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Chemical Structure| 159724-40-0
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Product Details of [ 159724-40-0 ]

CAS No. :159724-40-0 MDL No. :MFCD03197165
Formula : C10H14N2O Boiling Point : -
Linear Structure Formula :- InChI Key :ZJWLMZURLIHVHE-UHFFFAOYSA-N
M.W : 178.23 Pubchem ID :847768
Synonyms :

Calculated chemistry of [ 159724-40-0 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.4
Num. rotatable bonds : 1
Num. H-bond acceptors : 1.0
Num. H-bond donors : 1.0
Molar Refractivity : 56.57
TPSA : 38.49 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.69
Log Po/w (XLOGP3) : 0.68
Log Po/w (WLOGP) : 0.73
Log Po/w (MLOGP) : 0.83
Log Po/w (SILICOS-IT) : 1.25
Consensus Log Po/w : 1.04

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.65
Solubility : 4.0 mg/ml ; 0.0224 mol/l
Class : Very soluble
Log S (Ali) : -1.07
Solubility : 15.3 mg/ml ; 0.0861 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.22
Solubility : 1.07 mg/ml ; 0.006 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.76

Safety of [ 159724-40-0 ]

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 [ 159724-40-0 ]

* 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 [ 159724-40-0 ]
  • Downstream synthetic route of [ 159724-40-0 ]

