Structure of 851785-21-2
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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. : | 851785-21-2 |
Formula : | C11H16ClNO4S |
M.W : | 293.77 |
SMILES Code : | O=C(OC)[C@@H](N)CC1=CC=CC(S(=O)(C)=O)=C1.[H]Cl |
MDL No. : | MFCD29037384 |
InChI Key : | VUUYKOLKOIYVCR-PPHPATTJSA-N |
Pubchem ID : | 91933723 |
GHS Pictogram: |
![]() |
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 | 0.36 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 69.88 |
TPSA ? Topological Polar Surface Area: Calculated from |
94.84 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 |
1.24 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.02 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.21 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.77 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.05 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.36 |
Solubility | 1.28 mg/ml ; 0.00437 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.83 |
Solubility | 0.435 mg/ml ; 0.00148 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.88 |
Solubility | 0.383 mg/ml ; 0.0013 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 |
-7.21 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 |
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) |
2.61 |
* 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 triethylamine; In dichloromethane; at 0 - 20℃; for 12.0h; | EXAMPLE 16 [0322] This example describes the synthesis of which was prepared according to the procedure below. [0323] To a solution of 0.2 mmol of compound 8.4 (Example 8c or 8e) in 1 mmol of Et3N and 5 mL of dry CH2C12 was added 0.22 mmol of 2,6- dichlorobenzoyl chloride at 0C, the resulting mixture was stirred at room temperature for 12 hours. The solvent was removed and the residue was dried in vacuo. Subsequently, the residue was treated with 0. 8 mmol of LiOH-H20 in 2 mL of THF and 0.5 mL of H20. After stirring at room temperature for 30 minutes, the reaction mixture was added 1.0 mL of 1. ON aq. HC1. The organic solvent was removed, and the residue was diluted with 10 mL of brine. The mixture was extracted with EtOAc and the extract was dried with anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo to give the desired compound in 65% yield. 1H NMR (400 MHz, CD30D) 6 7.92 (s, 1 H), 7. 82 (d, J=6. 85 Hz, 1 H), 7.71 (d, J=6. 85 Hz, 1 H), 7.56 (t, J=7. 83 Hz, 1 H), 7.34 (m, 3 H), 5. 08 (dd, J=9. 78, 4.89 Hz, 1 H), 3.45 (dd, J=14. 67,4. 89 Hz, 1 H), 3.14 (dd, J=14. 67,9. 78 Hz, 1 H), 3.08 (s, 3 H) ppm; ESI-MS (m/z) : (M+H+) 416.00. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 14.0h; | k) 1 equivalent of compound 18.10, 1 equivalent compound 8.4 (Example 8c or 8e), and 3 equivalents of DIEA were dissolved in DMF. 1.1 equivalent of HATU was added. The reaction was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine. The combined organics were dried with MgS04, filtered, and concentrated. The residue was then purified on silica gel column chromatography (gradient elution using ethyl acetate and hexanes) to provide pure intermediate ester. The ester was dissolved in methanol followed by addition of 2 equivalents of 1M LiOH (aq). Upon completion, the excess solvents were removed under reduced pressure and the resulting acid was then purified by reverse phase HPLC to give pure compound 18. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 14.0h; | f) 1 equivalent of compound 20.5, 1 equivalent of compound 8.4 (Example 8c or 8e), and 3 equivalents of DIEA were dissolved in DMF. 1.1 equivalent of HATU was added. The reaction was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with water, brine. The combined organics were dried with MgS04, filtered, and concentrated. The residue was then purified on silica gel column chromatography (gradient elution using ethyl acetate and hexanes) to provide pure compound 20.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogen;palladium on activated charcoal; In methanol; | The compound 8.9 was hydrogenated (Pd/C, MeOH,) with a hydrogen balloon to afford compound 8.4 (yield 98%). ESI-MS (m/z) : (M+H+) 258. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With thionyl chloride; at 0 - 20℃; | 20 g of (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoic acid was charged in 100 ml Methanol and reaction mass cooled to 0-5C. Thionyl chloride (12 g) was added drop wise below 10C and reaction mass was stirred at room temperature. After completion of reaction, solvents were distilled under vacuum followed by addition of isopropyl ether (100 ml) and filtered the solid to get 23 g of methyl (S)-2-amino-3-(3- (methylsulfonyl)phenyl)propanoate hydrochloride (Yield-95%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | 2-(ieri-butoxycarbonyl)-5,7-dichloro- l,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (20 g), HATU (27.5 g) was charged in DMF (60 ml) and diisopropyl ethylamine (22,2 g) was added. Reaction mass was cooled to 0-5C and added methyl (S)-2-amino-3-(3- (m.ethylsuIfonyl)phenyl)propanoate hydrochloride (17.6g) lot wise at 0-5C. Temperature of reaction mass was raised to room temperature. Stirred and reaction monitored by TLC. After completion of reaction, Water (100 ml) and MDC (100 ml) was added. Stirred and separated the layers. Organic layer washed with brine and 10% sodium carbonate solution. Organic layer distilled and charged 1 N HC1 (100 ml) to the residue. After complete hydrolysis pH of reaction mass was adjusted to 5.0-5.5 using sodium hydroxide solution. Reaction mass was filtered and solid so obtained was dried to get (S)-2-(5 ,7-dichloro- 1 ,2,3 ,4- tetrahydroisoquinoline-6-carb^ acid (25 g, (0185) 91.8% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2-(ieri-butoxycarbonyl)-5,7-dichloro- l,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (20.0g) was added to 50.0 ml of DMF followed by addition of DIPEA (37.2 g), HATU (27.4g) and stirred the reaction mass for 30 min at room temperature. Charged methyl (S)-2- amino-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride (17.6g) and stirred the reaction mass at 100C for 1-2 hrs. After completion of reaction, cooled the reaction mass to 30-35C, charged the reaction mass to the mixture of ethyl acetate (200ml) and water (200 ml) and stirred for 15-30 min at 30-35C. Separated the ethyl acetate and washed with acidic water (200ml water + 18ml of cone. HC1) followed by washing with water. Distilled the ethyl acetate at 40-45C to get tert-butyl (S)-5,7-dichloro-6-((l-methoxy-3-(3- (xnethylsulfonyl)phenyl)- l-oxopropan-2-yl)carbamoyl)-3,4-dihydro isoquinoline-2( lH)- carboxylate (40g, crude). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; | Step D: methyl (2S)-2-(2,6-dichloro-4-((((3-hydroxyphenyl)(methyl)phosphoryl)methyl)amino)benzamido)-3-(3-(methylsulfonyl)phenyl)propanoate (Compound 29.4) Compound 11.4 was dissolved in DMF and <strong>[851785-21-2]methyl (2s)-2-amino-3-(3-(methylsulfonyl)phenyl)propionate hydrochloride</strong> (2 eq) was added, followed by DIPEA (10 eq) and HATU (2.5 eq). After stirring at normal temperature for 4 hours, 10 ml of dilute hydrochloric acid solution was added, and extracted with EA three times, and the organic phases were combined and spun-dried. Purification was made by reverse phase, and spun-dried under reduced pressure at 45 C. to obtain the target product. |