| 92% |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 4h; 0 deg C to r.t.; |
|
| 92% |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 25℃; for 4h; |
|
| 92% |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; Inert atmosphere; |
20.2 Synthesis of 7-Oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester
A solution of 3,6-Dihydro-2H-pyridine-1-carboxylic acid benzyl ester (8.58 g, 39.5 mmol) in DCM (80 mL) under argon was cooled to 0°C. m-Chloroperoxybenzoic acid (10.95 g, 75%), 47.6 mmol) in DCM (60 mL) was added dropwise over 20 minutes. The reaction was stirred at 0°C for 30 minutes then allowed to come to room temperature overnight. The reaction was diluted with DCM and washed successively with aqueous Na2S2O3, saturated NaHCO3, and brine. The organic layer was dried over Na2S04, filtered, and concentrated to provide 8.45 g (92%) of a white solid. ESI-MS m/z 256 (M+Na)+ |
| 90% |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 4h; |
|
| 79.8% |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 5 - 20℃; for 4.33h; |
61.2 Step 2: Preparation of 7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester
To a solution of 7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester (6.86g, 31.6mmol) in DCM (65ml_) at 0°C was added m-CPBA (8.28g, 48mmol) portion wise. After addition the reaction was maintained at 5°C for 20 minutes and then at RT for 4 hours. The reaction mixture was diluted with Et20 (150 ml_), washed with 1 N NaOH solution (2 x 50ml_), sat sodium thiosulphate solution (2 x 50ml_) and saturated aqueous sodium chloride. The organics were dried (MgS04) and concentrated in vacuo. Crude material was purified by automated column chromatography, eluting with iso-hexane to 10% EtOAc /iso- Hexane (gradient). Fractions found to contain product were combined and solvent removed in vacuo to afford the desired compound as a colourless gum, 5.88g, 79.8% |
| 79.8% |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 4.33h; |
61.2 Step 2: Preparation of 7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester
To a solution of 7-Oxa-3-aza-bicyclo[4.1.0]hep- tane-3-carboxylic acid benzyl ester (6.86 g, 31.6 mmol) in DCM (65 mE) at 0°C. was added m-CPI3A (8.28 g, 48 mmol) portion wise. Afier addition the reaction was maintained at 5° C. for 20 minutes and then at RT for 4 hours. The reaction mixture was diluted with Et20 (150 mE), washed with iN NaOH solution (2x50 mE), sat sodium thiosulphate solution (2x50 mE) and saturated aqueous sodium chloride. The organics were dried (Mg504) and concentrated in vacuo. Crude material was purified by automated column chromatography, eluting with iso-hexane to 10% EtOAc/iso-Hexane (gradient). Fractions found to contain product were combined and solvent removed in vacuo to afford the desired compound as a colourless gum, 5.88 g, 79.8% |
| 79% |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 18h; Inert atmosphere; Cooling with ice; |
Intermediate 36: Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate
Intermediate 36: Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate 3-Chlorobenzoperoxoic acid (16.79 g, 97 mmol) was added portionwise under an atmosphere of nitrogen to a stirred solution of benzyl 5,6-dihydropyridine-1(2H)-carboxylate (15.1 g, 69.5 mmol) (available, for example, from Fluorochem) in anhydrous dichloromethane (DCM) (100 mL) cooled using an ice bath. The resulting mixture was allowed to reach rt and stirred for 18 h. Water (100 mL) was added to the reaction mixture and the layers were partitioned. The organic layer was added dropwise to a stirred 5% aqueous solution of NaS2O5 (200 mL). At the end of the addition, the mixture was stirred for a further 1 h, then the layers were separated and the aqueous layer was back extracted with DCM (50 mL*2). The organics were combined and washed with 5% aqueous K2CO3 solution (100 mL*3), followed by brine (100 mL). At this stage peroxide test showed there was still 25 mg/mL peroxide in the organic layer. The organics were therefore added to a stirred solution of 5% NaS2O5(aq) (200 mL) and the resultant biphasic mixture stirred for 1 h. Peroxide test now showed <0.5 mg/mL peroxide. The layers were separated and aqueous layer washed with further DCM (2*50 mL). The combined organics were then dried (Na2SO4). and concentrated in vacuo to afford the crude product as a pale-gold oil. The crude product was purified by silica gel chromatography, (340 g Si), eluting with 30->80% EtOAc/cyclohexane. The appropriate fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil-benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (12.75 g, 54.7 mmol, 79% yield). LCMS (Method B): Rt=0.88 min, MH+=234.2 |
