Structure of 31865-25-5
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CAS No. : | 31865-25-5 |
Formula : | C12H13NO3 |
M.W : | 219.24 |
SMILES Code : | O=C(N1CC2OC2C1)OCC3=CC=CC=C3 |
MDL No. : | MFCD09608058 |
InChI Key : | FZDACFZWWMAUBO-UHFFFAOYSA-N |
Pubchem ID : | 22147363 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.42 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 60.79 |
TPSA ? Topological Polar Surface Area: Calculated from |
42.07 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.51 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.15 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.87 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.14 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.51 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.44 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.94 |
Solubility | 2.53 mg/ml ; 0.0116 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.63 |
Solubility | 5.16 mg/ml ; 0.0235 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.22 |
Solubility | 1.33 mg/ml ; 0.00608 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.82 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.96 |
* 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 |
---|---|---|
With sodium azide; water; ammonium chloride; In acetone; at 70℃; for 8h; | (3) To a mixture of <strong>[31865-25-5]benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate</strong> (15 g), acetone (120 g), water (34 mL), and ammonium chloride (8.1 g) was added sodium azide (23 g), and the mixture was stirred at 70C for 8 h. Water was added to the reaction solution, and the mixture was extracted with chloroform. 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 = 9:1-1:99) to obtain benzyl (3RS,4RS)-3-azide-4-hydroxypyrrolidine-1-carboxylate (13 g). MS: ESI+ (m/z) 285 (M++Na) | |
With sodium azide;acetone; In water; at 80℃; for 24h; | Method 195 (+/-)-benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylateTo a stirred mixture of <strong>[31865-25-5]benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate</strong> (5.2 g, 23.72 mmol) (Method 197) in DMF (30 mL) was added sodium azide (2.313 g, 35.58 mmol) in a mixture of acetone (20.00 mL) and water (10.00 mL). The resulting mixture was stirred at 80 C. for 24 h. The mixture was then diluted with water and ether, separated, and the organic layer was washed with brine, dried and conc. in vacuo. The resulting material was purified via silica gel chromatography (eluted with 15% to 35% ethyl acetate/hexane), yielding the title compound as a yellow solid (4.10 g, 65.9%). 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.50-7.25 (m, 5H), 5.43-5.25 (m, 2H), 4.31 (brs, 1H), 4.00 (brs, 1H), 3.77 (dd, 1H), 3.69 (dd, 1H), 3.53 (d, 1H), 3.44 (dd, 1 H), 2.17 (brs, 1H); m/z 263. | |
2.7 g | With sodium azide; ammonium chloride; In methanol; water; at 65℃; for 21h; | Stepl. Preparation of frans-(±)-Benzyl 3-azido-4-fluoroypyrrolidne-l-carobxylateTo a solution of benzyl-6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.5 g) in methanol (20 mL) was added water (5 mL), ammonium chloride (550 mg) and sodium azide (1.5 g). The resulting mixture was heated at 65 C for 21 hours. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was poured into 15% aqueous solution of sodium hydroxide (30 mL) and extracted with dichloromethane (50 mL). The organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford 2.7 g of trans-{±) benzyl-3-azido-4-hydroxypyrrolidne-l-carobxylate. MS obsd. (ESI+) [(M+H)+] 250. |
