[ CAS No. 317318-97-1 ] {[proInfo.proName]}

Name: 317318-97-1|5-(Chloromethyl)-4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole|97%
Brand: Ambeed
SKU: A289827
Price: 12.0 USD
Availability: InStock
Rating: 97 (40 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 317318-97-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 317318-97-1 ]

SDS Specification

Alternatived Products of [ 317318-97-1 ]

Product Details of [ 317318-97-1 ]

CAS No. :	317318-97-1	MDL No. :	MFCD03791173
Formula :	C₁₂H₉ClF₃NS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JQVJAQPUFIIRJP-UHFFFAOYSA-N
M.W :	291.72	Pubchem ID :	2783006
Synonyms :

Calculated chemistry of [ 317318-97-1 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.25
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	67.28
TPSA :	41.13 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.01 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.95
Log Po/w (XLOGP3) :	4.32
Log Po/w (WLOGP) :	5.88
Log Po/w (MLOGP) :	3.65
Log Po/w (SILICOS-IT) :	6.09
Consensus Log Po/w :	4.58

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.62
Solubility :	0.00693 mg/ml ; 0.0000237 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.9
Solubility :	0.00369 mg/ml ; 0.0000127 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-6.1
Solubility :	0.000233 mg/ml ; 0.000000798 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.66

Safety of [ 317318-97-1 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501	UN#:	3261
Hazard Statements:	H302-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 317318-97-1 ]

* 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 [ 317318-97-1 ]
Downstream synthetic route of [ 317318-97-1 ]

[ 317318-97-1 ] Synthesis Path-Upstream 1~12

1
[ 639784-17-1 ]
[ 121-44-8 ]
[ 317318-97-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: With methanesulfonyl chloride In dichloromethane at 0℃; for 2 h; Stage #2: at 0℃; for 2 h;	To a [COLD (0°C)] stirred solution of intermediate 1 (8. [2_G,] 30 [MMOL)] and Et3N (6.07 g, 8.36 mL, 60 [MMOL),] in dry CH2CI2 (120 mL) was slowly added MeSO2CI (5.49 g, 3. [71 ML,] 48 [MMOL).] After 2 hs at [0°C] more Et3N (6 [MMOL)] and [MES02CI] (4.8 [MMOL)] were added. After [2H] [MOREL] a [TLC] (hexane/EtOAc, 1: 1) showed complete reaction. The reaction mixture was diluted with CH2CI2 (120 mL) and washed with [NAHCO3] (sat. ) (2 x 240 mL) and water (2 x 240 mL), dried, filtered and evaporated to afford the title compound (8.0 g, 27 mmol, 90percent) as a yellow solid.

