Structure of 42726-73-8
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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. : | 42726-73-8 |
Formula : | C8H14O4 |
M.W : | 174.19 |
SMILES Code : | C(C(OC(C)(C)C)=O)C(OC)=O |
MDL No. : | MFCD00042856 |
InChI Key : | XPSYZCWYRWHVCC-UHFFFAOYSA-N |
Pubchem ID : | 2733872 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H227-H315-H319-H335 |
Precautionary Statements: | P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.75 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 43.18 |
TPSA ? Topological Polar Surface Area: Calculated from |
52.6 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.36 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.12 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.89 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.93 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.85 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.23 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.3 |
Solubility | 8.82 mg/ml ; 0.0506 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.82 |
Solubility | 2.65 mg/ml ; 0.0152 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.26 |
Solubility | 9.64 mg/ml ; 0.0553 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) |
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 |
-6.57 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 |
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 |
2.0 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) |
1.73 |
* 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 |
---|---|---|
92% | General procedure: To a solution of the malonate (2.53 mmol) in CH3CN (15 mL), para-acetoamidobenzenesulfonyl azide (669 mg, 2.78 mmol) was added. The solution was stirred and cooled to 0°C for 15 minutes then Et3N (1.1 mL, 7.89 mmol) was added. The temperature was maintained at 0°C for 15 minutes then the solution was warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure and the white residue was washed with 1:1 petroleum ether/Et2O. The washings were collected and the solvent was removed under reduced pressure. The crude yellow oil was subjected to column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N-methyl-acetamide; | Sodium hydride (3.04 g of a 50percent oil dispersion, 127 mmol) is suspended in dimethylformamide (300 ml) and the suspension is cooled to 0° C. t-Butyl methyl malonate (20.08 g, 115 mmol) is added dropwise slowly and the reaction mixture is warmed to room temperature. 1,7-Dibromoheptane (29.75 g, 115 mmol) is added dropwise and the mixture is stirred for 3 hours. The mixture is partitioned between diethyl ether (500 ml) and water (1000 ml). The organic layer is washed with water (3*500 ml), brine (1*500 ml), dried (MgSO4) and the solvent is evaporated. The product is purified by silica gel chromatography (10percent ethyl acetate/hexane) to give t-butyl methyl 7-bromoheptylmalonate as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Add a solution [OF T-BUTYL] methylmalonate (129 g, 0.75 mol) in THF (385 mL) to a slurry of LiH (14.9 g, 1.875 mol) in THF (900 mL) and [N, N-DIMETHYLPROPYLENE] urea (DMPU, 155 g, 1.2 mol) over 30 minutes while maintaining the temperature at [0-5 °C.] Heat the reaction mixture to [65 °C] and add a solution [OF CIS-1, 4-DICHLORO-2-BUTENE] (95percent, 100 g, 0.8 mol, 1. [08 EQ)] in THF (100 mL) over 5.5 hours, maintaining the temperature at [63-67 °C.] Stir the reaction for 4 hours at [65 °C.] A water/MTBE work-up of the reaction mixture yields [1- (METHOXYCARBONYL)-1- (TERT-BUTOXYCARBONYL)] cyclopent-3-ene. 'H NMR (300 MHz, [CDC13)] 8 5.57 (s, 2H, CH=CH), 3.71 [{S,] 3H, CH3), 2.95 (s, 4H, 2CH2), 1.42 (s, 9H, C (CH3) 3). IR (film) 1734 [(C=O),] 1646,1268, 1149 [CM-1.] Cool the reaction solution containing [1-(METHOXYCARBONYL)-1-(TERT-] butoxycarbonyl) cyclopent-3-ene to [10-15 °C] and add to a cooled solution [(10-15 °C)] of 1 N [NAOH] (1.3 L, 1.3 mol) over 30 minutes. Stir the reaction solution at [25 °C] for 24 hours and monitored by GC assay. When the hydrolysis reaction is complete, add MTBE (645 mL) to the reaction mixture and stir the solution for 5 minutes. Allow the layers to settle and separate. Discard the organic layer. Add 1.5 M [NAHS04] solution (1470 mL) to make the aqueous layer acidic (pH 2-3). Add MTBE (1.3 L) and separate the layers. Extract the aqueous layer with MTBE (385 mL) and wash the combined organic layers with 5percent [LICI] solution. Concentrate the organic layer under vacuum and dilute with heptane (780 mL). Concentrate the solution to approximately 500 mL and stir the resulting slurry 1 hour at ambient temperature. Filter the solid, wash with heptane (250 mL), and vacuum dry at [35 °C] to give 103.29 g (61percent yield) [OF L- (CARBOXYLIC ACID)-1- (TERT-] butoxycarbonyl) cyclopent-3-ene as a white solid. [MP=119°C.] 