[ CAS No. 33468-67-6 ]

Name: 33468-67-6|2-Methyl-4-(trifluoromethyl)-1H-imidazole|95%
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Quality Control of [ 33468-67-6 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 33468-67-6 ]

CAS No. :	33468-67-6	MDL No. :	MFCD10000863
Formula :	C₅H₅F₃N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UTUSYSDVLOWRJA-UHFFFAOYSA-N
M.W :	150.10	Pubchem ID :	591635
Synonyms :

Calculated chemistry of [ 33468-67-6 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.4
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	28.56
TPSA :	28.68 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.24 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.06
Log Po/w (XLOGP3) :	1.38
Log Po/w (WLOGP) :	2.89
Log Po/w (MLOGP) :	0.77
Log Po/w (SILICOS-IT) :	2.43
Consensus Log Po/w :	1.7

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.94
Solubility :	1.71 mg/ml ; 0.0114 mol/l
Class :	Very soluble
Log S (Ali) :	-1.59
Solubility :	3.9 mg/ml ; 0.026 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.49
Solubility :	0.486 mg/ml ; 0.00324 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.67

Safety of [ 33468-67-6 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P280-P305+P351+P338	UN#:
Hazard Statements:	H317-H319	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 33468-67-6 ]

* 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.

Upstream synthesis route of [ 33468-67-6 ]
Downstream synthetic route of [ 33468-67-6 ]

[ 33468-67-6 ] Synthesis Path-Upstream 1~4

1
[ 75-07-0 ]
[ 91944-47-7 ]
[ 33468-67-6 ]

Yield	Reaction Conditions	Operation in experiment
54%	With ammonium hydroxide In methanol at 0 - 20℃; Sealed tube	Compound 16.2. 2-MethyI-4-(trifluoromethyl)-lH-imidazole. Into a 10-mL sealed tube, was placed a solution of acetaldehyde (296 iL, 5.29 mmol), 3,3,3-trifluoro-2- oxopropanal (compound 16.1, 1.0 g, 7.9 mmol), and 25percent ammonium hydroxide (0.8 mL) in methanol (5 mL). The solution was stirred for 3 h at 0 °C, then stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure and then the residue was diluted with water (50 mL) The aqueous phase was extracted with ethyl acetate (3 x 20 mL) and the combined organic extracts were dried (Na₂S0₄), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography to yield 430 mg (54percent) of the title compound as a light yellow solid.
54%	With ammonium hydroxide In methanol at 0 - 20℃; Sealed tube	Compound 16.2. 2-Methyl-4-(trifluoromethyl)-lH-imidazole. Into a 10-mL sealed tube, was placed a solution of acetaldehyde (296 μ,, 5.29 mmol), 3,3,3-trifluoro-2- oxopropanal (compound 16.1, 1.0 g, 7.9 mmol), and 25percent ammonium hydroxide (0.8 mL) in methanol (5 mL). The solution was stirred for 3 h at 0 °C, then stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure and then the residue was diluted with water (50 mL) The aqueous phase was extracted with ethyl acetate (3 x 20 mL) and the combined organic extracts were dried ( a2S0₄), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography to yield light yellow solid.

Reference： [1] Patent: WO2014/8197, 2014, A1, . Location in patent: Page/Page column 89
[2] Patent: WO2015/95767, 2015, A1, . Location in patent: Page/Page column 104

2
[ 693-98-1 ]
[ 2926-29-6 ]
[ 33468-67-6 ]

Reference： [1] Journal of the American Chemical Society, 2016, vol. 138, # 18, p. 5809 - 5812

3
[ 693-98-1 ]
[ 33468-67-6 ]

Reference： [1] Journal of the American Chemical Society, 2017, vol. 139, # 40, p. 14315 - 14321

4
[ 693-98-1 ]
[ 2314-97-8 ]
[ 81769-59-7 ]
[ 33468-67-6 ]

Reference： [1] Journal of Organic Chemistry, 1982, vol. 47, # 15, p. 2867 - 2872

[ 33468-67-6 ] Synthesis Path-Downstream 1~68

1
[ 693-98-1 ]
[ 2314-97-8 ]
[ 81769-59-7 ]
[ 33468-67-6 ]

