Structure of 65854-91-3
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CAS No. : | 65854-91-3 |
Formula : | C11H14ClNO |
M.W : | 211.69 |
SMILES Code : | CC(C)(C)C(=O)NC1=CC=C(Cl)C=C1 |
MDL No. : | MFCD00095895 |
InChI Key : | IZISMXMXCLUHGI-UHFFFAOYSA-N |
Pubchem ID : | 182511 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H412 |
Precautionary Statements: | P273 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.36 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 59.93 |
TPSA ? Topological Polar Surface Area: Calculated from |
29.1 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.49 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.62 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.13 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.99 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.75 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.8 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.92 |
Solubility | 0.253 mg/ml ; 0.0012 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.88 |
Solubility | 0.278 mg/ml ; 0.00132 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.23 |
Solubility | 0.0124 mg/ml ; 0.0000587 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.73 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.25 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57 g (54%) | In tetrahydrofuran; hydrogenchloride; n-butyllithium; hexane; ethyl acetate; | Step B: 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone To an oven dried, 3L, 3 necked round bottomed flask with an overhead stirrer, argon inlet, and a 500 mL oven dried addition funnel was added <strong>[65854-91-3]N-(4-chlorophenyl)-2,2-dimethylpropanamide</strong> (100 g, 472 mmol) and dry THF (1L). This solution was cooled in an ice bath to 0 C. and the addition funnel was charged with n-butyllithium (387 mL of a 2.5 M solution in hexanes, 968 mmol). The n-butyllithium solution was added dropwise to the amide solution slowly over 1 h, maintaining the temperature below +5 C. The resulting solution was aged at 0 C. for 1 h during which time an orange precipitate formed. To this mixture was added ethyl 1,1,1-trifluoroacetate (115 mL, 968 mmol), dropwise over 1 h. The resulting clear solution was aged an additional 30 min. The reaction was quenched with 5% aqueous HCl. The mixture was diluted with 1L of EtOAc and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo, to give 160 g of a yellow oil. This material was suspended in 1L of 3N aqueous HCl and the solution was heated at reflux for 24 h. The cooled solution was diluted with 1L of EtOAc and the mixture was made basic with concentrated NH4 OH. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered, concentrated in vacuo, and chromatographed on 1.5 kg of silica gel using 15 % EtOAc in hexane as eluant. The chromatographed material was recrystallized from boiling hexane to give 57 g (54%) of pure 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone as bright yellow crystals, mp: 91-92 C. 1H NMR (CDCl3): delta6.46 (br s, 2H), 6.69 (d, 1H, J=9.2 Hz), 7.32 (dd, 1H, J=2.4, 9.2 Hz), 7.70 (d, 1H, J=2.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.7% | With sodium hydrogencarbonate; In water; ethyl acetate; at 15 - 20℃; for 2h; | Reference Example 2 N-pivaloyl-p-chloroaniline CAB (113 kg, 886 mol), city water (565L), and sodium bicarbonate (89.3 kg, 1.2 eq) were added to ethyl acetate (1695L), and pivaloyl chloride (112 kg, 1.05 eq) was added dropwise thereto at 15C or lower, and the solution was stirred at about 25C for 2 hours. After separating the layers, the organic layer was washed with city water (848L x 2), and concentrated under reduced pressure up to about 600L. Ethylcyclohexane (848L) was added thereto, and concentrated again under reduced pressure up to about 600L. The residue was cooled to about 5C, and stirred to mature for 1 hour. The precipitated crystals were collected by filtration, and dried under reduced pressure to give the title compound (187 kg, yield 99.7%). |