Reference： [1] Patent: WO2004/785, 2003, A2, . Location in patent: Page 43

2
[ 317318-96-0 ]
[ 317318-97-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With methanesulfonyl chloride; triethylamine In dichloromethane at 0℃;	To a cold (0°C) stirred solution of the product from Step 1 (2.51 g,9.19 mmol) and Et₃N (2.56 mL, 18.37 mmol) in dry CH₂C1₂ (150 mL), was slowly added MsCl (1.07 mL, 13.78 mmol). The reaction mixture was stirred at 0°C. The reaction mixture was diluted with 200 mL of CH2CI2 washed with saturated NaHCO₃, water, brine, and dried over Na2SC>4. Removal of solvent affords 2.65 g (99percent yield) of the desired product as brown solid. *H NMR (400 MHz, CDC1₃), 8 (ppm): 8.01 (d, 2H), 7.68 (d, 2H), 4.80 (s, 2H), 2.51 (s, 3H).
98.5%	With N-chloro-succinimide; triphenylphosphine In dichloromethane at 20℃;	[[4-METHYL-2- (4-TRIFLUOROMETHYL-PHENYL) THIAZOLE-5-YL] METHANOL] (10.0 [G, 36.] 6 mmol) obtained from Example 2 was dissolved in anhydrous dichloromethane (250 [MNo. ]) and then triphenylphosphine (TPP, 11.5 g, 44.0 mmol, 1.2 eq. ) and N- [CHLOROSUCCMIMIDE] (5.86 g, 44.0 mmol, 1.2 eq. ) were added to the mixture at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure. Subsequently, the remained triphenylphosphine oxide was precipitated by adding a mixed solvent of hexane and ethyl acetate (v/v = [5/1),] followed by filtration and evaporation under reduced pressure to thereby yield 10.5 g of the title compound (yield: 98.5percent).
98.5%	With N-chloro-succinimide; triphenylphosphine In dichloromethane at 20℃; for 2 h;	[4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (10.0 g, 36.6 mmol) obtained from Example 2 was dissolved in anhydrous dichloromethane (250 ml) and then triphenylphosphine (TPP, 11.5 g, 44.0 mmol, 1.2 eq.) and N- chlorosuccinimide (5.86 g, 44.0 mmol, 1.2 eq.) were added to the mixture sequentially at room temperature. After stirring for 2 hours, the solvent was evaporated under reduced pressure. Subsequently, the remained triphenylphosphine oxide was precipitated by adding a mixed solvent of hexane and ethyl acetate (v/v = 5/1), followed by filtration and evaporation under reduced pressure to thereby yield 10.5 g of the title compound (yield: 98.5percent).

78.4%	for 10 h; Heating / reflux	[[4-METHYL-2- (4-TRIFLUOROMETHYL-PHENYL) THIAZOLE-5-YL] METHANOL (5.] 0 g, [18. 3] mmol) obtained from Example 2 was dissolved in tetrachloromethane [(300 W),] and then triphenylphosphine (TPP, [6. 3] g, [23.] 8 mmol, 1.3 eq. ) was added and the mixture was stirred under reflux for 10 hours. After completion of the reaction, the temperature of the reactor was cooled to room temperature, and a mixed solvent of hexane and ethyl acetate [(V/V = 5/1)] was added thereto to precipitate the remained triphenylphosphine oxide, followed by filtration and evaporation under reduced pressure to thereby yield 8.4 g of the title compound (yield: 78.4percent). 'H-NMR [(300] MHz, [CDCI3)] : 8.01 (d, 2H, J= 8.1 Hz), 7.68 (d, 2H, J= 8.2 Hz), 4.79 (s, 2H), 2. [51] (s, 3H).
78.4%	for 10 h; Heating / reflux	[4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (5.0 g, 18.3 mmol) obtained from Example 2 was dissolved in tetrachloromethane (300 ml), and then triphenylphosphine (TPP, 6.3 g, 23.8 mmol, 1.3 eq.) was added and the mixture was stirred under reflux for 10 hours. After completion of the reaction, the temperature of the reactor was cooled to room temperature, and a mixed solvent of hexane and ethyl acetate (v/v = 5/1) was added thereto to precipitate the remained triphenylphosphine oxide, followed by filtration and evaporation under reduced pressure to thereby yield 8.4 g of the title compound (yield: 78.4percent). ¹H-NMR (300 MHz, CDCl₃): 8.01 (d, 2H, J = 8.1 Hz), 7.68 (d, 2H, J = 8.2Hz), 4.79 (s, 2H), 2.51 (s, 3H).

Reference： [1] Patent: WO2005/60958, 2005, A1, . Location in patent: Page/Page column 116
[2] Patent: WO2003/106442, 2003, A1, . Location in patent: Page 14
[3] Patent: WO2006/121223, 2006, A1, . Location in patent: Page/Page column 16
[4] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 9, p. 1517 - 1521
[5] Patent: WO2003/106442, 2003, A1, . Location in patent: Page 14
[6] Patent: WO2006/121223, 2006, A1, . Location in patent: Page/Page column 15-16
[7] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 1, p. 49 - 54
[8] Patent: WO2005/51945, 2005, A1, . Location in patent: Page/Page column 90; 160
[9] European Journal of Medicinal Chemistry, 2016, vol. 113, p. 246 - 257
[10] Patent: EP1586573, 2005, A1, . Location in patent: Page/Page column 15-16

