Structure of 130312-02-6
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 130312-02-6 |
Formula : | C12H13NO3 |
M.W : | 219.24 |
SMILES Code : | O=C(N1CC(CC1)=O)OCC2=CC=CC=C2 |
MDL No. : | MFCD03001711 |
InChI Key : | LMHWEUQNJRXMCD-UHFFFAOYSA-N |
Pubchem ID : | 561203 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 16 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 62.01 |
TPSA ? Topological Polar Surface Area: Calculated from |
46.61 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.27 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.17 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.07 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.06 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.72 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.45 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.95 |
Solubility | 2.46 mg/ml ; 0.0112 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.74 |
Solubility | 3.95 mg/ml ; 0.018 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.83 |
Solubility | 0.322 mg/ml ; 0.00147 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 |
-6.81 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) |
1.98 |
* 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 |
---|---|---|
96% | 6.iv. 3 -oxo-pyrrolidine- 1-carboxylic acid benzyl ester:A solution of intermediate .iii (1.10 g) in DCM (8 ml) was cooled to 0 0C and DIPEA (2.5 ml) was added dropwise, followed by a solution of sulfur trioxide pyridine complex (1.79 g) in DMSO (6.5 ml). The reaction mixture was stirred at 0 0C for 1 h and was quenched by the addition of water (6 ml). The aq. layer was extracted with Et2O/Hex (1 :1, 3 x 5 ml) and the combined org. layers were concentrated in vacuo. The residue obtained after work up (Et2O/Hex 1 :1) was purified by chromatography (Hex/EA 5:5) to give 1.05 g (96% yield) of a yellowish oil. 1H NMR (DMSOd6; delta ppm): 2.48-2.61 (2H, m); 3.61-3.80 (4H, m); 5.09 (2H, s); 7.27-7.41 (5H, m). | |
96% | With sulfur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine; In dichloromethane; dimethyl sulfoxide; at 0℃; | A solution of intermediate 6.iii (1.10 g) in DCM (8 mL) was cooled to 0 C. and DIPEA (2.5 mL) was added dropwise, followed by a solution of sulfur trioxide pyridine complex (1.79 g) in DMSO (6.5 mL). The reaction mixture was stirred at 0 C. for 1 h and was quenched by the addition of water (6 mL). The aq. layer was extracted with Et2O/Hex (1:1, 3*5 mL) and the combined org. layers were concentrated in vacuo. The residue obtained after work up (Et2O/Hex 1:1) was purified by chromatography (Hex/EA 5:5) to give 1.05 g (96% yield) of a yellowish oil. 1H NMR (DMSOd6; delta ppm): 2.48-2.61 (2H, m); 3.61-3.80 (4H, m); 5.09 (2H, s); 7.27-7.41 (5H, m). |
90% | With sulfur trioxide pyridine complex; dimethyl sulfoxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h; | To a stirred solution of intermediate B (15.50 g, 0.07 mol) in DCM (100 mL) was added DIPEA (35.2 mL 0.21 mol) at 0C . A solution of pyridine sulfur trioxide (25.2g, 0.16 mol) in DMSO (70 mL) was added dropwise and the resulting mixture stirred at 0C for 1 h. The reaction was quenched by addition of H20 and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried (Na2S04), filtered and concentrated. The crude product obtained was purified by flash chromatography (EtOAc/Pet ether=1 :2) to give compound C (13.80 g, 90%) as yellow solid. It's structure was confirmed by LC-MS spectra. TLC:Rf=0.7(silica gel,EA:PE=1 : 1 , v/v) LC-MS :[M+23]= 242. |
79% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione; In acetonitrile; at 70℃; for 2h; | A mixture of <strong>[95656-88-5]benzyl 3-hydroxypyrrolidinyl-1-carboxylate</strong> (14 g, 63.3 mmol) and IBX (21.3 g, 76 mmol) in acetonitrile (200 mL) was stirred at 70 C for 2 hours. The mixture was filtered and the filtrate concentrated. The remaining residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 1:1) to give benzyl 3-oxopyrrolidinyl-1- carboxylate (11 g, 79%) as a colorless oil.1H NMR (400 MHz, DMSO-d6) delta ppm 7.46 - 7.25 (m, 5H), 5.13 (s, 2H), 3.83 - 3.64 (m, 4H), 2.57 (s, 2H). |
