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Chemical Structure| 4474-86-6 Chemical Structure| 4474-86-6

Structure of Cbz-D-Asn-OH
CAS No.: 4474-86-6

Chemical Structure| 4474-86-6

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Product Details of [ 4474-86-6 ]

CAS No. :4474-86-6
Formula : C12H14N2O5
M.W : 266.25
SMILES Code : O=C(N)C[C@H](C(O)=O)NC(OCC1=CC=CC=C1)=O
MDL No. :MFCD00065696
InChI Key :FUCKRCGERFLLHP-SECBINFHSA-N
Pubchem ID :1712147

Safety of [ 4474-86-6 ]

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

Computational Chemistry of [ 4474-86-6 ] Show Less

Physicochemical Properties

Num. heavy atoms 19
Num. arom. heavy atoms 6
Fraction Csp3 0.25
Num. rotatable bonds 8
Num. H-bond acceptors 5.0
Num. H-bond donors 3.0
Molar Refractivity 64.6
TPSA ?

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

118.72 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.02
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

-0.08
Log Po/w (WLOGP)?

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

0.09
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.

0.14
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

-0.08
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.22

Water Solubility

Log S (ESOL):?

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

-1.15
Solubility 19.0 mg/ml ; 0.0714 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-1.96
Solubility 2.91 mg/ml ; 0.0109 mol/l
Class?

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

Very 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

-1.96
Solubility 2.91 mg/ml ; 0.0109 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

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

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.

-7.98 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<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)

2.8

Application In Synthesis of [ 4474-86-6 ]

* 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 [ 4474-86-6 ]

