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[ CAS No. 942947-94-6 ] {[proInfo.proName]}

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Chemical Structure| 942947-94-6
Chemical Structure| 942947-94-6
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Product Details of [ 942947-94-6 ]

CAS No. :942947-94-6 MDL No. :MFCD12407282
Formula : C5H4BrClN2 Boiling Point : -
Linear Structure Formula :- InChI Key :DDOFUMWLNSICHU-UHFFFAOYSA-N
M.W : 207.46 Pubchem ID :44181812
Synonyms :

Calculated chemistry of [ 942947-94-6 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 9
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 41.35
TPSA : 38.91 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) : -6.27 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.69
Log Po/w (XLOGP3) : 1.82
Log Po/w (WLOGP) : 2.09
Log Po/w (MLOGP) : 1.6
Log Po/w (SILICOS-IT) : 2.03
Consensus Log Po/w : 1.84

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.77
Solubility : 0.355 mg/ml ; 0.00171 mol/l
Class : Soluble
Log S (Ali) : -2.26
Solubility : 1.15 mg/ml ; 0.00553 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.14
Solubility : 0.15 mg/ml ; 0.000724 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.72

Safety of [ 942947-94-6 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 942947-94-6 ]

* 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 [ 942947-94-6 ]
  • Downstream synthetic route of [ 942947-94-6 ]