Intermediate 6Trans(+/-)benzyl 3-azido-4-hvdroxypyrrolidine- 1 -carboxylateBenzyl -oxa-S-azabicyclop.l.OJhexane-S-carboxylate (Intermediate 5, 9.09 g) was dissolved in MeOH (88 mL). To this was added water (15 mL), ammonium chloride (2.27 g), and sodium azide (5.47 g). The reaction mixture was heated to 65 0C for 21 h. The solids were removed by filtration and the solvent was removed in vacuo. The residue was taken up in 15% aqueous sodium hydroxide and extracted with DCM. The organic layers were washed with brine, dried (MgSO4) and the organic solvent was removed in vacuo to afford 10.73 g of product. MS (ES) MH+: 220 for C12H13NO3; NMR: 3.17 (m, IH), 3.27 (m, IH), 3.42 (m, IH), 3.58 (m, IH), 3.96 (m, IH), 4.09 (m, IH), 5.05 (m, 2H), 7.34 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium azide; ammonium chloride; In methanol; water; at 70℃; for 20h; | To a solution of 4:1 MeOH:H2O was added epoxide 9 (4.8 g, 22.0 mmol) followed by the addition of NaN3 (2.86 g, 44.0 mmol) and NH4Cl (1.8 g, 33.0 mmol) while stirring. The mixture was heated at 70 C. for 20 h and then diluted with H2O, extracted three times with CH2Cl2 and dried over Na2SO4. The organic layer was concentrated to afford a red oil, which was carried on to the next step. The air was removed from the flask and replaced with argon. Pyridine (13.0 mL) was added and cooled to 0 C. Methanesulfonyl chloride (1.9 mL, 24.2 mmol) was added slowly dropwise via syringe. The solution was allowed to warm to ambient temperature and stirred for 20 h. The reaction mixture was poured over ice cold H2O and extracted with CH2Cl2 twice and then washed with two 50 mL portions of 1M HCl followed by brine. The organic phase was concentrated to afford a red oil (6.1 g, 82%), which was diluted with EtOH (60 mL) and added to a 500 mL flask containing a 0 C. solution of CoBr2.H2O (0.92 g, 4 mmol) and 2,2'-dipyridyl (2.2 g, 14 mmol) in 300 mL absolute EtOH. Sodium borohydride (3.1 g, 82.0 mmol) was added very slowly in small portions over 1 h while keeping at 0 C. The mixture was allowed to slowly warm to ambient temperature and stirred for an additional 2 h. The mixture was then slowly poured over H2O (1000 mL) and extracted three times with CH2Cl2, dried over Na2SO4 and concentrated to afford a brown oil which was purified by flash column chromatography with CH2Cl2 and MeOH. Recovered 3.77 g, 97% of aziridine 11. | |
To a mixture of <strong>[31865-25-5]benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate</strong> (10 g, 44.70 mmol) and (1 R,2R)-(-)-[ 1 ,2-cyclohexanediamino-N N’ -bi s(3 , 5 -di-t-butyl salicylidene)]chromium (III) chloride (Jacobsen’s Chromium catalyst) (682 mg, 1.08 mmol) was added azidotrimethylsilane (6.52 g, 56.59 mmol) at 30 C. The reaction mixture was stirred for 16 h at 30 C. Methanol (30 mL) and trifluoroacetic acid (0.5 mL) were added. The resulting solution was stirred at 30 C for 3 h, then concentrated under vacuum. The residue was diluted with 100 mL of water and was extracted with ethyl acetate (3x100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by silica gel chromatography (eluting with 1:2 EtOAc/pet.ether) afforded benzyl (3S,4S)-3-azido-4- hydroxypyrrolidine-1-carboxylate as a light yellow oil. MS: (ESI, m/z): 263 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;palladium(II) hydroxide/carbon; In methanol; at 20℃; for 4h; | 20% Palladium hydroxide on carbon (1.3 g) was added to a solution of 6-Oxa-3- aza-bicyclo [3. [1. 0]] hexane-3-carboxylic acid benzyl ester (3.5 g, 16.0 mmol) dissolved in methanol (45 [ML).] The flask was charged with hydrogen gas and the mixture was stirred at room temperature for 4 h. The reaction mixture was filtered through celite and the solvent removed to provide the title compound which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(S,S)-(+)-N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino chromium(III) chloride; for 18h; | To benzyl 6-oxa-3-azabicyclo [3.1. 0] hexane-3-carboxylate (10.4g, 48 mmole) was added TMSN3 (6. 65ml, 1.05eq.) and 1S, 2S- (-)- [1, 2-CYCLOHEXANEDIAMINO-N, N'-bis (3,5-di-t- butylsalicylidene)] chromium (ILL) chloride (STREM 24-0851) (904mg, 0.03 eq. ). The reaction was stirred for 18h under N2. The red oil was used as is in the next STEP. HH NMR (400 MHz, CDCI3) 8 7.18 (m, 5 H), 4.98 (s, 2 H), 3.99 (m, 1 H), 3.69 (m, 1 H), 3.61-3. 51 (m, 2 H), 3.31- 3.05 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
