863127-76-8|(E)-N-(2-Chloro-6-methylphenyl)-3-ethoxyacrylamide| Ambeed

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Quality Control of [ 863127-76-8 ] Purity: 97% SDS Specification

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Product Details of [ 863127-76-8 ]

CAS No. :	863127-76-8
Formula :	C₁₂H₁₄ClNO₂
M.W :	239.70
SMILES Code :	O=C(NC1=C(C)C=CC=C1Cl)/C=C/OCC
MDL No. :	MFCD13185963
InChI Key :	DBYFNZJHXGNAGW-BQYQJAHWSA-N
Pubchem ID :	44557928

Safety of [ 863127-76-8 ]

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

Computational Chemistry of [ 863127-76-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	5
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	65.76
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.33 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.65
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.8
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.95
Log P_o/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.	2.29
Log P_o/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	2.97
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.53

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.41
Solubility	0.938 mg/ml ; 0.00391 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.	-2.22
Solubility	1.43 mg/ml ; 0.00597 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	-4.03
Solubility	0.0224 mg/ml ; 0.0000933 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	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	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	Yes
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.	-6.48 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.	0.56

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)	2.3

Application In Synthesis of [ 863127-76-8 ]

* 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 [ 863127-76-8 ]

[ 863127-76-8 ] Synthesis Path-Downstream 1~35

1
[ 6191-99-7 ]
[ 87-63-8 ]
[ 863127-76-8 ]

Yield	Reaction Conditions	Operation in experiment
73.6%	With pyridine; In tetrahydrofuran; at 0 - 20℃; for 2h;	To a cold stirring solution of 2-chloro-6-methylaniline (59.5 g 0.42 mol) and pyridine (68 ml, 0.63 mol) in THF (600 mL) was added 3-ethoxyacryloyl chloride (84.7 g, 0.63 mol) slowly keeping the temp at 0-5C. The mixture was then warmed and stirred for 2 h. at 20C. Hydrochloric acid (1N, 115 mL) was added at 0-10C. The mixture was diluted with water (310 mL) and the resulting solution was concentrated under vacuum to a thick slurry. The slurry was diluted with toluene (275 mL) and stirred for 15 min. at 20-22C then 1 h. at 0C. The solid was collected by vacuum filtration, washed with water (2 x 75 mL) and dried to give 74.1 g (73.6 % yield) of (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). lH NMR (400 Hz, DMSO-d6) 8 1. 26 (t, 3H, J= 7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J= 7 Hz), 5.58 (d, 1H, J=12.4 Hz), 7.10-7. 27 (m, 2H, J=7.5 Hz), 7.27-7. 37 (d, 1H, J=7.5 Hz), 7.45 (d, 1H, J=12.4 Hz), 9. 28 (s, 1H) ; l3c NMR (100MHz, CDC13) b : 14. 57, 18.96, 67.17, 97.99, 126. 80, 127. 44, 129. 07, 131.32, 132.89, 138. 25,161. 09,165. 36.
300 g	With pyridine; In tetrahydrofuran; at 10 - 30℃; for 4h;	Ethyl vinyl ether compound of formula-5 (500 gm) was slowly added to oxalyl chloride compound of formula-4 (670 ml) at 10-15C. Raised the temperature of the reaction mixture to 25-30C and stirred for 12 hours at the same temperature. Heated the reaction mixture to 120- 125C and stirred for 90 minutes at the same temperature. Cooled the reaction mixture to 30-35 C and (E)-3-ethoxyacryloyl chloride compound of formula-7 was collected by fractional distillation. Added tetrahydrofuran (1160 ml) to the obtained compound of formula-7 and cooled the reaction mixture to 10-15C. Slowly added a solution of 2-methyl-6-chloroaniline compound of formula-9 (290 gm), pyridine (248ml) & tetrahydrofuran (1160 ml) to the reaction mixture at same temperature. Raised the temperature of the reaction mixture to 25-30C and stirred the reaction mixture for 4 hours at the same temperature. Cooled the reaction mixture to 5-10C and acidified the reaction mixture using aqueous HC1 solution. Water and ethyl acetate were added to the reaction mixture and stirred for 10 minutes. Separated the both aqueous & organic layers and extracted the aqueous layer with ethyl acetate. Washed the total organic layer with aqueous sodium bicarbonate solution followed by with water. Distilled off the solvent completely from the organic layer under reduced pressure. Ethyl acetate was added to the obtained compound at 25-30C and cooled the reaction mixture to 0-5C. Stirred the reaction mixture for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled ethyl acetate and dried the material to get the title compound. Yield: 300 gm; M.R.: 160-164C; HPLC Purity: 99.66%.

References: [1]Archiv der Pharmazie,2011,vol. 344,p. 451 - 458.
[2]Patent: WO2005/77945,2005,A2 .Location in patent: Page/Page column 50-51.
[3]ARKIVOC,2010,vol. 2010,p. 32 - 38.
[4]Patent: WO2017/2131,2017,A1 .Location in patent: Page/Page column 17; 18.