[ 159724-40-0 ] Synthesis Path-Upstream   1~14

  • 1
  • [ 110-91-8 ]
  • [ 106-40-1 ]
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  • [ 159724-40-0 ]
Reference: [1] Organic Letters, 2003, vol. 5, # 19, p. 3515 - 3517
  • 2
  • [ 116922-22-6 ]
  • [ 159724-40-0 ]
YieldReaction ConditionsOperation in experiment
95.2% With hydrogen In methanol at 0 - 20℃; for 16 h; To a cooled (0° C.) solution of 4-(3-nitro-phenyl)-morpholine (43)(4.16 g, 20 mmol) in methanol (50 ml) was added Pd/C (10percent loading, 460 mg).
The mixture was stirred at room temperature under an H2 (1 atm) for 16 hrs.
The mixture was then filtered through a Celite.(TM). pad, the filtrate dried using MgSO4, filtered and concentrated in vacuo to give the title compound (3.39 g, 95.2percent) as an orange solid that was suitably clean to be used without any further purification. m/z (LC-MS, ESP): 179 [M+H]+, R/T=1.69 mins.
93% With hydrogen In ethanol; N,N-dimethyl-formamide at 20℃; for 4 h; b) Title compound; To a solution of 4-(3-nitrophenyl)morpholine ( 2.34 g, 11.3 mmol, obtained in section a) in a 4:1 mixture of EtOH and DMF (120 mL), 0.23 g of 10percent Pd on active carbon (wet, 50percent water) were added and it was stirred at room temperature under a hydrogen atmosphere for 4 h. The mixture was filtered through a pad of celite and the filtrate was concentrated to dryness to afford 1.87 g of the title compound (yield: 93percent). LC-MS (method 1): tR = 1.47 min; m/z = 179.2 [M+H]+.
93% With ammonium formate In methanol at 20℃; for 48 h; To a slurry of 97A (13. 6 g, 65 mmol) in methanol (225 mL) at rt were successively added ammonium formate (20.5 g, 326 mmol) and 10percent palladium on charcoal (2.0 g) and the mixture was stirred at rt for 48 h. The resulting mixture was filtered through a pad of celite and the clear filtrate was concentrated in vacuo and the resulting residue was partitioned between water (50 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous portion was extracted with additional ethyl acetate (2 x 50 mL). The combined extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 10.8 g (93percent) of 97B as a tan solid. LCMS (M+H+) = 179.2.
90% With ammonium chloride; zinc In methanol at -10 - 20℃; for 3 h; To a stirred solution of 4-(6-nitropyridin-3-yl)morpholine (0.9 g, 0.0043 mol) in methanol (10 mL) was cooled to 0°-10°C and zinc dust (1.4 g, 0.0216 mol) and ammonium chloride (1.16 g, 0.0216 mol) were added. The reaction was stirred at rt for 3 h. After completion, the mixture was filtered through a Celite® bed and washed with methanol. The organic layer was concentrated under reduced pressure to provide crude material which was purified by Combiflash™ chromatography using 5percent methanol/DCM as eluent to obtain 3-morpholinoaniline (0.70g, 90percent) as violet color solid. 1H NMR (400 MHz, DMSO-d6): δ 6.86 (t, 2H), 6.12 (s, 2H), 6.056 (s, 1H), 5.6 (d, 1H), 6.43 (s, 1H), 3.70 (s, 4H), 2.90 (s, 4H).
2.28 g With hydrogenchloride; tin(II) chloride dihdyrate In water at 100℃; for 0.5 h; Inert atmosphere 7.06 g (0.050 mol) of 3-fluoronitrobenzene and 13.07 g (0.150 mol) of morpholine were charged into a 200 mL two-necked flask, and while stirring with a magnetic stirrer under nitrogen flow (5 mL / min) , And reacted under reflux for 12 hours. After completion of the reaction, the reaction solution was cooled to room temperature, then the reaction solution was added to ion exchanged water, and the extraction operation was carried out with ethyl acetate. The obtained organic phase was concentrated with an evaporator, and the concentrate was purified by column chromatography on silica gel (developing solvent: ethyl acetate)8.25 g of Intermediate 2-1 (1- (3-nitrophenyl) morpholine) was obtained. The yield based on 3-fluoronitrobenzene was 79.2 molpercent. 8.25 g (0.040 mol) of Intermediate 2-1, 40.91 g (0.181 mol) of tin chloride.dihydrate and 204 g of concentrated hydrochloric acid were placed in a 200 mL two-necked flask, and under nitrogen flow (5 mL / min), while stirring with a magnetic stirrer, the temperature in the flask was maintained at 100 ° C. and the reaction was carried out for 30 minutes. After completion of the reaction, the reaction solution was cooled to room temperature and filtered to obtain white crystals. The obtained crystals were added to a 20 mass percent sodium hydroxide aqueous solution for neutralization, and then ethyl acetate was added to carry out the extraction operation. The obtained organic phase was concentrated with an evaporator, and the concentrate was purified by column chromatography on silica gel (developing solvent: ethyl acetate) to give Intermediate 2-2 (1- (3-aminophenyl) morpholine) 2.28 g was obtained.The yield based on the intermediate 2-1 was 32.3 molpercent. Then, in a 200 mL two-necked flask, 1.38 g (0.008 mol) of Intermediate 2-2, 3.19 g (0.015 mol) of trifluoroacetic anhydride, 1.74 g (0.017 mol) of triethylamine, 40 g And the mixture was allowed to react at room temperature for 12 hours while stirring with a magnetic stirrer under nitrogen flow (5 mL / min). After completion of the reaction, the reaction solution was added to ion-exchanged water and extraction operation was performed with ethyl acetate. The obtained organic phase was concentrated with an evaporator, and the concentrate was purified by column chromatography on silica gel (eluent: ethyl acetate) to give Intermediate 2-3 (2,2,2-trifluoro-N- ( 3-morpholinophenyl) acetamide) was obtained. The yield based on the intermediate 2-2 was 96.0 molpercent. Subsequently, 2.0 g (0.007 mol) of Intermediate 2-3, 0.43 g (0.004 mol) of squaric acid, 23 g of 1-butanol and 23 g of toluene were added to a 300 mL three-necked flask, and under nitrogen flow / Min), the mixture was stirred using a magnetic stirrer, and reacted under reflux for 3 hours while removing water eluted using a Dean-Stark apparatus. After completion of the reaction, the reaction solution was concentrated with an evaporator, the solvent was distilled off, 50 g of methanol was added thereto for crystallization. Precipitated crystals were obtained by filtration, and the obtained crystals were rinsed with methanol to obtain a wet cake. This wet cake was dried at 60 ° C. for 12 hours using a vacuum dryer to obtain 0.64 g of squarylium compound 2 shown in Table 1. The yield based on squaric acid was 23.7 molpercent
245 mg With iron; ammonium chloride In methanol; water at 100℃; The compound S1 (261 mg, 1.25 mmol), iron powder (210 mg, 4.76 mmol, 3 equiv.) and ammonium chloride (335 mg, 6.27 mmol, 5 equiv.) were dissolved in methanol : water (2 : 1, 15 mL). The reaction mixture was heated at 100 °C overnight, cooled to RT, filtered through celite and the solvent was reduced under vacuum. The condensed mixture was extracted with DCM, washed with brine, dried with sodium sulfate and all solvent was evaporated to furnish the condensed residue, which was purified by flash chromatography (elution system - EA/Hexane = 1 : 1 ) to obtain the title compound (245 mg, 1.43 mmol). Rf = 0.36 (EA/Hexane = 1 : 1).

