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Product Details of [ 183438-24-6 ]

CAS No. :183438-24-6 MDL No. :MFCD01318111
Formula : C4H2BrIN2 Boiling Point : -
Linear Structure Formula :- InChI Key :ZEZKXPQIDURFKA-UHFFFAOYSA-N
M.W : 284.88 Pubchem ID :7006651
Synonyms :

Calculated chemistry of [ 183438-24-6 ]

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 : 42.45
TPSA : 25.78 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.92 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.92
Log Po/w (XLOGP3) : 1.58
Log Po/w (WLOGP) : 1.84
Log Po/w (MLOGP) : 1.33
Log Po/w (SILICOS-IT) : 2.71
Consensus Log Po/w : 1.88

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.16
Solubility : 0.199 mg/ml ; 0.000697 mol/l
Class : Soluble
Log S (Ali) : -1.73
Solubility : 5.28 mg/ml ; 0.0185 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.45
Solubility : 0.101 mg/ml ; 0.000355 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.03

Safety of [ 183438-24-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338-P310 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 183438-24-6 ]

* 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 [ 183438-24-6 ]
  • Downstream synthetic route of [ 183438-24-6 ]

[ 183438-24-6 ] Synthesis Path-Upstream   1~15

  • 1
  • [ 183438-24-6 ]
  • [ 136902-53-9 ]
  • [ 4595-59-9 ]
  • [ 91891-74-6 ]
Reference: [1] Chemistry Letters, 2011, vol. 40, # 9, p. 992 - 994
  • 2
  • [ 75-24-1 ]
  • [ 183438-24-6 ]
  • [ 7752-78-5 ]
YieldReaction ConditionsOperation in experiment
36.2% With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; toluene at 110℃; for 12 h; Preparation 70 5-bromo-2-methylpyrimidine A solution of 5-bromo-2-iodopyrimidine (400 mg, 1.404 mmol), MesAl (2 M in toluene, 1053 μ, 2.106 mmol) and tetrakistriphenylphosphinepalladium(O) (32.5 mg, 0.028 mmol) in dioxane (4680 μΚ) was heated at 1 10 °C for 12 h. Water was added and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated in vacuo to give 5-bromo-2-methylpyrimidine (88 mg, 0.509 mmol, 36.2 percent yield) as a brown solid. NMR (500MHz, CHLOROFORM-d) δ 8.70 (s, 2H), 2.71 (s, 3H). MS (M+H)+: 174.91.
Reference: [1] Patent: WO2014/98831, 2014, A1, . Location in patent: Page/Page column 70; 71
[2] Patent: US2004/110785, 2004, A1, . Location in patent: Page 124
  • 3
  • [ 544-97-8 ]
  • [ 183438-24-6 ]
  • [ 7752-78-5 ]
Reference: [1] Patent: WO2014/75392, 2014, A1, . Location in patent: Page/Page column 66; 67
[2] Patent: WO2017/166104, 2017, A1, . Location in patent: Page/Page column 57-58
[3] Patent: WO2009/134668, 2009, A2, . Location in patent: Page/Page column 29
  • 4
  • [ 124-38-9 ]
  • [ 183438-24-6 ]
  • [ 37131-87-6 ]
Reference: [1] Journal of Medicinal Chemistry, 2009, vol. 52, # 18, p. 5685 - 5702
  • 5
  • [ 183438-24-6 ]
  • [ 98-80-6 ]
  • [ 38696-20-7 ]
YieldReaction ConditionsOperation in experiment
65% With potassium carbonate In 1,4-dioxane; water at 110℃; Microwave irradiation Intermediate 21; <n="54"/>A mixture of 5-bromo-2-iodopyrimidine (1.76 mmol, 0.500 g), phenylboronic acid (1.93 mrnol, 0.235 g), 2M aqueous solution of K2CO3 (4.40 mmo., 2.2 m.), Pd(PPh3J4 (0.18 mmol, 0.203 g) in dioxane (10 ml) was heated at 11O0C overnight in a microwave oven. The solvent was evaporated and the solid residue was extracted between water and ethyl acetate. The organic phase was evaporated and the crude residue was purified by chromatography over SiO2 eluting with hexane/ethyl acetate mixtures affording 0.329 g (yield 65percent) of the expected product.ESI/MS (m/e, percent): 235 [(M+1)\\ 100], 237 [(M+1)+, 97].
