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Product Details of [ 4214-76-0 ]

CAS No. :4214-76-0 MDL No. :MFCD00006325
Formula : C5H5N3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :UGSBCCAHDVCHGI-UHFFFAOYSA-N
M.W : 139.11 Pubchem ID :77888
Synonyms :

Calculated chemistry of [ 4214-76-0 ]

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 37.46
TPSA : 84.73 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.69 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.62
Log Po/w (XLOGP3) : 0.65
Log Po/w (WLOGP) : 0.58
Log Po/w (MLOGP) : -0.94
Log Po/w (SILICOS-IT) : -1.44
Consensus Log Po/w : -0.11

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.49
Solubility : 4.5 mg/ml ; 0.0324 mol/l
Class : Very soluble
Log S (Ali) : -2.01
Solubility : 1.38 mg/ml ; 0.00988 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.02
Solubility : 13.3 mg/ml ; 0.0957 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 2.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.98

Safety of [ 4214-76-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302+H312+H332-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 4214-76-0 ]

* 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 [ 4214-76-0 ]
  • Downstream synthetic route of [ 4214-76-0 ]

[ 4214-76-0 ] Synthesis Path-Upstream   1~44

  • 1
  • [ 4214-76-0 ]
  • [ 13534-97-9 ]
Reference: [1] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
  • 2
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  • [ 7252-83-7 ]
  • [ 235106-53-3 ]
Reference: [1] Patent: US2004/77605, 2004, A1,
  • 3
  • [ 4214-76-0 ]
  • [ 235106-53-3 ]
Reference: [1] Yakugaku Zasshi, 1949, vol. 69, p. 496[2] Chem.Abstr., 1950, p. 4474
  • 4
  • [ 4214-76-0 ]
  • [ 6628-77-9 ]
Reference: [1] Patent: CN105523995, 2016, A,
  • 5
  • [ 4214-76-0 ]
  • [ 15069-92-8 ]
Reference: [1] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
  • 6
  • [ 4214-76-0 ]
  • [ 24242-20-4 ]
Reference: [1] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
  • 7
  • [ 4214-76-0 ]
  • [ 30766-11-1 ]
Reference: [1] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
  • 8
  • [ 4214-76-0 ]
  • [ 32046-43-8 ]
Reference: [1] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
  • 9
  • [ 4214-76-0 ]
  • [ 100960-07-4 ]
Reference: [1] Synthesis, 2005, # 15, p. 2503 - 2506
  • 10
  • [ 4214-76-0 ]
  • [ 17965-80-9 ]
Reference: [1] Patent: US2012/178748, 2012, A1,
  • 11
  • [ 4214-76-0 ]
  • [ 456-24-6 ]
  • [ 5418-51-9 ]
Reference: [1] Canadian Journal of Chemistry, 1953, vol. 31, p. 1020,1024
  • 12
  • [ 4214-76-0 ]
  • [ 5418-51-9 ]
YieldReaction ConditionsOperation in experiment
88.02% With hydrogenchloride; sodium nitrite In water at 0 - 6℃; for 0.666667 h; 2-Amino-5-nitropyridine 13.9g (0.1mol) was dissolved in 55.6g of 15percent by mass concentration of diluted hydrochloric acid was added dropwise below 0 20percent of NaNO2An aqueous solution of 44.85g, after the addition was complete, 6 reaction was kept 40min, the reaction was concentrated under reduced pressure, cooling the precipitated pale yellow solid was washed with ice water and dried to give 2-hydroxy-5-nitropyridine 12.61g, HPLC purity 97.69percent, the yield was 88.02percent.