| 79% |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 18h; Inert atmosphere; Cooling with ice; |
73 Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate
3-Chlorobenzoperoxoic acid (16.79 g, 97 mmol) was added portionwise under an atmosphere of nitrogen to a stirred solution of benzyl 5,6-dihydropyridine-l(2H)-carboxylate (15.1 g, 69.5 mmol) (available, for example, from Fluorochem) in anhydrous dichloromethane (DCM) (100 mL) cooled using an ice bath. The resulting mixture was allowed to reach rt and stirred for 18 h. Water (100 mL) was added to the reaction mixture and the layers were partitioned. The organic layer was added dropwise to a stirred 5% aqueous solution of NaS205 (200 mL). At the end of the addition, the mixture was stirred for a further 1 h, then the layers were separated and the aqueous layer was back extracted with DCM (50 mL x 2). The organics were combined and washed with 5% aqueous K2C03solution (100 mL x 3), followed by brine (100 mL). At this stage peroxide test showed there was still 25 mg/mL peroxide in the organic layer. The organics were therefore added to a stirred solution of 5% NaS205(aq) (200 mL) and the resultant biphasic mixture stirred for 1 h. Peroxide test now showed <0.5 mg/mL peroxide. The layers were separated and the aqueous layer washed with further DCM (2 x 50 mL). The combined organics were then dried (Na2S04). and concentrated in vacuo to afford the crude product as a pale-gold oil. The crude product was purified by silica gel chromatography, (340g Si), eluting with 30->80% EtOAc/cyclohexane. The appropriate fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil - benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (12.75 g, 54.7 mmol, 79 % yield).LCMS (Method B): Rt = 0.88 min, MH+= 234.2 |
| 74% |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; |
6.2
Step 2. Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate A solution of benzyl 5,6-dihydropyridine-1(2H)-carboxylate (9.93 g, 45.76 mmol) in CH2Cl2 (75 mL) was cooled to 0° C. (ice/water bath), and solid m-chloroperoxybenzoic acid (77%, 15.38 g, 1.5 equiv) was added. After 10 min at 0° C., the reaction mixture was warmed slowly to rt. After stirring for 2 h, LC-MS showed the reaction was complete. The mixture was diluted with ether (300 mL), washed with 5% aq NaOH (2*40 mL), 25% aq Na2S2O3 solution (3*20 mL), brine (30 mL), and dried over Na2SO4. After concentration, the residue was purified by flash chromatography (120 g silica gel column, 12%-70% EtOAc in hexanes gradient, 2nd UV peak) to afford benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (7.87 g, 74% yield). LC-MS (3 min) tR=1.41 min., m/z 234 (M+1). |
| 72% |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 5.25h; |
15.2
Second StepBenzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylateCbz-protected pyridine obtained in the first step (0.369 g, 1.70 mmol) was dissolved in CH2Cl2 (2 mL) and cooled in at 0° C. A solution of mCPBA (0.411 g, 2.38 mmol) in CH2Cl2 (3 mL) was added drop wise to the reaction mixture over a period of 15 min. The reaction mixture was stirred at rt for 5 hrs after which TLC analysis indicated full conversion of the starting material. The completed reaction mixture was then washed three times with 5% aqueous K2CO2 (3×25 mL), and once with a saturated aqueous solution of NaCl (1×25 mL). The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. Purification by flash chromatography gave the title compound as a colourless oil (0.284 g, 72%); analytical data is in accordance with literature (Solares, L. F.; et al., Tetrahedron 2006, 62, (14), 3284-3291). |
| 64% |
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 7h; |
|
|
With 3-chloro-benzenecarboperoxoic acid In dichloromethane Ambient temperature; |
|
|
With Rhodococcus rhodochrous 9703; oxygen Enzymatic reaction; |
|
|
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 7h; |
1