98% | With sodium carbonate; In dichloromethane; water; | Step A2: To a biphasic solution of p-chloroaniline (15 mmol, 1.92 g) in dichloromethane and 10% aqueous solution of sodium carbonate, pivaloyl chloride (16.5 mmol, 2.03 ml) was added dropwise. The reaction mixture was stirred intensively for 30 min. The reaction progress was followed by TLC. After reaction was completed, organic layer was separated and volatiles removed under reduced pressure to obtain N-(4-chloro-phenyl)-2,2-dimethyl-propionamide as a white solid in excellent yield (3.1 g, 98% yield). 1H NMR (400 MHz, CDCl3): delta7.50 (m, 2H), 7.28 (m, 2H), 1.33 (s, 9H). 13C NMR (100 MHz, CDCl3): delta176.7, 136.6, 129.1, 128.9, 121.3, 39.6, 27.6. |
98% | With water; sodium hydroxide; In toluene; at 15 - 40℃; for 1h; | Step 1: Synthesis of N-(4-chlorophenyl)pivalamide 2 from p-chloroaniline: (0081) 4-Chloroaniline (1 mmol) was added to solution of aqueous NaOH (1.15 mmol in 1.2 times of water) in toluene (4 vol.). The reaction mixture was cooled to 15C and add pivaloylchloride (1.2 equiv.) slowly by maintaining the temperature below 40C. The reaction was maintained between 25-35C for 1 h. After completion of the reaction, it was cooled to - 10C for 2 h, filtered, washed with 10% aqueous methanol to afford 98% of N-(4- chlorophenyl)pivalamide . |
96.8% | With sodium hydroxide; In toluene; at 0 - 15℃; for 2h; | In the reactor, 40.2 g of p-chloroaniline was charged,250 mL of toluene,Cooling to 0 ~ 5 ,45.4 g of 30% sodium hydroxide solution was added,Control temperature in 5 ~ 15 ,41.6 g of pivaloyl chloride was added dropwise,1 hour drop finished,And then at 5 ~ 15 heat 1 hour, stratified, washed twice organic layer, cooled to -5 ,Insulation 2 hours, filtration, filter cake washed, drained,The filter cake was vacuum dried at 70 C for 24 hours,To obtain 64.5 g of 4-chloro-N-pivaloanilide,Content of 99.4%Yield 96.8%. |
95% | With sodium hydrogencarbonate; In water; ethyl acetate; at 5 - 30℃; for 2h; | [0107] 4-Chloroaniline (100 g) was dissolved in ethyl acetate (1500 mL), water (500 mL) and sodium hydrogen carbonate (79 g) were added, pivaloylchloride (99 g) was added at 5-15 C., and the mixture was stirred at 20-30 C. for about 2 hr. The mixture was partitioned, and the organic layer was washed twice with water (750 mL) and concentrated to about 500 mL under reduced pressure. Ethylcyclohexane (750 mL) was added, and the mixture was concentrated to about 500 mL. The concentrated residue was cooled to 0-5 C., and the mixture was stirred while aging the crystals at the same temperature for 1 hr. The precipitated crystals were collected by filtration, washed with cold ethylcyclohexane (200 mL), and dried under reduced pressure to give the title compound as crystals. Standard yield: 95±10% |
93% | With triethylamine; In dichloromethane; at 0 - 20℃; for 6h; | 2,2-dimethylpropionyl chloride (6.3 mL, 51.0 mmol) was added dropwise to a mixture of 4-chlorophenylamine (5 g, 39.2 mmol), Et3N (7.2 mL, 51.0 mmol) and anhydrous CH2Cl2 (35 mL) at 0 0C . The mixture was stirred for 6 h at rt, washed with water, dried (Na2SO4) and concentrated. The residue was crystallised from EtO Ac-petroleum ether to afford the sub-title compound (7.74 g, 93%). |
91% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; | To a solution of 4-Chloroaniline (32, 2.592 g, 20.32 mmol) in CH2Cl2 (40 ml) was added 4-(dimethylamino)pyridine (273 mg, 2.23 mmol), triethylamine (3.11 ml, 22.3 mmol), and pivaloyl chloride (2.63 ml, 251.3 mmol) at 0 C. The mixture was stirred at room temperature for 1 h. After water was added, the two layers were separated. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was recrystallized from n-hexane and CH2Cl2 to afford the title compound (33, 3.912 g, 18.48 mmol, 91%) as a colorless crystal. 1H NMR (CDCl3) delta 1.31 (9H, s), 7.26-7.30 (2H, m), 7.45-7.52 (2H, m). IR (ATR) cm-1 3294, 2966, 1655, 1593, 1523, 1491, 1396, 1309, 1244, 1173, 827. MS (ESI) m/z 212 (M+H)+. Anal. Calcd for C11H14ClNO: C, 62.41; H, 6.67; Cl, 16.75; N, 6.62; found: C, 62.37; H, 6.71; Cl, 16.59; N, 6.55. |
84.43% | With triethylamine; In benzene; at 0 - 20℃; for 3h; | To 4-Methyl pyrimidine (5.0 g, 0.053 mol) in pyridine (55ML) was added selenium dioxide (8.82 g, 0.079 mol) at RT with stirring. The reaction mixture was stirred at 55 C for 2 h and at 80 C for 3.5 hr. After cooling to RT and stirring over night, the reaction mixture was filtered and the residue was washed with pyridine. The combined pyridine solution was concentrated and the carboxylic acid obtained was washed with water to remove traces of selenium dioxide. Yield : 5.3 g, 80.5 %. [00157] To Pyrimidine-4-carboxylic acid (5.0 g, 0.04 mol) in methanol (170 ml) was added conc. HCI (2 ML) at RT. After refluxing overnight, the reaction mixture was cooled to RT and neutralized with 10 % sodium bicarbonate solution and concentrated. The ester was extracted with diethyl ether, dried over NA2SO4 AND concentrated to get the methyl ester as a yellow solid, yield : 3.3 g, 57.55 %. [00158] TRIMETHYL ACETYLCHLORIDE (11.30 g, 0.093 mol) was added to a benzene (500 ML) solution of triethylamine (15.75 g, 0.155 mol) and 4- CHLOROANILINE (10.0 g, 0.078 mol) at 0C. The reaction mixture was warmed to RT and stirred for 3h. The reaction mixture was then quenched with water, extracted with ethyl acetate, washed with water, brine solution and dried over NA2SO4. The solid product obtained was crystallized from pet ether. Yield : 14.0 g, 84. 43 %. [00159] To N- (4-chlorophenyl)-2, 2-dimethyl propanamide (3.5 g, 0.0165 mol) in THF (50 MI) at 0 C was added n-butyl lithium in hexane (2.64 g, 1.2 M, 0. 041 MOL). Stirring was continued at 0 C for 2 h, the reaction then cooled to-70 C, pyrimidine-4-methyl carboxylate (3.18 g, 0.023 mol) in THF (25 ML) was then added slowly and the solution was warmed to RT and stirred overnight. Diethyl ether (50 ml) and water (50 ml) were added and the organic layer was separated. The aqueous layer was further extracted with ether. The combined ether layers were washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 1.7 g, 32.69 %. [00160] The protected amino ketone (1.7 g, 0.0054 mol) in sulfuric acid (10 ML, 70 %) was heated at 95 C over night. The reaction mixture was cooled to RT and basified with 10% NAOH, extracted with DCM, washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography using basic alumina to yield title compound (0.20g, 16%). |
With triethylamine; In acetonitrile; at 0 - 20℃; for 5h; | To a solution of 4-chloroaniline (10.0 g) and triethylamine (16.4 ml) in acetonitrile (80 ml) was added dropwise pivaloyl chloride (14.5 ml) under ice-cooling. The mixture was allowed to warm to room temperature and stirred for 5 hrs. The obtained reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (1500 ml) and water (1500 ml). The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether and hexane to give N-(4-chlorophenyl)-2,2-dimethylpropionamide (15.0 g) as colorless crystals. 1H-NMR (CDCl3) delta:1.31 (9H, s), 7.26-7.50 (4H, m). | |