Reference： [1]Journal of Organic Chemistry,1982,vol. 47,p. 2867 - 2872

2
[ 1174013-25-2 ]
[ 33468-67-6 ]
[ 1215198-25-6 ]

Yield	Reaction Conditions	Operation in experiment
47%		To a stirred solution of 2-methyl-4-(trifluoromethyl)-1 /-/-imidazole (Chireach USA LLC, San Diego, CA) (197 mg, 1.3 mmol) in anhydrous THF (8 mL) under N2 was added a solution of lithium hexamethyldisilazide (1.24 mL, 1 M in hexanes, 1.24 mmol). After stirring for 45 minutes at room temperature, a solution of Intermediate (1-1 c) (400 mg, 1.32 mmol) in 8 mL of anhydrous THF was added dropwise and stirring was continued for 4 hours at room temperature. It was then quenched with aqueous saturated NH4CI and extracted with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (SiO2, heptane / ethyl acetate, O to 50%) to afford (1-17a) in 47% yield; m/z 305.4 (IvRH)+.

Reference： [1]Patent: WO2010/29461,2010,A1 .Location in patent: Page/Page column 55-56

3
[ 39856-50-3 ]
[ 33468-67-6 ]
[ 1415640-57-1 ]

Yield	Reaction Conditions	Operation in experiment
23%		Example 57 Preparation of N-(2,6-difluorobenzyl)-5-(2-methyl-4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-2-amine (106) A suspension of <strong>[33468-67-6]2-methyl-4-(trifluoromethyl)imidazole</strong> (300 mg, 2 mmol) and potassium carbonate (828 mg, 3 eq) in 4 mL DMSO was heated at 120 C. for 30 min before addition of 5-bromo-2-nitropyridine (406 mg, 2 mmol). The resulting suspension was heated at 120 C. for 4 more hours. After cooling down, the reaction mixture was worked up with EA/brine. Flash silica gel column purification furnished nitropyridine intermediate 103 (125 mg, yield 23%, purity>90%) as a light yellow solid.

Reference： [1]Patent: US2012/316182,2012,A1 .Location in patent: Page/Page column 104

4
[ 33468-67-6 ]
[ 1415640-60-6 ]

Reference： [1]Patent: US2012/316182,2012,A1

5
[ 33468-67-6 ]
[ 1415640-58-2 ]

Reference： [1]Patent: US2012/316182,2012,A1

6
[ 33468-67-6 ]
[ 1415640-59-3 ]

Reference： [1]Patent: US2012/316182,2012,A1

7
[ 33468-67-6 ]
[ 1431386-79-6 ]

Reference： [1]Patent: WO2013/59666,2013,A1

8
[ 33468-67-6 ]
[ 1431386-38-7 ]

Reference： [1]Patent: WO2013/59666,2013,A1

9
[ 33468-67-6 ]
[ 1431385-65-7 ]

Reference： [1]Patent: WO2013/59666,2013,A1

10
[ 33468-67-6 ]
[ 1431386-80-9 ]

Reference： [1]Patent: WO2013/59666,2013,A1

11
[ 33468-67-6 ]
[ 1431386-43-4 ]

Reference： [1]Patent: WO2013/59666,2013,A1

12
[ 33468-67-6 ]
[ 1431385-70-4 ]

Reference： [1]Patent: WO2013/59666,2013,A1

13
[ 369-34-6 ]
[ 33468-67-6 ]
[ 1431386-78-5 ]

Yield	Reaction Conditions	Operation in experiment
52%		A suspension of <strong>[33468-67-6]2-methyl-4-(trifluoromethyl)imidazole</strong> (300 mg, 2 mmol) and potassium carbonate (828 mg, 6 mmol) in 2 mL DMSO was heated at 120C for 30 min before addition of 3,4-difluoronitrobenzene (318 mg, 2 mmol). The resulting reaction mixture was heated at 120C for 3 more hours. After cooling down to room temperature, the reaction mixture was worked up with EA/brine. The organic phase was dried over sodium sulfate, concentrated and subjected to silica gel column purification using hexane and 50% EA in hexane to afford 122 (301 mg, yield: 52%, purity >95%) as a yellow solid. (LC-MS: calculated: 289.19, found:290.03).

