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Chemical Structure| 1012341-50-2 Chemical Structure| 1012341-50-2

Structure of 1012341-50-2

Chemical Structure| 1012341-50-2

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Product Details of [ 1012341-50-2 ]

CAS No. :1012341-50-2
Formula : C23H29NO4
M.W : 383.48
SMILES Code : O=C(O)[C@H](C)C[C@H](NC(OC(C)(C)C)=O)CC1=CC=C(C2=CC=CC=C2)C=C1
MDL No. :MFCD27955981
InChI Key :YNELJETWNMPEEH-UZLBHIALSA-N
Pubchem ID :46193546

Safety of [ 1012341-50-2 ]

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

Computational Chemistry of [ 1012341-50-2 ] Show Less

Physicochemical Properties

Num. heavy atoms 28
Num. arom. heavy atoms 12
Fraction Csp3 0.39
Num. rotatable bonds 10
Num. H-bond acceptors 4.0
Num. H-bond donors 2.0
Molar Refractivity 111.2
TPSA ?

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

75.63 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

3.39
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

5.0
Log Po/w (WLOGP)?

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

4.9
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.

3.83
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

4.43
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

4.31

Water Solubility

Log S (ESOL):?

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

-5.02
Solubility 0.00362 mg/ml ; 0.00000945 mol/l
Class?

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

Moderately soluble
Log S (Ali)?

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

-6.33
Solubility 0.00018 mg/ml ; 0.00000047 mol/l
Class?

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

Poorly 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

-6.47
Solubility 0.00013 mg/ml ; 0.00000034 mol/l
Class?

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

Poorly 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

No
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

Yes
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

Yes
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

Yes
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

Yes
Log Kp (skin permeation)?

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

-5.09 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.

0.56

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<3.0
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)

3.68

Application In Synthesis of [ 1012341-50-2 ]

* 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 [ 1012341-50-2 ]

[ 1012341-50-2 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 1012341-48-8 ]
  • [ 1012341-50-2 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogen; under 15001.5 - 18751.9 Torr; 7) To 61.4g (R, E) -5-([1,1'-biphenyl] -4-yl) -4-((tert-butoxycarbonyl) amino) -2-methyl-2-pentene acidHydrogen is introduced (hydrogen partial pressure is 2-2.5 MPa), and hydrogenation catalyzes to obtain 55.2g (2R, 4S) -5- (biphenyl-4-yl) -4-[(Tert-butoxycarbonyl) amino] -2-methylpentanoic acid;(90% yield);
86.9% With hydrogen;diiodo(p-cymene)ruthenium(II) dimer; (SP,S?P)-1,1?-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2?-bis[(R)-alpha-(dimethylamino)benzyl]ferrocene; In ethanol; at 40.0℃; under 15001.5 Torr; for 6.0h;Product distribution / selectivity; Example 2: (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid in crystalline form; [Show Image] To a suspension of <strong>[1012341-48-8](E)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid</strong> (200 g, 524.3 mmol) in degassed ethanol (900 ml) at 40 C a solution of diiodo(p-cymene)ruthenium(II) dimer (0.052 g, 0.0524 mmol) and (alphaR,alphaR)-2,2'-bis(alpha-N,N-dimethylaminophenylmethyl)-(S,S)-1,1'-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene (= Mandyphos SL-M004-1) (0.116 g, 0.110 mmol) was added in degassed ethanol (100 ml). The solution was degassed using vacuum and a pressure of 20 bar hydrogen applied. The mixture was stirred at 40 C for 6 h. Vessel was then purged with nitrogen. Ethanol (700 ml) was removed by distillation. Isopropyl acetate (600 ml) was added. Solvent (600 ml) was removed by distillation. Isopropyl acetate (600 ml) was added. Solvent (600 ml) was removed by distillation. Isopropyl acetate (300 ml) was added and the solution heated to reflux. Heptane fraction (1200 ml) was added and the mixture cooled to room temperature. The solid was collected by filtration and washed with heptane fraction-isopropyl acetate 2 : 1 mixture (360 ml). The solid was dried overnight at 50 C under 1-50 mbar vacuum to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (174.7 g, 86.9 %) as a white/off-white solid. Mpt 146-147 C; deltaH (500 MHz; DMSO) 1.07 (3H, d, J 7.0, 1-CH3), 1.34 (9H, s, (CH3)3), 1.38 (1H, m, 3-HA), 1.77 (1H, m, 3-HB), 2.43 (1H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H), 3.69 (1H, m, 4-H), 6.74 (1H, d, J 9.0, NH), 7.27 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.36 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-ortho-H), 12.01 (1H, s, CO2H); deltac (500 MHz, DMSO) 18.1 (1-CH3), 28.3 [(CH3)3], 35.9 (2-C), 37.9 (3-C), 40.7 (5-C), 50.0 (4-C), 77.4 [(C(CH3)3], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar-CH), 137.7 (Ar-ipso-C(Ph)), 138.3 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.2 (NCO), 177.2 (CO2H); mlz (+ESI) 406 ([MNa]+, 6%), 384 ([MH]+, 31), 328 (100), 284 (19); Found: [MH]+, 384.21691. C23H30NO4 requires MH 384.21693. Figure 1 shows the structure of crystalline (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid measured by x-ray diffraction. The crystals comprise the following unit cell dimensions, measured by 100 K:
73.8% With palladium 10% on activated carbon; hydrogen; In ethanol; at 25.0℃; under 7500.75 Torr; for 20.0h; (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methyl-pentane was added to the hydrogenation vessel with stirring. 2-enoic acid (Compound III) (75 g, 0.20 mol), 10% palladium on carbon (Pd/C) (3.0 g) and 750 ml of ethanol,Hydrogen was introduced and allowed to react (1.0 MPa, 25 C) for 20 hours. Filter and concentrate to dryness,It was recrystallized by adding an appropriate ratio of isopropyl acetate/petroleum ether, and dried to give a white solid (Compound II).
With diiodo(p-cymene)ruthenium(II) dimer; (SP,S?P)-1,1?-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2?-bis[(R)-alpha-(dimethylamino)benzyl]ferrocene; hydrogen; sodium hydroxide; In dichloromethane; water; at 60.0℃; under 30003 Torr; for 16.0h;Autoclave; Ionic liquid; Inert atmosphere; General procedure: [Ru(p-cimene)I2]2 (4.85 mg; 4.96 mumol) and (SP,S?P)-1,1?-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2?-bis[(R)-alpha-(dimethylamino)benzyl]ferrocene (Mandyphos, SL-M004-1) (12.0mg; 11.4 mumol) were weighted in two Schlenk tubes inside a glovebox. The Ru precursor was dissolved in CH2Cl2 (5 mL) and the resulting solution was transferred into the Schlenk tube containing the ligand and stirred at r.t. for 1 h. The ionic liquid 1-ethyl-3-methylimidazoliumbis(trifluoromethylsulfonyl)imide [EMIM][NTf2] (5 mL) was added and the CH2Cl2 was slowly evaporated under vacuum. An aliquot of this solution (0.2 mL) was diluted with additional [EMIM][NTf2] (1.8 mL) and the solution was transferred into a 13 mL window autoclave. (R)-1-CO2H (100 mg; 262 mumol) was dissolved in a basic aqueous solution (4 mL, pH 13) (see table 2 for detail) and transferred into the autoclave. The autoclave was heated to reaction temperature and pressurized with H2 (40 bar). The reaction was started by magnetic agitation. After 16 h, the autoclave was cooled to r.t. and gently vented. The upper water phase was removed with a needle and neutralized with an HCl solution (1 M), the white solid precipitated was collected by filtration and analyzed by HPLC.
With diiodo(p-cymene)ruthenium(II) dimer; hydrogen; In ethanol; under 22502.3 Torr; for 20.0h; Step 3 0.07853 mol of compound II was added to 130 g of absolute ethanol and 0.030 g of [RuI2] 2 and 0 ? 120 g Mandyphos chiral ligands were added. The hydrogen pressure was 3·0 MPa, and the pressure was stirred for 20 hours. Rate of 95.05%.
340 g With bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; N,N?-(1S,2S)-cyclohexane-1,2-diylbis[2-(diphenylphosphino)-1-naphthamide]; hydrogen; In ethanol; at 40.0℃; under 11251.1 Torr;Autoclave; To the autoclave is sequentially added in the Embodiment 3: (R, E) -5 - ([1, 1' - biphenyl] -4 - yl) -4 - ((tert-butoxy carbonyl) amino) -2 - methyl -2 - pentenoic acid 381g, ethanol 3.5 kg, double-(dicyclopentadiene) tetra fluoborate rhodium 99 mg and phosphine CK - 04 279 mg, replacing hydrogen, pressure 15 kg, temperature 40 C, stirring to LC in the control reaction is complete, filtering, crude job the filtrate turns on lathe, chiral analysis of II:III=90 the two isomers: 10. The crude product of ethyl acetate and petroleum ether beating, then using ethanol recrystallization, the crude product of ethyl acetate and petroleum ether beating, to obtain the product (2R, 4S) -5 - ([1, 1' - biphenyl] -4 - yl) -4 - ((tert-butoxy carbonyl) amino) -2 - methyl valeric acid 340g

