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Product Details of [ 4595-59-9 ]

CAS No. :4595-59-9 MDL No. :MFCD00006117
Formula : C4H3BrN2 Boiling Point : -
Linear Structure Formula :- InChI Key :GYCPLYCTMDTEPU-UHFFFAOYSA-N
M.W : 158.98 Pubchem ID :78344
Synonyms :

Calculated chemistry of [ 4595-59-9 ]

Physicochemical Properties

Num. heavy atoms : 7
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 : 29.73
TPSA : 25.78 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.76 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.49
Log Po/w (XLOGP3) : 0.72
Log Po/w (WLOGP) : 1.24
Log Po/w (MLOGP) : 0.35
Log Po/w (SILICOS-IT) : 1.77
Consensus Log Po/w : 1.11

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.91
Solubility : 1.94 mg/ml ; 0.0122 mol/l
Class : Very soluble
Log S (Ali) : -0.84
Solubility : 23.0 mg/ml ; 0.145 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.49
Solubility : 0.512 mg/ml ; 0.00322 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.25

Safety of [ 4595-59-9 ]

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 [ 4595-59-9 ]

* 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 [ 4595-59-9 ]
  • Downstream synthetic route of [ 4595-59-9 ]

[ 4595-59-9 ] Synthesis Path-Upstream   1~48

  • 1
  • [ 4595-59-9 ]
  • [ 124-38-9 ]
  • [ 4595-61-3 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 20, p. 2595 - 2598
[2] Patent: WO2010/102218, 2010, A1, . Location in patent: Page/Page column 27
[3] European Journal of Medicinal Chemistry, 2014, vol. 84, p. 404 - 416
  • 2
  • [ 4595-59-9 ]
  • [ 591-55-9 ]
Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 16, p. 6908 - 6916
  • 3
  • [ 4595-59-9 ]
  • [ 591-55-9 ]
  • [ 1298134-92-5 ]
Reference: [1] Organometallics, 2017, vol. 36, # 2, p. 251 - 254
  • 4
  • [ 30680-61-6 ]
  • [ 4595-59-9 ]
Reference: [1] Chemische Berichte, 1958, vol. 91, p. 2832,2841
[2] Patent: US3956301, 1976, A,
  • 5
  • [ 36082-50-5 ]
  • [ 4595-59-9 ]
Reference: [1] Patent: US2003/149064, 2003, A1,
  • 6
  • [ 766-38-1 ]
  • [ 77287-34-4 ]
  • [ 4595-59-9 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 1721 - 1722
  • 7
  • [ 183438-24-6 ]
  • [ 136902-53-9 ]
  • [ 4595-59-9 ]
  • [ 91891-74-6 ]
Reference: [1] Chemistry Letters, 2011, vol. 40, # 9, p. 992 - 994
  • 8
  • [ 37131-87-6 ]
  • [ 4595-59-9 ]
Reference: [1] Journal of the Chemical Society, 1953, p. 3129
  • 9
  • [ 7726-95-6 ]
  • [ 30680-61-6 ]
  • [ 4595-59-9 ]
Reference: [1] Chemische Berichte, 1958, vol. 91, p. 2832,2841
  • 10
  • [ 4595-59-9 ]
  • [ 19808-30-1 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 6, p. 1141 - 1145
[2] Journal of Organic Chemistry, 1985, vol. 50, # 17, p. 3073 - 3076
[3] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 14, p. 4060 - 4064
  • 11
  • [ 4595-59-9 ]
  • [ 31458-33-0 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: at 20℃;
Stage #2: at 110℃; sealed tube
Sodium (1.45 g, 63.0 mmol) was added portionwise to methanol (100 mL) and stirred at room temperature until a homogeneous solution was obtained. The solution was then treated with 5-bromopyrimidine 76 (5.00 g, 31.4 mmol) and heated in a sealed tube at 110° C. overnight. The mixture was cooled to room temperature, concentrated under reduced pressure at a temperature <40° C. to a volume of 20 mL, diluted with water (20 mL) and then extracted with methylene chloride (3.x.50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to afford 77 (2.99 g, 86percent) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.86 (s, 1H), 8.42 (s, 2H), 3.93 (s, 3H).
Reference: [1] Patent: US2006/173049, 2006, A1, . Location in patent: Page/Page column 28
  • 12
  • [ 4595-59-9 ]
  • [ 289-95-2 ]
  • [ 31458-33-0 ]
YieldReaction ConditionsOperation in experiment
70% With sodium methylate In methanol; ethyl acetate Preparation of 5-methoxypyrimidine
A Parr bomb is charged with 15 g (0.094 mol) of 5-bromopyrimidine and 5.4 g (0.10 mol) of sodium methoxide in 170 ml of methanol.
The whole is heated at 100-120° C. for 16 hours.
The deep brown mixture is neutralized with glacial acetic acid and extracted three times with ether.
The combined organic layers are then dried over Na2SO4 and concentrated in vacuo.
The resulting brown solid is purified by column chromatography on silica gel using 9:1 ethyl acetate:hexane as eluent.
The pyrimidine is thus obtained as pale yellow crystals (7 g, 70percent).
