Structure of 1408074-83-8
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CAS No. : | 1408074-83-8 |
Formula : | C9H16F2N2O2 |
M.W : | 222.23 |
SMILES Code : | O=C(N1CC(F)(F)C(N)C1)OC(C)(C)C |
MDL No. : | MFCD23105898 |
InChI Key : | DODJSPBKCAGGTQ-UHFFFAOYSA-N |
Pubchem ID : | 72207756 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.89 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 54.63 |
TPSA ? Topological Polar Surface Area: Calculated from |
55.56 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.13 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.68 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.66 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.86 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.51 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.17 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.45 |
Solubility | 7.92 mg/ml ; 0.0356 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.42 |
Solubility | 8.38 mg/ml ; 0.0377 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.19 |
Solubility | 14.3 mg/ml ; 0.0644 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 |
-7.17 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 |
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) |
2.93 |
* 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 tert-butyl alcohol; at 20 - 90℃; for 120.0h; | To a solution of tert-butyl 4-amino-3, 3-difluoropyrrolidine-l-carboxylate (880 mg, 4 mmol) in t-BuOH (5 mL) was added DIEA (0.7 mL, 4 mmol) and Intermediate IA (400 mg, 1.5 mmol) at RT. The mixture was heated to 90 °C and stirred at this temperature for 5 days. The solution was then cooled and the solvents were removed under reduced pressure. The residue obtained was purified by reverse-phase preparative HPLC (Column: Xbridge Prep C18 10 um OBD, 19 x 250 mm; Mobile phase: A: water (10 mM NH4HCO3), B: MeCN; Flow rate: 30 mL/min; UV detection: 214/254 nm) to afford tert-butyl 4-(9-ethyl-8-(2-methylpyrimidin-5-yl)-9H-purin-6- ylamino)-3,3-difluoropyrrolidine-l-carboxylate (1-21). 1H NMR (400 MHz, CD3OD) delta 9.22 - 9.10 (m, 2H), 8.39 (s, 1H), 5.52 - 5.43 (m, 1H), 4.41 (q, / = 7.2 Hz, 2H), 4.10 - 3.73 (m, 3H), 3.52 - 3.39 (m, 1H), 2.83 (s, 3H), 1.49 (s, 9H), 1.46 (t, / = 7.2 Hz, 3H). MS (ESI) calc'd for (C21H27F2N8O2) [M+H]+, 461 ; found, 461. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 15.0h;Inert atmosphere; | To a stirred solution of tert-butyl 4-azido-3, 3-difluoropyrrolidine-l-carboxylate (1.4 g, 5.6 mmol) in MeOH (10 mL) was added Pd/C (10percent by weight) (0.2 g, 10percent by weight, 0.188 mmol) at RT. The mixture was degassed with nitrogen, and subsequently the mixture was stirred under a balloon at RT for 15 h . The mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to provide tert-butyl 4-amino-3, 3-difluoropyrrolidine-l-carboxylate. MS (ESI) calc'd for (C5H9F2N202) [M-tBu+2H]+, 167; found, 167. | |
With palladium on carbon; hydrogen; In ethanol; for 16.0h; | A solution of tert-butyl 4-azido-3,3-difluoropyrrolidine-1-carboxylate (3.01 g, 12.1 mmol) in ethanol (300 mL) was degassed with nitrogen and 20percent Pd/C (300 mg) was added. The resulting mixture was stirred under hydrogen atmosphere (balloon) for 16 hr. The catalyst was removed by filtration. The filtrate was evaporated to give the title product as an oil (2.63 g, 98percent yield, >85percent purity). 1H NMR (400 MHz, chloroform-d) delta ppm 3.73-3.87 (m, 2H) 3.69 (d, J=10.64 Hz, 1H) 3.50-3.62 (m, 1H) 3.13 (d, J=6.85 Hz, 1H) 1.45-1.48 (m, 9H). 