[ CAS No. 161798-01-2 ] {[proInfo.proName]}

Name: 161798-01-2|Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate|98%
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Quality Control of [ 161798-01-2 ]

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Product Details of [ 161798-01-2 ]

CAS No. :	161798-01-2	MDL No. :	MFCD13194810
Formula :	C₁₄H₁₃NO₄S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NJRGQNNSIAFIJC-UHFFFAOYSA-N
M.W :	291.32	Pubchem ID :	135404723
Synonyms :

Calculated chemistry of [ 161798-01-2 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	11
Fraction Csp3 :	0.21
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	76.01
TPSA :	104.73 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.78 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.67
Log Po/w (XLOGP3) :	3.23
Log Po/w (WLOGP) :	2.81
Log Po/w (MLOGP) :	0.96
Log Po/w (SILICOS-IT) :	4.08
Consensus Log Po/w :	2.75

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.76
Solubility :	0.0508 mg/ml ; 0.000175 mol/l
Class :	Soluble
Log S (Ali) :	-5.1
Solubility :	0.0023 mg/ml ; 0.0000079 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.05
Solubility :	0.0261 mg/ml ; 0.0000897 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.07

Safety of [ 161798-01-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 161798-01-2 ]

* 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 [ 161798-01-2 ]
Downstream synthetic route of [ 161798-01-2 ]

[ 161798-01-2 ] Synthesis Path-Upstream 1~8

1
[ 161797-99-5 ]
[ 100-97-0 ]
[ 161798-01-2 ]

Yield	Reaction Conditions	Operation in experiment
81.3%	Stage #1: at 40 - 93℃; for 3 h; Large scale Stage #2: With acetic acid In water for 0.333333 h; Cooling with ice; Large scale	A method for controlling the impurity of non-bupretane intermediate is as follows:To 200L clean and dry reactor into the polyphosphoric acid 120kg,Stirring heated to 40 ~ 50 ,Stir with the sameWas added 20 kg (76.0 mol) of ethyl 2- (4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylate 11 kg (76.3 mol)HMTA (urotropine, chemical name hexamethylenetetramine)The Plus finished,Heating up to 93 ° C,Reaction 3h,(4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylic acid ethyl ester,Stop the reaction.The reaction ends,The reaction solution was added to the ice aqueous solution of dilute acetic acid,Hydrolyzed for 20 minutes,Extracted with ethyl acetate 300 L three times,Combined organic phase,Plus 10kg yuan Ming powder dry,filter,The filtrate was concentrated under reduced pressure to give 210 mg of solvent ethyl acetate.To the concentrate was added 100 kg of water,Stirring crystallization,Centrifugal,dry,To obtain a light yellow non-cloth he intermediate 18.0 kg.Yield 81.3percent.Intermediate 2- (3-formyl-4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylic acid ethyl ester Content 99.4percent, dicarboxylic acid impurity content0.008percent
72.3%	at 75℃; for 10 h;	Example 2: Synthesis of Ethyl-2-(3-Formyl-4-HvdroxyphenvD-4-Methyl-5-Thiazole CarboxylateHexamethylene tetramine (134 g, 0.971 mol) was added to a solution of ethyl 2-(4- hydroxyphenyl)-4-methyl-5-thiazol carboxylate (100 g, 0.38 mol) in methanesulfonic acid (500 mL) slowly over a period of about 30 minutes. The reaction mixture was heated to about 75°C and stirred for about 10 hours. After completion of reaction, the reaction mixture was cooled to about 30°C and water was added to it. The reaction mixture was further cooled to about 0°C and stirred for about 1 hour. The solid thus obtained was filtered, washed with water and dried to give the title compound. (Yield: 80 g, 72.3percent)