59% With tetrakis(triphenylphosphine)palladium (0) In hexane; water; ethyl acetate; toluene Step 1:
Synthesis of 5-bromo-2-phenylpyrimidine
First, 1.97 g of 5-bromo-2-iodopyrimidine, 0.85 g of phenylboronic acid, 7.0 mL of a 2M sodium carbonate aqueous solution, and 18 mL of toluene were put in a 200-mL three-neck flask equipped with a reflux pipe, and the atmosphere in the flask was replaced with nitrogen.
After the mixture was degassed by being stirred under reduced pressure, 0.081 g of tetrakis(triphenylphosphine)palladium(0) (abbreviation: Pd(PPh3)4) was added thereto and the mixture was refluxed for 8 hours.
Here, 0.040 g of Pd(PPh3)4 was added and the mixture was refluxed for 8 hours, and then, 0.040 g of Pd(PPh3)4 was further added and the mixture was further refluxed for 8 hours to cause a reaction.
Water was added to the resulted solution, and an organic layer was extracted with dichloromethane.
The obtained solution of the extract was washed with saturated brine, and magnesium sulfate was added for drying.
The solution obtained by the drying was filtrated.
The solvent of this solution was distilled off, and then the obtained residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 5:1, so that the objective pyrimidine derivative (white powder) was obtained in a yield of 59percent).
A synthetic scheme of Step 1 is shown in (b-1) below.
59% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; toluene for 24 h; Inert atmosphere; Reflux First of all, 5-bromo-2-iodopyrimidine 1.97g and phenyl boronic acid 0.85g, 2M sodium carbonate aqueous solution 7.0mL, toluene 18mL, reflux condenser put in a 200mL three-necked flask equipped with a, in the flask was replaced with nitrogen. After degassing with stirring under reduced pressure, tetrakis (triphenylphosphine) palladium (0) (abbreviation: Pd (PPh 3 ) 4 ) 0.081 g and the mixture was refluxed for 8 hours. Here, Pd (PPh 3 ) 4 0.040 g was added, and the mixture was refluxed for 8 hours, more Pd (PPh 3 ) 4 0.040 g was added and reacted by refluxing for 8 hours. Water was added to the reaction solution, and the organic layer was extracted with dichloromethane. The resulting extract was washed with saturated brine, and dried over magnesium sulfate. After the drying, the solution was filtered. After evaporating the solvent of this solution, the resulting residue, hexane: ethyl acetate = 5: 1 was purified by flash column chromatography as a developing solvent, to give a pyrimidine derivative of interest (white powder, yield: 59percent).
50% With sodium carbonate In water; toluene for 42 h; Heating / reflux Step 1:
5-Bromo-2-phenyl-pyrimidine
To a degassed solution of phenylboronic acid (8.93 g, 73.22 mmol, 1.0 equiv; commercially available), 5-bromo-2-iodo-pyrimidine (20.86 g, 73.22 mmol, 1.0 equiv; commercially available) and tetrakis(triphenylphosphine) palladium(0) (0.85 g, 0.73 mmol, 0.01 equiv) in toluene (180 mL) was added Na2CO3 (15.52 g, 146.45 mmol, 2.0 equiv), dissolved in water (60 mL), and the reaction mixture heated to reflux.
After 18 h, tetrakis(triphenylphosphine) palladium(0) (0.42 g, 0.37 mmol, 0.005 equiv) was added and the reaction mixture heated for an additional time period of 24 h.
The solvent was removed under reduced pressure and the crude reaction product extracted from a sat. solution of NaCl (200 mL) with ethyl acetate (3*150 mL).
The combined organic phases were dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluding with heptane/ethyl acetate (9:1) to provide 8.60 g (50percent) of the title compound.
