Structure of Cbz-D-Asn-OH
CAS No.: 4474-86-6
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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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 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
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 |
118.72 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.02 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.08 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.09 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.14 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.08 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.22 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.15 |
Solubility | 19.0 mg/ml ; 0.0714 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.96 |
Solubility | 2.91 mg/ml ; 0.0109 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.96 |
Solubility | 2.91 mg/ml ; 0.0109 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 |
No |
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 |
-7.98 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 |
0.56 |
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) |
2.8 |
* 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 |
---|---|---|
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). |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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). |
Yield | Reaction Conditions | Operation 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%). |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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. |
Yield | Reaction Conditions | Operation 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)-. |