Reference: [1] Patent: CN105523995, 2016, A, . Location in patent: Paragraph 0026; 0047; 0048
[2] Chemistry of Heterocyclic Compounds, 2002, vol. 38, # 7, p. 805 - 809
[3] Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 10, p. 3597 - 3602
[4] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1914, vol. 46, p. 1240[5] Chem. Zentralbl., 1915, vol. 86, # I, p. 1066
[6] Chemische Berichte, 1928, vol. 61, p. 1230[7] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 975
[8] Patent: US4149872, 1979, A,
[9] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 534
  • 13
  • [ 4214-76-0 ]
  • [ 456-24-6 ]
  • [ 5418-51-9 ]
Reference: [1] Canadian Journal of Chemistry, 1953, vol. 31, p. 1020,1024
  • 14
  • [ 4214-76-0 ]
  • [ 4487-59-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 5046 - 5050
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
[3] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
  • 15
  • [ 4214-76-0 ]
  • [ 29082-92-6 ]
Reference: [1] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
  • 16
  • [ 504-29-0 ]
  • [ 4214-76-0 ]
  • [ 4214-75-9 ]
Reference: [1] Chemistry of Heterocyclic Compounds, 2002, vol. 38, # 7, p. 805 - 809
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 527
[3] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1914, vol. 46, p. 1240[4] Chem. Zentralbl., 1915, vol. 86, # I, p. 1066
[5] Chemische Berichte, 1952, vol. 85, p. 1012,1019
[6] Journal of the American Chemical Society, 1955, vol. 77, p. 3154
[7] Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 10, p. 3597 - 3602
[8] Journal of Molecular Structure, 2013, vol. 1043, p. 15 - 27
[9] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 528
[10] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 14, p. 528
  • 17
  • [ 2530-26-9 ]
  • [ 4214-76-0 ]
  • [ 4214-75-9 ]
  • [ 1681-37-4 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 26, p. 4393 - 4395
  • 18
  • [ 2530-26-9 ]
  • [ 4214-76-0 ]
  • [ 4214-75-9 ]
  • [ 3346-63-2 ]
  • [ 1681-37-4 ]
Reference: [1] Liebigs Annalen der Chemie, 1991, # 9, p. 875 - 878
[2] Liebigs Annalen der Chemie, 1991, # 9, p. 875 - 878
  • 19
  • [ 26482-54-2 ]
  • [ 4214-76-0 ]
  • [ 4214-75-9 ]
Reference: [1] Acta Chimica Hungarica, 1983, vol. 113, # 2, p. 159 - 164
[2] Australian Journal of Chemistry, 1982, vol. 35, # 10, p. 2035 - 2040
  • 20
  • [ 7664-93-9 ]
  • [ 4214-76-0 ]
  • [ 4214-75-9 ]
Reference: [1] Chemische Berichte, 1928, vol. 61, p. 1812
  • 21
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  • [ 7664-93-9 ]
  • [ 142-08-5 ]
  • [ 4214-76-0 ]
  • [ 4214-75-9 ]
Reference: [1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 476[2] Chem. Zentralbl., 1923, vol. 94, # III, p. 1020
[3] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1915, vol. 47, p. 1290[4] Chem. Zentralbl., 1916, vol. 87, # II, p. 15
[5] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1928, vol. 60, p. 345[6] Chemische Berichte, 1927, vol. 60, p. 2437
  • 22
  • [ 4214-76-0 ]
  • [ 100367-55-3 ]
Reference: [1] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
  • 23
  • [ 4214-76-0 ]
  • [ 22353-38-4 ]
Reference: [1] Journal of the Chemical Society, 1951, p. 2590,2593
  • 24
  • [ 4214-76-0 ]
  • [ 22353-35-1 ]
YieldReaction ConditionsOperation in experiment
64% With N-chloro-succinimide In toluene at 80℃; for 1 h; Inert atmosphere Under an Ar atmosphere, N-chlorosuccinimide (0.53 g,3.95 mmol) was added to a solution of compound 1 (0.50 g,3.59 mmol) in anhydrous toluene (7.18 mL). The resulting reactionmixture was stirred at 80 C for 1 h. The reaction mixture wascooled to room temperature and 15 mL of H2O was added to thismixture. It was then extracted with EtOAc, washed with sat.NaHCO3 solution, brine, concentrated under vacuum, and purifiedby column chromatography (KANTO 60 N, Hex/EtOAc = 80/20 to60/40) to give a yellow solid 2a (0.40 g, 2.30 mmol, 64percent). 1HNMR (500 MHz, DMSO-d6) d (ppm) 8.84 (d, J = 2.5 Hz, 1H), 8.35(d, J = 2.5 Hz, 1H), 7.91 (brs, 1H). 13C NMR (125 MHz, DMSO-d6) d(ppm) 112.58, 132.14, 135.01, 145.25, 159.75. HRMS (ESI-TOF, m/z) Calcd. for C5H4ClN3O2Na [M+Na]+: 195.9884, 197.9856, Found:195.9878, 197.9847.
Reference: [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3853 - 3860
[2] Journal of the Chemical Society, 1951, p. 2590,2593
[3] Zhurnal Obshchei Khimii, 1940, vol. 10, p. 1827,1836[4] Chem. Zentralbl., 1940, vol. 111, # II, p. 614
[5] Journal of the Chemical Society, 1951, p. 2590,2593
[6] Zhurnal Obshchei Khimii, 1940, vol. 10, p. 1827,1836[7] Chem. Zentralbl., 1940, vol. 111, # II, p. 614
[8] Zhurnal Obshchei Khimii, 1940, vol. 10, p. 1827,1836[9] Chem. Zentralbl., 1940, vol. 111, # II, p. 614
  • 25
  • [ 4214-76-0 ]
  • [ 15862-31-4 ]
YieldReaction ConditionsOperation in experiment
32%
Stage #1: at 20℃;
Stage #2: With sodium hydrogencarbonate In water; ethyl acetateSaturated solution
Step a:
3-Bromo-5-nitropyridin-2-amine
To a solution of 5-nitro-pyridin-2-ylamine (30 g, 0.22 mol) in acetic acid (200 mL) at 10° C. was added Br2 (38 g, 0.24 mol) dropwise.