With triethylamine; In chloroform; at 20℃; for 1.5h; | To a solution of 4-chloroaniline (25.51 g) and triethylamine (69.73 ml) in chloroform (350 ml) were added 2,2-dimethyl-propionyl chloride (25.32 g) over a 30 minutes period. The resulting solution was stirred at r.t. for 1 hour, then water was added and the mixture extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 35.8 g of product. M.p. 149-150C; Retention Time HPLC 2.83 min; MS (ES+) 212 (M+H+). | |
With triethylamine; In acetonitrile; at 0 - 20℃; for 5h; | Reference Example 3 N-(4-Chlorophenyl)-2,2-dimethylpropionamide To an acetonitrile (80 ml) solution of 4-chloroaniline (10.0 g) and triethylamine (16.4 ml) was added dropwise pivaloyl chloride (14.5 ml) under ice-cooling. A temperature of the mixture was raised to room temperature, followed by mixing for 5 hours. The resulting reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (1500 ml) and water (1500 ml). The organic layer was washed successively with water, an aqueous saturated sodium bicarbonate solution, and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized using ethyl ether and hexane to obtain the title compound (15.0 g) as colorless crystals. 1H-NMR (CDCl3) delta: 1.31 (9H, s), 7.26-7.50 (4H, m). | |
With hydrogenchloride; In pyridine; | Example 3 Synthesis of N-(4-Chloro-phenyl)-2,2-dimethyl-propionamide To a solution of 4-chloroaniline (5.0 g, 39.2 mmol) in 25 mL pyridine was added 5.3 mL (43.1 mmol) of pivaloyl chloride and the reaction mixture stirred overnight at room temperature. The mixture was poured into vigorously stirring 6M HCl, and the solids were collected by vacuum filtration, washed well with H2O, and dried in vacuo to yield the title compound. 1H NMR (CDCl3) delta 7.47 (d, J=9.2 Hz, 2H) 7.30 (s, 1H) 7.27 (d, J=8.8 Hz, 2H) 1.32 (s, 9H) MS (ES) m/z=212.1. | |
With pyridine; | Trimethylacetyl chloride (35 g) was added drop wise to a SOLUTION OF 4-CHLOROANILINE (31. 9 g) in dry pyridine and the reaction was stirred under nitrogen overnight. About half of the pyridine was removed by rotary evaporation, then the mixture was treated with 6M hydrochloric acid and extracted with ethyl acetate. The extracts were washed with saturated aqueous NAHC03 and with water, then were dried (MGS04), FILTERED and concentrated by rotary evaporation. The resulting crystalline product was vacuum filtered and dried at high vacuum to constant weight, resulting in a good yield of N- (4-CHLORO-PHENYL)-2, 2-DIMETHYL-PROPIONAMIDE as fine needles. EDC (10 g) and 2-methyl-nicotinic acid (7.15 g) were magnetically stirred in ACETONITRILE-THF with N, O-dimethylhydroxylamine hydrochloride (9.75 g) and triethylamine (25 mL). After stirring overnight at ambient temperature, the resulting white suspension was added to ice water and extracted with ethyl acetate (3 x 100ML). The extracts were dried, filtered, and concentrated to give a light amber oil. [00176] To a magnetically stirred solution of N- (4-chloro-phenyl)- 2, 2-dimethyl-propionamide (3.16 g, 14.9 MMOL) in dry THF was added 2.5M n- butyllithium in hexane at-40C and the mixture was stirred at 0C for 2h and a suspension of white solid resulted. A solution of the Weinreb amide (1.80 g, 10.0 MMOL) in dry THF was added drop wise and the reaction was stirred at ambient temp overnight. The mixture was diluted with water and extracted with ethyl acetate and the organic layer was dried (MGS04), filtered and concentrated. Chromatography on silica gel (20-30% EtOAc/Hexane) provided the desired N- [4-Chloro-2- (2-methyl-pyridine-3-carbonyl)-phenyl]- 2, 2-dimethyl-propionamide as a waxy bright yellow solid (2.28 g, 6.89 MMOL) : 1H NMR (CD03) 5 11. 71 (s, 1H, NH), 8.82 (d, 1H, J = 9.2 Hz), 8.67 (dd, 1H, J = 4. 8 HZ, J = 1. 8 HZ), 7.55 (m, 2H), 7.28 (d, 1 H, J = 2. 