3
[ 124-63-0 ]
[ 317318-96-0 ]
[ 317318-97-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine In tetrahydrofuran	Preparation of 5-Chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (Compound 1B) Methanesulfonyl chloride (1.0 mL, 12.9 mmol) was added to a stirred solution of [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (2.2 g, 8.1 mmol) and triethylamine (2.2 mL, 16.1 mmol) in 25 mL THF at 0° C. After 3 hours, the reaction mixture was diluted with dichloromethane, washed with 1sat. NaHCO₃, 1brine, dried (Na₂SO₄) and the solvent removed in vacuo to give 2.0 g (84percent) of the title compound pure enough for subsequent use. 400 MHz ¹H NMR (DMSO-d₆) δ8.06 (d, 2H, J=8.3 Hz), 7.80 (d, 2H, J=8.3 Hz), 5.08 (s, 2H), 2.40 (s, 3H).

Reference： [1] Patent: US2003/207924, 2003, A1,

4
[ 72505-21-6 ]
[ 317318-97-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 9, p. 1517 - 1521
[2] Patent: WO2006/121223, 2006, A1,

5
[ 175277-03-9 ]
[ 317318-97-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 9, p. 1517 - 1521
[2] European Journal of Medicinal Chemistry, 2016, vol. 113, p. 246 - 257

6
[ 873066-23-0 ]
[ 317318-97-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 1, p. 49 - 54

7
[ 873066-26-3 ]
[ 317318-97-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 1, p. 49 - 54

8
[ 402-43-7 ]
[ 317318-97-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 1, p. 49 - 54

9
[ 86487-19-6 ]
[ 317318-97-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 1, p. 49 - 54

10
[ 1891-90-3 ]
[ 317318-97-1 ]

Reference： [1] European Journal of Medicinal Chemistry, 2016, vol. 113, p. 246 - 257

11
[ 1514-09-6 ]
[ 317318-97-1 ]

Reference： [1] European Journal of Medicinal Chemistry, 2016, vol. 113, p. 246 - 257

12
[ 144059-86-9 ]
[ 317318-97-1 ]

Reference： [1] Patent: EP1586573, 2005, A1,

[ 317318-97-1 ] Synthesis Path-Downstream 1~88

1
[ 14199-15-6 ]
[ 317318-97-1 ]
[ 317318-05-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1517 - 1521

2
[ 56077-47-5 ]
[ 317318-97-1 ]
[ 317318-69-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1517 - 1521
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 49 - 54

3
[ 105731-18-8 ]
[ 317318-97-1 ]
[ 317318-29-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1517 - 1521

4
[ 317319-05-4 ]
[ 317318-97-1 ]
[ 317318-61-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1517 - 1521

