Structure of 147118-37-4
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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. : | 147118-37-4 |
Formula : | C16H18FN3O3S |
M.W : | 351.40 |
SMILES Code : | CS(=O)(N(C1=NC(C(C)C)=C(C=O)C(C2=CC=C(F)C=C2)=N1)C)=O |
MDL No. : | MFCD08458342 |
Boiling Point : | No data available |
InChI Key : | WOCOTUDOVSLFOB-UHFFFAOYSA-N |
Pubchem ID : | 10473133 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 24 |
Num. arom. heavy atoms | 12 |
Fraction Csp3 | 0.31 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 6.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 90.56 |
TPSA ? Topological Polar Surface Area: Calculated from |
88.61 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.22 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.07 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
4.12 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.8 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.56 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.35 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.36 |
Solubility | 0.152 mg/ml ; 0.000434 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.56 |
Solubility | 0.0968 mg/ml ; 0.000275 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-5.22 |
Solubility | 0.00214 mg/ml ; 0.00000608 mol/l |
Class? Solubility class: Log S scale |
Moderately 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) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
Yes |
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 |
-6.97 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 |
1.0 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) |
2.91 |
* 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% | With potassium <i>tert</i>-butylate In tetrahydrofuran; water at -15 - 42℃; for 1 h; Inert atmosphere | The present embodiment of rosuvastatin calcium intermediate preparation,which is 6 - [(1E) -2- [4- (4- fluorophenyl) -6-isopropyl- 2- [methyl (methylsulfonyl) amino] -5-pyrimidinyl] ethenyl] -dimethyl-l, 3-dioxane-4-acetic acid tert-butyl ester comprises the following steps: (1) under the protection of N2,To a 1000 mL reaction flask was added 36 g of compound of formula 3,21 g of compound of formula 2 and 620 mL of tetrahydrofuran,Heated to 42 ° C and stirred until clear,Then cooled to -15 ° C, added 1.8mL of water, 20g of potassium tert-butoxide, the reaction was incubated for 60 minutes after the addition; (2) The reaction was quenched with 105mL saturated ammonium chloride, quenched after the addition of 600mL water, and then 600mL ethyl acetate extraction, washed with brine, dried and concentrated to give a pale yellow solid,Add 288mL of methanol and 48mL water recrystallization,Filtration and drying gave 31 g of a white solid, which was the target product. |
120 g | With sodium hydride In tetrahydrofuran at 0 - 35℃; | To a solution of N-[4-(4-fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N- methyl-methane sulfonamide (100 gms) and compound III (wherein Rl=l-phenyl-lH- tetrazol-5-yl, X=0 and R2= tert-butyl; 130 gms) in tetrahydrofuran (2000 mL) was added sodium hydride (34 gms) lot wise at 0°C to 5°C. The reaction mass was stirred for 30 min at 0°C to 5°C and then the temperature was gradually allowed to raise to 25 °C to 35 °C and stirred till reaction completion. The reaction mass was quenched with 10percent potassium carbonate solution (lOOOmL) and extracted with ethyl acetate. The organic layer was washed with 10 percent NaCl solution and concentrated under vacuum. The obtained residue was triturated with methanol (500mL) ; the precipitated white solid was filtered and dried at 55°C to afford 120 gms of the title compound. HPLC purity: >98percent and Z-isomer content: <0.2percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium hexamethyldisilazane In tetrahydrofuran at -75 - -10℃; for 2 h; | Example 6b Using NaHMDS N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (0.5 g, 1.4 mmol) and 2-((4 ,6S)-6-((benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetate te/f-butyl ester (0.7 g, 1.6 mmol) were added to 10 mL of dry THF. After