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Product Details of [ 766-11-0 ]

CAS No. :766-11-0 MDL No. :MFCD01863742
Formula : C5H3BrFN Boiling Point : -
Linear Structure Formula :- InChI Key :MYUQKYGWKHTRPG-UHFFFAOYSA-N
M.W : 175.99 Pubchem ID :2783168
Synonyms :

Calculated chemistry of [ 766-11-0 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 31.89
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) : -5.97 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.74
Log Po/w (XLOGP3) : 1.98
Log Po/w (WLOGP) : 2.4
Log Po/w (MLOGP) : 1.68
Log Po/w (SILICOS-IT) : 2.54
Consensus Log Po/w : 2.07

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.73
Solubility : 0.325 mg/ml ; 0.00185 mol/l
Class : Soluble
Log S (Ali) : -1.88
Solubility : 2.34 mg/ml ; 0.0133 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.15
Solubility : 0.124 mg/ml ; 0.000703 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.68

Safety of [ 766-11-0 ]

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

Application In Synthesis of [ 766-11-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 766-11-0 ]
  • Downstream synthetic route of [ 766-11-0 ]

[ 766-11-0 ] Synthesis Path-Upstream   1~46

  • 1
  • [ 766-11-0 ]
  • [ 1072-97-5 ]
Reference: [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7564 - 7567
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3436 - 3441
  • 2
  • [ 766-11-0 ]
  • [ 56673-34-8 ]
Reference: [1] Chemical Communications, 2017, vol. 53, # 95, p. 12738 - 12741
  • 3
  • [ 766-11-0 ]
  • [ 593-51-1 ]
  • [ 84539-30-0 ]
YieldReaction ConditionsOperation in experiment
63% With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 140℃; for 0.666667 h; microwave 2-fluoro-5-bromopyridine (2.00 g, 11.37 mmol), methylamine-hydrochloride (1.92 g, 28.40 mmol) and JV-ethyldiisopropylamine (2.14 mL, 12.50 mmol) in NMP (10 mL) are stirred for 40 min in a microwave reactor at 1400C. The crude mixture is purified by normal phase chromatography. Yield: 1.33 g (63 percent).
Reference: [1] Patent: WO2010/12747, 2010, A1, . Location in patent: Page/Page column 16
  • 4
  • [ 766-11-0 ]
  • [ 74-89-5 ]
  • [ 84539-30-0 ]
YieldReaction ConditionsOperation in experiment
24% at 23℃; for 16 h; A solution of 5-bromo-2-fluoropyridine (2.5 g, 14 mmol) in THF (50 mL) was stirred with a solution of methylamine in THF (c=2 mol/L) (35 mL, 70 mmol) at 23° C. for 16 h. Water was added and the mixture was extracted with ether, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a residue which was purified by silica gel column chromatography with heptane/ether, followed by trituration with heptane to give the title compound as a white solid (630 mg, 24percent). MS (ISP) 187.1 [(M+H)+], 189.2 [(M+2+H)+].
Reference: [1] Patent: US2006/217387, 2006, A1, . Location in patent: Page/Page column 31
  • 5
  • [ 766-11-0 ]
  • [ 124-40-3 ]
  • [ 26163-07-5 ]
YieldReaction ConditionsOperation in experiment
86% at 110℃; Sealed tube To sealed tube was added 5-bromo-2-fluoropyridine (825 mg, 5.1 mmol), dimethylamine/water (7.0 mL, 33percent) and THF (3.0 mL), then sealed and heated to 110 °C overnight. The reaction mixture was cooled to RT and extracted with EA, the organic layers were combined and washed with brine, then dried over a2S04 and concentrated to give compound 2-dimethylamino-5- bromopyridine as yellow oil (880 mg, yield 86percent). Coupling under standard conditions gave 127 mg from 300 mg of 6-methyl-N-{4-[4-(tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l,3-thiazol- 2-yl}pyridin-2-amine, yellow solid, 43percent yield.
75% at 100℃; Sealed tube To a sealed tube was added 5-bromo-2-fluoropyridine (2.0 g, 1 1 .36 mmol), dimethylamine (7.0 mL, 45.6 mmol) in water and tetrahydrofuran (3 mL) and the reaction was heated to 100 °C overnight. The reaction mixture was cooled to room temperature and extracted with EtOAc (15 mL x 3), the organic layers were combined and washed with brine and dried over Na2S04, filtered and concentrated under reduced pressure to give 5-bromo-N,N-dimethylpyridin-2-amine (1 .7 g, 8.46 mmol, 75 percent yield) as a white solid.
