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Chemical Structure| 220731-04-4
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Product Details of [ 220731-04-4 ]

CAS No. :220731-04-4 MDL No. :MFCD11182697
Formula : C10H15N3O2 Boiling Point : -
Linear Structure Formula :- InChI Key :NHVPESPHUUFULF-UHFFFAOYSA-N
M.W : 209.25 Pubchem ID :22064440
Synonyms :

Calculated chemistry of [ 220731-04-4 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.4
Num. rotatable bonds : 4
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 58.89
TPSA : 77.24 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) : -6.82 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.72
Log Po/w (XLOGP3) : 1.07
Log Po/w (WLOGP) : 1.83
Log Po/w (MLOGP) : 0.68
Log Po/w (SILICOS-IT) : 0.43
Consensus Log Po/w : 1.15

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.84
Solubility : 3.0 mg/ml ; 0.0143 mol/l
Class : Very soluble
Log S (Ali) : -2.28
Solubility : 1.09 mg/ml ; 0.00521 mol/l
Class : Soluble
Log S (SILICOS-IT) : -2.62
Solubility : 0.497 mg/ml ; 0.00238 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.31

Safety of [ 220731-04-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280 UN#:N/A
Hazard Statements:H302-H317 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 220731-04-4 ]

* 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 [ 220731-04-4 ]
  • Downstream synthetic route of [ 220731-04-4 ]