  • 2
  • [ 1012341-48-8 ]
  • (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid [ No CAS ]
  • [ 1012341-50-2 ]
YieldReaction ConditionsOperation in experiment
With diiodo(p-cymene)ruthenium(II) dimer; (SP,S?P)-1,1?-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2?-bis[(R)-alpha-(dimethylamino)benzyl]ferrocene; hydrogen; In dichloromethane; water; at 60.0℃; under 45004.5 Torr; for 16.0h;Autoclave; Ionic liquid; Inert atmosphere; General procedure: [Ru(p-cimene)I2]2 (4.85 mg; 4.96 mumol) and (SP,S?P)-1,1?-bis[bis(4-methoxy-3,5-dimethylphenyl)phosphino]-2,2?-bis[(R)-alpha-(dimethylamino)benzyl]ferrocene (Mandyphos, SL-M004-1) (12.0mg; 11.4 mumol) were weighted in two Schlenk tubes inside a glovebox. The Ru precursor was dissolved in CH2Cl2 (5 mL) and the resulting solution was transferred into the Schlenk tube containing the ligand and stirred at r.t. for 1 h. The ionic liquid 1-ethyl-3-methylimidazoliumbis(trifluoromethylsulfonyl)imide [EMIM][NTf2] (5 mL) was added and the CH2Cl2 was slowly evaporated under vacuum. An aliquot of this solution (0.2 mL) was diluted with additional [EMIM][NTf2] (1.8 mL) and the solution was transferred into a 13 mL window autoclave. (R)-1-CO2H (100 mg; 262 mumol) was dissolved in a basic aqueous solution (4 mL, pH 13) (see table 2 for detail) and transferred into the autoclave. The autoclave was heated to reaction temperature and pressurized with H2 (40 bar). The reaction was started by magnetic agitation. After 16 h, the autoclave was cooled to r.t. and gently vented. The upper water phase was removed with a needle and neutralized with an HCl solution (1 M), the white solid precipitated was collected by filtration and analyzed by HPLC.
 

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