117724-63-7|2-Methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid| Ambeed

Structure of 117724-63-7

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Quality Control of [ 117724-63-7 ] Purity: 95% SDS Specification

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Product Details of [ 117724-63-7 ]

CAS No. :	117724-63-7
Formula :	C₆H₄F₃NO₂S
M.W :	211.16
SMILES Code :	CC1=NC(=C(S1)C(O)=O)C(F)(F)F
MDL No. :	MFCD00173295
InChI Key :	REKJPVUFKQYMHW-UHFFFAOYSA-N
Pubchem ID :	1486080

Safety of [ 117724-63-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 117724-63-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	5
Fraction Csp3	0.33
Num. rotatable bonds	2
Num. H-bond acceptors	6.0
Num. H-bond donors	1.0
Molar Refractivity	39.04
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	78.43 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.23
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	2.13
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.32
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.	0.81
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	2.98
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.09

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.64
Solubility	0.48 mg/ml ; 0.00227 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.	-3.41
Solubility	0.0824 mg/ml ; 0.00039 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	-1.95
Solubility	2.37 mg/ml ; 0.0112 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	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.	-6.08 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	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)	2.4

Application In Synthesis of [ 117724-63-7 ]

* 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 [ 117724-63-7 ]

[ 117724-63-7 ] Synthesis Path-Downstream 1~35

1
[ 117724-63-7 ]
[ 117724-64-8 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;	REFERENCE EXAMPLE 3 Synthesis of 2-methyl-4-trifluoromethylthiazole-5-carbonyl chloride 0.50 g of <strong>[117724-63-7]2-methyl-4-trifluoromethylthiazole-5-carboxylic acid</strong> was added to 5 ml of thionyl chloride and reaction was carried out for 2 hours under reflux. After the reaction, the reaction mixture was concentrated to obtain 0.54 g of 2-methyl-4-trifluoromethylthiazole-5-carbonyl chloride.
10.7 g	With thionyl chloride; In 1,2-dichloro-ethane; for 0.5h;Reflux;	to the reaction of <strong>[117724-63-7]2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid</strong> (0.048mol) and 1, 2-dichloroethane (80 ml), stirring 0.5hr rear, adds by drops two chlorine Asia sulphone (0.102mol), reaction under reflux conditions after the drop finishes 3-4hr, removing solvent to obtain orange red liquid title object 10.7 g.
18.5 g	With thionyl chloride; In dichloromethane; at 35℃;	<strong>[117724-63-7]2-methyl-4-trifluoromethylthiazole-5-carboxylic acid</strong> (100 mmol),Thionyl chloride (150 mmol) and 1,2-dichloroethane (100 mL)React at 3-5 hrs at 35C to the system reflow temperature,Removal of the solvent afforded the title compound (18.5 g).

With bis(trichloromethyl) carbonate; In N,N-dimethyl-formamide; toluene; at 50℃; for 1.25h;

52.8 g (0.25 mol) of <strong>[117724-63-7]2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid</strong> was added to the reaction vessel. 33.4g (0.112mol) of triphosgene, dissolved in 100mL of toluene, and added 1g (0.014mol) of N,N-dimethylformamide at 50 C, and the addition time is 15min. After the addition is completed, it is added dropwise. The acid chloride reaction was carried out for 1 h at a temperature.

References: [1]Journal of Fluorine Chemistry,2004,vol. 125,p. 1287 - 1290.
[2]Patent: US4837242,1989,A .
[3]Patent: CN105254558,2016,A .Location in patent: Paragraph 0189; 0191.
[4]Patent: CN108117529,2018,A .Location in patent: Paragraph 0121.
[5]Patent: CN109369564,2019,A .Location in patent: Page/Page column 4-7.

