Structure of 907606-68-2
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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. : | 907606-68-2 |
Formula : | C14H23NO6 |
M.W : | 301.34 |
SMILES Code : | O=C([C@H]1NC[C@@]2([H])[C@]1([H])CCC2)OC(C)(C)C.O=C(O)C(O)=O |
MDL No. : | MFCD22124391 |
InChI Key : | ZCTXDLWZMFBZEV-PUBMXKGKSA-N |
Pubchem ID : | 67080120 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 21 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.79 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 7.0 |
Num. H-bond donors | 3.0 |
Molar Refractivity | 78.88 |
TPSA ? Topological Polar Surface Area: Calculated from |
112.93 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.32 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.48 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.49 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.54 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.74 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.92 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.14 |
Solubility | 21.7 mg/ml ; 0.0721 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.42 |
Solubility | 11.3 mg/ml ; 0.0376 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.08 |
Solubility | 2.48 mg/ml ; 0.00822 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) |
Yes |
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 |
-8.48 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 |
1.0 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) |
3.39 |
* 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 |
---|---|---|
59.7% | Stage #1: at 0 - 21℃; Stage #2: With methanesulfonic acid In dichloromethane; water at 0 - 21℃; for 18.25 h; Sealed tube |
6.2 Example 29:; Preparation of (1 S,3aR,6aS)-octahydrocyclopenta[c]pyrrole- 1 - carboxylic acid t-butyl ester oxalic acid 1 : 1 salt from (lS,3aR,6aS)- octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride.; [0419] Step 1 : To a 1650 mL thick- walled glass pressure bottle (Ace Glass, Inc., 8648-157) equipped with a magnetic stirring bar was charged 75 g (306.9 mmol) of the (lS,3aR,6aS)- octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride / ammonium chloride admixture prepared in Example 28, 375 mL dichloromethane, and 497 mL t-butyl acetate. The resulting mixture was stirred vigorously at ambient temperature (about 210C) to break large aggregates to provide a free-stirring suspension. This suspension was cooled to an internal temperature of 00C using a brine - ice bath and 75.4 mL (1162 mmol) methanesulfonic acid was added dropwise over 15 minutes, during which the internal temperature rose to 5°C. The pressure bottle was sealed and the reaction mixture was allowed to warm to ambient temperature (about 210C) with vigorous stirring over 18 hours, during which the reaction mixture became a suspension of white inorganic salts in an amber solution. The mixture was cooled in an ice bath and the pressure bottle carefully vented and uncapped. The mixture was transferred to a 3 L flask and cooled in an ice bath with stirring. 400 mL of 50percent (wt:wt) NaOH in water was added to the mixture over 35 minutes while maintaining its temperature below 200C. The stirring was halted and the phases were allowed to separate. The organic phase (-850 mL) was removed to a separate vessel. The remaining aqueous phase and rag layer (pH 13, -800 mL) were extracted with 375 mL dichloromethane. The organic phases were combined (-1250 mL) and washed with water (2 x 225 mL). The resulting organic phase was filtered to remove a rag layer and any insoluble material, and the solvent was removed by rotary vacuum evaporation to give 48.3 g dark-amber oil. The 1H NMR spectrum of the oil showed (lS,3aR,6aS)- octahydrocyclopenta[c]pyrrole-l-carboxylic acid ?-butyl ester.[0420] A second preparation following the same procedure yielded was 50.6 g of the trans- (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester oil.