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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. : | 21906-39-8 | 
| Formula : | C10H9F3O | 
| M.W : | 202.17 | 
| SMILES Code : | CC(CC1=CC=CC(C(F)(F)F)=C1)=O | 
| MDL No. : | MFCD00000397 | 
| InChI Key : | JPHQCDCEBDRIOL-UHFFFAOYSA-N | 
| Pubchem ID : | 89101 | 
| GHS Pictogram: |   | 
| Signal Word: | Warning | 
| Hazard Statements: | H315-H319-H335 | 
| Precautionary Statements: | P261-P305+P351+P338 | 
| Num. heavy atoms | 14 | 
| Num. arom. heavy atoms | 6 | 
| Fraction Csp3 | 0.3 | 
| Num. rotatable bonds | 3 | 
| Num. H-bond acceptors | 4.0 | 
| Num. H-bond donors | 0.0 | 
| Molar Refractivity | 46.22 | 
| TPSA ? Topological Polar Surface Area: Calculated from  | 17.07 Ų | 
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from  | 2.0 | 
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by  | 2.75 | 
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from  | 3.99 | 
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from  | 3.1 | 
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by  | 3.54 | 
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 3.08 | 
| Log S (ESOL):? ESOL: Topological method implemented from  | -2.95 | 
| Solubility | 0.229 mg/ml ; 0.00113 mol/l | 
| Class? Solubility class: Log S scale  | Soluble | 
| Log S (Ali)? Ali: Topological method implemented from  | -2.76 | 
| Solubility | 0.349 mg/ml ; 0.00172 mol/l | 
| Class? Solubility class: Log S scale  | Soluble | 
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by  | -4.03 | 
| Solubility | 0.0189 mg/ml ; 0.0000933 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)  | 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  | -5.58 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  | 0.0 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) | 1.56 | 
* 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 | 
|---|---|---|
| > 98% | With Kluyveromyces marxianus CBS 6556; In ethanol; at 30℃; for 96h;Microbiological reaction; Yeast maintenance medium; Enzymatic reaction; | Kluyveromyces marxianus CBS 6556 was stored on agar slants at 4 C. For inoculum preparation, a 250 mL conical Erlen-Meyer flask containing 100 mL of yeast maintenance medium (YMM) (previously autoclaved at 121 C, 1 atm, for 15 min), was inoculated with a single loopful of the microorganisms from the agar slants. The flask was then incubated aerobically at 30 C in a rotary shaker at 200 rpm for 24 h. Next, the growing cultures were inoculated (5% v/v) into a 250 mL conical Erlen-Meyer flask containing 100 mL of YMM and incubated for additional 24 h under the same conditions. These cultures were then used as a final inoculum (1% v/v) into a 1000 mL flask containing 400 mL of YMM. After 24 h of incubation at 30 C in the shaker (200 rpm), a mixture of 100 mg of the ketone 1a-o dissolved in 1 mL of absolute ethanol was added. The reactions were monitored by GC, by collecting suspension aliquots of 1 mL after 1, 3, 4 and 5 days of reaction from each flask: after extraction with ethyl acetate (2 mL), the organic phase was analyzed by GC. After the appropriate conversion, the suspension was centrifuged (3000 rpm, 6 min, 4 C), and the aqueous phase extracted with ethyl acetate (4 × 150 ml). The yellow organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate (90:10 or 80:20) as eluent to yield the desired alcohols. [50] and [51] | 
| 80% | With succinylated alginate yeast cells; In aq. phosphate buffer; at 30 - 35℃; for 24h;pH 7.5;Enzymatic reaction; | General procedure: The fermentation medium, in a total volume of 1L, consists of 20gL-1 glucose, 20gL-1 peptone and 10gL-1 yeast extract, to this yeast cells were inoculated, followed by incubation at 28-30C for 48h. After optimal growth, the medium was centrifuged to isolate fermented yeast cells, which were then washed with sterile distilled water. These fermented yeast cells were immobilized different alginate matrix i.e. a) Calcium alginate immobilized yeast beads and b) Succinyl modified alginate immobilized beads as described in our earlier studies [14]. The degree of succinylation was determined by the titration method as described by Wurzburg [15]. To the 4% sodium alginate/succinylated alginate solution, 2% (v/v) of fermented S.cerevisiae cells were added and the resultant cell suspension (107cfu/cm3) was extruded through a needle with diameter-0.5mm injector added as droplets into 2% calcium chloride solution under continuous stirring to get the calcium alginate/succinylated alginate-immobilized beads. Beads having a diameter in the range of 1.5-2.5mm were selected for subsequent fermentation experiments. Cell viability was determined by plate counts. The stability of yeast entrapped in the succinyl alginate matrix (beads) was measured as described in [14]. The binding efficiency of yeast cells in the alginate/functionalized alginate matrix has been confirmed by SEM studies (Fig. 1 ). To the above immobilized