Structure of 135072-32-1
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CAS No. : | 135072-32-1 |
Formula : | C14H19NO3 |
M.W : | 249.31 |
SMILES Code : | O=C(C1CN(CC2=CC=CC=C2)CCO1)OCC |
MDL No. : | MFCD14584462 |
InChI Key : | JDVADOGJQJZIOJ-UHFFFAOYSA-N |
Pubchem ID : | 15651196 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 18 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.5 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 72.12 |
TPSA ? Topological Polar Surface Area: Calculated from |
38.77 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.66 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.71 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.92 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.27 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.1 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.73 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.38 |
Solubility | 1.04 mg/ml ; 0.00417 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.14 |
Solubility | 1.81 mg/ml ; 0.00725 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.24 |
Solubility | 0.142 mg/ml ; 0.00057 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 |
-6.61 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) |
2.61 |
* 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 |
---|---|---|
87% | 4-Benzyl-morpholihe-2-carboxylic acid ethyl ester (1); A stirred solution of 4-benzyl-morpholine-2-carbonitrile (113.0 g, 0.56 mol) in ethanol (1030 mL) is treated with concentrated sulphuric acid (165 mL) added in portions. (exothermic, internal temperature rises from ambient to 65 C). The mixture is then warmed under reflux for 66hrs. The solution is cooled and then concentrated in vacuo to half volume, basified with aqueous potassium carbonate (beware frothing) and the product extracted into diethyl ether. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness in vacuo to yield an oil. This material is evacuated further under high vacuum. Yield = 121. 3g (87%). | |
87% | Alternatively, compound 1 may be synthesised as follows: A 100 L reactor attached to a scrubber filled with IN NaOH (60 L) is charged under nitrogen atmosphere with 4-benzyl-morpholine-2-carbonitrile (1867 g, 9.23 mol) and ethanol (20 L). At Tmass = 15-20C, concentrated sulfuric acid (2.76 L, 50 mol) is added to the solution over 20 min (highly exothermic). The solution is heated to reflux for 2.5 days. Then, 10 L of solvent is distilled off under vacuum and the reaction mixture is cooled to Tmass = 20-25C. Water (40 L) is added over 25 min followed by Na2C03 solution (1/2 saturated, 18 L) and NaHC03 (1/2 saturated, 7 L) to reach a pH-7. Ethyl acetate is added (15 L) and the phases are mixed for 15 min. The organic phase is separated and the aqueous phase is extracted with ethyl acetate (2x10 L). The combined organic layers are evaporated to dryness under vacuum to give 1 as a yellow to brown oil (1992g, 87%) | |
87% | With sulfuric acid; at 20 - 65℃; for 66h;Heating / reflux; | A stirred solution of 4-benzyl-morpholine-2-carbonitrile (113. 0g, 0.56mole) in ethanol (1030ml) is treated with concentrated sulphuric acid (165ml) added in portions. (exothermic, internal temperature rises from ambient to 65 C). The mixture is then warmed under reflux for 66hrs. The solution is cooled and then concentrated in vacuo to half volume, basified with aqueous potassium carbonate (beware frothing) and the product extracted into diethyl ether. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness in vacuo to yield an oil. This material is evacuated further under high vacuum. Yield = 121.3g (87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2,5-dihydrotoluene;palladium 10% on activated carbon; In ethanol; at 88℃; for 34h; | A mixture of <strong>[135072-32-1]4-phenylmethyl-2-morpholinecarboxylic acid ethyl ester</strong> (J. Med. Chem. 1993, 36 (6), 683-9), (8.4 g, 32.4 MMOL), di-tert-butyl dicarbonate (8.47 g, 38.9 mmol), 1-methyl- 1, 4-CYCLOHEXADIENE (12.37 ML, 110 MMOL) and 10% palladium on charcoal (900 mg) in ethanol (330 ml) was heated to 88 C for 22 hours. TLC analysis showed starting material remaining, so the reaction was cooled, and additional 1-methyl-1, 4-cyclohexadiene (2.37 ml, 21 MMOL) and 10% palladium on charcoal (900 mg) were added, and the reaction mixture heated for a further 12 hours at 88 C. The cooled mixture was filtered through ARBOCELE and the filtrate evaporated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using an elution gradient of DICHLOROMETHANE : methanol (100: 0 to 95: 5) to give the title compound as a pale yellow oil, 5. 