27% | With pyridinium chlorochromate; In dichloromethane; at 20℃; for 72h; | Benzyl 3-hydroxypyrrolidine-1-carboxylate (0.30 g, 1.34 mmol) was dissolved in DCM (20 mL) and pyridinium chlorochromate was added (0.44 g, 2.0 mmol). The resulting slurry was stirred at room temperature for 72 h. Benzyl 3-oxopyrrolidine-1-carboxylate (0.080 g, 27%) was isolated as a colorless oil by prep. HPLC YMC ODSA 30×100 mm, 20-100% MeOH/H2O (0.1% TFA) gradient over 10 mins at 20 mL/min flow rate at a retention time of 4.25 min. LCMS: 1.20 min [M+1] not observed (2 min gradient, MeOH/H2O 0.1% TFA). |
5.6% | (ii) N-Benzyloxycarbonyl-3-pyrrolidinone: To a chilled (-60C) solution of oxalyl chloride (23 mL, 98%, 258.6 mmol) in dichloromethane (400 mL) was added dropwise a solution of anhydrous dimethyl sulfoxide (36.7 mL, 517.3 mmol) in dichloromethane (20 mL) at such a rate to keep the temperature below -40C. The reaction mixture was then stirred at -60C for 15 min. Then a solution of <strong>[95656-88-5]N-benzyloxycarbonyl-3-pyrrolidinol</strong> (58.22 g, step i, no more than 224.9 mmol) in dichloromethane (80 mL) was added dropwise, keeping the reaction mixture temperature below -50C. The reaction mixture was then stirred at -60C for 30 min before adding triethylamine (158.3 mL, 99%, 1.125 mol). The resulting mixture was allowed to warm up to room temperature and then washed with water (600 mL), 1M HCl aqueous solution (580 mL) and water (400 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to leave 54.5 g of amber oil, which was further pumped under high vacuum with stirring at room temperature for 25 min. to give 52.08 g (5.6% over theoretical yield) of the crude title compound suitable for the next step without any further purification. | |
With triethylamine; In dichloromethane; water; | After addition, the mixture was stirred for an additional 25 min and then a solution of <strong>[95656-88-5]3-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester</strong> (11 g, 50 mmol, 1.0 equiv) in 20 mL of CH2Cl2 was added dropwise over a 10 min period. After complete addition the reaction was stirred an additional a hour at -78 C. Et3N (55 mL, 398 mmol, 8.0 equiv) was added over a period of 10 min. The cold-bath was removed and the mixture was stirred while warming for 2 h. The mixture was diluted with 500 mL of water. After thorough mixing, the layers were separated and the aqueous layer was extracted 2xl50 mL of CH2Cl2. The combined organic layers were washed with 200 mL of sodium bicarbonate solution and 200 mL of brine, dried over Na2SO4, decanted, and concentrated to a yellow oil. The product was purified by flash chromatography on silica gel using CH2Cl2 as eluent to yield the desired product as a colorless oil (8.5 g). | |
With dipyridinium dichromate; In dichloromethane; at 20℃; for 72h; | Reference Example 82 A mixture of benzyl 3-hydroxy-1-pyrrolidine carboxylate (10.0 g), pyridinium nichromate (14.6 g), and dichloromethane (150 mL) was stirred at room temperature for 3 days. Insolubles were filtered off using celite and washed with dichloromethane. Mother liquor was concentrated, and the obtained residue was purified by silica gel column chromatography to obtain benzyl 3-oxo-1-pyrrolidine carboxylate (4.39 g). 1H-NMR (300 MHz, CDCl3) delta: 2.61 (2H, t, J=7.5 Hz), 3.83-3.89 (4H, m), 5.18 (2H, s), 7.33-7.39 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.1 g (86%) | With dimethyl sulfoxide; triethylamine; In dichloromethane; water; | Example A 1-Benzyloxycarbonyl-3-pyrrolidone A dichloromethane (40 ml) solution of 16.58 ml (233.6 mmol) of dimethyl sulfoxide was added dropwise to a dichloromethane (200 ml) solution of 10.19 ml (116.8 mmol) of oxalyl chloride at -78 C., and the mixture was stirred for 10 minutes at the same temperature. To the reaction solution was added dropwise a solution of 23.50 g of literary known <strong>[95656-88-5]1-benzyloxycarbonyl-3-hydroxypyrrolidine</strong> in 200 ml of dichloromethane at -78 C., followed by 60 minutes of stirring at the same temperature. This solution was mixed with 74.02 ml (531.1 mmol) of triethylamine at -78 C., and stirred for 60 minutes at the same temperature and then at room temperature for 60 minutes. After completion of the reaction, 500 ml of water was added dropwise to the reaction solution, and the organic layer was separated. The aqueous layer was washed with dichloromethane (100 ml*2), and combined organic layer was washed with saturated brine (300 ml*1). After drying the organic layer over sodium sulfate, the solvent was evaporated. The resulting residue was subjected to a silica gel column chromatography to yield 20.1 g (86%) of the title compound as an oily product from the elude of n-hexane:ethyl acetate=1:1. 