Reference： [1] Patent: CN106366048, 2017, A, . Location in patent: Paragraph 0007; 0008; 0009; 0010; 0011; 0012
[2] Patent: WO2012/14117, 2012, A1, . Location in patent: Page/Page column 12
[3] Patent: WO2012/131590, 2012, A1, . Location in patent: Page/Page column 15; 21-23
[4] Patent: WO2012/168948, 2012, A2, . Location in patent: Page/Page column 10-11
[5] Letters in Organic Chemistry, 2015, vol. 12, # 3, p. 217 - 221
[6] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2015, vol. 54B, # 8, p. 1005 - 1010
[7] Patent: CN104529935, 2017, B, . Location in patent: Paragraph 0052

2
[ 161797-99-5 ]
[ 68-12-2 ]
[ 161798-01-2 ]

Yield	Reaction Conditions	Operation in experiment
96.6%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -10℃; for 0.2 h; Inert atmosphere Stage #2: at -10℃; for 0.5 h; Inert atmosphere Stage #3: With acetic acid In tetrahydrofuran; hexane at 10℃; for 0.166667 h; Inert atmosphere	(1) A 2000 ml reaction flask was charged with 600 ml of tetrahydrofuran and 70 g of ethyl 2- (4-hydroxyphenyl) -4-methylthiazole-5-carboxylate,Then pass into the nitrogen protection,Cooling to -10 ,Slowly dropping 1mol / L n-butyl lithium n-hexane solution 550ml,Dropping is completed, the temperature was controlled at -10 for 12 minutes,Then 23.0 g of N, N-dimethylformamide was added,Stir for 30 minutes; (2) temperature control below 10 added glacial acetic acid 50g,Stir for 10 minutes,The temperature of the water bath was controlled at 40 ° C. The reaction mixture was concentrated to dryness under reduced pressure,Then 1000ml of purified water was added thereto,Add sodium bicarbonate 95g,Stir for 30 minutes,To the reaction mixture, 1200 ml of ethyl acetate was added for extraction twice,The combined organic layers,Temperature control 50 ° C water bath temperature and concentrated organic solvent until no distillate flow out,210 ml of isopropanol was added thereto and heated to dissolve and then cooled to 0 ° C.,Continue stirring 30 minutes suction filtration,With 20ml isopropyl alcohol washing cake, temperature 50-60 drying,The pale yellow solid 74.8g, purity of 99.81percent, the yield of 96.6percent.

Reference： [1] Patent: CN106518802, 2017, A, . Location in patent: Paragraph 0009; 0020; 0021; 0022; 0023; 0024; 0025-0027

3
[ 161797-99-5 ]
[ 64-19-7 ]
[ 161798-01-2 ]

Yield	Reaction Conditions	Operation in experiment
29%	Stage #1: at 90℃; for 12 h; Stage #2: With hydrogenchloride In water at 75℃; for 0.5 h;	2-(4-Hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (3) (500 mg, 1.9 mmol) was dissolved in acetic acid (8 mL) and to this reaction, hexamethylenetetramine (667 mg, 4.76 mmol) added at rt. The reaction mixture was then heated at 90 °C for 12 h. To this reaction mixture ∼16 mL 20percent HCl was added when temperature 75 °C and heating continued for 30 min. The reaction mixture was diluted with dichloromethane. The combined organic solution was dried over sodium sulfate and concentrated. The crude mixture was purified by column chromatography on silica, product eluted with 10percentethyl acetate in hexane to afford 2-(3-Formyl-4-hydroxy-phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (4) (160 mg, 29percent) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 11.44 (s, 1H), 10.32 (s, 1H), 8.24 (s, 1H), 8.12 (d, J = 2.24 Hz, 1H), 7.13 (d, J = 8.64 Hz, 1H), 4.29 (q, J = 7.04 Hz, 2H), 2.65 (s, 3H), 1.3 (t, J = 7.08 Hz, 3H). MS (ESI): m/z calc. for C₁₄H₁₃NO₄S+: 291.0; found: 292.0 [M+H]⁺.

