 mL, round-bottomed Schlenk flask equipped with a magnetic stir bar was charged with 1-bromo-3-iodobenzene (5.754 g, 20.3 mmol), 3-pyridyl boronic acid (2.5 g, 20.3 mmol), 25 mL of a 2 M aqueous solution of Na2CO3, and 25 mL of 1,4-dioxane. Tetrakis (triphenylphosphine) palladium (0.54 g, 0.5 mmol) was added, the mixture was degassed using five vacuum/nitrogen back-fill cycles, and then was heated to 95° C. for 24 hours with vigorous stirring. The reaction mixture was allowed to cool to room temperature and diluted with CH2Cl2. The organic layer was washed with 1N HCl, H2O, and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The resulting yellow solid was purified by column chromatography on silica gel. Eluent ethyl acetate/hexane (3/97) gave compound 31 as a pale yellow oil 3.6 g (77percent). 1H NMR (400 MHz, CDCl3) δ 8.82 (br s, 1H), 8.63 (m, 1H), 7.85 (m, 1H), 7.73 (m, 1H), 7.53 (m, 2H), 7.36 (m, 2H).
46% With sodium hydrogencarbonate In 1,4-dioxane; water at 90℃; for 24 h; 149] 3-(3-Bromophenyl)pyridine (lib): A solution of pyridine 3-boronic acid 51 (1.0 g, 8.14 mmol), 3-bromo-l-iodobenzene 50 (2.0 g, 7.07 mmol) and sodium bicarbonate (1.5 g, 17.7 mmol) in dioxane (16 niL) and water (4 mL) was purged with N2 for 5 min.Tetrakis(triphenylphosphine)palladium (400 mg, 0.35 mmol) was added and the mixture was heated at 90 0C for 24 hr. The solution was cooled and the volatile organics were evaporated. The residue was partitioned between EtOAc (50 mL) and water and the layers were separated. The organic layer was washed with water, dried (Na2SO4), and concentrated to give 2.2 g of yellow oil. The crude material was purified on an Analogix automated system (24 g column, 0- 30percent EtOAc/heptane) to provide 760 mg (46percent) of pure lib. Some impure material was set aside.

Reference: [1] Patent: US2010/331547, 2010, A1, . Location in patent: Page/Page column 13
[2] Patent: WO2014/130597, 2014, A1, . Location in patent: Page/Page column 59; 60
[3] Patent: US2009/289547, 2009, A1, . Location in patent: Page/Page column 36
[4] Patent: WO2011/11712, 2011, A1, . Location in patent: Page/Page column 40-41
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 11, p. 4181 - 4205
  • 37
  • [ 76-09-5 ]
  • [ 1692-25-7 ]
  • [ 329214-79-1 ]
Reference: [1] Journal of the American Chemical Society, 2011, vol. 133, # 30, p. 11438 - 11441
  • 38
  • [ 3934-20-1 ]
  • [ 1692-25-7 ]
  • [ 483324-01-2 ]
YieldReaction ConditionsOperation in experiment
74.6% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; for 4 h; Inert atmosphere; Green chemistry In a 250 mL three-necked flask,2,4-dichloropyrimidine (5.0 g, 33.56 mmol)Dissolved in 1,4-dioxaneAnd water (4: 1, 50 mL) A solution of 3-boronic acid pyridine (4.95 g, 40.27 mmol),Potassium carbonate (9.28 g, 67.12 mmol)And Pd (dppf) Cl2 (2.45 g, 3.36 mmol);The system was replaced with argon three times,Gradually heated to 90 ° C,Reaction for 4 hours;After the reaction, the system was concentrated under reduced pressure to remove most of the solvent,Ethyl acetate (150 mL)And water (100 mL),Extraction and separation,The aqueous phase was then extracted with ethyl acetate (80 mL)The organic phases were combined,Re-water (80 mL x 2) and saturateWashed with brine (80 mL x 2)Liquid separation,The organic phase was dried over anhydrous sodium sulfate for 3 hours,Filtration and concentration,Crude;The crude product was added petroleum ether (32 mL)And ethyl acetate (6 mL) were stirred for 1 hour,filter,Dried in vacuo to give 4.8 g of 2-chloro-4- (3-pyridyl) pyrimidine,The yield was 74.6percentPurity HPLC was greater than 95percent.
