Structure of 549532-08-3
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CAS No. : | 549532-08-3 |
Formula : | C10H19NO3 |
M.W : | 201.26 |
SMILES Code : | O=C(N1C[C@H](OC)CC1)OC(C)(C)C |
MDL No. : | MFCD16620894 |
InChI Key : | NGIGLOKJPWGIJT-MRVPVSSYSA-N |
Pubchem ID : | 34179484 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P301+P312-P302+P352-P304+P340-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.9 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 57.68 |
TPSA ? Topological Polar Surface Area: Calculated from |
38.77 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.82 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.16 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.26 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.86 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.8 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.38 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.55 |
Solubility | 5.61 mg/ml ; 0.0279 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.57 |
Solubility | 5.43 mg/ml ; 0.027 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.13 |
Solubility | 15.0 mg/ml ; 0.0745 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 |
-6.7 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 |
0.0 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) |
2.82 |
* 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 |
---|---|---|
0.69 g | Boc2O (1.02 mL, 4.5 mmol) was added to a solution of (R)-3-hydroxylpyrrolidine hydrochloride (R)-2a·HCl (0.50 g, 4.1 mmol) in THF-satd NaHCO3 (1:1, 20 mL), and the reaction mixture was stirred at rt for 1.5 h. EtOAc was added, and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl (R)-3-hydoxypyrrolidine-1-carboxylate, which was used for the following reaction without further purification.The above-described tert-butyl (R)-3-hydoxypyrrolidine-1-carboxylate was dissolved in anhydrous DMF (20 mL), to which was added NaH (55% oil suspension, 0.71 g, 16.2 mmol) at 0 C. The ice-cold reaction mixture was stirred for 30 min, and Me2SO4 (0.77 mL, 8.1 mmol) was then added. The reaction mixture was stirred overnight at 50 C before being quenched with water. Hexane-EtOAc (1:1) was added, the layers were separated, and the aqueous layer was extracted three times with hexane-EtOAc (1:1). The combined organic layer was washed two times with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-EtOAc, 2:1) to afford 0.69 g of tert-butyl (R)-3-methoxypyrrolidine-1-carboxylate [85% from (R)-2a·HCl]. A colorless oil, -8.4 (c=0.52, CHCl3). 1H NMR (500 MHz, CDCl3) delta: 1.44 (9H, s), 1.84-2.02 (2H, m), 3.31 (3H, s), 3.34-3.49 (4H, m), 3.91 (1H, brs). 13C NMR (125 MHz, CDCl3) delta: 28.5, 30.0, 31.1, 43.5, 43.9, 50.3, 51.1, 56.5, 79.09, 79.14, 79.9, 154.5, 154.6. IR (CHCl3): 1686, 1416 cm-1. HRMS Calcd for C10H19NNaO3 [(M+Na)+] m/z: 224.1257, found: 224.1248.Under a nitrogen atmosphere, 4 M HCl in EtOAc (1.2 mL) was added to tert-butyl (R)-3-methoxypyrrolidine-1-carboxylate (50 mg, 0.25 mmol) at 0 C. The solution was stirred at rt for 30 min and concentrated in vacuo. The residue was dissolved in MeCN-water (10:1, 2.5 mL). Aqueous NH3 (30% w/w, 35 muL, 0.62 mmol) and 3 (162 mg, 0.62 mmol) were added to the solution at 0 C. The reaction mixture was stirred at rt for 30 min and concentrated in vacuo, and the residue was purified by flash column chromatography (CH2Cl2-MeOH, 15:1?10:1) to give 21 mg of (R)-1d (75%, 99% ee) and 7.1 mg of (R)-4-methoxy-1-pyrroline N-oxide (R)-4d (25%). The optical purity of (R)-1d was determined by Daicel CHIRALPAK AD-3 [hexane-iPrOH, 95:5, 2.0 mL/min; retention times 20.3 (R), 24.6 min (S)].