Alternatively, purification can be accomplished by distillation bp(10 mm/Hg) 76°.
Reference: [1] Patent: US2002/143025, 2002, A1,
  • 13
  • [ 4595-59-9 ]
  • [ 67-56-1 ]
  • [ 31458-33-0 ]
Reference: [1] Organic Letters, 2013, vol. 15, # 15, p. 3998 - 4001
  • 14
  • [ 4595-59-9 ]
  • [ 124-41-4 ]
  • [ 31458-33-0 ]
Reference: [1] Synthesis, 1996, # 7, p. 838 - 842
[2] Chemistry - A European Journal, 2003, vol. 9, # 20, p. 4997 - 5010
[3] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
[4] Chemische Berichte, 1958, vol. 91, p. 2832,2841
[5] Chemische Berichte, 1958, vol. 91, p. 2832,2841
[6] Patent: US2009/258876, 2009, A1, . Location in patent: Page/Page column 12
[7] Patent: EP2108649, 2009, A1, . Location in patent: Page/Page column 19
[8] Patent: US2012/214785, 2012, A1, . Location in patent: Page/Page column 47
[9] Patent: WO2009/125923, 2009, A2, . Location in patent: Page/Page column 33
  • 15
  • [ 4595-59-9 ]
  • [ 163133-86-6 ]
  • [ 1439-10-7 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 1285 - 1287
  • 16
  • [ 110-91-8 ]
  • [ 4595-59-9 ]
  • [ 57356-66-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
  • 17
  • [ 4595-59-9 ]
  • [ 109-94-4 ]
  • [ 10070-92-5 ]
YieldReaction ConditionsOperation in experiment
51%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.333333 h;
Stage #2: for 0.416667 h;
Stage #3: With hydrogenchloride In tetrahydrofuran for 1 h;
EXAMPLE 87A
Pyrimidine-5-carboxaldehyde
A modified procedure of Rho and Abuh (Syn. Commun. 1994, 24, 253-256) was followed for the preparation of the titled aldehyde.
Under nitrogen, to a solution of 5-bromopyrimidine (1 g, 6.3 mmol) in 60 mL anhydrous THF, was added BuLi (2.5 M, 2.6 mL, 6.5 mmol) at -78° C.
The resulting yellow solution was stirred for 20 min, after which ethyl formate (0.55 mL, 6.7 mmol) was added dropwise over 5 min.
After 20 min, the reaction was quenched with 1.5 M THF/HCl solution (4.5 mL, 6.7 mmol).
The cold bath was removed, and the reaction mixture was stirred for 1 h.
THF was removed in vacco, 10 mL of water was then added.
The mixture was extracted with CHCl3 (2*10 mL), and the combined organics were dried (MgSO4) and concentrated.
The crude product was purified via flash column chromatography (5percent MeOH/CHCl3) to give 0.35 g (51percent) of the titled pyrimidine-5-carboxaldehydepyrimidine-5-carboxaldehyde.
51%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.333333 h;
Stage #2: for 0.0833333 h;
A modified procedure of Rho and Abuh (Syn. Commun. 1994, 24, 253-256) was followed for the preparation of the titled aldehyde.
Under nitrogen, to a solution of 5-bromopyrimidine (1 g, 6.3 mmol) in 60 mL anhydrous THF, was added BuLi (2.5 M, 2.6 mL, 6.5 mmol) at -78° C.
The resulting yellow solution was stirred for 20 min, after which ethyl formate (0.55 mL, 6.7 mmol) was added dropwise over 5 min.
After 20 min, the reaction was quenched with 1.5 M THF/HCl solution (4.5 mL, 6.7 mmol).
The cold bathwas removed, and the reaction mixture was stirred for 1 h.
THF was removed in vacco, 10 mL of water was then added.
The mixture was extracted with CHCl3 (2*10 mL), and the combined organics were dried (MgSO4) and concentrated.
The crude product was purified via flash column chromatography (5percent MeOH/CHCl3) to give 0.35 g (51percent) of the titled pyrimidine-5-carboxaldehydepyrimidine-5-carboxaldehyde.
35%
Stage #1: With 3-Bromopyridine; n-butyllithium In tetrahydrofuran; ethanol; hexane at -100 - 100℃; for 0.333333 h; Inert atmosphere
Stage #2: at 100℃; for 0.333333 h;
1)
Preparation of pyrimidine-5-carbaldehyde
A solution of 5-bromo-pyrimidine (5 g, 31.4 mmol, 1.0 eq.) in anhydrous THF (300 mL) was placed under an argon atmosphere in a three-necked round bottom flask equipped with a low-temperature thermometer.
The mixture was cooled to -100° C. in a EtOH/N2(l) bath.
To the solution of 5-bromopyridine was added a solution of n-BuLi in hexane (20 mL, 1.6 M, 32.5 mmol, 1.0 eq.).
The resulting mixture was stirred for 20 minutes at 100° C. and the organolithium that formed was trapped with a solution of ethyl formate (2.7 mL, 33.5 mmol, 1.1 eq.) in THF (10 mL).
