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Type | HazMat fee for 500 gram (Estimated) |
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Structure of 13091-23-1
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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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Augustine N. Vu ; Santana P. Garcia ; Jenny H. Tran ; Adrian A. Godoy ; Joaquin M. Mesa ; Cassidy M. DiTirro , et al.
Abstract: An efficient synthesis of the exorbitantly priced Lambert–Eaton myasthenic syndrome drug amifampridine was developed and applied in the second-semester undergraduate organic chemistry laboratory. The two-step synthesis entails a nucleophilic aromatic substitution reaction of commercial 4-chloro-3-nitropyridine with methanolic ammonia to afford 4-amino-3-nitropyridine. Subsequent palladium-catalyzed nitro reduction provides amifampridine in high yield and purity. Amifampridine can alternatively be prepared by advanced undergraduate students in four linear steps beginning with 4-hydroxypyridine. Nitration of 4-hydroxypyridine to 4-hydroxy-3-nitropyridine and subsequent treatment with phosphoryl chloride provides the intermediate 4-chloro-3-nitropyridine, which is then subjected to the SNAr and reduction reactions to cleanly afford amifampridine without the need for column chromatography.
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Keywords: Second-Year Undergraduate ; Upper-Division Undergraduate ; Organic Chemistry ; Hands-On Learning ; Drugs/Pharmaceuticals ; Ethics ; Heterocycles
Show More >
CAS No. : | 13091-23-1 |
Formula : | C5H3ClN2O2 |
M.W : | 158.54 |
SMILES Code : | C1=NC=CC(=C1[N+]([O-])=O)Cl |
MDL No. : | MFCD02683025 |
InChI Key : | JOTRPRKONYTVBV-UHFFFAOYSA-N |
Pubchem ID : | 2735781 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H301-H318 |
Precautionary Statements: | P280-P301+P310-P305+P351+P338 |
Class: | 8(6.1) |
UN#: | 2923 |
Packing Group: | Ⅲ |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 38.07 |
TPSA ? Topological Polar Surface Area: Calculated from |
58.71 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.92 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.31 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.64 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.13 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.09 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.73 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.03 |
Solubility | 1.49 mg/ml ; 0.00941 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.14 |
Solubility | 1.14 mg/ml ; 0.00719 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.01 |
Solubility | 1.55 mg/ml ; 0.00979 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 |
-6.34 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 |
2.0 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) |
1.74 |
* 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 N-ethyl-N,N-diisopropylamine; In dichloromethane; at 60℃; for 15h;Product distribution / selectivity; | Example 78; Preparation of Compound 78B; Step A; To a vial were added 4-chloro-3-nitro pyridine (2 mmol) and spirocyclic amine (2 mmol). The starting materials were dissolved in 4 ml. of dichloromethane followed by the addition of DIPEA (6 mmol). The reaction was stirred at 60° for about 15 hours, then the reaction mixture was concentrated and using preparative liquid chromatography (0-5percent methanol in ethyl acetate) to provide compound 78A. Recovered 1.6 mmol (80percent) of 274. Mass calculated for formula C17H24N4O4 348.18, observed LCMS m/z 348.20 (M+H).; Using the methods described in Steps A and B above, and using the appropriate reactants, the following intermediate compounds were made: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5 g | With caesium carbonate; In N,N-dimethyl-formamide; at 10 - 35℃; for 16.0h; | A mixture of <strong>[21642-98-8]4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile</strong> (3.00 g), 4-chloro-3-nitropyridine (6.34 g), cesium carbonate (13.02 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 16 hr. The reaction mixture was slowly poured into saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added isopropyl ether (20 mL), and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (5.00 g). MS (ESI+): [M+H]+ 273.2 |
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