38% With sodium carbonate In water; toluene at 115℃; for 16 h; Inert atmosphere A mixture consisting of 5-bromo-2-iodopyrimidine (Bridge Organics, 10.0 g, 35.1 mmol), benzene boronic acid (Alfa Aesar, 4.25 g, 35.1 mmol), tetrakis(triphenylphosphine)palladium (Strem, 0.405 g, 0.351 mmol), toluene (150 mL), and a 2 M aqueous sodium carbonate solution (35 mL) was stirred at 115° C. (degrees Celsius) under a nitrogen atmosphere for 16 hours.
After cooling to room temperature, the mixture was partitioned between chloroform (250 mL) and brine (200 mL).
The phases were separated and the organic phase was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an orange oil (9.1 g).
The crude product was purified by flash silica column chromatography.
Elution through a 500-g Analogix.(R). flash silica cartridge with 100percent hexanes afforded the title intermediate as a white solid (3.15 g, 38percent yield). Rf 0.69 with 9:1 v/v hexanes-ethyl acetate; 1H-NMR (400 MHz; CDCl3) δ 8.83 (s, 2H), 8.44-8.38 (m, 2H), 7.52-7.46 (m, 3H); MS (APCI+) m/z 236.9 (M+1).
35% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In water; N,N-dimethyl-formamide at 20 - 80℃; for 2 h; Inert atmosphere To a stirred solution of compound 361 (1.4 g) in DMF: H20 (4:1, 20 mL) were added sodium carbonate (783 mg, 7.39 mmol) and phenylboronic acid 362 (451 mg, 3.69 mmol), purged under argon for 30 mm. To this was added Pd(PPh3)4 (570 mg, 0.49 mmol) at RT; heated to 80 °C and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mass was filtered through celite; the filtrate was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 2percent EtOAc/ hexanes to afford compound 363 (400 mg, 35percent) as white solid. TLC: 10percent EtOAc/ hexanes (R 0.9); 1H-NMR (DMSO-d6, 400 MHz): ö 8.83 (s, 2H), 8.41-8.39 (m, 2H), 7.50-7.48 (m, 3H).

Reference: [1] Organic Letters, 2002, vol. 4, # 4, p. 513 - 516
[2] Patent: WO2009/21696, 2009, A1, . Location in patent: Page/Page column 52-53
[3] Patent: US2015/349278, 2015, A1,
[4] Patent: JP2016/6041, 2016, A, . Location in patent: Paragraph 0250; 0251-0253
[5] Patent: US2008/64697, 2008, A1, . Location in patent: Page/Page column 27
[6] Patent: US2010/75990, 2010, A1, . Location in patent: Page/Page column 21
[7] Patent: WO2015/138895, 2015, A1, . Location in patent: Paragraph 000296
  • 6
  • [ 32779-36-5 ]
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YieldReaction ConditionsOperation in experiment
84%
Stage #1: With hydrogen iodide; sodium iodide In chloroform; water at 0 - 20℃; for 20 h;
Stage #2: With sodium hydroxide In chloroform; water for 0.166667 h;
Preparation of 5-Bromo-2-iodo-pyrimidine
To a suspension of 5-bromo-2-chloro-pyrimidine (5.80 g, 30 mmol) and sodium iodide (7.5 g, 50 mmol) in chloroform (20 ml) a Hydroiodic acid (57 wt. percent) (2.85 g, 25.6 mmol) is added at 0° C.
After removing the cooling the reaction mixture is stirred for 20 h at r.t. and then poured into a mixture of 200 ml ice water and 30 ml 10N NaOH. Chloroform (150 ml) is added and the mixture is stirred for 10 min.
The organic phase is separated, the aqueous layer is extracted with chloroform (2*100 ml) and the combined organic phases dried over MgSO4 and concentrated in vacuo to yielding 5-bromo-2-iodo-pyrimidine as a pale yellow solid.
Yield 6.29 g (84percent)
MS: M=284.8 (ESI+)
1H-NMR (300 MHz, CDCl3): 8.54 (s, 2H) 7.56(d, J=16.4 Hz, 1H), 7.59-7.66(m, 4H).