Reference： [1]Patent: WO2013/59666,2013,A1 .Location in patent: Paragraph 00672

14
[ 350-46-9 ]
[ 33468-67-6 ]
[ 362613-64-7 ]

Yield	Reaction Conditions	Operation in experiment
45.5%		A suspension of <strong>[33468-67-6]2-methyl-4-(trifluoromethyl)imidazole</strong> (300 mg, 2 mmol) and potassium carbonate (828 mg, 6 mmol) in 2 mL DMSO was heated at 120C for 30 min before addition of 4-fluoronitrobenzene (282 mg, 2 mmol). The resulting reaction mixture was heated at 120C for 3 more hours. After cooling down to room temperature, the reaction mixture was worked up with EA/brine. The organic phase was dried over sodium sulfate, concentrated, and subjected to silica gel column purification using hexane and 50%> EA in hexane as eluents to give 134 (247 mg, yield: 45.5%, purity >95%) as a light yellow solid. (LC-MS: calculated: 271.20, found: 272.07).

Reference： [1]Patent: WO2013/59666,2013,A1 .Location in patent: Paragraph 00685

15
[ 75-07-0 ]
[ 91944-47-7 ]
[ 33468-67-6 ]

Yield	Reaction Conditions	Operation in experiment
54%	With ammonium hydroxide; In methanol; at 0 - 20℃;Sealed tube;	Compound 16.2. 2-MethyI-4-(trifluoromethyl)-lH-imidazole. Into a 10-mL sealed tube, was placed a solution of acetaldehyde (296 iL, 5.29 mmol), 3,3,3-trifluoro-2- oxopropanal (compound 16.1, 1.0 g, 7.9 mmol), and 25% ammonium hydroxide (0.8 mL) in methanol (5 mL). The solution was stirred for 3 h at 0 C, then stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure and then the residue was diluted with water (50 mL) The aqueous phase was extracted with ethyl acetate (3 x 20 mL) and the combined organic extracts were dried (Na2S04), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography to yield 430 mg (54%) of the title compound as a light yellow solid.
54%	With ammonium hydroxide; In methanol; at 0 - 20℃;Sealed tube;	Compound 16.2. 2-Methyl-4-(trifluoromethyl)-lH-imidazole. Into a 10-mL sealed tube, was placed a solution of acetaldehyde (296 mu,, 5.29 mmol), 3,3,3-trifluoro-2- oxopropanal (compound 16.1, 1.0 g, 7.9 mmol), and 25% ammonium hydroxide (0.8 mL) in methanol (5 mL). The solution was stirred for 3 h at 0 C, then stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure and then the residue was diluted with water (50 mL) The aqueous phase was extracted with ethyl acetate (3 x 20 mL) and the combined organic extracts were dried ( a2S04), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography to yield light yellow solid.

Reference： [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 89
[2]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 104

16
[ 33468-67-6 ]
[ 112108-86-8 ]

Yield	Reaction Conditions	Operation in experiment
79%	With ammonium hydroxide; at 20℃; for 96h;	Compound 16.3. 2-Methyl-lH-imidazole-4-carbonitrile. Into a 100-mL round- bottom flask, was placed a solution of 2 -methyl-4-(trifluoromethyl)-lH- imidazole (compound 16.2, 300 mg, 2.00 mmol) in 5% ammonium hydroxide (35 mL). The resulting solution was stirred for 4 days at room temperature, then the pH of the solution was adjusted to 7 with acetic acid. The aqueous phase was extracted with of ethyl acetate (3 x 10 mL) and the combined organic layers were dried (Na2S04), filtered, and concentrated under reduced pressure to yield 170 mg (79%) of the title compound as a light yellow solid.
79%	With ammonium hydroxide; at 20℃; for 96h;	Compound 16.3. 2-Methyl-lH-imidazole-4-carbonitrile. Into a 100-mL round- bottom flask, was placed a solution of 2-methyl-4-(trifluoromethyl)- lH-imidazole (compound 16.2, 300 mg, 2.00 mmol) in 5% ammonium hydroxide (35 mL). The resulting solution was stirred for 4 days at room temperature, then the pH of the solution was adjusted to 7 with acetic acid. The aqueous phase was extracted with of ethyl acetate (3 x 10 mL) and the combined organic layers were dried ( a2S04), filtered, and concentrated under reduced pressur ompound as a light yellow solid.