[ 942947-94-6 ] Synthesis Path-Upstream   1~3

  • 1
  • [ 942947-94-6 ]
  • [ 73183-34-3 ]
  • [ 19798-80-2 ]
  • [ 944401-60-9 ]
Reference: [1] Patent: WO2007/84786, 2007, A1, . Location in patent: Page/Page column 96-97
[2] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 10, p. 774 - 779
[3] Patent: WO2012/109423, 2012, A1, . Location in patent: Page/Page column 22
  • 2
  • [ 19798-80-2 ]
  • [ 942947-94-6 ]
YieldReaction ConditionsOperation in experiment
99% With N-Bromosuccinimide In acetonitrile for 14 h; To a stirred solution of 4-chloropyridin-2-amine (8 g, 62.2 mmol) inacetonitrile (600 mL) at rt was added NBS (11.08 g, 62.2 mmol) in portions andthe reaction was stirred for 14 h. The reaction mixture was concentrated under reduced pressure. The residue was reconstituted in ethyl acetate and water. The organics were extracted with ethyl acetate (3X50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), and dried over sodium sulphate. The organics were concentrated under reduced pressure to afford 5-bromo-4-chloropyridin-2-amine as yellow solid (13 g, 99 percent yield) that was used without further purification in the next step. LCMS (ESI) mle 207.0 [(M+H), calcd for C5H5BrC1N2 206.9]; LC/MS retention time (method B): tR = 0.8 mm; ‘H NMR (400 MHz, CDC13) ö 8.17 (s, 1H), 6.63 (s, 1H), 4.59 (s, 2H).
99% With N-Bromosuccinimide In acetonitrile at 20℃; for 14 h; To a stirred solution of 4-chloropyridin-2-amine (8 g, 62.2 mmol) in acetonitrile (600 mL) at rt was added A^-bromosuccinimide (11.08 g, 62.2 mmol) in portions and the reaction was stirred for 14 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL) and dried over sodium sulfate. The organics were concentrated under reduced pressure to afford 5-bromo-4-chloropyridin-2-amine as yellow solid (13 g, 99percent) that was used as is without further purification.
99% With N-Bromosuccinimide In acetonitrile at 20℃; A solution of 4-chloropyridin-2-amine (10 g, 78 mmol) in acetonitrile (400 mL) was treated dropwise with a solution of N-bromosuccinimide (14.09 g, 79 mmol) in acetonitrile (200 mL) . The mixture was stirred at ambient temperature for 16 hours and concentrated in vacuo. The crude product was purified by chromatography (silica gel, 3: 2 hexane /ethyl acetate) to afford the title compound (16 g, 77 mmol, 99percent yield) .
88% With N-Bromosuccinimide; acetic acid In tetrahydrofuran at 0 - 10℃; for 3.5 h; Inert atmosphere To a 1 L 3 necked round bottomed flask equipped with a magnetic stirrer, cold bath, and N2 inlet was added 4-chloropyridin-2-amine (20 g, 156 mmol), tetrahydrofuran (100 mL), and acetic acid (13.36 mL, 233 mmol). The clear, colorless solution was cooled to 0 °C. A solution of N- bromosuccinimide (27.6 g, 148 mmol) in tetrahydrofuran (300 mL) was added via addition funnel over 1.5 hours maintaining the temperature between 0-10 °C. After 2 hours, H20 (200 mL), 50percent aqueous NaOH (27 g) and toluene (200 mL) were added. The layers were warmed to room temperature, separated and the aqueous layer was extracted with toluene (200 mL). The combined organic layers were washed with sodium thiosulfate (10 g) dissolved in 8percent aqueous NaHC03 (200 mL) then with 25percent aqueous NaCl (200 mL). The organic layer was concentrated to dryness and chased with toluene (100 mL). The crude beige solid (45.5 g) was precipiated from toluene (50 mL) and heptane (100 mL), collected by vacuum filtration, washed with heptane, and dried in a vacuum oven at 45 °C to afford 28.4 g (88percent) of the title compound. HPLC: 97.4 peak area purity; FontWeight="Bold" FontSize="10" H NMR (400 MHz, DMSO-ds) δ 8.08 (s, 1H), 6.66 (s, 1H), 6.44 (s, 2H). MS (CI, NH3): 228, 226, 224, 211, 209, 207.
83% With N-Bromosuccinimide In acetonitrile at 20℃; for 3 h; Inert atmosphere N-Bromosuccinimide (10.9 g, 61.3 mmol) was added to a solution of 4-chloro-2-aminopyridine (7.50 g, 58.3 mmol) in acetonitrile (130 mL) at RT under nitrogen atmosphere. The yellow solution was stirred for 3 hr. The solvent was evaporated under reduced pressure and the residue purified by chromatography on silica gel (cyclohexane/ethyl acetate) to give the title compound as a light yellow solid (10.0 g, 83percent). 1H-NMR (500 MHz, CDCl3) ppm = 8.16 (s, 1 H), 6.62 (s, 1 H), 4.57 (bs, 2 H). HRMS m/z (ESI+) [M+Hf C5H5BrClN2, calc 208.9297, found 208.9297, Rt = 2.96 min (HPLC method B).
81% With bromine In acetonitrile at 0 - 20℃; To a solution of 4-chloropyridin-2-amine (5.0 g, 39 mmol) in MeCN (200 mL) at 0 °C was added B (2.2 mL, 43 mmol) in portions over a period of 30 min. The reaction was warmed to rt and stirred overnight. The solid was filtered, washed with hexane (3x), and dried to afford Intermediate 12A (9.1 g, 81percent) as an off-white solid. LC-MS (ESI) m/z: 206.9/208.9 [M+H]+; 'H NMR (400MHZ, DMSO-d6) δ 8.30 (s, 1H), 7.02 (s, 1H).
80% With N-Bromosuccinimide In acetonitrile at 20℃; for 16 h; To a solution of 2-amino-4-chloropyridine (0.50 g, 3.9 mmol) in acetonitrile (20 ml) was added dropwise a solution of N-bromosuccinimide (0.730 g, 4.1 mmol) in acetonitrile (10 ml). The reaction mixture was stirred at room temperature for 16 h then concentrated in vacuo. The crude product was purified by chromatography on silica gel (hexane/ethyl acetate 6:4) to give the title compound as a white solid (0.65 g, 80percent); 1H-NMR (250 MHz, CDCl3) 6.63 (s, 1H) and 8.16 (s, 1H) (3-H, 6-H); LC-MS (ESI, m/z) Rt=4.8 min-206, 209 [(M+H+), BrCl isotopic pattern, 100percent];
60% With N-Bromosuccinimide In N,N-dimethyl-formamide at -20 - 20℃; for 16 h; Inert atmosphere General procedure: To a - 20°C solution of 2-aminopyridineor 2-amino-4-chloropyridine(1 equiv) in DMF was added N-bromosuccinimide(1.1 or 2.2 equiv.) in two portions. The reaction mixture was stirred for 16 hat room temperature and was then poured withstirring into a 1M solution of NaOH (50 mL). The phases were separated and theaqueous layer was extracted with EtOAc. The combined organic phases were washedwith water (2 x 50 mL) and brine (50 mL), dried over MgSO4,filtered and concentrated underreduced pressure. The residue was obtained as pure compound withoutfurther purification or purified bychromatography on silica gel using Petroleumether/EtOAc as eluent.
60.8% With N-Bromosuccinimide In acetonitrile at 20℃; for 24 h; 5.2.2.31
7-Bromo-8-chloro-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (31)
To a solution of 2-amino-4-chloropyridine (1.28 g, 10.0 mmol) in anhydrous CH3CN (40 mL) was added portionwise N-bromosuccinimide (1.96 g, 11.0 mmol).
The reaction mixture was stirred at room temperature for 24 h then poured into 100 mL ice-water and extracted with ethyl acetate.
The combined extracts were washed with 1 M NaOH and brine, dried and evaporated.
The residue was purified by column chromatography on silica gel to give 5-bromo-4-dichloropyridin-2-amine (1.53 g, 60.8percent).
Next steps followed the procedure of 30 and gave the title compound as white solid (63 mg, 12.5percent over 3 steps). IR (KBr) ν 3108, 3033, 1703, 1587, 1398, 1367 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 8.30 (1H, s, H-6), 11.82 (1H, s, NH-1), 12.59 (1H, s, NH-4); 13C NMR (100 MHz, DMSO-d6) δ 114.00, 121.88, 127.18, 139.80, 143.23, 155.49, 155.61; HRMS-EI C7H3BrClN3O2 calcd [M+Na]+ 297.8995, found 297.8993.
53% With dihydrogen peroxide; 1-butylpyridinium bromide; toluene-4-sulfonic acid In 1,2-dimethoxyethane at 80℃; for 24 h; Schlenk technique; Inert atmosphere; Green chemistry General procedure: To a mixture of 2-aminopyridine (0.5 mmol, 1 equiv), p-TSA (0.4 mmol,0.8 equiv), 1-butylpyridinium bromide (1.5 mmol, 3 equiv) in a 50 mL Schlenk tube were added 1,2-dimethoxyethane (2 mL) under air. Then H2O2 (1.2 mmol, 2.4 equiv) was added. The mixture was stirred at 80°C for 24 h. And then the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the products.
38%
Stage #1: With N-Bromosuccinimide In chloroform for 2 h;
Stage #2: With sodium hydroxide In dichloromethane; chloroform; water
[0254] To a solution of 4-chloro-2-pyridylamine (6.0 g, 46.7 mmol) in chloroform(180 rαL) was added N-bromosuccinimide (8.3 g, 46.7 mmol). The solution was stirred in the dark for 2 hours, at which time it was added to CH2Cl2 (800 mL) and IN NaOH (10O mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat) (10O mL), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (25-35percent EtOAc/hexanes) yielding 3.63 g (38percent) of 5-bromo-4-chloro-2-pyridylamine. LCMS (m/z): 206.9/208.9 (MH+). 1H NMR (CDCI3): δ 8.18 (s, IH), 6.62 (s, IH), 4.52 (bs, 2H).
38%
Stage #1: With N-Bromosuccinimide In chloroform for 2 h; Darkness
Stage #2: With sodium hydroxide In dichloromethane; chloroform
Synthesis of 5-bromo-4-chloro-2-pyridylamine[0098] To a solution of 4-chloro-2-pyridylamine (6.0 g, 46.7 mmol) in chloroform(180 mL) was added N-bromosuccinimide (8.3 g, 46.7 mmol). The solution was stirred in the dark for 2 hours, at which time it was added to CH2C12 (800 mL) and IN NaOH(100 mL). Upon mixing, the layers were separated and the organic layer was washed withNaCl(Sat.) (100 mL), dried over Na2S04, filtered and concentrated. The crude material was purified by Si02 chromatography (25-35percent EtOAc/hexanes) yielding 3.63 g (38percent) of 5- bromo-4-chloro-2-pyridylamine. LCMS (m/z): 206.9/208.9 (MH ). XH NMR (CDCI3): δ 8.18 (s, 1H), 6.62 (s, 1H), 4.52 (bs, 2H).