2
[ 117724-62-6 ]
[ 117724-63-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide;	REFERENCE EXAMPLE 2 Synthesis of 2-methyl-4-trifluoromethylthiazole-5-carboxylic acid 1.3 g of ethyl 2-methyl-4-trifluoromethylthiazole-5-carboxylate and 0.4 g of potassium hydroxide were dissolved in a mixture of 5 ml each of water and ethanol and reaction was effected at room temperature overnight. After the reaction, the reaction mixture was concentrated and acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was concentrated to obtain 0.89 g of 2-methyl-4-trifluoromethylthiazole-5-carboxylic acid.
21.5 g	With sodium hydroxide; In ethyl acetate; at 40℃; for 1h;	115 g of ethyl 2-methyl-4- (trifluoromethyl) thiazole-5-carboxylate (0.102 mol)Of ethyl acetate solution,50 g of a 40% sodium hydroxide solution was added dropwise to the reaction vessel at room temperature,Dropping speed was controlled so that the internal temperature of the system was lower than 40 C,After the dropwise addition of the sodium hydroxide solution,Insulation reaction 60min.After heat preservation,Taking the organic phase,To this was slowly added 10% hydrochloric acid,Adjusted to the system PH ? 2,At this point a large number of estimates of precipitation,The product was filtered,The filter cake was washed twice with 10% hydrochloric acid and dried in a vacuum oven.Methyl-4- (trifluoromethyl) thiazole-5-carboxylic acid as a light yellow solid, 21.5 g of 2-methyl-4- (trifluoromethyl) 98.8%, and the reaction yield was 98.70%.

References: [1]Journal of Fluorine Chemistry,2004,vol. 125,p. 1287 - 1290.
[2]Patent: US4837242,1989,A .
[3]Patent: CN103145639,2016,B .Location in patent: Paragraph 0035; 0036; 0037.
[4]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 3395 - 3402.

3
[ 117724-63-7 ]
N-tert-butyl-2-methyl-4-trifluoromethylthiazole-5-carboxamide [ No CAS ]

References: [1]Journal of Fluorine Chemistry,2004,vol. 125,p. 1287 - 1290.

4
[ 117724-63-7 ]
N-(1,1-dimethyl-prop-2-ynyl)-2-methyl-4-trifluoromethylthiazole-5-carboxamide [ No CAS ]

References: [1]Journal of Fluorine Chemistry,2004,vol. 125,p. 1287 - 1290.

5
[ 117724-63-7 ]
N-(tert-butylamino)-2-methyl-4-trifluoromethylthiazole-5-carboxamide [ No CAS ]

References: [1]Journal of Fluorine Chemistry,2004,vol. 125,p. 1287 - 1290.

6
[ 117724-63-7 ]
N-(3-dimethylamino)propyl-2-methyl-4-trifluoromethylthiazole-5-carboxamide [ No CAS ]

References: [1]Journal of Fluorine Chemistry,2004,vol. 125,p. 1287 - 1290.

7
[ 117724-63-7 ]
N-(1-ethyl-1-methyl-prop-2-ynyl)-2-methyl-4-trifluoromethylthiazole-5-carboxamide [ No CAS ]

References: [1]Journal of Fluorine Chemistry,2004,vol. 125,p. 1287 - 1290.

8
[ 117724-63-7 ]
N-(3-(1H-imidazol-1-yl)propyl)-2-methyl-4-trifluoromethylthiazole-5-carboxamide [ No CAS ]

References: [1]Journal of Fluorine Chemistry,2004,vol. 125,p. 1287 - 1290.

9
[ 117724-63-7 ]
N-(3-diethylamino)propyl-2-methyl-4-trifluoromethylthiazole-5-carboxamide [ No CAS ]

References: [1]Journal of Fluorine Chemistry,2004,vol. 125,p. 1287 - 1290.

10
[ 117724-63-7 ]
N-(3-(2-oxo-pyrrolidin-1-yl)propyl)-2-methyl-4-trifluoromethylthiazole-5-carboxamide [ No CAS ]

References: [1]Journal of Fluorine Chemistry,2004,vol. 125,p. 1287 - 1290.

Yield	Reaction Conditions	Operation in experiment
75.4%		C. The reaction mixture was stirred for 2.3 hours at room temperature during which time a yellow solid precipitated. Then triethylamine (1380 g, 13.64 mol) was added slowly. The reaction temperature rose to about 52 C. The contents were gently refluxed for one hour (internal temperature 75.8 C). After cooling to 46 C., a 40% sodium hydroxide solution (prepared from 1304 g 50% NaOH and 326 mL water, 16.3 mol) was added over 10 minutes. An exotherm to 53.6 C. was noted. The mixture was placed under a vacuum of 95 mm and the solvent distilled from the reaction until only water (of saponification) is present in the distillate. To the remaining reaction mixture was added 2 L water and 1.5 kg ice. Then concentrated HCl (1500 mL, 18 mol) was added over a 15 minute period to bring the pH to less than 2. Another 2 L water and 2 kg ice were added, and the product was filtered, washed on the filter with 12 L water, and dried in a vacuum oven to obtain 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid, 825 g as a beige solid, a 75.4% yield at 97.6% purity.