[0421] Step 2: 97.9 g (463.3 mmol) of (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester from the two preparations according to Step 1 were dissolved in 750 mL t-butyl acetate and charged to a 3 L four-neck flask equipped with overhead mechanical stirring, a thermometer, addition funnel, and reflux condenser. With stirring at ambient temperature (-210C), a solution of 44.0 g (488.6 mmol) of oxalic acid in 750 mL 2-propanol was added dropwise over 37 minutes, increasing the mixture's temperature to 31°C. Solids began to precipitate after addition of -50 mL of the oxalic acid solution, and resulted in a thick suspension after the addition of 450 mL. After addition of 500 mL of the oxalate solution, the precipitated solids redissolved to provide a dark yellow solution. Solids precipitated again rapidly after the addition of 600 mL of the oxalic solution and persisted through the end of the oxalic acid addition. This suspension was then heated 78°C to provide a thin suspension which was allowed to cool passively with stirring to ambient temperature (-210C). After 16 hours since the cooling began, the precipitated solids were collected by filtration and washed successively with isopropanol (450 mL), isopropyl acetate (450 mL), and methyl t-butyl methyl ether (450 mL). The solids were dried in a vacuum oven (300C, 25" vacuum, N2 stream) to provide 118.1 g (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester oxalic acid 1 : 1 salt (64percent yield from (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid hydrochloride) as a dense, tan free flowing powder (99.7percent purity by GC analysis), which exhibited the expected 1H-NMR spectrum for (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid ?-butyl ester oxalic acid (1 : 1) salt.[0422] Recrystallization of (1 S,3aR,6aS)- octahydrocyclopenta[c]pyrrole- 1 -carboxylic acid t-butyl ester oxalic acid (1 :1) salt: The tan powder from Step 2 above (118. I g, 391.9 mmol) and isopropanol (1950 mL) were charged to a 3 L four neck flask equipped with a mechanical stirring, a thermometer, and a reflux condenser. The suspension was stirred and heated to 74°C to completely dissolve the salt, resulting in a yellow solution. The stirring was slowed and the solution was allowed to cool passively to ambient temperature (-210C). After 20 hours since the cooling began, the precipitated solids collected by filtration and washed successively with isopropanol (1 L), isopropyl acetate (1 L), and methyl ?-butyl methyl ether (1 L). The solids were dried in a vacuum oven (400C, 28" vacuum, N2 stream) to provide 110.45 g (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l-carboxylic acid t-butyl ester oxalic acid 1 :1 salt (59.7percent yield from (lS,3aR,6aS)-octahydrocyclopenta[c]pyrrole-l -carboxylic acid hydrochloride) as fine, off-white needles of 99.9percent purity by GC analysis). Chiral GC analysis showed only the desired (lS,3aR,6aS)-stereoisomer. Its (2S)-epimer was not detected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.08 g | Stage #1: With methanesulfonic acid In chloroform at 0 - 25℃; for 18 h; Stage #2: at 75 - 80℃; for 0.5 h; |
[Isolation of Hydrogenoxalate] [0155] To 250 mg of the mixture of the hydrochloride of amino acid (i) and ammonium chloride prepared in Example 29 were added 4 mL of chloroform and 1.7 mL of tert-butyl acetate. The resulting suspension was cooled to 0° C. and then 0.25 mL of methanesulfonic acid was added. The mixture was warmed slowly to 25° C. and then stirred at this temperature for 18 hours. The resulting white suspension was cooled to 0° C., and then 1.3 mL of a 50percent aqueous sodium hydroxide solution was added carefully with the temperature kept at 20° C. or lower. Water (15 mL) and chloroform (15 mL) were added and then stirred for 15 minutes. The layers were separated and the aqueous layer was subjected to extraction with 15 mL of chloroform three times. The organic layers were combined, dried over magnesium sulfate, and filtered. The solvent was then evaporated under reduced pressure. To the pale green residue was added a solution of 2.5 mL of tert-butyl acetate and 146.7 mg of oxalic acid in 2-propanol (2.5 mL). The resulting mixture was heated to 75 to 80° C., stirred for 30 minutes, allowed to cool to ambient temperature (about 20° C.), stirred for 18 hours, and then filtered. The resulting cake was washed with 5 mL of 2-propanol and with 5 mL of methyl tert-butyl ether respectively and then dried, affording 0.08 g (0.27 mmol: overall yield from nitrile (h): 25percent) of hydrogenoxalate of tert-butyl (j) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: With sodium hydrogen sulfate In tert-butyl methyl ether; water for 0.5 h; Stage #2: With dmap; sodium hydrogen sulfate; di-<i>tert</i>-butyl dicarbonate In tert-butyl methyl ether; water at 20 - 25℃; for 5 - 6 h; |
