Structure of 31970-04-4
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CAS No. : | 31970-04-4 |
Formula : | C12H13NO2 |
M.W : | 203.24 |
SMILES Code : | O=C(N1CC=CC1)OCC2=CC=CC=C2 |
MDL No. : | MFCD01863559 |
InChI Key : | XSKKIFJNZPNVGO-UHFFFAOYSA-N |
Pubchem ID : | 643471 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | The title compound of Step 1 (3.0 g, 15 mmol) was dissolved in a mixture of acetonitrile (100 mL) and water (70 mL) containing ethylenediamine tetraacetate, disodium salt dihydrate (11 mg, 0.03 mmol). The solution was cooled to 0 C. and 1,1,1-trifluoroacetone (14.5 mL, 160 mmol) was added over 10 min. Potassium peroxymonosulfate (45 g, 74 mmol) was added portionwise over 40 min while maintaining the pH at 7 by adding sodium bicarbonate. The mixture was stirred at 0 C. for 1.5 hr then poured into water and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and concentrated to a colorless oil (3.45 g, 100%). | |
99% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; for 48h; | To a solution of the olefin (10. 0g, 49 MMOL) in CH2CI2 (250 ML, 0.2M) was added MCPBA (22g, 2.0 eq. ). The reaction was stirred for 48h and 200ML of saturated sodium thiosulfate was added. After 20 min, the layers were separated and the organic layer was washed with 2N NAOH (2 x 100ML). The organic layer was dried MgS04, filtered and concentrated to provide the title compound as an oil (10.79 G, 99%): 1H NMR (300 MHz, CDCI3) 8 7.35, 5.13, 3.93-3. 84,3. 71,3. 43-3.38 ; IR (LIQ.) 2209. (w), 2068 (w), 1958 (w), 1706 (s), 1455,1448, 1428 (s), 1397 (s), 1364, 1327 (s), 1214,1206, 1107 (s), 848 (s), 699, cm-1 Anal. CALCD for C12 H13 N 03 : C, 65.74 ; H, 5.98 ; N, 6.39. Found: C, 65.45 ; H, 6.07 ; N, 5.99. |
93% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; for 48h; | To a stirred solution of compound 1 (15g, 73.81 mmol, 1eq) inDCM (300mL) was added then the resulting mixture was stirred for 48h. TLC analysis indicated formation of a polar spot. The reaction mixture was basified with aqueous NaHC03 and extracted with EtOAc (3x100ml_). The combined organic layer was dried over Na2S04 then concentrated to crude compound. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) using 0-20% EtOAc in petroleum ether as eluent to afford compound 2 (15.2g, 93%) as yellow color liquid. |
88% | With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 46℃; for 20h; | Example 14; 8-(Y cis)-4-fluoropyrrol idin-3 -yloxy)-2-f 7-f 2-methoxyethoxy)imidazo fl,2-a1 pγridin-3 - yl)quinoline hydrochloride salt; Step A: Preparation of benzyl -oxa-S-azabicyclop.l.OJhexane-S-carboxylate:; Benzyl 2,5-dihydro-lH-pyrrole-l-carboxylate (11.0 g, 54.1 mmol, commercially available from Aldrich) and 3-chlorobenzoperoxoic acid (17.3 g, 70.4 mmol) were added to 150 mL of chloroform and heated to 46 0C for 20 hours. The mixture was cooled, dichloromethane was added, and the reaction was washed with a saturated solution OfNaHCO3 and Na2S2CO3. The combined organic layers were dried over MgSO4, filtered and concentrated to give 10.5 g (88% isolated yield) of the desired compound as an oil, which was used directly in the next step. |