5
[ 317318-96-0 ]
[ 317318-97-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With methanesulfonyl chloride; triethylamine; In dichloromethane; at 0℃;	To a cold (0C) stirred solution of the product from Step 1 (2.51 g,9.19 mmol) and Et3N (2.56 mL, 18.37 mmol) in dry CH2C12 (150 mL), was slowly added MsCl (1.07 mL, 13.78 mmol). The reaction mixture was stirred at 0C. The reaction mixture was diluted with 200 mL of CH2CI2 washed with saturated NaHCO3, water, brine, and dried over Na2SC>4. Removal of solvent affords 2.65 g (99% yield) of the desired product as brown solid. *H NMR (400 MHz, CDC13), 8 (ppm): 8.01 (d, 2H), 7.68 (d, 2H), 4.80 (s, 2H), 2.51 (s, 3H).
98.5%	With N-chloro-succinimide; triphenylphosphine; In dichloromethane; at 20℃;	[[4-METHYL-2- (4-TRIFLUOROMETHYL-PHENYL) THIAZOLE-5-YL] METHANOL] (10.0 [G, 36.] 6 mmol) obtained from Example 2 was dissolved in anhydrous dichloromethane (250 [MNo. ]) and then triphenylphosphine (TPP, 11.5 g, 44.0 mmol, 1.2 eq. ) and N- [CHLOROSUCCMIMIDE] (5.86 g, 44.0 mmol, 1.2 eq. ) were added to the mixture at room temperature. After completion of the reaction, the solvent was evaporated under reduced pressure. Subsequently, the remained triphenylphosphine oxide was precipitated by adding a mixed solvent of hexane and ethyl acetate (v/v = [5/1),] followed by filtration and evaporation under reduced pressure to thereby yield 10.5 g of the title compound (yield: 98.5%).
98.5%	With N-chloro-succinimide; triphenylphosphine; In dichloromethane; at 20℃; for 2h;Product distribution / selectivity;	[4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (10.0 g, 36.6 mmol) obtained from Example 2 was dissolved in anhydrous dichloromethane (250 ml) and then triphenylphosphine (TPP, 11.5 g, 44.0 mmol, 1.2 eq.) and N- chlorosuccinimide (5.86 g, 44.0 mmol, 1.2 eq.) were added to the mixture sequentially at room temperature. After stirring for 2 hours, the solvent was evaporated under reduced pressure. Subsequently, the remained triphenylphosphine oxide was precipitated by adding a mixed solvent of hexane and ethyl acetate (v/v = 5/1), followed by filtration and evaporation under reduced pressure to thereby yield 10.5 g of the title compound (yield: 98.5%).

78.4%	With tetrachloromethane; triphenylphosphine; for 10h;Heating / reflux;	[[4-METHYL-2- (4-TRIFLUOROMETHYL-PHENYL) THIAZOLE-5-YL] METHANOL (5.] 0 g, [18. 3] mmol) obtained from Example 2 was dissolved in tetrachloromethane [(300 W),] and then triphenylphosphine (TPP, [6. 3] g, [23.] 8 mmol, 1.3 eq. ) was added and the mixture was stirred under reflux for 10 hours. After completion of the reaction, the temperature of the reactor was cooled to room temperature, and a mixed solvent of hexane and ethyl acetate [(V/V = 5/1)] was added thereto to precipitate the remained triphenylphosphine oxide, followed by filtration and evaporation under reduced pressure to thereby yield 8.4 g of the title compound (yield: 78.4%). 'H-NMR [(300] MHz, [CDCI3)] : 8.01 (d, 2H, J= 8.1 Hz), 7.68 (d, 2H, J= 8.2 Hz), 4.79 (s, 2H), 2. [51] (s, 3H).
78.4%	With tetrachloromethane; triphenylphosphine; for 10h;Heating / reflux;Product distribution / selectivity;	[4-Methyl-2-(4-trifluoromethyl-phenyl)thiazole-5-yl]methanol (5.0 g, 18.3 mmol) obtained from Example 2 was dissolved in tetrachloromethane (300 ml), and then triphenylphosphine (TPP, 6.3 g, 23.8 mmol, 1.3 eq.) was added and the mixture was stirred under reflux for 10 hours. After completion of the reaction, the temperature of the reactor was cooled to room temperature, and a mixed solvent of hexane and ethyl acetate (v/v = 5/1) was added thereto to precipitate the remained triphenylphosphine oxide, followed by filtration and evaporation under reduced pressure to thereby yield 8.4 g of the title compound (yield: 78.4%). 1H-NMR (300 MHz, CDCl3): 8.01 (d, 2H, J = 8.1 Hz), 7.68 (d, 2H, J = 8.2Hz), 4.79 (s, 2H), 2.51 (s, 3H).
	With methanesulfonyl chloride; triethylamine; In dichloromethane; at 0 - 20℃; for 2 - 4h;	A solution of [4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (1.03 g, 3.75 mmol) and TEA (1.05 mL, 7.5 mmol) in methylene chloride (15mL) is cooled to 0 C, and then MeSC^Cl is added dropwise. After 2 hrs, TLC indicatedthat the reaction is not complete. Additional 10 mol % TEA and MeSC^Cl are added.After additional 2hrs, the mixture is diluted with methylene chloride and washed withsodium bicarbonate, water and brine, and then dried over sodium sulfate. Concentrationaffords the crude title compound, which is used for the next step without furtherpurification. MS (ES): 292 (M++l).
	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 40℃; for 4h;	General procedure: To a stirred mixture of NaBH4 (3 equiv), 1a-e or 13a-u (1 equiv) in reflux anhydrous THF (20 ml) was added MeOH (1ml). After refluxing for futher 30 min, the reaction mixture was pouring into ice water (10 ml), and extracted with ethyl acetate (3 × 15 mL), the organic fractions were combined, washed with saturated brine (2 × 15 ml) prior to drying over anhydrous Na2SO4. After filtration and concentrate using a rotary evaporator,the residual white solid in thenext step without further purification. To a solution of the obtained solid (1 equiv) indichloromethane (20 ml) was slowly added thionyl chloride (6 equiv) and a catalytic amount of DMF at room temperature. After stirring at 40 C for 4 h, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of petroleum ether/ethyl acetate (20:1, v/v) aseluent to afford the desired product.
	With methanesulfonyl chloride; triethylamine; In dichloromethane; at 20℃; for 2h;	3.0 g of [4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol were dissolved in 50 ml dichloromethane, 3.0 ml of triethylamine were added followed by the addition of 1.36 ml of methanesulfonylchloride. The reaction mixture was stirred at room temperature for two hours. 100 ml dichloromethane were added and the mixture washed with saturated sodium hydrogen carbonate solution, water and brine. The organic layer was dried over MgSO4. The solvent was removed in vacuo to obtain 3.3 g of crude 5-Chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole as a brown oil. C12H9CIF3NS (291.72), MS(ESI): 292.2 (M+H+).

