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Structure of 34351-19-4
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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. : | 34351-19-4 |
Formula : | C10H13Cl2NO |
M.W : | 234.12 |
SMILES Code : | N[C@@H](CC1=CC=CC=C1)C(CCl)=O.[H]Cl |
MDL No. : | MFCD00133443 |
InChI Key : | DLNJXAGVYFIVJM-FVGYRXGTSA-N |
Pubchem ID : | 56777393 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P301+P330+P331-P303+P361+P353-P363-P304+P340-P310-P321-P260-P264-P280-P305+P351+P338-P405-P501 |
Class: | 8 |
UN#: | 1759 |
Packing Group: | Ⅲ |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.3 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 60.5 |
TPSA ? Topological Polar Surface Area: Calculated from |
43.09 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.45 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.17 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.05 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.34 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.8 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.89 |
Solubility | 0.303 mg/ml ; 0.00129 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.0 |
Solubility | 0.235 mg/ml ; 0.001 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.46 |
Solubility | 0.0802 mg/ml ; 0.000343 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 |
-5.99 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) |
1.9 |
* 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 hydrogenchloride; In water; ethyl acetate; at 0 - 20℃; | (S)-4-Chloro-3-oxo-l-phenylbutan-2-aminiumchloride (8). Ketone 1 (5.00 g, 16.8 mmol) was dissolved in EtOAc (50 mL) and cooled to 0°C in an ice bath. Concentrated HC1 (15.3 mL, 503 mmol) was added dropwise to the solution. Upon complete addition of the acid, the ice bath was removed and the solution was stirred at room temperature for 1 hour. The white solid was filtered and washed with EtOAc and Et20 to give pure salt 8 (3.85 g, 16.4 mmol, 98percent): mp 170-172°C (lit mp 170°C); 1H NMR delta 3.17 (m, 2H), 4.51 (s, 1H), 4.62 (2H), 7.31 (m, 5H), 8.69 (s, 3H); 13C NMR 8 35.0, 48.0, 57.2, 127.4, 128.9, 129.5, 134.5, 198.3; LRMS (ES+) calcd for Ci0Hi3NOCl2 234.12, found 198.2 (CioHi3NOCl); Elemental analysis calcd for C10H13NOC12: C 51.30, H 5.60, N 5.98; found: C 54.41, H 5.62, N 6.01. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium chloride; triethylamine; In dichloromethane; water; | Example 13 Process for producing (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone Di-tert-butyl dicarbonate (85.8 mg) and triethylamine (29.1 mg) were dissolved in methylene chloride (2.6 ml), and an aqueous solution of (3S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (61.4 mg) in water (2.6 ml) was added thereto dropwise. The mixture was stirred at room temperature for 1 hour, then heated at 40° C., and further reacted for 1.5 hours. After the reaction solution was cooled to room temperature, a sodium chloride aqueous solution was added thereto, and the mixture was extracted twice with ethyl acetate. The resulting ethyl acetate layer was analyzed by HPLC, and it was identified that (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (66.3 mg) was obtained in a yield of 85percent. |
81% | With sodium chloride; triethylamine; In toluene; | Example 15 Process for producing (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone Di-tert-butyl dicarbonate (4.64 g) and triethylamine (5.28 ml) were dissolved in toluene (81.9 ml), and an aqueous solution (45.60 g) of (3S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (3.83 g) was added thereto dropwise over 10 minutes. The solution was stirred at room temperature for 1 hour, then heated at 40° C., and further reacted for 1 hour. After the reaction solution was cooled to room temperature, the aqueous layer was separated. The resulting toluene layer was washed with 2 N hydrochloric acid and with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Then, magnesium sulfate was removed. The resulting toluene layer was analyzed by HPLC, and it was identified that (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (3.94 g) was obtained in a yield of 81percent. |
