Structure of 16874-34-3
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CAS No. : | 16874-34-3 |
Formula : | C7H12O3 |
M.W : | 144.17 |
SMILES Code : | O=C(C1OCCC1)OCC |
MDL No. : | MFCD08063871 |
InChI Key : | GQQLWKZRORYGHY-UHFFFAOYSA-N |
Pubchem ID : | 10103286 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.86 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 36.02 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.11 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.89 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.73 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.35 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.26 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.07 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.1 |
Solubility | 11.5 mg/ml ; 0.0801 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.22 |
Solubility | 8.67 mg/ml ; 0.0601 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.96 |
Solubility | 15.9 mg/ml ; 0.11 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 |
-6.55 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) |
2.5 |
* 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 hydrazine; In butan-1-ol; for 3h;Heating / reflux; | a) (rac.)-(Tetrahydro-furan-2-yl)-acetic acid hydrazide A solution of (rac.)-(tetrahydro-furan-2-yl)-acetic acid ethyl ester (3.84 g, 24 mmol) in n-butanol (24 mL) was treated with hydrazine hydrate (1.4 mL, 29 mmol) and the resulting mixture was then heated under reflux for 3 h. The solvent was evaporated and residual volatile components were azeotropically removed by coevaporation with toluene. Chromatographic purification (SiO2, dichloromethane:methanol:aq.ammonia (25%)=100:0:0 to 90:10:1) afforded the title compound as a viscous, colorless oil (1.1 g, 32%). 1H-NMR (300 MHz, DMSO): delta=1.45 (mc, 1H), 1.70-1.95 (m, 3H), 2.13 (dd, J=6 Hz, J=14 Hz, 1H), 2.24 (dd, J=7 Hz, J=14 Hz, 1H), 3.56 (dd, J=8 Hz, J=14 Hz, 1H), 3.72 (dd, J=7 Hz, J=14 Hz, 1H), 4.05 (mc, 1H), 4.16 (s, 2H), 8.94 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.9% | With 5%-palladium/activated carbon; hydrogen; In ethanol; at 30 - 150℃; under 15001.5 Torr;Large scale; | 10359] 3010 g (21.5 mol) of thran-2-carboxylic acid ethyl ester, 500 ml of ethanol (1% MEK) and 20 g of catalyst, palladium on A-carbon dry, 5% Pd, type K-0227T) are initially introduced together and heated under a hydrogen pressure of 20 bat The reaction starts at 30-40C. and is relatively strongly exothermic. After 1-1.5 hat 60-70 C., the hydrogen absorption is as good as finished. The mixture is slowly heated to 140-150 C. and then stirred for a further 2-3 hat this temperature. GC control: starting material no longer present.10360] Filter off from the catalyst and concentrate the filtrate on a rotary evaporator (water bath: 60-70 C., 200-20 mbar). The crude yield is 3055 g.10361] The evaporated crude product is distilled with the addition of 0.1% by weight of Na2CO3 over a short column (b.p.: 9 1-93 C./40 mbar).10362] Yield: 2999 g (96.9% of theory)10363] ?H NMR (400 MHz, chioroform-d) oe 4.44 (dd, J=8.4, 5.2 Hz, 1H), 4.20 (qd, J=7.1, 1.7 Hz, 2H), 4.05-3.98 (m, 1H), 3.95-3.88 (m, 1H), 2.30-2.19 (m, 1H), 2.06-1.85 (m, 3H), 1.29 (t, J=7.1 Hz, 3H)10364] ?3C NMR (101 MHz, CDC13) oe 173.38, 76.80,69.33, 60.87, 30.20, 25.27, 14.24 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sulfuric acid; for 16h;Heating / reflux; | To a solution of TETRAHYDROFURAN-2-CARBOXYLIC acid (20 g, 172. 