After addition, the mixture was stirred at 20° C. for 30 min.
The solid was filtered and then dissolved in ethyl acetate (200 mL).
The mixture was basified to pH 8-9 with saturated aqueous NaHCO3.
The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL*3).
The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to afford 3-bromo-5-nitropyridin-2-amine (14.8 g, 32percent).
1H-NMR (CDCl3, 400 MHz) δ 8.94 (d, J=2.4 Hz, 1H), 8.50 (d, J=2.4 Hz, 1H), 5.67 (brs, 2H).
31% With N-Bromosuccinimide In toluene at 80℃; for 1 h; Inert atmosphere General procedure: Under an Ar atmosphere, N-chlorosuccinimide (0.53 g,3.95 mmol) was added to a solution of compound 1 (0.50 g,3.59 mmol) in anhydrous toluene (7.18 mL). The resulting reactionmixture was stirred at 80 C for 1 h. The reaction mixture wascooled to room temperature and 15 mL of H2O was added to thismixture. It was then extracted with EtOAc, washed with sat.NaHCO3 solution, brine, concentrated under vacuum, and purifiedby column chromatography (KANTO 60 N, Hex/EtOAc = 80/20 to60/40) to give a yellow solid 2a (0.40 g, 2.30 mmol, 64percent).
Reference: [1] Patent: US2009/253736, 2009, A1, . Location in patent: Page/Page column 25
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3853 - 3860
[3] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1920, vol. 50, p. 494[4] Chem. Zentralbl., 1923, vol. 94, # III, p. 1021
[5] Zhurnal Obshchei Khimii, 1940, vol. 10, p. 1827,1836[6] Chem. Zentralbl., 1940, vol. 111, # II, p. 614
  • 26
  • [ 4214-76-0 ]
  • [ 30651-24-2 ]
Reference: [1] Pharmazie, 1983, vol. 38, # 9, p. 591 - 596
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1951, vol. 288, p. 237,241
  • 27
  • [ 4214-76-0 ]
  • [ 2032-35-1 ]
  • [ 25045-82-3 ]
YieldReaction ConditionsOperation in experiment
77.6%
Stage #1: With hydrogenchloride In ethanol at 20℃; Reflux
Stage #2: at 20℃;
In a 250 mL single-necked flask, bromoacetaldehyde diethyl acetal (42.5 g, 215.7 mmol) was dissolved in 1 mol / L HCL(120 mL) and ethanol (20 mL), stirred at room temperature for 30 min, heated to reflux, stirred until the solution was clear, cooled to room temperature,Add NaHCO3 adjusted to near neutral,2-Amino-5-nitropyridine (15.0 g, 107.8 mmol) was added and reacted at room temperatureovernight. The reaction was completed, extracted with ethyl acetate (100mL × 3), the organic phase was collected and the solvent was evaporated to dryness under reduced pressure. The residue was passed through a silica gel column (PE:EA = 2: 1) to give 13.7 g of 6-nitroimidazo [1,2-a] pyridine yellow-brown crystals in a yield of 77.6percent.