Reference： [1] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 334, p. 1 - 12
[2] New Journal of Chemistry, 2018, vol. 42, # 1, p. 76 - 84

4
[ 84911-18-2 ]
[ 100-97-0 ]
[ 161798-01-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	for 20 h; Reflux	Compound 3 (24 mmol) and HMTA (1 mL) and trifluoroacetic acid (30 mL) were added to around-bottomed flask. The mixture was refluxed for 20 h. After completion of the reaction, thesolvent was removed by distillation. The residue was poured into ice water and stirred vigorously,the solid product was filtered and washed with water, then dried in a vacuum to give compound NL,recrystallized in toluene in 80percent yield

Reference： [1] Molecules, 2016, vol. 21, # 8,

5
[ 25984-63-8 ]
[ 161798-01-2 ]

Reference： [1] Patent: WO2012/14117, 2012, A1,
[2] Patent: WO2012/168948, 2012, A2,
[3] Letters in Organic Chemistry, 2015, vol. 12, # 3, p. 217 - 221
[4] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2015, vol. 54B, # 8, p. 1005 - 1010
[5] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 334, p. 1 - 12
[6] Patent: CN104529935, 2017, B,

6
[ 767-00-0 ]
[ 161798-01-2 ]

Reference： [1] Journal of Photochemistry and Photobiology A: Chemistry, 2017, vol. 334, p. 1 - 12
[2] Patent: CN104529935, 2017, B,

7
[ 609-15-4 ]
[ 161798-01-2 ]

Reference： [1] Patent: WO2012/14117, 2012, A1,
[2] Patent: WO2012/168948, 2012, A2,

8
[ 78-77-3 ]
[ 161798-01-2 ]
[ 161798-03-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 4 h;	Example 6 - Preparation of Compound of formula III)[0094] A compound of formula II (10.0 gr, 34.33 mmol) was reacted with iso- butyl bromide (18.9 gr, 137.3 mmol) in the presence of potassium carbonate (19.0 gr, 137.3 mmol) and potassium iodide (2.3 gr, 13.7 mmol) in 60 ml dimethylformamide. The reaction was performed at about 70°C during 4 hours. The reaction mixture was extracted at 70°C using 300 ml ethyl acetate and 600 ml water. The separated aqueous phase was washed twice with 100 ml ethyl acetate. The combined organic phase was washed twice with 100 ml water and then concentrated to dryness. The resulting solid residue was re- crystallized from 70 ml ethyl acetate, filtered and dried under reduced pressure at about 40°C to provide a compound of formula III (8.9 gr, yield - 83percent). The Compound of formula III purity is 99.1percent (by HPLC).
16.43 g	With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; for 4 h;	Dissolve 14.14g of ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (Formula III) in 55 ml dimethylformamide, at ambient temperature. Add 40g of potassium carbonate, along with 15.9 ml isobutyl bromide. Heat the reaction to 75-80 °C and stir for 4 hours. Cool to 25-30 °C, while 165 ml process water is added. Further cool to 0-5 °C and stir for 30 minutes at this temperature. Filter off the precipitated solid and wash the filter cake with 55 ml process water. The wet cake is dried under vacuum at 40 °C for 7 hours, to furnish 16.43 g of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula lib). of compound of formula Illb
34.2 g	With potassium carbonate In N,N-dimethyl-formamide at 60 - 115℃;	Formylation reaction is complete, no need to separate,Continue the next isobutylation reaction,DMF as the reaction solvent,164g of dimethylformamide was added, dissolved,Then add 14g potassium carbonate,21.7g bromoisobutane was added dropwise, the reaction was warmed,The reaction temperature is controlled at 60-115 ° C,The reaction time is 3-10 hours, the reaction was completely detected by HPLC,Slowly dropping 76g of water,Cooled to room temperature filtered, centrifuged,Centrifuge the filter cake first with 50g DMF (dimethylformamide) once, high-speed spin-dry;Then washed with 19g of water for the first time,High-speed centrifuge drying, washing with 19g water a second time,High-speed centrifuge drying;Finally, the first wash with 15g methanol,High-speed centrifuge drying, washed with 15g methanol second time,High-speed centrifuge drying;The wet product was dried to give 34.2 g of ethyl 2- (3-aldehyde-4-isobutyloxyphenyl) -4-methylthiazole-5-Chromatographic purity of 99.2percentContent of 99.5percent, two-step total yield of 68.2percent.