A mixture of the (S)-1,2,3,4-tetrahydro-1-naphthylammonium salt prepared as in Example 3, Method 1 (81.7 g, 0.203 mol), t-butyl methyl ether (400 mL) and 5percent NaHSO4-H2O (867 mL, 0.304 mol) was stirred for 30 minutes until all solids were dissolved. The organic phase was washed with water (334 mL) then concentrated to 259 mL. t-Butyl methyl ether (334 mL) was added and the solution was concentrated again to 259 mL. The addition-concentration process was repeated twice more. After the final concentration, t-BuOH (158 mL) and dimethylaminopyridine (5.04 g, 41.3 mmol) were added. A solution of Boc2O (67.6 g, 0.31 mol) in t-butylmethyl ether (52.0 mL) was added. After stirring for 5 hours at ambient temperature, t-butyl methyl ether (158 mL) and 5percent aqueous NaHSO4-H2O (260 mL) were added and the resultant mixture was stirred. The organic phase was washed with 5percent aqueous NaCl (twice, 260 mL each). The organic phase was concentrated to 320 mL, and tetrahydrofuran (320 mL) was added. The organic phase was concentrated again to 320 mL, and tetrahydrofuran (320 mL) was added. After concentrating to 320 mL once more, methane sulfonic acid (80.1 g, 0.62 mol) was added and the solution was stirred at ambient temperature for 4.5 hours. The reaction mixture was added to a 30percent aqueous solution of K2CO3 (571 mL) and stirred. The aqueous phase was extracted with isopropyl acetate (320 mL). The combined organic phases were concentrated to 320 mL, and isopropyl acetate (320 mL) was added. The organic solution was concentrated again to 320 mL. The organic phase was washed with water (320 mL). Isopropyl acetate (320 mL) was added to the organic phase and the solution was concentrated to 192 mL. Isopropyl acetate (320 mL) was added a second time, and the organic solution was concentrated to 192 mL. A solution of oxalic acid (24.1 g, 267 mmol) in isopropyl acetate (448 mL) was added to the organic solution over 2 hours. The mixture was stirred for 2-4 hours, and the slurry was filtered. The white solids were rinsed with isopropyl acetate (100 mL) and dried at 35-40° C. under vacuum to yield 52.6 g of the title compound (85percent yield); A mixture of (S)-1,2,3,4-tetrahydro-1-naphthylammonium salt as prepared by the method of Example 3, Method 2 (148 g, 0.609 mol), t-butyl methyl ether (726 mL) and 5percent NaHSO4-H2O (1.58 L, 0.913 mol) was stirred until all of the solids had dissolved. The phases were separated and the organic phase washed with water (726 mL). The organic phase was concentrated to about 400 mL. t-Butyl methyl ether (726 mL) was added and the mixture concentrated to 590 mL. The addition of t-butyl methyl ether and concentration was repeated to give a final volume of 350 mL. Dimethylaminopyridine (8.42 g, 68.9 mmol) and t-butyl alcohol (260 mL) were added, followed by addition of a solution of Boc2O (112 g, 0.52 mol) in MTBE (88 mL) over 0.5 hour. The mixture was stirred for 5 hours at 22-25° C. A solution of 5percent sodium bisulfate in water was added and the mixture stirred for 0.5 hour. The organic phase was washed with 5percent sodium chloride (twice, 440 mL each) and concentrated to 270 mL. Tetrahydrofuran (540 mL) was added and the mixture concentrated to 270 mL; this procedure was repeated twice more to give a final volume of 270 mL. Methane sulfonic acid (67 mL) was added over 0.5 hour while maintaining a temperature of lower than 30° C. and the mixture stirred at 22-25° C. for 12 hours. The mixture was added to a 30percent aqueous solution of potassium carbonate (478 mL) while maintaining a temperature of 22-25° C. The mixture was filtered, the phases separated and the aqueous phase extracted with isopropyl acetate (twice, 540 mL each). The organic phase was concentrated to 270 mL, then twice evaporated with isopropyl acetate (540 ml) to give a final volume of 540 mL. The organic phase was washed with water (twice, 540 mL), then twice evaporated with isopropyl acetate (320 mL) to give a final volume of 320 mL. Additional isopropyl acetate (429 mL) was added followed by addition of a solution of oxalic acid (40.4 g, 0.448 mol) in t-butylmethyl ether (321 mL) over 2 hours maintaining a temperature of 22-25° C. The mixture was stirred for 3 hours at 22-25° C. then filtered. The filter cake was washed with isopropyl acetate (100 mL) and the product dried at 35-40° C. under vacuum to give the title compound as a white solid (88.4 g, 81percent). |
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