7-oxa-3-aza-bicvclor4.1.01heptane-3-carboxylic acid benzyl ester (3); [0052] The 3,6-Dihydro-2H-pyridine-l-carboxylic acid benzyl ester 2 (2.6 g, 12 mmol) is dissolved in dichloromethane (100 mL). m-Chloroperbenzoic acid (4.5 g, 18 mmol) dissolved in dichloomethane (40 mL) is added dropwise over 20 min. The mixture is stirred at rt for 7 h, then the solution is washed with 1 M aqueous sodium carbonate three times and once with brine. The organic phase is separated, dried (MgSO4) and concentrated in vacuo to give the racemic epoxide 7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester (3) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ = 7.40-7.32 (m, 5H), 5.14 (s, 2H), 3.99 (m, IH), 3.80 (m, IH), 3.53 (m, IH), 3.31 (m, IH), 3.24 (m, IH), 2.10 (m, IH), 1.96 (m, IH). MS calcd. for Ci3H16NO3 (M+H+) 234.1, found 234.3. |
|
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 23℃; |
|
|
With glycerol In dimethyl sulfoxide at 4℃; for 48h; aq. phosphate buffer; Enzymatic reaction; |
|
|
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 4h; |
|
|
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 18h; Inert atmosphere; Cooling with ice; |
Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate
3-Chlorobenzoperoxoic acid (16.79 g, 97 mmol) was added portionwise under an atmosphere of nitrogen to a stirred solution of benzyl 5,6-dihydropyridine-i(2H)-carboxylate (15.1 g, 69.5 mmol) (available, for example, from Fluorochem) in anhydrous dichloromethane (DOM) (100 mL) cooled using an ice bath. The resulting mixture was allowed to reach rt and stirred for 18 h. Water (100 mL) was added to the reaction mixtureand the layers were partitioned. The organic layer was added dropwise to a stirred 5% aqueous solution of Na5205 (200 mL). At the end of the addition, the mixture was stirred for a further 1 h, then the layers were separated and the aqueous layer was back extracted with DCM (50 mL x 2). The organics were combined and washed with 5% aqueous K2003 solution (100 mL x 3), followed by brine (100 mL). At this stage peroxide test showed there was still 25 mg/mL peroxide in the organic layer. The organics were therefore added to astirred solution of 5% NaS2O5(aq) (200 mL) and the resultant biphasic mixture stirred for 1 h. Peroxide test now showed 80%EtOAc/cyclohexane. The appropriate fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil - benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3- carboxylate (12.75 g, 54.7 mmol, 79 % yield).LCMS (Method B): Rt = 0.88 mi MH = 234.2 |
|
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20 - 30℃; for 16h; |
24.2 Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate
mCPBA (14.6 g, 63.3 mmol) was added slowly to a stirred solution of benzyl 3,6-dihydropyridine-1(2H)-carboxylate (12.50 g, 57.5 mmol) in DCM (80 mL) which was cooled in an ice bath. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was then quenched with aq. Na2CO3 and the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound. LCMS calc. for C13H16NO3 (M+H)+: m/z=234.1. Found: 234.0. |
|
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at -15 - 20℃; for 15h; |
81.1 Step 1 : Synthesis of benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate
Step 1 : Synthesis of benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate To a solution of benzyl 5,6-dihydropyridine-l(2H)-carboxylate (3.8 g, 17 mmol) in DCM (60 ml) at -15 °C was added 3-chlorobenzoperoxoic acid (4.7 g, 70% pure, 19 mmol). The mixture was stirred at room temperature for 12 h and then washed with sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentration at reduced pressure. The crude mixture was purified by flash chromatography on silica gel (30% EtOAc/Heptane) to afford the desired product as a colorless oil. LC-MS (Acidic Method): ret.time= 1.08 min, M+H = 234.3. |
|
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; |
1 Intermediate I-11-2: Benzyl 7-oxa-3-azabicyclo [4.1.0] heptane-3-carboxylate
The solution of benzyl 5, 6-dihydropyridine-1 (2H) -carboxylate (25.0 g, 115 mmol) in dichloromethane (400 mL) was cooled to 0 . A solution of m-chloroperoxybenzoic acid (27.8 g, 160 mmol) in dichloromethane (100 mL) was added dropwise and the resulting colorless reaction mixture was warmed to room temperature. After stirred at room temperature overnight, the reaction mixture was washed with 5 %sodium sulfite aqueous solution (300 mL) three times and brine (500 mL) . The organic layer was dried over Na2SO4 (s), filtered and concentrated in vacuo to give the title compound (26.7 g, 84 %purity, 84 %yield) as yellow oil.[0530]LC-MS (ESI) : RT= 1.26 min, mass calcd. for C13H15NO3233.1, m/z found 251.2 [M+18]+. |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
