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Structure of 70298-88-3

Chemical Structure| 70298-88-3

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Product Details of [ 70298-88-3 ]

CAS No. :70298-88-3
Formula : C10H14N2O
M.W : 178.23
SMILES Code : CC(C(=O)NC1=CC=CN=C1)(C)C
MDL No. :MFCD00996243
InChI Key :VQXVCVTZSTYIMG-UHFFFAOYSA-N
Pubchem ID :4655044

Safety of [ 70298-88-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 70298-88-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 13
Num. arom. heavy atoms 6
Fraction Csp3 0.4
Num. rotatable bonds 3
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 52.71
TPSA ?

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

41.99 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.86
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

1.81
Log Po/w (WLOGP)?

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

1.88
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.

0.88
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

1.57
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.6

Water Solubility

Log S (ESOL):?

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

-2.23
Solubility 1.05 mg/ml ; 0.0059 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.

-2.31
Solubility 0.87 mg/ml ; 0.00488 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

-3.23
Solubility 0.104 mg/ml ; 0.000585 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.

-6.1 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)

1.64

Application In Synthesis of [ 70298-88-3 ]

* 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 [ 70298-88-3 ]

[ 70298-88-3 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 70298-88-3 ]
  • [ 113975-32-9 ]
YieldReaction ConditionsOperation in experiment
70% The reaction was performed according to a procedure in the literature (J. Org. Chem. 1988, 53, 2740-2744). A 3 L three-neck round-bottom flask was equipped with a mechanical stirrer, thermocouple, nitrogen inlet, and drying tube and placed in a cooling bath. The flask was charged with 2,2-dimethyl-N-(3-pyridyl)propanamide (42, 40 g), tetramethylethylenediamine (TMEDA, 84 mL) and THF (1400 mL), and stirring was initiated. The reaction mixture was cooled to -78 C. A suspension formed. n-BuLi (224 mL) was added over at least a 15 minute period at a rate to keep the temperature below -65 C. The reaction mixture was stirred continually at -78 C. for 15 minutes before being stirred for 2 h at -10 C. A yellow to white precipitate slowly developed. The reaction mixture was cooled back to -78 C. A solution of iodine (142 g) in THF (480 mL) was added over 30 minutes. The temperature increased from -78 C. to -65 C. The reaction mixture was stirred continually for 2 h at -78 C. The reaction mixture was continually stirred at -78 C. until the reaction was deemed complete, i.e., upon disappearance of 2,2-dimethyl-N-(3-pyridyl)propanamide (42). If reaction was not complete, it was stirred continually at -78 C. for additional 1 h then monitored again. The reaction was monitored by TLC (SiO2, [7:3] EtOAc:Hept, UV, two developments) by partitioning an aliquot of the reaction mixture (1 mL) between EtOAc (1 mL) and saturated ammonium chloride solution (3 mL), agitating, allowing the layers to separate, and spotting the organic layer. The starting material (2,2-dimethyl-N-(3-pyridyl)propanamide, 42) had an RF of 0.25, and the product (N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide, 43) had an RF of 0.33. Typically, the reaction conversion was 80% to product based on TLC. Materials used to synthesize N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide (43) are shown in Table 34. To isolate the product (N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide, 43), the reaction mixture was poured into a saturated (10%) NH4Cl solution (100 mL). The mixture was extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with a saturated (10%) sodium thiosulfate solution (2×100 mL) to remove excess iodine and brine (200 mL). The organic layer was dried over MgSO4 and charcoal, filtered through glass fiber filter paper, and concentrated to dryness. The above crude material was purified by passing through a silica plug (4 g of SiO2/1 g of crude mixture), and eluting the plug with 10-50% ethyl acetate in heptanes. All fractions that contained compound were combined and concentrated under reduced pressure at 45 C. to yield a beige solid. The solid was dried under vacuum at 25 C. for a minimum of 5 hours.N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide (43, lot No. 1358-77-1) was a beige solid, synthesized with a yield of 48 g (70%). N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide (43) was analyzed using HPLC (MPP-LC1, 240 nm), and according to results, it was 95.9% pure. 1H-NMR (300 MHz, CDCl3) was used to confirm the identity of N-(4-iodo(3-pyridyl))-2,2-dimethylpropanamide (43).