81%
Stage #1: With hydrogen iodide; sodium iodide In dichloromethane at 20 - 50℃; for 5 h;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Preparation of Compound A8:To a solution of compound A7 (50 g, 0.26 mol) in DCM (300 mL) was added NaI (80 g, 0.52 mol) at room temperature, then HI (75 g, 0.52 mol) was added. After stirred at 50° C. for 5 h, the mixture was poured into ice water and carefully neutralized by addition of solid sodium bicarbonate until mixture became colorless. Then the mixture was extracted with DCM (2.x.200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford compound A8 (60 g, yield: 81percent) as white solid.1H NMR (400 MHz, CDCl3): δ: 8.54 (s, 2H).
81% With hydrogen iodide; sodium iodide In dichloromethane at 20 - 50℃; for 5 h; Example A7 A8 A9 A10 [0412] Preparation of compound A8: To a solution of compound A7 (50 g, 0.26 mol) in DCM (300 mL) was added Nal (80 g, 0.52 mol) at room temperature, then HI (75 g, 0.52 mol) was added. After stirred at 50°C for 5h, the mixture was poured into ice water and carefully neutralized by addition of solid sodium bicarbonate until mixture became colorless. Then the mixture was extracted with DCM (2 x 200 mL). The organic layer was dried over Na2S04, filtered and concentrated to afford compound A8 (60 g, yield: 81percent) as white solid. [0413] 1H NMR (400 MHz, CDC13): δ: 8.54 (s, 2H). [0414] Preparation of compound A9: To the solution of compound A8 (50 g, 0.18 mol) in THF (300 mL) was added Pd(PPh3)4 (11.5 g, 0.01 mol), followed by addition of a solution of zinc reagent 3 (freshly prepared from iodomethyl 2,2-dimethylpropanoate) in THF (500 ml, 0.36 mol) and stirred at room temperature for 12h. Then ice water was added and the mixture was extracted with ethyl acetate (2 x 200 mL). The organic layer was dried over Na2S04, filtered and concentrated to afford crude product. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 10: 1) to afford the compound A9 (41 g, yield: 85percent) as yellow solid. [0415] 1H NMR (400 MHz, CDC13): δ: 8.75 (s, 2H), 5.26(s, 2H), 5.06 (s, 1H), 1.28 (s, 9H). [0416] Preparation of compound A10: To a stirred solution of compound A9 (15.0 g, 54.9 mmol) in dioxane (100 mL) was added bis(pinacolato)diboron (17.0 g, 65.4 mmol) under nitrogen, followed by Pd(dppf)Cl2 (2.20 g, 2.72 mmol) and KOAc (16 g, 163 mmol). The reaction mixture was heated at 85°C for 3h. The black suspension was cooled to room temperature, filtered, concentrated to afford crude product. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate = 15: 1) to afford compound A10 (15.4 g) as white solid, contaminated with pinacol derivatives. [0417] 1H NMR (400 MHz, CDC13): δ: 8.97 (s, 2H), 5.30 (s, 2H), 1.35 (s, 9H), 1.28 (s, 9H). [0418] Preparation of compound All: To a solution of compound A10 (15.6 g, 48.7 mmol) in MeOH (100 mL) was added H202 (16.0 g, 140 mmol). The mixture was stirred at room temperature for 12 h. 2N sodium thiosulphate (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL) The aqueous phase was adjusted pH to 4- 5 with 2N HCl; then the mixture was extracted with ethyl acetate (2 x 200 mL). The organic layer was dried over a2S04, filtered and concentrated to get compound All (9.4 g, yield: 82percent in two steps). [0419] 1H NMR (400 MHz, DMSO-i): δ: 10.48 (s, 1H), 8.31 (s, 2H), 5.1 1 (s, 2H), 1.21 (s, 9H). [0420] Preparation of compound A12: To a solution of compound All (10 g, 30 mmol) in MeOH (200 mL) was added MeONa (50 ml, 1M in MeOH). After stirred at room temperature for 12 h, the mixture was poured into water and extracted with ethyl acetate (2 x 200 mL). The organic layer was dried over a2S04, filtered and concentrated to afford the compound A12 (7.3 g, yield: 98percent) as white solid. [0421] 1H NMR (300 MHz, CDC13): δ: 8.43 (s, 2H), 7.35 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 4.78 (s, 2H).