Reference： [1] Patent: WO2011/31409, 2011, A1, . Location in patent: Page/Page column 15
[2] Patent: WO2011/141933, 2011, A2, . Location in patent: Page/Page column 46
[3] Patent: WO2012/131590, 2012, A1, . Location in patent: Page/Page column 15; 21; 23
[4] Patent: WO2012/168948, 2012, A2, . Location in patent: Page/Page column 11
[5] Patent: WO2015/18507, 2015, A2, . Location in patent: Page/Page column 12
[6] Patent: CN104529935, 2017, B, . Location in patent: Paragraph 0054-0059
[7] Patent: CN108084112, 2018, A, . Location in patent: Paragraph 0024

[ 161798-01-2 ] Synthesis Path-Downstream 1~62

1
[ 78-77-3 ]
[ 161798-01-2 ]
[ 161798-03-4 ]

Yield	Reaction Conditions	Operation in experiment
94.7%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 75 - 85℃; for 6h;	In a 500 ml round bottom flask, 129 g of DMF, 17 g (0.058 mol) of ethyl 2-(3-aldehyde-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate, 32.24 g (0.233) were added. Potassium carbonate and 0.2 g of potassium iodide.An additional 20 g (0.146) of isobutyl bromide (FBT-SM2) was added.After the addition, the temperature was raised to 75-85 C for 6 h.After the reaction is completed, the temperature is lowered to 20 to 30 C.136 g of purified water was added to the reaction vessel and incubated at 20 to 30 C for 1 h.After the heat preservation, filtration, the filter cake was beaten with purified water, and the pH of the beater was 10, filtered and dried to obtain 21.5 g of 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole. Crude product of -5-ethyl formate (FBT-1).In a 500 ml round bottom flask, 67 g of ethanol, 102 g of formic acid and 21.5 g of ethyl 2-(3-formyl-4-isobutoxy-phenyl)-4-methyl-thiazole-5-carboxylate (FBT-) were added. 1) The crude product is stirred and heated to 60-70 C, and after cooling, the temperature is lowered to 15-30 C for 1 h, the crystallization is completed, filtered and dried to obtain 19.2 g of 2-(3-formyl-4-isobutoxy) -Phenyl)-4-methyl-thiazole-5-carboxylic acid ethyl ester (FBT-1), refined 89.3%, total yield 94.7%, intermediate content 98.40%, maximum single impurity less than 0.10%.
90%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;	250 ml of N,N-dimethylformamide was added to the reaction flask. Add 50g in sequence with stirring Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylate, 58.78 g of bromoisobutane, Then add 71.16g of anhydrous potassium carbonate, and the feeding is completed. Heat to 80 C for about 8 h. Yellow turbid. TLC detects the reaction completely and drops to room temperature. Continue to drop to 0 C, add ice water to quench, violent exotherm, Slowly add ice water, the reaction solution becomes viscous, and stirring is continued for 30 minutes. After suction filtration, the vessel was washed with an appropriate amount of water and dried to obtain a solid 56.7 g. The yield is 95.1%, and the purity is 98.2%. The product obtained is further purified: a mixture of EA and PE is arranged, The obtained product and the mixed solution were mixed and beaten for 1 hour. Then filter and dry, wherein the EA:PE volume ratio is 2:1, Solid: total liquid volume = 1g: 6ml, The purity of the product obtained after purification was 99%, and the yield was about 90%.
83%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 70℃; for 4h;Product distribution / selectivity;	Example 6 - Preparation of Compound of formula III)[0094] A compound of formula II (10.0 gr, 34.33 mmol) was reacted with iso- butyl bromide (18.9 gr, 137.3 mmol) in the presence of potassium carbonate (19.0 gr, 137.3 mmol) and potassium iodide (2.3 gr, 13.7 mmol) in 60 ml dimethylformamide. The reaction was performed at about 70C during 4 hours. The reaction mixture was extracted at 70C using 300 ml ethyl acetate and 600 ml water. The separated aqueous phase was washed twice with 100 ml ethyl acetate. The combined organic phase was washed twice with 100 ml water and then concentrated to dryness. The resulting solid residue was re- crystallized from 70 ml ethyl acetate, filtered and dried under reduced pressure at about 40C to provide a compound of formula III (8.9 gr, yield - 83%). The Compound of formula III purity is 99.1% (by HPLC).

