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[ CAS No. 478832-21-2 ] {[proInfo.proName]}

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Chemical Structure| 478832-21-2
Chemical Structure| 478832-21-2
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Product Details of [ 478832-21-2 ]

CAS No. :478832-21-2 MDL No. :MFCD07368610
Formula : C11H21NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :CRFSWDBNKHNGGA-UHFFFAOYSA-N
M.W : 215.29 Pubchem ID :22933363
Synonyms :

Calculated chemistry of [ 478832-21-2 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 15
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.91
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 62.56
TPSA : 49.77 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.66 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.63
Log Po/w (XLOGP3) : 1.34
Log Po/w (WLOGP) : 1.39
Log Po/w (MLOGP) : 1.15
Log Po/w (SILICOS-IT) : 0.83
Consensus Log Po/w : 1.47

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.82
Solubility : 3.25 mg/ml ; 0.0151 mol/l
Class : Very soluble
Log S (Ali) : -1.99
Solubility : 2.22 mg/ml ; 0.0103 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -0.98
Solubility : 22.3 mg/ml ; 0.104 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.78

Safety of [ 478832-21-2 ]

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 [ 478832-21-2 ]

* 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 [ 478832-21-2 ]
  • Downstream synthetic route of [ 478832-21-2 ]

[ 478832-21-2 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 109162-29-0 ]
  • [ 34619-03-9 ]
  • [ 478832-21-2 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With ammonium formate In ethanol for 1 h; Heating / reflux
Stage #2: at 20℃; for 19 h;
Ammonium formate (900 mg) and 10percent Pd-C (200 mg) were added to a solution of 1-benzyl-4-azepanol (450 mg, 2.19 mmol) in ethanol (10 ml), and the resulting mixture was refluxed for 1 hour. The reaction mixture was filtered by the use of Celite and the filtrate was concentrated. To a solution of the resulting residue in dichloromethane (10 ml) was added di-tert-butyl dicarbonate (0.504 ml, 2.19 mmol) at room temperature, and stirred for 19 hours. A saturated aqueous sodium hydrogencarbonate solution and then water were added to the reaction mixture, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 2/1) to obtain tert-butyl 4-hydroxyazepane-1-carboxylate (333 mg, 70percent).1H-NMR (CDCl3) δ; 1.50-1.92 (6H, m), 2.39 (1H, s), 3.11-3.42 (4H, m), 3.77 (1H, m).
Reference: [1] Patent: EP1403255, 2004, A1, . Location in patent: Page 93-94
  • 2
  • [ 188975-88-4 ]
  • [ 478832-21-2 ]
YieldReaction ConditionsOperation in experiment
99.1% With lithium borohydride In tetrahydrofuran at 0℃; for 1 h; Intermediate Preparation 28; 4-Hydroxy-azepane-l-carboxylic acid tert-butyl ester; To a solution of 4-oxo-azepane-l-carboxylic acid tert-butyl ester (13.6 g, 63.8 mmol) in methanol (10 mL) and tetrahydrofuran (30 mL) at 0 0C is added lithium borohydride (1.40 g, 63.8 mmol). The mixture is stirred at 0 0C for 60 minutes. Hydrochloric acid (1.0 M, 40 mL) is added. The mixture is concentrated under reduced pressure and extracted with ethyl acetate (2x). The combined ethyl acetate layers are dried (Na2SO4) and concentrated to a residue. The residue is purified on silica using a gradient of ethyl acetate in hexanes (40 to 80percent) to yield the title compound (13.6 g, 99.1percent).
