Structure of 1460-16-8
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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. : | 1460-16-8 |
Formula : | C8H14O2 |
M.W : | 142.20 |
SMILES Code : | O=C(O)C1CCCCCC1 |
MDL No. : | MFCD00004152 |
InChI Key : | VZFUCHSFHOYXIS-UHFFFAOYSA-N |
Pubchem ID : | 15091 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.88 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 40.23 |
TPSA ? Topological Polar Surface Area: Calculated from |
37.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.67 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.5 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.04 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.57 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.6 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.88 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.23 |
Solubility | 0.836 mg/ml ; 0.00588 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.93 |
Solubility | 0.168 mg/ml ; 0.00118 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.94 |
Solubility | 16.2 mg/ml ; 0.114 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 |
-5.39 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 |
0.56 |
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<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.46 |
* 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 |
---|---|---|
With thionyl chloride; for 1h;Heating / reflux; | A mixture of cycloheptanecarboxylic acid (5.0 g, 35.2 mmol) in 25 mL of thionyl chloride is refluxed for 1 h, and concentrated. The crude cycloheptanecarboxylic acid chloride thus obtained is used directly in the next step. | |
With thionyl chloride; for 1h;Heating / reflux; | EXAMPLE 30 3- [4- (5-CHLORO-7-CYCLOHEPTYL [1,2, 4] triazolo[1, 5-a] PYRIMIDIN-6-YL)-3, 5- difluorophenoxy] propan-1-ol ; Step A: Ethyl 3-CYCLOHEPTYL-3-OXO-2- (2, 4, 6-trifluorophenyl) propanoate A mixture of 2,4, 6-trifluorophenylacetic acid (570 mg, 3.0 MMOL), iodoethane (1.56 g, 10 MMOL), and potassium carbonate (1.38 g, 10 MMOL) in 5 mL of dimethylsulfoxide is stirred at 50 C for 3 h, and cooled to room temperature. The mixture is partitioned between diethyl ether and water. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and filtered through hydrous magnesium silicate. The filtrate is concentrated to give ethyl 2,4, 6- trifluorophenylacetate as a light yellow oil (581 mg, 2.66 MMOL). A mixture of cycloheptanecarboxylic acid (5.0 g, 35.2 MMOL) in 25 mL of thionyl chloride is refluxed for 1 h, and concentrated. The crude CYCLOHEPTANECARBOXYLIC acid chloride thus obtained is used directly in the next step. A solution of ethyl 2,4, 6-trifluorophenylacetate (436 mg, 2.0 MMOL) in 3 mL of tetrahydrofuran is cooled TO-78 C, and lithium diisopropylamide (2.0 M in HEPTANE/TETRAHYDROFURAN/ETHYLBENZENE, 1.0 mL, 2.0 MMOL) is added dropwise with stirring. The mixture is stirred at-78 C for 1 h, and cycloheptanecarboxylic acid chloride (321 mg, 2.0 MMOL) is added dropwise. The mixture is warmed to room temperature and acidified with 2 mL of 1.0 N hydrochloric acid. The product is extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of hexanes to 10% ethyl acetate in hexanes. Concentration provides ethyl 3-CYCLOHEPTYL-3-OXO-2- (2, 4,6- trifluorophenyl) propanoate as a colorless oil (410 mg). MS: m/z 341.2 (M-H). | |
With oxalyl dichloride; In dichloromethane; at 20℃; for 0.5h; | Cycloheptanecarboxylic acid (25.0 g, 0.176 mol) was dissolved in methylene chloride (100 mL) and oxalyl chloride (23 mL, 0.264 mol) was added dropwise to the solution. The reaction mixture was stirred for 30 minutes at room temperature and then concentrated under vacuum to provide the acid chloride of cycloheptanecarboxylic acid as a yellow oil. |