Reference： [1]Patent: WO2005/60958,2005,A1 .Location in patent: Page/Page column 116
[2]Patent: WO2003/106442,2003,A1 .Location in patent: Page 14
[3]Patent: WO2006/121223,2006,A1 .Location in patent: Page/Page column 16
[4]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 1517 - 1521
[5]Patent: WO2003/106442,2003,A1 .Location in patent: Page 14
[6]Patent: WO2006/121223,2006,A1 .Location in patent: Page/Page column 15-16
[7]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 49 - 54
[8]Patent: WO2005/51945,2005,A1 .Location in patent: Page/Page column 90; 160
[9]European Journal of Medicinal Chemistry,2016,vol. 113,p. 246 - 257
[10]Patent: EP1586573,2005,A1 .Location in patent: Page/Page column 15-16

6
[ 32281-01-9 ]
[ 317318-97-1 ]
[ 636589-63-4 ]

Reference： [1]Archiv der Pharmazie,2010,vol. 343,p. 612 - 624
[2]Journal of Organic Chemistry,2003,vol. 68,p. 9116 - 9118

7
[ 2362-12-1 ]
[ 317318-97-1 ]
[ 636589-63-4 ]

Reference： [1]Tetrahedron Letters,2005,vol. 46,p. 6683 - 6686

8
[ 60577-30-2 ]
[ 317318-97-1 ]
[ 636589-63-4 ]