Reference： [1]Patent: WO2014/8197,2014,A1 .Location in patent: Page/Page column 90
[2]Patent: WO2015/95767,2015,A1 .Location in patent: Page/Page column 104; 105

17
[ 33468-67-6 ]
[ 1533440-58-2 ]

Reference： [1]Patent: WO2014/8197,2014,A1
[2]Patent: WO2015/95767,2015,A1

18
[ 105-36-2 ]
[ 33468-67-6 ]
[ 1571821-12-9 ]

Yield	Reaction Conditions	Operation in experiment
40%	With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; for 2h;	a) To a vial was added <strong>[33468-67-6]2-methyl-4-(trifluoromethyl)-1H-imidazole</strong> (750 mg, 5 mmol), 5 mL of THF, 2.5 mL of DMF, and K2CO3 (2.07 g, 15 mmol). To this mixture was slowly added ethyl bromoacetate (1.00 g, 6 mmol). After 2 hours, the slurry was diluted with EtOAc, filtered on Celite, and concentrated. The residue was purified by flash chromatography (SiO2, 80 g column, eluting with 15-100% EtOAc in hexanes) to provide 476 mg (40%) of the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 7.20 (s, 1H), 4.61 (s, 2H), 4.28 (q, J=7.0 Hz, 2H), 1.63 (s, 3H), 1.31 (t, J=7.0 Hz, 3H); MS: (ES) m/z calculated for C9H12F3N2O2 [M+H]+ 237.1, found 237.1. The regiochemistry of the system was confirmed by nOe between the alpha-methylene and both the imidazole ring and methyl protons.

Reference： [1]Patent: US2014/57937,2014,A1 .Location in patent: Paragraph 0146; 0147

19
[ 33468-67-6 ]
[ 535-11-5 ]
[ 1571821-93-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20 - 50℃;	a) A mixture of potassium carbonate (832 mg, 6.02 mmol), 2-methyl-5-(trifluoromethyl)-1H-imidazole (450 mg, 3.00 mmol) and ethyl 2-bromopropanoate (0.43 mL, 3.3 mmol) in dimethylformamide:tetrahydrofuran (2 mL:4 mL) was heated at 50 C. for 7 h with stirring and then at room temperature overnight. Most of the tetrahydrofuran was removed by gently blowing nitrogen over the reaction mixture. Ethyl acetate and water were then added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 17-50% ethyl acetate in hexanes) to afford the desired product (697 mg, 2.79 mmol, 93%).
	With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 45℃; for 16h;	A solution of ethyl 2-bromopropionate (3.98 g, 22 mmol), 4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazole (3.00 g, 20 mmol), and K2CO3 (5.53 g, 40 mmol) in THF/DMF (2:1, 39 mL) was allowed to stir at 45 C. for 16 h. The mixture was then concentrated in vacuo and diluted with EtOAc (70 mL). The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the product (5.3 g) as a colorless oil that was used without further purification.

Reference： [1]Patent: US2014/57937,2014,A1 .Location in patent: Paragraph 0214; 0215
[2]Patent: US2014/179733,2014,A1 .Location in patent: Paragraph 0148; 0149

20
[ 33468-67-6 ]
[ 1571821-27-6 ]

Reference： [1]Patent: US2014/57937,2014,A1
[2]Patent: WO2016/51193,2016,A1

21
[ 33468-67-6 ]
[ 1571821-96-9 ]

Reference： [1]Patent: US2014/57937,2014,A1
[2]Patent: US2014/179733,2014,A1

22
[ 33468-67-6 ]
[ 1571818-82-0 ]

