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Chemical Structure| 848497-98-3 Chemical Structure| 848497-98-3

Structure of 848497-98-3

Chemical Structure| 848497-98-3

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Product Details of [ 848497-98-3 ]

CAS No. :848497-98-3
Formula : C5H12ClN
M.W : 121.61
SMILES Code : CNC1CCC1.[H]Cl
MDL No. :MFCD11506003
InChI Key :AZXFWSPGAJVTRL-UHFFFAOYSA-N
Pubchem ID :50998946

Safety of [ 848497-98-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 848497-98-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 7
Num. arom. heavy atoms 0
Fraction Csp3 1.0
Num. rotatable bonds 1
Num. H-bond acceptors 1.0
Num. H-bond donors 1.0
Molar Refractivity 33.8
TPSA ?

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

12.03 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.0
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

1.51
Log Po/w (WLOGP)?

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

1.56
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.

1.14
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

1.1
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.06

Water Solubility

Log S (ESOL):?

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

-1.48
Solubility 4.03 mg/ml ; 0.0332 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.

-1.37
Solubility 5.18 mg/ml ; 0.0426 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

-1.09
Solubility 9.91 mg/ml ; 0.0815 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.

-5.97 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

2.0
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)

1.0

Application In Synthesis of [ 848497-98-3 ]

* 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 [ 848497-98-3 ]