Reference: [1] Patent: CN107129496, 2017, A, . Location in patent: Paragraph 0026-0028; 0014-0016; 0020-0022
  • 28
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  • [ 623-46-1 ]
  • [ 25045-82-3 ]
Reference: [1] Yakugaku Zasshi, 1949, vol. 69, p. 496[2] Chem.Abstr., 1950, p. 4474
  • 29
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  • [ 101083-92-5 ]
Reference: [1] Synthesis, 2005, # 15, p. 2503 - 2506
[2] Patent: WO2012/127506, 2012, A1,
[3] Organic Process Research and Development, 2015, vol. 19, # 9, p. 1282 - 1285
  • 30
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  • [ 2604-39-9 ]
  • [ 5418-51-9 ]
  • [ 27048-04-0 ]
Reference: [1] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
[2] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
  • 31
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  • [ 3073-30-1 ]
Reference: [1] Journal of Molecular Structure, 2013, vol. 1043, p. 15 - 27
  • 32
  • [ 15367-00-7 ]
  • [ 7664-93-9 ]
  • [ 4214-76-0 ]
  • [ 3073-30-1 ]
Reference: [1] Zhurnal Russkago Fiziko-Khimicheskago Obshchestva, 1915, vol. 47, p. 1290[2] Chem. Zentralbl., 1916, vol. 87, # II, p. 15
  • 33
  • [ 2530-26-9 ]
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  • [ 4214-75-9 ]
  • [ 1681-37-4 ]
Reference: [1] Tetrahedron Letters, 2001, vol. 42, # 26, p. 4393 - 4395
  • 34
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  • [ 4214-76-0 ]
  • [ 4214-75-9 ]
  • [ 3346-63-2 ]
  • [ 1681-37-4 ]
Reference: [1] Liebigs Annalen der Chemie, 1991, # 9, p. 875 - 878
[2] Liebigs Annalen der Chemie, 1991, # 9, p. 875 - 878
  • 35
  • [ 4214-76-0 ]
  • [ 21717-96-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 23, p. 9948 - 9956
  • 36
  • [ 4548-45-2 ]
  • [ 4214-76-0 ]
  • [ 2604-39-9 ]
  • [ 5418-51-9 ]
  • [ 27048-04-0 ]
Reference: [1] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
[2] Journal of Organic Chemistry, 1985, vol. 50, # 4, p. 484 - 487
  • 37
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  • [ 31040-15-0 ]
Reference: [1] Tetrahedron, 2015, vol. 71, # 3, p. 407 - 418
  • 38
  • [ 4214-76-0 ]
  • [ 70-23-5 ]
  • [ 38923-08-9 ]
YieldReaction ConditionsOperation in experiment
90% for 16 h; Reflux 5-Nitropyridine-2-amine (1.5 g, 10.80 mmol) and ethyl 3-bromo-2-oxopropanoate (1.6 mL, 13.00 mmol) were dissolved in EtOH (15.0 mL), followed by refluxing for 16 hours. After completing the reaction, the reaction mixture was filtered to obtain a pale yellow solid. The filtrate was extracted with EtOAc, washed with sat. NaHC03 aqueous solution and brine, dried over anhydrous Na2S04, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex : EtOAc = 2 : 1) to obtain ethyl 6-nitroimidazo[l,2-a]pyridine-2-carboxylate (2.3 g, 90percent) as a yellow solid. LC/MS ESI (+): 236 (M+l) -NMR (300MHz, CDC13): δ 9.30 (s, 1H), 8.38 (s, 1H), 8.06 (d, 1H, J=10.0Hz), 7.84 (d, 1H, J=10.4Hz), 4.50 (q, 2H, J=7.2Hz), 1.46 (t, 3H, J=7.2Hz)
89% at 85℃; for 22.75 h; Inert atmosphere 5-Nitropyridin-2-amine (19, 50 g, 359 mmol) was suspended in ethanol (700 ml, 99+percent)and bubbled through with argon. Next, 1.1 equivalents of ethyl bromopyruvate (18, 79 ml,503 mmol) were added and stirred for 45 mm. Then, the reaction mixture was warmed at 85°C for 6 hr, another 0.3 equivalents ethyl bromopyruvate (79 ml, 503 mmol) were added andwarmed to 85 °Cfor 16 hr.Afterwards, the reaction mixture was concentrated, water (300 ml) was added and theresulting suspension was filtered. The solid residue was washed with Et20 (600 ml) and dried to yield ethyl 6-nitroimidazo[1,2-a]pyridine-2-carboxylate (20) (75 g, 319 mmol, 89 percent yield) as a sand coloured solid. UPLC-MS confirmed that the desired product was obtained.
34% for 18 h; Heating / reflux A solution of 5-nitropyridin-2-amine (2.0 g, 14.38 mmol) and ethyl bromopyruvate (3.36 g, 17.25 mmol) in ethanol (EtOH) (20 mL) was stirred under reflux for 18 h. The reaction mixture was cooled to room temperature. The precipitated solids were collected by filtration and then suspended in ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 solution, dried (Na2SO4) and concentrated under reduced pressure to afford ethyl 6-nitroimidazo[l,2-a]pyridine-2-carboxylate as a brown solid (1.137 g, yield: 34percent ). 1H NMR (400 MHz, CDCl3) δ: 9.320 (IH, s), 8.402 (IH, s), 8.065 (IH, dd, J= 10.0 Hz), 7.905 (IH, d, J= 10.0 Hz), 4.479-4.533 (2H, q, J= 7.2 Hz), 1.469 (3H, t, J= 7.2 Hz).
