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[ CAS No. 372198-69-1 ] {[proInfo.proName]}

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Chemical Structure| 372198-69-1
Chemical Structure| 372198-69-1
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Product Details of [ 372198-69-1 ]

CAS No. :372198-69-1 MDL No. :MFCD10698068
Formula : C10H9BrN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :VMTDOHAWLUJHAI-UHFFFAOYSA-N
M.W : 269.10 Pubchem ID :22031055
Synonyms :

Calculated chemistry of [ 372198-69-1 ]

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 9
Fraction Csp3 : 0.2
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 58.98
TPSA : 43.6 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : Yes
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.8 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.66
Log Po/w (XLOGP3) : 3.01
Log Po/w (WLOGP) : 2.27
Log Po/w (MLOGP) : 1.64
Log Po/w (SILICOS-IT) : 1.76
Consensus Log Po/w : 2.27

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.65
Solubility : 0.0601 mg/ml ; 0.000224 mol/l
Class : Soluble
Log S (Ali) : -3.59
Solubility : 0.0691 mg/ml ; 0.000257 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.42
Solubility : 0.102 mg/ml ; 0.00038 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.11

Safety of [ 372198-69-1 ]

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

Application In Synthesis of [ 372198-69-1 ]

* 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 [ 372198-69-1 ]
  • Downstream synthetic route of [ 372198-69-1 ]

