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Structure of 60827-45-4
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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. : | 60827-45-4 |
Formula : | C3H7ClO2 |
M.W : | 110.54 |
SMILES Code : | OC[C@H](O)CCl |
MDL No. : | MFCD00210270 |
InChI Key : | SSZWWUDQMAHNAQ-GSVOUGTGSA-N |
Pubchem ID : | 148904 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H301-H312-H318 |
Precautionary Statements: | P264-P270-P280-P301+P310-P302+P352-P305+P351+P338-P310-P322-P330-P363-P405-P501 |
Class: | 6.1 |
UN#: | 2689 |
Packing Group: | Ⅲ |
Num. heavy atoms | 6 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 23.65 |
TPSA ? Topological Polar Surface Area: Calculated from |
40.46 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.17 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.49 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.42 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.18 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.16 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.05 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.08 |
Solubility | 91.0 mg/ml ; 0.823 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.11 |
Solubility | 142.0 mg/ml ; 1.28 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.14 |
Solubility | 79.7 mg/ml ; 0.721 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 |
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 |
-7.32 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 |
2.0 |
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) |
2.32 |
* 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 |
---|---|---|
With potassium phosphate; In dichloromethane; for 3h;Heating / reflux;Product distribution / selectivity; | To 1.2 L of a methylene chloride solution of (S)-3-chloro-l,2-propanediol (200 g, 99.5% ee) was added 519 g of potassium phosphate tribasic, and then the obtained solution was refluxed, under stirring, for 3 hours. The resulting solution was cooled to 0C, and 220 g of trie thy lamine, 4 g of 4-(dimethylamino)pyridine, and 315 g of butanoic acid anhydride were dropwisely added to the solution. After additional stirring for 1 hour at a room temperature, the reaction mixture was successively washed with 2.2 L of 5% aqueous potassium carbonate solution, 2 L of IN aqueous hydrogen chloride solution, and 1 L of water. The organic layer was dried with 50 g of anhydrous sodium sulfate and filtrated. The methylene chloride was evaporated under reduced pressure. Fractional distillation (90C/19 mmHg) of the resulting residue gave 242 g of the targeted compound:- Yield: 92.7%- Chemical purity: 99.4%- Optical purity (GC) 99.5% ee. | |
With potassium carbonate; In dichloromethane; for 25h;Heating / reflux;Product distribution / selectivity; | To 1.2 L of a methylene chloride solution of (S)-3-chloro-l,2-propanediol (200 g, 99.5% ee) was added 338 g of potassium carbonate, and then the obtained solution was refluxed, under stirring, for 25 hours. The resulting solution was cooled to 0C, and 220 g of triethylamine, 4 g of 4-(dimethylamino)pyridine, and 315 g of butanoic acid anhydride were dropwisely added to the solution. After additional stirring for 1 hour at a room temperature, the reaction mixture was successively washed with 2.2 L of 5% aqueous potassium carbonate solution, 2 L of IN aqueous hydrogen chloride solution, and 1 L of water. The organic layer was dried with 50 g of anhydrous sodium sulfate and filtrated. The methylene chloride was evaporated under reduced pressure. Fractional distillation (90C/19 mmHg) of the resulting residue gave ID g of the targeted compound:- Yield: 65.0%- Chemical purity: 97.4%- Optical purity (GC) 98.1% ee. | |