97 G. 'H NMR (400MHZ, CDCI3) : 8 1. 30 (t, 3H), 1.43 (s, 9H), 3.10 (m, 2H), 3.50-3. 70 (m, 2H), 4.01 (m, 1 H), 4.25 (q, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Resolution of racemate;Purification / work up; | -Benzyl-morpholine-2-carboxylic acid ethyl ester (lb); Compound 1 may be separated into its enantiomers by chiral HPLC under the following conditions: Daicel Chiralpak OJ 20, um ; 25cm; 100 % EtOH + 0.3 % DMEA; 0.4 mL/min; detection at 260 nm. The desired enantiomer lb is the peak eluting at RT = 20. 25 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 33: Preparation of 1,3-Bis-(2-methoxy-phenyl)-2-morpholin-2-yl-propan-2- ol hydrochloride (79). 2-(4-benzyl-morpholin-2-yl)-1, 3-his-(2-methoxy-phenyl)-propan-2-ol (78); Add a solution of <strong>[135072-32-1]4-benzyl-morpholine-2-carboxylic acid ethyl ester</strong> (1.12 g, 4.49 mmol) in tetrahydrofuran (5 mL) to a stirred solution of 2-methoxybenzylmagnesium chloride (54 mL, 0.25M solution in tetrahydrofuran, commercially available from Rieke Metals) at - 10C under nitrogen atmosphere. After 1 hour, add a saturated aqueous solution of sodium bicarbonate and extract with diethyl ether. Combine the organic layers and extract with brine, dry over magnesium sulfate, filter, and concentrate under reduced pressure to give a residue to be taken forward without further purification. MW 447. 58 ; C28H33NO4 ; LCMS (12 minute method): m/z) =448.2 [M+H] +) RT 4.8 min. 1, 3-Bis-(2-methoxy phenyl)-2-morpholin-2-yl-propan-2-ol hydrochloride (79) HO To a solution of 78 (2.2 g, 5 mmol) in EtOH (30 mL) under nitrogen atmosphere add ammonium formate (3.1 g, 50 mmol) followed by palladium on charcoal (10 %, 2.2 g). Stir and heat at reflux the resulting suspension for an hour. Allow the reaction mixture to cool to room temperature and then filter it through Celite . Wash the Celite X) with copious amounts of ethanol, combine the organic layers and concentrate under reduced pressure to obtain a residue. Purify and resolve the residue by Chiral HPLC to give 79 ; MW 393.91 ; C21H27NO4. HCl, lH NMR (DMSO-D6) : 8 2.41-2. 52 (m, 1H), 2.61-2. 78 (m, 1H), 2. 85-3. 44 (m, 8H), 3.50-3. 65 (m, 1H), 3.7 (s, 3H), 3.79 (s, 3H), 4.00-4. 12 (m, 1H), 6. 79-7. 01 (m, 4H), 7. 07-7. 25 (m, 3H), 7. 26-7. 35 (m, 1H) ; LCMS (12 minute method) : m/z 358. 1 [M-HC1+H]) RT 4.6 min single major peak |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Resolution of racemate;Purification / work up; | Resolution into the pure enantiomers was performed by preparative etaPLC using isocratic elution on Chiralcel OJ at 60 mL /mi, eluting with 20% ethanol, 20% methanol and 60% hexanes with 1 mL/L diethylamine as modifier. Under these conditions, the (R)-(-)-isomer elutes first. (-)-Ethyl (2J?)-4- benzylmorpholine-2-carboxylate: [alpha]D25 c= -31.75 (c = 2.0, MeOH) MS (m+1) = 179.1; 1eta nuMR (400 MHz, CDC13) 7.3 (m, 5H), 4.22 (q, 2H), 4.02 (dt, IH), 3.7 (td, IH), 3.5 (dd, IH), 2.22 (m, 2H), 2.95 (d, IH), 2.6 (d, IH), 2.4-2.3 (m, 2H), 1.3 (t, 3H). (+)-Ethyl (2S)-4-benzylmorpholine-2-carboxylate: [alpha]D25 c = +32.1 (c = 2.3, MeOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen;palladium on activated charcoal; In ethanol; at 25℃; for 4h; | Intermediate 16: Ethyl morpholine-2-carboxylate trifluoroacetate salt. A suspension of ethyl 4-(phenylmethyl)-2-morpholinecarboxylate (prepared according to procedure described on J. of Med. Chem. 1993, vol. 36, No. 6, 683-689) (900 mg, 3.61 mmol), TFA (0.278 ml_, 3.61 mmol), and Pd/C (150 mg, 1.410 mmol) in EtOH (15 ml), was degassed four times under nitrogen and then degassed three times under H2. The reaction mixture