Reference: [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 26, p. 8261 - 8269
[2] Patent: US2006/199804, 2006, A1, . Location in patent: Page/Page column 31
[3] Journal of Medicinal Chemistry, 2008, vol. 51, # 3, p. 407 - 416
[4] Patent: WO2007/339, 2007, A1, . Location in patent: Page/Page column 52
[5] Patent: WO2003/90912, 2003, A1, . Location in patent: Page/Page column 76
[6] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2253 - 2261
[7] Patent: WO2015/38417, 2015, A1, . Location in patent: Page/Page column 127; 128
[8] Patent: US2002/165218, 2002, A1,
[9] Patent: WO2004/31164, 2004, A1, . Location in patent: Page/Page column 42-43
[10] MedChemComm, 2015, vol. 6, # 3, p. 444 - 454
[11] Patent: US2004/87575, 2004, A1,
[12] Patent: US2003/13708, 2003, A1,
[13] Patent: US2004/110745, 2004, A1,
[14] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 6737 - 6746
[15] Patent: WO2003/93248, 2003, A1, . Location in patent: Page/Page column 20
[16] Patent: WO2004/10995, 2004, A1, . Location in patent: Page/Page column 28-29
[17] Patent: JP2017/179131, 2017, A, . Location in patent: Paragraph 0099
[18] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 593 - 619
[19] Patent: US6589950, 2003, B1,
  • 3
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YieldReaction ConditionsOperation in experiment
91% With hydrogenchloride In methanol at 20℃; A solution of tert-butyl (3-morpholinophenyl) carbamate (5.91 g. 21.20 mmol) in a solution of HCl (106 mL, 106.0 mmol, 1 M in MeOH) was stirred at rt overnight, then concentrated in vacuo. The residue was dissolved in water (100 mL). The soltution was basified with saturated Na2CO3 aqueous solution and extracted with CH2C12 (100 mL x 3). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2504 and concentrated in vacuo to give the title compound as a light brown solid (3.42 g, 91percent).
91% With hydrogenchloride In methanol at 20℃; A solution of tert-butyl (3-morpholinophenyl)carbamate (5.91 g, 21.20 mmol) in a solution of HCl (106 mL, 106.0 mmol, 1 M in MeOH) was stirred at rt overnight, then concentrated in vacuo.
The residue was dissolved in water (100 mL).
The soltution was basified with saturated Na2CO3 aqueous solution and extracted with CH2Cl2 (100 mL*3).
The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a light brown solid (3.42 g, 91percent).
91% With hydrogenchloride In methanol at 20℃; In a 100 mL round bottom flask, 5-morpholine t-butyloxycarbonylaniline (5.91 g, 21.20 mmol) was dissolved in 1M methanolic hydrogen chloride solution (106 mL, 106.0 mmol) and stirred at room temperature overnight.After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was added to water (100 mL), stirred until completely dissolved, and the solution was made alkaline by the addition of a saturated aqueous solution of sodium carbonate.The aqueous layer was extracted with dichloromethane (100 mL x 3), and the organic layers were combined and washed with saturated brine (150 mL).After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give a pale-brown solid (3.42 g, 91percent).
Reference: [1] Patent: WO2014/12360, 2014, A1, . Location in patent: Paragraph 00317
[2] Patent: US2015/87639, 2015, A1, . Location in patent: Paragraph 0582
[3] Patent: TWI607995, 2017, B, . Location in patent: Page/Page column 134
  • 4
  • [ 107-21-1 ]
  • [ 626-01-7 ]
  • [ 159724-40-0 ]
YieldReaction ConditionsOperation in experiment