With potassium carbonate; In dichloromethane; at 20℃; for 17.5h; | 200 g of 3-chloro-1,2-propanediol was dissolved in 2000 mL of dichloromethane, 625 g of potassium carbonate was added, and the mixture was stirred at room temperature for 17.5 hours.The precipitated insoluble materials were filtered,By washing the filtration residue with 1,000 mL of dichloromethane,(S) -oxiran-2-ylmethanolWas obtained.To the obtained solution,198 g of dihydropyran was added,After cooling to 0 C.,5.16 g of p-toluenesulfonic acid monohydrate was added at 10 C. or less,And the mixture was stirred at room temperature for 1.5 hours. 408 g of a 7.5% sodium bicarbonate aqueous solution was added,After stirring, the organic layer and the aqueous layer were separated. The obtained organic layer was concentrated,Distillation gave 247.8 g of the title compound as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With Aspergillus niger epoxide hydrolases immobilized onto modified Eupergit C; In aq. phosphate buffer; dimethyl sulfoxide; at 25℃; for 3h;pH 6.5;Enzymatic reaction;Kinetics; | General procedure: Asymmetric hydrolysis of (R/S)-SO, (R/S)-PO and (R/S)-ECH were examined in a batch type reactor (1.1 cm × 5 cm). To 1.5 mL of 100 mM phosphate buffer (pH = 7.0 for the free and EHIL; pH = 6.5 for EHIF and EHIE), 100 L of the free EH solution (1 mg mL-1) or 30 mg of each immobilized EH was loaded and the mixture kept at 25 C for 2 min. The reaction was initiated by the addition 0.4 mL of each racemic epoxide solution (0.5 M in DMSO). A hundred microliters of aliquots withdrawn at different time intervals (15, 30,60, 90, 120, 180 and 240 min) were mixed with 400 L of diethylether and analyzed by a Shodex ORpak CDC-453 HQ chiral HPLC column (4.6 mm × 150 mm) according to Yildirim et al. [23]. The enantiomers of styrene oxide and their vicinal diols were detected at 220 nm. The enantiomers of propylene oxide, epichlorohydrin and their vicinal diols were detected using a refractive index detector (Shimadzu RID-10A). The optical configurations of remaining epoxides and formed diols were identified by comparing the retention time of these compounds with their optically active standard forms. The enantiomeric excess (ee) values of formed vicinal diol and remaining epoxide were calculated from the equations: eeepoxide=([S-R]epoxide)/([S+R]epoxide) and eediol=([R-S]diol)/([R+S]diol) The enantiomeric ratio values (E) of free and immobilized EHs were calculated from the equation proposed by Chen et al. [27]. E=(Vmax(R)/Km(R))/(Vmax(S)/Km(S)) where Vmax(R) and Km(R) values are maximum velocity and Michealis-Menten constant of free and immobilized EH preparations toward (R)-enantiomer of epoxide and Vmax(S) and Km(S) are corresponding values toward (S)-enantiomer of epoxide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 3 This Example shows the conversion of (S)-3-amino-1,2-dihydroxypropane isopropylidene acetal 11 to (S)-1-chloro-2,3-dihydroxypropane 3. | ||
EXAMPLE 2 Sodium periodate (9.31 g) was added slowly to a cooled and stirred solution of 6,6'-dichloro-6,6'-dideoxy-sucrose (5.0 g) in water (250 ml). After stirring at room temperature for 2 hours, the solution was diluted with ethanol (750 ml) and the resulting suspension was stirred at room temperature for a further 2 hours. The suspension was then filtered and the filtrate was concentrated to a syrup (25 ml) which was diluted with water (100 ml). A solution of sodium borohydride (2.04 g) in water (50 ml) was added slowly with cooling to the solution of oxidised product. After the addition, the reaction mixture was stirred at room temperature for 20 hours, and then a few drops of acetic acid were added. Concentration in vacuo at 40 gave a semi-solid mass which was then dissolved in ethyl acetate (AR):ethanol (9:1) and eluted through a column of silica gel. Evaporation of the elude yielded a semi-solid mass (5.1 g). T.l.c. showed that this was a mixture. The components were identified by g.l.c. to be alpha-chlorohydrin, dihydroxyacetone (dimer) and hydroxyacetaldehyde. Chromatography and distillation of the product mixture gave S-3-chloro-1,2-propanediol identical with that obtained in Example 1. | ||