		To a stirred solution of ethyl 2-[3-formyl-4-hydroxyphenyl]-4-methylthiazole-5- carboxylate (10 gms) in dimethylformamide (40 ml) added potassium carbonate (9.78 gms) and potassium iodide (2.35 gms). Heated the reaction mixture to 70 - 75C and stirred for 30 minutes. To the above reaction added a solution of l-bromo-2- methylpropane (9.72 gms) in dimethyl formamide (10 ml) and stirred for 5 hours. Cooled the reaction mixture to 25C, quenched with water and stirred for one hour. Filtered the precipitated solid and dried the material to get the title compound. Yield: 9 gms.
	With potassium carbonate; N,N-dimethyl-formamide; at 87 - 93℃; for 4h;	b) Preparation of Ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate [Compound of formula IV1.350.0gm of Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate, [Compound of formula III] 332. Ogm of potassium carbonate and 330.0gm of isobutyl bromide were added to 1.751tr of DMF. Reaction mixture was heated to 90 +/- 3C and stirred for 4 hr. Reaction mixture was cooled to 25C and slowly added 10.50 ltr of water. Slurry of the product formed was stirred for 2.0hr, filtered, washed and dried under vacuum to give 389 gm of titled compound.Analytical Data- · ^NMR (CDC13, 400 MHz) : delta 1.079-1.101 (doublet, 6H); delta 1.366-1.413 (triplet,3H); delta 2.185-2.230 (multiplet, 1H); delta 2.769 (singlet, 3H); delta 3.914-3.935 (doublet, 2H); delta 4.316-4.387 (quartet, 2H); delta 7.045-7.074 (doublet, 1H); delta 8.188-8.225 (doublet of doublet, 1H); delta 8.353-8.361 (doublet, 1H).? Mass (m/e): 348.3
	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 25 - 85℃; for 5.08333h;	Example 3:Preparation of 2-(3-formyl-4-isobutoxyphenyI)-4-methyIthiazole-5-carboxylic acid ethyl esterTo a dimethylformamide (1250 ml) was added 2-(3-formyl-4-hydroxyphenyl)-4- methylthiazole-5-carboxylic acid ethyl ester (250 gm) at room temperature for 5 minutes to obtain a solution. To the solution was added potassium carbonate (250 gm) and potassium iodide (62.5 gm), and then added isobutyl bromide (100 gm) slowly for 2 hours. The temperature of the reaction mass was raised to 85C and maintained for 3 hours. The dimethylformamide solvent was distilled off under vacuum at 80C and then cooled to room temperature. The reaction mass was added water (2500 ml) and stirred for 2 hours at room temperature. The separated solid was filtered, washed with cycloheaxne and then dried to obtain 285 gm of 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5- carboxylic acid ethyl ester.
