Structure of 20386-22-5
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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. : | 20386-22-5 |
Formula : | C4H9ClN2O |
M.W : | 136.58 |
SMILES Code : | Cl[H].NN1CCCC1=O |
MDL No. : | MFCD09258892 |
InChI Key : | NYPFNJOTVWTWAF-UHFFFAOYSA-N |
Pubchem ID : | 21992845 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.75 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 35.91 |
TPSA ? Topological Polar Surface Area: Calculated from |
46.33 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.16 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.1 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.03 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.24 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.09 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.59 |
Solubility | 35.4 mg/ml ; 0.259 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.36 |
Solubility | 59.9 mg/ml ; 0.438 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
0.22 |
Solubility | 229.0 mg/ml ; 1.67 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 |
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 |
-7.25 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 |
2.0 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) |
1.09 |
* 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 |
---|---|---|
69.7% | With pyridine; at 20℃; for 10h; | Stir a mixture OF 2- (6-BROMO-QUINOLIN-4-YL)-1- (6-METHYL-PYRIDIN-2-YL)-ETHANONE (38. 5 g, 113 mmol) and <strong>[20386-22-5]1-aminopyrrolidinone hydrochloride</strong> (20 g, 147 mmol) in 115 mL pyridine at ambient temperature for 10 hours. Add about 50 g 4 A UNACTIVATED sieves. Continue stirring an additional 13 h and add 10-15 g silica and filter the mixture through a 50 g silica plug. Elute the silica plug with 3 L ethyl acetate. Combine the filtrates and concentrate in vacuo. Collect the hydrazone precipitate by filtration and suction dry to yield 33.3 g (69.7%) of the desired subtitled intermediate as an off-white solid. MS ES+ = 423 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With pyridine; In ethanol; for 18h; | The product of Preparation 4 (1.3 g, 1.47 mmol), the product of Preparation 1 (0. 315 g, 2.31 mmol) and pyridine (1.47 mL) are dissolved in ETOH (6 mL) and stirred for 18 h. The mixture is concentrated to dryness and the residue chromatographed on silica gel (90% EtOAc/Hexanes) to give the title compound, 1.2 g (75%), as a yellow foam. 'H NMR (CDC13) 8 8.80-8. 75 (m, 1H), 7.95-7. 85 (m, 2H), 7.70-7. 60 (m, 1H), 7.45-7. 20 (m, 4H), 4.90 (s, 2H), 3.10-3. 00 (m, 2H), 2.20-2. 15 (m, 2H), 1.48-1. 35 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; at 20℃; for 20h; | B. Preparation of 3-[6-Methyl-(pyridin-2-yl)]-3-(2-oxo-pyrrolidin-l-ylimino)-propionic acid ethyl ester; EPO <DP n="16"/> Add l-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem. 1969, 9(2), 58; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-[6-methyl-(pyridin-2-yl)]-3-oxo-propionic acid ethyl ester (Preparation 1, Part A; 154 g, 0.66 mol), and pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2 x 250 mL).Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS (ES) m/z = 290 (M+H). | |
With pyridine; at 20℃; for 20h; | Add L-AMINOPYRROLIDIN-2-ONE hydrochloride (Zubek, A. Z Chem. 1969, 9 (2), 58; 99.4 g, 0.73 mol) to a 3L flask equipped with mechanical stirrer and nitrogen inlet. Add 3- (6-methyl-pyridin-2-yl)-3-oxo-propionic acid ethyl ester (Preparation 1, Part A; 154 g, 0.66 mol), then pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2 x 250 mL). Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS ES+ m/e 290 (M+1). | |
In pyridine; at 20℃; for 20h; | Add l-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z Chem. 1969, 9 (2), 58 ; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3- [6-methyl- (pyridin-2-yl)]-3-oxo-propionic acid ethyl ester (154 g, 0.66 mol), and pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2 x 250 mL). Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS ES+ m/e 290 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In pyridine; at 20℃; for 16h; | Ethyl picolinoylacetate (4.7 g, 24.3 mmol) and the product of Preparation 1 (5.0 g, 36.5 mmol) are mixed in 10 ML of pyridine. The reaction mixture is stirred overnight at RT and then evaporated to a solid mass. The crude mixture is purified by MPLC on silica gel (40% EtOAc/Hexanes) to give the title compound, 6.63 g (95%), as a liquid. MS ES+ m/e 276. 1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine; at 20℃; for 20h; | B. Preparation of 3-(2-Oxo-pyrrolidin-l-ylimino)-3-(pyridin-2-yl)-propionic acid ethyl ester; Place l-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem., 1969, 9(2), 58; 155.6 g, 1.14 mol) in a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-oxo-3-pyridin-2-yl-propionic acid ethyl ester (Preparation 2, Part A; 200 g, 1.04 mol) and pyridine (400 mL). Stir the reaction mixture at room temperature for 20 h.Dilute the mixture with water (500 mL) and extract with toluene (2 x 500 mL). Combine EPO <DP n="19"/>the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield 280 g (98%) of the subtitled compound as a dark oil. MS (ES) m/z = 276 (M+H). |