Reference: [1] Patent: WO2014/196793, 2014, A1, . Location in patent: Page/Page column 64; 65
[2] Molecular Pharmaceutics, 2015, vol. 12, # 6, p. 1813 - 1835
[3] Patent: WO2015/185142, 2015, A1, . Location in patent: Page/Page column 20
[4] Patent: WO2008/100423, 2008, A1, . Location in patent: Page/Page column 111
[5] Patent: EP1657242, 2006, A1, . Location in patent: Page/Page column 27
[6] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 16, p. 4589 - 4593
[7] Patent: WO2010/62171, 2010, A2, . Location in patent: Page/Page column 152
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  • [ 158980-21-3 ]
Reference: [1] Molecular Pharmaceutics, 2015, vol. 12, # 6, p. 1813 - 1835
[2] Patent: WO2015/185142, 2015, A1,
[3] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 5, p. 1101 - 1111
  • 40
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  • [ 24424-99-5 ]
  • [ 161117-88-0 ]
YieldReaction ConditionsOperation in experiment
80% With dmap In dichloromethane at 20℃; Inert atmosphere 5-Nitropyridin-2-amine (1 eq), Boc2O (1.2 eq), DMAP (0.2 eq) was added to aflask under nitrogen atmosphere. Dichloromethane was added at room temperature and the mixture was stirred overnight. Ethyl acetate was added to the crude, the precipitated was filtered and washed with ethyl acetate to obtain the desired tert-butyl (5-n itropyrid in-2-yl)carbam ate.HPLC-MS (method A): Rt= 2.88 mm, [M+H]+ m/z: 240.Yield: 80percent.
70%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran for 0.25 h;
Stage #2: at 20℃; for 21 h;
A. Synthesis of (tert-butoxy)-N-(5-nitro(2-pyridyl))carboxamide (0132) To a solution of 2-amino-5-nitropyridine (0.555 g, 4 mmol) in THF (10 mL) was added 1 M NaHMDS in THF (8 mL, 8 mmol). The resulting dark red suspension was stirred for 15 min, followed by addition of a solution of Boc anhydride (0.87 mL, 3.8 mmol) in THF (5 mL). The reaction mixture was stirred at room temp for 21 hr, dilute with EtOAc, washed with 1 N HCl and brine, dried and concentrated in vacuo to give (tert-butoxy)-N-(5-nitro(2-pyridyl))carboxamide (0.63 g, 70percent). ES-MS (M+H-tBu)+ = 184.
63.9%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5 h;
Stage #2: at 20℃; for 3 h;
Synthesis of compound 223.2. To a solution of NaH (1.15g, 28.75mmol, l .Oeq.) in THF (20ml) was added 223.1 (4.0g, 28.75mmol, l .Oeq) at 0 °C. the reaction mixture was stirred at room temperature for 30 minutes. Boc anhydride (6.26g, 28.75mmol, l .Oeq.) in THF(lOmL) was added to the reaction mixture at room temperature and reaction was allowed to stir for 3 hours. After completion of the reaction, mixture was poured in water and solid product was filtered, dried to get pure 223.2 (4.4 g, 63.9 percent). MS(ES): m/z 239.23 [M+H]+.
62%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.333333 h;
Stage #2: at 20℃;
To 0.652 g (4.69 mmol) of 2-amino-5-nitropyridine in THF (5 mL) was added 3.5 mL of NaHMDS (2M solution in THF) at 0° C. After 20 min a solution of 1.085 g (4.97 mmol) of di-tert-butyl dicarbonate in THF (6 mL) was added and the mixture was slowly warmed to room temperature overnight. Water was added, and the mixture was extracted with EtOAc (.x.4). The organic layer was washed with brine, dried (Na2SO4), and concentrated. Chromatography on, silica with hexanes-EtOAc (7:3), gave 0.695 g (62percent yield) of tert-butyl-5-nitropyridin-2-ylcarbamate as an orange powder: 1H NMR (CDCl3) 89.19 (dd, J=2.8, 0.5 Hz, 1H), 8.93 (br s, 1H), 8.46 (ddd, J=9.4, 2.8, 0.5 Hz, 1H), 8.20 (dd, J=9.5, 0.5 Hz, 1H), 1.59 (s, 9H); LCMS (APCI-) m/z: 238 (MH+, 100percent).