19F NMR (376 MHz, chloroform-d) delta ppm ?115.05-?110.78 (m, 1F) ?120.95-?117.90 (m, 1F). m/z (APCI+) for C9H16F2N2O2 123 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetrabutylammoniun azide; In N,N-dimethyl-formamide; at 20℃; for 3.0h;Inert atmosphere; Cooling with ice; | tert-butyl 3,3-difluoro-4-(trifluoromethylsulfonyloxy)pyrrolidine-1-carboxylate (1500 mg, 4.22 mmol), prepared following WO2017103611 example 160, was dissolved in DMF (20 mL) and cooled in an ice bath under N2 atmosphere. tetrabutylammonium azide (1200 mg, 4.22 mmol) in DMF (20 mL) was added slowly over 15 min via an addition funnel. The reaction mixture was stirred in the cold bath and allowed to warm to ambient temperature gradually and stirred for 3 h. The reaction was diluted with ethyl acetate (50 mL), washed with sat. aq. NaHCO3 (×2) and brine (×2). The organic phase was dried over a phase separator and purged with vacuum/N2 (3 times) followed by 10 the addition of palladium, 10 wt. % on carbon powder, dry (150 mg, 1.4 mmol).3 cycles vacuum/H2 were then performed and the reaction was left stirring at RT overnight under an atmosphere of hydrogen. The crude was filtered through a plug of CeliteTM and the solvent removed in vacuo. The product was purified by silica column chromatography using as eluting with 0-5% MeOH in DCM to afford [tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (934 mg, 4.2 mmol, 99% yield) ] as a 15 colourless oil. UPLC-MS (ES+, Method A), 1.04 min, m/z 167.0 [M-(tBu)+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2.0h;Inert atmosphere; | To a reaction flask was added <strong>[1408074-83-8]tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate</strong> (1.36 g, 6.12 mmol), 3-(methylsulfonyl)propanoic acid (1.02 g, 6.73 mmol, 1.1 mol eq), DCM (31 mL, 0.4 M), NMM (1.35 mL, 12.2 mmol, 2 mol eq), HOBt (1.31 g, 9.2 mmol, 1.5 mol eq) and EDC-HCl (1.85 g, 9.2 mmol, 1.5 mol eq). The resulting suspension was stirred at ambient temperature under a nitrogen atmosphere for 2 hr. The reaction was diluted with DCM (80 mL), washed with aqueous NaHCO3 (2×30 mL) and the organic layer was dried over Na2SO4 and evaporated to give a residue that was purified via silica flash chromatography eluting with gradients from 100percent heptane to 100percent ethyl acetate to give the title product as a white foamy solid (1.65 g, 76percent yield, >95percent purity). 1H NMR (400 MHz, chloroform-d) delta ppm 6.45 (br. s., 1H) 4.68-4.89 (m, 1H) 3.94 (dd, J=10.70, 8.62 Hz, 1H) 3.62-3.86 (m, 2H) 3.43 (t, J=7.15 Hz, 2H) 3.18 (br. s., 1H) 2.97 (s, 3H) 2.84 (td, J=7.15, 1.96 Hz, 2H) 1.47 (s, 9H). 19F NMR (376 MHz, chloroform-d) delta ppm ?112.79-?110.52 (m, 1F) ?114.51-?113.30 (m, 1F). m/z (APCI+) for C13H22F2N2O5S 257.1 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 14.0h; | tert-Butyl 4-am ino-3,3-difluoropyrrolidine-1 -carboxylate (prepared using themethod described by D. C. Behenna et al., in U.S. Published Patent Application 20150141402 Al, May 21, 2015; 2.30 g, 10.3 mmol) was dissolved in acetonitrile (20 mL). N,N-Diisopropylethylamine (2.01 g, 15.5 mmol) and C224 (3.04 g, 13.0 mmol) were added to this solution, and the reaction mixture was stirred for 14 hours at 20 °C. After removal of volatiles in vacuo, purification via silica gel chromatography (Gradient: 9percent to17percent tetrahydrofuran in petroleum ether) provided the product as a pale yellow solid.Yield: 3.20 g, 7.63 mmol, 74percent. H NMR (400 MHz, CDCI3) 9.52 (5, 1H), 9.21-9.04 (brm, 1H), 8.48 (br s, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.00 (dd, J=8.6, 1.5 Hz, 1H), 4.88-4.74(m, 1H), 4.23 (br dd, J=9.7, 8.8 Hz, 1H), 4.05-3.89 (br m, 1H), 3.89-3.75 (m, 1H), 3.60(ddd, J=ii.4, 8.4, 1.3 Hz, 1H), 1.51 (5, 9H). |
74% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 14.0h; | tert-Butyl 4-amino-3,3-difluoropyrrolidine-1 -carboxylate (prepared using the method described by D. C. Behenna et al., in U.S. Patent Application 2015 0141402 Al May 21 2015; 2.30 g, 10.3 mmol) was dissolved in acetonitrile (20 mL). N,N15 Diisopropylethylamine (2.01 g, 15.5 mmol) and CII (3.04 g, 13.0 mmol) were added tothis solution, and the reaction mixture was stirred for 14 hours at 20 °C. After removal of volatiles in vacuo, purification via silica gel chromatography (Gradient: 9percent to 17percent tetrahydrofuran in petroleum ether) provided the product as a pale yellow solid. Yield:3.20g, 7.63mmol, 74percent. H NMR(400MHz, CDCI3)E9.52(s, 1H), 9.21-9.04(brm,1 H), 8.48 (br s, 1 H), 8.20 (d, J=8.8 Hz, 1 H), 8.00 (dd, J=8.6, 1.5 Hz, 1 H), 4.88-4.74 (m,1 H), 4.23 (br dd, J=9.7, 8.8 Hz, 1 H), 4.05-3.89 (br m, 1 H), 3.89-3.75 (m, 1 H), 3.60 (ddd, J=ll.4, 8.4, 1.3 Hz, 1H), 1.51 (5, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 48.0h; | To a 15°C solution of 4-chloro-6-fluoro-3-nitroquinoline (10.0 g, 44.1 mmol) inacetonitrile (50 mL) was added N,N-diisopropylethylamine (6.84 g, 52.9 mmol), followed by addition of <strong>[1408074-83-8]tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate</strong> (prepared usingthe method described by D. C. Behenna et al., in U.S. Patent Application 2015 0141402 Al May 21 2015; 9.81 g, 44.1 mmol). The reaction mixture was stirred at 20 °C for 48 hours, whereupon it was concentrated in vacuo and purified via chromatography onsilica gel (Gradient: 9percent to 17percent tetrahydrofuran in petroleum ether) to afford the product as a pale yellow solid. Yield: 16.8 g, 40.7 mmol, 92percent. 1H NMR (400 MHz, CDCI3) 9.39(5, 1H), 8.87-8.69(brm, 1H), 8.13(dd, J=9.5, 5.5 Hz, 1H), 7.79-7.70(brd, J=8 Hz, 1H),7.63 (ddd, J=9.0, 7.5, 2.5 Hz, 1H), 4.87-4.71 (br m, 1H), 4.31 -4.09 (br m, 1H), 4.04-3.84 (br m, 1 H), 3.84-3.69 (m, 1 H), 3.63-3.51 (br m, 1 H), 1.50 (5, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 32.0h; | To a solution of C7 (13.1 g, 53.9 mmol) in acetonitrile (60 mL) was added N,Ndiisopropylethylamine (11.3 mL, 64.9 mmol), followed by addition of a solution of tertbutyl 4-amino-3,3-difluoropyrrolidine-1 -carboxylate (prepared using the methoddescribed by D. C. Behenna et al., in U.S. Patent Application 2015 0141402 Al, May21 2015; 12.0 g, 54.0 mmol) in acetonitrile (5 mL). After the reaction mixture had beenstirred at 20 °C for 32 hours, it was diluted with water (100 mL). The resulting solid wascollected by filtration and purified via chromatography on silica gel (Gradient: 0percent to25percent tetrahydrofuran in petroleum ether), affording the product as a yellow solid. Yield:12.0 g, 28.0 mmol, 52percent. LCMS m/z 428.7 (chlorine isotope pattern observed) [M+H].1H NMR (400 MHz, CDCl3)9.4l (5, 1H), 8.91-8.78(brm, 1H), 8.08 (brs, 1H), 8.06(d, J=9.0 Hz, 1H), 7.79(dd, J=9.0, 2.0 Hz, 1H), 4.86-4.72 (brm, 1H), 4.30-4.12(brm, 1H), 4.03-3.86 (br m, 1 H), 3.86-3.71 (m, 1 H), 3.64-3.52 (br m, 1 H), 1.51 (5, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 23℃; for 2.0h; | To a solution of 5-(4- amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (130 mg, 0.368 mmol), <strong>[1408074-83-8]tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate</strong> (82 mg, 0.368 mmol) and DIPEA (0.193 mL, 1.104 mmol) in DMF (2 mL) was added BOP (195 mg, 0.442 mmol). The reaction mixture was stirred at 23 °C for 2 h. The reaction mixture was diluted with EtOAc (80 mL) which was washed with 10 percent LiCl solution (2 x 30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. Filtration and concentration yielded tert-butyl 4-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2- methoxynicotinamido)-3,3-difluoropyrrolidine-1-carboxylate (248 mg, 0.439 mmol, ~100 percent yield). (1207) MS ESI m/z 558.1 (M+H)+ (1208) 1H NMR (400 MHz, DMSO-d6) delta 8.94 (d, J=2.4 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.65 (d, J=8.7 Hz, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 5.14 - 4.94 (m, 1H), 4.03 (s, 3H), 3.90 - 3.47 (m, 4H), 1.43 (s, 9H). |
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