EXAMPLE 3 This Example shows the conversion of (S)-3-amino-1,2-dihydroxypropane isopropylidene acetal 11 to (S)-1-chloro-2,3-dihydroxypropane 3 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; acetic acid; In tetrahydrofuran; hexane; water; ethyl acetate; | To a solution of 1056 g (3.64 mol) of 2-Methylpropyl (4-bromo-3-fluorophenyl)carbamate in 6.65 L of THF cooled to -15 C. in a 22 L round bottom flask was added a solution of 428 g (4.55 mol, 1.25 equiv.) of lithium t-amylate over 10 min via an addition funnel, maintaining -15 to -12 C. In a separate 5 L flask, a solution of 438 g (4.37 mol, 1.20 equiv.) of (S)-3-chloro-1,2-propanediol in 1.75 L of THF was cooled to -25 C. and treated with a 20% t-BuOK solution in THF (2645 mL, 4.29 mol, 1.18 equiv) over 25 min, resulting in a thick but stirrable slurry. This was allowed to warm to 10 over 75 min and then poured into the 22 L flask containing the carbamate solution. The resulting slurry was allowed to warm from -7 to 7 over 1.5 h, monitoring reaction progress by HPLC. Upon completion (~2.5% each of remaining 2-Methylpropyl (4-bromo-3-fluorophenyl)carbamate and the over addition product) a quench solution composed of 1.05 AcOH and 3.5 L of water was added. The layers were separated. The aqueous layer was back-extracted with 1 L of THF, and the combined organic layers were washed with brine. The volatile were removed, giving white solids wet with acetic acid. This material was slurried in 1.6 L of EtOAc. Hexane (4L) was added over 1 h. The resulting slurry was cooled to 2 over 1 h and filtered, giving 916 g (87%) of (5R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxymethyl)-1,3-oxazolidin-2-one as coarse white crystals: TLC Rf=0.008 (50% EtOAc/hexane); HPLC rt=2.55 min; mp 114-121 ; [alpha]D=+52.2 c. =1, MeOH); 1H NMR (DMSO) delta7.49 (m, 2H), 7.15 (d,1H, J=8.5 Hz), 5.30 (br s, 1H), 4.54 (m,1H), 3.89 (t, 1H, J=8.6 Hz), 3.67 (m, 1H), 3.50 (dd, 1H, J=3.0, 11.8 Hz), 3.39 (dd, 1H, 3.8, 11.8 Hz); 13C NMR (DMSO) delta158.1 (s, JCF=241 hz), 154.2 (S), 139.7 (S, JCF=10 hz), 133.3 (D), 114.9 (D), 105.9 (d, JCF=29 Hz), 100.9 (s, JCF=21 Hz), 73.3(d), 61.5(t), 45.9 (t); Anal. calc'd for C10H9BrFNO3: C, 41.40; H, 3.13; N, 4.83: Br, 27.55; found: C, 41.11; H, 3.06; N, 4.83: Br, 26.97. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In water; isopropyl alcohol; at 60℃; for 72h; | Example 14 To a solution of 4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (100 mg, 0.296 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), (S)-3-chloro-1,2-propanediol (98 mg, 0.89 mmol) is added. The mixture is stirred at 60 C. for 24 h before another portion of (S)-3-chloro-1,2-propanediol (98 mg, 0.89 mmol) is added. Stirring is continued at 60 C. for 2 days. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with EA-heptane to give (S)-3-{4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol (14 mg) as a red oil; LC-MS: tR=0.93 min, [M+1]+=412.16. | |
With sodium hydroxide; In water; isopropyl alcohol; at 60℃; for 72h; | To a solution of 4-[5-(5,6-diethyl-pyridin-3-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (100 mg, 0.296 mmol) in isopropanol (10 ml.) and 3 N aq. NaOH (3 ml_), (S)-3-chloro-1 ,2- propanediol (98 mg, 0.89 mmol) is added. The mixture is stirred at 600C for 24 h before another portion of (S)-3-chloro-1 ,2-propanediol (98 mg, 0.89 mmol) is added. Stirring is continued at 600C for 2 days. The mixture is diluted with EA and washed with sat. aq. NaHCOs solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with EA-heptane to give (S)-3- {4-[5-(5,6-diethyl-pyridin-3-yl)-[1 ,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1 ,2- diol (14 mg) as a red oil; LC-MS: tR = 0.93 min, [M+1]+ = 412.16. |
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