2356 MMOL) in anhydrous ethanol (100 mL) was added concentrated sulfuric acid (0. 46 mL). The resulting mixture was stirred at reflux for 16 hours and then allowed to cool to ambient temperature. To this was added water (100 mL) and extracted with diethyl ether (3x100 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2X50 mL), saturated aqueous sodium chloride (100 ML), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the pure product as a colorless liquid (22. 5964 g, 91 %). LRMS (m/z) : 145 (M+H) +. 'H NMR (CDCI3, 300 MHz) 4. 38 (1H, dd, J= 4. 9, 8. 1 HZ), 4. 14 (2H, q, J= 7. 2 Hz), 3. 99-3. 92 (1 H, m), 3. 88-3. 81 (1 H, M), 2. 24-2. 12 (1 H, M), 2. 00-1. 79 (3H, m), 1. 22 (3H, t, J=7. 2Hz). |
With sulfuric acid; at 80℃; for 6h; | Step 1: Synthesis of ethyl tetrahydrofuran-2-carboxylate:To a stirred solution of tetrahydrofuran-2-carboxylic acid (about 10 g) in ethanol (150 ml), sulfuric acid (about 10 ml) was added and refluxed for 6 hours at 80 C. Completion of the reaction was monitored by TLC, reaction mixture was evaporated under reduced pressure, the residue was taken in water, neutralized with saturated NaHC03 and extracted with DCM, the organic layer was dried over a2S04 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% ethyl acetate in hexane as eluent to furnish the title compound (12 g) as a light yellow liquid. NMR (300 MHz, CDC13): 1.22- 1.27 (m, 3H); 1.57- 1.87 (m, 8H); 2.65-2.76 (m, 1H); 4.08-4.15 (m, 2H); ES Mass: [M+l ] 143 (100%). | |
With thionyl chloride; at 0 - 20℃; for 2h; | Example 228 - Preparation of Intermediate 55 The synthesis of Intermediate 55 followed the procedure of General Procedure 7 following: Intermediate 55 To a cooled solution (0C) of tetrahydrofuran-2-carboxylic acid (5.8 g, 43 mmol) in Ethanol (40 mL) was added thionyl chloride (9.6 mL, 129 mmol). After stirring at this temperature for 2 hours, the mixture was concentrated under reduced pressure. The mixture was diluted with water (20 mL) and extracted into Diethyl ether (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give ethyl tetrahydrofuran-2-carboxylate (Intermediate 55, 6 g, yield: 96%) as an oily residue that was used without further purification into the next step. m/z 145.03 [M+H]+; TLC System: 10% Methanol- dichloromethane; Rf-0.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Sodium (bis) trimethylsilyl amide (3. 18 mL of 1M solution in tetrahydrofuran, 3. 18 MMOL) was added dropwise to a solution of ethyl 2-tetrahydrofuranoate (0. 458 g, 3. 18 MMOL) in anhydrous tetrahydrofuran (4 mL) at-50 C. The mixture was stirred for 45 minutes and then a solution of 5- (iodomethyl)-2- [2- (5-methyl-2- phenyl-1, 3-oxazol-4-yl) ethoxy] pyridine (Preparation 28) (0. 267 g, 0. 64 MMOL) in anhydrous tetrahydrofuran (2 mL) was added dropwise. The resulting mixture was stirred at-50 C for 1. 5 hours then quenched with saturated aqueous ammonium chloride and warmed to ambient temperature. The mixture was extracted with ethyl acetate and the organic phase dried (anhydrous magnesium sulfate), filtered and evaporated. The residue was purified by flash column chromatography (25% to 35% ethyl ACETATE/HEXANES) to yield the title compound as a colorless oil (0. 250 G, 90%). LRMS (m/z) : 437 (M+H) +. H NMR (CDCI3, 300 MHz) 7. 95 (3H, m), 7. 51 (1H, dd, J = 2. 5, 8. 5 Hz), 7. 43-7. 36 (3H, m), 6. 61 (1H, D, J = 8. 5 Hz), 4. 51 (2H, t, J = 6. 8 Hz), 4. 29-4. 18 (9 H, M), 413 (2H, q, J = 7. 2 HZ), 3. 95-3. 82 (2H, m), 3. 10 (1H, d, J = 14. 1 HZ), 2. 95 (2H, T, J = 6. 8 Hz), 2. 