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[ CAS No. 85838-94-4 ] {[proInfo.proName]}

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Chemical Structure| 85838-94-4
Chemical Structure| 85838-94-4
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Product Details of [ 85838-94-4 ]

CAS No. :85838-94-4 MDL No. :MFCD04972245
Formula : C10H17NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :SHHHRQFHCPINIB-UHFFFAOYSA-N
M.W : 183.25 Pubchem ID :13094787
Synonyms :

Calculated chemistry of [ 85838-94-4 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.7
Num. rotatable bonds : 3
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 56.12
TPSA : 29.54 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) : -6.14 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.73
Log Po/w (XLOGP3) : 1.8
Log Po/w (WLOGP) : 1.8
Log Po/w (MLOGP) : 1.61
Log Po/w (SILICOS-IT) : 1.03
Consensus Log Po/w : 1.79

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.91
Solubility : 2.24 mg/ml ; 0.0122 mol/l
Class : Very soluble
Log S (Ali) : -2.04
Solubility : 1.67 mg/ml ; 0.00913 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.04
Solubility : 16.9 mg/ml ; 0.092 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.16

Safety of [ 85838-94-4 ]

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

Application In Synthesis of [ 85838-94-4 ]

* 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 [ 85838-94-4 ]
  • Downstream synthetic route of [ 85838-94-4 ]

