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Structure of 51498-33-0

Chemical Structure| 51498-33-0

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Product Details of [ 51498-33-0 ]

CAS No. :51498-33-0
Formula : C9H17NO2
M.W : 171.24
SMILES Code : CCOC(=O)C1CCC(N)CC1
MDL No. :MFCD01995051
InChI Key :WASRJUXSLHUONH-UHFFFAOYSA-N
Pubchem ID :409963

Safety of [ 51498-33-0 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 51498-33-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 0
Fraction Csp3 0.89
Num. rotatable bonds 3
Num. H-bond acceptors 3.0
Num. H-bond donors 1.0
Molar Refractivity 47.26
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

52.32 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.16
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

0.78
Log Po/w (WLOGP)?

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

1.07
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.

1.0
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

0.99
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.2

Water Solubility

Log S (ESOL):?

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

-1.2
Solubility 10.9 mg/ml ; 0.0638 mol/l
Class?

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

Very soluble
Log S (Ali)?

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

-1.46
Solubility 5.95 mg/ml ; 0.0347 mol/l
Class?

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

Very 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

-1.2
Solubility 10.7 mg/ml ; 0.0627 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.

-6.79 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.

0.55

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)

2.52

Application In Synthesis of [ 51498-33-0 ]

* 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 [ 51498-33-0 ]

[ 51498-33-0 ] Synthesis Path-Downstream   1~36

  • 1
  • [ 1776-53-0 ]
  • [ 64-17-5 ]
  • [ 51498-33-0 ]
YieldReaction ConditionsOperation in experiment
100% With thionyl chloride; at 80℃;Cooling with ice; To an ice-cold solution of 4-aminocyclohexanecarboxylic acid (5.0 g, 34.92 mmol) in ethanol (20 mL) was added thionyl chloride (7.60 ml, 104.76 mmol) and the mixture heated up to 80 C. for 2-3 h. After the completion of reaction (by TLC), the solvent was evaporated under reduced pressure to give the desired product in quantitative yield.
With thionyl chloride; at 20℃; for 16h; Thionyl chloride (0.32 ml, 4.40 mmol) was slowly added to a mixture of 4-aminocyclohexanecarboxylic acid (572 mg, 4.00 mmol) in EtOH (10 ml) and stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, azeotroping with toluene, to give the corresponding ethyl ester (650 mg) as a pale solid.A mixture of the ethyl ester (103 mg, 0.60 mmol), 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), EDC (115 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) in DMF (5 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgSO^ and reduced in vacuo to give 4-[4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carbonyl]-amino}- cyclohexanecarboxylic acid ethyl ester (112 mg).
With thionyl chloride; at 20℃; for 16h; Thionyl chloride (0.32 ml, 4.40 mmol) was slowly added to a mixture of 4-aminocyclohexanecarboxylic acid (572 mg, 4.00 mmol) in EtOH (10 ml) and stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, azeotroping with toluene, to give the corresponding ethyl ester (650 mg) as a pale solid.A mixture of the ethyl ester (103 mg, 0.60 mmol), 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), EDC (115 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) in DMF (5 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgSO^ and reduced in vacuo to give 4-[4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carbonyl]-amino}- cyclohexanecarboxylic acid ethyl ester (112 mg).
7.23 g With thionyl chloride; In ethanol; at 80℃; for 3h;Cooling with ice; To an ice-cold solution of 4-aminocyclohexanecarboxylic acid (5.0 g, 34.92 mmol) in EtOH (20 mL) was added thionyl chloride (7.60 mL, 104.76 mmol). The mixture was heated at 80 C. for 3 h. The solvent was evaporated in vacuo to obtain i (7.23 g). 1H NMR (400 MHz, DMSO-d6): delta 4.19 (q, J=7.20 Hz, 2H), 3.71 (m, 1H), 2.71 (m, 1H), 2.06 (m, 2H), 1.90 (m, 2H), 1.69 (m, 2H), 1.55 (m, 2H), and 1.25 (t, J=7.20 Hz, 3H).