86% | With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 45℃; | A mixture of commercially available 2,5-dihydro-pyrrole-1-carboxylic acid benzyl ester (5.0 g,24.6 mmol) and m-CPBA (77%, 11.1 g, 50 mmol) in chloroform (100 mL) was stirred at 45Covernight. The reaction mixture was diluted with DCM (100 mL) and washed sequentiallywith sat. aq. Na2S2O3, and iN NaOH. The organic layer was dried with anhydrous MgSO4 and then concentrated. The crude material was purified by chromatography on silica (20- 70% EtOAc in Petrol) to give the title compound (4.65 g, 86%) as an oil. MS: [M+H] = 220. |
83% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 18h; | Epoxidation of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate To a solution of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (33 g, 163 mmol; 90% from Aldrich) in dichloromethane (540 mL, 0.3 M solution) was added MCPBA (44 g, 340 mmol, 77% from Aldrich). After the reaction mixture was stirred at room temperature for 18 h, 500 mL of saturated Na2CO3 aqueous solution was added and the resulting mixture was stirred at room temperature for 1 h. The organic layer was separated, washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The desired product as a yellow oil was obtained in 83% yield (29.5 g) by flash column chromatography. 1H NMR (CDCl3, 400 MHz): δ 3.38 (2H, m), 3.68 (2H, m), 3.87 (2H, m), 5.11 (2H, s), 7.33 (5H, m). LC/MS (uplc): MH+ 220.0, 0.69 min. |
83% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 18h; | Step I: Epoxidation of alkene[00146] To a solution of benzyl 2,5-dihydro- 1 H-pyrrole- 1 -carboxylate (33 g, 163 mmol) in dichloromethane (0.3 M solution) was added MCPBA (44 g, 340 mmol, 77% from Aldrich). After the reaction mixture was stirred at room temperature for 18 h, 500 mL of saturated Na2C03 aqueous solution was added and the resulting mixture was stirred at room temperature for 1 h. The organic layer was separated, washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The desired product as a yellow oil was obtained in 83% yield (29.5 g) by flash column chromatography. NMR (CDCl3j 400 MHz): δ 3.38 (2H, m ), 3.68 (2H, m), 3.87 (2H, m), 5.1 1 (2H, s), 7.33( 5H, m). LC/MS (uplc): MH+ 220.0, 0.69 min. |
83% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 18h; | Benzyl 6-oxa-3-azabicvclo[3.1.Olhexane-3-carboxylate z To a solution of benzyl 2,5-dihydro-1 H-pyrrole-1-carboxylate (33 g, 163 mmol; 90% from Aldrich) in dichloromethane (540 ml_, 0.3 M solution) was added m-CPBA (44 g, 340 mmol, 77% from Aldrich). After the reaction mixture was stirred at room temperature for 18 h, 500 ml_ of saturated Na2C03 aqueous solution was added and the resulting mixture was stirred at room temperature for 1 h. The organic layer was separated, washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The desired product as a yellow oil was obtained in 83% yield (29.5 g) by flash column chromatography. Rf = 0.5 (30% EtOAc in hexanes). 1H NMR (CDCI3, 400 MHz): δ 3.38 (2H, dd, J = 12.8, 6.0 Hz ), 3.68 (2H, d, J = 3.6 Hz), 3.87 (2H, dd, J = 13.2, 19.6), 5.1 1 (2H, s), 7.33( 5H, m). LC/MS (uplc): MH+ 220.0, 0.69 min. |
80% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; | To a solution of benzyl 2,5-dihydropyrrole-1-carboxylate (62, 5.00 g, 24.6 mmol) in dichloromethane (30 mL) was added m-CPBA (8.59 g, 49.2 mmol). The mixture was stirred overnight at room temperature. The mixture was neutralized by using potassium carbonate, then extracted with chloroform 3 times. The combined organic layer was dried over sodium sulfate then concentrated. The residue was purified by amino silica gel column chromatography (hexane/ethyl acetate; 70:30 to 50:50) to give 63 as colorless oil (4.30 g, 80%). 1H-NMR (CDCl3) δ: 7.37-7.29 (5H, m), 5.11 (2H, dd, J = 16.2, 12.4 Hz), 3.86 (2H, dd, J = 19.4, 12.7 Hz), 3.67 (2H, d, J = 2.5 Hz), 3.40-3.36 (2H, m). MS:220 (M + H)+. |
71% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; | Part A: Phenylmethyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate. To a 0 0C solution of phenylmethyl 2,5-dihydro-1H-pyrrole-1-carboxylate (10.30 g, 50.68 mmol) in DCM (250 mL) was added m-CPBA (wet; ca. 75%; 17.49g). The solution was stirred and warmed to room temperature overnight. The solution was diluted with DCM and washed with 2 x 10% aq. NaHCO"3 - 1 N aq. NaOH (1 :1 ). The organic phase was dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by silica gel chromatography (40% EtOAc in hexanes) to give phenylmethyl 6-oxa-3- azabicyclo[3.1.0]hexane-3-carboxylate (7.90 g, 71 % yield) as a light yellow oil. |
70% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 48.3333h; | EXAMPLE 58; 2-(4-Chlorophenyl)-5-(6-((3i?,4i?)-3-hydroxy-4-(methylamino)pyrrolidin-l- yl)pyridin-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one; Example 58A. Benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate; [00268] A solution of benzyl 2,5-dihydro-lH-pyrrole-l-carboxylate (2 g, 9.8 mmol) in dichloromethane (50 niL) was cooled to 0 0C and m-CPBA (2.7 g, 11.8 mmol) was added over a period of 20 min. The reaction was stirred at room temperature for 2 days while a solid precipitated out of the solution. The solid was filtered off and the filtrate was successively washed with sat. aq. NaHSO3, 5% aq. K2CO3, and brine, dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography (5 to 60% ethyl acetate:hexanes) to afford Example 58A (1.5 g, 70 % yield). LC-MS, [M+H]+ = 220. 1H NMR (CDCl3, 400 MHz) δ 7.28 - 7.41 (m, 5 H), 5.12 (2d, J= 3.5 Hz, 2 H), 3.81 - 3.93 (m, 2 H), 3.66 - 3.71 (m, 2 H), 3.39 (m, 2 H). |
68% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 16h; | [BENZYL-3-PYRROLINE-1-CARBOXYLATE] (5 g, 24.6 mmol) and 3-chloroperoxybenzoic acid (8.5 g, 49.2 mmol) were dissolved in dichloromethane (250 [ML)] and stirred for 16 h at room temperature. The reaction mixture was washed with sat. [NAHC03,] brine and dried [(MGS04).] The title compound was isolated by silica gel chromatography (0-35% EtOAc-hexanes). Yield 3.6 g (68%). [1H NMR] (300 MHz, [CDC13)] : 3.34-3. 40 (d, [J=] 11 Hz, 2H), 3.66 (s, 2H), 3.80- 3.89 (t, [J=] 12 Hz, 2H), 5. [10] (s, 2H), 7.27-7. [38] (m, [5H).] |
68% | Example 1.3: Benzyl 3,4-epoxypyrrolidine-i-carboxylate (5); NBS (5.47 g, 31 mmol) is added to a solution of olefin 4 (5.02 g, 25 mmol) in DMSO (65 mL) and water (3.4 mL) at 0 0C. The reaction mixture is warmed to room temperature, stirred for 1.5 h then further NBS (1.1 g, 6.2 mmol) is added. After stirring for a further 3.5 h the reaction is quenched by the addition of water (150 mL) then extracted into EtOAc (3 x 150 mL). The combined organic phase is washed with brine (3 x 100 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The residue is dissolved in MeOH (80 mL), cooled to 0 0C and then an aqueous solution of NaOH (37 mL, 37 mmol, 1 M) is added in one portion. The reaction is warmed to room temperature, stirred for 5 h then the MeOH is removed under reduced pressure. The residue is diluted with water (100 mL) and extracted into EtOAc (3 x 200 mL). The combined organic phase is washed with brine (200 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Flash chromatography of the residue (3 : 7 then 4 : 6, EtOAc: Petrol) affords the title compound as a pale yellow oil (3.69 g, 68% over the 2 steps). 13C NMR (125 MHz, CDCI3): δ = 155.3, 136.6, 128.5, 128.0, 127.9, 67.0, 55.5, 54.9, 47.5 and 47.2 ppm; MS (ESI): 242 ([MNa]+, 100%); HRMS (ESI): found: 242.0791 , C12H13NO3Na ([MNa]+) requires: 242.0793. (Tetrahedron: Asymmetry, 2006, 17, 2876-2883). | |
