Structure of (S)-3-Pyrrolidinol
CAS No.: 100243-39-8
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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. : | 100243-39-8 |
Formula : | C4H9NO |
M.W : | 87.12 |
SMILES Code : | O[C@@H]1CNCC1 |
MDL No. : | MFCD00192426 |
InChI Key : | JHHZLHWJQPUNKB-BYPYZUCNSA-N |
Pubchem ID : | 2733874 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 6 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 27.11 |
TPSA ? Topological Polar Surface Area: Calculated from |
32.26 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.2 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.69 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-1.04 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.57 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.52 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.12 |
Log S (ESOL):? ESOL: Topological method implemented from |
0.05 |
Solubility | 98.8 mg/ml ; 1.13 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.49 |
Solubility | 268.0 mg/ml ; 3.07 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.13 |
Solubility | 64.4 mg/ml ; 0.74 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
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 |
-7.32 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 |
2.0 |
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) |
1.25 |
* 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 |
---|---|---|
92% | With triethylamine; In dichloromethane; at 5 - 20℃; for 48h; | Step 1: preparation of benzyl (3S)-3-hydroxypyrrolidine-1-carboxylate. A solution of (3S)-pyrrolidin-3-ol (10.0 g, 0.12 mol) in dichloromethane (130 mL) was cooled to 5C. Triethylamine (16.9 mL, 0.12 mol) was added, followed by drop wise addition ofbenzyl chloroformate (13.9 mL, 0.10 mol), ensuring that the temperature did not exceed5C. The reaction mixture was then allowed to stir at ambient temperature for 48h, after which it was poured into aqueous saturated sodium bicarbonate and extracted into dichloromethane. The combined organic layers were washed with aqueous saturated sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude oil was purified by silica gel column chromatography (50% ether hexanes followed by ether) to afford the title compound as a clear oil (14 g, 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(S)-3-Hydroxy-2-pyrrolidineon 9 (0.1 mol, 10.11 g), diglym (1.13 mol, 151.65 g) and NaBH (0.4 mol, 15.13 g) were added to a 500D round-bottom flask at 25oC°C, and sulfuric acid (20.2 g) was gently dropped thereto for 1 hour. After the dropping, the mixture was heated to 8O0C and kept for 12 hours to complete the reaction. When the reaction was completed, methanol was added thereto to inactivate the reaction, and the reaction mixture was neutralized with diluted hydrochloric acid (0.4 mol, 41.67 g). Then, pH of the reaction mixture was adjusted to 11 or more by using an aqueous sol ution of sodium hydroxide (ION 35D), and salts precipitated therefrom were removed through filtration. A resulting filtrate was concentrated under reduced pressure to obtain a (S)-3-hydroxypyrrolidine 1 residue. The residue was distilled under reduced pressure to obtain pure (S)-3-hydroxypyrrolidine 1.[122] 1H-NMR (CDCl ): delta 4.3-4.4 (m, IH), 3.05-3.15 (m, IH), 3.0 (bs, 2H), 2.75-2.9 (m,3H), 1.85-2.0 (m, IH), 1.6-1.75 (m, IH). EPO <DP n="15"/>[123] [124] | ||
EXAMPLE 9 Preparation of (S)-3-hydroxypyrrolidine 1 (S)-3-Hydroxy-2-pyrrolidineon 9 (0.1 mol, 10.11 g), diglym (1.13 mol, 151.65 g) and NaBH (0.4 mol, 15.13 g) were added to a 500.box. round-bottom flask at 25oC° C., and sulfuric acid (20.2 g) was gently dropped thereto for 1 hour. After the dropping, the mixture was heated to 80° C. and kept for 12 hours to complete the reaction. When the reaction was completed, methanol was added thereto to inactivate the reaction, and the reaction mixture was neutralized with diluted hydrochloric acid (0.4 mol, 41.67 g). Then, pH of the reaction mixture was adjusted to 11 or more by using an aqueous solution of sodium hydroxide (10N 35.box.), and salts precipitated therefrom were removed through filtration. A resulting filtrate was concentrated under reduced pressure to obtain a (S)-3-hydroxypyrrolidine 1 residue. The residue was distilled under reduced pressure to obtain pure (S)-3-hydroxypyrrolidine 1. 1H-NMR (CDCl3): delta 4.3-4.4 (m, 1H), 3.05-3.15 (m, 1H), 3.0 (bs, 2H), 2.75-2.9 (m, 3H), 1.85-2.0 (m, 1H), 1.6-1.75 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In methanol; at 20℃; for 1h; | Step A: To <strong>[85822-16-8]4-formylbenzenesulfonyl chloride</strong> (1.0 g) in MeOH (10 mL) was added NaHCO3 (0.425 g, s), followed by S-(-)-3-hydroxypyrrolidine (0.533 g), and the mixture stirred at RT for 1 h. The product was filtered through celite, concentrated to provide an oil, and chromatographed on silica (3% MeOH/DCM) to provide 4-(3-hydroxypyrrolidine-1-sulfonyl)-benzaldehyde (1.14 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium carbonate; In dimethyl sulfoxide; at 130℃; for 4h; | Step 1: (S)-tert-Butyl 4-(3-hydroxypyrrolidin-1-yl)benzoate (157)To a solution of <strong>[58656-98-7]ter<strong>[58656-98-7]t-butyl 4-fluorobenzoate</strong></strong> (1 g, 5.1 mmol) and (S)-pyrrolidin-3-ol (462 mg, 5.3 mmol) in DMSO (10 mL) was added powdered potassium carbonate (705 mg, 5.1 mmol). The mixture was stirred at 130 C. for 4 h and allowed to cool down to room temperature. The mixture was diluted with EtOAc (300 mL) and the solution was washed with water (2×100 mL), dried over Na2SO4, filtered and concentrated to provide title compound 157 (1.23 g, 88% yield) that was used in the next step without further purification. LRMS (ESI): (calc) 263.15 (found) 264.1 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; | A) (S)-1-(3-bromo-5-(trifluoromethyl)phenyl)pyrrolidin-3-ol A mixture of <strong>[130723-13-6]3-bromo-5-fluorobenzotrifluoride</strong> (1.07 g), (S)-3-pyrrolidinol (0.391 mL), cesium carbonate (1.72 g) and DMSO (10 mL) was irradiated with microwave at 120C for 30 min. The mixture was allowed to be cooled to room temperature, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.05 g). MS (API+): 310.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.3% | With potassium carbonate; In tetrahydrofuran; at 70℃; for 12h; | Step-2: Preparation of (S)-1-(4-amino-5-methyl-2-nitrophenyl)pyrrolidin-3-ol. A solution of <strong>[446-18-4]4-fluoro-2-methyl-5-nitroaniline</strong> (1 1g, 64.32mmol), potassium carbonate (35.5g, 257.30 mmol) and (S)-pyrrolidin-3-ol (8.7g, 70.76mmol) in THF was stirred at 70C for 12h. The reaction mixture was filtered and filtrate was purified by column chromatography elution with 50% ethyl acetate in hexane to obtain the title compound (11g, 72.3 %.). LCMS: 97.15% m/z = 238.3(M+1). |
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