Structure of 83282-91-1
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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. : | 83282-91-1 |
| Formula : | C9H8F4O2 |
| M.W : | 224.15 |
| SMILES Code : | OCC1=C(F)C(F)=C(COC)C(F)=C1F |
| English Name : | (2,3,5,6-Tetrafluoro-4-(methoxymethyl)phenyl)methanol |
| MDL No. : | MFCD08688060 |
| InChI Key : | YFHZSPDQKWFAPH-UHFFFAOYSA-N |
| Pubchem ID : | 11172116 |
| Num. heavy atoms | 15 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.33 |
| Num. rotatable bonds | 3 |
| Num. H-bond acceptors | 6.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 43.26 |
| TPSA ? Topological Polar Surface Area: Calculated from |
29.46 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.16 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.09 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.26 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.93 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.75 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.64 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.01 |
| Solubility | 2.17 mg/ml ; 0.00967 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-1.3 |
| Solubility | 11.2 mg/ml ; 0.05 mol/l |
| Class? Solubility class: Log S scale |
Very soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.88 |
| Solubility | 0.0293 mg/ml ; 0.000131 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) |
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 |
-6.89 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 |
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) |
1.77 |
* 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 |
|---|---|---|
| 68% | In 5,5-dimethyl-1,3-cyclohexadiene | 13 Example 13 Example 13 In a 10 ml test tube-type reactor, 0.34 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid, 0.45 g of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol, 4.7 mg of zirconium tetrachloride, and 5 ml of xylene were charged. The reactor was equipped with a Dean-Stark trap and a condenser, and the reaction mixture was stirred under reflux for 8 hours at 145° C. while water generated as a by-product during reaction was being separated and collected in the trap. A reaction mixture thereof was analyzed with gas chromatography to find that 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate was obtained in a yield of 68% (selectivity: 98%) based on the material alcohol. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 70% | In 5,5-dimethyl-1,3-cyclohexadiene | 31 Example 31 Example 31 In a 10 ml test tube-type reactor, 0.34 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid, 0.45 g of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol, 13.6 mg of a hafnium tetrachloride·2tetrahydrofuran complex, and 5 ml of xylene were charged. The reactor was equipped with a Dean-Stark trap and a condenser, and the reaction mixture was stirred under reflux for 8 hours at 145° C. while water generated as a by-product during reaction was being separated and collected in the trap. A reaction mixture thereof was analyzed with gas chromatography to find that 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate was obtained in a yield of 70% (selectivity: 99%) based on the material alcohol. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95% | With 1-methyl-4-butylimidazolium tetrafluoroborate; hydrogen at 160℃; for 4 - 8h; | 1; 2 Example 1; Into a 50 ml flask equipped with a reflux condenser, 5 g of slurry of sponge cobalt (commercially available from Aldrich, Raney (a registered trade mark of W. R. Grace) 2700 Cobalt), 5 g of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol and 5 g of 1-methyl-4-butylimidazolium tetrafluoroborate were charged. After removing water from the obtained mixture at 8 kPa and at an inner temperature of 80°C, a gas phase part in the flask was substituted with nitrogen. Further, the gas phase part was substituted with hydrogen and a 1L-volume rubber balloon full filed with hydrogen was equipped with the flask. The mixture was heated to 160°C to effect reaction at 160°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 20 g of hexane and 20 g of water were added thereto. After removing an insoluble matters by filtration from the mixture obtained, the filtrate obtained was left at rest and separated to an organic layer and an aqueous layer. The aqueous layer was extracted twice with 20 g of hexane. The hexane layers were mixed with the previous obtained organic layer to concentrate to obtain 4.5 g of a pale yellow oil containing 4-methoxymethyl-2,3,5,6-tetrafluorotoluene. The purity was 98% and the yield was 95%. Alternatively, 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol was recovered in 3%. GC-MS:M+=208 1H-NMR (δppm, CDCl3, TMS standard): 2.29 (s, 3H), 3.39 (s, 3H), 4.56 (s, 2H) Example 2 The reaction was conducted according to a same manner as that of Example 1, except that the used amount of slurry of cobalt sponge was 4.5 g and the reaction time was 8 hours, to obtain 4.6 g of a pale yellow oil containing 4-methoxymethyl-2,3,5,6-tetrafluorotoluene. The purity was 99% and the yield was 98%. Alternatively, 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol was recovered in 2%. |