(R)-1d. Pale yellow oil, +113 (c=0.85, CHCl3). 1H NMR (500 MHz, CDCl3) delta: 2.17 (1H, dddd, J=3.5, 5.0, 9.0, 14.5 Hz), 2.48-2.57 (1H, m), 3.35 (3H, s), 3.87 (1H, dddd, J=1.0, 6.5, 9.0, 15.5 Hz), 4.10-4.19 (1H, m), 4.56-4.61 (1H, m), 7.02 (1H, q, J=1.5 Hz). 13C NMR (125 MHz, CDCl3) delta: 27.0, 56.5, 61.4, 80.0, 133.3. IR (CHCl3): 1584, 1269, 1238 cm-1. HRMS Calcd for C5H9NNaO2 [(M+Na)+] m/z: 138.0526, found: 138.0534.(R)-4-Methoxy-1-pyrroline N-oxide [(R)-4d]. A pale yellow oil, -22.5 (c=0.66, CHCl3). 1H NMR (500 MHz, CDCl3) delta: 2.75 (1H, d, J=19.5 Hz), 2.94-3.03 (1H, m), 3.33 (3H, s), 3.94 (1H, d, J=15.0 Hz), 4.08-4.15 (1H, m), 4.19-4.24 (1H, m), 6.84-6.87 (1H, m). 13C NMR (125 MHz, CDCl3) delta: 36.1, 56.5, 67.3, 74.3, 133.1. IR (CHCl3): 1595, 1275, 1238 cm-1. HRMS Calcd for C5H9NNaO2 [(M+Na)+] m/z: 138.0526, found: 138.0533. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 4h; | To a solution of the product from step A(1.89 g, 10.0 mmol) and Mel (1.70 g, 12.0 mmol) in DMF (20 mL) was added NaH (360 mg, 80%, 12.0 mmol) in portion at rt. The mixture was stirred at rt for 4h. Water was added and was extracted with EA. The organic layers were washed with brine (20 mL x 2), dried over Na2SO4 and concentrated. The residue was purified by column chromatography eluting with PE EA (5 : 1) to give the title product (1.65 g, 82%) as a brown solid. |
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 18h; | (3R)-3-HYDROXY-PYRROLIDINE-1-CARBOXYLIC acid tert-butyl ester (12.5g, 66. 70MMOL) was dissolved in tetrahydrofuran (334ML) and the reaction mixture cooled to 0C in an ice bath. The reaction mixture was treated with sodium hydride (2.20g, 80% dispersion in mineral oil, 73. 3MMOL) and allowed to warm to room temperature. The reaction mixture was then treated with methyl iodide (14. 5g, 100MMOL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water (100ML) and concentrated in vacuo until just the aqueous remained. The aqueous was extracted with ethyl acetate (750ML), the organic layer separated, dried (MGS04) and CONCENTRATED IN VACUO to yield the title product as a brown oil, 12.48g. 'H NMR (CDCI3, 400MHZ) S : 1.44 (s, 9H), 1.92 (m, 2H), 3.27 (s, 3H), 3.40 (m, 4H), 3.86 (m, 1H) | |
1100 mg | To a solution of tert-butyl (3R)-3-hydroxypyrrolidine-l-carboxylate (1000 mg, 5.34 mmol) in THF (20 mL) was added NaH (256.36 mg, 6.41 mmol). The reaction mixture was stirred at 20 C for 0.5 hour. Then iodomethane (1516.13 mg, 10.68 mmol) was added. The reaction mixture was stirred at 20 C for 2 hours to give a mixture. The reaction mixture was diluted with sat.NH4Cl (30 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (15 mL), dried over Na2SC>4, filtered and concentrated to give the crude product (1100 mg, 5.47 mmol) as an oil. NMR (CDCI3, 400MHz) deltaH = 3.97 - 3.88 (m, 1H), 3.53 - 3.36 (m, 4H), 3.33 (s, 3H), 2.06 - 1.84 (m, 2H), 1.46 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In dichloromethane; at 0 - 20℃; for 48h; | Hydrogen chloride gas was bubbled through an ice-cooled solution of the compound from preparation 1 (6. 02g, 30. Ommol) in dichloromethane (30mL), and the reaction then allowed to warm to room temperature and stirred for 48 hours. The solution was concentrated under reduced pressure and the residue triturated with ether. The resulting crystals were filtered off and dried in vacuo to afford the title compound. 'H NMR(CD30D, 400MHz) b : 2.06 (m,1H), 2.20 (m,1H), 3.26-3. 42 (m, 7H), 4.17 (m,1H). | |