62%
Stage #1: With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 0.333333 h;
Stage #2: at 20℃;
Example 37Synthesis of N5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2,5-pyridinediamineThe compound was synthesized according to Method A.To 0.652 g (4.69 mmol) of 2-amino-5-nitropyridine in THF (5 mL) was added 3.5 mL of NaHMDS (2M solution in THF) at 0° C. After 20 min a solution of 1.085 g (4.97 mmol) of di-tert-butyl dicarbonate in THF (6 mL) was added and the mixture was slowly warmed to room temperature overnight. Water was added, and the mixture was extracted with EtOAc (.x.4). The organic layer was washed with brine, dried (Na2SO4), and concentrated. Chromatography on, silica with hexanes-EtOAc (7:3), gave 0.695 g (62percent yield) of tert-butyl-5-nitropyridin-2-ylcarbamate as an orange powder: 1H NMR (CDCl3) δ 9.19 (dd, J=2.8, 0.5 Hz, 1H), 8.93 (br s, 1H), 8.46 (ddd, J=9.4, 2.8, 0.5 Hz, 1H), 8.20 (dd, J=9.5, 0.5 Hz, 1H), 1.59 (s, 9H); LCMS (APCI-) m/z: 238 (MH+, 100percent).To 0.314 g (1.31 mmol) of the above nitro compound in THF-MeOH (16 mL, 1:1) was added 0.460 g of 10percent Pd/C and the mixture was stirred under hydrogen (40 in/Hg) for 4 hrs. The reaction mixture was filtered through celite, washed with MeOH and concentrated to give 0.277 g (99percent yield) of tert-butyl 5-aminopyridin-2-yl-carbamate as a white powder: 1H NMR (DMSO-d6) δ9.00 (br s, 1H), 7.62 (dd, J=2.7, 0.4 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 6.94 (dd, J=8.7, 2.8 Hz, 1H), 4.92 (s, 2H), 1.44 (s, 9H).To 0.277 g (1.33 mmol) of the above amino compound in THF (3 mL) was added 0.61 mL of n-butyllithium (2.5 M solution in hexanes) and the mixture was stirred for 10 min. A solution of 0.176 g (0.44 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (5 mL) was added and the resulting mixture was stirred for 1 hr at room temperature. The reaction mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed with water and aq. NH3, dried, and concentrated. Chromatography on silica, eluting with hexanes-EtOAc (7:3), then with CH2Cl2-EtOAc (3:1), gave 0.033 g (13percent yield) of tert-butyl 5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-2-pyridinylcarbamate: 1H NMR (DMSO-d6) δ10.02 (s, 1H), 9.66 (s, 1H), 8.54 (s, 1H), 8.17-7.80 (m, 4H), 7.39 (d, J=8.7 Hz, 1H), 6.97-6.93 (m, 1H), 3.98 (s, 3H), 3.82 (s, 4H), 3.74-3.72 (m, 4H), 1.48 (s, 9H).To 0.033 g (0.06 mmol) of the above carbamate in CH2Cl2 (3 mL) was added 0.1 mL (1.30 mmol) of trifluoroacetic acid, and the mixture was stirred for 5 hrs. The reaction mixture was diluted with CH2Cl2 and aq. NH4OH, and the organic layer was washed with brine, dried (Na2SO4), and concentrated. The residue was recrystallized from EtOH/CH2Cl2 to give 0.0133 g (49percent yield) of N5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2,5-pyridinediamine, as a brown powder: mp 267-270° C.; 1H NMR (DMSO-d6) δ9.67-9.49 (m, 1H), 8.18-7.27 (m, 5H), 6.96 (d, J=7.6 Hz, 1H), 6.48 (d, J=8.4 Hz, 1H), 5.87-5.75 (m, 2H), 3.98 (s, 3H), 3.81 (s, 4H), 3.71 (s, 4H); HRMS (ESI) M+H+ Calcd. for C21H22F2N9O2: m/z 470.1859. Found: m/z 470.1867.
94.6 g With dmap; triethylamine In dichloromethane at 20℃; for 18 h; A 3-L round-bottomed flask was charged with 5-nitro-2-pyridinamine (75.0 g, 539 mmol, Alfa Aesar, Ward Hill, MA) and 500 mL of DCM. To this was added triethylamine (82 g, 809 mmol), di-tert-butyl dicarbonate (129 g, 593 mmol, Sigma-Aldrich, St. Louis, MO), and DMAP (32.9 g, 270 mmol, Sigma- Aldrich, St. Louis, MO). After stirring at rt for 18 h, the mixture was diluted with water and the solid was collected by filtration. The yellow solid was washed with MeOH to give tert-butyl (5-nitro-2-pyridinyl)carbamate (94.6 g) as a slightly-yellow solid.