yeast cells (10gm in 250mL of phosphate buffer, pH 7.5), the pro-chiral ketones 1a-9a or azido ketones 10a-12a, (100mg/mL) each were added and incubated at 30-37C. The progress of the reactions at different time intervals was monitored by TLC and HPLC. After optimal biotransformation of ketones to respective chiral alcohols the immobilized beads containing yeast cells were separated and reused up to 7 cycles without much loss enzyme activity. Thus collected reaction medium containing products was extracted with equal amounts of ethyl acetate and the products obtained were isolated and purified by column chromatography. The spectral data of all the chiral products synthesized has confirmed by literature [9,10,17-23]. Further the chiral azido alcohols 10b-12b obtained were subjected to hydrogenation by using Pd nanoparticles to obtain chiral amino alcohols. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 88.3% | With sodium tris(acetoxy)borohydride; In methanol; water; at 25℃; for 16h; | Step 1: Reductive Amination (Preparation of Fenfluramine Free Base 1) (0107) A solution of ethylamine, water, methanol, and 1-(3-(trifluoromethyl)phenyl) acetone (Ketone 2) was treated with sodium triacetoxyborohydride and stirred for 16 h at 25 C. at which time HPLC analysis (IPC-1; In Process Control No. 1) showed the reaction to be complete and sodium hydroxide solution was added until pH>10. Toluene was added and the phases separated, and the aqueous phase (IPC-2) and organic phase (IPC-3) are checked for remaining Fenfluramine and Fenfluramine alcohol and the organic phase was reduced. Purified water was added and the pH adjusted to 10 using sodium hydroxide solution. The basic aqueous phase was extracted with MTBE until removal of Fenfluramine from the aqueous phase was observed by HPLC (<0.5 mg/ml) (IPC-6). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the intermediate product Fenfluramine Free Base 1 as a pale yellow oil tested per specifications described herein which showed by NMR the material to contain 2.93% toluene giving an active yield of 88.3% with a purity of 98.23% by HPLC (0.67% Fenfluramine alcohol). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| General procedure: Ketone or phenyl acetone derivatives (1.0 mmol) was added to a mixture of glyoxylic acid (2.5 mmol) and orthophosphoric acid (10 mL). The reaction mixture was stirred at 75 C for 5 h and then left to stand overnight at room temperature. Ice-cooled brine (20 mL) was added to the reaction mixture. The mixture was extracted in dichloromethane/diethyl ether (1:1, 3 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the crude keto acids or furanones. | 
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| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 59.1% | With sodium acetate; sodium nitrite;copper(I) chloride; In methanol; n-heptane; water; | EXAMPLE 4 1-(3-Trifluoromethyl)phenyl-propan-2-one 220 ml of water and 180 g of 37% (w/w) aqueous hydrochloric acid are put in a flask equipped with stirrer and dripping funnel. 97 Grams (0.602 moles) of m-trifluoromethylaniline are added after having cooled to 10 C. with an ice bath and then, at 5 C., an aqueous solution containing 42.2 g (0.612 moles) of sodium nitrite in 50 ml of water is slowly added. The reaction mixture is stirred for 30 minutes and then is added during 30 minutes to a mixture warmed at 40 C. consisting of 800 ml of water, 280 ml of methanol, 1.50 g (0.015 moles) of cuprous chloride, 49.2 g (1.200 moles) of anhydrous sodium acetate and 75.2 (0.751 moles) of isopropenyl acetate. The reaction temperature goes up till a maximum value of 60 C., the reaction mixture is kept under stirring for further 30 minutes at this temperature and then is cooled to 20 C. 350 ml of heptane are added and the two layers are separated. The aqueous layer is discarded while the organic layer is washed with water and concentrated under vacuum to remove the solvent. The obtained oil is distilled under vacuum at 10 mm Hg collecting the fraction that distils at 98÷102 C. 72 Grams of pure ketone are obtained with a yield equal to 59.1% calculated on the starting m-trifluoromethylaniline. | 
| 59.1% | With sodium acetate; sodium nitrite;copper(I) chloride; In methanol; n-heptane; water; | EXAMPLE 4 1-(3-Trifluoromethyl)phenyl-propan-2-one 220 Ml of water and 180 g of 37% (w/w) aqueous hydrochloric acid are put in a flask equipped with stirrer and dripping funnel. 97 Grams (0.602 moles) of m-trifluoromethylaniline are added after having cooled to 10C with an ice bath and then, at 5C, an aqueous solution containing 42.2 g (0.612 moles) of sodium nitrite in 50 ml of water is slowly added. The reaction mixture is stirred for 30 minutes and then is added in 30 minutes to a mixture warmed at 40C made by 800 ml of water, 280 ml of methanol, 1.50 g (0.015 moles) of cuprous chloride, 49.2 g (1.200 moles) of anhydrous sodium acetate and 75.2 (0.751 moles) of isopropenyl acetate. The reaction temperature goes up till a maximum value of 60C, the reaction mixture is kept under stirring for further 30 minutes at this temperature and then is cooled to 20C. 350 Ml of heptane are added and the two layers are separated. The aqueous layer is discarded while the organic layer is washed with water and concentrated under vacuum to remove the solvent. The obtained oil is distilled under vacuum at 10 mm Hg collecting the fraction that distils at 98÷102C. 72 Grams of pure ketone are obtained with a yield equal to 59.1% calculated on the starting m-trifluoromethylaniline. | 