98% | With pyridine; at 20℃; for 20h; | Place L-AMINOPYRROLIDIN-2-ONE hydrochloride (Zubek, A. Z. CHEM., 1969, 9 (2), 58; 155.6 g, 1.14 mol) in a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-oxo-3-pyridin-2-yl-propionic acid ethyl ester (200 g, 1.04 mol) then pyridine (400 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (500 mL), and-extract with toluene (2 x 500 mL). Combine the organic layers, dry (sodium sulfate), filter and concentrate in vacuo to yield the subtitled compound as a dark oil (280 g, 98%). MS ES+ M/E 276 (M+1). |
98% | In pyridine; at 20℃; for 20h; | Place l-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem., 1969, 9 (2), 58 ; 155. 6 g, 1.14 mol) in a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-oxo-3-pyridin-2-yl-propionic acid ethyl ester (Preparation 3-A ; 200 g, 1.04 mol) and pyridine (400 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (500 mL) and extract with toluene (2 x 500 mL). Combine the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield 280 g (98%) of the subtitled compound as a dark oil. MS ES+ m/e 276 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With hydrogenchloride; In water; for 1.5h;Heating / reflux; | 4-Chlorobutyryl chloride (57 mL, 510 mmol) is added to a solution of benzophenone hydrazone (100 g, 510 mmol) and pyridine (41 mL, 510 mmol) in anhydrous CH2C12 (520 mL) under nitrogen at a rate that maintained a gentle reflux throughout the addition. The mixture is stirred for 0.5 h and poured into water (1 L). The layers are separated and the organic layer is washed with brine, dried (NA2S04), filtered, and concentrated in vacuo to yield 4-chloro-butyric acid benzhydrylidene-hydrazide as a residue. MS ES+ M/E 301. 1 (M+1). This residue is dissolved in THF (1.5 L), and the solution cooled in an ice-water bath, treated with portions of NaH (60% suspended in mineral oil, 20 g, 498 mmol) and stirred for 1 h. To the mixture is added saturated aqueous NH4CL solution (1 L) and EtOAc (1 L). The layers are separated and the organic solution washed with brine, dried (NA2SO4), filtered and concentrated in vacuo to yield 1- (BENZHYDRYLIDENEAMINO) pyrrolidin-2-one as a residue. 'H NMR (CDCl3) : 8 7.58-7. 62 (m, 2H), 7.39-7. 46 (m, 4H), 7.29-7. 36 (m, 4H) 3.31 (t, J = 7 Hz, 2H), 2.32 (t, J = 7 Hz, 2H), 1.91 (quintet, J = 7 Hz, 2H); MS ES+ M/E 265.1 (M+1). This residue is suspended in water (3 L), treated with concentrated HC1 solution (80 mL), and heated to reflux for 1.5 h. The reaction is cooled to RT and extracted twice with CH2CL2. The aqueous portion is concentrated in vacuo followed by azeotropic removal of water with three portions of absolute ethanol and three portions of toluene to yield the title compound, 56 g (81%), as a white solid. 'H NMR (DMSO-d6): 8 3.58 (t, J = 7 Hz, 2H), 2.33 (t, J = 7Hz, 2H), 2.04 (quintet, J = 7 Hz, 2H), TOF MS ES+ exact mass calculated for C4H8N2 (M+): M/Z = 100.0637. Found: 100.0641. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | To a solution of [1-AMINO-PYRROLIDINE-2-ONE] hydrochloride (3.8 g, 27.8 mmol) (WO 02/094833) add ethylbenzoylacetate (4.3 mL, 25 mmol) followed by pyridine (10 mL) at room temperature under nitrogen. Stir the mixture at room temperature for 20 hours and then, dilute with water (50 mL) and extract with toluene (2 x 50 mL). Dry the combined organic layers [(MGS04)] and concentrate in vacuo to give a brown oil, 6.23 g, [82%] yield, and treat with NaOEt (freshly prepared, 3.1 g, 45.4 mmol, 2 equiv) in toluene at [120C] for 8 hours. Cool the mixture to room temperature and add water (100 mL) and concentrated HCl until a pH of 4 is reached. Extract the mixture with EtOAc (3 x 200 mL) and dry [(MGS04)] the combined organic layers and concentrate in vacuo. Purify the residue in a biotage system (eluent: [CH2C12/MEOH] 40: 1) to obtain a yellow solid, 1. [8] g, 36% yield. MS [(ES+)] : [NEZ] = 257.1 [(M+H) +] |
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