| 95% | With hydrogen In toluene at 150℃; for 18h; | 4 Example 4; Into a 200 ml pressure-resistant reaction tube, 4.5 g of slurry of sponge cobalt (commercially available from Aldrich, Raney (a registered trade mark of W. R. Grace) 2700 Cobalt), 5 g of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol and 15 g of toluene were charged. After a gas phase part in the reaction tube was substituted with nitrogen, the gas phase part was substituted twice with hydrogen at 0.4 MPa. The hydrogen pressure in the reaction tube was adjusted to a gauge pressure of 0.4 MPa, and then, the tube was heated to 150°C to effect reaction at 150°C for 18 hours. During this period, the gauge pressure was increased up to 0.8 MPa and then decreased to 0.6 MPa. After completion of the reaction, the reaction mixture was cooled to room temperature and 10 g of water was added thereto. After removing an insoluble matters by filtration from the mixture obtained, the insoluble matters were washed with 10 g of toluene. The wash liquid obtained was mixed with the previously obtained filtrate, leaving at rest followed by separating an organic layer. The organic layer was concentrated to obtain 4.7 g of a pale yellow oil containing 4-methoxymethyl-2,3,5,6-tetrafluorotoluene. The purity was 94% and the yield was 95%. |
| 86% | With hydrogen; methyltrioctylammonium bistriflamide at 150℃; for 5h; | 3 Example 3; Into a 50 ml flask equipped with a reflux condenser, 900 mg of slurry of sponge cobalt (commercially available from Aldrich, Raney (a registered trade mark of W. R. Grace) 2700 Cobalt), 1.12 g of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol and 5 g of trioctylmethylammonium bis(trifluoromethanesulfonyl)imide were charged. After removing water from the obtained mixture at 8 kPa and at an inner temperature of 80°C, a gas phase part in the flask was substituted with nitrogen. Further, the gas phase part was substituted with hydrogen and a 1L-volume rubber balloon full filed with hydrogen was equipped with the flask. The mixture was heated to 150°C to effect reaction at 150°C for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 5 g of hexane and 10 g of water were added thereto. After removing an insoluble matters by filtration from the mixture obtained, the filtrate obtained was left at rest and separated to an organic layer, an aqueous layer and an ionic liquid layer. The ionic liquid layer was extracted twice with 5 g of hexane. The hexane layers were mixed with the previous obtained organic layer to concentrate to obtain 916 mg of a pale yellow oil containing 4-methoxymethyl-2,3,5,6-tetrafluorotoluene. The purity was 98% and the yield was 86%. Alternatively, 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol was recovered in 4%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | With sulfuric acid; water at 50℃; for 0.5h; | 6 Example 6 Into a 50 ml flask, 190 mg of the oil containing 4-methoxymethyl-2,3,5,6-tetrafluorotoluene, which was obtained in the above-mentioned Example 1, and 2 g of 90% sulfuric acid were charged and the resultant mixture was heated to 50°C and kept while stirring at 50°C for 30 minutes. After the reaction, the mixture was cooled to room temperature and diluted with 10g of water and then, 5 g of ethyl acetate was added thereto. The organic layer obtained was analyzed by a gas chromatography internal standard method to find out that the yield of 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol was 85%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 18h; | 2 Production Example 2To a solution of 273 mg (1.22 mmol) of 4- methoxymethyl-2, 3, 5, 6-tetrafluorobenzylalcohol and 240 mg (1.46 mmol) of ( IR) -trans-3-difluoromethyl-2, 2- dimethylcyclopropane carboxylic acid in 5 mL of chloroform were added 335 mg (1.75 mol) of l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride and 5 mg of 4-dimethylaminopyridine, and the mixture was stirred at room temperature for 18 hours. Water was poured into the reaction mixture, followed by extraction with ethyl acetate The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (product name: silica gel, 60 N (spherical, neutral), manufactured by Kanto Chemical Co., Inc.) to obtain 182 mg of 4- methoxymethyl-2, 3, 5, 6-tetrafluorobenzyl (IR) -trans-3- difluoromethyl-2 , 2-dimethylcyclopropanecarboxylate represented by the following formula:(Present compound (2))(hereinafter referred to as the present compound (2)) as a clear colorless liquid. 