5 HZ), 7.25 (m, 1 H), 2.54 (s, 3H), 1.39 (s, 9H). [00177] The N- [4-CHLORO-2- (2-METHYL-PYRIDINE-3-CARBONYL)-PHENYL]- 2, 2-DIMETHYL-PROPIONAMIDE intermediate (2.28g, 6.89 MMOL) was magnetically stirred with 70% sulfuric acid and heated at 75C and progress of the SOLVOLYSIS was monitored by LC/MS. The reaction was allowed to cool to ambient temperature, and was washed with ether-hexane to remove oily by- products. The acidic aqueous layer was cooled in an ice bath and aqueous NAOH was added drop wise to basify the mixture. The product was extracted with ethyl acetate and the extracts were washed with saturated aqueous NAHC03 (2 x 100 mL), with saturated aqueous sodium chloride, dried (MGS04), FILTERED and concentrated. The bright yellow product crystallized on standing: 1H NMR (CD03) 6 8.54 (dd, 1H, J = 5.2 Hz, J = 1.6 Hz), 7.45 (dd, 1H, J=7. 6HZ, J= 1. 5HZ), 7.15 (m, 2H), 7.00 (d, 1H, J=2. 6Hz), 6.61 (d, 1H, J = 9. 1 Hz), 6.39 (BR S, 2H), 2.42 (s, 3H). | |
With triethylamine; In dichloromethane; at 20℃; | To a mixture of 2.3 g of 4-chloroaniline and 3 mL of triethylamine in 20 [ML] of dichloromethane, was added 2.3 g of trimethylacetyl chloride. The reaction mixture was stirred overnight at room temperature, then washed with 1 N [HC1.] The organic layer was separated and dried over [MGS04.] Removal of the solvent afforded 4.5 g of pure product. | |
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 12h;Inert atmosphere; | General procedure: To a solution of aniline (1 mmol) in THF (10 mL) were added triethylamine (2 mmol) and pivaloyl chloride (1.2 mmol) at 0 C under inert atmosphere. After stirring for 12 h at room temperature, the triethylammonium chloride was removed by filtration and the filtrate was evaporated under reduced pressure to afford crude product which was washed with heptane to afford pure N-pivaloyl anilines. | |
41.27 g | With sodium hydroxide; In tert-butyl methyl ether; at 10 - 20℃; for 6.66667h; | S1: Add 25.50 g of p-chloroaniline to a mixture of 70 ml of methyl tert-butyl ether and 24 ml of sodium hydroxide solution (10 mol/L).Cool down to 10 C,Slowly add 25.60 g of pivaloyl chloride,After 40 minutes,Stirring reaction at 10~15 C for 2 h,The reaction was further stirred at room temperature for 4 h.Cool to 0 C,There are white crystals,Filtering,The filter cake is washed with water,Dry at 55 C for 5 h under reduced pressure.Obtaining a white solid N-(4-chlorophenyl)-2,2-dimethylpropanamide 41.27 g; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.8% | In the reactor, 52.9 g of 4-chloro-N-pivaloanilide and methyl tert-butyl were chargedEther ether 500mL, tetramethylethylenediamine 29g, stirring, cooling to -20 , the concentration of 2.0M DingBase lithium hexane solution 250mL, drop control temperature is lower than 5 , drop complete, at -5 ~ 0 under the insulation 2.5 small, The mixture was cooled to -20 C, 42.6 g of ethyl trifluoroacetate was rapidly added thereto, and the mixture was stirred for 0.5 hour,Water, 100mL, stirring, layered, organic layer to neutral water, combined water layer, with 200mL methyl tert-butylEther extraction, the combined organic layer, concentrated to dryness under vacuum to get oily substance 77.4g, content 95.2%, conversionThe yield was 95.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 2 g of pivaloyl protected 4-chloroaniline in 50 [ML] of THF was cooled to-78 C under nitrogen. A solution of n-butyl lithium (14 mL of 2 N in hexane) was added dropwise. The mixture was allowed to warm 0 C and stirring continued at [0 C] for one hour. A pyridine 4-carboxaldehyde was added to the solution and the reaction was stirred at [0 C] for one hour. The reaction mixture was poured into ethyl acetate and washed with water. The organic layer was separated and dried over [MGS04.] Removal of the solvent followed by chromatography on silica gel (hexane: ethyl acetate 2: 1 as eluent) afforded 1 g of the desired product. |
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