The reaction was stirred for another 20 minutes at 100° C. and quenched with a solution of hydrochloric acid in ether (17 mL, 2M, 34 mmol).
Then, the cold bath was removed and the mixture stirred at room temperature for 1 hour.
The solution was concentrated under reduced pressure, and then treated with water and saturated aqueous sodium carbonate (10 mL).
The mixture was extracted with dichloromethane and the organic layer was dried over MgSO4.
The solvent was removed under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/AcOEt, 60:40 to 50:50) to afford pyrimidine-5-carbaldehyde as beige crystals (1.2 g, 35percent).
Reference: [1] Journal of medicinal chemistry, 2004, vol. 47, # 20, p. 4829 - 4837
[2] Patent: US2005/70712, 2005, A1, . Location in patent: Page/Page column 42
[3] Patent: US2005/171131, 2005, A1, . Location in patent: Page/Page column 41
[4] Patent: US9212138, 2015, B2, . Location in patent: Page/Page column 42
[5] ChemMedChem, 2017, vol. 12, # 3, p. 257 - 270
[6] Synthetic Communications, 1994, vol. 24, # 2, p. 253 - 256
[7] Patent: WO2013/127266, 2013, A1, . Location in patent: Page/Page column 144
[8] Patent: WO2013/127267, 2013, A1, . Location in patent: Page/Page column 95; 96
[9] Patent: WO2013/127268, 2013, A1, . Location in patent: Page/Page column 69; 70
[10] Patent: WO2013/130935, 2013, A1, . Location in patent: Paragraph 0217
  • 18
  • [ 4595-59-9 ]
  • [ 68-12-2 ]
  • [ 10070-92-5 ]
YieldReaction ConditionsOperation in experiment
29%
Stage #1: With n-butyllithium In tetrahydrofuran at -100℃; for 1 h;
Stage #3: With hydrogenchloride In tetrahydrofuran; water
Step 1. Pyrimidine-5-carbaldehyde 2: To a solution of 5-bromopyrimidine (1Og, 56.96 mmol) in THF (500 mL) under the an inert atmosphere of nitrogen was added butyllithium (20 ml, 3.6 M) dropwise with stirring while cooling to a temperature of -100 C. The resulting solution was allowed to stir for an additional 1 hour at -100 C, followed by adding HCl (5 ml) dropwise with stirring while keeping the temperature at - 80 C and then warmed up to room temperature. The reaction progress was monitored by TLC (EtOAc/PE = 1:1). The resulting solution was extracted with ethyl ether (3 x 500 ml) and the organic layer was combined and dried over Na2SO4 and concentrated by evaporation under vacuum using a rotatory evaportator yield 2 g (29percent) of pyrmidine-5-cabaldehyde as an colorless oil.
3%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at -78℃; for 0.5 h; Inert atmosphere
[0745] Synthesis of pyrimidine-5-carbaldehyde: [0746] To a stirred solution of 5-bromopyrimidine (5 g, 31.66 mmol) in THF (50 mL) under argon atmosphere was added n-butyl lithium (2.2 g, 34.83 mmol) drop wise for 10 min at -78 °C and stirred for 20 min. To this was added DMF (2.3 g, 31.66 mmol) at -78 °C and stirred for 30 min. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (40 mL) and extracted with EtOAc (3 x 40 mL). The combined organic extracts were washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 25percent EtOAc/ Hexanes to afford pyrimidine-5-carbaldehyde (200 mg, 3percent) as colorless thick syrup. TLC: 30percent EtOAc/ Hexanes (R 0.2).
Reference: [1] Patent: WO2007/101213, 2007, A2, . Location in patent: Page/Page column 48
[2] Patent: WO2013/142269, 2013, A1, . Location in patent: Paragraph 0745; 0746
  • 19
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Reference: [1] Patent: WO2013/130943, 2013, A1, . Location in patent: Paragraph 0225
  • 20
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  • [ 4595-59-9 ]
  • [ 497-19-8 ]
  • [ 109-94-4 ]
  • [ 10070-92-5 ]
YieldReaction ConditionsOperation in experiment
35% With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane; water 1)
Preparation of pyrimidine-5-carbaldehyde
A solution of 5-bromo-pyrimidine (5 g, 31.4 mmol, 1.0 eq.) in anhydrous THF (300 mL) was placed under an argon atmosphere in a three-necked round bottom flask equipped with a low-temperature thermometer.
The mixture was cooled to -100°C in a EtOH/N2(1) bath.
To the solution of 5-bromopyridine was added a solution of n-BuLi in hexane (20 mL, 1.6 M, 32.5 mmol, 1.0 eq.).
The resulting mixture was stirred for 20 minutes at 100°C and the organolithium that formed was trapped with a solution of ethyl formate (2.7 mL, 33.5 mmol, 1.1 eq.) in THF (10 mL).
The reaction was stirred for another 20 minutes at 100°C and quenched with a solution of hydrochloric acid in ether (17 mL, 2M, 34 mmol).
Then, the cold bath was removed and the mixture stirred at room temperature for 1 hour.
The solution was concentrated under reduced pressure, and then treated with water and saturated aqueous sodium carbonate (10 mL).