Reference： [1]Patent: US2014/57937,2014,A1

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[ 33468-67-6 ]
[ 1571822-10-0 ]

Reference： [1]Patent: US2014/57937,2014,A1

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[ 33468-67-6 ]
[ 1571818-84-2 ]

Reference： [1]Patent: US2014/57937,2014,A1

25
[ 33468-67-6 ]
[ 1571822-01-9 ]

Reference： [1]Patent: US2014/57937,2014,A1

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[ 33468-67-6 ]
[ 1571822-13-3 ]

Reference： [1]Patent: US2014/57937,2014,A1

27
[ 33468-67-6 ]
[ 533-68-6 ]
[ 1571822-05-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20 - 50℃;	a) A mixture of potassium carbonate (834 mg, 6.04 mmol), 2-methyl-5-(trifluoromethyl)-1H-imidazole (449 mg, 2.99 mmol) and methyl 2-bromobutyrate (0.38 mL, 3.3 mmol) in dimethylformamide:tetrahydrofuran (2 mL:4 mL) was heated at 50 C. for 7 h with stirring and then at room temperature overnight. Most of the tetrahydrofuran was then removed by gently blowing nitrogen over the reaction mixture. Ethyl acetate and water were added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 20-50% ethyl acetate in hexanes) to afford the desired product (641 mg, 2.56 mmol, 86%).

Reference： [1]Patent: US2014/57937,2014,A1 .Location in patent: Paragraph 0218; 0219

28
[ 25966-39-6 ]
[ 33468-67-6 ]
[ 1613396-36-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; In acetonitrile; at 80℃; for 48h;	Example 42 Synthesis of (S)-l-(l-(4-chlorophenyl)-5-isopropyl-lH-pyrazol-4-yl)-3-(2-methyl-4- (trifluoromethyl)-lH-imidazol-l-yl)pyrrolidin-2-one and ( ?)-l-(l-(4-chlorophenyl)-5- isopropyl-lH-pyrazol-4-yl)-3-(2-methyl-4-(trifluoromethyl)-lH-imidazol-l- yl)pyrrolidin-2-one step e [0203] a) To a solution of a-bromo-y-valerolactone (19.8 g, 120 mmol) and 2-methyl-4- (trifluoromethyl)- lH-imidazole (4.50 g, 30 mmol) in acetonitrile (60 mL) was added K3PO4 (19.1 g, 90 mmol). The slurry was heated to 80 C for 2 days, then cooled to room temperature, diluted with EtOAc (200 mL), filtered through Celite, and concentrated. The residue was purified by flash chromatography (S1O2, 0 - 3.5% methanol/CH2Cl2) to give the product as a pasty colorless solid. [0204] b) A mixture of the lactone intermediate (700 mg, 5.1 mmol) from step a and (5)- phenylglycinol (1.09 g, 4.64 mmol) was heated at 80 C for 18 h, cooled to room temperature, and purified by flash chromatography (Si02, 0.5-2% methanol/EtOAc) to give two diastereomeric products as colorless foams. The first eluting isomer (310 mg) was obtained in 99: 1 diastereomeric ratio (XH NMR) and the second eluting isomer (200 mg) in 1 1 : 1 diastereomeric ratio (XH NMR). Each diastereomer was carried through steps c and d independently. [0205] c) To a mixture of the product from step b (186 mg, 0.5 mmol) in dioxane (2 mL) was added 6 M H2S04 (1.25 mL, 7.5 mmol). The resulting slurry was heated at 80 C for 1 h, cooled to room temperature, and purified by reverse phase HPLC (CI 8 column, acetonitrile-H20 with 0.1% TFA as eluent). The resulting lactone FontWeight="Bold" FontSize="10" TFA salt was neutralized to provide a colorless solid (53 mg, 0.23 mmol) that was used without further purification. [0206] d) A mixture of the lactone product from step c and l-(4-chlorophenyl)-5- isopropyl- lH-pyrazol-4-amine (50 mg, 0.21 mmol) in 1 ,2-dichloroethane (1 mL) was treated with AlMe3 (2 M solution in toluene, 210 mu, 0.42 mmol) at room temperature for 30 min. The reaction was quenched with saturated NH4C1 (5 mL) and extracted with EtOAc (3 x 3 mL). The organic layer was dried on MgS04, filtered, concentrated, and purified by flash chromatography (Si02, 0 - 100% EtOAc/CH2Cl2) to give the desired product (50 mg, 0.1 mmol, 50% yield). [0207] e) The product from step d (50 mg, 0.1 mmol) in dichloromethane (0.5 mL) was treated with Et3N (40 mu, 0.29 mmol) and methanesulfonyl chloride (20 mu, 0.23 mmol) for 30 min at room temperature. The mixture was then diluted with 1,2-dichloroethane (1 mL) and washed with water (1 mL). The organic layer was dried on Na2S04 and filtered. To the filtrate was added triethylamine (100 mu^, 0.7 mmol) and the mixture was stirred at 65 C for 90 min, concentrated, and purified by reverse phase HPLC (CI 8 column, acetonitrile-H20 with 0.1% TFA as eluent). The resulting TFA salt was neutralized to provide the titled compound (19 mg, 0.041 mmol) as a white solid. XH NMR (400 MHz, CDC13) delta 7.55 (s, 1 H), 7.48 (d, J= 8.6, 2 H), 7.36 (d, J= 8.6, 2 H), 7.22 (d, J= 0.8 Hz, 1 H), 5.07 (dd, J= 10.5, 8.9 Hz, 1 H), 3.91-3.77 (m, 2 H), 3.05 (hept, J= 7.0 Hz, 1 H), 2.90-2.82 (m, 1 H), 2.52 (s, 3 H), 2.42-2.31 (m, 1 H), 1.24 (d, J= 3.2 Hz, 3 H), 1.23 (d, J= 3.2 Hz, 3 H); MS: (ES) m/z calculated for C2iH22ClF3N50 [M + H]+ 452.1, found 451.9. The titled compounds were analyzed by chiral normal phase chromatography (Regis Cell cat 784104, 25 cm x 4.6 mm, 5 micron; eluent: 0.1% diethylamine/IPA, 0.6 ml/min). The (5)-enantiomer generated from the first-eluting diasteromer from step b had a retention time of 6.8 min (isolated in 8: 1 er). The (R)-enantiomer generated from the second-eluting diasteromer from step b had a retention time of 7.3 min (isolated in 78: 1 er).