Reference: [1] Patent: WO2013/33037, 2013, A2, . Location in patent: Paragraph 0751
[2] Patent: WO2017/98440, 2017, A1, . Location in patent: Page/Page column 169
  • 6
  • [ 766-11-0 ]
  • [ 870521-31-6 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: at 25℃; for 16.0833 h;
Stage #2: at 130℃; for 4.16667 h;
To isopropanol (11 mL, 143 mmol) under nitrogen at 25° C. was added sodium hydride (95percent, 1.94 g, 76.7 mmol) portion wise over 5 minutes. The reaction was stirred for 16 hours and a solution of 2-fluoro-5-bromopyridine (9 g, 51 mmol) in N,N-dimethyl formamide (250 mL) was added over 10 minutes. The resulting mixture was heated at 130° C. for 4 hours and cooled to 25° C. The mixture was diluted with ether (500 mL,) and washed with water (600 mL) and brine (300 mL). The organic layer was dried (MgSO4), filtered, and concentrated to provide 10.1 g of the title compound (92percent) as light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.25 Hz, 6 H) 5.08-5.28 (m, 1 H) 6.75 (d, J=8.82 Hz, 1 H) 7.86 (dd, J=8;82, 2.57 Hz, 1 H) 8.26 (d, J=2.57 Hz, 1 H); MS (ESI) m/z 217.9 (M+H)+.
Reference: [1] Patent: US2007/225332, 2007, A1, . Location in patent: Page/Page column 52-53
  • 7
  • [ 766-11-0 ]
  • [ 67-63-0 ]
  • [ 870521-31-6 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: at 80℃; for 1 h;
Stage #2: at 80℃; for 15 h;
In a 2-Propanol (i00 ml) NaH (2.73g, 68.2 mmol) was added slowly then the mixture was heated at 80 °C for ih. 5-bromo-2-fluoropyridine (5g, 28.4 mmol) was added and the resultant mixture was heated at 80 °C for further 1 5h. Reaction was monitored by TLC. The solvent was evaporated under vacuum, water was added in the residue and extractedwith ethyl acetate. The combined organic layer was washed with water, brine, dried overNa2SO4 and concentrated under vacuum to obtain title compound as an oil (5 g, 81 percent).1H NMR (400 MHz, Chloroform-d) 8.20 (d, J = 3.2 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H),6.62 (dd, J= 8.7, 2.6 Hz, 1H), 5.26 (Quint, J= 6.6 Hz, 1H), 1.41 — 1.32 (d, 6H).
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 13, p. 3770 - 3773
[2] Patent: WO2017/37682, 2017, A1, . Location in patent: Page/Page column 71
[3] Patent: WO2015/65937, 2015, A1, . Location in patent: Paragraph 000254
  • 8
  • [ 766-11-0 ]
  • [ 100-51-6 ]
  • [ 83664-33-9 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 12, p. 3565 - 3569
  • 9
  • [ 766-11-0 ]
  • [ 77992-44-0 ]
YieldReaction ConditionsOperation in experiment
91% With hydrazine hydrate In ethanol for 16 h; Reflux To a solution of 5-bromo-2-fluoropyridine (1 Og, 56.8 mmol) in EtOH (120 ml) was added hydrazine hydrate (14.22 g, 284 mmol), the mixture was heated to reflux and stirred overnight (16hr).The solvent of the reaction mixture was evaporated about half under reduced pressure, then cooling in an ice bath there precipitation was ocurred, filtered and washed the product with a minimun of EtOH and water, dried in vacuum to obtain pure desired product as white powder (10.2g, yield 91 percent ).LCMS (method A): [M+H]+ = 188.1 , 190.1 ,tR = 0.62 min.
91% With hydrazine hydrate In ethanol for 16 h; Reflux To a solution of 5-bromo-2-fluoropyridine (10 g, 56.8 mmol) in EtOH (120 ml) was added hydrazine hydrate (14.22 g, 284 mmol), the mixture was heated to reflux and stirred overnight (16 hr). The solvent of the reaction mixture was evaporated about half under reduced pressure, then cooling in an ice bath there precipitation was occurred, filtered and washed the product with a minimum of EtOH and water, dried in vacuum to obtain pure desired product as white powder (10.2 g, yield 91percent). LCMS (method A): [M+H]+=188.1, 190.1, tR=0.62 min.
Reference: [1] Patent: WO2013/38362, 2013, A1, . Location in patent: Page/Page column 82
[2] Patent: US2013/245002, 2013, A1, . Location in patent: Paragraph 0732
[3] Patent: WO2013/74390, 2013, A1, . Location in patent: Page/Page column 37
[4] Patent: KR2015/2661, 2015, A, . Location in patent: Paragraph 0362; 0363
  • 10
  • [ 766-11-0 ]
  • [ 77992-44-0 ]
Reference: [1] Patent: US2003/96838, 2003, A1,
  • 11
  • [ 403-45-2 ]
  • [ 766-11-0 ]
YieldReaction ConditionsOperation in experiment
63% With bromine In tetrachloromethane; hexane A.
