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Chemical Structure| 1694-31-1 Chemical Structure| 1694-31-1

Structure of 1694-31-1

Chemical Structure| 1694-31-1

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Product Citations

Gülten ; Şirin ; Gezer ; Ufuk ; Gündoğan ; Elmas A.

Abstract: Tetrahydropyrimidine (THPM) synthesis has an enormous importance in organic chemistry and especially in pharmaceutical applications. Pyrimidines are the most active class of N-containing heterocyclic compounds and have different biological properties. The heterocyclic ring system with a thio group occupy a unique position in medicinal chemistry. This type of compounds play an important role in synthetic drugs and in biological processes. Dihydropyrimidinethione derivatives occur widely in nature. Several modifications of THPM-5-carboxamides have attracted considerable interest of medicinal chemists due to their pharmacological and therapeutic properties. A series of 1,2,3,4-tetrahydro- 2-pyrimidinone/thione derivatives bearing a phenylcarbamoyl group at C-5 position were synthesized by one-pot three-component Biginelli condensation reaction. The reaction of acetoacetanilide as the 1,3-dicarbonyl component with various aromatic aldehydes and urea/thiourea in the presence of a catalytic amount of p-toluenesulfonic acid monohydrate (PTSA·H2O) or concentrated HCl as an efficient catalyst leads to Biginelli compounds. We have prepared eight THPM 5-carboxamide derivatives, four of them are new compounds. Their structures were confirmed by spectroscopic techniques and elemental analysis. These compounds have potential applications in organic synthesis and medicinal chemistry. We have synthesized a series of THPM-5-carboxamides by simple and efficient threecomponent Biginelli condensation reaction. Significant benefits of the present procedure include: a) application of inexpensive, non-toxic, environmentally friendly and easily available catalysts, b) the reactions are easy to carry out without high temperature and the workup is very simple, c) the required reaction times are relatively short (30-80 min with HCl and 8-24 h with PTSA·H2O), d) compatibility with various functional groups, e) the products are isolated in good to excellent yields (50-95%).

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Product Details of [ 1694-31-1 ]

CAS No. :1694-31-1
Formula : C8H14O3
M.W : 158.20
SMILES Code : CC(CC(OC(C)(C)C)=O)=O
MDL No. :MFCD00008811
InChI Key :JKUYRAMKJLMYLO-UHFFFAOYSA-N
Pubchem ID :15538

Safety of [ 1694-31-1 ]

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

Computational Chemistry of [ 1694-31-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 0
Fraction Csp3 0.75
Num. rotatable bonds 4
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 42.09
TPSA ?

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

43.37 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.08
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

0.95
Log Po/w (WLOGP)?

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

1.31
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.

0.97
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

1.22
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.31

Water Solubility

Log S (ESOL):?

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

-1.16
Solubility 11.1 mg/ml ; 0.0699 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.

-1.45
Solubility 5.64 mg/ml ; 0.0357 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

-1.51
Solubility 4.92 mg/ml ; 0.0311 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.

-6.59 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

1.0 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)

1.61

Application In Synthesis of [ 1694-31-1 ]

* 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 [ 1694-31-1 ]