1H-NMR (400 MHz, CDCl3) delta: 2.58-2.62 (2H, m), 3.82-3.87 (4H, m), 5.18 (2H, s), 7.30-7.37 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
silica gel; In dichloromethane; | Part B. Preparation of N-(benzyloxycarbonyl)-3-pyrrolidinone. To a stirring solution of N-(benzyloxycarbonyl)-3-pyrrolidinol (1600 mg, 7.2 mmol) and 4-methylmorpholine oxide (1269 mg, 10.8 mmol, Aldrich) in dry CH2Cl2 (100 mL) with activated molecular sieves (1000 mg) was added tetrapropylammonium perruthenate (127 mg, 0.36 mmol, Aldrich). The reaction was stirred for 1 h and then filtered through a pad of silica gel. The silica gel was washed with EtOAc (500 mL). The organic filtrates were combined and conc. in vacuo to a colorless oil of pure N-(benzyloxycarbonyl)-3-pyrrolidinone. MS (ESI) 220 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide; In dichloromethane; for 2h;Molecular sieve; Inert atmosphere; | Step 2: preparation of benzyl 3-oxopyrrolidine-1-carboxylate. To a solution of<strong>[100858-32-0]benzyl (3S)-3-hydroxypyrrolidine-1-carboxylate</strong> (7.5 g, 33.9 mmol) in dichloromethane(1.2 L) was added 4-methylmorpholine N-oxide (5.96 g, 50.0 mmol), tetrapropylammonium perruthenate (0.60 g, 1 .7 mmol), and 4 A molecular sieves (7.0 g). The reaction mixture was allowed to stir under nitrogen for 2 h, after which it was filtered through a silica gel plug and eluted with diethyl ether. The filtrate canconcentrated to afford the title compound as clear oil (6.5 g, 88%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.9% | With sodium tetrahydroborate; N-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-2-carboxamide; at 20℃; for 2h; | TDI01272-1 (10.0 g, 45.7 mmol) was dissolved in anhydrous methanol (100 mL), sodium borohydride (3.38 g,91.4 mmol) was added in portions under cooling of an ice bath, and the reaction was performed at room temperaturefor 2 h. Thin layer chromatography (ethyl acetate) indicated the reaction was complete. The reaction solution wasquenched by water (80 mL), and extracted with dichloromethane (300 mL). The combined organic phase was washedwith saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, andthe crude product was separated and purified by column chromatography (petroleum ether : ethyl acetate=1:1 to 0:1)to afford TDI01272-2 (5.20 g, yellow oil, yield: 51.9%).1H NMR (400 MHz, CDCl3) delta 7.34 - 7.21 (m, 5H), 4.32 - 4.28 (m, 1H), 3.60 (s, 2H), 2.86 - 2.79 (m, 1H), 2.66 - 2.63 (m,1H), 2.54 - 2.51 (m, 1H), 2.31 - 2.26 (m, 1H), 2.22 - 2.12 (m, 1H), 1.75 - 1.65 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With recombinant Rhodococcus erythropolis DSM 43297 ketoredutase; nicotinamide adenine dinucleotide; In aq. phosphate buffer; isopropyl alcohol; at 50℃; for 21h;pH 7.0;Enzymatic reaction; | General procedure: The reaction mixture containing 200 mM substrate, 1mM NAD+, 5% (v/v) 2-propanol and 10mg crude enzyme READH in 1mL potassium phosphate buffer (100mM, pH 7.0) was incubated at 50 C. For ChKRED20, 40% (v/v) 2-propanol and a reaction temperature of 40 C were applied instead. The reaction was monitored by TLC, and terminated by extracting with methyl tert-butyl ether (1 mL). The organic extract was dried over anhydrous sodium sulfate and concentrated. The samples were subjected to chiral HPLC to determine the conversion and enantiomeric excess. The products were purified by silica gel column chromatography, and identified by NMR analysis, optical rotation measurements and mass spectrometry. |
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