  • 2
  • [ 1943-83-5 ]
  • [ 51498-33-0 ]
  • [ 13908-22-0 ]
  • 3
  • [ 6138-90-5 ]
  • [ 51498-33-0 ]
  • [ 51857-72-8 ]
  • 4
  • [ 6138-90-5 ]
  • [ 51498-33-0 ]
  • [ 51857-73-9 ]
  • 5
  • [ 90942-89-5 ]
  • [ 51498-33-0 ]
  • 6
  • [ 51498-33-0 ]
  • [ 90942-89-5 ]
YieldReaction ConditionsOperation in experiment
B. In a similar manner, the following esters are made: 1-ethoxycarbonyl-2-aminocyclopentane; 1-ethoxycarbonyl-2-aminocyclohexane; 1-ethoxycarbonyl-3-aminocyclohexane; 1-ethoxycarbonyl-4-aminocyclohexane; 3-ethoxycarbonylmethyl-2-oxopiperazine; 1,1-diethoxycarbonyl-4-aminocyclohexane; 1,3-diethoxycarbonyl-4-aminocyclohexane; 1-ethoxycarbonyl-1,2-dihydroxycyclobutane; 1-ethoxycarbonyl-3-hydroxycyclobutane; ...
  • 9
  • [ 150-13-0 ]
  • [ 51498-33-0 ]
  • 10
  • [ 57555-71-2 ]
  • [ 51498-33-0 ]
  • 11
  • [ 825618-95-9 ]
  • [ 51498-33-0 ]
  • 4-[4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carbonyl]-amino}-cyclohexanecarboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
Thionyl chloride (0.32 ml, 4.40 mmol) was slowly added to a mixture of 4-aminocyclohexanecarboxylic acid (572 mg, 4.00 mmol) in EtOH (10 ml) and stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, azeotroping with toluene, to give the corresponding ethyl ester (650 mg) as a pale solid.A mixture of the ethyl ester (103 mg, 0.60 mmol), 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), EDC (115 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) in DMF (5 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgSO^ and reduced in vacuo to give 4-[4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carbonyl]-amino}- cyclohexanecarboxylic acid ethyl ester (112 mg).
Thionyl chloride (0.32 ml, 4.40 mmol) was slowly added to a mixture of 4-aminocyclohexanecarboxylic acid (572 mg, 4.00 mmol) in EtOH (10 ml) and stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, azeotroping with toluene, to give the corresponding ethyl ester (650 mg) as a pale solid.A mixture of the ethyl ester (103 mg, 0.60 mmol), 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), EDC (115 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) in DMF (5 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgSO^ and reduced in vacuo to give 4-[4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carbonyl]-amino}- cyclohexanecarboxylic acid ethyl ester (112 mg).
With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h; Thionyl chloride (0.32 ml, 4.40 mmol) was slowly added to a mixture of 4- aminocyclohexanecarboxylic acid (572 mg, 4.00 mmol) in EtOH (10 ml) and stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, azeotroping with toluene, to give the corresponding ethyl ester (650 mg) as a pale solid. A mixture of the ethyl ester (103 mg, 0.60 mmol), 4- (2, 6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), EDC (115 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) in DMF (5 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgS04) and reduced in vacuo to give 4-[4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carbonyl]0amino}-cyclohexanecarboxylic acid ethyl ester (112 mg).
  • 12
  • [ 1776-53-0 ]
  • [ 51498-33-0 ]
YieldReaction ConditionsOperation in experiment
With thionyl chloride; In ethanol; at 20℃; for 16h; Thionyl chloride (0.32 ml, 4.40 mmol) was slowly added to a mixture of 4- aminocyclohexanecarboxylic acid (572 mg, 4.00 mmol) in EtOH (10 ml) and stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, azeotroping with toluene, to give the corresponding ethyl ester (650 mg) as a pale solid. A mixture of the ethyl ester (103 mg, 0.60 mmol), 4- (2, 6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (134 mg, 0.50 mmol), EDC (115 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) in DMF (5 ml) was stirred at ambient temperature for 16 hours. The mixture was reduced in vacuo, the residue taken up in EtOAc and washed successively with saturated aqueous sodium bicarbonate, water and brine. The organic portion was dried (MgS04) and reduced in vacuo to give 4-[4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carbonyl]0amino}-cyclohexanecarboxylic acid ethyl ester (112 mg).