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40% | With triethylamine tris(hydrogen fluoride); at 155℃; for 3h; | A mixture of TEA trihydrofluoride (1.95 mL, 12 mmol) and the title compound of Step 2 (2.62 g, 12 mmol) was heated to 155 C. for three hr, cooled, and partitioned between water and dichloromethane. The aqueous phase was extracted again with dichloromethane and the combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash-chromatography (1% methanol in dichloromethane) to give the title compound as a pale oil (1.14 g, 40%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation 120 Preparation of benzyl (3R,4R)-3-(2lambda~5~-triaza-1,2-dienyl)-4-[(trimethylsilyl)oxy]pyrrolidine-1-carboxylate To <strong>[31865-25-5]benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate</strong> (10.4 g, 48 mmole) was added TMSN3 (6.65 ml, 1.05 eq.) and 1S,2S-(-)-[1,2-cyclohexanediamino-N,N'-bis(3,5-di-t-butylsalicylidene)]chromium(III) chloride (STREM 24-0851) (904 mg, 0.03 eq.). The reaction was stirred for 18 h under N2. The red oil was used as is in the next step. 1H NMR (400 MHz, CDCl3) δ7.18 (m, 5 H), 4.98 (s, 2 H), 3.99 (m, 1 H), 3.69 (m, 1 H), 3.61-3.51 (m, 2 H), 3.31-3.05 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide; In ammonium hydroxide; | Preparation 114 Preparation of benzyl (trans)-3-amino-4-hydroxypyrrolidine-1-carboxylate <strong>[31865-25-5]benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate</strong> (10.5 g) was stirred in 200 ml of saturated ammonium hydroxide at 35 C. for 40 h. The reaction mixture was poured into 100 ml of 2 N NaOH, extracted methylene chloride (4*200 ml), dried MgSO4, filtered and concentrated to provide the title compound as an oil (10.15 g, 95%): 1H NMR (300 MHz, CDCl3) δ) 7.34, 5.14, 3.99, 3.78, 3.37, 3.19, 1.77; HRMS (FAB) calcd for C12H16N2O3+H 237.1239, found 237.1244. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydroxide; In water; acetonitrile; | EXAMPLE 3 21.9 g (0.1 mol) of 3,4-epoxy-1-carbobenzyloxy-pyrrolidine [S. Oida et al., Chem. Pharm. Bull., 18 (12), 2478 (1970)] are dissolved, together with 18.8 g (0.2 mol) of phenol and 100 ml of 2 N sodium hydroxide solution (0.2 mol) in 300 ml of acetonitrile. The reaction mixture is heated under reflux for 5 hours and after cooling is diluted with 600 ml of water and extracted by shaking with methylene chloride. The organic phase is washed with 2 N sodium hydroxide solution and then with water, dried over sodium sulphate and evaporated under a water pump vacuum and trans-3-hydroxy-4-phenoxy-1-carbobenzyloxy-pyrrolidine is obtained in the form of a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | Step B: Preparation of (trans)-benzyl 3-fluoro-4-hydroxypyrrolidine-l- carboxylate:; benzyl -oxa-S-azabicyclop.l.OJhexane-S-carboxylate (10.5 g, 47.9 mmol) and pyridine-hydrogen fluoride (14.2 g, 144.0 mmol) were added to a Teflon bottle containing dichloromethane and stirred vigorously overnight. After 20 hours, the reaction was slowly and carefully quenched with excess saturated solution of NaHCO3 over several minutes and allowed to stir for one hour, and then the organic layer was isolated and washed with NaHCO3 and a solution of brine. The combined organic layers were dried over MgSO4, filtered and evaporated to yield an oil. This crude oil was purified on silica gel using ethyl acetate-hexane to produce 2.0 g (17% isolated yield) of the desired product as an oil. |
Yield | Reaction Conditions | Operation in experiment |