1H-NMR(CDCl3) δ (ppm) : 1.25 (3H, s) , 1.28 (3H, s) , 1.80-1.82 (IH, m) , 1.88-1.95 (IH, m) , 3.41 (3H, s) , 4.59 (2H, s) , 5.26 (2H, m) , 5.63 (IH, dt, J=6.2, 55.9Hz) . |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 97% | Stage #1: 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol With zircornium(IV) n-propoxide In propan-1-ol; xylene at 143 - 145℃; Stage #2: chrysanthemumic acid With 2,6-di-tert-butyl-4-methyl-phenol In propan-1-ol; xylene at 145 - 147℃; for 8h; | 1 Example 1; To 500 ml four-neck flask, 186 g of xylene, 1.70 g of a solution of tetrapropoxyzirconium in propanol (75% in content) and 44.8 g of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol were charged, and the resultant solution was heated to 143 to 145° C. under stirring at a normal pressure, and then 18.6 g of a mixture of propanol and xylene was distilled off to obtain a solution containing an zirconium catalyst. The resultant solution was cooled below 80° C., and then 37.0 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropane-carboxylic acid, 18 g of xylene and 0.74 g of 2,6-di-tert-butyl-4-methylphenol as stabilizing agent were charged. To the reactor, Dean-Stark trap was equipped, and the reaction was conducted under stirring for eight hours at 145 to 147° C., removing water by-produced during the reaction into the trap, and a solution containing 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(2-methyl-1-propenyl) cyclopropanecarboxylate was obtained. Yield: 97% (based on 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol) Content of by-product: 0.5% of propyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate; Comparative Example 1; To 500 ml four-neck flask, 186 g of xylene and 1.70 g of a solution of tetrapropoxyzirconium in propanol (75% in content) were charged, and the resultant solution was heated to 143 to 145° C. under stirring at a normal pressure, and then 18.6 g of a mixture of propanol and xylene was distilled off. The resultant solution was cooled below 80° C., and then 44.8 g of 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol, 37.0 g of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid, 18 g of xylene and 0.74 g of 2,6-di-tert-butyl-4-methylphenol as stabilizing agent were charged. To the reactor, Dean-Stark trap was equipped, and the reaction was conducted under stirring for eight hours at 145 to 147° C., removing water by-produced during the reaction into the trap, and a solution containing 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate was obtained. Yield: 97% (based on 2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl alcohol. Content of by-product: 5.2% of propyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With pyridine In toluene at 20℃; for 12h; | 1 Production Example 14-methoxymethyl-2 , 3, 5, 6-tetrafluorobenzyl alcohol (0.70 g, 3.13 mmol) and 0.7 mL of pyridine were added to mL of toluene, and a toluene solution (5 mL) of (lR)-trans-3- [ (1EZ) -2-cyano-2- (methylthio) ethenyl ] -2 , 2- dimethylcyclopropanecarboxylic acid chloride (0.71 g, 3.10 mmol) was added thereto. After stirring the mixture at room temperature for 12 hours, the reaction solution was poured into 5 mL of 5% hydrochloric acid and 30 mL of ice water and the solution was extracted with ethyl acetate. The organic layer was washed with 20 mL of saturated brine and 5 mL of saturated sodium bicarbonate water respectively, and then dried over magnesium sulfate. After concentration of the organic layer under reduced pressure, the residue was subjected to silica gel chromatography to obtain 0.43 g of4-methoxymethyl-2 , 3, 5, 6-tetrafluorobenzyl= (1R) -trans-3- [ (IE) -2-cyano-2- (methylthio) ethenyl] -2,2- dimethylcyclopropane carboxylate (hereinafter referred to as the compound of the present invention (1) ) represented by the following formula:as a fraction having higher polarity.Pale yellow liquid: 1 H-NMR (CDC13 , MS) δ (ppm) : 1.23(s,3H),1.33(s,3H), 1.80(d,lH), 2.40(s,3H), 2.52 (dd, 1H) , 3.41(s,3H), 4.59(s,2H), 5.26(s,2H), 6.15(d,lH) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 3h; | 1 To a chloroform solution (10 mL) of 4-methoxymethyl- 2, 3, 5, 6-tetrafluorobenzyl alcohol (594 mg, 2.65 mmol) and (1R) -trans-3- ['(1Z) -2-cyano-l , 3-butadienyl ] -2 , 2- dimethylcyclopropanecarboxylic acid (478 mg, 2.50 mmol), 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (516 mg, 2.70 mmol) and 4-dimethylaminopyridine (15 mg) were added. After stirring at room temperature for 3 hours, water was poured into the reaction solution and the solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure condition, and the residue was subjected to silica gel column chromatography to obtain 771 mg of 4- methoxymethyl-2 , 3, 5, 6-tetrafluorobenzyl= (1R) -trans-3- [ (1Z) - 2-cyano-l, 3-butadienyl] -2, 2-dimethylcyclopropane carboxylate (hereinafter referred to as the present invention compound (1)) represented by the following formula: Pale yellow liquid: 1 H-NMR (CDC13 , TMS) δ (ppm) : 1.21 (s, 3H) , 1.35(s,3H), 1.81(d,lH), 2.54(m,lH), 3.41(s,3H), 4.58(d,2H), 5.26(s,2H), 5.28(d,lH), 5.56(d, 1H) , 5.95(d,lH), 6.24(dd,lH) |

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