73% With sodium carbonate In tetrahydrofuran; water for 16 h; Heating; Reflux; Inert atmosphere Example 11 Preparation of 2-chloro-4-(pyridin-3-yl)pyrimidine[00106] Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen were placed a solution of pyridin-3-ylboronic acid (4.42 g, 36.0 mmol, 1.00 equiv) in THF/H2O (30 mL), a solution of 2,4-dichloropyrimidine (5.40 g, 36.2 mmol, 1.00 equiv) in THF/H2O (30 mL), Na2CO3 (11.5 g, 108 mmol, 3.00 equiv) and PdCl2(PPh3)2 (1.80 g, 2.57 mmol, 0.06 equiv). The resulting solution was heated to reflux for 16 hrs in an oil bath. The reaction mixture was cooled and quenched by the addition of 100 mL of water. The resulting solution was extracted with 5x200 mL of ethyl acetate. The organic layers were combined, washed with 3x200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1: 1). This resulted in 5 g (73percent) of 2-chloro-4-(pyridin-3-yl)pyrimidine as a yellow solid.
52% With bis-triphenylphosphine-palladium(II) chloride In 1,4-dioxane for 14 h; Reflux; Inert atmosphere General procedure: To a solution of 2,4-dichloro-5-methylpyrimidine (500 mg, 3.1 mmol) and 4-trifluoromethoxylphenylboronic acid (644 mg, 3.1 mmol) in dioxane (15 mL), Pd(PPh3)2Cl2 (215 mg, 0.3 mmol) and 2M Na2CO3 (920 mg, 8.7 mmol) were added. The mixture was stirred at reflux for 14 h under N2 atmosphere. The reaction mixture was cooled to room temperature and filtrated. The filtrate was diluted with H2O (100 mL) and then extracted with EtOAc, and the organic layer was dried over anhydrous Na2SO4, After filtration, the filtrate was evaporation and purified by chromatography (petroleum ether/ EtOAc, 5:1) to give the product as oil (700 mg, 73 percent).
Reference: [1] Patent: CN106243083, 2016, A, . Location in patent: Paragraph 0037-0039; 0044-0046; 0051-0053
[2] Patent: WO2011/8788, 2011, A1, . Location in patent: Page/Page column 28-29
[3] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 15, p. 3259 - 3263
[4] Patent: US2004/122237, 2004, A1, . Location in patent: Page 179
[5] Patent: WO2013/66839, 2013, A2, . Location in patent: Page/Page column 31
[6] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 18, p. 5029 - 5036
  • 39
  • [ 1692-25-7 ]
  • [ 1122-91-4 ]
  • [ 127406-55-7 ]
Reference: [1] European Journal of Organic Chemistry, 2009, # 13, p. 2051 - 2054
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 224 - 239
[3] Dalton Transactions, 2007, # 35, p. 3952 - 3958
[4] European Journal of Medicinal Chemistry, 2016, vol. 115, p. 453 - 462
  • 40
  • [ 104-88-1 ]
  • [ 1692-25-7 ]
  • [ 127406-55-7 ]
Reference: [1] European Journal of Organic Chemistry, 2009, # 13, p. 2051 - 2054
[2] Advanced Synthesis and Catalysis, 2008, vol. 350, # 6, p. 846 - 862
  • 41
  • [ 1692-25-7 ]
  • [ 873-76-7 ]
  • [ 127406-55-7 ]
Reference: [1] Dalton Transactions, 2014, vol. 43, # 26, p. 10235 - 10247
  • 42
  • [ 1692-25-7 ]
  • [ 404844-11-7 ]
Reference: [1] Tetrahedron Letters, 2012, vol. 53, # 49, p. 6657 - 6661
  • 43
  • [ 84249-14-9 ]
  • [ 1692-25-7 ]
  • [ 865604-20-2 ]
YieldReaction ConditionsOperation in experiment
