Structure of 195202-08-5
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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. : | 195202-08-5 |
Formula : | C13H18O5 |
M.W : | 254.28 |
SMILES Code : | CC[C@@H](C1=CC(OC)=C(OC)C(OC)=C1)C(O)=O |
MDL No. : | MFCD06245370 |
InChI Key : | WBULUDGUWZFLMO-VIFPVBQESA-N |
Pubchem ID : | 2771669 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.46 |
Num. rotatable bonds | 6 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 67.08 |
TPSA ? Topological Polar Surface Area: Calculated from |
64.99 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.26 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.23 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.29 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.37 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.27 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.08 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.67 |
Solubility | 0.541 mg/ml ; 0.00213 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.23 |
Solubility | 0.15 mg/ml ; 0.000589 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.0 |
Solubility | 0.254 mg/ml ; 0.001 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 |
Yes |
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 |
-6.27 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 |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.58 |
* 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% | Cpd9' (99 g, 0.39 mol) was dissolved in 1 L of dichloromethane, and <strong>[18650-39-0](S)-piperidine-2-carboxylic acid methyl ester hydrochloride</strong> (71.3 g, 0.40 mol), 2-chloro-1-methylpyridine Iodide (CMPI, 126.4 g, 0.50 mol), triethylamine (165 ml, 1.167 mol) was added dropwise, and the reaction was completed at room temperature for 2 h. TLC showed the reaction was completed and concentrated directly to give an oil. 50 ml of water, and then added LiOH (81.8 g, 3.41 mol), stirred at room temperature overnight, TLC showed the reaction was complete;Post-reaction treatment: 500 ml of water was added dropwise to the reaction, 40 C, concentrated to remove methanol, then added EA 500 ml and water 200 ml, and the extract was separated, and the organic phase was saturated NaHCO.3After washing, water was added and the aqueous phase was separated. The combined aqueous phases were acidified to pH 4 with 2N HCl solution and filtered to give white solid Cpd6' (120 g, yield 84%). | |
73% | (lh) Step 8. Synthesis of [S-(R*,R*)]-l-[l-oxo-2-(3,4,5-trimethoxyphenyl)butyl]-2- piperdinecarboxylic acid (API 7362). A solution of AP17360 (10.0 g, 0.039 moles) in CH2C12 (100 mL) was treated with methyl-L- pipecolate hydrochloride (7.2 g, 0.04 moles) followed by 2-chloro-l-methylpyridinium iodide (12.77 g, 0.050 moles). The reaction mixture was then treated dropwise with triethylamine (16.66 mL, 0.120 moles) resulting in a 22C rise in the temperature of the reaction mixture. The solution was allowed to stir for 2 hours, after which time the CH2C12 was removed on a rotary evaporator, the residue (~ 50 mL volume) was dissolved in MeOH (60 mL), and the solution was treated with water (5 mL) followed by lithium hydroxide monohydrate (8.26 g, 0.197 moles). The mixture was stirred overnight then treated with water (20 mL) and the MeOH removed on a rotary evaporator at 40C. The resulting aqueous solution was treated with EtOAc (60 mL) followed by a saturated aqueous NaHC03 solution (60 mL) and the organic layer washed with water (10 mL). The combined aqueous layers were then acidified