The mixture was extracted with dichloromethane and the organic layer was dried over MgSO4.
The solvent was removed under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/AcOEt, 60:40 to 50:50) to afford pyrimidine-5-carbaldehyde as beige crystals (1.2 g, 35percent).
Reference: [1] Patent: EP2266562, 2010, A1,
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  • [ 20461-86-3 ]
  • [ 10070-92-5 ]
Reference: [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 6, p. 1500 - 1505[2] Angew. Chem., 2017, vol. 129, # 6, p. 1522 - 1527,6
  • 22
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  • [ 78191-00-1 ]
  • [ 10325-70-9 ]
YieldReaction ConditionsOperation in experiment
45%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h;
Stage #2: at -78 - 0℃;
Step A:
5-Acetylpyrimidine
5-Bromopyrimidine (3.18 g, 20 mmol) was dissolved in 50 mL of tetrahydrofuran, While cooled to -78 °C, 15 mL of 1.6 M n-butolithium in hexane solution was added dropwise with stirring, After the solution was stirred for 30 minutes, a solution of N-methoxyl-N-methylacetamide (2.58 g, 25 mmol) in tetrahydrofuran solution (10 mL) was added slowly.
The mixture was stirred at -78 °C for 1 hour and then allowed to be warmed slowly.
When the temperature of the mixture was at 0 °C, aqueous ammonium chloride solution was added.
The solution obtained was extracted with ethyl acetate for 3 times, The pooled extracts were washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using 5percent methanol / methylene chloride as eluent to obtain 1 g of the title compound (45percent yield). MS(M+1)=123.05.
175 mg
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 0.5 h;
Stage #2: at -78℃; for 1 h;
The5-bromo-pyrimidine (9.4 mmol) is dissolved in tetrahydrofuran steams again 30ml in. At -78 ° C lower, will n-BuLi (11.3 mmol) in drops to the reactionsystem, and stirring 30 minutes. N-methoxy-N-methyl acetamide (11.8 mmol) oftetrahydrofuran solution (15 ml) at -78 ° C in the system dropping, andstirring 1 hour. Under room temperature, add saturated ammonium chlorideaqueous solution, ethyl acetate extraction 3 times. Concentrated extract,column chromatography (ethyl acetate: petroleum ether = 1 the [...] 10)separated to obtain title compound 175 mg per litre. 1 H-NMR (CDCl 3)δ 9.37 (1H, s), 9.24 (2H, s), 2.66 (3H, s).
Reference: [1] Patent: EP2385035, 2011, A1, . Location in patent: Page/Page column 18-19
[2] Patent: CN103130792, 2016, B, . Location in patent: Paragraph 0178-0180
  • 23
  • [ 4595-59-9 ]
  • [ 917-54-4 ]
  • [ 1439-09-4 ]
YieldReaction ConditionsOperation in experiment
15%
Stage #1: at 20℃; for 1 h;
Stage #2: With water; 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran; diethyl ether at 20℃; for 16 h;
To 5-bromopyrimidine (17.3 g, 109 mmol) in diethyl ether (100 mL) , methyllithium in diethyl ether (109 mmol, 1.09 M, 100 mL) was gradually added dropwise at room temperature, and the resulting reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was stirred with water (1.96 mL, 109 mmol) and 2 , 3-dichloro-5 , 6-dicyano-p- benzoquinone (24.7 g, 109 mmol) in tetrahydrofuran (150 mL) at room temperature for 16 hours. After completion of the reaction, water and ethyl acetate were added, and the organic layer was separated. The organic layer was washed with IM aqueous sodium hydroxide, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) to give the desired product (2.9 g, 15percent yield) . Morphology: yellow oil 1H-NMR(CDCl3) δ :2.65 (s, 3H), 8.72 (s, 1H), 8.98 (s, 1H)
Reference: [1] Patent: WO2009/57827, 2009, A1, . Location in patent: Page/Page column 167
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  • [ 32779-36-5 ]
YieldReaction ConditionsOperation in experiment
80% at 0 - 120℃; for 4.16667 h; Synthesis of Compound 11-2 (0399) Compound 11-1 (5.0 g, 2.86 mmol) was added portionwise to POCl3 (15 mL) at 0° C. during 10 min. The reaction mixture was stirred at 120° C. for 4 h, then cooled to room temperature and added to ice-water (100 mL). Sat. Na2CO3 was added to adjust pH=7 and extracted with ethyl acetate (200 mL×4). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford 11-2, which was used in the next step without further purification (4.50 g, 80percent).