[ 848497-98-3 ] Synthesis Path-Downstream   1~10

  • 1
  • [ 87055-64-9 ]
  • [ 848497-98-3 ]
  • 2
  • [ 611-10-9 ]
  • [ 848497-98-3 ]
  • 2-(cyclobutylmethyl-amino)-cyclopentanecarboxylic acid ethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With sodium acetate; sodium cyanoborohydride; In methanol; at 25℃; for 16h;4A molecular sieves; 2-Oxo-cyclopentanecarboxylic acid ethyl ester (0.24 mL, 1.64 mmol) and C-<strong>[848497-98-3]cyclobutyl-methylamine hydrochloride</strong> (0.20 g, 1.64 mmol) were dissolved in methanol (8 mL). Sodium acetate (0.27 g, 3.28 mmol) was added followed by 4A powdered molecular sieves (0.20 g) and sodium cyanoborohydride (0.21 g, 3.28 mmol). The reaction was stirred at 25 0C for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The <n="189"/>organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, 2-(cyclobutylmethyl- amino)-cyclopentanecarboxylic acid ethyl ester (0.29 g, 1.30 mmol, 79%) as a clear oil. LC-MS (ESI) calcd for Ci3H23NO2 225.33, found 226.2 [M+H+].
  • 3
  • [ 109183-71-3 ]
  • [ 848497-98-3 ]
  • [ 848497-97-2 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; Example 1 Step 1 (2S)-N-CYCLOBUTYL-N-METHYL-2- (TERT-BUTOXYCARBONYLAMINO)-2- cyclohexylacetamide N-Methylcyclobutylamine hydrochloride (159 mg) synthesized by the method described in Journal of Medicinal Chemistry, 1994, 37,3482 was dissolved in N, N-DIMETHYLFORMAMIDE (4 ml), and L- tert-butoxycarbonylcyclohexylglycine hydrate (159 mg), (benzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (676 mg) and diisopropylethylamine (0.453 ml) were added. The mixture was stirred overnight at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (hexane : ethyl acetate=3: 1) to give the title compound. 1H-NMR (8PPM, CDC13) 1.13-1. 37 (5H, m), 1.42 (9H, s), 1.59-1. 71 (9H, m), 2.10-2. 29 (4H, m), 4.39-4. 55 (lH, m), 4.80-4. 90 (0. 4H, m), 5.25- 5.33 (0.6H, m).
  • 4
  • [ 848498-05-5 ]
  • [ 848497-98-3 ]
  • [ 848498-06-6 ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; Step 3 (S)- [ (N-CYCLOBUTYL-N-METHYLCARBAMOYL)- (4- oxocyclohexyl) methyl] carbamic acid tert-butyl ester A solution of (S)-2- (TERT-BUTOXYCARBONYLAMINO)-2- (4- oxocyclohexyl) acetic acid (29.47 g) obtained in Step 2 in N, N- DIMETHYLFORMAMIDE (150 ml) was COOLEDTO 0OC. N- hydrochloride (19. 1 G) SYNTHESIZED in accordance with the method described in Journal of Medicinal Chemistry, 1994,37, 3482, and diisopropylethylamine (35.07 ml) were added, (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (59.84 g) was gradually added. After the completion of the addition, the mixture was allowed to warm to room temperature. Water (150 ml) was added and the mixture was extracted with a mixture of ethyl acetate-hexane. The organic layer was washed successively with 5% aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and dried over sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate=2: 3) to give the title compound (23.5 g). H-NMR (8PPM, CDCL3) 1.23-2. 49 (24H, m), 2.88-3. 09 (3H, s), 4.30- 4.58 (lH, m), 4.58-4. 75 (0.6H, m), 4.76-4. 93 (0.4H, m), 5.26-5. 49 (lH, m).
  • 5
  • (S)-N-tert-butoxycarbonyl-2-(trans-4-azidocyclohexyl)glycine [ No CAS ]
  • [ 848497-98-3 ]
  • (S)-[(trans-4-azidocyclohexyl)-(N-cyclobutyl-N-methylcarbamoyl)methyl]carbamic acid tert-butyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 20℃; Example 29 Step 1 (S)- [ (TRANS-4-AZIDOCYCLOHEXYL)- (N-CYCLOBUTYL-N- methylcarbamoyl) methyl] carbamic acid tert-butyl ester (S)-N-TERT-BUTOXYCARBONYL- (TRANS-4-AZIDOCYCLOHEXYL) glycine (2.72 g) synthesized in accordance with the method described in W002/076450, <strong>[848497-98-3]N-methylcyclobutylamine hydrochloride</strong> (1.1 g) synthesized in accordance with the method described in Journal of Medicinal Chemistry, 1994,37, 3482, and triethylamine (3.17 ML) were dissolved in N, N-dimethylformamide (25 ml), and (benzotriazole-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (5.2 g) was added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate: hexane=2: 5-1: 2) to give the title compound (2.84 g). 1H-NMR (6PPM, CDCL3) 1.06-1. 37 (4H, m), 1.42 (9H, s), 1.45-1. 80 (5H, m), 1.97-2. 34 (6H, m), 2.92 (1. 8H, s), 2.99 (1. 2H, s), 3.13-3. 24 (lH, m), 4.36-4. 48 (lH, m), 4.51-4. 58 (0.6H, m), 4.78-4. 89 (0.4H, m), 5.26- 5.37 (lH, m).
  • 6
  • [ 1163790-69-9 ]
  • [ 848497-98-3 ]
  • [ 1163790-92-8 ]
  • 7
  • [ 2969-81-5 ]
  • [ 848497-98-3 ]
  • [ 1580508-51-5 ]
  • 8
  • [ 1180501-53-4 ]
  • [ 848497-98-3 ]
  • 9
  • [ 1199809-26-1 ]
  • [ 848497-98-3 ]
  • (2R,3R,4R,5R)-5-(2-amino-6-(N-methyl-cyclobutylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
86% Step 1. Preparation of (2R,3R,4R,5R)-5-(2-amino-6-(N-methyl-cyclobutylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (21) To a solution of compound 3 (150 mg, 0.29 mmol) in MeOH (4 mL) was added <strong>[848497-98-3]N-methylcyclobutylamine hydrochloride</strong> (105 mg, 0.90 mmol) and triethylamine (190 muL, 1.00 mmol). The reaction mixture was heated at 100 C. in a sealed tube for 15 h and cooled down to room temperature. An aqueous solution containing 30% NH4OH (1 mL) was added and the reaction mixture was heated at 100 C. in a sealed tube for 2 h, cooled down and concentrated. The residue was purified by column chromatography (gradient DCM/MeOH 100:0 to 90:10) to afford product 21 (90 mg, 0.25 mmol, 86%) as a pale yellow solid.
  • 10
  • (2R)-2-(4-bromophenyl)-2-[[(tert-butoxy)carbonyl]amino]acetic acid [ No CAS ]
  • [ 848497-98-3 ]
  • tert-butyl N-[(R)-(4-bromophenyl)[cyclobutyl(methyl)carbamoyl]methyl]carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
91% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; Step 1 Into a 50-mL round-bottom flask, was placed (2R)-2-(4-bromophenyl)-2-[[(tert-butoxy)carbonyl]amino]acetic acid (1 g, 3.029 mmol, 1 equiv) in DMF (15 mL), to which was added diisopropylethylamine (1.57 g, 12.115 mmol, 4 equiv), <strong>[848497-98-3]N-methylcyclobutanamine hydrochloride</strong> (368 mg, 3.03 mmol, 1 equiv), and BOP (1.61 g, 3.63 mmol, 1.2 equiv) in sequence. The resulting solution was stirred for 2 hours at room temperature. The reaction was then quenched by the addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (4*30 mL), and the combined organic layer was washed with brine (2*10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1/1). This resulted in 1.1 g (91%) of tert-Butyl N-[(R)-(4-bromophenyl) [cyclobutyl(methyl)carbamoyl]methyl]carbamate as a yellow solid.
 

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