Reference： [1]Patent: WO2014/89495,2014,A1 .Location in patent: Paragraph 0202; 0203

29
[ 1613396-96-5 ]
[ 33468-67-6 ]
[ 1613395-28-0 ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 2h;	Example 40 Synthesis of l-[l-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]-3-[2-methyl-4- (trifluoromethyl)imidazol-l-yl]pyrrolidin-2-one [0200] A mixture of 3-bromo-l-[l-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2- one (0.110 g, 0.29 mmol), <strong>[33468-67-6]2-methyl-4-(trifluoromethyl)-lH-imidazole</strong> (0.080 g, 0.53 mmol) and K2C03 (0.080 g, 0.58 mmol) in DMF (1.8 mL) was stirred at 65 C for 2 hrs. The mixture was then cooled to room temperature, quenched with water (30 mL), extracted with EtOAc (50 mL), and purified by reverse phase HPLC (CI 8 column, acetonitrile-H20 with 0.1% TFA as eluent) to yield the title compound (0.035 g, TFA salt, 21%). XH NMR (TFA salt) (400 MHz, CDC13) delta 7.58 (s, 1 H), 7.49 (m, 2 H), 7.35 (m, 2 H), 7.27 (s, 1 H), 5.03 (dd, J= 10.4, 8.8 Hz, 1 H), 3.89 (m, 1 H), 3.81 (m, 1 H), 3.04 (heptet, J= 6.8 Hz, 1 H), 2.88 (m, 1 H), 2.58 (s, 3 H), 2.40 (m, 1 H), 1.23 (m, 6 H); MS: (ES) m/z calculated for C2iH21ClF3 50 [M + H]+ 452.1, found 452.1.

