Structure of 1837-55-4
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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. : | 1837-55-4 |
Formula : | C4H2Cl2N2 |
M.W : | 148.98 |
SMILES Code : | ClC1=CC(=CN=N1)Cl |
MDL No. : | MFCD10698048 |
InChI Key : | JZSAUQMXKHBZEO-UHFFFAOYSA-N |
Pubchem ID : | 19959687 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 32.05 |
TPSA ? Topological Polar Surface Area: Calculated from |
25.78 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.61 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.43 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.78 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.21 |
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 |
1.68 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.22 |
Solubility | 0.899 mg/ml ; 0.00603 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.58 |
Solubility | 3.95 mg/ml ; 0.0265 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.87 |
Solubility | 0.203 mg/ml ; 0.00136 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 |
-6.19 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 |
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) |
1.78 |
* 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 |
---|---|---|
91% | In tetrahydrofuran; at 23℃; for 18h;Inert atmosphere; | Example 95: 5-[(3R)-3-(Methylamino)pyrrolidin-1-yl]-N-(2- methylpropyl)pyridazin-3-arnine. [1 -(delta-Chloro-pyridazin-^yO-pyrrolidin-S-yO-methyl-carbamic acid tert-butyl ester. A solution of 3,5-dichloropyridazine (149 mg, 1.0 mmol) in THF (3 ml_) at 23 0C was treated with (RJ-methyl-pyrrolidin-S-yl-carbamic acid tert-butyl ester (440 mg, 2.2 mmol) and the reaction stirred at 23 0C for 18 h. The reaction diluted with EtOAc (30 ml) and solution washed with water (2 x 5 ml) and combined organic solution dried and concentrated and crude material purified on 16 g SiO2 (O to 30% EtOAc : Hex) to yield 283 mg (91 % yield) of the desired regioisomer and 17 mg (5% yield) of the undesired regioisomer. MS (ESI): mass calcd. for Ci4H2iCIN4O2, 312.5 m/z found, 313.5 [M+H]+. [1 -(delta-lsobutylamino-pyhdazin^-yO-pyrrolidin-S-yO-methyl-carbamic acid tert- butyl ester. A solution of [1-(6-chloro-pyhdazin-4-yl)-pyrrolidin-3-yl]-methyl- carbamic acid tert-butyl ester (32 mg, 0.1 mmol) in isobutylamine (1.0 ml) in a sealed tube was heated to 120 0C for 72 h. The resulting solution was purified directly on 12 g SiO2 (0 to 5% NH3/Me0H:CH2CI2) to yield 20 mg (55% yield). lsobutyl-[5-(3-methylamino-pyrrolidin-1 -yl)-pyhdazin-3-yl]-amine dihydrochlohde. To a stirring solution of [1-(6-isobutylamino-pyhdazin-4-yl)- pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (19 mg, 0.06 mmol) in 96% formic acid (0.5 ml_) was added 0.05 ml of aqueous 6N HCI. The mixture was stirred for 2 hr, diluted with MeOH and concentrated under reduced pressure (repeat 3X) to give the desired product as a white solid (101 mg, >99%). MS (ESI): mass calcd. for Ci3H23N5, 249.4 m/z found, 250.2 [M+H]. 1H NMR (400 MHz, CD3OD): 8.12 (d, J = 2.5, 1 H), 6.08 (s, 1 H), 4.1 1 - 4.01 (m, 1 H), 4.04 - 3.47 (m, 4H), 3.35 (s, 1 H), 3.15 (d, J = 7.0, 2H), 2.82 (s, 3H), 2.65 - 2.53 (m, 1 H), 2.43 - 2.31 (m, J = 5.6, 1 H), 1.96 (dt, J = 13.4, 6.7, 1 H), 1.03 (d, J = 6.7, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In tetrahydrofuran; at 0 - 60℃; for 10h; | 5-cWoro-3-(3,5-dimethyl-lH-l,2,4-triazol-l-yl)pyridazine (23-2): To a stirring solution of 3,5-dichloropyridazine (23-1, 5.00 g , 33.5 mmol, 1.0 eq.) in tetrahydrofuran (125 ml) at 0 °C was added cesium carbonate (17.7 g, 