Reference: [1] Angewandte Chemie - International Edition, 1999, vol. 38, # 5, p. 659 - 661
[2] Patent: US2005/222228, 2005, A1, . Location in patent: Page/Page column 15-16
[3] Chemical Communications, 1996, # 24, p. 2719 - 2720
[4] Patent: US2012/238751, 2012, A1, . Location in patent: Page/Page column 30
[5] Patent: WO2014/43272, 2014, A1, . Location in patent: Paragraph 0411; 0412; 0413
[6] Journal of Organic Chemistry, 2002, vol. 67, # 18, p. 6550 - 6552
[7] Molecular Crystals and Liquid Crystals Science and Technology Section A: Molecular Crystals and Liquid Crystals, 2001, vol. 368, p. 279 - 292
[8] Patent: US2006/194801, 2006, A1, . Location in patent: Page/Page column 37
[9] Patent: EP2258697, 2010, A1, . Location in patent: Page/Page column 122
[10] Patent: WO2015/138895, 2015, A1, . Location in patent: Paragraph 000295
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Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 16, p. 6908 - 6916
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  • [ 38353-09-2 ]
  • [ 183438-24-6 ]
Reference: [1] Chemistry - A European Journal, 2009, vol. 15, # 33, p. 8251 - 8258
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Reference: [1] Journal of Organic Chemistry, 2012, vol. 77, # 16, p. 6908 - 6916
  • 10
  • [ 183438-24-6 ]
  • [ 108-95-2 ]
  • [ 257280-25-4 ]
YieldReaction ConditionsOperation in experiment
92% at 165℃; for 4 h; Inert atmosphere Step A:
Preparation of 5-bromo-2-phenoxypyrimidine
A mixture consisting of 5-bromo-2-iodopyrimidine (Bridge Organics, 1.01 g, 3.57 mmol), phenol (Aldrich, 3.35 g, 35.7 mmol), and potassium carbonate (Aldrich, 4.93 g, 35.7 mmol) was stirred neat at 165° C. under a nitrogen atmosphere for four hours.
After cooling to room temperature, the mixture was partitioned between ethyl acetate (250 mL) and 1 N hydrochloric acid (4*200 mL).
The organic layer was washed with 1 N hydrochloric acid until disappearance of color in the aqueous layer.
The phases were separated and the organic phase was washed with water (100 mL) and brine (100 mL).
The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide an orange oil (1.1 g).
The product was purified by flash silica column chromatography.
Elution through an 80-g Silicycle.(R). flash silica cartridge with 10percent ethyl acetate in hexanes afforded the title compound as a white solid (0.82 g, 92percent yield); Rf 0.51 with 8:2 v/v hexanes-ethyl acetate; 1H-NMR (400 MHz; CDCl3) δ 8.56 (s, 2H), 7.46-7.41 (m, 2H), 7.30-7.24 (m, 1H), 7.20-7.16 (m, 2H); MS (APCI+) m/z 252.9 (M+1).