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Part A: Phenylmethyl (trans)-3-hydroxy-4-methyl-1-pyrrolidinecarboxylate. To a stirred suspension of CuI (10.2 g, 54 mmol) in ether (120 ml.) at -10 0C was added dropwise MeLi (73 mL, 109 mmol, 1.5 M in ether) ensuring that the temperature remained below -5 0C. The resulting solution was stirred at -10 0C for 20 min and a solution of phenylmethyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (Example 1 13) (5 g, 23 mmol) in ether (50 mL) was added, maintaining the temperature below -2 0C. The reaction was stirred at -10 0C for 1 hour after which time it was quenched with water and partitioned with DCM. A standard work up yielded phenylmethyl (trans)-3-hydroxy-4-methyl-1 -pyrrolidinecarboxylate, which was purified and subjected to chiral chromatography, producing two enantiopure compounds of undetermined absolute stereochemistry. (Yield of E1= 1.55 g, yield of E2= 1.58 g). |
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 |
---|---|---|
66% | A2. Benzyl 3-hydroxy-4-(1H-indol-3-yl)pyrrolidine-1-carboxylate; Indole (15.4 g) is dissolved in tetrahydrofuran (270 ml) and the solution is cooled to O0C (ice bath). Methylmagnesium chloride (3M in tetrahydrofuran, 44 ml) is added drop by drop within 45 min. The mixture is stirred at room temperature for 2 h, then a solution of benzyl 6-oxa-3- azabicyclo[3.1.0]hexane-3-carboxylate (example A1 ) (28.5 g) in tetrahydrofuran (100 ml) is added drop by drop within 20 min. The mixture is stirred for 18 h at room temperature. After that, it is poured into 10% aqueous sodium hydrogencarbonate solution (200 ml). The aqueous phase is extracted with ethyl acetate (3 x 200 ml), the combined organic extracts are washed with water (1 x 400 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 :1 (v/v) to ethyl acetate) to obtain 28.8 g (66%) of the title compound as an orange oil. 1H-NMR (300 MHz, d6-DMSO); δ = 3.19-3.32 (m, 1 H), 3.40-3.52 (m, 1 H), 3.53-3.67 (m, 2H), 3.80- 3.93 (m, 1 H), 4.28-4.36 (m, 1 H), 5.09 (s, 2H), 5.29 (d, J = 4.2 Hz, 1 H), 6.98 (dd, J = 7.2 Hz, 7.6 Hz, 1 H), 7.02-7.13 (m, 2H), 7.26-7.41 (m, 6H), 7.58 (d, J = 7.9 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In water; at 20℃; | Example 58B. (3i?,4i?)-Benzyl 3-hydroxy-4-(methylamino)pyrrolidine-l-carboxylate; [00269] A mixture of Example 58A (1.5 g, 6.8 mmol) and 40% w/w methylamine (13.5 g, 174 mmol) in water solution was stirred at room temperature O/N. The solvent was evaporated to afford Example 58B as an oil (1.7 g, 100 % yield), which was carried on to the next step without purification. LC-MS, [M+H]+ = 251. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.92% | With ammonium hydroxide; at 100℃; for 16h; | Benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.40 g, 24.63 mmol, 1.00 eq) and ammonia (43.17 g, 1.23 mol, 47.43 mL, 50.00 eq) were mixed, the mixture was then stirred at 100 C for 16 hours. The mixture was concentrated under reduced pressure to deliver benzyl 3-amino-4-hydroxy-pyrrolidine-1-carboxylate (5.00 g, 21.16 mmol, 85.92% yield) as a slightly yellow oil. |
With ammonia; In water; for 4h;Reflux; | A mixture of benzyl 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (5 g, 23 mmol) and aqueous ammonia (60 mL) was heated at reflux for 4 h. The solution was concentrated in vacuo to afford the crude product benzyl 3-amino-4-hydroxypyrrolidine- 1-carboxylate as a light oil, which was used without further purification (5 g, 93%). | |
6.1 g | With ammonium hydroxide; for 20h;Sealed tube; | 6.01.28.04 Benzyl 3-amino-4-hydroxypyrrolidine-1-carboxylate 6.5 g <strong>[31865-25-5]benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate</strong> in 80 mL 33% aqueous ammonia solution was stirred 20 h in a closed vessel. The reaction was cooled and extracted with dichlormethane. The organic layer was washed with sodium chloride solution and evaporated to give 6.1 g of the desired product. Rt: 2.37 min. (method AG) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Example 2: (+/-)-frans-4-(Cvclohexylmethvh-1 -r(9-deaza-adenin-9-yl)methyll-3-hvdroxy- pyrrolidine (1. X = cvclohexylmethyl. A = CH. B = NH9. D = H); Example 2.1: Benzyl (+/-)-frans-4-(cyclohexylmethyl)-3-hydroxypyrrolidine-1-carboxylate (6, X = cyclohexylmethyl); A