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Chemical Structure| 240401-09-6
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Product Details of [ 240401-09-6 ]

CAS No. :240401-09-6 MDL No. :MFCD09749842
Formula : C13H23NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :HCDWHGFENXBNSC-UHFFFAOYSA-N
M.W : 257.33 Pubchem ID :22744549
Synonyms :

Calculated chemistry of [ 240401-09-6 ]

Physicochemical Properties

Num. heavy atoms : 18
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.92
Num. rotatable bonds : 3
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 71.18
TPSA : 59.0 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) : -7.27 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.81
Log Po/w (XLOGP3) : 0.85
Log Po/w (WLOGP) : 1.16
Log Po/w (MLOGP) : 0.88
Log Po/w (SILICOS-IT) : 1.0
Consensus Log Po/w : 1.34

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.77
Solubility : 4.34 mg/ml ; 0.0169 mol/l
Class : Very soluble
Log S (Ali) : -1.67
Solubility : 5.47 mg/ml ; 0.0213 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.26
Solubility : 14.1 mg/ml ; 0.0547 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.59

Safety of [ 240401-09-6 ]

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 [ 240401-09-6 ]

* 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 [ 240401-09-6 ]
  • Downstream synthetic route of [ 240401-09-6 ]

[ 240401-09-6 ] Synthesis Path-Upstream   1~6

  • 1
  • [ 954236-44-3 ]
  • [ 240401-09-6 ]
YieldReaction ConditionsOperation in experiment
96% at 0 - 23℃; for 2 h; Inert atmosphere Sodium borohydride (445 mg, 11.8 mmol) was added to a 0° C. solution of tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.50 g, 5.88 mmol) in methanol (59 mL) and the reaction mixture was stirred at 23° C. for 2 hours.
After removal of solvent in vacuo, the residue was partitioned between ethyl acetate and water.
The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a mixture of C74 and C75 as a colorless oil.
Yield of racemic product: 1.45 g, 5.63 mmol, 96percent. GCMS m/z 257.1 [M+].
1H NMR (400 MHz, CDCl3) δ 4.54-4.48 (br m, 1H), 3.93 (dd, half of ABX pattern, J=10.2, 4.3 Hz, 1H), 3.85-3.79 (m, 1H), 3.67-3.53 (br m, 2H), 3.40-3.28 (m, 2H), 1.97 (dd, half of ABX pattern, J=13.7, 6.2 Hz, 1H), 1.89-1.48 (m, 6H, assumed; partially obscured by water peak), 1.46 (s, 9H). A portion of this racemic material (1.30 g, 5.05 mmol) was separated into its component enantiomers via supercritical fluid chromatography [Column: Phenomenex Lux Amylose-1, 5 μm; Mobile phase: 85:15 carbon dioxide/(methanol containing 0.2percent ammonium hydroxide)]. (0402) The first-eluting product, obtained as a gum that exhibited a negative (−) rotation, was designated as C74. Yield: 650 mg, 2.53 mmol, 50percent for the separation. The second-eluting product, obtained as a solid that exhibited a positive (+) rotation, was designated as C75. Yield: 620 mg, 2.41 mmol, 48percent for the separation. The indicated absolute stereochemistries of C74 and C75 were assigned on the basis of conversion of C74 to C72 (see step 4).
96% With sodium tetrahydroborate In methanol at 0 - 23℃; for 2 h; Sodium borohydride (445 mg, 11.8 mmol) was added to a 0° C. solution of tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.50 g, 5.88 mmol) in methanol (59 mL) and the reaction mixture was stirred at 23° C. for 2 hours. After removal of solvent in vacuo, the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a mixture of C32 and C33 as a colorless oil. Yield of racemic product: 1.45 g, 5.63 mmol, 96percent. GCMS m/z 257.1 [M+]. 1H NMR (400 MHz, CDCl3) δ 4.54-4.48 (br m, 1H), 3.93 (dd, half of ABX pattern, J=10.2, 4.3 Hz, 1H), 3.85-3.79 (m, 1H), 3.67-3.53 (br m, 2H), 3.40-3.28 (m, 2H), 1.97 (dd, half of ABX pattern, J=13.7, 6.2 Hz, 1H), 1.89-1.48 (m, 6H, assumed; partially obscured by water peak), 1.46 (s, 9H).
Reference: [1] Patent: US2018/208607, 2018, A1, . Location in patent: Paragraph 0226; 0384; 0400-0402
[2] Patent: US2018/208608, 2018, A1, . Location in patent: Paragraph 0322; 0339
[3] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 21, p. 6545 - 6553
  • 2
  • [ 757239-75-1 ]
  • [ 240401-09-6 ]
YieldReaction ConditionsOperation in experiment
48%
Stage #1: With borane-THF In tetrahydrofuran at 0 - 20℃; for 1 h;
Stage #2: With sodium hydroxide; dihydrogen peroxide In tetrahydrofuran; water at 0 - 20℃; for 18 h;