[ 220731-04-4 ] Synthesis Path-Upstream   1~4

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YieldReaction ConditionsOperation in experiment
100% With palladium 10% on activated carbon; hydrogen In ethyl acetate at 20℃; tert-Butyl (5-nitropyridin-2-yl)carbamate (1 eq), Pd/C (10percent w/w) and ethyl acetate was added to a flask under H2 atmosphere. The mixture was stirred at room temperature overnight. The mixture was filtered through a celite pad andthe filtrate concentrated under reduced pressure to obtain tert-butyl (5- am inopyridin-2-yl)carbamate.HPLC-MS (method A): Rt= 1.50 mm, [M+H] m/z: 210. Yield: quantitative yield.
99% With hydrogen In tetrahydrofuran; methanol at 20℃; for 4 h; 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).
99% With hydrogen In tetrahydrofuran; methanol at 20℃; for 4 h; 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.
97% With hydrogen In tetrahydrofuran; methanol for 6 h; PREPARATION 47
tert-Butyl 5-aminopyridin-2-ylcarbamate
tert-Butyl 5-nitropyridin-2-ylcarbamate (4.00 g, 16.72 mmol, Preparation 46) was dissolved in THF/MeOH. Pd/C (2.03 g, 1.91 mmol) was added and the reaction mixture was put under a hydrogen atmosphere.
The reaction mixture was stirred for a total of 6h.
The reaction mixture was filtered and evaporated to yield the desired product as a purple solid (3.40 g, 97percent yield) which was stored at -20 °C.
LRMS (m/z): 210 (M+1)+
97% With hydrogen In tetrahydrofuran; methanol for 6 h; ferf-Butyl 5-nitropyridin-2-ylcarbamate (4.00 g, 16.72 mmol, Preparation 46) was dissolved in THF/MeOH. Pd/C (2.03 g, 1 .91 mmol) was added and the reaction mixture was stirred under hydrogen atmosphere. The reaction mixture was stirred for a total of 6h. The reaction mixture was filtered and evaporated to yield the desired product as a purple solid (3.40 g, 97percent yield) which was stored at -20 °C.LRMS (m/z): 210 (M+1 )+
97% With palladium 10% on activated carbon; hydrogen; triethylamine In methanol; ethyl acetate for 20 h; B. Synthesis of N-(5-amino(2-pyridyl))(tert-butoxy)carboxamide (0133) To a suspension of (tert-butoxy)-N-(5-nitro(2-pyridyl))carboxamide (0.27 g, 1.13 mmol) in methanol (2 mL), ethyl acetate (4 mL) and TEA (0.16 mL) was added 10percent Pd/C (60 mg, 0.056 mmol) under argon. The reaction mixture was hydrogenated under 1 atm H2 for 20 hr, filtered through Celite and concentrated in vacuo to give N-(5-amino(2-pyridyl))(tert-butoxy)carboxamide (0.226 g, 97percent). 1H-NMR (DMSO-d6): δ 1.40 (s, 9H), 4.92 (br s, 2H), 6.89-6.91 (dd, 1 H), 7.35-7.37 (d, 1 H), 7.58 (d, 1 H), 9.06 (s, 1 H).
64% With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 1 h; Synthesis of compound 223.3. To a suspension of 10percent Pd/C (0.0 lOg) in methanol (5ml) was added 223.2 (0.500g, 2.1mmol, l .Oeq) in M eOH (5mL). Suspension was purged with hydrogen gas for lh at room temperature. Reaction mixture was filtered through celite washed with methanol and obtained filtrate was concentrated under reduced pressure and purified by flash chromatography to get pure 223.3 (0.28 g, 64.0 percent) MS (ES): m/z 209.25 [M+H]+.
38.6 g With ammonium chloride; zinc In tetrahydrofuran; methanol; water at 20℃; for 12 h; A 3-L round-bottomed flask was charged with tert-butyl (5-nitro-2- pyridinyl)carbamate (96.4 g, 403 mmol), 500 mL of MeOH, 500 mL of THF, and 100 mL of sat aq NH4C1. To this was slowly added (over 10 min) zinc dust (105 g, 1612 mmol, Strem Chemical Inc, Newburyport, MA). The mixture was stirred at room temperature for 12 h, then filtered. The filtrate was concentrated and then diluted with EtOAc and washed with water. The organic extracts were dried with MgS04, filtered, and concentrated to give a solid which was recrystallized from MeOH to give tert-butyl (5-amino-2-pyridinyl)carbamate (38.6 g) as a light yellow solid.
38.6 g With ammonium chloride; zinc In tetrahydrofuran; methanol; water at 20℃; for 12 h; A 3-L round-bottomed flask was charged with tert-butyl (5-nitro-2- pyridinyl)carbamate (96.4 g, 403 mmol), 500 mL of MeOH, 500 mL of THF, and 100 mL of sat aq NH4Cl. Zinc (105 g, 1610 mmol, Strem Chemical Inc, Newburyport, MA) was slowly added (over 10 min) to this solution. The mixture was stirred at room temperature for 12 h, then filtered. The filtrate was concentrated and then diluted with EtOAc and washed with water. The organic extracts were dried over MgS04, filtered, and concentrated. The resulting solid was recrystallized from MeOH to give tert-butyl(5-amino-2-pyridinyl)carbamate (38.6 g) as a light-yellow solid.

Reference: [1] Patent: WO2016/120808, 2016, A1, . Location in patent: Page/Page column 104
[2] Patent: US2010/249099, 2010, A1, . Location in patent: Page/Page column 96
[3] Patent: US2011/9405, 2011, A1, . Location in patent: Page/Page column 54
[4] Patent: EP2518071, 2012, A1, . Location in patent: Page/Page column 41-42
[5] Patent: WO2012/146667, 2012, A1, . Location in patent: Page/Page column 95-96
[6] Patent: EP2314593, 2016, B1, . Location in patent: Paragraph 0133
[7] Letters in Drug Design and Discovery, 2011, vol. 8, # 5, p. 401 - 405
[8] Patent: WO2015/131080, 2015, A1, . Location in patent: Paragraph 001167; 001169
[9] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 8, p. 2270 - 2273
[10] Patent: WO2013/123444, 2013, A1, . Location in patent: Page/Page column 60
[11] Patent: WO2014/35872, 2014, A1, . Location in patent: Page/Page column 69
[12] Journal of Medicinal Chemistry, 2014, vol. 57, # 7, p. 3094 - 3116
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  • [ 220731-04-4 ]
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,
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  • [ 24424-99-5 ]
  • [ 220731-04-4 ]
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,
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  • [ 24424-99-5 ]
  • [ 220731-04-4 ]
Reference: [1] Patent: WO2016/120808, 2016, A1,
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