With hydrogenchloride; In dichloromethane; at 0 - 20℃; for 48h; | Preparation 45; (3R)-3-Methoxypyrrolidine hydrochloride; Hydrogen chloride gas was bubbled through an ice-cooled solution of the compound from preparation 43 (6.02g, 30.0mmol) in dichloromethane (30mL), and the reaction then allowed to warm to room temperature and stirred for 48 hours. The solution was concentrated under reduced pressure and the residue triturated with ether. The resulting crystals were filtered off and dried in vacuo to afford the title compound. ¹H NMR (CD30D, 400MHz) 8: 2.06 (m, 1 H), 2.20 (m, 1 H), 3.26-3.42 (m, 7H), 4.17 (m, 1 H). | |
With hydrogenchloride; In 1,4-dioxane; at 0 - 20℃; for 4h; | A solution of HCI in dioxan (4M, 13ML) was added drop wise to an ice-cooled solution of the product of preparation 46 (2.12g, 10. 5MMOL) in dioxan (2ML). The reaction was allowed to warm to room temperature and stirred for a further 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue azeotroped with ether. The solid was triturated with ether, and the solid filtered off and DRIED IN VACUO to give the product as a brown oil, 1.34g. |
1000 mg | With hydrogenchloride; In 1,4-dioxane; at 20℃; for 16h; | A mixture of tert-butyl (3R)-3-methoxypyrrolidine-l-carboxylate (1100 mg, 5.47 mmol) in 4M HCl/dioxane (15 mL, 60 mmol) was stirred at 20 C for 16 hours to give a mixture. The reaction mixture was concentrated to give the crude (1000 mg, 7.27 mmol) as an oil. *H NMR CDC13, 400MHz deltaH = 10.10 - 9.39 (m, 2H), 4.13 - 4.04 (m, 1H), 3.51 - 3.35 (m, 4H), 3.31 (s, 3H), 2.24 - 2.12 (m, 1H), 2.08 - 1.95 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; paraffin oil; at 20℃; for 1h;Cooling with ice; | General procedure: To a mixture of ethyl (R)-4-(3-hydroxypyrrolidin-1-yl)benzoate obtained in (1) (4.06 g), methyl p-toluenesulfonate (6.43 g), DMF (20 mL), and THF (40 mL) was added sodium hydride (1.38 g, 60%, dispersed in fluidized paraffin) under ice-cooling. The mixture was warmed to room temperature and stirred for 1 hour, and then 1 mol/L hydrochloric acid (15 mL) and ethyl acetate were added thereto. The organic layer was collected by separation, and washed with water and a saturated aqueous sodium chloride solution, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; 100%-60% n-hexane/ethyl acetate] to obtain ethyl (R)-4-(3-methoxypyrrolidin-1-yl)benzoate as a yellow oily substance. MS (ESI m/z): 250 (M+H) RT (min): 1.48 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
TERT-BUTYL (3R)-3-HYDROXYPYRROLIDINE-1-CARBOXYLATE (25g, 133. 4MMOL) was dissolved in tetrahydrofuran (668mL) and the reaction mixture cooled to 0C on an ice bath. The reaction mixture was treated with sodium hydride (4.40g, 80% dispersion in mineral oil, 146. 6MMOL) and stirred until back at room temperature. The reaction mixture was then treated with methyl iodide (29. 