12
[ 363-58-6 ]
[ 62-55-5 ]
[ 117724-63-7 ]

Yield	Reaction Conditions	Operation in experiment
75.4%	With hydrogenchloride; sodium hydroxide; triethylamine; In water; acetonitrile;	Example 2 Preparation of 2-Methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid. The reaction of Example 1 may be carried out as generally described and the ester may be converted to the acid by conventional methods without isolation. The following is an example of one method. To a 22 L flask fitted with a mechanical stirrer, thermocouple, and a reflux condenser, was charged thioacetamide (500.6 g, 6.66 mol) and acetonitrile (4 L). This resulted in an endothermic dissolution. To this solution was added ethyl 2-chloro-4,4,4-trifluoroacetoacetate (1105 g, 5.06 mol) over a period of 40 minutes. A slight exotherm occurred which raised the temperature to 55.8 C. The reaction mixture was stirred for 2.3 hours at room temperature during which time a yellow solid precipitated. Then triethylamine (1380 g, 13.64 mol) was added slowly. The reaction temperature rose to about 52 C. The contents were gently refluxed for one hour (internal temperature 75.8 C). After cooling to 46 C, a 40% sodium hydroxide solution (prepared from 1304 g 50% NaOH and 326 mL water, 16.3 mol) was added over 10 minutes. An exotherm to 53.6 C was noted. The mixture was placed under a vacuum of 95 mm and the solvent distilled from the reaction until only water (of saponification) is present in the distillate. To the remaining reaction mixture was added 2 L water and 1.5 kg ice. Then concentrated HCl (1500 mL, 18 mol) was added over a 15 minute period to bring the pH to less than 2. Another 2 L water and 2 kg ice were added, and the product was filtered, washed on the filter with 12 L water, and dried in a vacuum oven to obtain 2-methyl-4-(trifluoromethyl)thiazole-5-carboxylic acid, 825 g as a beige solid, a 75.4% yield at 97.6% purity.

References: [1]Patent: EP650963,1995,A1 .

13
[ 915416-45-4 ]
[ 117724-63-7 ]
[ 915416-41-0 ]

References: [1]Patent: WO2006/122933,2006,A1 .Location in patent: Page/Page column 27-28.

14
9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalene-5-amine [ No CAS ]
[ 117724-63-7 ]
2-methyl-4-trifluoromethylthiazole-5-carboxylic acid (9-dichloromethylidenebenzonorbornene-5-yl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In dichloromethane; at 25℃; for 20h;	9-Dichloromethylidene-5-amino-benzonorbomene (175 mg, 0.73 mmol), 2- methyl-4-trifluoromethyl-thiazole-5-carboxylic acid (162 mg, 0.77 mmol, 1.05 eq.) and triethylamine (184 mg, 1.8 mmol, 2.5 eq.) were reacted with bis-(2-oxo-3-oxazolidinyl)- phosphinic acid chloride (278 mg, 1.09 mmol, 1.5 eq.) in dichloromethane (10 ml) at 25 0C for 20 hours. The reaction mixture in ethyl acetate was washed successively with water and saturated. Sodium chloride solution, dried over sodium sulphate, evaporated and purified on silica gel (ethyl acetate-hexane-(l:2) to give 250 mg colourless crystals (m.p. 136-139 0C).

References: [1]Patent: WO2007/48556,2007,A1 .Location in patent: Page/Page column 37-38.