| 41.9% | With sodium hydrogencarbonate; sodium nitrite;copper(I) chloride; In methanol; n-heptane; water; | EXAMPLE 6 1-(3-Trifluoromethyl)phenyl-propan-2-one 220 ml of water and 224 g of 30% (w/w) aqueous hydrochloric acid are put in a flask equipped with stirrer and dripping funnel. 97 Grams (0.602 moles) of m-trifluoromethylaniline are added after having cooled to 10 C. with an ice bath and then, at 5 C., an aqueous solution containing 49.80 g (0.722 moles) of sodium nitrite in 180 ml of water is slowly added. The reaction mixture is stirred for 30 minutes and then is added during 30 minutes to a mixture warmed at 40 C. consisting of 450 ml of water, 151.2 g (1.800 moles) of sodium bicarbonate, 280 ml of methanol, 1.50 g (0.015 moles) of cuprous chloride and 75.2 g (0.751 moles) of isopropenyl acetate. The reaction temperature goes up till a maximum value of 60 C., the reaction mixture is kept under stirring for further 30 minutes at this temperature then is cooled to 20 C. 350 ml of heptane are added and the two layers are separated. The aqueous layer is discarded while the organic layer is washed with water. The product is purified through bisulfite complex as before described. 51 Grams of pure ketone are obtained with a yield equal to 41.9% calculated on the starting m-trifluoromethylaniline. | 
| 41.9% | With sodium hydrogencarbonate; sodium nitrite;copper(I) chloride; In methanol; n-heptane; water; | EXAMPLE 6 1-(3-Trifluoromethyl)phenyl-propan-2-one 220 Ml of water and 224 g of 30% (w/w) aqueous hydrochloric acid are put in a flask equipped with stirrer and dripping funnel. 97 Grams (0.602 moles) of m-trifluoromethylaniline are added after having cooled to 10C with an ice bath and then, at 5C, an aqueous solution containing 49.80 g (0.722 moles) of sodium nitrite in 180 ml of water is slowly added. The reaction mixture is stirred for 30 minutes and then is added in 30 minutes to a mixture warmed at 40C made by 450 ml of water, 151.2 g (1.800 moles) of sodium bicarbonate, 280 ml of methanol, 1.50 g (0.015 moles) of cuprous chloride and 75.2 g (0.751 moles) of isopropenyl acetate. The reaction temperature goes up till a maximum value of 60C, the reaction mixture is kept under stirring for further 30 minutes at this temperature then is cooled to 20C. 350 Ml of heptane are added and the two layers are separated. The aqueous layer is discarded while the organic layer is washed with water. The product is purified through bisulfite complex as before described. 51 Grams of pure ketone are obtained with a yield equal to 41.9 % calculated on the starting m-trifluoromethylaniline. | 
| Example 5 Additional Method for Preparation of 1-(3-trifluoromethyl)phenyl-propan-2-one 35 mL of water and 45 g of 37% (w/w) aqueous hydrochloric acid are put in a flask equipped with stirrer and dropping funnel. 24.25 Grams (0.151 moles) of m-trifluoromethylaniline are added after having cooled to 10 degree C. with an ice bath and then, at 5 degree C., an aqueous solution containing 12.43 g (0.180 moles) of sodium nitrite in 150 ml of water is slowly added. The reaction mixture is stirred for 30 minutes and then is poured during 30 minutes into a mixture made by 90 ml of water, 1.35 g (0.014 moles) of cuprous chloride, 2.30 g (0.013 moles) of cupric chloride dihydrate, 50 ml of acetone, 40.8 g (0.300 moles) of sodium acetate trihydrate and 23 g (0.230 moles) of isopropenyl acetate while keeping the reaction temperature at 30 degree C. After further 30 minutes of stirring, the reaction mixture is brought to 20 degree C., 50 ml of methylene chloride are added and the two layers are separated. The aqueous layer is discarded while the organic layer is concentrated under vacuum until an oil is obtained which is treated with 35 g of sodium metabisulfite, 70 ml of water and 150 ml of heptane under stirring at room temperature for 12 hours. The suspension is filtered, the bisulfite complex is washed on the filter with 50 ml of heptane and then suspended in a two-phase mixture made by 100 ml of methylene chloride and 150 ml of a 10% (w/v) aqueous solution of sodium hydroxide. The layers are separated after one hour of stirring at room temperature, the aqueous phase is discarded while the organic layer is washed with water and evaporated under vacuum to give pure ketone. | 


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