stirring for 10 min at 20°C, the reaction mixture was cooled to -70°C. At this temperature 1.9 mL of NaHMDS solution (1 M in THF, total 3.8 mmol) was added in 60 min keeping the temperature between -70 and -75°C. When dosing was completed, the temperature of the reaction mixture was allowed to increase to -10°C. After stirring at this temperature for 1 h, the reaction was quenched with 10percent aqueous NaHC03 (5 mL). The phases were separated. The aqueous layer was extracted with 2 x 20 mL of ethyl acetate. The combined organic phases were washed with 5percent aqueous Na2C03 and concentrated under vacuum. H PLC analysis indicated an E to Z ratio of >99: 1 . The residue was crystallized from methanol to give 2-((4f?,6S)-6-((E)-2-(4-(4-fluorophenyl)-6- isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)vinyl)-2,2-dimethyl-1 ,3-dioxan- 4-yl)acetate, te/f-butyl ester as a solid (0.52 g, 0.9 mmol, 64percent yield). |
65 g | With potassium <i>tert</i>-butylate In tetrahydrofuran at -80 - 45℃; for 1.75 h; | EXAMPLE-6PREPARATION OF tert-BUTYL 2-[(4R,6-2,2-DIMETIIYL-6-[(E)-2-[4-(4- FLUOROPHENYL)-6-ISOPROPYL-2-[N-METHYL(N-METHYLSULFONYL)-AMINOIPYRIMIDIN-5-YL]VINYLI-1,3-DIOXAN-4-YLIACETATE [DIPROTECTED ROSUVASTATIN)A mixture of 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl arnino)pyrimidine-5-ylcarboxaldehyde (50 g, 0.142 mole) and chiral diol sulphone (62.82 g, 0.142 mole) was dissolved in tetrahydrofuran (750 ml) at 40-45°C. The above reaction mass was cooled to -75 to -80°C and thereafter potassium tertbutoxide (22.33 g, 0.199 mole) was dissolved in tetrahydrofuran (100 ml) slowly at -80°C to -75°C over a period of 45 mi Stirring was continued till pyrimidine carboxaldehyde was consumed (—1 h) and the progress of reaction was monitored by HPLC. After completion of the reaction, 20percent aqueous ammonium chloride solution (500 ml) was added to the reaction mass at -75° to -80°C. Thereafter, temperature was raised to 20-30°C. The product was extracted with ethyl acetate (2 x 250 ml), washed with 10percent w/w aqueous sodium chloride (500 ml) and solvent was evaporated under reduced pressure at 40-45°C. Thereafter, methanol (750 ml) was added to the concentrated mass and heated to 60-65°C to obtain a clear solution. It was cooled to 0-5°C and the title compound was isolated by filtration.Yield: 65 gChroinatographic Purity (by HPLC): 99percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With lithium hexamethyldisilazane In tetrahydrofuran at -75 - -10℃; for 2.33333 h; | Example 6 Preparation of 2-((4 ?,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1 ,3-dioxan-4- yl)acetate, ferf-butyl ester (P) from N-(4-(4-fluorophenyl)-5-formyl-6- isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (J) and 2-((4 ?,6S)-6- ((benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2-dimethyl-1 ,3-dioxan-4-yl)acetate ferf- (E) (J) (P)Example 6a Using Li HMDS N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfon ( J , 1 . 0 g, 2.9 mmol) and 2-((4ft,6S)-6-((benzo[d]thiazol-2-ylsulfonyl)methyl)-2,2- dimethyl-1 ,3-dioxan-4-yl)acetate te/f-butyl ester (E, 1.4 g, 3.1 mmol) were added to dry THF (12 mL). After stirring for 10 min at 20°C, the reaction mixture was cooled to -70°C and 3.8 mL of Li HM DS solution (1 M in TH F, total 3.8 mmol) was added in 80 min keeping the temperature between -70 and -75°C. When dosing was completed, the temperature of the reaction mixture was allowed to increase to -10°C. After stirring at this temperature for 1 h, the reaction was quenched with 10percent aqueous NaHC03 (5 mL). The phases were separated. The aqueous layer was extracted with 2 x 20 mL of ethyl acetate. The combined organic phases were washed with 5percent aqueous Na2C03 and concentrated under vacuum. H PLC analysis indicated an E to Z ratio of 70:30. The residue was crystallized from methanol to give 2-((4f?,6S)-6-((E)-2-(4-(4-fluorophenyl)-6- isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)vinyl)-2,2-dimethyl-1 ,3-dioxan- 4-yl)acetate, te/f-butyl ester as a solid (P, 0.87 g, 1.5 mmol, 52percent yield). |
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