Structure of 1-Ethylpiperazine-2,3-dione
CAS No.: 59702-31-7
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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. : | 59702-31-7 |
Formula : | C6H10N2O2 |
M.W : | 142.16 |
SMILES Code : | O=C1N(CC)CCNC1=O |
MDL No. : | MFCD00051825 |
InChI Key : | ZBEKOEYCWKIMGU-UHFFFAOYSA-N |
Pubchem ID : | 108812 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.67 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 42.77 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.41 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.99 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.43 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-1.8 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.96 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.18 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.4 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.38 |
Solubility | 58.7 mg/ml ; 0.413 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.14 |
Solubility | 102.0 mg/ml ; 0.72 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.92 |
Solubility | 17.0 mg/ml ; 0.12 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 |
-7.47 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 |
1.0 |
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) |
1.32 |
* 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 |
---|---|---|
With chloro-trimethyl-silane; triethylamine; In tetrahydrofuran; 1,4-dioxane; | (2)--To a suspension of 0.71 g of the abovementioned 1-ethyl-2,3-dioxo-piperazine in 15 ml of anhydrous dioxane were added with stirring 0.70 g of trimethylsilyl chloride and 0.83 ml of triethylamine. The resulting mixture was stirred at room temperature for 20 hours to deposit triethylamine hydrochloride. This hydrochloride was separated by filtration, and the filtrate was dropped at 5 to 10 C. into a solution of 0.70 g of phosgene in 10 ml of anhydrous tetrahydrofuran. Subsequently, the resulting mixture was reacted at 5 to 10 C. for 30 minutes and at room temperature for 2 hours, and then the solvent was removed by distillation under reduced pressure to obtain 1.0 g of pale yellow crystals of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride. IR (KBr) cm-1: -- νC=O 1780, 1660 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.3% | With pyridine; dmap; chloro-trimethyl-silane; In dichloromethane; at -25 - -20℃; | 1) taking N-ethyldioxypiperazine 14.2 g (0.10 mol),Transfer to a 500 mL three-necked flask, stir, and add 200 mL of dichloromethane.Cool down to -25 to -20 C, add 16.3 g (0.15 mol) TMCS,Control temperature -25 ~ -20 C, add 11.9g (0.15mol) pyridine,Adding 0.018 g of DMAP, adding 11.9 g (0.04 mol) of triphosgene in batches at a temperature of -25 to -20 C, and maintaining the reaction for 30-60 minutes;After the reaction was completed, suction filtration, washing with 30 mL of dichloromethane and distillation to dryness under reduced pressure.Add 100 mL of n-hexane to crystallize and filter by suction.Drying gave 19.3 g of N-ethylbisoxypiperazine chloride in a yield of 94.3%. |
93.9% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dichloromethane; at 10 - 20℃; for 1.06667h;Green chemistry; | add 85.2g ofdichloromethane, 14.2g(0.10mol)N-ethyl-2,3-dioxypiper in the reaction flaskReduce the temperature of oxazine to 15C, add 10.1g(0.034mol) triphosgene; control the temperature to 10-20C,add15.5g(0.102mol)dropwiseDBU, it took 34 minutes to complete the dripping, and the reaction was kept for 30 minutes; after the reaction, the dichloride ofN-ethyl-2,3-dioxypiperazinyl chloridewas obtained by suction filtrationMethane feed liquid (external standard contains 19.2g(0.094mol)N-ethyl-2,3-dioxypiperazine acid chloride, yield 93.9%); add to the filter residueAdd 30% sodium hydroxide solution and water to adjustpH=9.6, vacuum distillation to recoverDBU, the fraction is dried after potassium hydroxide to recover DBU. |
1-Ethylpiperazine-2,3-dione (455 mg, 3.20 mmol, 1.00 eq.) was dissolved in dry dichloromethane (8.9 mL) under argon atmosphere at room temperature. After cooling to 0 C, dry triethylamine (616 pL, 4.42 mmol, 1.38 eq.) and then TMSCI (447 pL, 3.53 mmol, 1.10 eq.) were added and the resulting mixture stirred for one hour at room temperature.The reaction was then cooled to -30 C, triphosgene (361 mg, 1.21 mmol, 0.38 eq.) was added in one batch and stirring was continued for another hour. Thorough drying in vacuo yielded intermediate 4 as moisture sensitive foam, which was directly redissovled in dry dichloromethane (8.9 mL) for further synthesis. Meanwhile, D-(-)-a-Phenylglycine (1, 500 mg, 3.20 mmol. 1.00 eq.) was dissolved in dry dichloromethane (8.9 mL) under argon atmosphere at room temperature. Thereto, dry triethylamine (693 pL, 6.72 mmol, 2.10 eq.) and then TMSCI (894 pL, 7.04 mmol, 2.20 eq.) were added at 0 C and the resulting mixture stirred for two hours at room temperature. Afterwards, the beforehand prepared solution of intermediate 4 was added at -40 C and the reaction was stirred for 30 min., warmed to 0 C and stirred for another hour. The reaction was quenched via the addition of dest. water (ca. 10 mL). After in vacuo removal of dichloromethane, the resulting aqueous suspension was mixed with ethyl acetate (ca. 50 mL). The pH of the aqueous phase was adjusted to 8.0 via the addition of solid NaHCOs and the layers were then separated. The aqueous layer was washed with ethyl acetate (20 mL, 3 times). The aqueous phase was then adjusted to pH = 2.0 via the addition of aqueous concentrated HCI, before it was extracted with ethyl acetate (50 mL, 5 times). The combined organic layers were dried over Na2S04, filtered and concentrated in vacuo. Thus, Acid 5 (1.04 g, 3.04 mmol, 95%) was obtained as colorless foam with a residual content of ethyl acetate (ca. 5 wt-%). |
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