0G, 200. OMMOL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water (200mL) and CONCENTRATED IN VACUO UNTIL just the aqueous remained. The reaction mixture was treated with ethyl acetate (1500ML), the organic layer separated, dried over magnesium sulphate and concentrated IN VACUO TO yield the title product as a brown oil. This oil (24.75g, 123. Ommol) was dissolved in diethyl ether (615mL) and hydrogen chloride bubbled through the solution for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and re-dissolved in ether and stirred for a further 2 hours. The ether was decanted off and the reaction mixture concentrated in vacuo. The crude product was dissolved in ethanol and treated with trifluoroacetic acid (200mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated IN VACUO TO YIELD the title product. 1 H NMR (CD30D, 400MHZ) 8 : 1.96 (m, 1 H), 2.09 (m, 1 H), 3.08-3. 37 (m, 4H), 4.06 (m, 1 H), 4.80 (s, 3H). | ||
tert-Butyl(3R)-3-hydroxypyrrolidine-1-carboxylate (12. 5g, 66.70mmol) was dissolved in tetrahydrofuran (334mL) and the reaction mixture cooled to0 C in an ice bath. The reaction mixture was treated with 80% sodium hydride in mineral oil (2.20g, 73.3mmol) and stirred until back at room temperature. The reaction mixture was then treated with methyl iodide(14. 5g,100. 0mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water(100mL) and concentrated in vacuo until just the aqueous remained. The aqueous solution was treated with ethyl acetate (750mL), the organic layer separated, dried over magnesium sulphate and concentrated in vacuo to yield the title product as a brown oil, 12.48g. 'H NMR (CDCI3, 400MHz) b : 1.41 (s, 9H), 1.95 (m, 2H), 3.30 (s, 3H), 3.40 (m, 4H), 3.86 (m, 1 H) | ||
Preparation 43; tert-Butvl (3R)-3-methoxyDvrrolidine-1-carboxylate; (3R)-3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (12.5g, 66.70mmol) was dissolved in tetrahydrofuran (334mL) and the reaction mixture cooled to 0C in an ice bath. The reaction mixture was treated with 80% sodium hydride in mineral oil (2.20g, 73.3mmol) and stirred until back at room temperature. The reaction mixture was then treated with methyl iodide (14.5g, 100.0mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with water (100mL) and concentrated in vacuo until just the aqueous remained. The aqueous solution was extracted with ethyl acetate (750mL), the organic layer separated, dried over magnesium sulphate and concentrated in vacuo to yield the title product as a brown oil, 12.48g. ¹H NMR (CDCl3,400MHz) No.: 1.41 (s, 9H), 1.95 (m, 2H), 3.30 (s, 3H), 3.40 (m, 4H), 3.86 (m, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Add sodium hydride (60% dispersion in oil, 0.048 g, 1.20 mmol) to a solution of iV-Boc-(i?)-(-)-3-pyrrolidinol (0.20 g, 1.09 mmol), under nitrogen. Leave to stir at room temperature for 10 minutes then add methyl iodide (0.10 mL, 1.64 mmol). Stir the mixture for 2 days then add methanol (10 mL). Load the methanol solution onto an Isolute SCX-2 (5 g) column. Wash the column with methanol then concentrate this methanol fraction in vacuo to give an orange/red oil (0.42 g) containing oil from the sodium hydride dispersion and the title compounds: MS (m/e): 102(M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A stirred solution of <strong>[549532-08-3](R)-3-(methoxy)-N-(tert-butoxycarbonyl)pyrrolidine</strong> (0.63 g) and dirhodium(II) tetrakis[(S)-N-[p-(dodecylphenyl)sulfonyl]prolinate] {Rh2(S-DOSP)4} (113 mg) in 2,2-dimethylbutane (50 mL) was stirred under reflux. Diazo-(2-naphthylacetic acid methyl ester) (1.41 g) in a 1:4 mixture of trifluorotolune: 2,2-diethylbutane