94.6 g With dmap; triethylamine In dichloromethane at 20℃; for 18 h; A 3-L round-bottomed flask was charged with 5-nitro-2-pyridinamine (75.0 g, 539 mmol, Alfa Aesar, Ward Hill, MA) and 500 mL of DCM. To this was added triethylamine (82 g, 810 mmol), di-tert-butyl dicarbonate (129 g, 593 mmol, Sigma-Aldrich, St. Louis, MO), and N,N-dimethylpyridin-4-amine (32.9 g, 270 mmol, Sigma-Aldrich, St. Louis, MO). After stirring at rt for 18 h, the mixture was diluted with water and the solid was collected by filtration. The yellow solid was washed with MeOH to give tert-butyl (5-nitro-2- pyridinyl)carbamate (94.6 g) as a light yellow solid.

Reference: [1] Patent: WO2016/120808, 2016, A1, . Location in patent: Page/Page column 103; 104
[2] Patent: EP2314593, 2016, B1, . Location in patent: Paragraph 0132
[3] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 001167; 001168
[4] Patent: US2010/249099, 2010, A1, . Location in patent: Page/Page column 96-97
[5] Patent: US2011/9405, 2011, A1, . Location in patent: Page/Page column 54
[6] Tetrahedron Letters, 1994, vol. 35, # 48, p. 9003 - 9006
[7] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 8, p. 2270 - 2273
[8] Patent: WO2011/19538, 2011, A1, . Location in patent: Page/Page column 111-112
[9] Patent: EP2518071, 2012, A1, . Location in patent: Page/Page column 41
[10] Patent: WO2012/146667, 2012, A1, . Location in patent: Page/Page column 95
[11] Patent: WO2013/123444, 2013, A1, . Location in patent: Page/Page column 59; 60
[12] Patent: WO2014/35872, 2014, A1, . Location in patent: Page/Page column 68
[13] Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 3094 - 3116
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YieldReaction ConditionsOperation in experiment
94%
Stage #1: at 80℃;
5-nitropyridin-2-amine (14 g, 10 mmol), KI (16.6 g, 10 mmol), KIO3 (10.7 g, 5 mmol) were mixed in dilute sulfuric acid (2N, 200 ml). The mixture was stirred at 80°C overnight, after which NaOH solution (5N, 80 ml) was added to adjust the pH to about 10. The resulting solids were collected by filtration, washed with water and ethanol successively, and then dried in vacuo to give the titled compound (25 g, 94percent yield). 1H NMR (300 MHz, DMSO-/) δ 6.80-8.40 (brs, 2H), 8.57 (d, J= 2.4 Hz, IH), 8.84 (d, J =2.4 Hz, IH).MS (ESY) m/z 264 (M-I)
92% With potassium iodate; sulfuric acid; potassium iodide In water at 100℃; for 2 h; Compound 1 (0.50 g, 3.59 mmol) was dissolved in 2 M H2SO4(7.18 mL). KIO3 (0.31 g, 1.44 mmol) was slowly added at room temperature.After heating at 100 C, a solution of KI in water (1 M,3.59 mL, 0.60 g, 3.59 mmol) was dropwise added to the reactionmixture. Heating at reflux was continued for 2 h, then the mixturewas cooled to room temperature. The mixture was adjusted to pH7.0 with the careful addition of a sat. NaHCO3 solution. It was thendiluted with EtOAc and solid sodium thiosulfate was added withvigorous stirring until the iodine coloration disappeared. A significantamount of a yellowish solid precipitated out of the solution,which was collected by filtration, washed with water and dried to give a yellow solid as a pure compound. On the other hand,the organic layer was washed with brine and evaporated to givea yellow solid as a pure compound. These combined yellow solidswere used in the next reaction without further purification. All ofthe solids totaled 0.88 g. 1H NMR (500 MHz, DMSO-d6) d (ppm)8.85 (d, J = 2.5 Hz, 1H), 8.58 (d, J = 2.5 Hz, 1H), 7.61 (brs, 1H). 13CNMR (125 MHz, DMSO-d6) d (ppm) 75.07, 134.74, 141.63, 145.75,162.25. HRMS (ESI-TOF, m/z) Calcd. for C5H4IN3O2Na [M+Na]+:287.9246, Found: 287.9226
89.4%
Stage #1: at 100℃;
Stage #2: With potassium iodide In water for 2.5 h; Heating
Stage #3: With sodium hydrogencarbonate In water at 20℃;
To a solution of compound 1 (50 g, 359.71 mmol) in H2S04 (2 M, 750 mL) potassium periodate (30.79 g, 143.88 mmol) was added portion-wise at room temperature. It was heated under reflux and aqueous potassium iodide was added drop-wise over 1 h and heating continued further for 1.5 h. Reaction mixture was cooled to room temperature and neutralized by solid sodium bicarbonate. The reaction mixture was diluted with water (200 mL) and dichloromethane (200 mL). To this solid sodium thiosulphate was added with stirring. A green colored solid that separated out was filtered and dried to get 3-iodo-5-nitro-pyridin-2- amine (85 g, 89.4 percent). 1HNMR (400MHz, DMSO-i/6): δ 7.15 (br s, 2H), 8.56 (d, J = 2.8 Hz, 1H), 8.84 (d, J= 2.8 Hz, 1H).