[ 372198-69-1 ] Synthesis Path-Upstream   1~13

  • 1
  • [ 1072-97-5 ]
  • [ 1004550-24-6 ]
  • [ 372198-69-1 ]
YieldReaction ConditionsOperation in experiment
55% With sulfuric acid In ethanol at 90℃; for 18 h; To a solution of cone. H2SO4 (2.7 mL) in EtOH (140 mL) were added 2- amino-5-bromopyridine (Aldrich, 5.92 g, 34.2 mmol) and ethyl 2-chloro-3- oxopropanoate potassium salt (20.0 g, 106.0 mmol; see Tetrahedron, 56, 7915-7921 <n="43"/>(2000)) in a sealed tube. The reaction vessel was purged with N2, sealed and heated to 90 0C. After 18 h, the resultant slurry was cooled to rt, filtered and concentrated under reduced pressure. The residue was diluted with EtOAc, washed with IN NaOH followed by brine and the combined aqueous layers were back-extracted with 95:5 EtOAc/MeOH. The combined extracts were dried over Na2SO4 and decolorizing carbon, filtered through a pad of Celite.(R). and concentrated under reduced pressure. The residue was recrystallized from 1 : 1 EtOAc/hexanes (100 mL) to give 5.09 g (55percent) of the title compound as an off- white solid. MS(ES)+ m/e 271.2 [M+H]+.
Reference: [1] Patent: WO2008/14219, 2008, A2, . Location in patent: Page/Page column 41-42
  • 2
  • [ 1072-97-5 ]
  • [ 372198-69-1 ]
YieldReaction ConditionsOperation in experiment
32% With sulfuric acid In ethanol at 0 - 80℃; for 5 h; To a solution of H2S04 (1.81 g, 18.50 mmol, 986 uL, 1.6 eq) and EtOH (25 mL) at 0 °C was added Example 102A (6.76 g, 35.8 mmol, 3.1 eq) and 2-amino-5- bromopyridine (2.00 g, 11.56 mmol, 1 eq). The reaction was stirred at 80 °C for 5 hr. The reaction was cooled to 25 °C. To the mixture was added water and the pH of the solution was adjusted to 7 with saturated NaHC03. The mixture was extracted with ethyl acetate (300 mL*3). The combined organic phase was washed with brine (200 mL*2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel (0343) chromatography (Petroleum ether: Ethyl acetate=10/l, 3/1). Example 112A (1.00 g, 3.72 mmol, 32 percent yield) was obtained as a white solid. ESI m/z 268.9[M +1]+. (0344) [0175] MR: (CDC13, 400MHz): ppm 9.56 (s, 1H), 8.38 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.6 (dd, J=1.6, 9.6 Hz, 1H), 4.47-4.42 (m, 2H), 1.43(t, J=7.2 Hz, 3H).
Reference: [1] Patent: WO2017/214413, 2017, A1, . Location in patent: Paragraph 0174-0175
[2] Patent: US2013/59832, 2013, A1, . Location in patent: Paragraph 0435; 0436
  • 3
  • [ 1072-97-5 ]
  • [ 33142-21-1 ]
  • [ 372198-69-1 ]
YieldReaction ConditionsOperation in experiment
21% Reflux To a solution of ethyl formylchloroacetate (prepared according to the procedure described by Plouvier et al. Heterocycles 1991, 32, 693) (2.41 g, 16.0 mmol) in ethanol (60 mL) was added 5-bromopyridin-2-amine (2.77 g, 16.0 mmol), and the mixture was heated to reflux overnight. After cooling, the solvent was removed by rotary evaporation, and the residue was treated with CHCI3 (50 mL) and a saturated solution of aqueous NaHC03. The layers were separated and the aqueous layer was further extracted with CHC13 (2 x 30 mL). The combined organic layer was dried over Na2S04, filtered, and concentrated to dryness. Purification by flash column chromatography (20-35percent ethyl acetate in hexane) gave the title compound (0.9 g, 21percent). 1H-NMR (DMSO-d6, 400 MHz) δ 9.61 (s, 1 H), 8.32 (s, 1 H), 8.00 (d, J = 9.6 Hz, 1 H), 7.74 (d, J = 9.6 Hz, 1 H), 4.48 (q, J = 7.2 Hz, 2 H), 1.45 (t, J = 7.2 Hz, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C10H10BrN2O2: 269, obtained: 269.
Reference: [1] Patent: WO2011/50245, 2011, A1, . Location in patent: Page/Page column 104-105
[2] Patent: WO2012/87519, 2012, A1, . Location in patent: Page/Page column 112; 113
[3] Patent: WO2013/71272, 2013, A1, . Location in patent: Paragraph 00298-00320
[4] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[5] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 67
[6] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 345
  • 4
  • [ 1072-97-5 ]
  • [ 372198-69-1 ]
YieldReaction ConditionsOperation in experiment
55% With sulfuric acid In ethanol for 2 h; Heating / reflux Add concentrated sulfuric acid (0.56 g, 5.78 mmol) to a suspension of 2-chloro-3- oxo-propionic acid ethyl ester potassium salt (Tetrahedron 2000, 58 (40), 7915-7921 ; 3.27 g, 17.3 mmol) and 2-amino-5-bromopyridine (1.0 g, 5.78 mmol) in ethanol (100 mL). Reflux for 2 h, cool, and carefully dilute with saturated aqueous sodium bicarbonate. Extract in ethyl acetate, combine organic extracts, and concentrate. Flash chromatography using appropriate ethyl acetate/methanol mixtures gives 0.85 g (55percent) of the subtitled compound as a white solid. MS ES+m/e 269.0, 271.0 (M+1) bromine isotopes NMR (400 MHz, DMSO-d6) B 9.32 (m, 1H), 8.28 (s, 1H), 7.79 (d, J = 10 Hz, 1H), 7.70 (dd, J = 10,2 Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H).
Reference: [1] Patent: WO2004/50659, 2004, A1, . Location in patent: Page 41