to pH 4 by careful addition of a 2N HC1 solution and the resulting suspension cooled to 10 C. The precipitate was filtered, triturated with a 1% aqueous citric acid solution (100 mL) and air dried under vacuum at 58 C to provide product, AP17362, (10.5 g, 73%): mp 173.5-174 "C; [ ] 2D +10.9 (c = 1.01, DMSO, 30 min); UV (MeOH) max 270 (epsilon 990), 232 (epsilon 11,161), 207 (epsilon 49,079) nm; NMR (DMSO- d6, 300 MHz) 6.55 (s, 2 H), 5.13 (d, J = 4.4 Hz, 1 H), 3.85-3.64 (m, 1 1 H), 2.77-2.70 (m, 1 H), 2.12 (d, J = 13.4 Hz, 1 H), 1.99-1.85 (m, 1 H), 1.65-1.55 (m, 4 H), 1.38-1.18 (m, 2 H), 0.84 (t, J = 7.2 Hz, 3 H); NMR (CD3OD, 300 MHz) 6.74 (s, 2 H), 5.43 (d, J = 4.0 Hz, 1 H), 4.13-3.83 (m, 1 1 H), 3.03 (td, J = 13.5, 3.0 Hz, 1 H), 2.44 (d, J = 13.8 Hz, 1 H), 2.24-2.14 (m, 1 H), 1.90-1.40 (m, 6 H) 1.09 (t, J = 7.3 Hz, 3 H); ,3C NMR (DMSO-d6, 75 MHz) 172.9, 172.2, 153.0, 136.2, 105.4, 60.2, 56.2, 56.0, 51.8, 49.4, 43.1, 28.5, 26.8, 25.3, 21.0, 12.8; 13C NMR (CD3OD, 75 MHz) 175.4, 174.5, 154.9, 137.5, 106.8, 61.5, 57.1, 53.9, 52.1, 45.2, 29.9, 28.2, 26.8, 22.3, 13.2; HRMS (FAB): (M-H)- calcd: 364.1760, meas: 364.1774. Anal. Calcd for C,9H2706: C, 62.45; H, 7.45; N, 3.83. Found: C, 62.32; H, 7.61 ; N, 3.88. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-chloro-1-methyl-pyridinium iodide; triethylamine; In dichloromethane; at 12 - 25℃; | (2S)-2-(3,4,5-Trimethoxyphenyl)butanoic acid 9 (93.0 g, 0.37 mol), Methyl (2S)- piperidinecarboxylate hydrochloride 11 (69.0 g, 0.38 mol, 1.1 eq.) and 2-chloro-1-methylpyridinium iodide (117.0 g, 0.46 mol, 1.3 eq.) were dissolved in DCM (720 ml_, 8.0 vol.) and cooled to 12 C. To the reaction mixture was added a solution of triethylamine (111.0 g, 1.10 mol, 3.0 eq.) in DCM (180 ml_, 2.0 vol.) while maintaining the internal temperature below 25 C. The reaction was then allowed to stir for 3-4 hours at 22 C. [IPC HPLC (C18: ACN/H20 10-90%, 20 min, 1 mL/min) 9: rrt 0.53 min, Intermediate ester: rrt 0.69, 14: rrt 0.58] Upon completion, the DCM was removed by rotary evaporation and exchanged for MeOH (225 ml_, 2.5 vol.). To the methanolic solution was added a solution of UOH.H2O (77.0 g, 1.83 mol, 5.0 eq.) in Dl water (225 ml_, 2.5 vol.) and the reaction was stirred for 12 hours at 22 C. Upon completion, as determined by IPC, additional water (180 ml_, 2.0 vol.) was added and the solution is vacuum distilled to remove methanol. EtOAc (450 ml_, 5.0 vol.) was added and the biphasic solution stirred vigorously for 10 minutes after which the phases were separated. The aqueous layer containing the product was removed and the organic phase was washed again with water (180 ml_, 2.0 vol.) and 10% NaHCC>3 sol. (360 ml_, 4.0 vol.). The combined aqueous layers were cooled to 4 C. A solution of 5M HCI was slowly added until the pH 4. The resulting slurry was stirred at 4 C for 3 hours then the solid was collected by vacuum filtration. The crude 14 (117.0 g, 0.32 mol) was dissolved in EtOH (1080 ml_, 12.0 vol.), heated and maintained at 50 C for 30 minutes. The ethanolic solution was then cooled to 0 C over 6 hours. The resulting crystalline solid is collected by vacuum filtration and washed with cold EtOH (90 ml_, 1.0 vol.). The product 14 (87.5 g, 0.24 mol, 66% yield) was obtained a colorless crystalline solid.Reverse phase HPLC analysis showed crystalline 14 (11.64 min) to be excellent purity with no detectable impurities. Chiral HPLC analysis shows crystalline 14 (32.58 min) to be excellent purity with no detectable chiral impurities. |
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