Yield	Reaction Conditions	Operation in experiment
86%		500 mg (2.14 mmol) of <strong>[60577-30-2]4-iodo-2-methylphenol</strong> was dissolved in 20 ml of anhydride tetrahydrofuran in the presence of nitrogen and, at that time, temperature was maintained at 0C. 1.1 ml of isopropylmagnesiumchloride (2 M-ether solution, 2.16 mmol) was slowly added thereto, followed by reaction for 10 minutes. The reaction solution was cooled down to -78 C, to which 2.77 ml of tert-butyl lithium (1.7 iVf-heptane solution, 4.70 mmol) was slowly added. After reacting for 20 minutes, 69 mg of S (2.14 mmol) was slowly added thereto, followed by further reaction until the temperature of the reactant reached 15C. 40 minutes later, 624 mg (2.14 mmol) of 5-chloromethyl- 4-methyl-2- [ (4-trifluoromethyl) phenyl] -thiazole represented by formula 7 was dissolved in 2 ml of anhydride THF, which was slowly added thereto at the same temperature. After one more hour of reaction, the reaction was terminated by adding 20 ml of ammonium chloride solution. The organic layer was separated and dried over magnesium sulfate. After filtering, the solvent was distillated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl <n="27"/>acetate=3/l, v/v) to give 728 mg (yield: 86%) of the target compound.1H NMR(300 MHz, CDCl3) delta 7.96 (d, 2H, J = 8.1 Hz) , 7.65(d, 2H, J = 8.3 Hz) , 7.19 (d, IH, J = 1.5 Hz) , 7.01 (dd, IH, J = 8.2, 2.0 Hz) , 6.62 (d, IH, J = 8.2 Hz) , 5.86 (brs, IH) , 4.07 (s, 2H) , 2.19 (s, 3H) , 2.12(s, 3H)13C NMR(75.5 MHz, CDCl3) delta 163.9, 155.5, 151.7, 137.4, 136.9, 133.5. 131.9 (q, J = 32.6 Hz) , 131.7, 126.8, 126.3, (q, J = 3.9 Hz) , 125.8, 123.8, 115.7, 33.2, 16.2, 14.8
86%		To a stirred solution of <strong>[60577-30-2]2-methyl-4-iodophenol</strong> (500 mg, 2.14 mmol) in anhydrous THF (20 ml) at 0 C was added 2.0 M isopropyl magnesium chloride solution (1.1 ml, 2.16 mmol). The reaction mixture was stirred at 0 C for 10 min under N2 atmosphere and cooled to -78 C in dryice-acetone bath. A 1.7 M tert-butyllithium solution (2.77 ml, 4.70 mmol) was added dropwise to reaction mixture and stirred at same temperature for 30 min. Sulfur power (69 mg, 2.14 mmol) was added in one-portion to reaction mixture and then the reaction mixture was warmed to room temperature for 1 h. After the reaction mixture was cooled to 0 C again, a solution of 4 (624 mg, 2.14 mmol) in THF (3 ml) was added dropwise to reaction mixture and stirred at room temperature for 1 h. After completion of the reaction, sat. NH4Cl solution (50 ml) and ethyl acetate (25 ml) were added to reaction mixture. The organic layer was washed by distilled water, dried by MgSO4, and concentrated under reduced pressure to give crude compound. The crude compound was purified by column chromatography on silica gel (n-hexnane/ethyl acetate = 5/1) to obtain 5 as white crystal (728 mg, 86%). 1H NMR (300 MHz, CDCl3): delta 7.96 (d, 2H, J = 8.1 Hz), 7.65 (d, 2H, J = 8.3 Hz), 7.19 (d, 1H, J = 1.5 Hz) 7.01 (dd, 1H, J = 8.2, 2.0 Hz), 6.62 (d, 1H, J = 8.2 Hz), 5.86 (brs, 1H), 4.07 (s, 2H), 2.19 (s, 3H), 2.12 (s, 3H). 13C NMR (75 MHz, CDCl3): delta 163.9, 155.5, 151.7, 137.4, 136.9, 133.5, 131.9 (q, J = 32.6 Hz), 131.7, 126.8, 126.3 (q, J = 3.9 Hz), 125.8, 123.8, 115.7, 33.2, 16.2, 14.8 HRMS: calcd for C19H16F3NOS2 [M + H] + 395.0625, found 395.0622.