solution of epoxide 5 (243 mg, 1.1 mmol) and CuBrSMe2 (50 mg, 0.22 mmol) in THF (10 mL) is cooled to -30 0C. Cyclohexylmethylmagnesium bromide (11 mL, 5.5 mmol, 0.5 M solution in THF) is added drop-wise over 20 min. After complete addition the reaction is allowed to warm to -25 0C over 30 min then quenched with 10% aqueous solution NH4CI (20 mL) and EtOAc (20 mL). The mixture is stirred at room temperature for 30 min then the layers are separated. The aqueous phase is extracted into EtOAc (3 x 30 mL). The combined organic phase is dried (MgSO4), filtered and concentrated under reduced pressure. Flash chromatography of the residue (gradient 2 : 8 to 4 :6, EtOAc: Petrol) affords the title compound 6 (X = cyclohexylmethyl) as an off-white solid (286 mg, 81%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Example 8: (+/-)-fra/?s-1-r(9-Deaza-adenin-9-yl)methvn-4-butyl-3-hvdroxypyrrolidine. (1. X = putyl. A = CH. B = NH7. D = H); Example 8.1 : Benzyl (+/-)-frans-4-butyl-3-hydroxypyrrolidine-1-carboxylate (6, X = butyl); A solution of epoxide 5 (80 mg, 0.4 mmol) and CuBrSMe2 (7 mg, 0.03 mmol) in THF (3 mL) is cooled to -30 0C. ϖ-Butylmagnesium chloride (1 mL, 2 mmol, 2 M solution in THF) is added drop-wise over 10 min, keeping the temperature below -25 0C. After complete addition the reaction is allowed to warm to -15 0C over 45 min then quenched with 10% aqueous solution NH4CI (10 mL) and EtOAc (20 mL). The mixture is stirred at room temperature for 1h 15 min then the layers are separated. The aqueous phase is extracted into EtOAc (2 x 20 mL). The combined organic phase is dried (MgSO4), filtered and concentrated under reduced pressure. Flash chromatography of the residue (4 : 6 then 1 : 1 , EtOAc : Petrol) affords the title compound 6 (X = butyl) as a pale yellow oil (72 mg, 71%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Example 4: (+/-)-frans-4-CvclopropyH-r(9-deaza-adenin-9-yl)methvϖ -3-hvdroxypyrrolidine (1. X = cvclopropyl. A = CH. B = NH,. D = H); Example 4.1 : Benzyl (+/-)-frans-4-Cyclopropyl-3-hydroxypyrrolidine-1-carboxylate (6, X = cyclopropyl); A solution of epoxide 5 (283 mg, 1.3 mmol) and CuBrSMe2 (43 mg, 0.21 mmol) in THF (10 mL) is cooled to -30 0C. Cyclopropylmagnesium bromide (10 mL, 5.0 mmol, 0.5 M solution in THF) is added drop-wise over 25 min. After complete addition the reaction is allowed to slowly warm to -15 0C over 45 min then quenched with 10% aqueous solution NH4CI (20 mL) and EtOAc (50 mL). The mixture is stirred at room temperature for 40 min then the layers are separated. The aqueous phase is extracted into EtOAc (3 x 50 mL). The combined organic phase is dried (MgSO4), filtered and concentrated under reduced pressure. Flash chromatography of the residue (3 : 7 then 4 : 6, EtOAc: Petrol) affords the title compound 6 (X = cyclopropyl) as a pale yellow oil (311 mg, 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 10: (+/-Hrans-1 -r(9-Deaza-adenin-9-yl)methvn-3-hvdroxy-4-(pent-3-yl)pyrrolidine (1. X = pent-3-yl. A = CH. B = NH,. D = H); Example 10.1: Benzyl (+/-)-fraϖs-3-hydroxy-4-(pent-3-yl)pyrrolidine-1-carboxylate (6, X = pent-3-yl); A solution of epoxide 5 (230 mg, 1.05 mmol) and CuBrDMS (28 mg, 0.22 mmol) in THF (10 mL) is cooled to -30 0C. 3-Pentylmagnesium bromide (2.3 ml_, 4.6 mmol, 2 M solution in ether) is added drop-wise over 10 min. After complete addition the reaction is allowed to warm to -20 0C over 30 min then quenched with 10% aqueous solution NH4CI (40 mL) and EtOAc (40 mL). The mixture is stirred at room temperature for 1 h then the layers are separated. The aqueous phase is extracted into EtOAc (3 x 40 ml_). The combined organic phase is dried (MgSO4), filtered and concentrated under reduced pressure. Flash chromatography of the residue (2 : 8, EtOAc: Petrol) affords the title compound 6 (X = pent-3-yl) and an unknown co-running impurity as a pale yellow oil (195 mg). |
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