16.43 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 80℃; for 4h;	Dissolve 14.14g of <strong>[161798-01-2]ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate</strong> (Formula III) in 55 ml dimethylformamide, at ambient temperature. Add 40g of potassium carbonate, along with 15.9 ml isobutyl bromide. Heat the reaction to 75-80 C and stir for 4 hours. Cool to 25-30 C, while 165 ml process water is added. Further cool to 0-5 C and stir for 30 minutes at this temperature. Filter off the precipitated solid and wash the filter cake with 55 ml process water. The wet cake is dried under vacuum at 40 C for 7 hours, to furnish 16.43 g of ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (Formula lib). of compound of formula Illb
34.2 g	With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 115℃;	Formylation reaction is complete, no need to separate,Continue the next isobutylation reaction,DMF as the reaction solvent,164g of dimethylformamide was added, dissolved,Then add 14g potassium carbonate,21.7g bromoisobutane was added dropwise, the reaction was warmed,The reaction temperature is controlled at 60-115 C,The reaction time is 3-10 hours, the reaction was completely detected by HPLC,Slowly dropping 76g of water,Cooled to room temperature filtered, centrifuged,Centrifuge the filter cake first with 50g DMF (dimethylformamide) once, high-speed spin-dry;Then washed with 19g of water for the first time,High-speed centrifuge drying, washing with 19g water a second time,High-speed centrifuge drying;Finally, the first wash with 15g methanol,High-speed centrifuge drying, washed with 15g methanol second time,High-speed centrifuge drying;The wet product was dried to give 34.2 g of ethyl 2- (3-aldehyde-4-isobutyloxyphenyl) -4-methylthiazole-5-Chromatographic purity of 99.2%Content of 99.5%, two-step total yield of 68.2%.
	With triethylamine; at 75℃; for 15h;Large scale;	Add 400 kg of DMAC, 100 kg of 2- (3-formyl-4-hydroxyphenyl) -4-methylthiazole-5-carboxylic acid ethyl ester to the reaction tank,50kg bromoisobutane, 35kg triethylamine,The temperature was raised to 75 C for 15h.Then, 25 kg of hydroxylamine hydrochloride was added at a reduced temperature, and reacted at 75 C for 3 hours.Then 30 kg of acetyl chloride was added dropwise and reacted at 80 C for 7 hours.After the reaction was completed, the temperature was lowered to 20-30 C, water was added, 20 kg of sodium hydroxide was added, and hydrolysis was performed at 45 C for 6 hours.Then add hydrochloric acid dropwise to adjust the pH to 6.0-7.0. Reduce the temperature to 0-5 C, then add water and crystallize for 2h.After centrifugation, a white solid powder was obtained, and the obtained powder was crude febuxostat with a wet weight of 128 kg.

