Structure of rac-Sitagliptin 3-Ketone
CAS No.: 764667-65-4
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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. : | 764667-65-4 |
| Formula : | C16H12F6N4O2 |
| M.W : | 406.28 |
| SMILES Code : | O=C(N1CC2=NN=C(C(F)(F)F)N2CC1)CC(CC3=CC(F)=C(F)C=C3F)=O |
| MDL No. : | MFCD11111443 |
| InChI Key : | QAEDTLFWHIEVPK-UHFFFAOYSA-N |
| Pubchem ID : | 9887588 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H302-H315-H319-H335 |
| Precautionary Statements: | P261-P305+P351+P338 |
| Num. heavy atoms | 28 |
| Num. arom. heavy atoms | 11 |
| Fraction Csp3 | 0.38 |
| Num. rotatable bonds | 6 |
| Num. H-bond acceptors | 10.0 |
| Num. H-bond donors | 0.0 |
| Molar Refractivity | 84.74 |
| TPSA ? Topological Polar Surface Area: Calculated from |
68.09 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.35 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.13 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.14 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.85 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.65 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.82 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.97 |
| Solubility | 0.44 mg/ml ; 0.00108 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.15 |
| Solubility | 2.85 mg/ml ; 0.00702 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.07 |
| Solubility | 0.00347 mg/ml ; 0.00000853 mol/l |
| Class? Solubility class: Log S scale |
Moderately 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) |
Yes |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
| 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 |
-7.98 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 |
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) |
2.96 |
* 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 |
|---|---|---|
| 84% | In 2000 mL of three necked flask , 150g(0.789mil)2,4,5- Trifluorophenylacetic acid,125g(0.86mol) isopropylidene malonate and 7.7g(63mol)DMAP(4-dimethylaminopyridine) were addded , plus 525 ml DMA (N,N- Dimethylacetamide) was dissolved with magnetic stirring .296mL(1.696mol)DIPEA(N,N-Diisopropylethylamine) was added at room temperature . The oil bath was heated to a reaction temperature of 50 C and 107 mL (0.868 mol) of pivaloyl chloride was added dropwise,Keeping the temperature above 55 C (1-2h). After completion of the dropwise addition at 55 C for 2 h, 3- (trifluoromethyl) -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyrazine (0.789 mol) was added, followed by 18 mL (0.237 mol) of trifluoroacetic acid was added dropwise, keeping the temperature at 55 C for 6 h. After cooling, 625 mL of 5% sodium bicarbonate solution was added, after adding 5g of the compound shown in the formula I keep temperature at 20 ~ 30 C and stirring for 2h,add 5% of sodium bicarbonate solution dropwise for 3 h, Stir at room temperature until no more solids are produced, after cooling to 5 C for 1 h, filtered and washed using three times with 200 mL of 20% DMA solution, washed with 400 mL of water and vaccum drying to obtain 269 g of solid which was tested as a compound of formula I in 84% yield,m/z:407.15[M+H]+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 82% | With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 1h; | Potassium tert-butoxide (2.24 g, 20 mmol) was dissolved in 40 mL of tetrahydrofuran in a 100 mL single-necked flask.Stir at room temperature for one minute. Then compound III (1.91 g, 10 mmol) was added in sequence.Compound II (2.60 g, 10 mmol) was stirred at room temperature for 60 min.Thereafter, the reaction solvent tetrahydrofuran was distilled off under reduced pressure, and then 50 mL of water and 50 mL of dichloromethane were added.The organic phase was extracted and the organic phase was dried with anhydrous sodium sulfate and evaporatedThe crude product was recrystallized from dichloromethane and cyclohexane to give 3.33 g of Compound IV.The yield was 82% and the purity was 99%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | Dichloromethane (100 ml) and the keto acid compound (10.0 g, 43.07 mmol) prepared in Example 8 were added to a 250 ml three-necked flask, and dissolved by stirring. Oxalyl chloride (6.56 g, 51.68 mmol) was added dropwise at 10 to 15 C, and the dropwise addition was completed, and the mixture was heated to 30 to 35 C to stir the reaction. The reaction was completed, and concentrated under reduced pressure at 30 to 40 C to dryness to pale-yellow liquid (10.91 g, 43.64 mmol), methylene chloride (100 ml), triethylamine (5.79 g, 57.24 mmol) and the above yellow liquid (10.0 g, 52.04 mmol) was dissolved by stirring. The solution of the free base (13.0 g, 52.04 mmol) / dichloromethane (20 ml) of the compound of the formula a was added dropwise to 0 to 5 C, and the dropwise addition was completed. After the completion of the dropwise addition, the mixture was heated to 10 to 15 C to stir the reaction. The reaction was completed, water was added and stirred. Layering, taking the lower organic phase and discarding the upper aqueous phase. The organic phase was washed with a 5% aqueous solution of sodium chloride and concentrated to dryness to dryness to dryness to afford white solid (19.24 g, 47.36 mmol) as a ketoamide compound in a molar yield of 91%. |

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