15
[ 942312-66-5 ]
[ 117724-63-7 ]
[ 942312-61-0 ]

Yield	Reaction Conditions	Operation in experiment
34%		Example 2 0.21 g (1.0 mmol) of <strong>[117724-63-7]2-methyl-4-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid</strong>, 0.49 g (2.4 mmol) of 1,3-dicyclohexylcarbodiimide and 0.14 g (1.0 mmol) of 1-hydroxybenzotriazole are suspended in 15 ml of dichloromethane. After 5 minutes, 0.24 g (1.0 mmol) of 5-(3,4-dichlorophenyl)-4-pyrimidinylamine is added. The reaction solution is stirred at room temperature for 8 h and then at 40 C. for 16 h. For work-up, the reaction mixture is filtered, washed with saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated. Column chromatography (cyclohexane/ethyl acetate 2:1) gives 0.15 g (34% of theory) of N-[5-(3,4-dichlorophenyl)-4-pyrimidinyl]-2-methyl-4-(trifluoromethyl)-1,3-thiazole-5-carboxamide of logP (pH 2.3)=2.85.

References: [1]Patent: US2009/163516,2009,A1 .Location in patent: Page/Page column 20.

16
[ 877169-04-5 ]
[ 117724-63-7 ]
[ 877168-97-3 ]

Yield	Reaction Conditions	Operation in experiment
73%		0.10 ml (1.1 mmol) oxalylchloride and 0.1 ml dimethylformamide are added to a solution consisting of 211.2 mg (1.0 mmol) <strong>[117724-63-7]2-methyl-4-trifluoromethyl-thiazole-5-carboxylic acid</strong> in 9 ml dichloromethane. After stirring for 2 hours at room temperature, this solution is added to a solution consisting of 240.0 mg (1.0 mmol) 4'-chloro-5,3'-difluoro-biphenyl-2-yl-amine and 0.18 ml (1.3 mmol) triethylamine in 9 ml dichloromethane. The reaction mixture is stirred for 16 hours at room temperature and subsequently mixed with 7 ml 2 N hydrochloric acid. The organic phase is dried over magnesium sulphate and concentrated in vacuum.The reaction yields 316.5 mg (73% of the theoretical yield) of N-(4'-chloro-3',5-difluorobiphenyl-2-yl)-2-methyl-4-(trifluoromethyl)-1,3-thiazole-5-carboxamide [log P (pH 2.3)=3.67].

References: [1]Patent: US2008/242708,2008,A1 .Location in patent: Page/Page column 20.

17
[ 5369-16-4 ]
[ 117724-63-7 ]
3'-isopropyl-2-methyl-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid anilide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.54 g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h;Cooling with ice; Reflux;	0.46 g of <strong>[117724-63-7]2-methyl-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid</strong> (manufactured by Sigma-Aldrich Japan) and 0.30 g of 3-isopropylaniline were dissolved in 20 ml of methylene chloride, and 0.47 g of WSCI/HCl was added thereto while being cooled in ice. The mixture was stirred at room temperature for one hour, and refluxed for one hour to cause reaction. Then, the same reaction and posttreatment operation were performed as in Synthesis Example 1 to thereby obtain 0.54 g of pale yellow oily compound of 3'-isopropyl-<strong>[117724-63-7]2-methyl-4-trifluoromethyl-1,3-thiazole-5-carboxylic acid</strong> anilide. 1H-NMR (CDCl3) deltappm; 7.78-7.00 (5H, m), 2.99-2.79 (1H, m), 2.75 (3H, s), 1.29 (3H, s), 1.22 (3H, s)

References: [1]Patent: US2013/59014,2013,A1 .Location in patent: Paragraph 0087-0088.

18
(1S,3R,4S,5S,7S)-4-amino-adamantan-1-ol hydrochloride [ No CAS ]
[ 117724-63-7 ]
N-(trans-5-hydroxy-2-adamantyl)-2-methyl-4-(trifluoromethyl)thiazole-5-carboxamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 970 - 986.

19
[ 117724-63-7 ]
3-{2,6-dichloro-4-[(3,3-dichloroprop-2-en-1-yl)oxy]phenoxy}propyl 2-methyl-4-(trifluoromethyl)-1,3-thiazolidine-5-carboxylate [ No CAS ]

References: [1]Patent: CN105254558,2016,A .