[ 85838-94-4 ] Synthesis Path-Upstream   1~2

  • 1
  • [ 85838-94-4 ]
  • [ 156496-89-8 ]
Reference: [1] Patent: WO2013/138210, 2013, A1,
  • 2
  • [ 85838-94-4 ]
  • [ 161157-50-2 ]
YieldReaction ConditionsOperation in experiment
94% With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 16 h; According to WO 97/10212, to a solution of tert-butyl 5, 6-dihydropyridine-l (2H) -carboxylate (2.00 g, 10.9 mmol) in DCM was added MCPBA (4.16 g, 18.6 mmol) and the mixture was stirred for 16 hours. It was then washed with saturated aqueous sodium metabisulfite, saturated aqueous sodium bicarbonate, IN NaOH, and brine. The organic layer was dried (sodium sulfate) , filtered, and concentrated in vacuo to give tert-butyl 7-oxa-3-aza-bicyclo [4.1.0]heptane-3-carboxylate(2.04 g, 94percent) as an oil: 1H NMR (400 MHz, CDCl3) δ 1-45 (s, <n="138"/>9H) , 1 . 91 (m, IH) , 2 . 04 (br, IH) , 3 . 11 (m, IH) , 3 . 21 (br , IH) , 3 . 29 (m, IH) , 3 . 45 (br , IH) , 3 . 70 (br, IH) , 3 . 88 (br, IH ) .
93% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 14 h; Step 3) 3-(tert-butoxycarboxyl)-7-oxa-3-azabicyclo[4.1.0]heptane [0243] To a solution of m-CPBA (20 g, 87.4 mmol) in DCM (150 mL) was added l-(tert- butoxycarboxyl)-l,2,3,6-tetrahydropyridine (8 g, 43.7 mmol) dropwise at 0 °C.The reaction was stirred at rt for 14 h,then filtered. The filter cake was washed with DCM (50 mL x 2), and the combined filtrates were washed with saturated aqueous a2C03 (300 mL x 2). The solution was dried over anhydrous Na2S04, concentrated in vacuo, and then purified by a silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as colorless oil (8 g, 93 percent). NMR (400 MHz, CDC13) δ (ppm): 3.92-3.82 (m, 1H), 3.71 (m, 1H), 3.44 (m, 1H), 3.29-3.28 (m, 1H), 3.21-3.10 (m, 2H), 2.04 (m, 1H), 1.95-1.88 (m, 1H), 1.45 (s, 9H).
93% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 14 h; To a solution of m-CPBA (2 mmol) in DCM (8 v) was added tertbutyl5,6-dihydropyridine-1(2H)-carboxylate (1 mmol) in DCM (2v) drop-wise at 0 C. The reaction mixture was stirred at rt for 14 h,then filtered. The filter cake was washed with DCM (10 v x 2) andthe combined filtrates were washed with saturated aqueousNa2CO3 (300mL x 2). The solution was dried over anhydrousNa2S04, concentrated in vacuo and purified by a silica gel columnchromatography to give the title compound as colorless oil in 93percentyield. 1H NMR (400 MHz, DMSO‑d6): d 3.60 (s, 2H), 3.29e3.10 (m,4H), 1.88e1.81 (m, 2H), 1.38 (s, 9H); 13C NMR (100 MHz, DMSO‑d6):d 154.02, 78.69, 49.68 & 49.32, 47.27 & 41.67, 37.91, 36.68, 27.96,23.42; LC-MS (ESI) m/z Calcd. for C10H17NO3: 199.12, Found: 144.32[M-tBu].
87% With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 5 h; .1 g (11.5 mmol) of t-butyl 3,6-dihydroxypyridin-l(2H)-carboxylate (product of step 1) and 3.1 g (12.6 mmol) of m-chloro benzoic acid was dissolved in 30 mL of methylene chloride, and after stirring for 5 hour, 100 mL of ethylacetate was added thereto. After washing with water, an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography to give 2.1 g (10.5 mmol) of the title compound in a yield of 87percent.[1193] Mass (m/e) 200 (M+l)
80% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; Step 3: A solution of 3-chloroperoxybenzoic acid (21.18 g, 122.7mmol) in dichloromethane (150 mL) was added to a solution of N-boc-1,2,3,6-tetrahydropyridine (15.0 g, 81.8mmol) in dichloromethane (150 mL) at 0°C. The mixture was stirred at room temperature overnight and washed with saturated solution of Na2CO3. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuoand purified by column chromatography using silicagel 60-120 mesh to yield the title compound Int A1(13.0 g, 80percent). 1H NMR (400 MHz, CDCl3): 3.93 (s, 1H), 3.83 (s, 1H), 3.70 (s, 1H), 3.44 (s, 1H),3.30 (d, J = 2.00 Hz, 1H), 3.14 (s, 1H),1.88-1.89 (m, 1H), 1.46 (s, 9H). 3,6-difluoro-9H-carbazole IntB1 is prepared according to the protocol of Bedford, Robin B. et al Tetrahedron 2008, 64, 6038-6050.
78% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 18.5 h; A solution of (3a) (15.0 g, 81.9 mmole) in CH2Cl2 (150 mL) was treated with a solution of meta-chloroperbenzoic acid (18. 36 g, 106.4 mmole) in CH2Cl2 (300 mL) which was added over 30 minutes at 0 °C. The solution was allowed to warm to room temperature and stirred for 18 hr. The reaction solution was washed with 5percent aqueous K2CO3 and saturated NaCl solution, then dried over Na2SO4 and concentrated in vacuo to yield an off-white solid. This was flash chromatographed on silica gel (20percent EtOAc/hexanes) to yield a white solid (12.80 g, 78percent). MS (ES) nilz 200 (M + H) +.
72.6% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 1 h; To a solution of mt 4-6 (617 g, 3.37 mol) in anhydrous DCM (10 L) was added m-CPBA (989 g, 5.73 mol) in portions at 0°C, then the mixture was allowed to stir at room temperature for 1 hours. TLC (petroleum ether:EtOAc = 5:1) showed the reaction was complete. Saturated Na25203 (1 L) was added and separated, then the organic layer was washedwith 5percent aqueous K2C03 (5 L x 2), brine (4 L), dried over Na2504, concentrated in vacuo to get crude compound mt 4-7 which was purified using column chromatography (PE:EA=100:1-20:1) to obtain pure compound mt 4-7 (460 g, 72.6 percent). ‘H NMR: (CDC13) ö 3.85 (m, 1H), 3.65 (m, 1H), 3.39 (m, 1H), 3.26 (s, 1H), 3.18 (bs, 1H), 3.11 (m, 1H), 2.00 (m, 1H), 1.85 (m, 1H), 1.45 (s, 9H).
71% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0℃; tert-Butyl-1,2,3,6-tetrahydropyridine-1-carboxylate 15 (30 g, 164 mmol) was then dissolved in dichloromethane (200 mL) and cooled to 0°C. A solution of m-chloroperbenzoic acid (70percent w/w, 46.4 g, 188 mmol) in dichloromethane (200 mL) was added dropwise over 30 min. The ice-bath was removed and the resulting colourless mixture stirred overnight. The solution was filtered to remove salts and washed with 5percent aqueous potassium carbonate, brine and three times with saturated aqueous sodium thiosulfite. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 12 as a clear yellow oil. The crude product was subjected to flash chromatography (SiO2, pentane/diethylether 70/30) to afford the pure title compound 12 (23 g, 71percent). Rf=0.31 (SiO2, pentane/diethylether 7/3); 1H NMR (200 MHz, CDC13) δ: 1.32 (s, 9H), 1.67–2.0 (m, 2H), 2.9–3.35 (m, 4H), 3.51–3.78 (m, 2H); 13C NMR (150 MHz, CDCl3) δ: 154.8, 79.8, 50.6, 50.1 (br), 42.8, 41.9, 37.9, 36.4, 28.4, 24.4.
67% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; The product from Part A (14.9 g, 81.4 mmol) was dissolved in CH2CI2 (100 mL), and the solution was cooled in an ice-water bath. M-CPBA (18.25 g, 106 mmol) in CH2Cl2 (200 mL) was then added over 30 min. The reaction mixture was allowed to warm to rt and stirred overnight. The mixture was washed with 5percent aqueous K2CO3 (2X100 mL) and saturated NACI (2X100 ML), dried over MGSO4, and concentrated in vacuo to yield a white foam. Further purification by flash chromatography (ISCO system, 20percent EtOAc/Hex) GAVE 7-OXA-3-AZA- bicyclo [4.1. 0] heptane-3-carboxylic acid tert-butyl ester as a colorless oil (10.96 G, 67percent). LC-MS: (M+H) : 200.
64% With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 35℃; for 16 h; Inert atmosphere m-Chloroperbenzoic acid (11.9 g, 229.19 mmol) was added to a solution of tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate (30 g, 163.71 mmol) in dichloromethane (150 mL) at 0°C, and the mixture was stirred under a nitrogen gas atmosphere at room temperature for 16 hr.
To the reaction mixture was added ice water (500 mL), and the mixture was extracted with ethyl acetate (2*500 mL).
The organic layer was washed with an aqueous sodium hydrogen carbonate solution, brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column chromatography (solvent gradient; 15→20percent ethyl acetate/hexane) to give tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (21 g, 64percent) as a pale-yellow oil.
1H NMR (400 MHz, CDCl3):δ 1.43(9H,s), 1.85-1.92(1H,m), 2.02(1H,m), 3.09(1H,t,J=8.9 Hz), 3.19(1H,br s),3.27(1H,s), 3.41(1H,br s),3.68(1H,br s),3.81-3.95(1H,m).
460 g With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 1 h; Step G- Preparation of Int 4-7 Int 4-6 Int 4-7 To a solution of Int 4-6 (617 g, 3.37 mol) in anhydrous DCM (10 L) was added m-CPBA (989 g, 5.73 mol) in portions at 0°C, then the mixture was allowed to stir at room temperature for 1 hours. TLC (petroleum ether:EtOAc = 5:1) showed the reaction was complete. Saturated Na2S203 (1 L) was added and separated, then the organic layer was washed with 5percent aqueous K2C03 (5 L x 2), brine (4 L), dried over Na2S04, concentrated in vacuo to get crude compound Int 4-7 which was purified using column chromatography (PE:EA=100: 1-20: 1) to obtain pure compound Int 4-7 (460 g, 72.6 percent). 1H NMR: (CDC13) δ 3.85 (m, 1H), 3.65 (m, 1H), 3.39 (m, 1H), 3.26 (s, 1H), 3.18 (bs, 1H), 3.11 (m, 1H), 2.00 (m, 1H), 1.85 (m, 1H), 1.45 (s, 9H).
29.25 g With sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 4 h; Step 2. tert-Butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate. Sodium bicarbonate (29 g, 346.2 mmol) was added in portions to a solution of tert-butyl 5,6-dihydropyridine-1(2H)-carboxylate (39.6 g, 216.3 mmol) in DCM (871 mL) at 0° C. m-Chloroperbenzoic acid (78 g, 454.4 mmol) was then added portionwise at 0° C. and stirred for 2 h at the same temperature, and then at room temperature for another 2 h. The insoluble material was filtered away and the filtrate was washed with water, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica (100-200 mesh), eluting with 10percent ethyl acetate in petroleum ether to give tert-butyl 7-oxa-3-azabicyclo[4.1.0]hep-tane-3-carboxylate (29.25 g, 69percent) as a pale yellow liquid. TLC system: Rf=0.3 (30percent Ethyl acetate in petroleum ether). 1H NMR (300 MHz, DMSO-d6) δ 3.7 (t, 2H), 3.05-3.45 (overlapping signals, 4H), 1.7-2.0 (m, 2H), 1.4 (s, 9H). GCMS: (m/z) 199.2 (M+); (Purity: 98percent).
0.43 g With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 18 h; To a solution of 0.50 g (2.73 mmol) of tert-butyl 3,6-dihydro-2H-pyridine-i-carboxylate in 30 mL of DCM was added 0.92 g (4.09 mmol) of mCPBA. The resultant solution was stirred at 20°C for 18 h. TLCindicated that the reaction was complete. The reaction was diluted with DCM, washed with aq. NaHCO3, aq. Na2S2O3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE/EA, 5/i, R1= 0.2) to give 0.43 g of tert-butyl 7-oxa-4-azabicyclo[4.i.0]heptane-4- carboxylate as a colorless oil.MS (+ESI): 144.1 [M+H].‘H NMR (400 MHz, CDC13) ppm: 4.09-3.58 (m, 2H), 3.57-3.02 (m, 4H), 2.18-1.84 (m, 2H), 1.47 (s,9H).
6.8 g With 3-chloro-benzenecarboperoxoic acid In toluene at 20℃; for 16 h; A)
(cis-4-Azido-3-hydroxypiperidin-1-yl)(3,4-dimethoxyphenyl)methanone
To a solution of tert-butyl 5,6-dihydropyridine-1(2H)-carboxylate (5.1 g) in toluene (50 mL), 70percent m-CPBA (7.4 g) was added at room temperature, and the mixture was stirred at room temperature for 16 hours.
The deposit was filtered off, and the solvent in the filtrate was distilled off under reduced pressure.
An aqueous sodium thiosulfate solution was added to the residue, followed by extraction with ethyl acetate.
The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (6.8 g).

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[4] Patent: WO2013/138210, 2013, A1, . Location in patent: Paragraph 0243
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[6] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 16, p. 4523 - 4526
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