was added via syringe pump over a 3 hour period. The mixture was stirred under reflux for an additional 2 hours and then stirred at room temperature overnight. The mixture was then concentrated, diluted with dichloromethane (100 mL) and charged with trifluoroacetic acid (1.97 mL, 26.6 mmol). After 16 hours, the solution was concentrated, the residue dissolved in Et2O (100 mL), and extracted with 10% HCl (3×100 mL). The aqueous layers were basified with solid NaHCO3 (solid) and 1M NaOH to pH=8-9. The aqueous phase was then back extracted ethyl acetate (3×50 mL) and the organic phases were washed with brine (25 mL), dried with Na2SO4, and filtered. The extraction was reduced and purified by chromatography to afford a 1:2.6 mixture of (R)-methyl 2-((2S,4R)-4-methoxypyrrolidin-2-yl)-2-(naphthalen-2-yl)acetate hydrochloride (DC-16) and (S)-methyl 2-((2R,3R)-3-methoxypyrrolidin-2-yl)-2-(naphthalen-2-yl)acetate hydrochloride: 391 mg (549 mg, 59% yield). The two regioisomers are separated by silica gel chromatography. (R)-methyl 2-((2S,4R)-4-methoxypyrrolidin-2-yl)-2-(naphthalen-2-yl)acetate. (DC-16): [alpha]D23=+64.2 (c=1.2, CHCl3); 1H NMR (500 MHz, CDCl3) delta 7.82-7.79 (m, 4H), 7.52-7.43 (d, J=7 Hz, 3H), 4.04-3.98 (m, 2H), 3.92 (s, 1H), 3.30 (s, 3H), 3.12-3.07 (m, 1H), 2.87-2.84 (m, 1H), 2.20-2.15 (m, 1H), 1.69-1.62 (m, 2H). 13C NMR (75 MHz, CDCl3) delta 172.9 (C), 134.8 (C), 133.3 (C), 132.7 (C), 128.3 (CH), 127.8 (CH), 127.5 (CH), 126.1 (CH), 125.9 (CH), 81.2 (CH), 59.5 (CH), 57.8 (CH3), 56.3 (CH2), 51.9 (CH), 51.8 (CH2), 36.5 (CH3). IR (neat): 1732 cm-1; HRMS (ESI) m/z Calc'd for [C18H21NO3]+(M+23): 299.1521. Found 322.1412. (S)-methyl 2-((2R,3R)-3-methoxypyrrolidin-2-yl)-2-(naphthalen-2-yl)acetate: [alpha]D23=-174.2 (c=1.0, CHCl3); 1H NMR (500 MHz, CDCl3) delta 7.83-7.80 (m, 4H), 7.57-7.55 (d, 1H), 7.48-7.43 (m, 2H), 3.84-3.83 (d, 1H), 3.72-3.64 (m, 4H), 3.34 (s, 3H), 3.03-2.88 (m, 2H), 1.99-1.92 (m, 1H), 1.87-1.82 (m, 1H), 1.65 (bs, 1H). 13C NMR (75 MHz, CDCl3) delta 172.9 (C), 134.1 (C), 133.3 (C), 132.8 (C), 128.3 (CH), 127.9 (CH), 127.6 (CH), 126.4 (CH), 125.9 (CH), 84.4 (CH), 65.7 (CH), 56.8 (CH3), 55.4 (CH2), 51.9 (CH), 44.2 (CH2), 30.9 (CH3). IR (neat): 1732 cm-1; HRMS (ESI) m/z Calc'd for [C18H21NO3]+ (M+23): 299.1521. Found 322.1412. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75%; 25% | Boc2O (1.02 mL, 4.5 mmol) was added to a solution of (R)-3-hydroxylpyrrolidine hydrochloride (R)-2a·HCl (0.50 g, 4.1 mmol) in THF-satd NaHCO3 (1:1, 20 mL), and the reaction mixture was stirred at rt for 1.5 h. EtOAc was added, and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl (R)-3-hydoxypyrrolidine-1-carboxylate, which was used for the following reaction without further purification.The above-described tert-butyl (R)-3-hydoxypyrrolidine-1-carboxylate was dissolved in anhydrous DMF (20 mL), to which was added NaH (55% oil suspension, 0.71 g, 16.2 mmol) at 0 C. The ice-cold reaction mixture was stirred for 30 min, and Me2SO4 (0.77 mL, 8.1 mmol) was then added. The reaction mixture was stirred overnight at 50 C before being quenched with water. Hexane-EtOAc (1:1) was added, the layers were separated, and the aqueous layer was extracted three times with hexane-EtOAc (1:1). The combined organic layer was washed two times with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (hexane-EtOAc, 2:1) to afford 0.69 g of <strong>[549532-08-3]tert-butyl (R)-3-methoxypyrrolidine-1-carboxylate</strong> [85% from (R)-2a·HCl]. A colorless oil, -8.4 (c=0.52, CHCl3). 