97%
Stage #1: With sodium tetrahydroborate In methanol at 20℃; for 1.5 h;
Intermediate 141,1-Dimethylethyl 4-hydroxyhexahydro-1 H-azepine-1 -carboxylate To a solution of 1 ,1-dimethylethyl 4-oxohexahydro-1 H-azepine-1 -carboxylate (for example, as disclosed in patent application WO 2000/00203A1 , see Example 1A) (2.146 g, 10.0 mmol) in MeOH (60 ml) was added sodium borohydride (commercially available, for example, from Aldrich) (0.426 g, 12.2 mmol), portionwise. The solution was stirred at 20 0C for 1.5 h. The solution was cautiously quenched with MeOH and water (1 :1, 10 ml). The solvent was removed in vacuo. The residue was partitioned between EtOAc (100 ml) and saturated aq. sodium hydrogen carbonate (100 ml). The phases were separated and the organic extract washed with brine (50 ml). The organic extract was dried over MgSO4. The solvent was removed in vacuo to give the title compound as a waxy solid (2.094 g, 97percent). LCMS RT = 2.40 min, ES+ve m/z 216 (M+H)+.
94% With sodium tetrahydroborate In tetrahydrofuran; methanol at 0℃; for 1 h; Step 7; 4-Hydroxy-azepane-l-carboxylic acid tert-butyl ester; To a solution of Ig (4.69mmol)of 4-oxo-azepane-l-carboxylic acid tert-butyl ester), in 2 mL of Methanol and 8mL of THF, is added at O0C (ice bath) sodium tetrahydroborate (0.18g, 4.69mmol). The resulting mixture is stirred at O0C for 1 h. To the reaction mixture is added at O0C (ice bath), a solution of HCl (IN) (2 mL), then solvent is removed and the resulting slurry is diluted with water and extracted with EtOAc (250 mL). The organic layers are combined, dried (Na2SO4), filtered and concentrated to afford the title compound as a colorless oil (0.95g, 94percent). MS (m/e): 216 (M+l).
92% at 20℃; for 67.67 h; To a solution of 1 ,1-dimethylethyl 4-oxohexahydro-1 /τd-azepine-1 -carboxylate (970 mg, 4.55 mmol) in methanol (23 ml_) was added polymer-supported borohydride resin (3.16 mmol/g, 1.15 g, 3.64 mmol). The reaction stirred at room temperature for 67.67 h and was then filtered to remove the resin, washing with dichloromethane (2 x 20 ml_). The eluant was concentrated to afford 902 mg (92percent) of the title compound. 1H NMR (300 MHz, CDCI3): δ 3.88 (m, 1 H), 3.53-3.20 (m, 4H), 2.03-1.61 (m, 6H), 1.46 (s, 9H), 1.41 (br s, 1 H).
1.62 g With sodium tetrahydroborate In methanol at 0 - 20℃; Inert atmosphere Sodium borohydride (0.35 g, 9.38 mmol) was added slowly to a solution of intermediate (38) (2 g, 9.38 mmol) in MeOH (20 mL) under nitrogen flow at 0°C. The mixture was stirred 2 hours at room temperature. The mixture was poured out into water. The organic layer was extracted with EtOAc, washed with brine, dried over MgS04, filtered off and concentrated, yielding 1.62 g of intermediate (61).
1.62 g at 0 - 20℃; for 2 h; Inert atmosphere Sodium borohydride (0.35 g, 9.38 mmol) was added slowly to a solution of intermediate (38) (2 g, 9.38 mmol) in MeOH (20 mL) under nitrogen flow at 0° C. The mixture was stirred 2 hours at room temperature. The mixture was poured out into water. The organic layer was extracted with EtOAc, washed with brine, dried over MgSO4, filtered off and concentrated, yielding 1.62 g of intermediate (61).