20
3-hydroxy-3-(2-methyl-4-trifluoromethylthiazol-5-yl)-2-(2-phenylthiazol-4-yl)acrylonitrile [ No CAS ]
[ 117724-63-7 ]
[ 947674-89-7 ]

Yield	Reaction Conditions	Operation in experiment
22.3 g	With thionyl chloride; In 1,2-dichloro-ethane; at 20℃;Reflux;	(2-methyl-4-trifluoromethyl-thiazol-5-yl)(1H-pyrazol-1-yl)methanone at room temperature and under stirring, a solution of <strong>[117724-63-7]2-methyl-4-trifluoromethylthiazole-5-carboxylic acid</strong> (23.1 g, 100 mmol) in 1,2-dichloroethane (120 mL) was added dropwise to a solution of thionyl chloride (250 mmol), after completion of the dropwise addition, the reaction was heated to reflux for 4-6 hr, removal of the solvent and excess thionyl chloride gave a brown liquid. To the above brown liquid was added methylene chloride (150 mL), the reaction mixture was poured into water, and the dichloromethane layer was separated. The aqueous phase was extracted twice with methylene chloride and the organic phase was combined. Dried over anhydrous sodium sulfate, and the solvent was removed to obtain 22.3 g of the crude title product, which was used in the next step.

References: [1]Patent: CN106187936,2016,A .Location in patent: Paragraph 0127; 0128.

21
[ 372-31-6 ]
[ 75-05-8 ]
[ 117724-63-7 ]

Yield	Reaction Conditions	Operation in experiment
85.05%		Step 1: In a four-necked reaction flask equipped with a mechanical stirrer, thermometer and air duct, 92 gTrifluoroacetoacetate, 230 g of acetonitrile and 2.24 g of KOH, and the mixture was cooled in an ice bath to 0 to 25 C,Slowly enter the 39.4 g of chlorine and 21 g of hydrogen sulfide gas, ventilation time of about 3-5h. After the completion of access to the gas insulation reaction 1h, and then blow off the generated hydrogen chloride gas, excessive chlorine and hydrogen sulfide gas.Step 2: To the above reaction, dropwise add 112g of triethylamine. After adding dropwise, the mixture is heated to reflux and refluxed for 3 hours. The resulting triethylamine hydrochloride is filtered and the filtrate is distilled to recover the solvent.Step 3: temperature control 25-35 , dropping 30% sodium hydroxide solution 170g, insulation reaction 2 ~ 3h.Step four: 180g 30% hydrochloric acid solution for acidification, a large number of white precipitate precipitation. After the completion of the dropwise addition, the reaction was allowed to proceed for 1 h, followed by filtration and drying to obtain 92.55 g of the substance, content: 97.02%, yield: 85.05%.

References: [1]Patent: CN106316978,2017,A .Location in patent: Paragraph 0010; 0011; 0012; 0013; 0014; 0015; 0016-0029.

22
[ 62-55-5 ]
[ 372-31-6 ]
[ 117724-63-7 ]

Yield	Reaction Conditions	Operation in experiment
90.8%		(1) into a chain130 kg of acetonitrile into the reactor,32 kg of thioacetamide was added with stirring,90 kg of ethyl trifluoroacetoacetate was added dropwise at 30 C,Drop finished,Continue to maintain the chain reaction for 2.5 hours. (2) to form a ringAfter the completion of the chain reaction,120 kg of tri-n-propylamine was added dropwise at 30 C,Dropping time for 1 hour,Drop finished,The temperature was raised to 70 C for 3 hours to form a ring-forming reaction. (3) hydrolysisAfter the ring-forming reaction,The acetonitrile, water and tri-n-propylamine were separated by vacuum distillation,Respectively, with water acetonitrile fraction and tri-n-propylamine fraction. After acetonitrile and tri-n-propylamine were removed,The reaction solution was cooled to 30 C,Add 45% NaOH alkaline solution 93kg,The temperature was raised to 55 C for 1 hour to carry out hydrolysis reaction.(4) acidificationAfter the hydrolysis reaction is complete,Cooling to 40 ,30% hydrochloric acid was added dropwise for acidification,Transferred to pH = 1-2, and then continue to cool to 0 ,Add 200kg of water,Stirring for 0.5 hours,Filter,Centrifugal,The filter cake is dried and dried2-methyl-4-trifluoromethyl-5-thiazolecarboxylic acid 82.0 kg,Content of 95.3%,Yield 90.8% (based on ethyl trifluoroacetoacetate).The raw materials used in the preparation are commercially available.

