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Structure of 135072-32-1

Chemical Structure| 135072-32-1

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Product Details of [ 135072-32-1 ]

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

Safety of [ 135072-32-1 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 135072-32-1 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

38.77 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.66
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.71
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

0.92
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.27
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

2.1
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.73

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.38
Solubility 1.04 mg/ml ; 0.00417 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.14
Solubility 1.81 mg/ml ; 0.00725 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-3.24
Solubility 0.142 mg/ml ; 0.00057 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.61 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.61

Application In Synthesis of [ 135072-32-1 ]

* 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.

  • Downstream synthetic route of [ 135072-32-1 ]

[ 135072-32-1 ] Synthesis Path-Downstream   1~12

  • 1
  • [ 64-17-5 ]
  • [ 147767-51-9 ]
  • [ 135072-32-1 ]
YieldReaction ConditionsOperation 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%).
  • 3
  • [ 135072-32-1 ]
  • [ 107904-07-4 ]
  • 4
  • [ 1030837-46-7 ]
  • [ 135072-32-1 ]
  • 6
  • [ 24424-99-5 ]
  • [ 135072-32-1 ]
  • [ 768371-16-0 ]
YieldReaction ConditionsOperation 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).
  • 7
  • [ 135072-32-1 ]
  • [ 852237-31-1 ]
YieldReaction ConditionsOperation 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
  • 8
  • [ 135072-32-1 ]
  • [ 480438-46-8 ]
  • [ 852237-12-8 ]
YieldReaction ConditionsOperation 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
  • 9
  • [ 135072-32-1 ]
  • [ 852237-31-1 ]
  • [ 941710-14-1 ]
YieldReaction ConditionsOperation 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).
  • 10
  • [ 135072-32-1 ]
  • [ 76-05-1 ]
  • [ 1111640-52-8 ]
YieldReaction ConditionsOperation 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).
  • 11
  • [ 5725-96-2 ]
  • [ 75-24-1 ]
  • [ 135072-32-1 ]
  • [ 852237-32-2 ]
YieldReaction ConditionsOperation 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.
  • 12
  • [ 5725-96-2 ]
  • [ 135072-32-1 ]
  • [ 852237-32-2 ]
YieldReaction ConditionsOperation 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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Technical Information

Categories

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