87% With 2-Picolinic acid; potassium phosphate; copper(l) iodide In dimethyl sulfoxide at 100℃; for 20 h; Inert atmosphere Procedure: 5-bromo-2-iodopyrimidine (3 mmol), phenol (3.2 mmol), 2-picolinic acid (0.3 mmol), cuprous iodide CuI (0.3 mmol), potassium phosphate (4.5 mmol) was placed in 25 mL dry In a flask, 15 mL of DMSO was added and the mixture was heated to 100° C. under Ar protection. After about 20 hours of reaction, TLC conversion was complete. After the mixture was cooled to room temperature, a large amount of ethyl acetate was added, washed with water four times and extracted twice with ethyl acetate. The EA phases were combined and washed with saturated brine. The organic phase was dried, filtered, evaporated to dryness and purified by silica gel column chromatography to give 1.1 g of a white product. , Yield 87percent
Reference: [1] Patent: US2010/75990, 2010, A1, . Location in patent: Page/Page column 40
[2] Patent: CN108069974, 2018, A, . Location in patent: Paragraph 0194-0196
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  • [ 183438-24-6 ]
  • [ 799557-86-1 ]
YieldReaction ConditionsOperation in experiment
18% With potassium fluoride; copper(l) iodide In 1-methyl-pyrrolidin-2-one; N,N-dimethyl-formamide at 20℃; for 16 h; Example 54: 5-bromo-2-(trifluoromethyl)pyrimidine:; A mixture of 1.77 g (30.35 mmoles, 1.33 eq.) of KF and 5.79 g (30.35 mmoles, 1.33 eq.) of CuI were stirred and heated together using a heat gun under vacuum (1 mm) for 20 min. After cooling, 20 ml_ of DMF and 20 ml of NMP were added followed by 4.1 ml_ (27.38 mmoles, 1.20 eq.) of CF3-TMS and 6.5 g (22.82 mmoles, 1.0 eq.) of 5-bromo-2- iodopyrimidine. The mixture was stirred at RT for 16h. The crude mixture was poured onto 200 ml_ of NH4OH 6N and the aqueous phase was extracted six times with 50 mL of AcOEt. The combined organic layers were washed three times with 50 mL of a saturated solution of Na2CO3, once with 50 mL of brine, dried over Na2SO4, filtered and evaporated to dryness. The crude compound was purified by flash chromatography on silica gel to give 940 mg of a white solid.Yield : 18 percent M.P. : 33-39°C EPO <DP n="94"/>LC-MS : T1. = 4.32 min. (100 percent) (no ionization)) [Column : Nucleosil C-18HD, 4x70 mm, 3μm, gradient CH3CN/H2O/TFA 0.05percent : 20-100percent CH3CN (6 min.), 100percent CH3CN (1.5 min.), flow : 1 mL/min].1H-NMR (CDCI3, 300 MHz) δ : 8.93 (s, 2H). 19F-NMR (CDCI3, 282 MHz) δ : -70.8.
16.7% With potassium fluoride; copper(l) iodide In N,N-dimethyl-formamide at 20℃; A mixture of 5-bromo-2-iodo-pyrimidine (30 g, 0.11 mol), TMSCF3 (30 g, 0.21 mol), KF (9.2 g, 0.16 mol) and CuI (30 g, 0.16 mol) in DMF (300 mL) was stirred at room temperature overnight. The reaction mixture was quenched by NH3.H2O (600 mL) and extracted with EtOAc (500 mL×3). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (Petroleum ether) to give 5-bromo-2-trifluoromethyl-pyrimidine (4 g, yield: 16.7percent). 1H NMR (CDCl3 400 Hz): δ8.90 (s, 2H)
14% With potassium fluoride; copper(l) iodide In 1-methyl-pyrrolidin-2-one at 70℃; Inert atmosphere A mixture of 5-bromo-2-iodopyrimidine (10 g, 35.10 mmol, 1.00 equiv), trimethyl(trifluoromethyl)silane (20 g, 140.65 mmol, 4.00 equiv), KF (4.1 g, 70.57 mmol, 2.00 equiv), and CuT (13 g, 68.26 mmol, 2.00 equiv) in NMP (80 mL) was stirred overnight at 70°C under nitrogen. The reaction was quenched by 200 mL of ammonia hydroxide, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with petroleum ether to afford the title compound 1.1 g (14percent) of 5-bromo-2- (trifluoromethyl)pyrimidine as a light yellow solid.