References: [1]Patent: CN106349183,2017,A .Location in patent: Paragraph 0029-0047.

23
[ 196698-26-7 ]
[ 62-55-5 ]
[ 117724-63-7 ]

Yield	Reaction Conditions	Operation in experiment
93.5%	With sodium hydroxide; for 2h;Reflux;	Add to a 500 mL four-necked flaskTrifluoroacetoacetate (36.8 g, 0.20 mol)Stirring to cool to -15 C,25.0 g (0.185 mol) of sulfuryl chloride was slowly added dropwise at -15 C to -10 C,About 2.5h drops finished,Slowly warm to 10 C to 15 C.Insulation reaction 15h,The content of ethyl 2,2-dichlorotrifluoroacetoacetate in the mixture was 0.18%The unreacted ethyl trifluoroacetoacetate was recovered by distillation under reduced pressure (3.1 g (35 C or less / 10 mmHg).The residue was washed with 110 mL of absolute ethanol and 14.5 g (0.193 mol) of thioacetamide,Stirring and heating to reflux,Insulation reaction 12h,Adding 90% aqueous solution of 15% sodium hydroxide,Stirring reflux reaction 2h.Vacuum recovery of ethanol,Cooled to room temperature, diluted with water 200mL, concentrated hydrochloric acid to pH = 1, aging 2h, suction filtration, washing, to obtain white solid products2-methyl-4-trifluoromethylthiazole-5-carboxylic acid36.1g,Yield 93.5%HPLC content of 98.8%.

References: [1]Patent: CN104672168,2017,B .Location in patent: Paragraph 0025; 0026; 0027; 0028; 0029; 0030-0036.

24
[ 117724-63-7 ]
(E)-(2-cyano-2-(2-phenylthiazol-4-yl)-1-(2-methyl-4-trifluoromethylthiazol-5-yl)vinyl) cyclopentyl carbonate [ No CAS ]
(Z)-(2-cyano-2-(2-phenylthiazol-4-yl)-1-(2-methyl-4-trifluoromethylthiazol-5-yl)vinyl) cyclopentyl carbonate [ No CAS ]

References: [1]Patent: CN106187937,2016,A .
[2]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 3395 - 3402.

25
[ 117724-63-7 ]
(E)-(2-cyano-2-(2-phenylthiazol-4-yl)-1-(2-methyl-4-trifluoromethylthiazol-5-yl)vinyl) (tetrahydrofuran-3-yl) carbonate [ No CAS ]

References: [1]Patent: CN106187937,2016,A .

26
[ 117724-63-7 ]
3-hydroxy-3-(2-methyl-4-trifluoromethylthiazol-5-yl)-2-(2-phenylthiazol-4-yl)acrylonitrile [ No CAS ]

References: [1]Patent: CN106187937,2016,A .
[2]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 3395 - 3402.

27
[ 288-13-1 ]
[ 117724-63-7 ]
[ 947674-89-7 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of thionyl chloride (250 mmol) was added dropwise to a solution of <strong>[117724-63-7]2-methyl-4-trifluoromethylthiazole-5-carboxylic acid</strong> (100 mmol) in 1,2-dichloroethane (120 mL) at room temperature under stirring (150 mL). After the dropwise addition, the reaction was carried out under reflux for 4-6 hr, After removal of the solvent and excess of thionyl chloride, dichloromethane (150 mL) was added. Pyrazole (200 mmol) was added in portions and reacted at room temperature for 3-5 hr. The reaction solution was poured into ice water, the dichloromethane layer was separated and the aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed to give the title crude product 22.3 g, directly for the next step.

References: [1]Patent: CN106187937,2016,A .Location in patent: Paragraph 0115; 0117.
[2]Journal of Heterocyclic Chemistry,2017,vol. 54,p. 3395 - 3402.

28
[ 117724-63-7 ]
(Z)-2-cyano-1-(2-methyl-4-(trifluoromethyl)thiazol-5-yl)-2-(2-phenylthiazol-4-yl)vinyl 2-(methylthio)propanoate [ No CAS ]
(E)-2-cyano-1-(2-methyl-4-(trifluoromethyl)thiazol-5-yl)-2-(2-phenylthiazol-4-yl)vinyl 2-(methylthio)propanoate [ No CAS ]