38% A solution of 2,2-dimethyl-N-pyridin-3-ylpropanamide [(1g, 5.61mmol), J. Org. Chem, 48(20), 3401;1998] in tetrahydrofuran (10mL) and diethyl ether (30mL) was cooled to -78C and TMEDA (2.1mL, 14mmol) and nbutyl lithium (1.6M in hexane, 8.8mL, 14mmol,) were added dropwise. The mixture was stirred for 15 minutes and was then warmed to -10C and stirred for a further 2 hours. The reaction mixture was again cooled to -78C and a solution of iodine (3.56g, 14mmol) in tetrahydrofuran (10mL) was added dropwise. The resulting slurry was stirred at -78C for 2 hours. The mixture was warmed to 0C and was quenched with saturated aqueous sodium thiosulfate solution (50mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2x30mL). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluding with pentane:ethyl acetate, 50:50 afforded the title compound as a yellow solid in 38% yield, 655mg. 1H-NMR(CDCl3, 400MHz) δ: 1.38(s, 9H), 7.65(bs, 1H), 7.73(d, 1H), 7.97(d, 1H), 9.35(s, 1H) MS APCI+ m/z 305 [MH]+
37% To a solution of 2,2-dimethyl-N-pyridin-3-yl-propionamide (7 g, 39.32 mmol) in THF (50 mL) was added TMEDA (20 mL, CAS RN 110-18-9) at 25 C. The mixture was cooled to-70 C., n-butyllithium was added (66 mL, 1.6M solution in n-hexane, CAS RN 109-72-8) within a period of 30 min under an atmosphere of argon. The reaction mixture was allowed to stir at -15 C. for 1 h, followed by another 1 h at 0 C. The reaction mixture was re-cooled to -70 C., then a solution of iodine (29.2 g, 115.1 mmoL) in THF (120 mL) was added slowly during 1 h, and the resultant mixture was allowed to stir at 25 C. for 16 h. Water and saturated aqueous Na2S2O3 solution was added to the mixture, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude residue which was purified by column chromatography over silica gel (40% EtOAc in n-hexane) to give the title compound. Pale yellow solid (800 mg, 37%). MS (ESI): m/z=305.4 [M+H]+.
23% Preparation 5; N-(4-Iodo-pyridin-3-yl)-2,2-dimethyl-propionamide; Equip a 250 mL 3 -neck round bottom flask with: a magnetic stirrer, a thermocouple, a dry ice/acetone bath, a nitrogen atmosphere, and an addition funnel. Charge 2,2-dimethyl-N-pyridin-3-yl-propionamide (3.0 g, 16.8 mmol), diethyl ether (67 mL), tetramethylene diamine (4.68 g, 6.08 mL, 40.3 mmol). Cool the reaction to -78 0C. Add slowly via glass syringe w-butyllithium (2.5 M solution in hexane, 16.2 mL, 40.3 mmol) over 10 min. Allow the reaction to warm to -13 0C over 2 hours. Cool the <n="10"/>-9-reaction to -78 0C. Add an iodine solution (8.5 g, 33.6 mmol in 20 mL THF) to the reaction via the addition funnel and mix 2.5 hours at -68 0C. Quench the reaction by the addition of saturated aqueous NH4Cl solution (40 mL). Extract with ethyl acetate (100 mL) and discard the aqueous phase. Wash the organic layer with a saturated aqueous sodium thiosulfate solution (100 mL) and saturated aqueous sodium chloride. Dry the organic phase over sodium sulfate and filter. Concentrate in vacuo to give brown oil. Chromatograph on silica (80 g) eluting with a gradient of 100 % dichloromethane to 70 % ethyl acetate /30 % dichloromethane to afford the title compound (1.19 g, 23 %). MS (ES) m/z 305 [M+ 1]+
23% Preparation 65N-(4-Iodo-pyridin-3-yl)-2,2-dimethyl-propionamide Equip a 250-mL round bottom flask with a magnetic a stirrer, a thermocouple, a dry ice/acetone bath, a ν2 atmosphere, and an addition funnel. Charge with 2,2-dimethyl- N-pyridin-3-yl-propionamide (3.0 g, 16.8 mmol), diethylether (67 mL), and tetramethylene diamine (4.68 g, 6.08 mL, 40.3 mmol). Cool the reaction to -78 0C. Add slowly via glass syringe w-butyllithium (2.5 M solution in hexane, 16.2 mL, 40.3 mmol) over 10 min. Warm the reaction to -13 0C over 2 h. Cool the reaction to -78 0C. Prepare an iodine solution (I2 8.5 g, 33.6 mmol in THF (20 mL)). Add the iodine solution to the reaction via the addition funnel and stir 2.5 h. at -68 0C. Quench the reaction with the addition of a saturated NH4Cl solution (40 mL) and transfer into a separatory funnel. Add ethyl acetate (100 mL). Extract and discard the lower aqueous phase. Wash the organic layer with a saturated sodium thiosulfate solution (100 mL) and extract. Wash the organic phase with saturated aqueous sodium chloride and extract. Dry the organic phase over Na2SO4 and filter. Concentrate the product via rotary evaporation. Chromatograph on silica (80 g) eluting with gradient of 100 % DCM to 70 % ethyl acetate/30 % DCM to afford 1.19 g (23 %) of the title compound. MS (ES) mk 306 [M+ 1]+.
To a solution of 2,2-dimethyl-N-pyridin-3-yl-propionamide (7 g, 39.32 mmol) in THF (50 mL) was added TMEDA (20 mL, CAS RN 110-18-9) at 25 C. The mixture was cooled to -70 C, n-butyllithium was added (66 mL, 1.6M solution in n-hexane, CAS RN 109-72-8) within a period of 30 min under an atmosphere of argon. The reaction mixture was allowed to stir at -15 C for 1 h, followed by another 1 h at 0 C. The reaction mixture was re-cooled to -70 C, then a solution of iodine (29.2 g, 115.1 mmoL) in THF (120 mL) was added slowly during 1 h, and the resultant mixture was allowed to stir at 25 C for 16 h. Water and saturated aqueous Na2S203 solution was added to the mixture, and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo to afford the crude residue which was purified by column chromatography over silica gel (40% EtOAc in n-hexane) to give the title compound. Pale yellow solid (800 mg, 37%). MS (ESI): m/z = 305.4 [M+H]+.