2
[ 863127-76-8 ]
[ 17356-08-0 ]
[ 302964-24-5 ]

Yield	Reaction Conditions	Operation in experiment
98.8%		23.9 g (100 mmol) of N- (2-chloro-6-methylphenyl) -3-ethoxyacrylamide was mixed with 7.2 g (35 mmol) of iodine monobromide at room temperature,And 10.9 g (50 mmol) of 1-butyl-3-methylimidazolium bromide were added to a flask and stirred in 120 ml of THFAnd the temperature was raised to 40 C. 22.8 g (300 mmol) of thiourea was added to the mixture obtained by the above-mentioned mixingThe reaction was stirred for 1.5 hours, cooled to room temperature, poured into ice water, extracted with methylene chloride, the organic phase was concentrated, washed with water and then ethanolAnd then dried to obtain 26.4 g of 2-amino-N- (2-chloro-6-methylphenyl) thiazole-5-carboxamide in a yield of 98.8%purity99.61%.
90%		Example 2; [0164] To a mixture of compound 1 (5.30 g, 22.1 1 mmol) in 1 ,4-dioxane (100 mL) and water (70 mL) was added NBS (4,40 g, 24,72 mmol) at -10 to 0C. The slurry v/as warmed and stirred <n="55"/>at 20-22C, for 3 h. Thiourea (1 ,85 g, 26, 16 mmol) was added and the mixture heated to 100C. After 2 h, the resulting solution was cooled to 20-22C and cone, ammonium hydroxide (6 mL) was added dropwise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5 "C. The solid was collected by vacuum filtration, washed with cold water, and dried to give 5.4 g (90% yield) of compound 2 as deep-yellow solids, 1H NMR (500 MHz1 DMSOd6) delta 2, 19 (s, 3H), 7.09-7.29 (m, 2H, J=7,5), 7.29-7,43 (d, IH, J=7,5), 7.61 (s, 2H)1 7,85 (s, IH)1 9.63 (s, IH); ESI-MS: calcd for (Cl 1H10C1N3OS) 267, found 268 MH+),
90%		Example 2[0157] To a mixture of compound 1 (5.30 g, 22.11 mmol) in 1,4-dioxane (100 mL) and water (70 mL) was added NBS (4.40 g, 24.72 mmol) at -10 to 0 C. The slurry was warmed and stirred at 20-22 C for 3 h. Thiourea (1.85 g, 26.16 mmol) was added and the mixture heated to 100 C. After 2 h, the resulting solution was cooled to 20-22 C and cone, ammonium hydroxide (6 mL) was added drop wise. The resulting slurry was concentrated under vacuum to about half volume and cooled to 0-5 C. The solid was collected by vacuum filtration, washed with cold water, and dried to give 5.4 g (90% yield) of compound 2 as deep-yellow solids. 1H NMR (500 MHz, DMSO-d6) delta 2.19 (s, 3H), 7.09-7.29 (m, 2H, J=7.5), 7.29-7.43 (d, IH, J=7.5), 7.61 (s, 2H), 7.85 (s, IH), 9.63 (s, IH); ESI-MS: calcd for (C?HioClN3OS) 267, found 268 MH+).

213 g

E)-<strong>[863127-76-8]N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide</strong> compound of formula-8 (240 gm) was added to a mixture of N-bromosuccinimide (267.1 gm), water (960 ml) and 1,4-dioxane (480 ml) at 25-30C and stirred the reaction mixture for 3 hours at the same temperature. Thiourea (76.8 gm) was added to the reaction mixture at 25-30C. Heated the reaction mixture to 65-70C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 15-20C. The reaction mixture was added slowly to a pre-cooled (15-20C) aqueous ammonia solution (600 ml of ammonia in 960 ml of water) at 15-20C and stirred the reaction mixture for 2 hours at same temperature. Filtered the precipitated solid and washed with water. Water was added to the obtained compound and stirred for 40 minutes at 25-30C. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 213 gm; MR.: 195-200C; HPLC Purity: 98.77%.

References: [1]Patent: CN106117195,2016,A .Location in patent: Paragraph 0029; 0030; 0031.
[2]Patent: WO2008/76883,2008,A2 .Location in patent: Page/Page column 53-54.
[3]Patent: WO2010/144338,2010,A1 .Location in patent: Page/Page column 84.
[4]Patent: WO2017/2131,2017,A1 .Location in patent: Page/Page column 17; 18.

