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Chemical Structure| 1460-16-8

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Product Details of [ 1460-16-8 ]

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

Safety of [ 1460-16-8 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 1460-16-8 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

37.3 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.67
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

2.5
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.04
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.57
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.6
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.88

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.23
Solubility 0.836 mg/ml ; 0.00588 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-2.93
Solubility 0.168 mg/ml ; 0.00118 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-0.94
Solubility 16.2 mg/ml ; 0.114 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.39 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.56

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.46

Application In Synthesis of [ 1460-16-8 ]

* 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.

  • Downstream synthetic route of [ 1460-16-8 ]

[ 1460-16-8 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 1460-16-8 ]
  • [ 6557-86-4 ]
YieldReaction ConditionsOperation 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).

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  • 2
  • [ 79-37-8 ]
  • [ 1460-16-8 ]
  • [ 6557-86-4 ]
YieldReaction ConditionsOperation 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).
  • 3
  • [ 1460-16-8 ]
  • [ 6557-86-4 ]
  • cycloheptanecarboxylic acid anhydride [ No CAS ]
YieldReaction ConditionsOperation 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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