was left stirring under H2 at 250C for 4h. MS monitor showed the reaction was complete.The reaction mixture was filtered and solvent was removed to give the title compound (950 mg); m/z (ES): 160 [M+H]+; 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 10.5(bs, 1 H) 4.53- 4.50 (m, 1 H) 4.33-4.27 (q, 2 H) 4.22-4.19 (m, 1 H) 4.05-3.98 (m, 1 H) 3.79-3.74 (m, 1 H) 3.65-3.61 (m, 1 H) 3.34-3.31 (m, 1 H) 3.24-3.18 (m, 1 H) 1.35-1.32 (t, 2 H) 1.29-1.25 (t, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | 4-Benzyl-morpholine-2-carboxylic acid metho. xy-methyl-amide (2); To a stirred suspension of N, N dimethylhydroxylamine (6.6 g, 67.6 mmol) in anhydrous DCM (200 mL) under nitrogen at 0C is added dropwise a solution of trimethylaluminium (2M solution in hexane, 34 mL, 67.6 mmol) over 30 minutes. The reaction mixture is allowed to warm up to room temperature and left stirring for 1 hour. A solution of the ester 1 (6.74 g, 27 mmol) in anhydrous DCM (100 mL) is then added dropwise over 30 minutes and the reaction mixture is left stirring overnight before quenching by cautious addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution. The precipitate is removed by filtration through a celite pad and the residue washed with chloroform. The organic phase is then concentrated in vacuo and washed with water. The aqueous layer is re-extracted with chloroform and the organic phases are combined, washed with brine, dried over magnesium sulphate and the solvent evaporated in vacuo to give 2 as a yellow oil. Alternatively, the reaction could be worked up as follows: upon addition of a solution of the ester 1 (1 eq) the reaction mixture is left stirring for 1 hour before quenching by addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution, followed by addition of water. The aqueous layer is re- extracted with DCM and the organic phases are combined, dried over magnesium sulphate and the DCM evaporated in vacuo to give 2 as a yellow oil (3.36 g, 47 %). MW 264.33 ; Cl4H20N203 ; lH NMR (CDC13) : 7.47-7. 22 (SH, m), 4.55 (1H, d, 1.5 Hz), 4.00 (1H, dd, 11.5 Hz, 1.7 Hz), 3.75 (1H, dt, 11.5 Hz, 2.2 Hz), 3.65 (3H, s), 3. 56 (2H, m), 3.17 (3H, s), 2.93 (1H, d, 11.3 Hz), 2.68 (1H, d, 11.3 Hz), 2.30 (2H, 11.3 Hz); LCMS: (6 min method) m/z 265 [M+H] +, RT 0.65 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | To a stirred suspension of N, N dimethylhydroxylamine (6.6 g, 67.6 mmol) in anhydrous DCM (200 ml) under nitrogen at 0C is added dropwise a solution of trimethylaluminium (2M solution in hexane, 34 ml, 67.6 mmol) over 30 minutes. The reaction mixture is allowed to warm up to room temperature and left stirring for 1 hour. A solution of the ester la, 1b (6.74 g, 27 mmol) in anhydrous DCM (100 ml) is then added dropwise over 30 minutes and the reaction mixture left stirring overnight before quenching by cautious addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution. The precipitate is removed by filtration through a celite pad and the residue washed with chloroform. The organic phase is then concentrated in vacuo and washed with water. The aqueous layer is re-extracted with chloroform and the organic phases are combined, washed with brine, dried over magnesium sulphate and the solvent evaporated in vacuo to give 2a, 2b as a yellow oil. Alternatively, the reaction could be worked up as follows: upon addition of a solution of the ester la, lb (1 eq) the reaction mixture is left stirring for 1 hour before quenching by addition of phosphate buffer (disodium hydrogen phosphate, pH 8) solution, followed by addition of water. The aqueous layer is re- extracted with DCM and the organic phases are combined, dried over magnesium sulphate and the DCM evaporated in vacuo to give 2a, 2b as a yellow oil (3.36 g, 47 %). MW 264.33 ; C14H20N2O3; 1H NMR (CDC13) : 7.47-7. 22 (5H, m), 4.55 (1H, d, 1.5 Hz), 4.00 (1H, dd, 11.5 Hz, 1.7 Hz), 3.75 (1H, dt, 11.5 Hz, 2.2 Hz), 3.65 (3H, s) 3.56 (2H, m), 3.17 (3H, s), 2.93 (1H, d, 11.3 Hz), 2.68 (1H, d, 11.3 Hz), 2.30 (2H, AB, 11.3 Hz); LCMS: (6 min method) m/z 265 [M+H] +, Rt 0.65 min. |
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