3
[ 6191-99-7 ]
[ 87-63-8 ]
[ 863127-76-8 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In tetrahydrofuran; at 20℃;	Example 1; [0163] A mixture of ethyl beta-ethoxyacrylate (26.50 g, 183 rnmol) and 2 N sodium hydroxide(110 mL, 220 mrnol) was refluxed for 2 h and cooled to 0C , water was removed under vacc, and the yellow solids were triturated with toluene and evaporated to give the sodium beta- ethoxyacrylate (25 g, 97%). The mixture of sodium beta-thoxyacrylate (10.26 g, 74.29 mrnol) and thionyl chloride (25 mL, 343 mmol) was refluxed for 2 h, and evaporated, to give the beta- ethoxyacryloyl chloride crude product, which was used without purification, To a cold stirring solution of 3-ethoxyacryloyl chloride in THF (100 mL) was added 2-chloro-6-methylaniline (6.2 mL, 50,35 mmol) and pyridine (9 ml, 1 1 1 mmol) The mixture was then wanned and stirred overnight at room temperature. Water was added at 0-10C, extracted with EtOAc, The organic layer was washed with CuSO4 (3x50 mL) and the resulting solution was passed a pad of silica gel, concentrated under vacuum to give solids, The solids was diluted with toluene and kept, at 0C, The solid was collected by vacuum filtration, washed with water and dried to give 5,2 g (43% yield) of compound 1 , (E)-N-(2-chloro-6-methylphenyl)-3-ethoxyacrylamide). 1H NMR (500 Hz1 CDCl3) delta 1 ,26 (t, 3H1 J=7 Hz), 2, 15 (s, 3H), 3 94 (q, 2H, J=7 Hz), 5,58 (d, IH, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7,27-7.37 (d, IH, J=7.5 Hz), 7,45(d, 1Hf J=12.4 Hz); ESI-MS: calcd for (Cl 2H14C1NO2) 239, found 240 MH+),
	With pyridine; In tetrahydrofuran; at 20℃;	Example 1[0156] A mixture of ethyl beta-ethoxyacrylate (26.50 g, 183 mmol) and 2 N sodium hydroxide (110 mL, 220 mmol) was refluxed for 2 h and cooled to 0 C water was removed under vacc, and the yellow solids were triturated with toluene and evaporated to give the sodium beta-ethoxyacrylate (25 g, 97%). The mixture of sodium beta-thoxyacrylate (10.26 g, 74.29 mmol) and thionyl chloride (25 mL, 343 mmol) was refluxed for 2 h, and evaporated, to give the beta-ethoxyacryloyl chloride crude product, which was used without purification. To a cold stirring solution of 3-ethoxyacryloyl chloride in THF (100 mL) was added 2-chloro-6- methylaniline (6.2 mL, 50.35 mmol) and pyridine (9 ml, 111 mmol). The mixture was then warmed and stirred overnight at room temperature. Water was added at 0-10 C, extracted with EtOAc. The organic layer was washed with CuSO4 (3x50 mL) and the resulting solution was passed a pad of silica gel, concentrated under vacuum to give solids. The solids was diluted with toluene and kept, at O0C. The solid was collected by vacuum filtration, washed with water and dried to give 5.2 g (43% yield) of compound 1, (E)-N-(2-chloro-6- methylphenyl)-3-ethoxyacrylamide). 1H NMR (500 Hz, CDCl3) delta 1.26 (t, 3H, J=7 Hz), 2.15 (s, 3H), 3.94 (q, 2H, J=7 Hz), 5.58 (d, IH, J=12.4 Hz), 7.10-7.27 (m, 2H, J=7.5 Hz), 7.27- 7.37 (d, IH, J=7.5 Hz), 7.45(d, IH, J=12.4 Hz); ESI-MS: calcd for (C12Hi4ClNO2) 239, found 240 MH+).

References: [1]Patent: WO2008/76883,2008,A2 .Location in patent: Page/Page column 53.
[2]Patent: WO2010/144338,2010,A1 .Location in patent: Page/Page column 83.

4
[ 863127-76-8 ]
C₁₂H₁₃BrClNO₂ [ No CAS ]

References: [1]ARKIVOC,2010,vol. 2010,p. 32 - 38.

5
[ 863127-76-8 ]
[ 57-13-6 ]
[ 1258411-46-9 ]

Yield	Reaction Conditions	Operation in experiment
63%		Example 35 [0190] To a mixture of compound 1 (180 g, 0.75 mmol) in 1,4-dioxane (3 mL) and water (3 mL) was added NBS (160 mg, 0.90mmol) at 0 C. The slurry was warmed and stirred at 20-22 C for 3 h. Urea (58 mg, 0.97 mmol) was added and the mixture heated to 100 C. After 2 h, the resulting solution was cooled to 20-22 C and cone, ammonium hydroxide (0.2 mL) was added dropwise. The resulting slurry was concentrated under vacuum. The remaining water was removed by co-evaporating with toluene. The residue was purified by column chromatography on silica gel (0-6% 2N ammonia in methanol/100-94% dichloromethane) to give compound 35 as white solids. (120 mg, 63% yield). 1H NMR (500 MHz, DMSO-d6) delta 9.57 (s, IH), 7.60 (s, IH), 7.36 (d, J = 7.5 Hz, IH,), 7.31 (s, 2H), 7.09- 7.29 (m, 2H), 2.19 (s, 3H); ESI-MS: calcd for (Ci .H10ClN3O2) 251, found 252 (MH+), 250 ([M-H]").

References: [1]Patent: WO2010/144338,2010,A1 .Location in patent: Page/Page column 98.

6
[ 1001-26-9 ]
[ 863127-76-8 ]