'H NMR (300 MHz, [CD13),] 8 5.61 (s, 2H, CH=CH), 3.00 (s, 4H, 2CH2), 1.46 (s, 9H, C (CH3) [3).] IR: 3800-3000 (br, COOH), 1741 [(CO2R),] 1705 [(CO2H),] 1283), 1149 [CM-APOS;.] Dissolve [1-(CARBOXYLIC ACID)-1-(TERT-BUTOXYCARBONYL) CYCLOPENT-3-ENE] (50 g, [236] mmol) in 850 mL of 70: 30 toluene: MTBE under nitrogen in a 1 L flask with mechanical stirrer. Add thionyl chloride (33.6 g, 283 mmol, 1.2 equiv) to the [STIRRED] reaction mixture, maintaining the temperature at [23 °C.] Cool the reaction solution to [0-5 °C] and add triethylamine (32.2 g, 318 mmol, 1.35 equiv) dropwise over 30 minutes. Warm the reaction mixture to [23 °C] and stir for 1 hour. Add the reaction mixture rapidly dropwise to deionized water (625 mL), maintaining the temperature at [20-25 °C.] Separate the layers and wash the organic layer with 500 mL 1 M [NAHC03] solution. Concentration of the organic layer isolates [1-(CHLOROCARBONYL)-1-(TERT-BUTOXYCARBONYL)] cyclopent-3-ene as a light yellow liquid. 'H NMR (300 MHz, [CDC13)] [8] 5.61 (s, 2H, CH=CH), 3.04 (app q, J = 15.1 Hz, 4H, 2CH2), 1.49 (s, 9H, C (CH3) [3).] IR (film) 1796 [(COCI),] 1743 [(C02R),] [1274,] 1233,1158 [CMAPOS;APOS;.] Add a solution of tetrabutyl ammonium hydrogen sulfate (0.81 g, 2.4 mmol) in deionized water (700 mL) to sodium azide (20.16 g, 310 mmol). Add the solution containing [1- (CHLOROCARBONYL)-1- (TERT-BUTOXYCARBONYL)] cyclopent-3-ene in MTBE/toluene to the azide solution over 45 minutes. Stir the reaction mixture for 3 hours at [23 °C] until the [1-(CHLOROCARBONYL)-1-(TERT-BUTOXYCARBONYL)] cyclopent-3-ene is consumed, as [CONFIRMED] by GC analysis of the reaction solution. Separate the layers and wash the organic layer with 1 M [NAHC03] (540 mL) and deionized water (540 mL, then 270 mL). Dry the organic layer with [NA2SO4] and filter. Concentrate the solution under vacuum to yield [1-(ACYL AZIDE)-1-(TERT-BUTOXYCARBONYL)] cyclopent-3-ene as as an oil. [APOS;H] NMR (300 MHz, [CDCIS) 8] 5.58 (s, 2H, CH=CH), 2.96 (app t, J = 2.3 Hz, 4H, 2CH2), 1.46 (s, 9H, C (CH3) [3).] IR (film) 2137 [(CON3),] 1720 [(C02R),] 1246 (s, 1185,1136 [CMAPOS;APOS;.] Add the solution [OF L-(ACYL AZIDE)-L-(TERT-BUTOXYCARBONYL)] cyclopent-3-ene over 1 hour to 110 mL of toluene at [95 °C.] Evolution of nitrogen gas is addition rate controlled under these conditions. Distill MTBE from the reaction during the addition. Stir the reaction for 1 hour at [95 °C,] and allow to cool to [23APOS;C OVERNIGHT.] Concentration of the solvent under vacuum yields [1-(ISOCYANATE)-1-(TERT-BUTOXYCARBONYL)] cyclopent-3-ene as an oil. 'H NMR (300 MHz, [CDCI3)] 8 5.67 (s, 2H, CH=CH), 3.01 (d, J = 15.6 Hz, 2H), 2.61 (d, J [= 15.] 6 Hz, 2H), 1.50 (s, 9H, C [(CH3)] [3).] IR (film) 2258 (-NCO), 1732 [(-CO2R),] 1157 cm-'. Add t-butanol (35 g, 471 mmol) to a solution of potassium t-butoxide [(1M] in THF, 471 mL, 471 mmol) under nitrogen. Cool the reaction solution was cooled to 0-5 [°C] and add the toluene solution containing [1- (ISOCYANATE)-L- (TERT-] butoxycarbonyl) cyclopent-3-ene over 60 minutes, maintaining the temperature at 0-10 [°C.] Warm the reaction to [23 °C,] stir f... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 24h;Inert atmosphere; | Under a nitrogen atmosphere, 2-chloro-5-nitro pyridine (2.0 g, 12.61 mmol) was dissolved in DMF (21 mL, 0.6 M). To this was added tert butylmethyl malonate (2.56 mL, 15.1 mmol) followed by potassium carbonate (3.49 g, 25.2 mmol) at 25 °C.The reaction was heated to 85 °C for 12 h, at which point the temperature was adjusted to 100 °C for 12h. The reaction was cooled to 25 °C, and saturated ammonium chloride (30 mL) was added. The layerswere separated, and the aq. phase was extracted with EtOAc (3 x 30 mL), dried with MgSO4 andconcentrated. The crude product was purified via column chromatography (0-60percent EtOAc/heptane) todeliver the product (3.18 g, 85percent). 1H NMR (400 MHz, CDCl3) delta 9.38 (s, 1H), 8.51-8.49 (dd, J = 8.8, 2.3 Hz, 1H), 7.75-7.74 (d, J = 8.8 Hz, 1H),5.00 (s, 1H), 3.80 (s, 3H), 1.47 (s, 9H).13C NMR (101 MHz, CDCl3) delta 167.24, 165.31, 159.27, 144.58, 131.65, 124.28, 83.70, 61.24, 53.16, 27.81.LRMS (ESI) m/z: calc?d for C13H16N2O6 [M+H] 297.11, found 297.7. |
51% | Synthesis of compound 18.2. To a solution of compound 18.1 (2.5 g, 15.8mmol, 1.00 equiv) in dry DMF (25mL) at 0°C, was added sodium hydride (60percent suspension in mineral oil) (1.45 g, 36.2mmol, 2.3 eq.) and the suspension was stirred at room temperature for 30 minutes. Tert-butyl methyl malonate (3.3g, 18.9 mmol, 1.2 equiv.) was added dropwise to the above reaction mixture at 0 °C. The reaction mixture was stirred at same temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with water and brine. Then dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by column chromatography to furnish compound 18.2 (2.4g, 51percent). MS (ES) m/z=297 [M+H]+. |
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