Structure of H-D-Pro-NH2
CAS No.: 62937-45-5
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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.
Synonyms: (R)-Pyrrolidine-2-carboxamide
4.5
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| CAS No. : | 62937-45-5 |
| Formula : | C5H10N2O |
| M.W : | 114.15 |
| SMILES Code : | O=C(N)[C@@H]1NCCC1 |
| Synonyms : |
(R)-Pyrrolidine-2-carboxamide
|
| English Name : | D-Prolinamide |
| MDL No. : | MFCD00153457 |
| InChI Key : | VLJNHYLEOZPXFW-SCSAIBSYSA-N |
| Pubchem ID : | 447554 |
| Num. heavy atoms | 8 |
| Num. arom. heavy atoms | 0 |
| Fraction Csp3 | 0.8 |
| Num. rotatable bonds | 1 |
| Num. H-bond acceptors | 2.0 |
| Num. H-bond donors | 2.0 |
| Molar Refractivity | 33.66 |
| TPSA ? Topological Polar Surface Area: Calculated from |
55.12 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.71 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.87 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-1.16 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.78 |
| 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 |
-0.42 |
| Log S (ESOL):? ESOL: Topological method implemented from |
0.07 |
| Solubility | 133.0 mg/ml ; 1.17 mol/l |
| Class? Solubility class: Log S scale |
Highly soluble |
| Log S (Ali)? Ali: Topological method implemented from |
0.19 |
| Solubility | 178.0 mg/ml ; 1.56 mol/l |
| Class? Solubility class: Log S scale |
Highly soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.34 |
| Solubility | 51.8 mg/ml ; 0.454 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 |
-7.61 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 |
1.0 |
| 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) |
1.47 |
* 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 |
|---|---|---|
| 100% | With 10% palladium on carbon; hydrogen In methanol for 7h; | |
| 87.3% | With hydrogen In methanol for 9h; Ambient temperature; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With benzotriazol-1-ol; dicyclohexyl-carbodiimide |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sodium hydroxide In tetrahydrofuran | 18.C Amino Acid→diamine C) To a suspension of 0.380 gm of lithium aluminum hydride in 15 ml of dry tetrahydrofuran is carefully added a solution of the D-proline amide (prepared in B above) in 10 ml tetrahydrofuran. The mixture is refluxed for 2 hrs then cooled and quenched with 2 ml of 2.5N sodium hydroxide. The mixture is filtered through a pad of sodium sulfate and the filter cake washed with 2*50 ml of ether. The combined filtrates are concentrated in vacuo to yield 0.80 gm of desired 2-(1-pyrrolidinylmethyl) pyrrolidine. | |
| With sodium hydroxide In tetrahydrofuran | 18.C C C To a suspension of 0.380 gm of lithium aluminum hydride in 15 ml of dry tetrahydrofuran is carefully added a solution of the D-proline amide (prepared in B above) in 10 ml tetrahydrofuran. The mixture is refluxed for 2 hrs then cooled and quenched with 2 ml of 2.5N sodium hydroxide. The mixture is filtered through a pad of sodium sulfate and the filter cake washed with 2*50 ml of ether. The combined filtrates are concentrated in vacuo to yield 0.80 gm of desired 2-(1-pyrrolidinylmethyl) pyrrolidine. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: (R)-2-carbamoylpyrrolidine-1-carboxylic acid tert-butyl ester With trifluoroacetic acid at 25℃; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 25℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 20℃; | Intermediate 19tert-Butyl 2-(3-[(2R)-2-carbamoylpyrrolidin-1-yl]carbonyl}phenyl)-hydrazinecarboxylate 3-(2-Tert-butoxycarbonyl)hydrazinyl)benzoic acid (1.96 g, 7.77 mmol) was dissolved in NMP (10 ml) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (5.91 g, 15.55 mmol), N-ethyl-N-isopropylpropan-2-amine (4.1 ml, 23.32 mmol) and (R)-pyrrolidine-2-carboxamide (0.89 g, 7.77 mmol) were added at room temperature. Stirring was continued overnight, the mixture was poured into aqueous HCl (0.5 M) and the product was extracted with EtOAc (3 times 100 ml). The combined organic extracts were washed with aqueous NaHCO3, brine and dried with Na2SO4. The crude product (1.3 g) was obtained after filtration and evaporation of the solvent in vacuo and was used in the next step without any further purification. APCI-MS m/z: 293 [MH+]. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80% | With ammonia In ethanol at 0 - 20℃; Large scale; | 6 Preparation of D-prolinamide The D-proline ethyl ester hydrochloride obtained in Example 3 was dissolved in 400 L of ethanol, cooled to 0 to 10 ° C with stirring, and started to react with ammonia gas at a temperature of 15 to 20 ° C for 10 to 20 hours.At the end of the reaction, ethanol was evaporated to dryness under reduced pressure.700 L of methylene chloride was added to the solution, and the mixture was dissolved with stirring, and cooled to 0 to 10C.Began to drop concentrated concentrated potassium hydroxide solution (75kg dissolved in 45kg of water) drained, drop complete, heat stirring reaction 1 hour.The inorganic salt was removed by filtration.The filtrate was separated and the aqueous layer was extracted twice more with 250 ml of dichloromethane.The organic layers were combined and the dichloromethane was evaporated under reduced pressure.Ethyl acetate (50 L) was added and the residue was evaporated to dryness under reduced pressure.Adding ethyl acetate 440L dissolved in heat, activated carbon decolorization, hot filtration, cooling to 0-5 ° C stirring crystallization 2 hours.Filtered and dried in an oven at about 45 ° C under reduced pressure to obtain 79.3 kg of the target product D-prolinamide in a yield of 80.0%.Product purity (HPLC): 99.7%; titration content: 99.5%; L-prolinamide (GC): 0.15%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 94.14 % | With potassium carbonate In 1,4-dioxane; water at 20℃; | 1, 2, 3 tert-Butyl (R)-2-carbamoylpyrrolidine-1-carboxylate: In a 5L four-mouth flask, add 2.5L of dioxacyclo, add 500g of D-prolinamide, stir to dissolve, add 2.5L of water and 362.6g of potassium carbonate, stir mechanically, add 1240g of Boc anhydride dropwise, and react for 15h at room temperature. After the reaction, dioxane was dihydrolated, extracted 3 times (3×0.15L) with ethyl acetate, the extract was concentrated, pulped with petroleum ether with a boiling range of 60-90 °C, and dried to obtain (R)-2-carbamoylpyrrolidine-1-carboxylic acid tert-butyl ester 881.7g, with a product yield of 94.14%. |