Structure of Repaglinide Related Compound B
CAS No.: 99469-99-5
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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.
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| CAS No. : | 99469-99-5 |
| Formula : | C13H16O5 |
| M.W : | 252.26 |
| SMILES Code : | O=C(O)CC1=CC=C(C(OCC)=O)C(OCC)=C1 |
| MDL No. : | MFCD08704233 |
| InChI Key : | OTGSESBEJUHCES-UHFFFAOYSA-N |
| Pubchem ID : | 10131212 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H319 |
| Precautionary Statements: | P305+P351+P338 |
| Num. heavy atoms | 18 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.38 |
| Num. rotatable bonds | 7 |
| Num. H-bond acceptors | 5.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 65.37 |
| TPSA ? Topological Polar Surface Area: Calculated from |
72.83 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.41 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.94 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.89 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.83 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.31 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.08 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.41 |
| Solubility | 0.979 mg/ml ; 0.00388 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-3.09 |
| Solubility | 0.203 mg/ml ; 0.000806 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.19 |
| Solubility | 0.161 mg/ml ; 0.000638 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 |
Yes |
| 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) |
Yes |
| 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 |
-6.46 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<0.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.24 |
* 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 |
|---|---|---|
| 93% | Example 11 (S)(+)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonyl-methyl]-benzoic acid ethyl ester 20.77 g (82.4 mmol) of 2-(3-Ethoxy-4-(ethoxycarbonyl)phenyl)-acetic acid were slowly added to a solution of N,N'-carbonyldiimidazole (13.36 g, 82.4 mmol, 97%) in dichloromethane (240 ml) at room temperature. After activation for 1.5h at 20-25C a solution of (S)-3-methyl-1-(2-(piperidin-1-yl)phenyl)butan-1-amine (19.70 g, 80.0 mmol) in dichloromethane (80 ml) was added dropwise and the resulting mixture was stirred for 2h. The reaction mixture was quenched by adding water (2 x 160 ml). The organic phase was then evaporated under reduced pressure. The yield of the crude repaglinide ester product of formula IV was 35.7 g (93%; HPLC: 97.58%). | |
| 89.5% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 0 - 20℃; for 18.5h; | To a mixture of (1 3-METHYL-1-(2-PIPERIDIN-1-YLPHENYL) BUTAN-1-AMINE (499, 0.2 MOL), [3-ETHOXY-4- (ETHOXYCARBONYL) PHENYL] acetic acid (50 g, 0.2 mol) and triethylamine (100 g, 0.99 mol) in ethyl acetate (1.0 L), a solution (50% w/w) of propane phosphonic acid anhydride (278 g, 0.44 mol) in ethyl acetate was added dropwise over a period of 30 minutes, maintaining the temperature at 0-5 C and stirred for 18 hours at ambient temperature. The reaction mixture was washed with 1.5 N HCI, 5% sodium bicarbonate solution and brine. The organic layer was concentrated to give title compound. Yield : 86 g, 89.5% |
| 89.6% | With phenylboronic acid; In toluene; for 16 - 18h;Heating / reflux;Product distribution / selectivity; | EXAMPLE 2 Preparation of Ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoate In a round bottom flask fitted with a dean stark condenser, 3-Ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0426 mol) was dissolved in toluene (100 ml) followed by slow addition of phenylboronic acid (0.494 g, 0.0040 mol) and (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was cooled at 25-30 C. followed by filtration. The toluene layer was washed with water and 1% sodium bicarbonate solution followed by complete distillation of toluene. Hexane (50 ml) was added to the resulting residue after complete removal of toluene in order to precipitate the solid, with stirring for 1 hour. The resulting solid was filtered and washed with hexane (10 ml). The wet material was further dried at 50-55 C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]benzoate (Yield=89.6%; HPLC Purity: 99.66%). |