Borane-tetrahydrofuran-complex solution in tetrahydrofuran (16. 7mL, 1M. 16. 7MMOL) was added to a solution of tert-butyl 1-oxa-8-azaspiro [4.5] dec-3-ene-8- carboxylate (from step (iv) above; 2g, 8. 37MMOL) in tetrahydrofuran (25mL) at 0°C. After lh at room temperature, a mixture of 35 percent w/w hydrogen peroxide solution (6ML, ca. 67mmol) and 4 M sodium hydroxide solution (17mL) was slowly added at 0°C. Then the reaction mixture was stirred at room temperature for 18h before it was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium sulfite solution, then brine and finally dried over magnesium sulfate, filtered and concentrated to give the crude mixture of products as a colourless oil. The mixture was separated by flash chromatography on silica gel, eluting with a gradient solvent system of 50-100 percent ethyl acetate in hexane, then 1-2 percent methanol in ethyl acetate to furnish 1.03g of the title compound (48 percent). H NMR (360 MHz, CDC13) : 8 4.51-4. 49 (1H, m), 3.92 (1H, dd, J4. 4, 10. LHZ), 3. 84- 3.79 (1H, m), 3.59 (1H, br s), 3.38-3. 30 (1H, m) 1.96 (1H, dd, J 6. 3,13. 6Hz), 1. 85- 1.79 (2H, m), 1.73-1. 63 (2EI, m), 1. 58-1. 50 (2H, m), 1.45 (9H, s).
Reference: [1] Patent: WO2004/78750, 2004, A1, . Location in patent: Page 88-89
  • 3
  • [ 203662-51-5 ]
  • [ 240401-09-6 ]
YieldReaction ConditionsOperation in experiment
35%
Stage #1: With sodium periodate In water; <i>tert</i>-butyl alcohol at 50℃; for 0.5 h; Industry scale
Stage #2: With sodium disulfite In water; <i>tert</i>-butyl alcohol at 20 - 50℃; for 59 h; Industry scale
tert-butyl (3RS)-3-hydroxy-1-oxa-8-azaspiro[4.5ldecane-8-carboxylate tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (1153 g, 4.8 mol) was dissolved in tert-butanol (10 L) and water (4 L). To the solution sodium periodate (1124 g, 5.3 mol, 1.1 eq) was added and the mixture was stirred at 50 0C for 30 minutes. At 50 0C a solution of Na2S2O5 (1007 g, 5.3 mol, 1.1 eq) in water (4.2 L) was added dropwise over 4 hours to the solution. After addition the reaction mixture was stirred for 7 hours at 50 0C and another 48 hours at RT. The mixture was transferred to an extraction vessel and the organic layer was separated from the aqueous layer. The aqueous layer was extracted (3x) with ethyl acetate. The organic layers were combined and washed with a saturated solution of Na2S2O3 (3x) to give a colorless solution. The solution was washed with brine and evaporated to give crude product (987 g, 80percent). The crude product was purified by flash chromatography (10-80percent EtOAc/Heptane) to give the title compound (287 g, 35percent). m/z 158 (MH+ minus Boc).
Reference: [1] Patent: WO2010/58318, 2010, A1, . Location in patent: Page/Page column 26
  • 4
  • [ 240401-08-5 ]
  • [ 240401-09-6 ]
Reference: [1] Patent: US6498159, 2002, B1,
  • 5
  • [ 79099-07-3 ]
  • [ 240401-09-6 ]
Reference: [1] Patent: WO2018/26371, 2018, A1,
  • 6
  • [ 240401-09-6 ]
  • [ 954236-44-3 ]
YieldReaction ConditionsOperation in experiment
97% With pyridine-SO3 complex; triethylamine In dimethyl sulfoxide at 0 - 20℃; tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5ldecane-8-carboxylateTo a solution of tert-butyl (3RS)-3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (30 g, 120 mmol) in DMSO (300 mL) and triethylamine (58.5 mL, 420 mmol) at 0 0C was added pyridine sulfur trioxide (65 g, 410 mmol, CASNo. 26412-87-3) in 10 g batches. The reaction was stirred at room temperature for 2 hr. The reaction was followed by TLC (10percent IPA/Heptane) visualizing with iodine stain. The solution was poured into ice-cold water (1 L) and extracted with EA (3x 300 mL). The combined organic layers were washed with 0.5 N HCI (3 x 400 mL), sodium sulfite (1 x 400 mL), and brine (1 x 400 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give -33 g of an orange oil. The oil was purified by flash chromatography (2-20percent IPA/Heptane) to give the title compound as a white solid (28.8 g, 97percent). 1H NMR (400 MHz, CDCI3) δ ppm 1.44 - 1.52 (m, 9 H), 1.61 - 1.73 (m, 2 H), 1.75 - 1.87 (m, 2 H), 2.38 (s, 2 H), 3.40 (ddd, J=13.48, 10.24, 3.24 Hz, 2 H), 3.67 (dt, J=13.57, 4.48 Hz, 2 H), 4.04 (s, 2 H).
2 g With Dess-Martin periodane In dichloromethane at 25℃; for 3 h; C. To a solution of tert-butyl 3-hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (5.2 g, 20.2 mmol) in DCM (200 mL) was added Dess-Martin periodinane (12.8 g, 30.3 mmol) at 25 °C. The reaction was stirred at ambient temperature for 3 h. Saturated aqueous Na2CO3 (100 mL) was added to the reaction vessel and the resulting biphasic mixture was transferred to a separatory funnel. The layers were separated and the aqueous phase was extracted with DCM (50 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with a gradient elution of EtOAc (5percent) and hexanes (95percent) to EtOAc (10percent) and hexanes (90percent) to provide tert-butyl 3-oxo-1-oxa-8- azaspiro[4.5]decane-8-carboxylate (2.00 g, 7.83 mmol) as a white solid.
Reference: [1] Patent: WO2010/58318, 2010, A1, . Location in patent: Page/Page column 26-27
[2] Patent: WO2018/26371, 2018, A1, . Location in patent: Paragraph 0320
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