[ 4474-86-6 ] Synthesis Path-Downstream   1~28

  • 1
  • [ 4474-86-6 ]
  • [ 2058-58-4 ]
  • 2
  • [ 29880-22-6 ]
  • [ 4474-86-6 ]
  • 4
  • [ 29880-22-6 ]
  • [ 4474-86-6 ]
  • [ 2304-96-3 ]
  • 5
  • [ 4474-86-6 ]
  • [ 6306-52-1 ]
  • [ 17460-89-8 ]
  • 6
  • [ 4474-86-6 ]
  • [ 7146-15-8 ]
  • [ 17460-90-1 ]
  • 7
  • [ 4474-86-6 ]
  • [ 634614-25-8 ]
YieldReaction ConditionsOperation in experiment
6.16 g With bromine; sodium hydroxide; In water; at 55℃; for 3h;Cooling with ice; Under ice-cooling, to a 1M aqueous solution of sodium hydroxide (124 ml) was added dropwise bromine (6.60 ml), and then after adding <strong>[4474-86-6](R)-2-benzyloxycarbonylaminosuccinamic acid</strong> (10.0 g), the mixture was stirred at 55 C. for 3 hours. This reaction solution was cooled to room temperature, washed twice with diethyl ether, and then a 6M aqueous solution of hydrochloric acid (21 ml) was added thereto. This reaction mixture was left to stand at 4 C. for 3 days, and a precipitated solid was collected by filtration to give the titled compound (6.16 g). 1H-NMR (DMSO-D6) delta: 3.19-3.22 (m, 1H), 3.63 (dd, 1H, J=10.2, 5.0 Hz), 4.67 (dd, 1H, J=10.2, 3.3 Hz), 5.14-5.18 (m, 2H), 7.28-7.40 (m, 5H), 7.56 (s, 1H), 13.24 (br s, 1H).
To a solution of [NAOH] (2.48 g, 61.97 mmole) in water (50 ml) at [0C] is added bromine (3.305 g, 20.66 mmole). After 5 min, (R)-NCbz- Asparagine is added to the above solution and the mixture is stirred at [50C] for lh. Addition of 5% Na2S203 and then extraction with Et20 [(1X100] [ML).] The aqueous phase is acidified to pH 2 with 6N [HC1] and the reaction mixture is left in the fridge for 6 days. Filtration of the crystals, and recrystalization in hot water to afford (4R)-3- [ (benzyloxy) carbonyl] -2-oxoimidazolidine-4-carboxylic acid as a white powder. 1H NMR (DMSO-D6) [delta] 7.5-7.2 (M, 5H), 6.5 (SL, 1H), 5.28 (S, 2H), 4.88 (M, 1H), 3.88 (M, 1H), 3.5 (M, 1H) ; MS 263.2 (M-1).
  • 9
  • [ 4474-86-6 ]
  • (R)-2-Benzyloxycarbonylamino-3-cyano-propionic acid [ No CAS ]
  • 11
  • [ 4474-86-6 ]
  • DCC*3pentachlorophenol complex [ No CAS ]
  • [ 31202-36-5 ]
  • 12
  • [ 4474-86-6 ]
  • [ 159002-15-0 ]
  • 13
  • [ 4474-86-6 ]
  • Nα-benzyloxycarbonyl-β-guanidino-D-α-alanine [ No CAS ]
  • 14
  • [ 4474-86-6 ]
  • Nα-benzyloxycarbonyl-β-(2,2,5,7,8-pentamethylchroman-6-sulfonyl)guanidino-D-α-alanine [ No CAS ]
  • 15
  • [ 4474-86-6 ]
  • DCC*3pentachlorophenol complex [ No CAS ]
  • [ 219911-36-1 ]
  • 17
  • [ 4474-86-6 ]
  • 3-amino-N-<(benzyloxy)carbonyl>-D-alanine methyl ester hydrochloride [ No CAS ]
  • 18
  • [ 4474-86-6 ]
  • (3R)-3-(N-Cbz-amino)azolane-2,5-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
With 1-hydroxy-pyrrolidine-2,5-dione; dicyclohexyl-carbodiimide; Intermediate 7; (3R)-3-(N-Cbz-amino)azolane-2,5-dioneCyclisation of N(alpha)-Cbz-D-asparagine (10 g, 37.5 mmol) in the presence of DCC(7.8 g, 37.5 mmol) and N-hydroxysuccinimide (4.4 g, 37.5 mmol) in DMF (50 ml) as described above gave 4.2 g of the product as white solid, mp 66-69 C; 1H NMR (300 MHz, CDC13) delta 6 2.80-2.89 (m, 1 H), 3.04-3.12 (m, 1 H), 4.33-10 4.41 (m, 1 H), 5.11 (s, 2 H), 4.61 (brs, 1 H), 7.34 (s, 5 H), 8.55 (brs, 1 H).
  • 19
  • [ 501-53-1 ]
  • [ 5794-24-1 ]
  • [ 4474-86-6 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; sodium hydrogencarbonate; ethyl acetate; (a) (R)-4-Amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutanoic acid A solution of benzyl chloroformate (58.32 ml., 0.41 mole) in tetrahydrofuran (50 ml.) is added dropwise to a solution of D(-)asparagine hydrate (50 g., 0.33 mole) dissolved in 1 l. of saturated sodium bicarbonate. The solution is allowed to stir at room temperature for 6 hours and then extracted with ethyl acetate (3*200 ml.). The aqueous layer is concentrated in vacuo to remove traces of ethyl acetate, then acidified to pH of 3. A white precipitate is collected and subsequently washed with water and then dried over phosphorus pentoxide to give 74 g. of (R)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutanoic acid, m.p. 206-210.
  • 20
  • [ 4474-86-6 ]
  • [ 352665-38-4 ]
  • 21
  • [ 4474-86-6 ]
  • C20H40N4O7 [ No CAS ]
  • C32H52N6O11 [ No CAS ]
YieldReaction ConditionsOperation in experiment
2.5 g With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 48h; Step 3f: To a stirred solution of <strong>[4474-86-6]Cbz-D-Asn-OH</strong> (1.78 g, 6.7 mmol) and compound 3g (3.0 g, 6.8 mmol) in DMF (75 mL), DCC (4.12 g, 20.3 mmol) and HOBT (1.8 g, 13.5 mmol) were added slowly at 0 C. The reaction mixture was stirred for 48 h at room temperature. Progress of reaction was monitored by TLC. After completion, the reaction mass was partitioned between ethyl acetate and water. Organic layer was washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to yield crude. The crude compound was purified by silica gel (60-120 mesh) column chromatography (Eluent: 4% MeOH in DCM) to yield 2.5 g of Compound 3h, LCMS: 697.50 (M+H)+.