Reference： [1]Tetrahedron Letters,2005,vol. 46,p. 6683 - 6686
[2]Patent: WO2008/84962,2008,A1 .Location in patent: Page/Page column 10; 25-26
[3]European Journal of Medicinal Chemistry,2012,vol. 53,p. 190 - 202

9
[ 1706-60-1 ]
[ 317318-97-1 ]
[ 317318-65-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 49 - 54

10
[ 1013634-99-5 ]
[ 317318-97-1 ]
[ 1013635-00-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium iodide; potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide;	Step 1. Preparation of a Compound of Formula (6) in which R1 is 4-Methyl-2-[4-(trifluoromethyl)phenyl](1,3-thiazol-5-yl) and W is Methylene A mixture of 7-hydroxy-3-iodochromen-4-one (864 mg, 3.0 mmol), <strong>[317318-97-1]5-(chloromethyl)-4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole</strong>) (875 mg, 3.0 mmol), sodium iodide (450 mg, 3.0 mmol), and potassium carbonate (552 mg, 4.0 mmol) was dissolved in N,N-dimethylformamide (10 ml) at room temperature under nitrogen. The mixture was heated at 60 for 1 hour, cooled to room temperature, and water (30 ml) added to the mixture. The aqueous mixture was extracted with methylene chloride (3*30 ml), and the combined organic layer washed with brine (30 ml), dried over sodium sulfate, and solvent removed from the filtrate under reduced pressure. Crystallization of the crude product from ethyl acetate (4 ml) gave 3-iodo-7-({4-methyl-2-[4-(trifluoromethyl)phenyl](1,3-thiazol-5-yl)}methoxy)chromen-4-one, a compound of formula (6).
	With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 60℃; for 1h;	Step 1. Preparation of a Compound of Formula (6) in which R1 is 4-Methyl-2-[4-(trifluoromethyl)phenyl](1,3-thiazol-5-yl) and W is Methylene A mixture of 7-hydroxy-3-iodochromen-4-one (864 mg, 3.0 mmol), <strong>[317318-97-1]5-(chloromethyl)-4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole</strong>) (875 mg, 3.0 mmol), sodium iodide (450 mg, 3.0 mmol), and potassium carbonate (552 mg, 4.0 mmol) was dissolved in N,N-dimethylformamide (10 ml) at room temperature under nitrogen. The mixture was heated at 60 for 1 hour, cooled to room temperature, and water (30 ml) added to the mixture. The aqueous mixture was extracted with methylene chloride (3*30 ml), and the combined organic layer washed with brine (30 ml), dried over sodium sulfate, and solvent removed from the filtrate under reduced pressure. Crystallization of the crude product from ethyl acetate (4 ml) gave 3-iodo-7-({4-methyl-2-[4-(trifluoromethyl)phenyl](1,3-thiazol-5-yl)}methoxy)chromen-4-one, a compound of formula (6).
	With potassium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 20 - 60℃;Inert atmosphere;	Step 1. Preparation of a Compound of Formula (6) in which R1 is 4-Methyl-2-r4- (trifluoromethyl)phenyl"\|(l,3-thiazol-5-yl), and W is Methylene[0170] A mixture of 7-hydroxy-3-iodochromen-4-one (864 mg, 3.0 mmol), 5- (chloromethyl)-4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole) (875 mg, 3.0 mmol), sodium iodide (450 mg, 3.0 mmol), and potassium carbonate (552 mg, 4.0 mmol) was dissolved in N,N-dimethylformamide (10 ml) at room temperature under nitrogen. The mixture was heated at 60 for 1 hour, cooled to room temperature, and water (30 ml) added to the mixture. The aqueous mixture was extracted with methylene chloride (3 x 30 ml), and the combined organic layer washed with brine (30 ml), dried over sodium sulfate, and solvent removed from the filtrate under reduced pressure. Crystallization of the crude product from ethyl acetate (4 ml) gave 3-iodo-7-({4-methyl-2-[4- (trifluoromethyl)phenyl](l,3-thiazol-5-yl)}methoxy)chromen-4-one, a compound of formula (6).