Reference: [1] Patent: US9138427, 2015, B2, . Location in patent: Page/Page column 289
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5849 - 5853
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  • [ 69927-50-0 ]
  • [ 2426-94-0 ]
Reference: [1] Organic Letters, 2016, vol. 18, # 15, p. 3594 - 3597
  • 26
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  • [ 40805-79-6 ]
YieldReaction ConditionsOperation in experiment
95% With 1-Butylimidazole In toluene at 160℃; for 16 h; In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
82% With 1-methyl-1H-imidazole In toluene at 160℃; for 16 h; In an autoclave, 1 equiv. of aryl halide or heteroaryl halide, 2 equiv. of 1-alkylimidazole, 0.1 equiv. of CuI, 0.2 equiv. of dried K4[Fe(CN)6] (potassium hexacyanoferrate(II)), tetradecane as an internal standard for the GC analysis and a suitable amount of toluene were combined under argon and heated to 160 C. (The K4[Fe(CN)6] was dried by heating powdered K4[Fe(CN)6]x3H2O in a vacuum of 1 mbar to 80 C. for at least 24 hours.) After 16 hours, the reaction mixture was cooled to room temperature. Conversion and yield were determinable by means of gas chromatography. An isolation of the product took place according to the customary workup (distillation, crystallization or chromatography).
Reference: [1] Patent: US2009/62541, 2009, A1, . Location in patent: Page/Page column 4
[2] Patent: US2009/62541, 2009, A1, . Location in patent: Page/Page column 4
[3] New Journal of Chemistry, 2012, vol. 36, # 11, p. 2334 - 2339
[4] Synlett, 2007, # 4, p. 555 - 558
[5] Synthesis, 2008, # 20, p. 3351 - 3355
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Reference: [1] Chemistry - A European Journal, 2007, vol. 13, # 21, p. 6249 - 6254
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  • [ 40805-79-6 ]
Reference: [1] Journal of the American Chemical Society, 2016, vol. 138, # 5, p. 1709 - 1716
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  • [ 40805-79-6 ]
Reference: [1] Journal of Organic Chemistry, 2018, vol. 83, # 9, p. 4922 - 4931
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  • [ 31462-58-5 ]
Reference: [1] Organic Letters, 2017, vol. 19, # 15, p. 3974 - 3977
[2] Journal of the American Chemical Society, 2015, vol. 137, # 26, p. 8328 - 8331
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  • [ 675-21-8 ]
Reference: [1] Journal of the American Chemical Society, 2014, vol. 136, # 10, p. 3792 - 3795
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  • [ 98-80-6 ]
  • [ 3543-46-2 ]
Reference: [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 18, p. 4312 - 4320
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  • [ 109299-78-7 ]
YieldReaction ConditionsOperation in experiment
44%
Stage #1: With n-butyllithium; Triisopropyl borate In tetrahydrofuran; hexane; toluene at -70 - -20℃; for 0.5 h;
Stage #2: With hydrogenchloride; water In tetrahydrofuran; hexane; toluene at -20 - 20℃;
Stage #3: With potassium hydroxide In water
5-Pyrimidineboronic acid; "BuLi (3.02 ml, 2M solution in hexane, 7.55 mmol) was added dropwise to a stirring solution of 5-bromopyrimidine (1 g, 6.29 mmol) and triisopropylborate (1.46 ml, 7.55 mmol) in anhydrous toluene (16 ml) and anhydrous THF (4 ml) at-70°C under a nitrogen atmosphere. The reaction mixture was stirred at-70°C for 30 mins and then removed from the cold bath. When the internal temp. reached-20°C, the reaction was quenched by the dropwise addition of 2M HCI (10 ml). The mixture was allowed to warm to RT and then separated. The aqueous phase was taken to pH 5.5 with 2M KOH and extracted into THF (3 x 25 ml). The combined organic extracts were dried (MgS04), filtered and concentrated in vacuo to provide a colourless solid. The solid was slurried in acetonitrile (2 ml), collected by filtration and dried on the sinter to give the target boronic acid as a brilliant white solid (340 mg, 44percent). 8H(MeOD; 250MHz) 8.98 (2H, s), 9.14 (1H, s).
Reference: [1] Synthetic Communications, 2003, vol. 33, # 5, p. 795 - 800
[2] Organic and Biomolecular Chemistry, 2004, vol. 2, # 6, p. 852 - 857
[3] Patent: WO2005/103019, 2005, A1, . Location in patent: Page/Page column 16
[4] Journal of Organic Chemistry, 2002, vol. 67, # 15, p. 5394 - 5397
[5] Patent: US2006/111394, 2006, A1, . Location in patent: Page/Page column 17
  • 34
  • [ 4595-59-9 ]
  • [ 121-43-7 ]
  • [ 109299-78-7 ]
YieldReaction ConditionsOperation in experiment
64% With n-butyllithium In tetrahydrofuran; hexane; toluene at -78 - -15℃; To a solution of compound 5-bromopyrimidine (8 g, 50 mmol), trimethyl borate (4.6g, 60 mmol) in toluene and THF (150 mL,V/V=4: 1) was added n-BuLi (24 mL, 60 mmol, 2.5 M in hexane) at <n="135"/>-780C. The reaction mixture was stirred for 1 h at -780C, then warmed to -150C and quenched with 2 N HCl (50 mL, 100 mmol). The mixture was concentrated and purification by chromatography (MeOHrDCM=I : 10) to give pyrimidin-5-ylboronic acid (4 g, 64percent) as light yellow solid. MS (m/z) (IvT+H): 125.