[ 1694-31-1 ] Synthesis Path-Downstream   1~17

  • 1
  • [ 38956-79-5 ]
  • [ 1694-31-1 ]
  • [ 69579-14-2 ]
  • 2
  • [ 1694-31-1 ]
  • [ 67442-07-3 ]
  • 6-chloro-3-hydroxy-5-oxo-hex-2-enoic acid <i>tert</i>-butyl ester [ No CAS ]
  • 3
  • [ 1694-31-1 ]
  • [ 615-43-0 ]
  • [ 124-41-4 ]
  • [ 65417-22-3 ]
  • 4
  • [ 1694-31-1 ]
  • [ 124-41-4 ]
  • [ 615-36-1 ]
  • [ 65417-22-3 ]
  • 5
  • [ 1694-31-1 ]
  • [ 14205-43-7 ]
  • [ 147959-19-1 ]
  • [ 596828-12-5 ]
  • 6
  • [ 1694-31-1 ]
  • [ 146137-72-6 ]
  • [ 1044741-28-7 ]
  • 7
  • [ 27421-51-8 ]
  • [ 852443-61-9 ]
  • [ 1694-31-1 ]
  • [ 1369959-35-2 ]
  • 8
  • [ 6639-57-2 ]
  • [ 852443-61-9 ]
  • [ 1694-31-1 ]
  • [ 1369959-29-4 ]
  • 9
  • [ 3012-80-4 ]
  • [ 852443-61-9 ]
  • [ 1694-31-1 ]
  • [ 1369959-32-9 ]
  • 10
  • [ 17115-51-4 ]
  • [ 1694-31-1 ]
  • [ 2646-91-5 ]
  • tert-butyl 5-methyl-7-(2,3-difluorophenyl)-2,3,4,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide [ No CAS ]
  • 11
  • [ 17115-51-4 ]
  • [ 1694-31-1 ]
  • [ 6334-18-5 ]
  • tert-butyl 5-methyl-(2,3-dichlorophenyl)-2,3,4,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide [ No CAS ]
  • 12
  • [ 17115-51-4 ]
  • [ 1694-31-1 ]
  • [ 85070-48-0 ]
  • tert-butyl 5-methyl-7-(2-fluoro-3-chlorophenyl)-2,3,4,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate-1,1-dioxide [ No CAS ]
  • 13
  • [ 652-12-0 ]
  • [ 1694-31-1 ]
  • [ 29045-72-5 ]
  • 14
  • [ 28466-26-4 ]
  • [ 1694-31-1 ]
  • [ 1314389-50-8 ]
YieldReaction ConditionsOperation in experiment
lH-Pyrazol-4-amine (10.4 g, 125 mmol) was dissolved in concentrated HCl (36.8 mL)/water (186 mL) and cooled to 0C. A solution of sodium nitrite (9.05g, 131 mmol) in water (122 mL) was added dropwise while maintaining the internal temperature below 4C. On complete addition, the mixture was stirred at 0C for 30 min. The resulting diazonium chloride solution was added via a pipette to a solution of tert-butyl acetoacetate (21.8 mL, 131 mmol) and sodium acetate (124 g, 1.51 mol) in water (122 mL) and EtOH (122 mL) at 0C. The resulting mixture was stirred between 0-1 C for two hours. The solid was filtered and dried in-vacuo to afford terf -butyl 3-oxo-2-[lH-pyrazol-4-yldiazenyl]butanoate as a yellow-brownish powder. LRMS (ESI) calc'd for CI 1Eta17Nu403 [M+H]+: 253, Found: 253.
  • 15
  • [ 652-40-4 ]
  • [ 1694-31-1 ]
  • 4,7-difluoro-1H-indene-1,3(2H)-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
A solution of <strong>[652-40-4]3,6 difluorophthalic anhydride</strong> (4.25 g, 23.1 mmol), tert-butyl 3-oxobutanoate (4.29 mL, 25.9 mmol) and acetic anhydride (21.0 mL, 221.6 mmol) at 25 °C was treated with triethylamine (1 1.7 mL, 84.3 mmol) and stirred at ambient temperature for 18 hours. The reaction mixture was cooled to 0 °C and treated with 10percent hydrochloric acid (65 mL, 21 1 mmol) by dropwise addition. Once the addition was complete, the ice bath was removed and the mixture stirred at ambient for 10 minutes. The mixture was then heated to 75 °C for 10 minutes. During this time gas evolution was observed. The suspension slowly broke up to form a clear red mixture. The reaction mixture was poured into 100 mL of water and extracted with 3 x 50 mL CH2C12. The combined organics were dried with MgS04, filtered, and concentrated to dryness. The product was used without further purification.