Reference: [1] Patent: WO2015/38112, 2015, A1, . Location in patent: Page/Page column 92; 93
[2] Patent: JP2015/528018, 2015, A, . Location in patent: Paragraph 0207
[3] Patent: WO2018/68283, 2018, A1, . Location in patent: Paragraph 00263
[4] Patent: WO2015/157360, 2015, A1, . Location in patent: Page/Page column 39-40
[5] Patent: WO2014/63778, 2014, A1, . Location in patent: Page/Page column 22; 23
[6] Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 1078 - 1101
[7] Patent: WO2015/2915, 2015, A1, . Location in patent: Page/Page column 108
[8] Patent: US2009/247507, 2009, A1, . Location in patent: Page/Page column 8
[9] Journal of Medicinal Chemistry, 2010, vol. 53, # 14, p. 5213 - 5228
[10] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 114 - 120
[11] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 19 - 32
[12] Tetrahedron Letters, 2014, vol. 55, # 36, p. 5058 - 5061
[13] Patent: WO2007/84786, 2007, A1, . Location in patent: Page/Page column 96
[14] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 10, p. 774 - 779
[15] Patent: WO2012/109423, 2012, A1, . Location in patent: Page/Page column 21-22
[16] Patent: US2013/237555, 2013, A1, . Location in patent: Paragraph 0205
[17] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 507 - 512
[18] Patent: WO2015/116060, 2015, A1, . Location in patent: Page/Page column 102
[19] Patent: WO2016/124553, 2016, A1, . Location in patent: Page/Page column 71-73
[20] Patent: WO2018/11138, 2018, A1, . Location in patent: Page/Page column 69-70; 71
  • 3
  • [ 942947-94-6 ]
  • [ 942947-95-7 ]
Reference: [1] Patent: US2009/247507, 2009, A1, . Location in patent: Page/Page column 8
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 14, p. 5213 - 5228
[3] European Journal of Medicinal Chemistry, 2016, vol. 117, p. 19 - 32
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