  • 2
  • potassium thiosulfate [ No CAS ]
  • [ 20485-44-3 ]
  • [ 70298-88-3 ]
  • Nitryl chloride [ No CAS ]
  • [ 5029-67-4 ]
  • [ 113975-32-9 ]
YieldReaction ConditionsOperation in experiment
700 mg (23%) With n-butyllithium; iodine; In tetrahydrofuran; EXAMPLE 10 Compounds of the following general formula II-10 may be made, for example by the following general scheme. Iodopyridine 16. The 3-(Pivaloylamino)pyridine 15 (1.9 g, 11 mmol) and tetramethylethylene-diamine (4.0 mL, 26 mmol) were dissolved in dry THF (60 mL) and cooled to -78 C. While maintaining the temperature between -78 C. and -65 C., nBuLi (2.5 M solution in hexanes, 10.6 mL, 26.5 mmol) was added dropwise. The reaction was allowed to warm to -10 C. for 2 h, and then cooled back down to -78 C. Iodine (6.73 g, 26.5 mmol) dissolved in dry THF (20 mL) was added slowly. After stirring for 2 h at -78 C., the reaction was quenched with ice. Excess iodine was destroyed with addition of saturated potassium thiosulfate solution. The product was extracted with CH2Cl2, and the organic layers were washed with brine. The mixture was concentrated in vacuo to a black oil which was chromatographed (1:1 EtOAc/Hexanes; 2:1 EtOAc/Hexanes) to give 700 mg (23%) of 2,2-dimethyl-N-(4-iodo-3-pyridinyl)propanamide as a yellow solid. 1H-NMR (DMSO-d6 300 MHz) δ 9.24 (s, 1H), 8.35 (s, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 1.26 (s, 9H). MS (ES+)=305.
 

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Technical Information

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