87% With potassium iodate; sulfuric acid; potassium iodide In water at 200℃; for 1.5 h; Prepared in two steps from 3-iodo-5-nitropyridin-2-amine:Step 1: To a 25 mL three-necked flask charged with 5-nitropyridin-2-amine (1 g, 7.1 mmol, 1 equiv), was added concentrated sulfuric acid (12 mL, 0.6 M) and potassium iodate (653 mg, 2.8 mmol, 0.4 equiv) portionwise, before subsequent heating to 200 °C. Potassium iodide (1.18 g, 7.1 mmol, 1 equiv) was then added dropwise as an aqueous solution (4 mL), and the reaction mixture was stirred at 200 °C for 1.5 h. Upon completion, the reaction mixture was allowed to cool to room temperature before the slow addition of saturated sodium bicarbonate solution (20 mL) and EtOAc (20 mL). The reaction mixture was separated and the organics were washed with an aqueous solution of saturatedNa2S2O3 (2 × 30 mL). The organics were then passed through a hydrophobic frit and concentrated under reduced pressure to give a yellow solid, 3-iodo-5-nitropyridin-2-amine, which was used without further purification (1.64 g, 87 percent).Step 2: To a 100 mL round-bottomed flask charged with 3-iodo-5-nitropyridin-2-amine (1.29 g, 4.86 mmol, 1 equiv) was added THF (40 mL, 0.13 M) and the reaction mixture was cooled to 0 °C. Sodium hydride (224 mg, 9.72 mmol, 2 equiv) was added portionwise and the reaction mixture wasstirred at 0 °C for 20 minutes. 4-Methylbenzenesulfonyl chloride (1.09 g, 4.86 mmol, 1 equiv) was added portion wise, and the reaction mixture was allowed to slowly warm to room temperature and was stirred for 18 h. Upon completion of the reaction, water (50 mL) and CH2Cl2 (50 mL) were added and the reaction mixture was separated and the organics washed with 1 M NaOH (2 × 50 mL), 1 MHCl (2 × 50 mL), and brine (2 × 50 mL). The organics were passed through a hydrophobic frit and concentrated under reduced pressure to give a crude residue, which was purified by flash chromatography (silica gel, 0–30percent EtOAc in petroleum ether) to afford the title compound as a yellow solid (1.43 g, 70percent).max (solid): 3581, 3268, 3064, 2919, 1571, 1444, 1320 cm-1.1H NMR (DMSO-d6, 500 MHz): δ 8.66 (d, J = 2.6 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 3.35 (bs, 1H), 2.32 (s, 3H).13C NMR (DMSO-d6, 126 MHz): δ 161.9, 145.0, 142.3, 140.9, 140.7, 134.7, 128.9, 127.4, 86.7, 21.4.HRMS: exact mass calculated for [M+H]+(C12H11IN3O4S) requires m/z 419.9509, found m/z 419.9510.Characterisation data is consistent with literature reported values.4

Reference: [1] Synthesis, 2005, # 15, p. 2503 - 2506
[2] Patent: WO2010/32, 2010, A1, . Location in patent: Page/Page column 78-79
[3] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3853 - 3860
[4] Patent: WO2012/127506, 2012, A1, . Location in patent: Page/Page column 56-57
[5] Organic Process Research and Development, 2015, vol. 19, # 9, p. 1282 - 1285
[6] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2005 - 2011
[7] Patent: WO2010/62171, 2010, A2, . Location in patent: Page/Page column 148
[8] Patent: WO2010/111483, 2010, A1, . Location in patent: Page/Page column 72
[9] Chemical Communications, 2016, vol. 52, # 56, p. 8703 - 8706
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Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 8, p. 2270 - 2273
[2] Patent: EP2518071, 2012, A1,
[3] Patent: WO2012/146667, 2012, A1,
[4] Patent: WO2013/123444, 2013, A1,
[5] Patent: WO2014/35872, 2014, A1,
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 3094 - 3116
[7] Patent: WO2015/131080, 2015, A1,
[8] Patent: EP2314593, 2016, B1,
  • 43
  • [ 4214-76-0 ]
  • [ 24424-99-5 ]
  • [ 220731-04-4 ]
Reference: [1] Patent: WO2016/120808, 2016, A1,
  • 44
  • [ 4214-76-0 ]
  • [ 896160-69-3 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3853 - 3860
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