  • 14
  • [ 51498-33-0 ]
  • trans-4-aminocyclohexanecarboxylic acid ethyl ester hydrochloride [ No CAS ]
  • cis-4-aminocyclohexane-carboxylic acid ethyl ester hydrochloride [ No CAS ]
  • 15
  • [ 51498-33-0 ]
  • trans-4-aminocyclohexanecarboxylic acid ethyl ester hydrochloride [ No CAS ]
  • 16
  • [ 51498-33-0 ]
  • [ 501-53-1 ]
  • [ 820232-35-7 ]
YieldReaction ConditionsOperation in experiment
98.5% With sodium carbonate; In water; toluene; at 10℃; for 0.5h; To the residue of <strong>[51498-33-0]ethyl 4-aminocyclohexanecarboxylate</strong> (Net 33 g, 0.2 mol) obtained in (1) above is dissolved in toluene (165 mL) and water (165 mL), and thereto is added sodium carbonate (31.8 g, 0.3 mol). Benzyloxycarbonyl chloride (34.1 g, 0.2 mol) is added dropwise to the mixture at 10C or below over 30 minutes, and thereto is added water to dissolve the resulting salts, whereby the solution is partitioned. The aqueous layer is re-extracted with ethyl acetate. The organic layers are combined, dried over magnesium sulfate, and concentrated to give ethyl 4-benzyloxycarbonylaminocyclohexanecarboxylate (60.17 g, yield: 98.5%) as oil. IR : nu = 3346, 1710 cm-1 MS: m/z = 306 [(M+1)+] .
  • 17
  • [ 4857-06-1 ]
  • [ 51498-33-0 ]
  • cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In ethanol; ethyl acetate; A mixture of 2-Chlorobenzimidazole (I) (0.9 g, 5.9 mmol) and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were placed in a glass high pressure tube. Diisopropylethylamine (2.8 mL, 16.2 mmol) was added, the reaction vessel was sealed and heated to 200 C. for 4 h and allowed to cool to room temperature. Next was added 5 mL EtOH and heated to dissolve the reaction mixture. The reaction mixture was partitioned between aqueous NaHCO3 and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. Purification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc) gave the cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (J) (0.5 g) and the trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (0.5 g). Data for (J): 1H NMR (300 MHz, CDCl3) delta 7.28 (br s, 2 H), 7.02 (m, 2 H), 5.16 (br s, 1 H), 4.15 (q, 2 H), 3.97 (br s, 1 H), 2.40 (br s, 1 H), 1.80-1.54 (m, 8 H), 1.22 (t, 3 H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288].
With N-ethyl-N,N-diisopropylamine; In ethanol; ethyl acetate; A mixture of 2-Chlorobenzimidazole (I) (0.9 g, 5.9 mmol) and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were placed in a glass high pressure tube. Diisopropylethylamine (2.8 mL, 16.2 mmol) was added, the reaction vessel was sealed and heated to 200 C. for 4 h and allowed to cool to room temperature. Next was added 5 mL EtOH and heated to dissolve the reaction mixture. The reaction mixture was partitioned between aqueous NaHCO3 and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. Purification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc) gave the cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (J) (0.5 g) and the trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (0.5 g). Data for (J): 1H NMR (300 MHz, CDCl3) delta7.28 (br s, 2 H), 7.02 (m, 2 H), 5.16 (br s, 1 H), 4.15 (q, 2 H), 3.97 (br s, 1 H), 2.40 (br s, 1 H), 1.80-1.54 (m, 8 H), 1.22 (t, 3 H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288].