2-Fluoro-5-bromopyridine
A suspension of 2.2 g (15.6 mmol) of 2-fluoro-5-pyridine-carboxylic acid, 5.1 g of HgO (red) and 1.2 ml of bromine in 100 ml of CCl4 was irradiated (by) under reflux for 5 h, cooled to room temperature, filtered through celite, and the filtrate was concentrated in vacuo.
The residue was dissolved in hexane, filtered, and the filtrate was concentrated in vacuo to afford 1.73 g (63percent) of 2-fluoro-5-bromopyridine, as a pale yellow oil.
Reference: [1] Patent: US5618821, 1997, A,
  • 12
  • [ 39856-50-3 ]
  • [ 766-11-0 ]
Reference: [1] Organic Letters, 2005, vol. 7, # 4, p. 577 - 579
[2] Organic Letters, 2015, vol. 17, # 8, p. 1866 - 1869
  • 13
  • [ 53939-30-3 ]
  • [ 766-11-0 ]
Reference: [1] Organic Letters, 2015, vol. 17, # 8, p. 1866 - 1869
[2] Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12137 - 12145
  • 14
  • [ 766-11-0 ]
  • [ 109-94-4 ]
  • [ 36404-90-7 ]
Reference: [1] Journal of Organometallic Chemistry, 1990, vol. 382, # 3, p. 319 - 332
  • 15
  • [ 766-11-0 ]
  • [ 171197-80-1 ]
Reference: [1] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10480 - 10483
  • 16
  • [ 766-11-0 ]
  • [ 55758-32-2 ]
Reference: [1] Patent: WO2006/44707, 2006, A1, . Location in patent: Page/Page column 68-69
  • 17
  • [ 766-11-0 ]
  • [ 351019-18-6 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: With n-butyllithium In tetrahydrofuran; hexanes; toluene at -50 - -35℃; for 5 h; Industry scale
Stage #2: With hydrogenchloride In tetrahydrofuran; hexanes; water; toluene at -15 - 23℃; for 16 h; Industry scale
Preparation of 6-fluoropyridin-3-ylboronic acid (4)[000361] A 72 L reactor equipped with reflux condenser, and temperature probe. To the reactor 5-bromo-2-fluoropyridine (1.17 L, 0.568 mol), toluene (18.2 L), and triisopropyl borate (3.13 L, 0.68 mol, 1.2 equiv.) were charged and stirred. Tetrahydrofuran (4.4 L) was added to the reactor and the reaction mixture was cooled to between -35 to -50 0C. While maintaining a temperature between -35 to -45 0C, n-butyl lithium (2.5 M solution of hexanes, 5.44 L, 0.68 mol, 1.2 equiv.) was cautiously added to the reactor. After 5 h, the reaction was deemed complete and the reaction mixture was warmed to between -15 to -20 0C. To the reaction was added 2M HCl (11.80L) to the reactor while maintaining a temperature between -15 0C and 0 0C. The reaction mixture was stirred at 18 to 23 0C for (16 h) and the phases were separated. The organics were then extracted with 6 M sodium hydroxide (6.0 L). The acidic anbasic aqueous phases were mixed in the reactor and 6 M HCl (2.5 L) was added until pH 7.5 was achieved. Sodium chloride (6.0 kg) was then added to the aqueous phase. The aqueous phase was then extracted with THF (3 x 20 L). The combined organics were dried with magnesium sulfate and concentrated to give 1300 g of a tan solid (81percent crude yield).; Step 2: Preparation of 6-fluoropyridin-3-ylboronic acid (4)[000345] The formation of boronic acid 4 was improved in several ways by changing the order of addition and solvents. The initial procedure called for adding an M-BuLi solution in hexanes to a cold solution of MTBE. The anionic solution was then cooled to below -75 0C and a second solution of 5-bromo-2-fluoropyridine in MTBE was slowly added. To the resulting mixture was added triisopropylborate in portions in rapid sequence. This process was not amendable to scaling up due to the rapid addition of triisopropylborate. Development of this procedure had precedence by following a published procedure (Li, et al., J. Org. Chem. 2002, 67, 5394-5397). One improvement was to premix 5-bromo-2- fluoropyridine and triisopropylborate in a solution of toluene and THF. The mixture was cooled between -50 to -35 0C and an n-BuLi solution was then added to form the aryl anion which was then quenched in situ by triisopropylborate to form the aryl borate. This procedure not only controlled the exothermic event, but also was conducted at warmer temperatures than below -75 0C as previously described. It was thought that if warmer temperatures were obtained during the reaction, a competitive reaction of elimination of HBr from bromobutane was observed. Whether n-BuLi or the aryl anion was the base in the side reaction was not explored. The work up was modified by adding an extraction with aqueous sodium hydroxide instead of just aqueous hydrochloric acid. The aqueous extractions were carefully combined, which resulted in only needing a minor pH adjustment. [000346] The preparation of 6-fluoropyridin-3-ylboronic acid (4) proceeded well to convert 5050 g of 5-bromo-2-fluoropyridine to give 3515 g of boronic acid 4 in 3 batches. The details can be seen in Table 3.