68.49% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 16h; | Benzyl 2,5-dihydropyrrolidine-1-carboxylate (10 g, 49.24 mmol) was dissolved in dichloromethane (30 mL) and slowly added dropwise to m-chloroperoxybenzoic acid (10.55 g, 61.14 mmol)In a mixture of dichloromethane (70 mL),The reaction was stirred at room temperature for 16 hours.Filtered and the filtrate washed once each with saturated sodium thiosulfate (100 mL) and saturated sodium bicarbonate (100 mL), dried over anhydrous Na2SO4. The solvent was distilled off under reduced pressure, the residue was directly column chromatography (EA / PE (V / V) = 1/3) to give the product (7.39g, 68.49%). |
68.49% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 16h; | 2,5-dihydro-1-carboxylic acid benzyl ester (10g, 49.24mmol)Dissolved in dichloromethane (30 mL), slowly added dropwise to a mixture of m-chloroperoxybenzoic acid (10.55 g, 61.14 mmol) in dichloromethane (70 mL).The reaction was stirred at room temperature for 16 hours.Filtration, the filtrate was saturated sodium thiosulfate (100 mL) and saturated sodium bicarbonate (100 mL)Each was washed once and dried over anhydrous Na 2 SO 4 (10 g).Evaporate the solvent under reduced pressure.The residue was separated by column chromatography (ethyl acetate / petroleum ether (V/V) = 1/3) to give product (7.39 g, 68.49%). |
56% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃;Cooling with ice; | Compound 73a (17 g, 83.6 mmol) was dissolved in 120 mL dichloromethane, and m-CPBA (29.4g, 167.2 mmol) was added in batches under an ice bath for reacting overnight at room temperature. After the reaction was completed, the reaction solution was filtered to obtain a filtrate. A sodium hydrogen sulfite solution was added in the filtrate and stirred for 0.5h, extracted with EA and separated by column chromatography (PE : EA= 10:1) to obtain compound 73b (10g), with a yield of 56%. MS (ESI) m/z: 242 (M+Na+). |
56% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃;Cooling with ice; | Compound 73a (17 g, 83.6 mmol) was dissolved in 120 mL dichloromethane, and m-CPBA (29.4g, 167.2 mmol) was added in batches under an ice bath for reacting overnight at room temperature. After the reaction was completed, the reaction solution was filtered to obtain a filtrate. A sodium hydrogen sulfite solution was added in the filtrate and stirred for 0.5h, extracted with EA and separated by column chromatography (PE : EA= 10:1) to obtain compound 73b (10g), with a yield of 56%. MS (ESI) m/z: 242 (M+Na+). |
52% | Example 051A: To benzyl 2, 5-dihydro- l H-pyrrole-l-carboxy late ( 1 g, 4.9 mmol) in DCM (10 mL) at 0 C was added 3-chloroperbenzoic acid ( 1.43 g, 6.4 mmol). The solution was allowed to warm to rt and stir for 5 h. Aq sodium thiosulfate and IN NaOH were added and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-70% ethylacetate in hexanes to afford benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate as an oil (560 mg, 52%); LCMS (ESI) m/z 220 (M + H) | |
37% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; | Benzyl 2H-pyrrole-l(5H)-carboxylate (25 g, 0.12 mol) was dissolved in DCM (500 mL) at 00C. m-CPBA (42 g, 0.24 mol) was added in portions at 00C, and the mixture was stirred at RT for 3 days. The reaction mixture was filtered, and the filtrate was washed Na2S2O3 (3 M, 100 mL), NaHCO3 (1 M, 100 mL) and brine (100 mL). The organic layer was dried over Na2SO4 and purified by silica gel chromatography (PE : EtOAc = 10:1) to afford the product benzyl 6-oxa-3-aza-bicyclo[3.1.0]hexane-3- carboxylate (10 g, 37%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.39-7.26 (m, 5H), 5.11 (d, 2H), 3.83 (dd, 2H), 3.68 (d, 2H), 3.39 (dd, 2H). |
With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 0 - 20℃; for 24h; | (2) Benzyl 2,5-dihydropyrrole-1-carboxylate (25 g) was dissolved in chloroform (125 mL), and mCPBA (39 g) was slowly added with ice cooling. The mixture was stirred at room temperature for 1 day, then diluted with chloroform, and washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium hydrogencarbonate. The organic layer was dried with anhydrous sodium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 8:2-1:99) to obtain benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (18 g). MS: ESI+ (m/z) 242 (M++Na) | |
To a solution of benzyl 2,5-dihydro-lH-pyrrole-l-carboxylate (33 g, 163 mmol) in dichloromethane (540 mL) was added MCPBA (77 wt. , 44 g) and the reaction mixture was stirred at room temperature for 18 hrs. The mixture was diluted with saturated aqueous sodium carbonate solution (500 mL) and the resulting mixture was stirred at room temperature for 1 hr. The separated organic layer washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel] providing benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (29.5 g) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ [ppm]: 3.38 (dd, J = 12.8, 6.0 Hz, 2 H), 3.68 (d, J = 3.6 Hz, 2 H), 3.87 (dd, J = 13.2, 19.6, 2 H), 5.11 (s, 2 H), 7.33 (m, 5 H). LCMS (m/z): 220.0 [M+H]+; Rt = 0.69 min. | ||
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; | Method 197 benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylateTo a stirred mixture of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (5 g, 24.60 mmol) in DCM (80 mL) was added 3-chlorobenzoperoxoic acid (6.89 g, 30.75 mmol) at 0 C. The mixture was then stirred at rt overnight. The reaction mixture was then filtered through a bed of Celite and the filtrate was washed with sat'd aqueous Na2CO3 and brine. The organic was then separated and dried over anhydrous Na2SO4, filtered, and conc. in vacuo to yield the title compound that was used for next step without further purification. | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 18h; | To a solution of benzyl 2,5-dihydro-1 H-pyrrole-1-carboxylate (33 g, 163 mmol) in dichloromethane (540 ml_) was added MCPBA (77 wt.%, 44 g) and the reaction mixture was stirred at room temperature for 18 hrs. The mixture was diluted with saturated aqueous sodium carbonate solution (500 ml_) and the resulting mixture was stirred at room temperature for 1 hr. The separated organic layer washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel] providing benzyl 6-oxa-3- azabicyclo[3.1.0]hexane-3-carboxylate (29.5 g) as a yellow oil. H NMR (400 MHz, chloroform-d) δ [ppm]: 3.38 (dd, J = 12.8, 6.0 Hz, 2 H), 3.68 (d, J = 3.6 Hz, 2 H), 3.87 (dd, J = 13.2, 19.6, 2 H), 5.1 1 (s, 2 H), 7.33 (m, 5 H). LCMS (m/z): 220.0 [M+H]+; Rt = 0.69 min. | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 18h; | To a solution of benzyl 2,5-dihydro-1 H-pyrrole-1 -carboxylate (33 g, 163 mmol) in dichloromethane (540 mL) was added MCPBA (77 wt.