2.5 g With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 48h; To a stirred solution of <strong>[4474-86-6]Cbz-D-Asn-OH</strong> (1.78 g, 6.7 mmol) and compound 3g (3.0 g, 6.8 mmol) in DMF (75 mL), DCC (4.12 g, 20.3 mmol) and HOBT (1.8 g, 13.5 mmol) were added slowly at 0 C. The reaction mixture was stirred for 48 h at room temperature.Progress of reaction was monitored by TLC. After completion, the reaction mass was partitioned between ethyl acetate and water. Organic layer was washed with water, brine,dried over Na2SO4 and evaporated under reduced pressure to yield crude. The crude compound was purified by silica gel (60-120 mesh) column chromatography (Eluent: 4% MeOH in DCM) to yield 2.5 g of Compound 3h, LCMS: 697.50 (M+H).
  • 22
  • [ 4474-86-6 ]
  • [ 77999-24-7 ]
  • 23
  • [ 4474-86-6 ]
  • [ 59760-01-9 ]
YieldReaction ConditionsOperation in experiment
39.4% With bromine; sodium hydroxide; In water; at 55℃; for 3h; Sodium hydroxide (4.51 g, 113 mmol) was dissolved in distilled water (200 mL) and bromine (2.21 g, 0.708 mL,((Benzyloxy) carbonyl) amino) -4-oxobutanoic acid (10.0 g, 37.6 mmol).The resulting reaction was heated to 55 C and stirred for 3 hours.The reaction mixture was then cooled to room temperature and extracted with ethyl acetate (2x50 mL). The separated aqueous phase was adjusted to pH = 1 with 6 M hydrochloric acid. At this point a white solid precipitated and was transferred to a refrigerator and stored overnight at 4 C.Filtration afforded the title compound as a white solid (3.91 g, 39.4%).
  • 24
  • [ 4474-86-6 ]
  • tert-butyl (2-((2S,5R,8S,11S,14S,17S,22S)-22-((S)-2-amino-4-((tert-butoxycarbonyl)amino)butanamido)-5-benzyl-11,14-bis(2-((tert-butoxycarbonyl)amino)ethyl)-17-((R)-1-hydroxyethyl)-8-isobutyl-3,6,9,12,15,18,23-heptaoxo1,4,7,10,13,16,19-heptaazacyclotricosan-2-yl)ethyl)carbamate [ No CAS ]
  • C62H95N13O18 [ No CAS ]
YieldReaction ConditionsOperation in experiment
A solution of Z-D-Asn-OH (87.9 mg, 0.33 mmol) and HOBT hydrate (70.7 mg, 0.463 mmol) in anhydrous DMF (1 mL) was cooled in an ice-water bath. EDC-HCI (76.8 mg, 0.4 mmol) was added, and the resulting mixture was stirred for 15 minutes. It was then added with a solution of INT-1 1 (319 mg, 0.3 mmol) in anhydrous DMF (1 mL) and DIPEA (130 mg, 1 mmol). After the reaction mixture was stirred for 1 hour, it was directly purified through C18 RPLC (50 g, 10 to 90 % MeOH and water). The collected fractions were concentrated by rotary evaporation to a white solid (LCMS: [(M - 2Boc + 2H)/2]+ = 555). The material was re-dissolved in MeOH (~ 15 mL), and the solution was added with Pd/C. The resulting mixture was stirred under hydrogen for 4 hours. Pd/C was filtered off, and the filtrate was concentrated by rotary evaporation to dryness. Yield 1 85.2 mg, 52.5 %. Ion found by LCMS: [(M - Boc + 2H)/2]+ = 538.
  • 25
  • [ 4474-86-6 ]
  • (R)-3-(acetylamino)-2-[[(benzyloxy)carbonyl]amino]propanoic acid [ No CAS ]
  • 26
  • [ 4474-86-6 ]
  • (R)-3-amino-2-[[(benzoyloxy)carbonyl]amino]propanoic acid [ No CAS ]
  • [ 62234-37-1 ]
YieldReaction ConditionsOperation in experiment
With pyridine; bis-[(trifluoroacetoxy)iodo]benzene; In water; N,N-dimethyl-formamide; (b) (R)-3-Amino-2-[[(benzyloxy)carbonyl]amino]propanoic acid [Bis(trifluoroacetoxy)iodo]benzene (6.45 g., 15.0 mmole) is dissolved in water-dimethylformamide 1:1 (80 ml.) and (R)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutanoic acid (2.4 g., 9.0 mmole) is added over a 10 minute period. The reaction is allowed to stir at room temperature for 30 minutes, until dissolution occurs. Pyridine (1.62 ml., 20 mmole) is added dropwise over a 5 minute period. The reaction is allowed to stir for 3 hours then stripped of solvent to yield a yellow precipitate. This semi-solid is triturated with a combination of isopropanol:ethyl ether. The precipitate is filtered and dried over phosphorus pentoxide to yield 1.35 g. of (R)-3-amino-2-[[(benzoyloxy)carbonyl]amino]propanoic acid as a white solid.
  • 27
  • [ 14464-29-0 ]
  • [ 4474-86-6 ]
  • [ 26117-27-1 ]
YieldReaction ConditionsOperation in experiment
N2-Acetyl-D-asparagine The title compound was prepared by conventional methods of peptide chemistry, at first by esterification of N2-[(benzyloxy)carbonyl]-D-asparagine with (2-trimethylsilyl)ethanol with EDCI/DMAP in DCM, followed by hydrogenolytic detachment of the benzyl ester over 10percent palladium/activated carbon in DCM/methanol 1:1, then by reaction with 1-acetoxypyrrolidine-2,5-dione in the presence of N,N-diisopropylethylamine and finally by detachment of the Teoc protecting group by stirring at 50° C. with 6 equivalents of zinc chloride in trifluoroethanol for 1 h. LC-MS (Method 1): Rt=0.15 min; MS (ESIneg): m/z=173 (M-H)-.
  • 28
  • [ 4474-86-6 ]
  • N-acetyl-D-asparaginyl-N1-{(2S)-4-[{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-pyrrol-2-yl]-2,2-dimethylpropyl}(glycoloyl)amino]-1-[(2-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)acetyl]-amino} ethyl)amino]-1-oxobutan-2-yl}-L-aspartamide [ No CAS ]
 

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