87% With sodium carbonate In water; toluene for 1.5 h; Heating / reflux 2N Na2C03 (20 mL, 0.04 mol) was added to a suspension of aminopyridine (1) (l. OOg, 5. 78 mmol) and boronic acid (2) (1.06 g, 8. 67 mmol) in toluene (60 mL) and the mixture was purged with nitrogen gas. Bis (diphenylphosphino) ferrocenepalladium (II) chloride, dichloromethane complex [hereinafter"PdCl2 (dppf)"] (0.17 g, 0.21 mmol) was added and the mixture was refluxed under nitrogen for 1.5 hours. Ethyl acetate was added and the solution was washed with water, dried over Na2S04 and adsorbed onto silica by removal of solvent in vacuo. The residue was chromatographed on silica, eluting with MeOH/EtOAc (1: 15) to give product (3) as a powder (0. 87 g, 87percent). APCI-MS found: [M+H] +=172.
Reference: [1] Patent: WO2005/89763, 2005, A1, . Location in patent: Page/Page column 32
[2] Patent: WO2008/121687, 2008, A2, . Location in patent: Page/Page column 59
  • 44
  • [ 19798-80-2 ]
  • [ 1692-25-7 ]
  • [ 865604-20-2 ]
Reference: [1] Journal of Organic Chemistry, 2007, vol. 72, # 14, p. 5104 - 5112
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 3, p. 894 - 899
  • 45
  • [ 1692-25-7 ]
  • [ 183208-35-7 ]
  • [ 918511-92-9 ]
YieldReaction ConditionsOperation in experiment
82% With potassium carbonate In water; acetonitrile at 170℃; Step 1-Preparation of 5-pyridin-3-yl-1H-pyrrolo[1,3-b]pyridine (22)To 5-bromo-7-azaindole (1, 1.00 g, 5.08 mmol) in water (13.0 mL) and acetonitrile (36 mL) were added pyridine-3-boronic acid (21, 1.0 g, 8.1 mmol), potassium carbonate (1.79 g, 0.0130 mol) and Tetrakis(triphenylphosphine)palladium(0) (50.0 mg, 0.043 mmol) under an atmosphere of nitrogen. The reaction mixture was heated to 170° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting with 25percent ethyl acetate in hexane to provide a light yellow solid (22, 820 mg, 82percent). MS (ESI)[M+H+]+=196.1.
82% With potassium carbonate In water; acetonitrile at 170℃; Example 4: Synthesis of 5-Pyridin-3-yl-lH-pyrrolo[2,3-b] pyridine 20 and related compounds.[0137] 5-Pyndin-3-yl-l H-pyrrolo[2,3-b]pyπdine 20 was synthesized in one step from 5-bromo-lH- pyrrolo[2,3-b]pyridme 1 as described m Scheme 6Scheme 6Step 1 - Preparation of5-Pyndιn-3-yl-LH-ρyrrolo[2,3-b]pyndιne (20)[0138] To 5-bromo-7-azaindole (1, 1 00 g, 5 08 mmol) m water (13 0 mL) and acetonitnle (36 mL) were added pyridine-3-boronic acid (19, 1 0 g, 8 1 mmol), potassium carbonate (1 79 g, 0 0130 mol) and Tetrakis(tnphenylphosphine)palladmm(0) (50 0 mg, 0 043 mmol) under an atmosphere of nitrogen The reaction mixture was heated to 170 0C overnight. The reaction mixture was poured into water and extracted with ethyl acetate The organic layer was washed with brine, dried over sodium sulfate, and concentrated The residue was purified with silica gel column chromatography elutmg with 25percent ethyl acetate in hexane to provide a light yellow solid (20, 820 mg, 82percent) 1
82% With potassium carbonate In water; acetonitrile at 170℃; To 5-bromo-7-azaindole (67, 1.00 g, 5.08 mmol) in water (13.0 mL) and acetonitrile (36 niL) were added pyridine-3-boronic acid (609, 1.0 g, 8.1 mmol), potassium carbonate (1.79 g, 0.0130 mol) and Tetrakis(triphenylphosphine)palladium(0) (50.0 mg, 0.043 mmol) under an atmosphere of nitrogen. The reaction mixture was heated to 170 0C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting with 25percent ethyl acetate in hexane to provide a light yellow solid (89, 820 mg, 82percent). MS(ESI)[M+Hf]+ = 196.1.