Reference： [1]Patent: US2009/124672,2009,A1
[2]Patent: US2008/32995,2008,A1 .Location in patent: Page/Page column 23
[3]Patent: WO2009/94028,2009,A1 .Location in patent: Page/Page column 58

11
[ 1011531-26-2 ]
[ 317318-97-1 ]
(S)-3-(isoxazol-3-yl)-3-(4-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methoxy)phenyl)propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(S)- 3-(Isoxazol-3-yl)-3-(4-((4-methyl-2-(4- (trifluoromethyl)phenyl)thiazol-5-yl)methoxy)phenyl)propanoic acid (7); .Cesium carbonate (360 mg, 1.1 mmol) was added to a mixture of 7.5 (392mg mg, 1 mmol) and <strong>[317318-97-1]5-(chloromethyl)-4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole</strong> (292 mg, 1 mmol, commercially available from Maybridge) in DMSO (8.mL). The resulting mixture was stirred at room temperature for 2 hours and at 35 0C for 4 hours. After cooling, the mixture was treated with EtOAc (5 mL) and brine (5 <n="115"/>mL). The organic layer was separated, washed twice with brine, dried, and concentrated. The crude product (220 mg, 0.34 mmol) was treated with THF (6 mL) and hydrogen peroxide (30%, 154 mg, 1.36 mmol) and cooled to 00C. LiOH (29 mg, 0.68 mmol) in 2 mL of water was added. The resulting mixture was stirred at 00C for 4 hours. The organic solvent was blown away by nitrogen, and the aqueous mixture was acidified by adding HCl (0.24 mL, 3 N). The aqueous mixture was extracted with DCM. The organic layer was dried, concentrated, and purified by flash chromatography to give 7 (150 mg). MS API-ES m/e: 487.0 (M- H). 1H NMR (500 MHz) (DMSOd6) delta 8.76 (IH, s); 8.13 (2H, d, J=7Hz); 7.86 (2H, m); 7.26 (2H, d, J=6Hz); 7.01 (2H, m); 6.50 (IH, s); 5.23 (2H, s); 4.51 (IH, m); 3.20 (IH, m), 2.80 (IH, m), 2.47 (3H, s).

Reference： [1]Patent: WO2008/30520,2008,A1 .Location in patent: Page/Page column 113-114

12
[ 929713-71-3 ]
[ 317318-97-1 ]
C₂₅H₂₆N₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In dimethyl sulfoxide; at 45℃; for 3h;	3-(4,5-Dihydroisoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoic acid (8). Cesium carbonate (108 mg, 0.33 mmol) was added into a mixture of 8.1 (25 mg, 0.11 <n="117"/>mmol) and <strong>[317318-97-1]5-(chloromethyl)-4-methyl-2-(4-(trifluoromethyl)phenyl)thiazole</strong> ( 79 mg, 0.27 mmol, commercially available from Maybridge) in DMSO (1 mL). The mixture was stirred at 45 0C for 3 hours. After cooling, the mixture was treated with EtOAc (5 mL) and brine (5 mL). The organic layer was separated, washed twice with brine, dried, and concentrated. The crude product was treated with THF (1 mL), MeOH (1 mL), water (0.5 mL) and NaOH (0.05 mL, 10 N). The resulting mixture was stirred at room temperature for 4 hours. The organic solvent was then blown away by nitrogen, and the aqueous mixture was acidified by adding HCl (0.1 S mL, 3 N). The aqueous mixture was extracted with DCM and the organic layer was dried, concentrated, and purified by flash chromatography to give 8 (25 mg). MS ESI (pos.) m/e: 491 (M+H). 1H NMR (CDCl3) delta 8.05(d, 2H), 7.70(d, 2H), 7.23(d, 2H), 6.95(d, 2H), 5.15(s, 2H), 4.20(m, 2H), 4.00(t, IH), 3.20(dd, IH), 2.70(m, 3H), 2.52(s, 3H).

Reference： [1]Patent: WO2008/30520,2008,A1 .Location in patent: Page/Page column 115-116

13
[ 726174-52-3 ]
[ 317318-97-1 ]
[ 945773-91-1 ]