| 89.6% | With phenylboronic acid; In toluene;Reflux; | Example 8Preparation of Ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoateIn a round bottom flask fitted with a Dean Stark condenser, 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0426 moles) was dissolved in toluene (100 ml) followed by slow addition of phenylboronic acid (0.494 g, 0.0040 moles) and (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 moles). The reaction mixture was refluxed for 16-18 hours. The reaction mixture was cooled at room temperature followed by filtration. The toluene layer was washed with water and 1% sodium bicarbonate solution. This was followed by complete distillation of toluene. Hexane (50 ml) was added to the resulting residue in order to precipitate the solid and then stirred for 1 hour. The resulting solid was filtered and washed with hexane (10 ml). The wet material was further dried at 50-55 C. under vacuum for 4-6 hours to produce ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoate (Yield: 89.6%; HPLC purity: 99.46%; and Chiral purity: 99.98%). |
| 87.2% | With tetramethylorthosilicate; In toluene; for 11h;Inert atmosphere; Reflux; | Under nitrogen, compound 370.3g (0.285mol, 1eq), 4- carboxy-methyl-2-ethoxy ethyl benzoate 72.0g (0.285mol ,, 1eq), tetramethoxysilane 86.8g (152.22,0.57 mol, 2eq) and 285g of toluene, heated to reflux for 11 hours, HPLC control the starting material the reaction was complete, cooled, concentrated under reduced pressure, from ethanol / MTBE to give white crystalline solid 119.4g, HPLC98.8%, yield 87.2%, 99.5% ee. |
| 73.3% | With boric acid; In toluene; for 16 - 18h;Heating / reflux;Product distribution / selectivity; | EXAMPLE 1 Preparation of Ethyl (S)-2-ethoxy-4-[N-[1-(2-piperidinophenyl)-3-methyl-1-butyl]aminocarbonylmethyl]benzoate In a round bottom flask fitted with a dean stark condenser, (S)-3-methyl-1-(2-piperidinophenyl)-1-butylamine (10 g, 0.0406 mol) was dissolved in toluene (100 ml), followed by the addition of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid (10.26 g, 0.0407 mol) and boric acid (0.26 g, 0.0042 mol). The reaction mixture was refluxed for 16-18 hours. The resulting mass was then cooled to 25-30 C. followed by filtration. The filtrate was washed with water and 1.0% sodium bicarbonate solution followed by complete distillation of toluene and the resulting residue was stirred with hexane (50 ml) for 1 hour. The precipitated solid was filtered and washed with hexane (10 ml). The wet product was dried at 50-55 C. under vacuum for 4-6 hours to produce Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonyl methyl]-benzoate (Yield=73.3%; HPLC Purity: 99.50%). |
| With triethylamine; triphenylphosphine; In tetrachloromethane; acetonitrile; | EXAMPLE 1 Ethyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate 0.48 g (1.91 mMol) of 3-ethoxy-4-ethoxycarbonylphenylacetic acid, 0.60 g (2.29 mMol) of triphenylphosphine, 0.80 ml (5.73 mMol) of triethylamine and 0.18 ml (1.91 mMol) of carbon tetrachloride are added successively to a solution of 0.47 g (1.91 mMol) of (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 5 ml of anhydrous acetonitrile and the resulting mixture is stirred for 20 hours at ambient temperature. It is then evaporated down in vacuo and distributed between ethyl acetate and water. The organic extract is dried and filtered and evaporated down in vauco. The evaporation residue is purified by column chromatography on silica gel (toluene/ethyl acetate=10/1). Yield: 0.71 g (77.3% of theory), Melting point: 110-112 C. Calculated: C 72.47; H 8.39; N 5.83. Found: C 72.29; H 8.42; N 5.80. | |
| With dicyclohexyl-carbodiimide; In toluene; at 25 - 40℃; | EXAMPLE 5; PREPARATION OF REPAGLINIDE; 3-Ethoxy-4-(ethoxycarbonyl)benzene acetic acid (2.25 g, 0.0089 moles) was added to a solution of (alphaS)-alpha-(2-methylpropyl)-2-(1-piperidinyl)benzenemethanamine (2g, .008 moles) in toluene (20 ml). Then N,N-dicyclohexylcarbodiimide (1.95 g, 0.0094 moles) was added and the reaction mixture was stirred till completion of the reaction at 25-40C. The solid was filtered under suction and toluene filtrate was distilled under reduced pressure. The product was crystallized from ethanol / water and dried to yield ethyl 2-ethoxy-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzoate (3 g). 1N aqueous sodium hydroxide solution (8.0 ml) in ethanol (30 ml) was added to ethyl-2-ethoxy-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzoate (3 g) at 60-65C and stirred. After completion of the reaction the reaction mixture was cooled, pH was adjusted to 5 with 1N aqueous hydrochloric acid and product was filtered and dried at reduced pressure. The dried product was recrystallised from aqueous ethanol to give repaglinide. Yield: 2.27 g |