With N-ethyl-N,N-diisopropylamine; In ethanol; ethyl acetate; A mixture of 2-Chlorobenzimidazole (I) (0.9 g, 5.9 mmol) and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were placed in a glass high pressure a tube. Diisopropylethylamine (2.8 mL, 16.2 mmol) was added, the reaction vessel was sealed and heated to 200 C. for 4 h and allowed to cool to room temperature. Next was added 5 mL EtOH and heated to dissolve the reaction mixture. The reaction mixture was partitioned between aqueous NaHCO3 and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. Purification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc) gave the cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (J) (0.5 g) and the trans 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (0.5 g) Data for (J): 1H NMR (300 MHz, CDCl3) delta 7.28 (br s, 2H), 7.02 (m, 2H), 5.16 (br s, 1H), 4.15 (q, 2H), 3.97 (br s, 1H), 2.40 (br s, 1H), 1.80-1.54 (m, 8H), 1.22 (t, 3H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288].
  • 18
  • [ 4857-06-1 ]
  • [ 51498-33-0 ]
  • cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester [ No CAS ]
  • trans 4-(1H-benzirnidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; In ethanol; ethyl acetate; A mixture of 2-Chlorobenzimidazole (I) (0.9 g, 5.9 mmol) and ethyl-4-amino-cyclohexane carboxylate (1.1 g, 5.4 mmol) were placed in a glass high pressure tube. Diisopropylethylamine (2.8 mL, 16.2 mmol) was added, the reaction vessel was sealed and heated to 200 C. for 4 h and allowed to cool to room temperature. Next was added 5 mL EtOH and heated to dissolve the reaction mixture. The reaction mixture was partitioned between aqueous NaHCO3 and EtOAc, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. Purification of the crude product on silica gel (gradient, 1:1 hexanes:EtOAc to EtOAc) gave the cis 4-(1H-benzimidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (J) (0.5 g) and the trans 4-(1H-benzirnidazol-2-ylamino)-cyclohexanecarboxylic acid ethyl ester (K) (0.5 g). Data for (J): 1H NMR (300 MHz, CDCl3) delta 7.28 (br s, 2 H), 7.02 (m, 2 H), 5.16 (br s, 1 H), 4.15 (q, 2 H), 3.97 (br s, 1 H), 2.40 (br s, 1 H), 1.80-1.54 (m, 8 H), 1.22 (t, 3 H); mass spectrum m/z 288 [(M+H)+; calcd for C16H22N3O2: 288].
  • 19
  • CH2 Cl2 -MeOH [ No CAS ]
  • [ 51498-33-0 ]
  • [ 135689-93-9 ]
  • [ 137864-30-3 ]
YieldReaction ConditionsOperation in experiment
a) Ethyl cis-4-[(2'-cyanobiphenyl-4-yl)methylamino]cyclohexane-1-carboxylate is obtained from 4.145 g of 2'-cyanobiphenyl-4-carbaldehyde and 5.137 g of ethyl 4-aminocyclohexane-1-carboxylate analogously to Example 1b) and purified on silica gel 60 (40-63 mum) using CH2 Cl2 -MeOH 99.5:0.5, Rf =0.18 (system N6).
  • 20
  • [ 51498-33-0 ]
  • [ 168273-05-0 ]
  • C26H26Cl3N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; Scheme 2 describes how the conversion of the carboxylic acid from Scheme 1 to its acid chloride using thionyl chloride or oxalyl chloride in dichloroethane at elevated temperatures followed by treatment with ethyl 4-aminocyclohexane carboxylate in the presence of triethyl amine should afford the amide ester (step a). Hydrolysis of the ester with lithium hydroxide and acidification with dilute hydrochloric acid solution should yield the amide carboxylic acid (step b). When this acid is further treated with Boc anhydride (Boc2O) in THF in the presence of pyridine, followed by a solution of ammonia in THF at 0 degrees to ambient temperature, the carboxamido compound will be produced (step c).
  • 21
  • 1-(2-methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole [ No CAS ]
  • [ 51498-33-0 ]
  • 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
99.7% In 1,4-dioxane; at 110℃; for 5h; A mixture of 1-(2-methanesulfinyl-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (25 g, 64 mM) and <strong>[51498-33-0]4-amino-cyclohexanecarboxylic acid ethyl ester</strong> (16.3 g, 95.3 mM) in dioxane (400 mL) and heated at 110 C. for approximately 5 h. The solution was concentrated in vacuo to give a white residue. The residue was suspended in H2O, filtered and washed in H2O, and dried at 60 C. in vacuo to yield 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (31.7 g, 99.7%).