Reference: [1] Patent: WO2008/82637, 2008, A1, . Location in patent: Page/Page column 74-75; 81
  • 18
  • [ 766-11-0 ]
  • [ 351019-18-6 ]
YieldReaction ConditionsOperation in experiment
81%
Stage #1: With Triisopropyl borate In tetrahydrofuran; toluene at -50 - -35℃;
Stage #2: at -45 - -15℃; for 5 h;
Preparation of 6-fluoropyridin-3-ylboronic acid (4); [000254] A 72 L reactor equipped with reflux condenser, and temperature probe. To the reactor 5-bromo-2-fluoropyridine (1.17 L, 0.568 mol), toluene (18.2 L), and triisopropyl borate (3.13 L, 0.68 mol, 1.2 equiv.) were charged and stirred. Tetrahydrofuran (4.4 L) was added to the reactor and the reaction mixture was cooled to between -35 to -50 0C. While maintaining a temperature between -35 to -45 0C, n-butyl lithium (2.5 M solution of hexanes, 5.44 L, 0.68 mol, 1.2 equiv.) was cautiously added to the reactor. After 5 h, the reaction was deemed complete and the reaction mixture was warmed to between -15 to -20 0C. To the reaction was added 2M HCl (11.80L) to the reactor while maintaining a temperature between -15 0C and 0 0C. The reaction mixture was stirred at 18 to 23 0C for (16 h) and the phases were separated. The organics were then extracted with 6 M sodium hydroxide (6.0 L). The acidic anbasic aqueous phases were mixed in the reactor and 6 M HCl (2.5 L) was added until pH 7.5 was achieved. Sodium chloride (6.0 kg) was then added to the aqueous phase. The aqueous phase was then extracted with THF (3 * 20 L). The combined organics were dried with magnesium sulfate and concentrated to give 1300 g of a tan solid (81percent crude yield).
Reference: [1] Patent: WO2009/51848, 2009, A1, . Location in patent: Page/Page column 65
[2] Tetrahedron, 2002, vol. 58, # 14, p. 2885 - 2890
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 224 - 239
[4] Synthesis, 2003, # 7, p. 1035 - 1038
[5] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 10, p. 2858 - 2862
[6] Patent: US2002/115640, 2002, A1,
[7] Patent: US2003/87940, 2003, A1,
  • 19
  • [ 766-11-0 ]
  • [ 121-43-7 ]
  • [ 351019-18-6 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h;
Stage #2: at 20℃;
To a mixture of 5-BROMO-2-FLUORO-PYRIDINE (1.71 g, 6.20 mmol) in dry ether (100 mL) was added n-BuLi (1.6M in hexane, 41.4 mL, 0.0663 mol) AT-78 oC. After 30 minutes, trimethyl borate (8.2 mL, 0.0722 mol) was added to the above mixture and the reaction was warmed to room temperature and stirred overnight. The reaction was quenched with water and brine and acidified with 10percent HC1 until pH=8. The mixture was extracted with EtOAc, washed with 50percent brine, dried over MGS04, filtered, concentrated to give 5.1 g (60percent) of the desired product. The crude product was used in the next step without further purification.
Reference: [1] Patent: WO2004/80973, 2004, A1, . Location in patent: Page 116-117
  • 20
  • [ 766-11-0 ]
  • [ 1038395-61-7 ]
  • [ 351019-18-6 ]
Reference: [1] Patent: WO2008/82637, 2008, A1, . Location in patent: Page/Page column 63-64; 66-67
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  • [ 766-11-0 ]
  • [ 1038395-61-7 ]
  • [ 351019-18-6 ]
Reference: [1] Patent: WO2009/51848, 2009, A1, . Location in patent: Page/Page column 54-55; 57-58
  • 22
  • [ 766-11-0 ]
  • [ 73183-34-3 ]
  • [ 444120-95-0 ]
YieldReaction ConditionsOperation in experiment
82.85% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane for 6 h; Inert atmosphere; Reflux Pd(dppf)Cl2 (4.16g, 5.68mmol) was added in one batch to a solution of 5-bromo-2-fluoro-pyridine (10g, 56.82mmol), bispinacolatoboronate (21.64g, 85.23mmol), potassium acetate (16.73g, 170.46mmol) in dioxane (100mL)at room temperature under nitrogen atmosphere, and the mixture was stirred for 10 minutes and heated to reflux for 6hours. Upon the completion of the reaction, the solvent was evaporated off directly and the residue was purified by flashsilica gel column chromatography to give the title compound (10.5g, yield 82.85percent). 1H NMR (400 MHz, CHLOROFORMd)ppm 8.59 (s, 1H), 8.15 (dt, J=1.76, 8.41 Hz, 1H), 6.91 (dd, J=2.26, 8.28 Hz, 1H), 1.35 (s, 12H).
60% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In N,N-dimethyl-formamide at 80℃; for 3 h; Inert atmosphere 5-bromo-2-fluoropyridine (2.0 g, 11.3 mmol), K2CO3 (4.46 g, 45 mmol) and bis(pinacolato)diboron (3.17 g, 12.4mmol) were dissolved in 38 mL of DMF and charged with nitrogen gas for 5 minutes. After addition of catalytic amountof PdCl2(dppf)-DCM, the mixture was stirred at 80°C for 3 hours. Solids were filtered and purified by column chromatographyto obtain the title compound (1.59 g, 60 percent).1H-NMR (DMSO-d6) δ 8.45 (1H, d), 8.16 (1H, m), 7.20 (1H, dd), 1.30 (12H, s)
Reference: [1] Patent: EP3333157, 2018, A1, . Location in patent: Paragraph 0255; 0256
[2] Patent: EP3239143, 2017, A2, . Location in patent: Paragraph 0215
[3] Patent: WO2006/38116, 2006, A2, . Location in patent: Page/Page column 40
[4] Patent: EP2891656, 2015, A1, . Location in patent: Paragraph 0245
[5] Patent: WO2006/126081, 2006, A2, . Location in patent: Page/Page column 52-53
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  • [ 76-09-5 ]
  • [ 766-11-0 ]
  • [ 444120-95-0 ]
Reference: [1] Tetrahedron, 2002, vol. 58, # 14, p. 2885 - 2890
  • 24
  • [ 766-11-0 ]
  • [ 579525-46-5 ]
Reference: [1] Patent: WO2017/98440, 2017, A1,
  • 25
  • [ 766-11-0 ]
  • [ 108-95-2 ]
  • [ 59717-96-3 ]
YieldReaction ConditionsOperation in experiment
95%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1.5 h; Reflux
Stage #2: for 12 h; Reflux
General procedure: To a solution of alcohol 1a-r or benzyl mercaptan 1s (1.5 equiv.) in anhydrous THF (100 mL) was slowly added 60percent sodium hydride (2.0 equiv.). The mixture was allowed to react at room temperature for 30 min then it was heated to reflux for 1 h. 5-bromo-2-fluoropyridine (1 equiv.) was added and the reaction was continued for 12 h. After cooling down to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried on MgSO4, filtered, evaporated and purified by silica gel chromatography.
Reference: [1] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 185 - 198
  • 26
  • [ 766-11-0 ]
  • [ 57260-71-6 ]
  • [ 153747-97-8 ]
YieldReaction ConditionsOperation in experiment
87.66% With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 12 h; Step 1: K2CO3 (2.76 g, 20 mmol) was added into a mixture of 270-2 (1.76 g, 10 mmol) and 270-1 (2.24 g, 12 mmol) in DMF (20 mL). The mixture was stirred at 110°C for 12h, poured into H2O (100 mL). The obtained mixture was extracted with EtOAc (150 mL×3). The organic phases were combined and washed with brines (150 mL), dried over anhydrous sodium sulfate, filtrated, and concentrated under vacuum. The residue was purified by column chromatography (PE/EtOAc=7:1) to deliver 270-3 (3 g, yield 87.66percent) as colorless oil. MS ESI calcd for C14H2OBrN3O2 [M+H]+ 342, found 342.
Reference: [1] Patent: EP3124482, 2017, A1, . Location in patent: Paragraph 0711; 0712
[2] Patent: US2012/184520, 2012, A1, . Location in patent: Page/Page column 17
  • 27
  • [ 766-11-0 ]
  • [ 153747-97-8 ]
Reference: [1] Patent: CN104650049, 2018, B,
  • 28
  • [ 766-11-0 ]
  • [ 53242-51-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 13, p. 3603 - 3607
  • 29
  • [ 766-11-0 ]
  • [ 875781-17-2 ]
Reference: [1] Patent: WO2014/73904, 2014, A1,
[2] Patent: CN103980272, 2016, B,
[3] Patent: WO2017/23987, 2017, A1,
[4] Patent: WO2017/23981, 2017, A1,
[5] Patent: WO2017/23973, 2017, A1,
[6] Patent: WO2017/23996, 2017, A1,
  • 30
  • [ 766-11-0 ]
  • [ 100243-39-8 ]
  • [ 946002-90-0 ]
YieldReaction ConditionsOperation in experiment
72% at 120℃; for 0.75 h; Microwave irradiation Preparation 53; (S)-l-(5-Bromo-pyridin-2-yl)-pyrrolidin-3-ol; Heat 5-bromo-2-fluoro-pyridine (10.33 g, 57.39 mmmol) in THF (50 mL) with (S)-3-hydroxypyrrolidine (5.00 g, 57.39 mmol) and Et3N (9.2 mL, 68.87 mmol) in a microwave reactor at 120 0C for 45 min. Dilute with EtOAc (150 mL), and wash with saturated NaHCO3 (2 x 50 mL) and water (100 mL). Dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 100percent EtOAc to give 10.13 g (72percent) of the title compound. MS/ES m/z (79Br) 244.0 [M+H]+.