With acetic anhydride; triethylamine; at 0 - 25℃; for 18h; A solution of <strong>[652-40-4]3,6 difluorophthalic anhydride</strong> (4.25 g, 23.1 mmol), tert-butyl 3-oxobutanoate (4.29 mL, 25.9 mmol) and acetic anhydride (21.0 mL, 221.6 mmol) at 25 °C was treated with triethylamine (11.7 mL, 84.3 mmol) and stirred at ambient temperature for 18 hours. The reaction mixture was cooled to 0 °C and treated with 10percent hydrochloric acid (65 mL, 211 mmol) by dropwise addition. Once the addition was complete, the ice bath was removed and the mixture stirred at ambient for 10 minutes. The mixture was then heated to 75 °C for 10 minutes. During this time gas evolution was observed. The suspension slowly broke up to form a clear red mixture. The reaction mixture was poured into 100 mL of water and extracted with 3 x 50 mL CH2C12. The combined organics were dried with MgS04, filtered, and concentrated to dryness. The product was used without further purification.
With acetic anhydride; triethylamine; at 20 - 25℃; for 18h; A solution of <strong>[652-40-4]3,6 difluorophthalic anhydride</strong> (4.25 g, 23.1 mmol), tert-butyl 3-oxobutanoate (4.29 mL, 25.9 mmol) and acetic anhydride (21.0 mL, 221.6 mmol) at 25 °C was treated with triethylamine (11.7 mL, 84.3 mmol) and stirred at ambient temperature for 18 hours. The reaction mixture was cooled to 0 °C and treated with 10percent hydrochloric acid (65 mL, 211 mmol) by dropwise addition. Once the addition was complete, the ice bath was removed and the mixture stirred at ambient for 10 minutes. The mixture was then heated to 75 °C for 10 minutes. During this time gas evolution was observed. The suspension slowly broke up to form a clear red mixture. The reaction mixture was poured into 100 mL of water and extracted with 3 x 50 mL CH2Cl2. The combined organics were dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification.
With hydrogenchloride; acetic anhydride; triethylamine; Step A: Preparation of 4,7-difluoro-1H-indene-1,3(2H)-dione A solution of <strong>[652-40-4]3,6 difluorophthalic anhydride</strong> (4.25 g, 23.1 mmol), tert-butyl 3-oxobutanoate (4.29 mL, 25.9 mmol) and acetic anhydride (21.0 mL, 221.6 mmol) at 25° C. was treated with triethylamine (11.7 mL, 84.3 mmol) and stirred at ambient temperature for 18 h. The reaction mixture was cooled to 0° C. and treated with 10percent hydrochloric acid (65 mL, 211 mmol) by dropwise addition. Once the addition was complete, the ice bath was removed and the mixture stirred at ambient for 10 minutes. The mixture was then heated to 75° C. for 10 minutes. During this time gas evolution was observed. The suspension slowly broke up to form a clear red mixture. The reaction mixture was poured into 100 mL of water and extracted with 3*50 mL CH2Cl2. The combined organics were dried with MgSO4, filtered, and concentrated to dryness. The product was used without further purification.

  • 16
  • [ 23687-26-5 ]
  • [ 1694-31-1 ]
  • N-(isoquinolin-6-yl)-3-oxobutanamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
In acetonitrile; at 120℃; for 2h;Sealed tube; tert-Butyl acetoacetate (1.82 ml, 11 mmol) and <strong>[23687-26-5]isoquinoline-6-amine</strong> (1.44 g, 10 mmol) in MeCN (10 ml) were sealed in a reaction tube and heated to 120° C. for 2 h. The reaction mixture was evaporated then triturated with a mixture of MeCN and diethyl ether to give an off-white solid (1.50 g). Although this material contained approximately 10percent SM, it was used in the next step without further purification. LCMS (Method 3): Rt=0.46 min, m/z 229 [M+H]+
  • 17
  • [ 120-72-9 ]
  • [ 1694-31-1 ]
  • [ 621-63-6 ]
  • tert-butyl 4-(1H-indol-3-yl)-2-methyl-4,5-dihydrofuran-3-carboxylate [ No CAS ]
 

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