%, 44 g) and the reaction mixture was stirred at room temperature for 18 hrs. The mixture was diluted with saturated aqueous sodium carbonate solution (500 mL) and the resulting mixture was stirred at room temperature for 1 hr. The separated organic layer washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel] providing benzyl 6-oxa-3- azabicyclo[3.1 .0]hexane-3-carboxylate (29.5 g) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ [ppm]: 3.38 (dd, J = 12.8, 6.0 Hz, 2 H), 3.68 (d, J = 3.6 Hz, 2 H), 3.87 (dd, J = 13.2, 19.6, 2 H), 5.1 1 (s, 2 H), 7.33 (m, 5 H). LCMS (m/z): 220.0 [M+H]+; Rt = 0.69 min. | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 18h; | Step A. Benzyl 6-oxa-3-azabicyclo[3.i.Olhexane-3-carboxylateTo a solution of benzyl 2,5-dihydro-1H-pyrrole-i-carboxylate (4.9 mmol, 1.0 g) in CH2C12 (30 mL) at 0 C was added m-CPBA (20 mmol, 3.4 g) in portions. The reaction was stirred at RT for 18 h. The mixture was filtered and the filtrate was washed with aqueous NaHCO3 and brine. The organic layer was dried over Na2504 and purified by silica gel chromatography (heptane/EtOAc=90/10 to 0/100) to afford the title compound. MS (ESI) mlz = 242 (M+Na) | |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 96h; | Intermediate 5Benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylateBenzyl 2,5-dihydro-lH-pyrrole-l-carboxylate (9.92 g) was dissolved in DCM (200 mL) and mCPBA (13.20 g) was added. The reaction was allowed to stir at room temperature for 96 h. The reaction mixture was diluted with Et2O and washed with saturated aqueous sodium thiosulfate solution, saturated aqueous NaHCO3 solution and brine. The organic layer was dried (MgSO4) and the organic solvent was removed in vacuo. The crude product was purified by silica gel column chromatography (gradient of 12.5 to 50% EtOAc in hexanes) to afford 9.13 g of product. MS (ES) MH+: 220 for C12H13NO3; NMR: 3.33 (dd, 2H), 3.64 (dd, 2H), 3.77 (s, 2H)5 5.04 (s, 2H)5 7.34 (m5 5H). | |
16.8 g | With 3-chloro-benzenecarboperoxoic acid; In toluene; at 0 - 20℃; | To a mixture of benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (18.0 g) and toluene (180 ml) was added m-chloroperbenzoic acid (32.8 g) by small and small at 0 C. The mixture was stirred overnight at room temperature. To the mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (16.8 g). 1H NMR (300 MHz, DMSO-d6) δ 3.34 (2H, dd, J=18.4, 12.7 Hz), 3.64 (2H, dd, J=12.7, 9.7 Hz), 3.78 (2H, s), 5.05 (2H, s), 7.21-7.46 (5H, m). |
16.8 g | With 3-chloro-benzenecarboperoxoic acid; In toluene; at 0 - 35℃; | To a mixture of benzyl 2,5-dihydro-H-pyrrole-1-carboxylate (18.0 g) and toluene (180 ml) was added m-chloroperbenzoic acid (32.8 g) by small and small at 0 C. The mixture was stirred overnight at room temperature. To the mixture was added aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (16.8 g). 