Reference: [1] Patent: WO2009/155527, 2009, A2, . Location in patent: Page/Page column 133-134
  • 35
  • [ 4595-59-9 ]
  • [ 1066-54-2 ]
  • [ 216309-28-3 ]
YieldReaction ConditionsOperation in experiment
85% With copper(l) iodide; diisopropylamine In toluene at 60℃; for 3 h; Example 3 N-((1R,2R)-2-Hydroxy-cyclohexyl)-6-(2-pyrimidin-5-yl-ethyl)-5-(4-trifluoromethyl-phenyl)-nicotinamidea) 5-Trimethylsilanylethynyl-pyrimidine; Tetrakis(triphenylphosphine)palladium(O) (727 mg, 0.6 mmol) was added to a stirred, degassed suspension of 5-bromopyrimidine (5.0 g, 31.4 mmol) and copper(I)iodide (120 mg, 0.6 mmol) in toluene and diisopropylamine (1:1, 200 ml) under nitrogen. The reaction mixture was heated to 60° C., trimethylsilylacetylene (4.89 ml, 34.6 mmol) was added and the reaction mixture was stirred for 3 hours at 60° C.. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (200 ml) and washed with saturated aqueous ammonium chloride solution (3.x.100 ml). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography (5percent ethyl acetate/heptane) to give 5-trimethylsilanylethynyl-pyrimidine as a pale brown solid, 4.71 g (85percent yield). LC at 215 nm; Rt 2.07: 88percent, m/z (ES+): 177 (M+H).
Reference: [1] Monatshefte fur Chemie, 1998, vol. 129, # 10, p. 1035 - 1048
[2] Patent: US2008/70931, 2008, A1, . Location in patent: Page/Page column 12
[3] Organic and biomolecular chemistry, 2003, vol. 1, # 3, p. 498 - 506
[4] Journal of Organic Chemistry, 2007, vol. 72, # 13, p. 4750 - 4755
[5] Patent: WO2003/91226, 2003, A1, . Location in patent: Page/Page column 47
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 12, p. 3743 - 3748
[7] Organic Letters, 2014, vol. 16, # 17, p. 4524 - 4527
  • 36
  • [ 4595-59-9 ]
  • [ 216309-28-3 ]
Reference: [1] Journal of Organic Chemistry, 2002, vol. 67, # 18, p. 6287 - 6290
  • 37
  • [ 4595-59-9 ]
  • [ 14047-29-1 ]
  • [ 216959-91-0 ]
Reference: [1] Archiv der Pharmazie, 2008, vol. 341, # 8, p. 478 - 484
[2] Synlett, 2000, # 6, p. 829 - 831
  • 38
  • [ 4595-59-9 ]
  • [ 73183-34-3 ]
  • [ 321724-19-0 ]
Reference: [1] Patent: WO2008/88881, 2008, A1, . Location in patent: Page/Page column 38
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 12, p. 5053 - 5074
  • 39
  • [ 4595-59-9 ]
  • [ 87199-17-5 ]
  • [ 198084-12-7 ]
YieldReaction ConditionsOperation in experiment
99% With sodium carbonate In 1,2-dimethoxyethane; water at 90℃; for 18 h; To a stirred solution of a halide (1 equivalent), a boronic acid (1.3-3.0 equivalents), sodium carbonate mono-hydrate (1.3-3.0 equivalents) in a mixture of dimethoxyethane/water 4:1 (concentration ~0.05-0.2M) was added palladium tetrakis- triphenylphosphine (Pd(Ph3P)4) (0.1 equivalents). The solution was stirred at 90 0C for ~18 hours and then treated with water. In a standard work-up, the mixture was extracted with CH2Cl2 and the organic layer was dried (Na2SO4 or MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography or by radial chromatography on silica gel.; Using general procedure D, 5-bromopyrimidine (199 mg, 1.25 mmol) and 4- formylbenzene boronic acid (469 mg, 3.13 mmol) afforded 4-pyrimidm-5-yl-benzaldehyde (162 mg, 99percent).
Reference: [1] Patent: WO2007/22371, 2007, A2, . Location in patent: Page/Page column 25; 71
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 20, p. 8049 - 8065
  • 40
  • [ 4595-59-9 ]
  • [ 87199-16-4 ]
  • [ 198084-12-7 ]
YieldReaction ConditionsOperation in experiment
60%
Stage #1: With sodium carbonate In water; toluene for 0.333333 h;
Stage #2: at 80℃; for 16 h;
Example 271; 4- (5-pyrimidinyl) benzaldehyde; 5-Bromopyrimidine (159 mg, 1 mmol) was dissolved in toluene (5 mL) and treated with tetrakis (triphenylphosphine)-palladium (0) (116 mg, 0.1 equivalent) and a 2 M solution of sodium carbonate (1 mL, 2 equivalents). The mixture was stirred under an argon atmosphere for 20 min. followed by addition of 3-formylphenyl boronic acid (165 mg, 1.1 equivalensts) in ethanol (1 mL). The reaction was heated to 80 C and stirred for 16 hrs. The mixture was filtered and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed by evaporation. This material was purified using hexanes: dichloromethane (1: 1) followed by dichloromethane: methanol (97: 3) to give 110 mg (60percent) of the title compound.