86 (1 H, D, J = 14. 1 Hz), 2. 31 (3H, s), 2. 26-2. 20 (1 H, M), 1. 92-1. 77 (2H, m), 1. 70-1. 61 (1H, m), 1. 21 (3H, t, J= 7. 2 HZ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With ammonium chloride; lithium diisopropyl amide; In tetrahydrofuran; n-heptane; ethylbenzene; ethyl acetate; | Preparation c-81 Ethyl 2-[(6-bromopyridin-3-yl)methyl]tetrahydrofuran-2-carboxylate To a solution of <strong>[16874-34-3]ethyl tetrahydrofuran-2-carboxylate</strong> (52.9 mmol, 9.10 g, 1.5 eq.) cooled to -78 degrees C. in THF (90 mL) was added dropwise a solution of 2 M lithium diisopropylamide (52.9 mmol, 1.5 eq.) in a mixture of heptane/THF/ethylbenzene. The enolate was allowed to form for one hour at the same low temperature whereupon a solution of 2-bromo-5-(bromomethyl)pyridine (35.3 mmol, 8.85 g, 1.0 eq.) in THF was added dropwise. The reaction was allowed to warm slowly to room temperature overnight. The reaction was quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate and the organic extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow oil. This crude product was purified on a Biotage Sp4 65i over a gradient of 5% to 95% ethyl acetate in hexanes to afford a golden oil (8.70 g, 78%). LRMS: 315 (M+H)+. 1H NMR (DMSO-d6, 400 MHz): delta 8.21 (1 H, s) 7.40-7.49 (2 H, m) 3.94 (2 H, q, J=7.0 Hz) 3.71-3.85 (2 H, m) 3.05-3.11 (1 H, m) 2.91-2.97 (1 H, m) 2.38-2.47 (1 H, m) 1.83-2.09 (3 H, m) 1.09 (3 H, t, J=7.0 Hz) |
78% | To a solution of <strong>[16874-34-3]ethyl tetrahydrofuran-2-carboxylate</strong> (52. 9 mmol, 9. 10 g, 1. 5 eq.) cooled to-78 degrees C in THF (90 mL) was added dropwise a solution of 2 M lithium DIISOPROPYLAMIDE (52. 9 mmol, 1. 5 eq.) in a mixture of heptane/THF/ethylbenzene. The enolate was allowed to form for one hour at the same low temperature whereupon a solution of 2-BROMO-5- (BROMOMETHYL) pyridine (35. 3 MMOL, 8. 85 g, 1. 0 eq.) in THF was added dropwise. The reaction was allowed to warm slowly to room temperature overnight. The reaction was quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate and the organic extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow oil. This crude product was purified on a Biotage SP4 65i over a gradient of 5% to 95 % ethyl acetate in hexanes to afford a golden oil (8. 70 g, 78%). LRMS : 315 (M+H) T. H NMR (DMSO-D6, 400 MHz) :. 8. 21 (1 H, s) 7. 40-7. 49 (2 H, m) 3. 94 (2 H, q, J=7. 0 Hz) 3. 71-3. 85 (2 H, m) 3. 05-3. 11 (1 H, m) 2. 91-2. 97 (1 H, m) 2. 38-2. 47 (1 H, m) 1. 83-2. 09 (3 H, m) 1. 09 (3 H, t, J=7. 0 HZ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sulfuric acid; In ethanol; water; | Preparation c-90 Ethyl tetrahydrofuran-2-carboxylate To a solution of tetrahydrofuran-2-carboxylic acid (20 g, 172.2356 mmol) in anhydrous ethanol (100 mL) was added concentrated sulfuric acid (0.46 mL). The resulting mixture was stirred at reflux for 16 hours and then allowed to cool to ambient temperature. To this was added water (100 mL) and extracted with diethyl ether (3*100 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (2*50 mL), saturated aqueous sodium chloride (100 mL), dried (anhydrous magnesium sulfate), filtered and concentrated in vacuo to afford the pure product as a colorless liquid (22.5964 g, 91%). LRMS (m/z): 145 (M+H)+. 1H NMR (CDCl3, 300 MHz) delta 4.38 (1H, dd, J=4.9, 8.1 Hz), 4.14 (2H, q, J=7.2 Hz), 3.99-3.92 (1H, m), 3.88-3.81 (1H, m), 2.24-2.12 (1H, m), 2.00-1.79 (3H, m), 1.22 (3H, t, J=7.2 Hz). |
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