Structure of Boc-Pro-NH2
CAS No.: 35150-07-3
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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. : | 35150-07-3 |
Formula : | C10H18N2O3 |
M.W : | 214.26 |
SMILES Code : | O=C(N1[C@H](C(N)=O)CCC1)OC(C)(C)C |
MDL No. : | MFCD00190827 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.8 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 59.5 |
TPSA ? Topological Polar Surface Area: Calculated from |
72.63 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.9 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.05 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.49 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.33 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.02 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.55 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.94 |
Solubility | 24.8 mg/ml ; 0.116 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.13 |
Solubility | 15.9 mg/ml ; 0.0744 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.59 |
Solubility | 54.8 mg/ml ; 0.256 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 |
-7.57 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 |
0.55 |
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) |
2.58 |
* 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 |
---|---|---|
76% | With 1,3,5-trichloro-2,4,6-triazine; In N,N-dimethyl-formamide; at 20℃; for 1h; | General procedure: A mixture of compound 2 (5 g, 23.3 mmol) and cyanuric chiloride (2.58 g, 14.0 mmol) in DMF (10 mL) was stirred at room temperature for 1 h (monitored by TLC). After the reaction completed, the solution was extracted with EtOAc, washed, dried, concentrated, and purified by flash chromatography on silica gel, eluted with a mixture of PE/EA (1/1, v/v), to afford 3 (3.48 g, 76%) as a white solid. 1H NMR (300 MHz, CDCl3) delta 4.76 (s, 1H), 3.51 (s, 2H), 2.34-2.31 (m, 1H), 2.17-2.10 (m, 2H), 1.90-1.87 (m, 1H), 1.49 (s, 9H). MS (ESI) m/z 197 [M+H]+. |
76% | With 1,3,5-trichloro-2,4,6-triazine; In N,N-dimethyl-formamide; at 20℃; for 1h; | A mixture of compound 9 (5 g, 23.3 mmol) and cyanuric chiloride (2.58 g, 14.0 mmol) in DMF (10 mL) was stirred at roomtemperature for 1 h (monitored by TLC). After the reaction completed, thesolution was extracted with EtOAc, washed, dried, concentrated, and purified byflash chromatography on silica gel, eluted with a mixture of PE/EA (1/1, v/v)to afford 10 (3.48 g, 76%) as a white solid. 1H NMR (CDCl3,300 MHz): delta4.76(s, 1H), 3.51 (s, 2H), 2.34-2.31 (m, 1H), 2.17-2.10 (m, 2H), 1.90-1.87 (m, 1H),1.49 (s, 9H). MS (ESI) m/z 197[M+H]+. |
With 1,3,5-trichloro-2,4,6-triazine; N,N-dimethyl-formamide; In dichloromethane; at 20 - 40℃;Inert atmosphere; | Dichloromethane (500 ml), L-Prolinamide (100 g), potassium carbonate (60.50 g) were mixed and stirred under nitrogen atmosphere in round bottom flask The reaction mass was cooled to 10-15C and then Di-tert-butyl dicarbonate (210.30 g) was added. Reaction mixture was stirred till completion of the reaction. After completion water (500m1) was added and product was extracted in dichloromethane. Dichloro methane was removed and then dimethyl formamide (140 ml) and dichloromethane (700 ml) were added under nitrogen atmosphere. Cyanuric chloride (72.70 g) was charged in 2-3 equal lots to the reaction mass at 20-25C under nitrogen atmosphere. The reaction mass was maintained at 35-40C for 4-5 hrs. After completion of the reaction solid was filtered and washed with MDC. Methane sulfonic acid (252.60 g) was added to the filtrate and heated the reaction mass to 40-45C for 3-4 hrs. After completion of the reaction the reaction mass was cooled at 0-5C and Triethyl amine (88.65 g) and Chloroacetyl chloride (118.70 g) were added. The reaction mass was maintained at 20-30C for 1-2 hrs under nitrogen atmosphere. After completion of the reaction water was charged and product was extracted in dichloromethane. Organic layer was washed first with dilute HC1 solution and then with ammonia solution. Organic solvent was removed and product was crystallized using isopropyl alcohol. Yield: 75.0gm |
55 g | With triethylamine; trifluoroacetic anhydride; In dichloromethane; at -15℃; for 3h; | step 1:The first reaction solution containing the compound represented by Formula II was cooled to -15.0 C., 30.0 g of triethylamine,A dichloromethane solution containing 0.357 mol of trifluoroacetic anhydride (TFAA) was added dropwise,Dropping time 2h, after the addition was completed, incubated for 1h,Insulation temperature was -15.0 , TLC monitoring showed that the reaction was completed;Step 2: To the solution in Step 1 was added purified water 100mL, washed and stratified;The pH was adjusted to 1 with 1 M hydrochloric acid, the temperature was controlled below 0 C,Stirring for 30-45min, standing stratification;Step 3: The mass concentration of 5% -10% dilute salt water 100mL wash phase;The organic layer was dried over sodium sulfate, filtered and the methylene chloride removed under reduced pressure.55.0 g (0.280 mol) of an oil was obtained as a compound of the formula III. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With pyridine; In ethyl acetate; N,N-dimethyl-formamide; acetonitrile; | Preparation 116 tert-butyl (2S)-2-cyano-1-pyrrolidinecarboxylate A solution of oxalyl chloride (11.0 ml, 0.126 mol) and DMF (11.4 ml, 0.138 mol) in MeCN (170 ml) was treated dropwise with a solution of N-Boc-L-proline amide (12.3 g, 0.57mol) and pyridine (20.4 ml, 0.253 mol) in MeCN (30 ml) at 0 C. and stirred at this temperature for 15 minutes. The reaction mixture was diluted with EtOAc and washed with H2O (*3). The organic extract was dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was purified on a silica column eluding with a solvent gradient of pentane:EtOAc (80:20) gradually changing to (60:40) to afford the title compound (7.40 g, 66%). 1H nmr: (d6DMSO) 1.40 (9H, s), 1.88 (2H, brs), 2.05-2.30 (2H, m), 3.21 (1H, m), 3.35 (1H, brs), 4.60 (1H, d). MS: 214 (MNH4+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In N,N-dimethyl-formamide; at 0℃; for 1h; | [0530] (S)-tert-butyl 2-cyanopyrrolidine-1-carboxylate (71b): To a solution of (S)-tert-butyl 2- carbamoylpyrrolidine-1-carboxylate 71a (86 mg, 0.40 mmol) in DME (2 mL) at 0 C, 2,4,6-trichloro-1,3,5- triazine (104 mg, 0.56 mmol) was added. After stirring for one hour at 0C, the reaction mixture was quenched with a cold 0.5 M NaOH solution. The mixture was then extracted with ethyl acetate. Organic layers were combined and washed with water and brine twice, dried over Na2SO4, and concentrated via vacuum. The crude reside was purified by silica gel column chromatography (15% ethyl acetate hexane to yield 71b (56 mg, 71%) as an oil. 1H NMR (500 MHz, CDCI3) 6 4.56-4.39 (m, 1H), 3.58-3.22 (m, 2H),2.28-1.94 (m, 4H), 1.47 (d, i=16.4 Hz, 9H); 13C NMR (126 MHz, CDCI3) 6 153.09, 119.23, 81.50, 47.27,45.79, 31.74, 28.39, 23.89; HRMS (ESI+): Calcd for C10H17N2O2 [M+H]: 197.1290, Found: 197.1287. |