  • 22
  • [ 1231716-64-5 ]
  • [ 51498-33-0 ]
  • 4-[4-(4-bromoindol-1-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
89% In 1,4-dioxane; at 110℃; for 5.5h;Inert atmosphere; (C) A mixture of 4-bromo-1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-indole (4.98 g) and <strong>[51498-33-0]4-amino-cyclohexanecarboxylic acid ethyl ester</strong> (5.07 g) in 1,4-dioxane (100 mL) was stirred at 110 C. under N2 for 5.5 h. The solvent was removed in vacuo to provide an oil, which solidified at RT. The product was flash chromatographed on silica, eluding with hexanes/EtOAc (7:3 to 6:4) to provide 4-[4-(4-bromoindol-1-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (5.82 g, 89%) as a white powder.
  • 23
  • [ 1231716-55-4 ]
  • [ 51498-33-0 ]
  • 4-[4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-ylamino]-cyclohexane-carboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% In 1,4-dioxane; at 110℃; for 4h; (F) A mixture of 4-iodo-1-(2-methylsulfinyl-pyrimidin-4-yl)-1H-benzotriazole (2.0 g) and <strong>[51498-33-0]4-amino-cyclohexanecarboxylic acid ethyl ester</strong> (1.8 g) in 1,4-dioxane (25 mL) was stirred at 110 C. for 4 h. The solvent was removed in vacuo to provide an oil, which was taken up in EtOH and heated in a water bath until a light orange solid formed. The solid was filtered, washed with Et2O, and dried to provide 4-[4-(4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-ylamino]-cyclohexane-carboxylic acid ethyl ester (3.56 g, 93%) as a light orange powder.
  • 24
  • [ 1296653-98-9 ]
  • [ 51498-33-0 ]
  • [ 1296654-04-0 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In toluene; for 3h;Reflux; Example 3:4-ir 4-hvdroxy-l-methvI-2-oxo-l,2-dihydropyridazinofl,6-fl1indol-3-yl)carbonyll amino} cyclohexanecarboxylic acid (Compound no. 22)Step A : Preparation of Ethyl 4- { r(4-hydroxy-l-methyl-2-oxo-1.2-dihydropyridazino l,6-a]indol-3-yl)carbonyllamino|cyclohexanecarboxylate . To the solution of 0.4 g (1.39 mmol) of the product of Step G of example 1 in toluene (10 ml) containing triethylamine (0.8 ml, 2.79 mmol), the ethyl-4-amino cyclohexyl carboxylate (0.3 g, 1.7 mmol) was added and refluxed for 3 h. After completion of reaction, the mixture was diluted with water (20 ml) and partitioned between water and ethyl acetate (2 x 50 ml). The combined organic layers was dried over anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by column chromatography on silica gel using 70% ethyl acetate in hexane as the eluent to provide the titled compound (0.15 g) as yellow solid. NMR (400 MHz, DMSOd6) delta : 1.18 - 1.22 (3H, t), 1.7 - 1.74 (8H, m), 4.0 - 4.12 (5H, m), 7.24 - 7.31 (2H, m), 7.34 - 7.38 (1H, t), 7.83 - 7.85 (1H, d), 8.13 - 8.15 (lH, d), 10.19 (lH, s). m/z = 412 (M+H)+ - '
  • 25
  • [ 51498-33-0 ]
  • [ 3306-69-2 ]
YieldReaction ConditionsOperation in experiment
In toluene;Reflux; Example 4.48b. Synthesis of 2-azabicvclor2.2.21octan-3-oneA solution of <strong>[51498-33-0]ethyl 4-aminocyclohexanecarboxylate</strong> (0.6 g, 3.49 mmol), toluene (1 mL) in oil bath (170 C) was heated for 2-3 h to dryness. After cooling to rt, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over Na2S04. After filtration and concentration, 300 mg of the desired product was obtained by column chromatography purification. MS (ESI): 126 (MH+).
  • 26
  • [ 17159-79-4 ]
  • [ 51498-33-0 ]
YieldReaction ConditionsOperation in experiment
