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Chemical Structure| 764667-65-4 Chemical Structure| 764667-65-4

Structure of rac-Sitagliptin 3-Ketone
CAS No.: 764667-65-4

Chemical Structure| 764667-65-4

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Product Details of [ 764667-65-4 ]

CAS No. :764667-65-4
Formula : C16H12F6N4O2
M.W : 406.28
SMILES Code : O=C(N1CC2=NN=C(C(F)(F)F)N2CC1)CC(CC3=CC(F)=C(F)C=C3F)=O
MDL No. :MFCD11111443
InChI Key :QAEDTLFWHIEVPK-UHFFFAOYSA-N
Pubchem ID :9887588

Safety of [ 764667-65-4 ]

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

Computational Chemistry of [ 764667-65-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 28
Num. arom. heavy atoms 11
Fraction Csp3 0.38
Num. rotatable bonds 6
Num. H-bond acceptors 10.0
Num. H-bond donors 0.0
Molar Refractivity 84.74
TPSA ?

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

68.09 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.35
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

1.13
Log Po/w (WLOGP)?

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

4.14
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.

2.85
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

3.65
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.82

Water Solubility

Log S (ESOL):?

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

-2.97
Solubility 0.44 mg/ml ; 0.00108 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.

-2.15
Solubility 2.85 mg/ml ; 0.00702 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

-5.07
Solubility 0.00347 mg/ml ; 0.00000853 mol/l
Class?

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

Moderately 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

Yes
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

Yes
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.

-7.98 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

0.0
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

2.0 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)

2.96

Application In Synthesis of [ 764667-65-4 ]

* 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 [ 764667-65-4 ]

[ 764667-65-4 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 486460-21-3 ]
  • [ 764667-64-3 ]
  • [ 764667-65-4 ]
  • 2
  • [ 2033-24-1 ]
  • [ 486460-21-3 ]
  • [ 209995-38-0 ]
  • [ 764667-65-4 ]
YieldReaction ConditionsOperation in experiment
84% In 2000 mL of three necked flask , 150g(0.789mil)2,4,5- Trifluorophenylacetic acid,125g(0.86mol) isopropylidene malonate and 7.7g(63mol)DMAP(4-dimethylaminopyridine) were addded , plus 525 ml DMA (N,N- Dimethylacetamide) was dissolved with magnetic stirring .296mL(1.696mol)DIPEA(N,N-Diisopropylethylamine) was added at room temperature . The oil bath was heated to a reaction temperature of 50 C and 107 mL (0.868 mol) of pivaloyl chloride was added dropwise,Keeping the temperature above 55 C (1-2h). After completion of the dropwise addition at 55 C for 2 h, 3- (trifluoromethyl) -5,6,7,8-tetrahydro-1,2,4-triazolo [4,3-a] pyrazine (0.789 mol) was added, followed by 18 mL (0.237 mol) of trifluoroacetic acid was added dropwise, keeping the temperature at 55 C for 6 h. After cooling, 625 mL of 5% sodium bicarbonate solution was added, after adding 5g of the compound shown in the formula I keep temperature at 20 ~ 30 C and stirring for 2h,add 5% of sodium bicarbonate solution dropwise for 3 h, Stir at room temperature until no more solids are produced, after cooling to 5 C for 1 h, filtered and washed using three times with 200 mL of 20% DMA solution, washed with 400 mL of water and vaccum drying to obtain 269 g of solid which was tested as a compound of formula I in 84% yield,m/z:407.15[M+H]+.
  • 3
  • [ 1151240-88-8 ]
  • [ 486460-21-3 ]
  • [ 764667-65-4 ]
YieldReaction ConditionsOperation in experiment
82% With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 1h; Potassium tert-butoxide (2.24 g, 20 mmol) was dissolved in 40 mL of tetrahydrofuran in a 100 mL single-necked flask.Stir at room temperature for one minute. Then compound III (1.91 g, 10 mmol) was added in sequence.Compound II (2.60 g, 10 mmol) was stirred at room temperature for 60 min.Thereafter, the reaction solvent tetrahydrofuran was distilled off under reduced pressure, and then 50 mL of water and 50 mL of dichloromethane were added.The organic phase was extracted and the organic phase was dried with anhydrous sodium sulfate and evaporatedThe crude product was recrystallized from dichloromethane and cyclohexane to give 3.33 g of Compound IV.The yield was 82% and the purity was 99%.
  • 4
  • [ 1256815-03-8 ]
  • [ 486460-21-3 ]
  • [ 764667-65-4 ]
YieldReaction ConditionsOperation in experiment
91% Dichloromethane (100 ml) and the keto acid compound (10.0 g, 43.07 mmol) prepared in Example 8 were added to a 250 ml three-necked flask, and dissolved by stirring. Oxalyl chloride (6.56 g, 51.68 mmol) was added dropwise at 10 to 15 C, and the dropwise addition was completed, and the mixture was heated to 30 to 35 C to stir the reaction. The reaction was completed, and concentrated under reduced pressure at 30 to 40 C to dryness to pale-yellow liquid (10.91 g, 43.64 mmol), methylene chloride (100 ml), triethylamine (5.79 g, 57.24 mmol) and the above yellow liquid (10.0 g, 52.04 mmol) was dissolved by stirring. The solution of the free base (13.0 g, 52.04 mmol) / dichloromethane (20 ml) of the compound of the formula a was added dropwise to 0 to 5 C, and the dropwise addition was completed. After the completion of the dropwise addition, the mixture was heated to 10 to 15 C to stir the reaction. The reaction was completed, water was added and stirred. Layering, taking the lower organic phase and discarding the upper aqueous phase. The organic phase was washed with a 5% aqueous solution of sodium chloride and concentrated to dryness to dryness to dryness to afford white solid (19.24 g, 47.36 mmol) as a ketoamide compound in a molar yield of 91%.
 

Historical Records

Technical Information

Categories

Pharmaceutical Intermediates of
[ 764667-65-4 ]

Sitagliptin Intermediates

Chemical Structure| 486460-20-2

[486460-20-2]

3-(Trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine

Related Functional Groups of
[ 764667-65-4 ]

Fluorinated Building Blocks

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(2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine

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8-Methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine

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Aryls

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A180769 [767340-03-4]

(2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine

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A211352 [1159553-30-6]

3-(4-Fluorobenzyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine

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Amides

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Chemical Structure| 1448428-04-3

A156190 [1448428-04-3]

5-(4-Cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide

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Trifluoromethyls

Chemical Structure| 767340-03-4

A180769 [767340-03-4]

(2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine

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Related Parent Nucleus of
[ 764667-65-4 ]

Other Aromatic Heterocycles

Chemical Structure| 767340-03-4

A180769 [767340-03-4]

(2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine

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A211352 [1159553-30-6]

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