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Product Details of [ 174799-52-1 ]

CAS No. :174799-52-1
Formula : C14H22N2O2
M.W : 250.34
SMILES Code : CC(C)(C)OC(=O)NCCNCC1=CC=CC=C1
MDL No. :MFCD04114275
InChI Key :ZSJCBAQDXIZTTC-UHFFFAOYSA-N
Pubchem ID :10634443

Safety of [ 174799-52-1 ]

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

Computational Chemistry of [ 174799-52-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 18
Num. arom. heavy atoms 6
Fraction Csp3 0.5
Num. rotatable bonds 8
Num. H-bond acceptors 3.0
Num. H-bond donors 2.0
Molar Refractivity 72.37
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

50.36 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.13
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

1.99
Log Po/w (WLOGP)?

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

2.15
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.

2.07
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

2.06
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.28

Water Solubility

Log S (ESOL):?

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

-2.36
Solubility 1.08 mg/ml ; 0.00432 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.

-2.67
Solubility 0.531 mg/ml ; 0.00212 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

-4.62
Solubility 0.00601 mg/ml ; 0.000024 mol/l
Class?

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

Moderately 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

Yes
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.

-6.41 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)

2.06

Application In Synthesis of [ 174799-52-1 ]

* 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.

  • Upstream synthesis route of [ 174799-52-1 ]

[ 174799-52-1 ] Synthesis Path-Upstream   1~10

  • 1
  • [ 57260-73-8 ]
  • [ 100-52-7 ]
  • [ 174799-52-1 ]
YieldReaction ConditionsOperation in experiment
92%
Stage #1: at 20℃; Molecular sieve
Stage #2: at -10 - 20℃; for 16 h;
Preparation 63
Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A)
To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3 Å.
After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10° C. (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min.
After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h.
The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL).
The organic layer was extracted with 0.5 N HCl (3*100 mL).
The combined aqueous solution was cooled to 0° C., basified with sat.
NaHCO3 and extracted with CHCl3 (3*100 mL).
The combined organic layers were washed with brine (200 mL).
After drying over MgSO4 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2+H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30.
92%
Stage #1: at 20℃; molecular sieve 3Å
Stage #2: at -10 - 20℃; for 16.5 h;
Example 34: Synthesis of N-((S)-l-{2-[(Dihydrocodein-6-enyloxycarbonyl)-methylamino]- ethylcarbamoyl-4-guanidino}-butyl)-malonamic acid (Compound KC-4)Preparation 63: Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A)To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 °C (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HC1 (3 x 100 mL). The combined aqueous solution was cooled to 0 °C, basified with sat. NaHC03 and extracted with CHC13 (3 x 100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgS04 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2 +H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification.
92%
Stage #1: at 20℃; Molecular sieve 3 Å
Stage #2: With sodium tetrahydroborate In methanol at -10 - 20℃; for 16.5 h; Cooling with ice
Preparation 63: Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A)To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 °C (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HC1 (3 x 100 mL). The combined aqueous solution was cooled to 0 °C, basified with sat. NaHC03 and extracted with CHC13 (3 x 100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgS04 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2 +H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification.
92%
Stage #1: at 20℃; Molecular sieve
Stage #2: at -10 - 20℃; for 16.5 h;
To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL), Benzaldehyde (4.7 g, 44.0 mmol)And molecular sieves 3 Å were added.After stirring overnight at ambient temperature, the mixture was cooled to about -10 ° C. (ice / salt bath) and treated in portions with NaBH 4 (9.1 g, 240.0 mmol) for 30 minutes. After all addition, the bathtub was removed and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was taken up in EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3 × 100 mL). The combined aqueous solution was cooled to 0 ° C., basified with saturated NaHCO 3 and extracted with CHCl 3 (3 × 100 mL). The combined organic layers were washed with brine (200 mL). After drying and filtering over MgSO 4, the solvent was evaporated under reduced pressure to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil.
51%
Stage #1: at 20℃; for 2 h;
Stage #2: at 0 - 20℃;
Example 3Atert-butyl [2-(benzylamino)ethyl]carbamate; 2.0 g (18.4 mmol) benzaldehyde and 3.32 g (20.7 mmol) N-Boc-ethylendiamine are dissolved in 25 ml methanol. The mixture is stirred 2 h at rt before cooled to 00C and 3.57 g (94.2 mmol) sodium borohydride and water are added to generate a solution, which is stirred over night at rt. Solvents are removed in vacuo and the residue is dissolved in dichloromethane and washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by reverse phase HPLC (water / acetonitrile) to afford 2.4 g (51percent of th.) of the title compound.HPLC (method 1): R, = 3.70 min; MS (ESIpos): m/z = 251 (M+H)+1H-NMR (400 MHz, DMSOd6): δ = 7.30 (m, 4H), 7.21 (m, IH), 6.72 (m, IH), 3.68 (s, 2H), 3.02 (m, 2H), 2.53 (m, 2H), 2.08 (bs, IH), 1.37 (s, 9H).
23%
Stage #1: With sodium tris(acetoxy)borohydride; magnesium sulfate; triethylamine In 1,2-dichloro-ethane at 20℃; for 16 h;
Stage #2: With water; sodium hydrogencarbonate In 1,2-dichloro-ethane
To a solution of tert-butyl 2-aminoethylcarbamate (3.7 g, 22.3 mmol), benzaldehyde (2.36 g, 22.3 mmol) and MgSO4 (1.33 g) in 1,2-dicholoroethane (300 mL) and Et3N (3.1 mL, 22.3 mmol) at RT was added NaHB(AcO)3. The mixture was stirred (RT, 16 h) and filtered. The solution was washed with saturated NaHCO3 (200 ml), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with MeOH-DCM (0-10percent) to afford tert-butyl 2-(benzylamino)ethylcarbamate (1.4 g, 23percent). Mass calculated for C14H22N2O2=250.34; found: [M+H]+=251.3.