Reference: [1] Patent: WO2007/146759, 2007, A2, . Location in patent: Page/Page column 37
  • 31
  • [ 766-11-0 ]
  • [ 84331-14-6 ]
Reference: [1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 2, p. 279 - 291
  • 32
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  • [ 107-31-3 ]
  • [ 677728-92-6 ]
Reference: [1] Patent: EP1595867, 2005, A1, . Location in patent: Page/Page column 31
[2] Organic Letters, 2014, vol. 16, # 19, p. 4972 - 4975
  • 33
  • [ 766-11-0 ]
  • [ 68-12-2 ]
  • [ 677728-92-6 ]
Reference: [1] Patent: WO2009/89083, 2009, A1, . Location in patent: Page/Page column 28; 30
  • 34
  • [ 766-11-0 ]
  • [ 871839-91-7 ]
Reference: [1] Patent: WO2017/37682, 2017, A1,
  • 35
  • [ 2591-86-8 ]
  • [ 766-11-0 ]
  • [ 875781-15-0 ]
YieldReaction ConditionsOperation in experiment
68%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃;
Stage #2: at -78℃;
Intermediate 1; Preparation of 5-bromo-1H-pyrazolo[3,4-b]pyridine; a) 5-bromo-2-fluoro-3-pyridinecarbaldehyde; Following the procedure described in WO2006015124 and trituration of the crude product in hexanes instead of crystallization from cyclohexane afforded the title compound as an off-white solid (68percent). MS (ES)+ m/e 203.8, 205.7 [M+H]+.
52%
Stage #1: With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; hexanes at -78℃; for 1.75 h;
Stage #2: at -78℃; for 0.0166667 h;
A solution of lithium di-iso-propylamine (5 mL, 35 mmol) in anhydrous THF (40 mL) was cooled to -78° C. under nitrogen and n-butyl lithium (2.5 M in hexanes, 12 mL, 30 mmol) was added. The mixture was then stirred at -78° C. for 15 min before 5-bromo-2-fluoro-pyridine (5 g, 28 mmol) was added. The resulting mixture was then stirred at -78° C. for 90 min. N-formylpiperidine (4 mL, 36 mmol) was added very rapidly to the suspension at -78° C. and the mixture stirred vigorously for 60 sec. The reaction was immediately quenched by the addition of a 10percent (w/v) aqueous solution of citric acid. The mixture was warmed to room temperature and distributed between water and dichloromethane. The aqueous phase was extracted three times with dichloromethane and the organic phases were combined, dried over sodium sulfate, filtered and concentrated. Crystallization of the crude product from cyclohexane afforded 5-bromo-2-fluoro-pyridine-3-carbaldehyde (2.993 g, 52percent yield) as pale beige flaky crystals. 1H-NMR (500 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.70 (dd, 1H), 8.55 (dd, 1H). MS: m/z 236, 238 [MNa+], 204, 206 [MH+], 176, 178 [MH-CO+].
Reference: [1] Patent: US2008/293706, 2008, A1, . Location in patent: Page/Page column 27; 85
[2] Patent: US2008/261921, 2008, A1, . Location in patent: Page/Page column 73-74
  • 36
  • [ 766-11-0 ]
  • [ 109-94-4 ]
  • [ 875781-15-0 ]
YieldReaction ConditionsOperation in experiment
99%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - 0℃; for 0.666667 h;
Stage #2: at -78℃; for 0.0333333 h;
Preparation of 3-Methyl-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazolo[3,4-b]pyridine (79) <n="54"/>7475 76 77Step 1 :7475To a stirred solution of diisopropyl-amine (50 g, 0.5 mol) in dry THF (1000 mL) was added dropwise n- BuLi (200 mL, 0.5 mol) at -780C under N2 atmosphere. After the addition, the resulting mixture was allowed to warm up to O0C, maintained for 10 minutes and cooled to -780C again. A mixture of compound 74 (80 g, 0.455 mol) in THF (1000 mL) was added dropwise to the LDA solution at -780C under N2 atmosphere. After the addition, the reaction mixture was stirred at -780C for 30 minutes. Then formic acid ethyl ester (50 g, 0.68 mol) was added portionwise to the mixture at -780C. After 2 minutes, the resulting mixture was quenched with a solution of 10percent citric acid in THF (400 mL) at -780C. The mixture was allowed to warmed up to room temperature and poured into H2O (500 mL), extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4 and concentrated in vacuo to give compound 75 (92 g, 99percent) as a yellow solid.
