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Structure of 49844-90-8
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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.
4.5
*For Research Use Only !
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Norman, Jacob Patrick ;
Abstract: Pd-catalyzed cross-couplings rank among the most powerful methods for constructing substituted biaryls, polyaryls, and heteroarenes. Frequently, di- or polyhalogenated (hetero)arenes are employed as starting materials in cross-couplings to access products with increased structural complexity via multiple cross-coupling or substitution steps. N-heteroarenes bearing multiple reactive handles—such as halides, are of particular interest as starting materials since their crosscoupled products can be medicinally relevant. Non-symmetrical dihalogenated N-heteroarenes typically exhibit a site-selectivity bias for C—X bonds which are adjacent to at least one heteroatom in Pd-catalyzed cross-couplings. However, some Pd catalysts—particularly those with hindered ligands, promote atypical selectivity at distal C—X bonds of 2,X-dichloropyridines and related heterocycles during the selectivity-determining oxidative addition step. This dissertation explores the mechanistic origins of these ligand trends and emphasizes the critical importance of Pd’s ligation state—either mono (PdL) or bis (PdL2), in controlling the site of oxidative addition. Ligation state is also relevant when selecting for the products of mono- vs difunctionalization in cross-couplings of dihalogenated substrates, since bisligated 14 e- Pd dissociates quickly from the monofunctionalized intermediate after an initial cross-coupling cycle, whereas monoligated 12 e- Pd is slow to dissociate and may "ring-walk" to the remaining reactive site(s). Additionally, this dissertation explores alternative methods to access minor regioisomers in cross-couplings of dichloro-azines. One approach involves ligand-free conditions where atypical site-selectivity at dichloropyridines and dichloropyrimidines arises from a change in Pd’s speciation from mono- to multinuclearity. Another approach employs a thiolation/Liebeskind-Srogl arylation sequence to achieve site-selectivity which is orthogonal to that of Suzuki-Miyaura couplings.
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CAS No. : | 49844-90-8 |
Formula : | C5H5ClN2S |
M.W : | 160.62 |
SMILES Code : | CSC1=NC=CC(Cl)=N1 |
MDL No. : | MFCD00006083 |
InChI Key : | DFOHHQRGDOQMKG-UHFFFAOYSA-N |
Pubchem ID : | 97113 |
GHS Pictogram: |
![]() |
Signal Word: | Danger |
Hazard Statements: | H314 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 1760 |
Packing Group: | Ⅱ |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 38.76 |
TPSA ? Topological Polar Surface Area: Calculated from |
51.08 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.88 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.01 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.85 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.81 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.12 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.73 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.53 |
Solubility | 0.475 mg/ml ; 0.00295 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.71 |
Solubility | 0.313 mg/ml ; 0.00195 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.75 |
Solubility | 0.282 mg/ml ; 0.00176 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 |
-5.85 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) |
1.73 |
* 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 |
---|---|---|
53% | EXAMPLE 24 A solution of phenylmagnesium bromide (1M in THF, 4.2 mL, 4.2 mmol) is added to a solution of 4-chloro-2-methylthio-pyrimidine (296 mg, 1.84 mmol) and Fe(acac)3 (32 mg, 0.09 mmol) in THF (10 mL) at -30 C. After stirring for 50 min at that temperature, the reaction is quenched with brine, the aqueous layer is extracted with Et2O, the combined organic phases are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexane/ethyl acetate, 10:1). After eluding a first fraction containing biphenyl (90 mg), one obtains 2-methylthio-4-phenyl-pyrimidine as a pale yellow solid (197 mg, 53%). 1H NMR (300 MHz, CD2Cl2) delta8.53 (d, 1H), 8.09-8.13 (m, 2H), 7.53-7.48 (m, 3H), 7.39 (d, 2H), 2.63 (s, 3H); 13C NMR (75 MHz, CD2Cl2) delta173.0, 164.0, 158.0, 136.7, 131.1, 131.0, 129.2, 127.5, 127.4, 112.2, 14.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; 1,3-dimethylimidazolim iodide; In tetrahydrofuran; for 0.5h;Reflux; | To a mixture of 4-chloro-2-(methylthio)pyrimidine (0.36 mL, 3.11 mmol), 2- bromo-3-methylbenzaldehyde (0.744 g, 3.74 mmol), and l,3-dimethyl-l//-imidazol-3- ium iodide (0.697 g, 3.11 mmol) in THF (3 mL) was added NaH (0.149 g, 3.74 mmol) and the resulting mixture was refluxed for 30 min. Product was observed and the reaction went to completion. The mixture was brought to RT and poured into ice-water, extracted with DCM and purified using hexanes to afford a light yellow solid as (2-bromo-3- methylphenyl)(2-(methylthio)pyrimidin-4-yl)methanone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; In acetonitrile; at 80℃; for 8h; | To a solution of ethyl 3-methyl-iif-pyrazole-4-carboxylate 2 (5.0 g, 32.4 mmol) in anhydrous acetonitrile (60 mL) were added potassium carbonate (8.96 g, 64.9 mmol) and 4-chloro-2-(methylthio)pyrirnidine 11 (5.47g, 34.1 mmol) at room temperature (rt). The resulting suspension was heated at 80 C for 8 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). It was diluted with ethyl acetate and washed with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacou. The resulting residue was recrystallized with methanol to give 7.88 g (83 %) of ethyl 3-methyl-l- (2-(memyltMo)pyrimidin-4-yl)-2fl-pyrazole-4-carboxylate 12; MS (ESI) m/z 279 [M+H]+ The resulting pyrazole-4-carboxylate 12 (7.44g, 26.7 mmol) was dissolved in 30 mL of DCM and then cooled to 0 C. To this was added 3-chloroperbenzoic acid (mCPBA, 13.2g, 58.8 mmol) at the same temperature. The reaction was warmed to room temperature, stirred for 2 hours and then quenched by addition of saturated NaHC<¾ solution. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacou. The resulting residue was recrystallized with iso-propylether to give 7.88 g (83 %) of ethyl 3-methyl-l-(2- (methylsulfonyl)pyrimidin-4-yl)-i/i'-pyrazole-4-carboxylate 13 as a coloress solid (6.92g, 83%); m/z 311 [M+H]+. The obtained sulfoxide 13 (3.0 g, 9.7 mmol) was mixed with acetic acid (0.42 mL, 9.7 mmol) and 3,5-dimethylaniline (1.4 mL, 9.7 mmol) in 10 mL of n-butanol. After being heated at reflux for 2 hours, the mixture was concentrated in vacou. The resulting residue was extracted with DCM, washed with a saturated NaHCC solution. The collected organic layer was dried over anhydrous sodium sulfate, concentrated in vacou and then recrystallized with ethyl acetate to afford 0.86 g (26 %) of Compound No. 2 as a pale yellow solid; m/z 352 [M+H]+. |
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