With ammonia; hydrogen;palladium 10% on activated carbon; In methanol; at 0 - 20℃; under 760.051 Torr; for 36h; Example 4.48a. Synthesis of ethyl 4-aminocvclohexanecarboxylateEthyl 4-oxocyclohexanecarboxylate (3.0 g, 17.65 mmol) was dissolved in 150 mL methanol saturated with ammonia at 0 C, and to the solution was added wet 10% Pd/C catalyst (4.0 g). The mixture was stirred at room temperature under hydrogen (1 atm) for about 36 h. Then the catalyst was then removed by filtration and the filtrate was concentrated to give the crude product, which was purified by chromatography on silica gel to give 2.0 g of the desired product. MS (ESI): 172 (MH+).
  • 27
  • [ 3618-04-0 ]
  • [ 51498-33-0 ]
YieldReaction ConditionsOperation in experiment
With (carbonyl)chloro(hydrido)tris(triphenylphosphine)ruthenium(II); ammonia; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tert-Amyl alcohol; at 130℃; for 20h;Inert atmosphere; Cooling; Example 6Direct Single-Stage Amination of Alcohols andHydroxy Acids by Means of Ammonia Over aHomogeneous Ruthenium Catalyst and Xantphos ata high V7J Vgas (according to the invention)Under an argon atmosphere, m g of starting material, mRU g of [carbonylchlorohydridotris(triphenylphosphane)ruthenium(II)] and mp g of 9,9-dimethyl-4,5-bis (diphenylphosphino)xanthene as catalyst and V07 ml of 2-methyl-2-butanol as solvent were introduced into a 50 mlsteel tube. The vessel was closed, pressurized three times with 20 bar of argon and depressurized each time. The vessel was then cooled by means of dry ice and m g of ammonia were condensed in. The reactor is heated to T C. and maintained at this temperature for 20 hours. Afier cooling to room temperature, the reactor was depressurized and opened, the solvent was removed on a rotary evaporator and the residue was dissolved in methanol and then analysed by gas chromatography. Reaction parameters and conversions and selectivities to the desired reaction product are shown in Tab. 5. The results show that many different hydroxy-thnctionalized substrates can be aminated by the method described.
  • 28
  • [ 51498-33-0 ]
  • [ 1357280-81-9 ]
  • 29
  • [ 51498-33-0 ]
  • [ 1310478-81-9 ]
  • 30
  • [ 51498-33-0 ]
  • [ 1372547-78-8 ]
  • 31
  • [ 51498-33-0 ]
  • [ 1372547-79-9 ]
  • 32
  • [ 85-44-9 ]
  • [ 51498-33-0 ]
  • [ 709638-18-6 ]
YieldReaction ConditionsOperation in experiment
34% With triethylamine; In toluene;Reflux; A solution of <strong>[51498-33-0]ethyl 4-aminocyclohexanecarboxylate</strong> (0.50 g, 2.92 mmol) in toluene (10 mL) was added Et3N (1.02 mL, 7.30 mmol) and phthalic anhydride (0.56 g, 3.80 mmol) and the mixture refluxed for 6-8 h using dean-stark apparatus to remove water. After completion of the reaction (by TLC), the solvent was evaporated under reduced pressure, water (50 mL) added and stirred for 30 min at rt. The solid material thus obtained was collected by filtration under vacuum and dried to obtain the desired product as off-white solid (0.30 g, 34%). 1H NMR (DMSO-d6): delta 7.84 (s, 4H), 4.19 (q, J=7.20 Hz, 2H), 3.71 (m, 1H), 2.71 (m, 1H), 2.06 (m, 2H), 1.90 (m, 2H), 1.69 (m, 2H), 1.60 (m, 2H), and 1.23 (t, J=7.20 Hz, 3H).
34% With triethylamine; In toluene; for 8h;Reflux; Dean-Stark; A solution of i (0.50 g, 2.92 mmol) in toluene (10 mL) was added Et3N (1.02 mL, 7.30 mmol) and phthalic anhydride (0.56 g, 3.80 mmol). The mixture was refluxed for 8 h using a dean-stark apparatus for removal of H2O. The solvent was evaporated in vacuo, H2O (50 mL) added and the mixture stirred for 30 min at RT. The solid material thus obtained was collected by filtration and dried to obtain ii (0.30 g, 34%). 1H NMR (400 MHz, DMSO-d6): delta 7.84 (s, 4H), 4.19 (q, J=7.20 Hz, 2H), 3.71 (m, 1H), 2.71 (m, 1H), 2.06 (m, 2H), 1.90 (m, 2H), 1.69 (m, 2H), 1.60 (m, 2H), and 1.23 (t, J=7.20 Hz, 3H).
  • 33
  • [ 611-35-8 ]
  • [ 51498-33-0 ]
  • ethyl 4-(quinolin-4-ylamino)cyclohexanecarboxylate [ No CAS ]
  • 34
  • [ 364-74-9 ]
  • [ 51498-33-0 ]
  • C15H19FN2O4 [ No CAS ]
  • 35
  • [ 51498-33-0 ]
  • C15H21FN2O2 [ No CAS ]
  • 36
  • [ 51498-33-0 ]
  • C16H20FN3O2 [ No CAS ]
 

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