1H NMR (500 MHz, CDCl3) delta: 1.44 (9H, s), 1.84-2.02 (2H, m), 3.31 (3H, s), 3.34-3.49 (4H, m), 3.91 (1H, brs). 13C NMR (125 MHz, CDCl3) delta: 28.5, 30.0, 31.1, 43.5, 43.9, 50.3, 51.1, 56.5, 79.09, 79.14, 79.9, 154.5, 154.6. IR (CHCl3): 1686, 1416 cm-1. HRMS Calcd for C10H19NNaO3 [(M+Na)+] m/z: 224.1257, found: 224.1248.Under a nitrogen atmosphere, 4 M HCl in EtOAc (1.2 mL) was added to <strong>[549532-08-3]tert-butyl (R)-3-methoxypyrrolidine-1-carboxylate</strong> (50 mg, 0.25 mmol) at 0 C. The solution was stirred at rt for 30 min and concentrated in vacuo. The residue was dissolved in MeCN-water (10:1, 2.5 mL). Aqueous NH3 (30% w/w, 35 muL, 0.62 mmol) and 3 (162 mg, 0.62 mmol) were added to the solution at 0 C. The reaction mixture was stirred at rt for 30 min and concentrated in vacuo, and the residue was purified by flash column chromatography (CH2Cl2-MeOH, 15:1?10:1) to give 21 mg of (R)-1d (75%, 99% ee) and 7.1 mg of (R)-4-methoxy-1-pyrroline N-oxide (R)-4d (25%). The optical purity of (R)-1d was determined by Daicel CHIRALPAK AD-3 [hexane-iPrOH, 95:5, 2.0 mL/min; retention times 20.3 (R), 24.6 min (S)].(R)-1d. Pale yellow oil, +113 (c=0.85, CHCl3). 1H NMR (500 MHz, CDCl3) delta: 2.17 (1H, dddd, J=3.5, 5.0, 9.0, 14.5 Hz), 2.48-2.57 (1H, m), 3.35 (3H, s), 3.87 (1H, dddd, J=1.0, 6.5, 9.0, 15.5 Hz), 4.10-4.19 (1H, m), 4.56-4.61 (1H, m), 7.02 (1H, q, J=1.5 Hz). 13C NMR (125 MHz, CDCl3) delta: 27.0, 56.5, 61.4, 80.0, 133.3. IR (CHCl3): 1584, 1269, 1238 cm-1. HRMS Calcd for C5H9NNaO2 [(M+Na)+] m/z: 138.0526, found: 138.0534.(R)-4-Methoxy-1-pyrroline N-oxide [(R)-4d]. A pale yellow oil, -22.5 (c=0.66, CHCl3). 1H NMR (500 MHz, CDCl3) delta: 2.75 (1H, d, J=19.5 Hz), 2.94-3.03 (1H, m), 3.33 (3H, s), 3.94 (1H, d, J=15.0 Hz), 4.08-4.15 (1H, m), 4.19-4.24 (1H, m), 6.84-6.87 (1H, m). 13C NMR (125 MHz, CDCl3) delta: 36.1, 56.5, 67.3, 74.3, 133.1. IR (CHCl3): 1595, 1275, 1238 cm-1. HRMS Calcd for C5H9NNaO2 [(M+Na)+] m/z: 138.0526, found: 138.0533. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; In ethyl acetate; at 20℃; | To a solution of the product from step B(1 .65 g, 8.21 mmol) in EA(5 mL) was added HC1/EA (10 mL). The mixture was stirred at rt for 6 h. The solvent was removed to give the title product (1.14 g) as a brown oil which was used directly in the next step. | |
With hydrogenchloride; at 50℃; for 0.5h; | (2) tert-Butyl (R)-3-methoxypyrrolidine-1-carboxylate To a mixture of <strong>[549532-08-3]tert-butyl (R)-3-methoxypyrrolidine-1-carboxylate</strong> obtained in (1) (487 mg) and cyclopentylmethyl ether (5 mL) was added 4.0 mol/L hydrogen chloride/cyclopentyl methyl ether (5 mL) at room temperature. The mixture was warmed and stirred at 50 C. for 30 minutes, and the separated solvent was removed to obtain an oily substance (370 mg). To a mixture of the obtained oily substance and 1,2-dimethoxyethane (10 mL) were added DOWEX (registered trademark) and MONOSPHERE (registered trademark) 550A (1 g), and the mixture was neutralized. The reaction mixture was dried by the addition of anhydrous sodium sulfate, the insoluble matters were removed by filtration and filtered, and the residue was washed with 1,2-dimethoxyethane (5 mL). The filtrate and the washing liquid were combined to obtain a 1,2-dimethoxyethane solution of (R)-3-methoxypyrrolidine. |