Structure of 486460-00-8
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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. : | 486460-00-8 |
Formula : | C15H18F3NO4 |
M.W : | 333.30 |
SMILES Code : | O=C(O)C[C@H](NC(OC(C)(C)C)=O)CC1=CC(F)=C(F)C=C1F |
MDL No. : | MFCD06659147 |
InChI Key : | TUAXCHGULMWHIO-SECBINFHSA-N |
Pubchem ID : | 7146288 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 23 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.47 |
Num. rotatable bonds | 8 |
Num. H-bond acceptors | 7.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 76.02 |
TPSA ? Topological Polar Surface Area: Calculated from |
75.63 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.38 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.75 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.28 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
3.4 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.39 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
3.24 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.3 |
Solubility | 0.166 mg/ml ; 0.000497 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.99 |
Solubility | 0.0339 mg/ml ; 0.000102 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.39 |
Solubility | 0.0136 mg/ml ; 0.0000407 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 |
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 |
-6.38 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 |
0.56 |
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) |
3.2 |
* 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 |
---|---|---|
86% | EXAMPLE 7 This example is about step 7 of the process of the invention, production of tert-butyl-4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl-carbamate, compound (X) with R = tert-butyl (amide formation with EDC/N-HOBT) N-hydroxybenzotriazole (150 mg, 1.08mmol) is added at 0 C to a solution of (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (300 mg, 0.90 mmol) and <strong>[486460-21-3]3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine</strong> (170 mg, 0.90 mmol) in CH2Cl2 (10ml); after 10 minutes EDC (260 mg, 1.35mmol) is added. The mixture is stirred under nitrogen at room temperature for 4 hours monitoring by TLC (AcOEt). The reaction is quenched by addition of a saturated solution of NaHCO3 (5 mL); after phase separation the organic layer is washed with brine (5 mL), dried over sodium sulphate, concentrated to a residue and purified by flash chromatography eluting with AcOEt obtaining the title product (406 mg, 86%) as a off-white solid. 1H NMR (400 MHz, CDCl3) delta 7.14-7.04 (m, 1 H), 6.97-6.83 (m, 1 H), 5.32-5.24 (bs, 1 H), 5.16-5.00 (m, 1 H), 4.94 (s, 1 H), 4.33-3.94 (m, 5H), 3.02-2.62 (m, 4H) 1.38 (s, 9H). | |
82% | To a solution of (R)-3-[(tert-butyloxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)- butanoic acid (1.36 g, 4.080 mmol) in acetonitrile (20 ml) was added Diisopropylethylamine (2.47 g, 19.12 mmol) and 1 ,1-Carbonyl diimidazole (0.94 g, 5.82 mmol) at room temperature. The reaction mixture was stirred for 30 min at room temperature. S-iTrifluoromethylJ-S.ej.e-tetrahydro-l ,2,3-triazolo[4,3- a]pyrazine (0.750 g, 3.88 mmol) was added to the above reaction mixture at room temperature. The reaction mixture was heated to 65-70C for 22 h. After completion of the reaction, the mixture was concentrated under vacuum and the crude mass was dissolved in ethyl acetate (15 ml) and washed with 5% aqueous NaHC03 solution followed by twice with water (2 x 30 ml). The ethyl acetate layer was concentrated under reduced pressure to get crude mass and recrystallized from mixture of 10 % ethyl acetate and petroleum ether (50 ml) to get 1.5 g (82%) of tert-butyl{(1 R)-3-oxo-1 -(2,4,5-trifluorobenzyl)-3-[3-(trifluoromethyl)-5-6- dihydro[1 ,2,4] triazole[4,3-a]pyrazin-7(8H)-yl]propyl}carbamate. | |
81% | With hydrogenchloride; benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 15h; | 3.0 g of intermediate V (4.5 mmol) was dissolved in 25 mL of DMF,2.06 g of EDC.HCl (10.8 mmol) and1.46 g of HOBT (10.8 mmol) followed by 1.80 g of starting material X (9.0 mmol) and 1.30 mL of triethylamine (9.0 mmol)Stirred at room temperature for 15 h,Add water to extract the reaction,Ethyl acetate extraction, organic NaHCO3 aqueous solution and saturated brine,No waterNa2SO4. The solvent was evaporated under reduced pressure and the column chromatography (EtOAc / petroleum ether = 7: 3) gave the product as a white solid intermediate |
71.8% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; | To a solution of (R) -3- [N- (tert- butoxycarbony1) amino] -4- (2, 4, 5-trifluoro-phenyl) butanoic acid ( 0.333 g, lmmol) of Example 8 and 3- ( trif luoromethyl- 5, 6, 7, 8-tetrahydro-l, 2, 4-triazolo [4, 3a] pyrozine (0.192 g, 1 mmol) in DMF (12 ml) was added HOBT (0.162 g, 1.2mmol) and EDC (0.230 g. 1.2 mmol) at 0 0C. After being stirred at room temperature for 16 h, DMF was evaporated and the residue extracted with ethyl acetate (3 X 20 ml) . The organic extracts were washed with NaHSO4 aq, then NaHCO3, then brine, and then dried over Na2SO4. Concentration was followed by purification by flash chromatography to afford 0.375 g of the title compound (71.8%) . 1H NMR (300 MHz, CDCl3) 7.10-7.00 (m, IH), 7.00-6.90 (m, IH), 5.25-5.35 (br, IH), 5.10-5.00 (m, IH), 4.90 (s, IH), 4.30-3.90 (m, 5H), 3.00-2.90 (m, 2H), 2.80-2.60 (m, 2H), 1.35 (s, 9H) |
47.5% | Comparative Example 1: Preparation of Compound of formula 2 wherein R is Boc, according to the method disclosed in U.S. Patent No. 6,699,871, Example 7, STEP A [42] (R)-3-Boc-amino-4-(2,4,5-trifluorophenyl)-butanoic acid (50.1mg, 0.15mmol) was dissolved in dichloromethane (2.5ml) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-alpha]pyrazine (39.2mg, 0.20mmol) was added thereto. While maintaining a temperature of 0 to 5C, HOBT (17.2mg, 0.21mmol) was added to the mixture, followed by reaction for 10 minutes. Thereafter, EDC (48.3mg, 0.25mmol) was added at 0C, and the reaction mixture was warmed to room temperature and stirred for 14 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure and a desired compound was purified by column chromatography eluting with 100% ethyl acetate to afford 29mg (yield: 47.5%) of the title compound as a solid. |
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