88%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78℃; for 0.166667 h;
Diisopropylamine (2.6ml, 25mmol) was dissolved in tetrahydrofuran (100ml), 2.5M solution of butyllithium in tetrahydrofuran (10ml, 25mmol) was slowly added dropwise at 0 and then the mixture was stirred for 1 minute. A solution of 5-bromo-fluoro-2-pyridine (4.0g, 22.7mmol) in tetrahydrofuran (20ml) was slowly added dropwise at -78 and stirred for 30 minutes. Ethylformate (2.8ml, 34mmol) was added dropwise and then the mixture was stirred for 10 minutes at -78. After completion of the reaction, 1N hydrochloric acid solution was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. Filtrate was distilled under reduced pressure and separated by column chromatography to obtain the title compound (4.1g, 88percent).
85%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -65 - 0℃; for 1.5 h;
Stage #2: for 0.166667 h;
Example D-1 : Preparation of (2S)-1-(4-(1-isopropyl-3-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-pyrazol-4- yl)pyrimidin-2-ylamino)propan-2-ol <n="100"/>-J B-B; i/Pd(PPh3)2CI2, KOAc, DMF Preparation of 5-bromo-2-fluoronicotinaldehyde (D-1-2).D-1-1 D-1-2To a solution of diisopropylamine (17 mL, 0.17 mol) in dry THF (200 mL) was added 2.5 M n-BuLi in hexane (68 mL, 0.17 mol) dropwise at O 0C under N2 atmosphere. After the addition, the resulting mixture was cooled to -65°C. A solution of 5-bromo-2-fluoropyridine (25 g, 0.14 mol) in dry THF (100 mL) was then added dropwise. The resulting mixture was stirred at -65°C for 90 minutes. Then ethyl formate (15.6 g, 0.21 mol) was added dropwise to the mixture. After stirred for 10 minutes, the reaction mixture was quenched with a solution of 10percent citric acid in THF (100 mL) at -650C. The resulting mixture was warmed up to room temperature, poured into water (100 mL) and extracted with EtOAc (200 mL). The organic layer was separated and washed with saturated aqueous NaCI (100 mLχ2), dried over Na2SO4 and concentrated in vacuo to yield compound D-1-2 (25 g, 85percent) as a yellow solid.
Reference: [1] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 52-53
[2] Patent: WO2014/73904, 2014, A1, . Location in patent: Paragraph 1492-1494
[3] Patent: WO2009/16460, 2009, A2, . Location in patent: Page/Page column 98-99
[4] Patent: CN103980272, 2016, B, . Location in patent: Paragraph 0031; 0032
[5] Patent: WO2017/23987, 2017, A1, . Location in patent: Paragraph 0610; 0611
[6] Patent: WO2017/23981, 2017, A1, . Location in patent: Paragraph 0610; 0611
[7] Patent: WO2017/23973, 2017, A1, . Location in patent: Paragraph 0632
[8] Patent: WO2017/23996, 2017, A1, . Location in patent: Paragraph 0611
  • 37
  • [ 766-11-0 ]
  • [ 875781-15-0 ]
YieldReaction ConditionsOperation in experiment
52%
Stage #1: With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; hexane at -78℃; for 1.75 h;
Stage #2: With N-Formylpiperidine In tetrahydrofuran; hexane at -78℃; for 0.0166667 h;
Stage #3: With citric acid In tetrahydrofuran; hexane; dichloromethane; water at -78 - 20℃;
Step 1: Synthesis of 5-bromo-2-fluoro-pyridine-3-carbaldehyde.[0217] A solution of lithium di-zso-propylamine (5 mL, 35 mmol) in anhydrous THF (40mL) was cooled to -78 °C under nitrogen and n-butyl lithium (2.5 M in hexanes, 12 mL, 30mmol) was added. The mixture was then stirred at -78 °C for 15 min before 5-bromo-2-fluoro-pyridine (5 g, 28 mmol) was added. The resulting mixture was then stirred at -78 °Cfor 90 min. 7V-formylpiperidine (4 mL, 36 mmol) was added very rapidly to the suspensionat -78 °C and the mixture stirred vigorously for 60 sec. The reaction was immediately quenched by the addition of a 10 percent (w/v) aqueous solution of citric acid. The mixture waswarmed to room temperature and distributed between water and dichloromethane. Theaqueous phase was extracted three times with dichloromethane and the organic phases werecombined, dried over sodium sulfate, filtered and concentrated. Crystallization of the crudeproduct from cyclohexane afforded 5-bromo-2-fluoro-pyridine-3-carbaldehyde (2.993 g,52percent yield) as pale beige flaky crystals.
