Structure of 1060816-67-2
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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. : | 1060816-67-2 |
Formula : | C7H6ClN3 |
M.W : | 167.60 |
SMILES Code : | CN1C=CC2=CN=C(Cl)N=C21 |
MDL No. : | MFCD13189420 |
InChI Key : | WOIRQILACBXPIQ-UHFFFAOYSA-N |
Pubchem ID : | 57415888 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 9 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 43.8 |
TPSA ? Topological Polar Surface Area: Calculated from |
30.71 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.09 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.58 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.62 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.11 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.58 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.6 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.48 |
Solubility | 0.555 mg/ml ; 0.00331 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.84 |
Solubility | 2.45 mg/ml ; 0.0146 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.71 |
Solubility | 0.328 mg/ml ; 0.00195 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 |
-6.2 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) |
1.44 |
* 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 |
---|---|---|
77% | Step-1: 2-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine [0182] To a stirred solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 6.5 mmol) in MeCN (25 mL) at 5 oC was added NaH (313 mg, 7.8 mmol). The resultant mixture was brought to room temperature and stirred for 30 min. Then MeI was added at 0 oC and continued stirring at room temperature for overnight. The reaction mixture was filtered through a pad of celite and washed with MeCN (10 mL). The filtrate was concentrated and recrystallized from Et2O. The mother liquor was concentrated and purified by ISCO (SiO2: DCM/EtOAc 0 to 30%). Altogether, the recrystallized and purified provided the pure compound (835 mg, 77%). | |
47% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;Sealed tube; | Step 1. 2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidineTo a solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (27 mg, 0.16 mmol, prepared as reported in Bioorganic and Medicinal Chemistry Letters, 16(22), 5778-5783 (2006)) in DMF (0.15 mL) was added potassium carbonate (67 mg, 0.48 mmol), followed by methyl iodide (10 microL, 0.16 mmol). The mixture was stirred in a sealed vial at RT for 3 h. The reaction was diluted with DCM and acetonitrile, filtered and concentrated. The product was purified by flash column chromatography on silica gel, eluting with 0-50% ethyl acetate in hexanes to afford product as a white solid (13 mg, 47%). LCMS (M+H)+: 167.9, 169.9. |
47.4% | To a solution of NaH (106.6 mg, 2.67 mmol) in THF (5 mL) was added 2-chloro- 7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.54 mmol) at 0C and stirred for 30 minutes at the same temperature. CH3I (1.5 g, 10.2 mmol) was added at 0C and the combined mixture stirred for 3 h at 15C. After TLC showed the reaction was complete, the mixture was diluted with water 20 mL) and extracted with ethyl acetate EA (2x20 mL) and the combined organic layers were washed with brine (30 mL), dried over Na2S04 and concentrated to give the title compound (254 mg, 47.4%) as colorless oil which was used in next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2. 3-[1-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidin-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile3-Pyrrolidin-3-yl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (26 mg, 0.060 mmol; from Example 15, Step 3) and <strong>[1060816-67-2]2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (12.0 mg, 0.0716 mmol) were dissolved in NMP (0.050 mL) and N,N-diisopropylethylamine (42 microL, 0.24 mmol) was added. The mixture was heated to 135 C. for 60 min in the microwave. After removal of solvent, the residue was stirred sequentially in 1:1 TFA/DCM for 1.5 h, concentrated, then in a solution in 1.0 mL methanol containing 0.2 mL EDA for 30 min. The product was purified via preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH). 1H NMR (400 MHz, d6-DMSO): delta 12.13 (br s, 1H), 8.89 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 7.61 (d, 1H), 7.08 (d, 1H), 7.00 (d, 1H), 6.33 (d, 1H), 4.84 (dt, 1H), 3.91 (dd, 1H), 3.67 (dd, 1H), 3.62 (s, 3H), 3.46-3.27 (m, 4H), 2.96-2.84 (m, 1H), 1.77-1.59 (m, 2H); LCMS (M+H)+: 439.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | To a solution of <strong>[1060816-67-2]2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (100 mg, 0.6 mmol) in dioxane (4 ml) and H20 (1 mL) was added l-(3,4-dihydroisoquinolin-2(lH) -yl)-3- ((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)amino)propan-2-ol (292 mg, 0.716 mmol), Pd(dppf)Cl2 (44 mg, 0.06 mmol) and K2C03 (249 mg, 1.8 mmol) at 27C. The mixture was stirred for 16 h at 100C. After shown to be complete by TLC the reaction mixture was concentrated and the crude residue purified by prep-HPLC separation to give the desired title compound as a formate salt as a white solid (30.0 mg, 12%). 1H NMR (400 MHz, CHLOROFORM- J) ppm 3.21 (br. s., 2 H) 3.31 - 3.39 (m, 2 H) 3.53 - 3.71 (m, 4 H) 3.93 (s, 3 H) 4.34 (br. s., 1 H) 4.44 (s, 2 H) 6.67 (d, J=3.51 Hz, 1 H) 7.17 (d, J=7.40 Hz, 1 H) 7.24 - 7.31 (m, 3 H) 7.52 (d, J=3.51 Hz, 1 H) 7.63 (d, J=5.27 Hz, 1 H) 7.72 (s, 1 H) 7.93 (d, J=5.52 Hz, 1 H) 8.40 (br. s., 2 H) 9.01 (s, 1 H). LCMS (m/z): 415.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.4% | To a solution of <strong>[1060816-67-2]2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (70 mg, 0.407 mmol) in dioxane (4 ml) and H20 (1 mL) was added compound l-(3,4-dihydroisoquinolin- 2(lH)-yl)-3-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy)propan-2-ol (200 mg, 0.4886 mmol), Pd(dppf)Cl2 (30 mg, 0.041 mmol) and K2C03 (169 mg, 1.221 mmol) at 15C. The reaction mixture was then stirred for 16 h at 100C after which, TLC analysis showed the reaction to be complete. The reaction mixture was the filtered and the filtrate concentrated to remove the solvent with the residue purified by prep-HPLC to give the formate salt of the title compound (23 mg, 11.4%) as a white solid. 1H NMR (400 MHz, CDC13): delta 8.99 (s, IH), 8.10-8.08 (m, 2 H), 7.47-7.42 (m, 2H), 7.39-7.24 (m, 3H), 7.20 (d, J=6.8 Etazeta,IotaEta), 7.10 (dd, J=2.0, 8.0 Hz, IH), 6.66 (d, J=3.6 Etazeta,IotaEta), 4.55-4.52 (m, IH), 4.42 (s, 2H), 4.20-4.17 (m, 2H), 3.94(s, 3H), 3.57-3.54 (m, 2H), 3.45-3.25 (m, 2H), 3.19 (d, J=3.6 Hz, 2H) ppm. LCMS (m/z): 326.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; In water; tert-butyl alcohol; at 20℃; for 3h; | Step-2: 5,5-Dibromo-2-chloro-7-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one [0183] To a solution of <strong>[1060816-67-2]2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine</strong> (835 mg, 5 mmol) in t-BuOH/H2O ((10 mL/3 mL) was added NBS (2.67 g, 15 mmol) and stirred for 3 h at room temperature. The reaction mixture was concentrated and dissolved in EtOAc (30 mL). The EtOAc layer was washed with NaHCO3, brine, dried (Na2SO4) and concentrated to give crude 5,5-Dibromo-2-chloro-7-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (1.72 g) which was used for the next step. |
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