Reference: [1] Patent: US2008/167338, 2008, A1, . Location in patent: Page/Page column 37-38
[2] Patent: WO2008/80001, 2008, A2, . Location in patent: Page/Page column 60
[3] Patent: WO2007/2325, 2007, A1, . Location in patent: Page/Page column 123
[4] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 12, p. 1238 - 1243
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 23, p. 9470 - 9489
  • 46
  • [ 1692-25-7 ]
  • [ 939430-30-5 ]
Reference: [1] Patent: US2010/331547, 2010, A1,
[2] Patent: WO2014/130597, 2014, A1,
  • 47
  • [ 1692-25-7 ]
  • [ 929203-04-3 ]
Reference: [1] Patent: CN105753849, 2016, A,
[2] Chemistry - A European Journal, 2017, vol. 23, # 60, p. 15089 - 15097
  • 48
  • [ 5305-59-9 ]
  • [ 1692-25-7 ]
  • [ 1192814-34-8 ]
YieldReaction ConditionsOperation in experiment
40% at 125℃; for 0.333333 h; Microwave irradiation Step A: 6-(pyridin-3-yl)pyrimidin-4-amine
A mixture of 6-chloropyrimidin-4-amine (0.324 g, 2.5 mmol), pyridin-3- ylboronic acid (0.384 g, 3.13 mmol), Na2C03 (0.795 g, 7.50 mmol) andbis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspended in a mixture of DME/EtOH/water. The mixture was heated in the microwave synthesizer at 125 °C for 20 min and concentrated. The residue was purified by silica gel chromatography (10-60 percent ethyl acetate in hexanes, then 5-25 percent 9: 1methanol: ammonium hydroxide-ethyl acetate) to afford 6-(pyridin-3-yl)pyrimidin-4- amine (0.17 g, 0.987 mmol, 40 percent yield) as an off-white solid. LCMS R.T. = 0.31; [M+H]+ = 173.11.
40% With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,2-dimethoxyethane; ethanol; water at 125℃; for 0.333333 h; Microwave irradiation A mixture of 6-chloropyrimidin-4-amine (0.324 g,2.5 mmol), pyridin-3-ylboronic acid (0.384 g, 3.13 mmol),Na2C03 (0.795 g, 7.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.050 mmol) was suspendedin a mixture ofDME/EtOH/water. The mixture was heated inthe microwave synthesizer at 125° C. for 20 min and concentrated.The residue was purified by silica gel chromatography(10-60percent ethyl acetate in hexanes, then 5-25percent 9: I methanol:ammonium hydroxide-ethyl acetate) to afford 6-(pyridin-3yl)pyrimidin-4-amine (0.17 g, 0.987 mmol, 40percent yield) as an off-white solid.
Reference: [1] Patent: WO2011/53292, 2011, A1, . Location in patent: Page/Page column 249
[2] Patent: JP5714745, 2015, B2, . Location in patent: Paragraph 0445; 0446
[3] Patent: WO2011/56503, 2011, A1, . Location in patent: Page/Page column 49
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