Reference： [1]Patent: WO2014/89495,2014,A1 .Location in patent: Paragraph 0199; 0200

30
[ 1613395-45-1 ]
[ 33468-67-6 ]
[ 1613394-86-7 ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium carbonate; In N,N-dimethyl-formamide; at 65℃; for 12h;	Example 3 Synthesis of 1- [l-(4-fluorophenyl)-5-methylpyrazol-4-yl] -3- [2-methyl-4- (trifluoromethyl)imidazol-l-yl]pyrrolidin-2-one [0103] a) Trimethylaluminum (0.26 mL, 2 M in toluene, 0.52 mmol) was slowly added under nitrogen to a solution of the l-(4-fluorophenyl)-5-methylpyrazol-4-amine (50 mg, 0.26 mmol) and a-bromo-y-butyrolactone (85 mg, 0.52 mmol) in 1,2-dichloroethane (2 mL) at room temperature. The mixture was allowed to stir for 1 h before the reaction was carefully quenched by adding a few drops of 1 N HCl. After bubbling subsided, the thick mixture was diluted with additional 1 N HCl and extracted with CH2CI2 (2 x 20 mL). The combined organic extracts were dried over MgSC^, filtered, and concentrated in vacuo. The crude material was carried to the next step without further purification. [0104] b) To a solution of the crude alcohol intermediate (assumed 0.26 mmol) from step a and triethylamine (0.11 mL, 0.78 mmol) in CH2CI2 (3 mL) was slowly added methanesulfonyl chloride (0.030 mL, 0.39 mmol). The reaction mixture was allowed to stir at room temperature for 15 min before it was diluted with CH2CI2 and washed with water. The organic layer was separated, dried over MgS04, filtered, and concentrated in vacuo. The crude material was carried to the next step without further purification. [0105] c) To the crude mesylate intermediate (assumed 0.61 mmol) from step b in tetrahydrofuran (2 mL) was added sodium hydride (40 mg, 60% in mineral oil, 1.0 mmol) in one portion at room temperature. After stirring for 30 min, the reaction was quenched by the addition of saturated aqueous NH4C1 and extracted with CH2CI2 (2 x 20 mL). The organic layers were combined, dried over MgSC , filtered, and concentrated in vacuo. The crude material was carried to the next step without further purification. [0106] d) A mixture of the crude bromide intermediate (assumed 0.26 mmol) from step c, <strong>[33468-67-6]2-methyl-4-trifluoromethylimidazole</strong> (40 mg, 0.26 mmol), and potassium carbonate (40 mg, 0.29 mmol) in DMF (2 mL) was stirred at 65 C for 12 h. The mixture was cooled to room temperature, diluted with EtOAc (20 mL) and washed with water. The aqueous layer was back-extracted with EtOAc (1 x 10 mL) and CH2CI2 (1 x 10 mL). The organic layers were combined, dried over MgS04, filtered, and concentrated in vacuo. Purification of the crude material by reverse phase HPLC (CI 8 column, acetonitrile-H20 with 0.1% TFA as eluent) afforded the trifluoroacetate salt of the titled compound (28 mg, 0.0054 mmol, 21% over four steps) as a white solid. XH NMR (400 MHz, CDC13) delta 7.69 (s, 1 H), 7.43 (dd, J= 8.8, 4.8 Hz, 2 H), 7.30-7.28 (m, 1 H), 7.21 (dd, J= 8.0, 8.0 Hz, 2 H), 5.07 (dd, J= 10.4, 8.8 Hz, 1 H), 3.98 (ddd, J= 10.0, 10.0, 6.8 Hz, 1 H), 3.89 (ddd, J= 10.8, 9.2, 2.0 Hz, 1 H), 2.94-2.88 (m, 1 H), 2.61 (s, 3 H), 2.48-2.39 (m, 1 H), 2.27 (s, 3 H); MS: (ES) m/z calculated for Ci9H17F4 50 [M + H]+ 408.1, found 408.1.

Reference： [1]Patent: WO2014/89495,2014,A1 .Location in patent: Paragraph 0102; 0106

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[ 33468-67-6 ]
[ 1613395-12-2 ]