With oxalyl dichloride; In dichloromethane; at 20℃; for 0.5h; | Preparation of N-Methoxy-N-methyl Cycloheptyl Amide cycloheptanecarboxylic acid (25.0 g, 0.176 mol) was dissolved in methylene chloride (100 ML) and oxalyl chloride (23 ML, 0.264 mol) was added dropwise to the solution.. The reaction mixture was stirred for 30 minutes at room temperature and then concentrated under vacuum to provide the acid chloride of cycloheptanecarboxylic acid as a yellow oil. N,O-dimethylhydroxylamine hydrochloride (18.03 g, 0.185 mol) was suspended in methylene chloride (200 mL) and treated with triethylamine (49.1 mL, 0.35 mol). The mixture was stirred for 15 minutes at room temperature and then cooled to 0 C. The above-formed acid chloride of cycloheptanecarboxylic acid dissolved in methylene chloride (30 mL) was added dropwise to the cooled solution. After addition was complete, the reaction mixture was warmed to room temperature and allowed to stir for 17 hours. The mixture was then poured into water (200 mL). The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to provide N-methoxy-N-methyl cycloheptyl amide. | |
With oxalyl dichloride; In dichloromethane; at 20℃; for 0.5h; | Cycloheptanecarboxylic acid (25.0 g, 0.176 mol) was dissolved in methylene chloride (100 mL) and oxalyl chloride (23 mL, 0.264 mol) was added dropwise to the solution. The reaction mixture was stirred for 30 minutes at room temperature and then concentrated under vacuum to provide the acid chloride of cycloheptanecarboxylic acid as a yellow oil. | |
With thionyl chloride; for 1h;Heating / reflux; | A mixture of cycloheptanecarboxylic acid (5.0 g, 35.2 mmol) in 25 mL of thionyl chloride is refluxed for 1 h, and concentrated. The crude cycloheptanecarboxylic acid chloride thus obtained is used directly in the next step. | |
With oxalyl dichloride; In benzene; at 20℃; for 1h;Inert atmosphere; | Cycloheptanecarboxylic acid (520 mg, 3.66 mmol) was added to a stirred solution of oxalyl chloride (0.59 mL, 7.0 mmol) in benzene (2 mL) at room temperature. The resulting mixture was stirred at this temperature for 1 h. The product was concentrated and used in the second step without any further purification. To a stirred solution of triethylamine (3.1 mL, 22.3 mmol), ethyl vinyl ether (3.2 mL, 33mmol) and anhydrous acetonitrile (10 mL) was added dropwise over 10 min a solution ofcycloheptanecarbonyl chloride (779 mg, 4.85 mmol) in acetonitrile (5 mL). The reaction mixture washeated to reflux for 3 h. After cooling, the mixture was filtrated and was evaporated in vacuo toremove the solvent. Purification using column chromatography on silica gel (hexane/ethyl acetate =30 : 1) to afford 1b (127 mg, 0.65 mmol, 13 %) as a yellow oil. | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 1h;Inert atmosphere; | General procedure: To the solution of carboxylic acid 10-13 (2.43 mM) in dry CH2Cl2 (5.5 mL) that had been pre-cooledto 0 C, were gradually added the catalytic amount of DMF (1-2 drop) and oxalyl chloride (7.29 mM).The resulting mixture was stirred for 5 min at 0 C and then at room temperature for a further 55 min.Subsequently the solvent was evaporated under vacuum and the crude product was used further. | |
With thionyl chloride; In dichloromethane; at 40℃; for 1.5h; | Example 191 : λ/-[4-(5-[3-(1-piperidinyl)propyl]amino}-1,3,4-oxadiazol-2- yl)phenyl]cycloheptanecarboxamide; Thionyl chloride (417 mg, 3.5 mmol) was added to a solution of cycloheptanecarboxylic acid (50 mg, 0.35 mmol) in dichloromethane (1 mL) and the solution heated to 40 0C for 1.5 h. The mixture was concentrated in vacuo and the residue re-dissolved in dichloromethane (2 mL) and added to a solution of 1 ,1-dimethylethyl [5-(4-aminophenyl)- 1 ,3,4-oxadiazol-2-yl][3-(1-piperidinyl)propyl]carbamate (2 mL) followed by triethylamine (71 mg, 0.7 mmol). The reaction was stirred at room temperature overnight, after which time only partial reaction was observed. Further cycloheptanecarbonyl chloride (1.1 mmol) was synthesised as above and added to the reaction mixture along with further