Reference: [1] Patent: WO2006/136442, 2006, A1, . Location in patent: Page/Page column 92-93
[2] Patent: US2014/107340, 2014, A1, . Location in patent: Paragraph 0131
[3] Patent: WO2015/52264, 2015, A1, . Location in patent: Paragraph 01615; 01616
[4] Patent: WO2004/101546, 2004, A1, . Location in patent: Page 26-27
[5] Patent: WO2005/14571, 2005, A1, . Location in patent: Page/Page column 26-27
[6] Patent: WO2005/40144, 2005, A1, . Location in patent: Page/Page column 13
[7] Patent: WO2006/40192, 2006, A1, . Location in patent: Page/Page column 38
[8] Patent: EP2258697, 2010, A1, . Location in patent: Page/Page column 122
[9] Patent: WO2016/128529, 2016, A1, . Location in patent: Paragraph 0727; 0728; 0729
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  • [ 799557-86-1 ]
Reference: [1] Chemistry--A European Journal, 2015, vol. 21, # 1, p. 96 - 100
  • 13
  • [ 23719-80-4 ]
  • [ 183438-24-6 ]
  • [ 304902-96-3 ]
YieldReaction ConditionsOperation in experiment
35% With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 70℃; for 2 h; Inert atmosphere 5-Bromo-2-iodo-pyrimidine (5.00 g, 17.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.70 mg, 5.00 mmol) were dissolved in tetrahydrofuran (80 ml), and cyclopropylmagnesium bromide (0.5 mol/L in THF, 70.0 ml, 35.0 mmol) was slowly added dropwise thereto in the presence of nitrogen gas. The reaction liquid was stirred at 70° C. for 2 hours, and then diluted with water (20 ml), followed by extraction with ethyl acetate (50 ml×3). The extraction liquids were combined and dried over sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50:1) to obtain the title compound (1.20 g, 35percent). [1353] 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 2H), 2.17-2.11 (m, 1H), 1.04-1.02 (m, 4H).; MS (ESI) m/z 199 (M+H)+
Reference: [1] Patent: US2015/51395, 2015, A1, . Location in patent: Paragraph 1352-1353
  • 14
  • [ 557-20-0 ]
  • [ 183438-24-6 ]
  • [ 873331-73-8 ]
YieldReaction ConditionsOperation in experiment
73% With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 0℃; for 0.5 h; Inert atmosphere 5-Bromo-2-iodo-pyrimidine (50.0 g, 176 mmol) was dissolved in tetrahydrofuran (1.0 L), and Pd(PPh3)4 (10.2 g, 9.00 mmol) was added thereto. After cooling to 0° C., diethylzinc (250 ml, 250 mmol) was added dropwise, followed by stirring for 30 minutes in the presence of nitrogen gas. The reaction solution was diluted with ethyl acetate (500 ml), and then washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride. After the extraction liquid was dried over sodium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 to 5:1) to obtain the title compound (24.0 g, 73percent). [1284] 1H NMR (400 MHz, DMSO-d6): δ 8.86 (s, 4H), 2.89-2.81 (m, 2H), 1.26-1.21 (t, 3H)
Reference: [1] Patent: US2015/51395, 2015, A1, . Location in patent: Paragraph 1283-1284
  • 15
  • [ 97674-02-7 ]
  • [ 183438-24-6 ]
  • [ 1189169-37-6 ]
YieldReaction ConditionsOperation in experiment
70% With bis-triphenylphosphine-palladium(II) chloride In toluene at 130℃; for 18 h; Inert atmosphere 5-bromo-2-iodopyrimidine (16 g, 56.16 mmol) and tributyl(l- ethoxyethenyl)stannane (25 g, 69.22 mmol) were dissolved in toluene (500 mL) and purged with N2for 10 mins. Palladium (2+) chloride - triphenylphosphane (1 :2:2) (3.5 g, 4.99 mmol) was added and the reaction mixture was heated at 130 °C for 18 h. The reaction was allowed to cool to r.t. Water (70 ml) and 6M HC1 (280 ml) were added and - -the reaction mixture was allowed to stir vigorously for 4 h. The pH of the mixture was adjusted to pH 7 by the addition of saturated aqueous Na2C03(approximately 300 mL) and the mixture extracted with EtOAc (3 x 350 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (Si02, 20-100percent EtOAc in Heptane) to afford the title compound as a golden-yellow solid (7.9 g,70percent). 1H NMR (500 MHz, CDC13) δ 8.97 (s, 2H), 2.77 (s, 3H).
Reference: [1] Patent: WO2015/86526, 2015, A1, . Location in patent: Page/Page column 153; 154
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