48% With morpholine In isopropyl alcohol at 90℃; for 18 h; Example 39: (3-Momholin-4-vl-phenvl)-( 5-thiophen-3-vl-pvrimidin-2-vl)-amine; A 5-mL reaction vial equipped with a magnetic stirrer was charged with 3-lodo-phenylamine (438 mg, 2.00 mmol), morpholine (348 mg, 4.00 mmol), copper iodide (38 mg, 0.20 mmol), potassium phosphate (850 mg, 4.0 mmol), ethylene glycol (248 mg, 4.00 mmol), and isopropanol (2.0 mL). After stirring at 90 °C for 18 h the reaction was concentrated under reduced pressure, dissolved in methylene chloride (3.0 mL) and washed with water (3.0 mL). The organic layer was then dried over sodium sulfate, filtered, concentrated under reduced pressure and the residue purified by column chromatography (methanol/methylene chloride) affording a 48percent yield (172 mg) of 3-morpholin-4-yl-phenylamine as a colorless oil.
Reference: [1] Patent: WO2005/113548, 2005, A1, . Location in patent: Page/Page column 46
  • 5
  • [ 68621-88-5 ]
  • [ 111-44-4 ]
  • [ 159724-40-0 ]
YieldReaction ConditionsOperation in experiment
58% With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 150℃; Inert atmosphere Under nitrogen protection,5-amino-tert-butoxycarbonylaniline (7.59 g, 36.40 mmol)Potassium carbonate (10.06 g, 72.80 mmol) and sodium iodide (16.37 g, 109.20 mmol) were suspended in DMF (300 mL) and heated to 150°C.To the above reaction system, 2,2'-dichloroethyl ether (5.73 g, 40.1 mmol) was slowly added, and the addition was completed, and the reaction was maintained at 150°C overnight.After the reaction was completed, the mixture was cooled to room temperature, poured into water (700 mL), and the aqueous solution was extracted with dichloromethane (200 mL x 3). The organic layers were combined and washed with water (200 mL x 3) and saturated brine (200 mL).After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure.The crude product was purified by column chromatography (petroleum ether/ethyl acetate (V/V) = 4/1) to give a yellow solid (5.91 g, 58percent).
Reference: [1] Patent: TWI607995, 2017, B, . Location in patent: Page/Page column 134
  • 6
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Reference: [1] Journal of Organic Chemistry, 2002, vol. 67, # 9, p. 3029 - 3036
  • 7
  • [ 402-67-5 ]
  • [ 159724-40-0 ]
Reference: [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 7, p. 2253 - 2261
[2] Journal of Medicinal Chemistry, 2005, vol. 48, # 26, p. 8261 - 8269
[3] Patent: WO2004/101533, 2004, A1, . Location in patent: Page 92
[4] Patent: WO2015/38417, 2015, A1,
[5] Patent: JP2017/179131, 2017, A,
[6] Patent: US6589950, 2003, B1,
[7] Patent: WO2003/90912, 2003, A1,
  • 8
  • [ 108-37-2 ]
  • [ 159724-40-0 ]
Reference: [1] Organic Letters, 2018, vol. 20, # 8, p. 2301 - 2305
  • 9
  • [ 110-91-8 ]
  • [ 106-40-1 ]
  • [ 2524-67-6 ]
  • [ 159724-40-0 ]
Reference: [1] Organic Letters, 2003, vol. 5, # 19, p. 3515 - 3517
  • 10
  • [ 99-09-2 ]
  • [ 159724-40-0 ]
Reference: [1] Patent: WO2014/12360, 2014, A1,
[2] Patent: US2015/87639, 2015, A1,
[3] Patent: TWI607995, 2017, B,
  • 11
  • [ 18437-64-4 ]
  • [ 159724-40-0 ]
Reference: [1] Patent: WO2014/12360, 2014, A1,
[2] Patent: US2015/87639, 2015, A1,
[3] Patent: TWI607995, 2017, B,
  • 12
  • [ 68621-88-5 ]
  • [ 159724-40-0 ]
Reference: [1] Patent: WO2014/12360, 2014, A1,
[2] Patent: US2015/87639, 2015, A1,
  • 13
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Reference: [1] MedChemComm, 2015, vol. 6, # 3, p. 444 - 454
  • 14
  • [ 645-00-1 ]
  • [ 159724-40-0 ]
Reference: [1] European Journal of Medicinal Chemistry, 2018, vol. 158, p. 593 - 619
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