1H NMR (300 MHz, DMSO-d6) δ 3.34 (2H, dd, J=18.4, 12.7 Hz), 3.64 (2H, dd, J=12.7, 9.7 Hz), 3.78 (2H, s), 5.05 (2H, s), 7.21-7.46 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | 6. Ui. (RS) -3 -hydroxy-pyrrolidine- 1-carboxylic acid benzyl ester:A M solution of borane in THF (9 ml) was added to a solution of intermediate 6.ii (1.81 g) in THF (25 ml) at 0 0C under nitrogen. The reaction mixture was stirred at rt for 16 h and was cooled to 0 0C. 20% NaOH (1.8 ml) was carefully added dropwise followed by 35% aq. hydrogen peroxide (1.2 ml). The mixture was stirred at 0 0C for 30 min and at rt for 2 h. Et2O and an aq. 40% sodium bisulfite solution were added and the reaction mixture stirred vigorously for 15 min. The residue obtained after work up (Et2O) was purified by chromatography (Hex/EA 5:5 to 3:7) to give 1.01 g (51% yield) of a colourless oil. 1H NMR (DMSOd6; delta ppm): 1.67-1.82 (IH, m); 1.82-1.96 (IH, m); 3.16-3.25 (IH, m); 3.28-3.44 (3H, m); 4.20-4.29 (IH, broad); 4.92 (IH, d, J = 3); 5.06 (2H, s); 7.27-7.41 (5H, m). | |
51% | A 1M solution of borane in THF (9 mL) was added to a solution of intermediate 6.ii (1.81 g) in THF (25 mL) at 0 C. under nitrogen. The reaction mixture was stirred at rt for 16 k and was cooled to 0 C. 20% NaOH (1.8 mL) was carefully added dropwise followed by 35% aq. hydrogen peroxide (1.2 mL). The mixture was stirred at 0 C. for 30 min and at rt for 2 h. Et2O and an aq. 40% sodium bisulfite solution were added and the reaction mixture stirred vigorously for 15 min. The residue obtained after work up (Et2O) was purified by chromatography (Hex/EA 5:5 to 3:7) to give 1.01 g (51% yield) of a colorless oil. 1H NMR (DMSOd6; delta ppm): 1.67-1.82 (1H, m); 1.82-1.96 (1H, m); 3.16-3.25 (1H, m); 3.28-3.44 (3H, m); 4.20-4.29 (1H, broad); 4.92 (1H, d, J=3); 5.06 (2H, s); 7.27-7.41 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In dichloromethane; at 20℃; for 18h; | A1. Benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate; Benzyl-3-pyrroline-1-carboxylate (90%, 30.0 g) is dissolved in dichloromethane (900 ml), m-chloro- perbenzoic acid (46.0 g) is added and the solution is stirred for 18 h at room temperature. After that, the mixture is poured into 10% aqueous sodium hydrogencarbonate solution (200 ml), the aqueous phase is extracted with dichloromethane (2 x 200 ml), the combined organic extracts are washed with 10% aqueous sodium hydrogencarbonate solution (2 x 200 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with gradient ethyl acetate / petroleum ether 1 :4 to 1 :1 (v/v)) to yield 28.6 g (98%) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCI3); δ = 3.30-3.41 (m, 2H), 3.61-3.71 (m, 2H), 3.84 (d, AB, J = 12.7 Hz, 1 H), 3.89 (d, AB, J = 12.9 Hz, 1 H), 5.09 (d, AB, J = 12.4 Hz, 1 H), 5.13 (d, AB, J = 12.4 Hz, 1 H), 7.26-7.39 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of benzyl 2,5-dihydro-l H-pyrrole-1 -carboxylate (33 g, 163 mmol) in dichloromethane (540 mL) was added MCPBA (77 wt.%, 44 g) and the reaction mixture was stirred at room temperature for 18 hrs. The mixture was diluted with saturated aqueous sodium carbonate solution (500 mL) and the resulting mixture was stirred at room temperature for 1 hr. The separated organic layer washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel] providing benzyl 6-oxa- 3-azabicyclo[3.1.0]hexane-3-carboxylate (29.5 g) as a yellow oil. NMR (400 MHz, chloroform-d) δ [ppm]: 3.38 (dd, J = 12.8, 6.0 Hz, 2 H), 3.68 (d, J = 3.6 Hz, 2 H), 3.87 (dd, J = 13.2, 19.6, 2 H), 5.1 1 (s, 2 H), 7.33 (m, 5 H). LCMS (m/z): 220.0 [M+H]+; Rt = 0.69 min. |
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