81% | With triethylamine; In toluene; | EXAMPLE 7 Process for Producing (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone Di-tert-butyl dicarbonate (4.64 g) and triethylamine (5.28 ml) were dissolved in toluene (81.9 ml). An aqueous solution (45.60 g) of (3S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (3.83 g) was added dropwise to the obtained solution for a period of 10 minutes. After stirring at room temperature for 1 hour, the reaction mixture was heated to 40° C. and the reaction was conducted for additional 1 hour. The reaction mixture was cooled to room temperature, and the aqueous layer was separated. The resultant toluene layer was washed with 2 N hydrochloric acid and saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Magnesium sulfate was removed. The obtained toluene layer was analyzed by HPLC to find that (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (3.94 g) was obtained in a yield of 81percent. |
75% | With N-ethyl-N,N-diisopropylamine; In toluene; | Example 16 Process for producing (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone Di-tert-butyl dicarbonate (1.20 g) and diisopropylethylamine (2.65 ml) were dissolved in toluene (11.5 ml), and an aqueous solution (11.27 g) of (3S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (1.00 g) was added thereto dropwise over 35 minutes. The mixture was reacted overnight at room temperature by being stirred, and the aqueous layer was then separated. The resulting toluene layer was washed with an aqueous solution of 1 mol/liter of citric acid and with water. The resulting toluene layer was analyzed by HPLC, and it was identified that (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (0.95 g) was obtained in a yield of 75percent. |
70% | With sodium hydrogencarbonate; In methanol; hexane; | Example 12 Process for producing (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone Di-tert-butyl dicarbonate (1.39 g) and sodium hydrogencarbonate (0.34 g) were dissolved in a 50percent methanol aqueous solution (22 ml), and an aqueous solution of (3S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (0.94 g) was added thereto. The mixture was stirred at 40° C. for 1.5 hours. The reaction solution was extracted twice with ethyl acetate, the resulting ethyl acetate layer was dried over anhydrous magnesium sulfate, and magnesium sulfate was removed. The ethyl acetate layer was concentrated, and crystallized by adding hexane thereto. Crystals precipitated were collected by filtration, and dried to obtain (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (0.84 g) in a yield of 70percent. Further, the crystals obtained and the reaction solution were analyzed by HPLC using an optically active column, and it was identified that the optical purity thereof was >99.5percente.e., and that a series of reactions proceeded while maintaining the optical purity of L-phenylalanine methyl ester hydrochloride. 1H-NMR(CDCl3) deltappm: 1.41 (s, 9H), 3.00 (dd, J=6.9, 13.8 Hz), 3.08 (dd, J=6.9, 13.8 Hz, 1H), 3.98 (d, J=16.2 Hz, 1H), 4.17 (d, J=16.2 Hz, 1H), 4.68 (q, J=6.9 Hz, 1H), 5.02 (bd, J=6.9 Hz, 1H), 7.16 (m, 2H), 7.26-7.36 (m, 3H) mass spectrum m/e: 296.1 (M-H-) |
70% | With sodium hydrogencarbonate; In methanol; | EXAMPLE 3 Process for Producing (3S)-3-tert-butoxycarbonylamino-1 -chloro-4-phenyl-2-butanone Di-tert-butyl dicarbonate (1.39 g) and sodium hydrogencarbonate (0.34 g) were dissolved in 50percent aqueous methanol solution (22 ml). An aqueous solution of (3S)-3-amino-1-chloro-4-phenyl-2-butanone hydrochloride (0.94 g) was added to the obtained solution, and they were stirred at 40° C. for 1.5 hours. After the extraction with ethyl acetate twice, the obtained ethyl acetate layer was dried over anhydrous magnesium sulfate. Magnesium sulfate was removed. The solvent was evaporated under reduced pressure. Crystals formed by the crystallization with ethyl acetate and hexane were taken by filtration and then dried to obtain (3S)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (0.84 g) in a yield of 70percent. The obtained crystals and the reaction mixture were analyzed by HPLC with an optically active column to confirm that the product had an optical purity of >99.5percent e.e. 1H-NMR(CDCl3, 300 MHz) delta ppm: 1.41 (s, 9H), 3.00(dd, J=6.9, 13.8 Hz), 3.08 (dd, J=6.9, 13.8 Hz, 1H), 3.98 (d, J=16.2 Hz, 1H), 4.17 (d, J=16.2 Hz, 1H), 4.68 (q, J=6.9 Hz, 1H), 5.02 (bd, J=6.9 Hz, 1H), 7.16 (m, 2H), 7.26-7.36 (m, 3H) mass spectrum m/e: 296.1 (M-H-) |