50.3 mmol, 1.5 eq.), followed by 3,5-dimethyl-lH-l,2,4~triazole (3.25 g, 33.5 mmol, 1.0 eq.) in tetrahydrofuran (125 mL) dropwise. The resulting reaction mixture was stirred for 1 hour at the same temperature and then warmed to room temperature and stirred for another 3 hours, then heated to 60 °C and stirred for 6 hours. The solvent was removed under reduced pressure and the residue was diluted with water (200 mL) and extracted with DCM (3 chi 80 mL). The combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by silica gel column chromatography (70percent ethyl acetate in hexanes) to afford 5-chloro-3-(3,5-dimethyl-lH-l,2,4-triazol-l-yl)pyridazine (23-2) as a white solid. 1H NMR (300 MHz, CDC13) delta 9.11 (d, 1H, J= 2.1 Hz), 8.20 (d, 1H, J= 2.1 Hz), 2.96 (s, 3H), 2.43 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 1h; | To a soluton of<strong>[4522-35-4]3-iodopyrazole</strong> (500 mg, 2.58mmol) and 3,5-dichloropyridazine(384 mg, 2.58 mmol) in anhydrous DMF (5 mL) at room temperature was addedpotassium tert-butoxide (289 mg, 2.58 mmol) in one portion. It was heated at100 C for 1 h. It was cooled to room temperature, diluted with EtOAc (50 mL),washed with satd aq. NaHC03 (10 mL) and water (100 mL). The aqueous layerwas separated and extracted with EtOAc (3 x 50 mL). The combined organiclayers were washed with water (1 00 mL), brine (1 00 mL), dried over Na2S04,filtered and concentrated. The residue was purified by flash chromatography(ISCO Combiflash, Gold 40 g, 0-60% EtOAc in hexanes) to give 3-chloro-5-(3-iodo-1H-pyrazol-1-yl)pyridazine, as a white solid. LCMS calc.= 306.92, found= 306.96 (M+Ht. 1H NMR (500 MHz, CHCh-d): o 9.54 (d, J= 2.3 Hz, 1 H);7.94 (d, J= 2.7 Hz, 1 H); 7.90 (d, J= 2.3 Hz, 1 H); 6.81 (d, J= 2.7 Hz, 1 H). | |
With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 1h; | 3-Chloro-5-(3-iodo-lH-pyrazol-l -vDpyridazine To a soluton of <strong>[4522-35-4]3-iodopyrazole</strong> (500 mg, 2.58 mmol) and 3,5-dichloropyridazine (384 mg, 2.58 mmol) in anhydrous DMF (5 mL) at room temperature was added potassium teri-butoxide (289 mg, 2.58 mmol) in one portion. It was heated at 100 C for 1 h. It was cooled to room temperature, diluted with EtOAc (50 mL), washed with satd aq. NaHC03 (10 mL) and water (100 mL). The aqueous layer was separated and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography (ISCO Combiflash, Gold 40 g, 0-60% EtOAc in hexanes) to give 3-chloro-5-(3- iodo-lH-pyrazol-l-yl)pyridazine, as a white solid. LCMS calc. = 306.92, found = 306.96 (M+H)+. NMR (500 MHz, CHCl3-d): delta 9.54 (d, J= 2.3 Hz, 1 H); 7.94 (d, J= 2.7 Hz, 1 H); 7.90 (d, J= 2.3 Hz, 1 H); 6.81 (d, J= 2.7 Hz, 1 H). | |
With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 1h; | INTERMEDIATE 40 3-Chloro-5-(3-iodo-lH-pyrazol-l-yl pyridazine To a soluton of <strong>[4522-35-4]3-iodopyrazole</strong> (500 mg, 2.58 mmol) and 3,5-dichloropyridazine (384 mg, 2.58 mmol) in anhydrous DMF (5 mL) at room temperature was added potassium tert-butoxide (289 mg, 2.58 mmol) in one portion. It was heated at 100 C for 1 h. It was cooled to room temperature, diluted with EtOAc (50 mL), washed with satd aq. NaHC03 (10 mL) and water (100 mL). The aqueous layer was seperated and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography (ISCO Combiflash, Gold 40 g, 0-60% EtOAc in hexanes) to give 3-chloro-5-(3-iodo-lH-pyrazol-l-yl)pyridazine, as a white solid. LCMS calc. = 306.92, found = 306.96 (M+H)+. NMR (500 MHz, CHC13- d): 5 9.54 (d, J= 2.3 Hz, 1 H); 7.94 (d, J= 2.7 Hz, 1 H); 7.90 (d, J= 2.3 Hz, 1 H); 6.81 (d, J= 2.7 Hz, 1 H). |