  • 5
  • [ 1072-97-5 ]
  • [ 372198-69-1 ]
Reference: [1] Patent: US2013/59846, 2013, A1, . Location in patent: Paragraph 0433; 0434; 0435; 0436; 0437
[2] Patent: WO2013/33116, 2013, A1, . Location in patent: Page/Page column 95; 96; 97
  • 6
  • [ 474706-74-6 ]
  • [ 541-41-3 ]
  • [ 372198-69-1 ]
Reference: [1] Patent: EP1382603, 2004, A1, . Location in patent: Page 144
  • 7
  • [ 1072-97-5 ]
  • [ 913287-11-3 ]
  • [ 372198-69-1 ]
YieldReaction ConditionsOperation in experiment
48% for 16 h; Reflux A. To a suspension of 2-chloro-3-oxopropanoate potassium salt (6.3 g, 33 mmol) (prepared according to Ikemoto, T. er a/., Tetrahedron 2000, 56, 7915-7921) and 2-amino-5-bromopyridine (1.93 g, 11.1 mmol) in ethanol (150 mL) was added concentrated sulfuric acid (1.1 g) and the reaction mixture was heated at reflux for 16 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (100 mL) and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-50percent gradient of ethyl acetate in hexanes to afford ethyl 6-bromoimidazo[1 ,2-a]pyridine-3-carboxylate as a yellow solid in 48percent yield (1.45 g): 1H NMR (300 MHz, CDCI3) δ 9.48-9.42 (m, 1 H), 8.26-8.19 (m, 1H), 7.63- 7.55 (m, 1 H), 7.49-7.40 (m, 1 H), 4.45-^.31 (m, 2H), 1.44-1.31 (m, 3H); MS (ES+) m/z 268.9 (M + 1), 270.9 (M + 1).
Reference: [1] Patent: WO2013/64984, 2013, A1, . Location in patent: Page/Page column 81
  • 8
  • [ 138240-34-3 ]
  • [ 105-36-2 ]
  • [ 372198-69-1 ]
Reference: [1] Journal of Chemical Sciences, 2018, vol. 130, # 5,
  • 9
  • [ 1072-97-5 ]
  • [ 105-39-5 ]
  • [ 109-94-4 ]
  • [ 372198-69-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2455 - 2466
  • 10
  • [ 1072-97-5 ]
  • [ 372198-69-1 ]
Reference: [1] Journal of Chemical Sciences, 2018, vol. 130, # 5,
  • 11
  • [ 372198-69-1 ]
  • [ 1083326-28-6 ]
  • [ 1276110-06-5 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 7, p. 2455 - 2466
  • 12
  • [ 372198-69-1 ]
  • [ 944896-42-8 ]
YieldReaction ConditionsOperation in experiment
10169 g With hydrogenchloride In water at 0 - 5℃; Large scale [002981 Example 4[00299] Preparation of compound 8:[00300] 1. Anethanol solution of compound 5 (12400 g in 51 L of ethanol) was added to an appropriately sized stainless steel reactor at room temperature under nitrogen atmosphere.[00301] 2. Compound 6 (9500 g) was added as a solid in one portion at room temperature.[00302] 3. The reaction mixture was heated to reflux (~78°C) and stirred for 1-2 days.[00303] 4. The reaction was monitored by HPLC.[00304] 5. Upon completion, the reaction mixture was allowed to cool to room temperature.[00305] 6. NaOH solution (9884 g solid pellets dissolved in 38 L of water) was added as a stream over a30 min period at an internal temperature below 35 °C.[00306] 7. The reaction mixture was heated to reflux (~78°C) for 3 to 4 hours.[00307] 8. The reaction was monitored by HPLC.[00308] 9. Upon completion, the reaction mixture was cooled to an appropriate temperature to start solvent removal.[00309] 10. All ethanol (approximately 5 volumes of ethanol) was removed under vacuum at 40 to 45 °C.[00310] 11. The reaction mixture was cooled to room temperature.[00311] 12. Water (57 L; 6 vol) was added at room temperature.[00312] 13. The aqueous solution was washed with ethyl acetate (2 x 38 L) to remove all organic impurities.[00313] 14. The lower aqueous layer was cooled to 0-5 °C and acidified with cone. HCl (~15 L) until reaching pH 1-2.[00314] 15. The reaction mixture was stirred for 1 to 2 hours at 0 to 5 °C.[00315] 16. The mixturewas filtered and the cake was washed with water (2 x 38 L) and acetone (2 x 19L) followed by drying for 1-2 hours.[00316] 17. The solid collectedwas transferred back into an appropriately sized reactor.[00317] 18. Heptane (95 L; 10 vol) was addedto the reactor; the suspension was stirred for 4 to 5 hours at roomtemperature.[00318] 19. The solidwas collected by filtration and washed with heptane (2 x 19 L).[00319] 20. The solid (15 kg) was suspended in methanol (75 L; 5 vol) at room temperature for 2 hours.[00320] 21. The suspension was filtered and the solid collected was washed with methanol (2x 5L).22. The solid was dried under vacuum at 50°C to constant weight to give compound 8 as an off-white to white solid (10169 g, 83.3 percent yield; HPLC purity 99.2percent;1HNMR (DMSO-d6, 300 MHz) ? 9.4 (s, 1H), 8.3(s, 1H), 7.85-7.67 (m, 2H)).
Reference: [1] Patent: WO2011/50245, 2011, A1, . Location in patent: Page/Page column 105
[2] Patent: WO2013/71272, 2013, A1, . Location in patent: Paragraph 00298-00320
[3] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[4] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 67
[5] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 345
  • 13
  • [ 372198-69-1 ]
  • [ 1268454-23-4 ]
Reference: [1] Patent: WO2013/71272, 2013, A1,
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