Reference: [1] Patent: WO2006/15124, 2006, A2, . Location in patent: Page/Page column 57-58
  • 38
  • [ 766-11-0 ]
  • [ 496786-98-2 ]
Reference: [1] Patent: CN104650049, 2018, B,
  • 39
  • [ 766-11-0 ]
  • [ 947191-69-7 ]
Reference: [1] Patent: US2014/99333, 2014, A1,
[2] Patent: WO2014/56938, 2014, A1,
[3] Patent: WO2015/150564, 2015, A1,
[4] Patent: WO2015/150565, 2015, A1,
[5] Patent: WO2015/150563, 2015, A1,
[6] Patent: US2018/237419, 2018, A1,
  • 40
  • [ 766-11-0 ]
  • [ 917023-06-4 ]
Reference: [1] Patent: WO2018/31988, 2018, A1,
[2] Journal of Medicinal Chemistry, 2018, vol. 61, # 11, p. 4704 - 4719
  • 41
  • [ 766-11-0 ]
  • [ 411235-57-9 ]
  • [ 1034467-80-5 ]
YieldReaction ConditionsOperation in experiment
647 mg With potassium phosphate; palladium diacetate; tricyclohexylphosphine In water; toluene at 80℃; for 16 h; Inert atmosphere 5-Bromo-2-fluoro - pyridine (1.41 g, 8 mmol) and cyclopropyl boronicacid (1.37 g, 16 mmol) mixed in toluene / water (26 mL / 1.3 mL), to which was added potassium phosphate (7.46 Under g, 28 mmol), argon was added theretopalladium acetate (90 mg, 0.4 mmol) and tricyclohexylphosphine (224 mg, 0.8mmol), the mixture was heated to 80  °C the reaction 16h. After completion of the reaction by TLC, cooled to room temperature,water was added thereto, extracted with ethyl acetate, the organic phase wasdried over anhydrous sodium sulfate, filtered, and the solvent was evaporatedto dryness, purified by silica gel column chromatography to give 5-cyclopropyl-2-fluoro- pyridine (yellow oil, 647 mg). 
Reference: [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5579 - 5598
[2] Patent: CN103420977, 2016, B, . Location in patent: Paragraph 0229-0232
  • 42
  • [ 766-11-0 ]
  • [ 78191-00-1 ]
  • [ 1111637-74-1 ]
YieldReaction ConditionsOperation in experiment
44.6%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - -65℃; for 1 h; Inert atmosphere
Stage #2: at -78℃; for 1 h; Inert atmosphere
Preparative Example 7 Step 1: l-(5-bromo-2-fluoropyridin-3-yl)ethanone To a solution of diisopropylamine (46.3 g, 458.4 mmol) in tetrahydrofuran (lOOOmL) was added butyllithium (176 mL, 440 mmol, 2.5 M) at -78 °C under nitrogen. After addition, the reaction mixture was stirred for 30 min at -78 °C. 5-bromo-2-fluoropyridine (86.7 g, 442.3 mmol) was added (keeping the temperature under -65 °C). After addition, the mixture was stirred for 1 h. N-methoxy- N-methylacetamide (50 g, 485.4 mmol) was added and stirred at -78 °C for 1 h. The reaction mixture was quenched with water (lOOOmL), extracted with ethyl acetate (3 x 500 mL), washed with brine, dried over sodium sulfate and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography (silica gel, 100-200 mesh, 0.5percent ethyl acetate in petroleum ether) affording 1- (5-bromo-2-fluoropyridin-3-yl)ethanone (43 g, 44.6 percent): H NMR (400 MHz, Chloroform-d): δ 8.46- 8.42 (m, 2H), 2.70 (s, 3H).
Reference: [1] Patent: WO2016/142310, 2016, A1, . Location in patent: Page/Page column 68
[2] Patent: WO2015/187437, 2015, A1, . Location in patent: Page/Page column 59
  • 43
  • [ 766-11-0 ]
  • [ 1111637-74-1 ]
Reference: [1] Patent: US2014/107109, 2014, A1,
  • 44
  • [ 766-11-0 ]
  • [ 1111637-76-3 ]
Reference: [1] Patent: WO2016/142310, 2016, A1,
  • 45
  • [ 766-11-0 ]
  • [ 1198408-35-3 ]
Reference: [1] Patent: CN107759563, 2018, A,
  • 46
  • [ 766-11-0 ]
  • [ 1036991-24-8 ]
Reference: [1] Patent: WO2017/98440, 2017, A1,
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