Reference: [1] Patent: WO2009/12125, 2009, A1, . Location in patent: Page/Page column 30
[2] Patent: WO2007/122156, 2007, A1, . Location in patent: Page/Page column 66
[3] Patent: WO2009/12125, 2009, A1, . Location in patent: Page/Page column 71
[4] Patent: WO2007/30366, 2007, A1, . Location in patent: Page/Page column 130-131
[5] Patent: WO2010/22076, 2010, A1, . Location in patent: Page/Page column 80; 81
[6] Patent: US2012/232039, 2012, A1, . Location in patent: Page/Page column 14
[7] Patent: WO2013/21051, 2013, A1, . Location in patent: Page/Page column 32
[8] Patent: US2014/171418, 2014, A1, . Location in patent: Paragraph 0165; 0166
[9] Patent: WO2015/110481, 2015, A1, . Location in patent: Page/Page column 99
[10] Patent: US2016/332963, 2016, A1, . Location in patent: Paragraph 0580
[11] Process Biochemistry, 2017, vol. 56, p. 90 - 97
  • 3
  • [ 39888-51-2 ]
  • [ 24424-99-5 ]
  • [ 478832-21-2 ]
YieldReaction ConditionsOperation in experiment
70% at 20℃; for 19 h; (c)
Synthesis of tert-butyl 4-hydroxyazepane-1-carboxylate
Ammonium formate (900 mg) and 10percent palladium/carbon (200 mg) were added to a solution of 1-benzyl-4-azepanol (450 mg, 2.19 mmol) in ethanol (10 ml), and the resulting mixture was refluxed for 1 hour.
The reaction mixture was filtered by the use of Celite and the filtrate was concentrated.
To a solution of the resulting residue in dichloromethane (10 ml) was added di-tert-butyl dicarbonate (0.504 ml, 2.19 mmol) at room temperature, and stirred for 19 hours.
A saturated aqueous sodium hydrogencarbonate solution and then water were added to the reaction mixture, followed by extraction with chloroform.
The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 2/1) to obtain tert-butyl 4-hydroxyazepane-1-carboxylate (333 mg, 70percent).
Reference: [1] Patent: EP1500643, 2005, A1, . Location in patent: Page 48
  • 4
  • [ 3612-20-2 ]
  • [ 478832-21-2 ]
Reference: [1] Patent: EP1403255, 2004, A1,
[2] Patent: EP1500643, 2005, A1,
  • 5
  • [ 1208-75-9 ]
  • [ 478832-21-2 ]
Reference: [1] Patent: EP1403255, 2004, A1,
[2] Patent: EP1500643, 2005, A1,
  • 6
  • [ 109162-29-0 ]
  • [ 478832-21-2 ]
Reference: [1] Patent: EP1500643, 2005, A1,
  • 7
  • [ 24424-99-5 ]
  • [ 478832-21-2 ]
Reference: [1] Patent: WO2013/21051, 2013, A1,
[2] Patent: US2014/171418, 2014, A1,
  • 8
  • [ 79099-07-3 ]
  • [ 478832-21-2 ]
Reference: [1] Patent: WO2015/110481, 2015, A1,
[2] Patent: US2016/332963, 2016, A1,
  • 9
  • [ 1208-76-0 ]
  • [ 478832-21-2 ]
Reference: [1] Patent: US2014/171418, 2014, A1,
  • 10
  • [ 478832-21-2 ]
  • [ 188975-88-4 ]
YieldReaction ConditionsOperation in experiment
81% With sulfur trioxide pyridine complex; triethylamine In dimethyl sulfoxide at 20℃; for 3.5 h; (d)
Synthesis of tert-butyl 4-oxoazepane-1-carboxylate
Triethylamine (35 ml) and a sulfur trioxidepyridine complex (20 g, 130 mmol) were added to a solution of tert-butyl 4-hydroxyazepane-1-carboxylate (3.5 g, 16.3 mmol) in dimethyl sulfoxide (90 ml), and the resulting mixture was stirred at room temperature for three and a half hours.
The reaction mixture was poured into water and extracted with ethyl acetate.
The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then filtered.
The filtrate was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate = 4/1) to obtain tert-butyl 4-oxoazepane-1-carboxylate (2.80 g, 81percent).
Reference: [1] Patent: EP1500643, 2005, A1, . Location in patent: Page 48
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