References: [1] Patent: US2011/262355, 2011, A1, . Location in patent: Page/Page column 135.
[2] Patent: WO2011/133149, 2011, A1, . Location in patent: Page/Page column 297-298.
[3] Patent: WO2011/133150, 2011, A1, . Location in patent: Page/Page column 299-300.
[4] Patent: JP2016/41698, 2016, A, . Location in patent: Paragraph 0364; 0375.
[5] Chemical Communications, 2016, vol. 52, # 63, p. 9837 - 9840.
[6] Journal of Medicinal Chemistry, 2005, vol. 48, # 22, p. 7024 - 7039.
[7] Patent: WO2007/17092, 2007, A1, . Location in patent: Page/Page column 22.
[8] Patent: US2010/41748, 2010, A1, . Location in patent: Page/Page column 120.
[9] Journal of Organic Chemistry, 1997, vol. 62, # 2, p. 411 - 416.
[10] Organic Letters, 2014, vol. 16, # 24, p. 6366 - 6369.
[11] Synthesis (Germany), 2015, vol. 47, # 16, p. 2391 - 2406.
[12] Patent: US2016/168138, 2016, A1, . Location in patent: Paragraph 0120-0121.
[13] Journal of Organic Chemistry, 2016, vol. 81, # 19, p. 8696 - 8709.
  • 2
  • [ 58632-95-4 ]
  • [ 4152-09-4 ]
  • [ 174799-52-1 ]
YieldReaction ConditionsOperation in experiment
96% at 20℃; for 72 h; 55 (15.861 g, 105.58 mmol) was dissolved in eOH at rt. To this stirred solution was added 2-(tert- butoxycarbonyloxyimino)-2-phenylacetonitrile (26.00g, 105.58 mmol, 1 eq), in portions, allowing dissolution before next addition. The resulting yellow solution was stirred at rt for 3 days (over weekend) before removal of all volatiles under reduced pressure. The crude residue was dissolved in EtOAc (300 mL) before washing with aq. 1 NaOH (2 x 100 mL). The combined aqueous layers were again washed with EtOAc (100 mL). Combining and concentrating the organic portions gave 29.8g of crude product. This was further purified by FCC (eluent DCIWPE 1 :1 to load column, continued until impurities wash off, then 100percent DC , followed eOH/DC 1 :1 0). This gave 25.3g (96percent) of pale yellow oil.
References: [1] Patent: WO2012/4549, 2012, A1, . Location in patent: Page/Page column 53.
  • 3
  • [ 19811-52-0 ]
  • [ 174799-52-1 ]
References: [1] Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4131 - 4134.
[2] Patent: WO2003/106405, 2003, A1, . Location in patent: Page 226-230.
[3] Patent: US2004/147454, 2004, A1, . Location in patent: Page 73-74.
  • 4
  • [ 57260-73-8 ]
  • [ 174799-52-1 ]
References: [1] Patent: US2011/262359, 2011, A1, .
  • 5
  • [ 39684-80-5 ]
  • [ 100-46-9 ]
  • [ 174799-52-1 ]
References: [1] Organic Preparations and Procedures International, 2009, vol. 41, # 4, p. 301 - 307.
  • 6
  • [ 57260-73-8 ]
  • [ 100-39-0 ]
  • [ 174799-52-1 ]
References: [1] European Journal of Medicinal Chemistry, 2017, vol. 137, p. 117 - 125.
  • 7
  • [ 250296-58-3 ]
  • [ 4152-09-4 ]
  • [ 174799-52-1 ]
References: [1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 16, p. 2233 - 2234.
  • 8
  • [ 4530-20-5 ]
  • [ 174799-52-1 ]
References: [1] Journal of Organic Chemistry, 1998, vol. 63, # 12, p. 4131 - 4134.
  • 9
  • [ 24424-99-5 ]
  • [ 174799-52-1 ]
References: [1] Journal of Organic Chemistry, 1997, vol. 62, # 2, p. 411 - 416.
  • 10
  • [ 126402-59-3 ]
  • [ 174799-52-1 ]
References: [1] Tetrahedron Letters, 1989, vol. 30, # 32, p. 4241 - 4244.
 

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