triethylamine (213 mg, 2.1 mmol) and the reaction stirred for a further 24 h. The solvent was removed in vacuo and the residue dissolved in 4M HCI in dioxan (2 mL) and stirred at room temperature overnight. The solvent was removed in vacuo and the crude product partially purified by column chromatography [silica gel, 2M ammonia in methanokdichloromethane (5-10 %)]. The product was further purified by MDAP and the product applied on SCX cartridge, washed with methanol and eluted with 2M ammonia in methanol before removal of solvent in vacuo to give the title compound (85 mg). LCMS (ES+ve): [M+H]+ at m/z 426 (C24H35N5O2 requires [M+H]+ at m/z 426). | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 5h; | General procedure: An oven-dried flask was charged with aliphatic carboxylic acid (1.00 equiv) and CH2Cl2 (0.50 M). Three drops of N,N-dimethylformamide (DMF) and oxalyl chloride (1.20 equiv, 1.00 M) in DCM were added dropwise. The reaction mixture was stirred vigorously at room temperature for 5 h and then evaporated DCM and redundant oxalyl chloride under the vacuum. The crude acid chloride was used for the next reaction without any further purification | |
With oxalyl dichloride; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; Sealed tube; | General procedure: Cycloheptane carboxylic acid (0.86mL, 6.29mmol) was dissolved in C2O2Cl2 (1.59mL, 18.87mmol) and 3 drops of DMF, in a vial under nitrogen. The solution was stirred at room temperature for 30min to allow the production of acyl chloride. Then the excess of C2O2Cl2 was removed by evaporation under nitrogen flux. In the meantime, compound 10-18 (4.71mmol) was dissolved in anhydrous DMF, and then triethylamine (3.18mL, 23.56mmol) was added. This latter solution was added dropwise, under nitrogen and at 0C, to the solution of acyl chloride previously prepared. Reaction mixture was stirred at room temperature for 24h. DMF was removed under reduced pressure. The residue obtained was dissolved in CHCl3 and washed three times with a solution of 5% HCl. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure to give a brown oil. 4.1.3.1 N-(1-(2-fluorobenzyl)-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)-cycloheptane-carboxamide (19) Purification by Isolera Prime - Biotage chromatography (1:1 hexane-ethyl acetate). Brown solid (0.940g, 2.64mmol, Yield: 56%). 1H NMR (CDCl3) δ: 7.54 (bs, 1H, NH); 7.39-7.36 (m, 1H, Ar-H), 7.30-7.27 (m, 1H, Ar-H), 7.16 (d, 1H, J=7.2Hz, H6-Py), 7.14-7.03 (m, 2H, Ar-H), 6.10 (d, 1H, J=7.2Hz, H5-Py), 5.14 (s, 2H, PhCH2N), 2.50-2.49 (m, 1H, CHCO), 2.11 (s, 3H, CH3-Py), 2.03-1.99 (m, 2H, CH2), 1.81-1.70 (m, 4H, 2×CH2), 1.59-1.48 (m, 6H, 3×CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; N,N-dimethyl-formamide; | The cycloheptanecarbonyl chloride was synthesised as follows: cycloheptane carboxylic acid (1.37 ml, 1.42 g, 10 mmole) was added to a dried 25 ml round bottom flask and purged with N2. To the flask was added oxalyl chloride (7.5 ml, 2 M in CH2Cl2) via syringe followed by one drop DMF. The reaction was stirred at RT overnight and the reaction concentrated under vacuum. Methylene chloride (5 ml) was added and concentrated under vacuum to remove residual oxalyl chloride (repeated 5 times). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a flamed-dried flask with magnetic stir bar, was added aliphatic acid (1.0 equiv), dried DCM (1.0 M) and triethylamine (1.05 equiv) successively. The solution was stirred for 30 minutes at 0 0C. Then acyl chloride (1.05 equiv) was added dropwise to the mixture and stirred overnight at rt. The solvent was evaporated by vacuum to afford the crude mixture. And the mixture was dissolved in n-hexane. Then the residue was filtered through a small plug of celite and concentrated to afford the anhydrides. This product was used to next catalytic reaction without any further purification. |
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