60%
Stage #1: With sodium carbonate In water; toluene for 0.333333 h;
Stage #2: at 80℃; for 16 h;
EXAMPLE 271
4-(5-pyrimidinyl)benzaldehyde
5-Bromopyrimidine (159 mg, 1 mmol) was dissolved in toluene (5 mL) and treated with tetrakis(triphenylphosphine)-palladium(0) (116 mg, 0.1 equivalent) and a 2 M solution of sodium carbonate (1 mL, 2 equivalents).
The mixture was stirred under an argon atmosphere for 20 min. followed by addition of 3-formylphenyl boronic acid (165 mg, 1.1 equivalensts) in ethanol (1 mL).
The reaction was heated to 80° C. and stirred for 16 hrs.
The mixture was filtered and partitioned between ethyl acetate and water.
The organic layer was washed with brine, dried over magnesium sulfate, filtered, and the solvent was removed by evaporation.
This material was purified using hexanes:dichloromethane (1:1) followed by dichloromethane:methanol (97:3) to give 110 mg (60percent) of the title compound.
Reference: [1] Patent: WO2005/61487, 2005, A1, . Location in patent: Page/Page column 157
[2] Patent: US2005/159469, 2005, A1, . Location in patent: Page/Page column 104
  • 41
  • [ 4595-59-9 ]
  • [ 57260-71-6 ]
  • [ 634468-96-5 ]
YieldReaction ConditionsOperation in experiment
58.7% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In toluene at 90℃; for 12 h; (1)
Preparation of tert-butyl 4-(pyrimidin-5-yl)piperazin-1-carboxylate
To a 100 mL eggplant-shaped bottle were added 5-bromopyrimidine (3.16 g, 20 mmol), tert-butyl piperazin-1-carboxylate (3.72 g, 20 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.49 g, 4 mmol), cesium carbonate (13.0 g, 40 mmol) and tris(dibenzylideneacetone)dipalladium (1.83 g, 2 mmol); and toluene (80 mL) was added.
The reaction was carried out at 90°Cunder the protection of nitrogen for 12 h.
The mixture was filtrated under suction, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol=50:1) to get the title compound (3.1 g, yield: 58.7percent).
Reference: [1] Tetrahedron Letters, 2006, vol. 47, # 15, p. 2549 - 2552
[2] Patent: EP3091008, 2016, A1, . Location in patent: Paragraph 0380; 0381
[3] Patent: US2005/176722, 2005, A1, . Location in patent: Page/Page column 20
  • 42
  • [ 4595-59-9 ]
  • [ 40138-16-7 ]
  • [ 640769-71-7 ]
YieldReaction ConditionsOperation in experiment
220 mg With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In water; acetonitrile at 150℃; for 0.0833333 h; Sealed tube; Microwave irradiation The microwave vials (20 ml) were charged with 2-formylphenylboronic acid (290 mg, 2.0 mmol), 5-bromo-pyrimidine (316 mg,2.0 mmol) and 8 ml of acetonitrile. To the mixture was added 4 ml of an aqueous solution of sodium carbonate (1 M), followed by the addition of 100 mg of dichlorobis (triphenylYlphosphine) -palladium (II). The reaction vessel was sealed and heated at 150 & lt; 0 & gt; C for 5 minutes with microwave irradiation. After cooling the reaction mixtureExtracted with ethyl acetate. The organic layer was evaporated to provide a crude material which was purified by ISCO to give 220 mg of 2-pyrimidin-5-yl-benzaldehyde.
Reference: [1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 18, p. 8607 - 8618
[2] Patent: US2008/153852, 2008, A1, . Location in patent: Page/Page column 27
[3] Patent: CN104045626, 2017, B, . Location in patent: Paragraph 0318
  • 43
  • [ 4595-59-9 ]
  • [ 1256169-22-8 ]
  • [ 640769-71-7 ]
Reference: [1] Chemistry - A European Journal, 2010, vol. 16, # 36, p. 11072 - 11081
  • 44
  • [ 4595-59-9 ]
  • [ 40138-16-7 ]
  • [ 497-19-8 ]
  • [ 640769-71-7 ]
Reference: [1] Patent: US2009/29993, 2009, A1,
  • 45
  • [ 4595-59-9 ]
  • [ 269409-73-6 ]
  • [ 852180-74-6 ]
YieldReaction ConditionsOperation in experiment
45% With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate In 1,4-dioxane; water at 95℃; Inert atmosphere General procedure: The halo aryl (1.0 equiv) was dissolved in a mixture of water:dioxane (1:1). The boronic acid or ester(1.5 equiv) and potassium phosphate (5.0 equiv) were added. The solution was degassed byvacuum/argon cycles (10 times) before addition of PdCl2(PPh3)2 (10 molpercent) and further degassed (5times). The resulting mixture was stirred at 95 °C under argon atmosphere for 16-20 hours. Thereaction mixture was filtered through Celite and diluted with water (approx. 30 mL) before washingwith chloroform (3 x 30 mL). If not stated otherwise, the aqueous phase was concentrated underreduced pressure and applied to a C18 precolumn before purification on a 10g or 60 g C18 column witha gradient of acetonitrile in water (10-100percent) to yield the desired product.
34% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.5 h; Inert atmosphere; Microwave irradiation 3-(4.4,5.5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid (496 mg, 2.00 mmol), 5- bromopyrimidine (382 mg, 2.40 mmol), PdC (dppf) DCM complex (82 mg, 5 molpercent) were stirred in 1 ,4-dioxane (10 mL) under nitrogen and a solution of potassium carbonate (829 mg, 6.00 mmol) in water (5 mL) was added. The mixture was degassed with a stream of nitrogen bubbles and heated in the microwave (120 C/30 minutes). The volatiles were removed in vacuo and the aqueous residue diluted with water (50 mL) and DCM (50 mL). The mixture was filtered through celite, the DCM phase discarded and the aqueous phase extracted with further DCM (2 50 mL). The DCM extracts were again discarded, the aqueous phase was adjusted to pH 3 with 30percent w/v aqueous NaHSCU and the precipitate collected by filtration and dried under vacuum (40 C/3 hours over P2O5) to give the desired compound (137 mg, 34percent yield) as a grey solid. LCMS-B: RT 3.25 min; m/z 201.1 [M+H]+
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 145, p. 634 - 648
[2] Patent: WO2016/34673, 2016, A1, . Location in patent: Page/Page column 80
  • 46
  • [ 4595-59-9 ]
  • [ 25487-66-5 ]
  • [ 852180-74-6 ]
Reference: [1] Patent: WO2005/58837, 2005, A1, . Location in patent: Page/Page column 16
  • 47
  • [ 4595-59-9 ]
  • [ 1370724-99-4 ]
  • [ 1009826-93-0 ]
Reference: [1] Synlett, 2012, # 3, p. 443 - 447
  • 48
  • [ 4595-59-9 ]
  • [ 23719-80-4 ]
  • [ 1346697-39-9 ]
YieldReaction ConditionsOperation in experiment
41% With 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran at 20℃; for 17 h; 5-Bromopyrimidine (8 g, 50.3 mmol) was taken in anhydrous THF (160 mL) followed by the addition of cyclopropylmagnesium bromide (106 mL, 52.8 mmol, 0.5 M solution in THF) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, and then treated with a solution of 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (1 1.42 g, 50.3 mmol) in THF (26 mL). The resultant brown mixture was allowed to stir at room temperature for 16 hours and then evaporated under reduced pressure. The brown solid was suspended in water and extracted with dichloromethane (3x50 mL). The combined organics were washed with a IN aqueous solution of sodium hydroxide (2x15 mL), water, and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using 160 g BIOTAGE.(R). column eluting with hexanes/EtOAc (9: 1) to provide Intermediate 61 as a pale yellow solid (4.1 g, 41 percent yield). MS (ES): m/z=199.05 [M+H]+. Intermediate 61 was used in the synthesis of Example 214.
20% at 0 - 20℃; for 1 h; Inert atmosphere To a solution of 5-bromopyrimidine (3 g, 18.87 mmol) in Et20 (120 mL) and THF (20ml) was added cyclopropylmagnesium bromide (39.6 mL, 19.81 mmol) at 0°C. The resulting white suspension was stirred at rt for lh and quenched with water (0.340 mL, 18.87 mmol) followed by addition of DDQ (4.28 g, 18.87 mmol) in THF (10ml). The resulting black mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with NaOH (IN) and brine. The crude product was purified by Biotage (0-15percent EtOAc/hexanes, 1.2L) to afford the title compound (700 mg, 20percent) as a yellow solid. XH NMR (500 MHz, CC13D) δ ppm 8.87 (1 H, s), 8.66 (1 H, s), 2.40-2.56 (1 H, m), 1.13-1.32 (4 H, m).
20%
Stage #1: at 0 - 20℃;
Stage #2: With water; 2,3-dicyano-5,6-dichloro-p-benzoquinone In tetrahydrofuran; diethyl ether at 20℃;
Preparation 11 A: 5-Bromo-4-cyclopropylpyrimidine [00148] To a solution of 5-bromopyrimidine (3 g, 18.87 mmol) in Et20 (120 mL) and THF (20ml) was added cyclopropylmagnesium bromide (39.6 mL, 19.81 mmol) at 0 °C. The resulting white suspension was stirred at room temperature for lh and quenched with water (0.340 mL, 18.87 mmol) followed by addition of DDQ (4.28 g, 18.87 mmol) inTHF (10ml). The resulting black mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with NaOH (IN) and brine. The crude product was purified by BIOTAGE® (0-15percent EtOAc/hexanes, 1.2L) to afford the title compound (700 mg, 20percent) as a yellow solid. XH NMR (500 MHz, chloroform-d) δ ppm 8.87 (1 hr, s), 8.66 (1 hr, s), 2.40-2.56 (1 hr, m), 1.13-1.32 (4 hr, m).
Reference: [1] Patent: WO2012/15723, 2012, A1, . Location in patent: Page/Page column 107; 108
[2] Patent: WO2012/9510, 2012, A1, . Location in patent: Page/Page column 54; 55
[3] Patent: WO2013/49263, 2013, A1, . Location in patent: Paragraph 00147; 00148
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