Reference： [1]Patent: CN109912531,2019,A .Location in patent: Paragraph 0006; 0028-0037
[2]Patent: CN109320474,2019,A .Location in patent: Paragraph 0069-0072; 0080; 0081
[3]Patent: WO2011/31409,2011,A1 .Location in patent: Page/Page column 15
[4]Patent: WO2011/141933,2011,A2 .Location in patent: Page/Page column 46
[5]Patent: WO2012/131590,2012,A1 .Location in patent: Page/Page column 15; 21; 23
[6]Patent: WO2012/168948,2012,A2 .Location in patent: Page/Page column 11
[7]Patent: WO2015/18507,2015,A2 .Location in patent: Page/Page column 12
[8]Patent: CN104529935,2017,B .Location in patent: Paragraph 0054-0059
[9]Patent: CN108084112,2018,A .Location in patent: Paragraph 0024
[10]Patent: CN110229117,2019,A .Location in patent: Paragraph 0066-0068; 0071-0073; 0076-0078

2
[ 78-77-3 ]
[ 161798-01-2 ]
[ 1271738-74-9 ]

Yield	Reaction Conditions	Operation in experiment
73%		Example 13 - Preparation of Compound of formula Vl-a[00101] A compound of formula II (10.0 gr, 34.33 mmol) was reacted with iso- butyl bromide (18.9 gr, 137.3 mmol) in the presence of potassium carbonate (19.0 gr, 137.3 mmol) and potassium iodide (2.3 gr, 13.7 mmol) in 100 ml dimethylformamide. The reaction was performed at about 70°C during 4 hours. Hydroxylamine hydrochloride (Then 3.6 gr, 51.8 mmol) was then added at about 70°C and stirred at this temperature during 7 hours. The reaction mixture was diluted with 80 ml toluene, 100 ml water was added and the mixture was allowed for the phase separation. The organic phase was washed first time with 100 ml water and second time with 50 ml water at about 70°C, cooled to about 55°C, stirred at this temperature during 1 hour to deepen precipitation and then cooled to about 10°C, filtered, washed with 10 ml toluene and dried under reduced pressure at about 40°C to provide a compound of formula Vl-a (8.2 gr, yield - 73percent). The Compound of formula Vl-a purity is 96.4percent (by HPLC).

Reference： [1]Patent: WO2011/31409,2011,A1 .Location in patent: Page/Page column 18

3
[ 161798-01-2 ]
febuxostat [ No CAS ]

Reference： [1]Patent: WO2011/31409,2011,A1
[2]Patent: WO2011/141933,2011,A2
[3]Patent: WO2011/141933,2011,A2
[4]Patent: WO2012/14117,2012,A1
[5]Patent: WO2012/66561,2012,A1
[6]Patent: WO2012/66561,2012,A1
[7]Patent: WO2012/131590,2012,A1
[8]Patent: WO2012/131590,2012,A1
[9]Patent: WO2012/131590,2012,A1
[10]Patent: WO2012/168948,2012,A2
[11]Patent: US2013/303780,2013,A1
[12]Patent: WO2015/18507,2015,A2
[13]Patent: WO2015/18507,2015,A2
[14]Patent: CN106187940,2016,A
[15]Patent: CN109320474,2019,A
[16]Patent: CN109912531,2019,A
[17]Patent: CN110229117,2019,A

4
[ 161798-01-2 ]
[ 160844-75-7 ]

Reference： [1]Patent: WO2011/31409,2011,A1
[2]Patent: WO2011/141933,2011,A2
[3]Patent: WO2012/14117,2012,A1
[4]Patent: WO2012/66561,2012,A1
[5]Patent: WO2012/131590,2012,A1
[6]Patent: WO2012/168948,2012,A2
[7]Patent: US2013/303780,2013,A1
[8]Patent: WO2015/18507,2015,A2
[9]Patent: WO2015/18507,2015,A2
[10]Patent: CN106187940,2016,A
[11]Patent: CN109320474,2019,A
[12]Patent: CN109912531,2019,A
[13]Patent: CN110229117,2019,A

5
[ 161798-01-2 ]
[ 144060-62-8 ]

Reference： [1]Patent: WO2011/141933,2011,A2
[2]Patent: WO2012/131590,2012,A1

6
[ 161798-01-2 ]
[ 1271738-74-9 ]

Reference： [1]Patent: WO2011/141933,2011,A2

7
[ 161798-01-2 ]
[ 1350352-70-3 ]

Reference： [1]Patent: WO2011/141933,2011,A2

8
[ 161798-01-2 ]
[ 1350352-71-4 ]

Reference： [1]Patent: WO2011/141933,2011,A2
[2]Patent: WO2011/141933,2011,A2

9
[ 161798-01-2 ]
[ 1350352-72-5 ]

Reference： [1]Patent: WO2011/141933,2011,A2
[2]Patent: WO2011/141933,2011,A2

10
[ 161798-01-2 ]
[ 1350352-73-6 ]

Reference： [1]Patent: WO2011/141933,2011,A2

11
[ 161798-01-2 ]
[ 1350352-74-7 ]

Reference： [1]Patent: WO2011/141933,2011,A2

12
[ 161798-01-2 ]
[ 1350352-75-8 ]

Reference： [1]Patent: WO2011/141933,2011,A2

13
[ 161798-01-2 ]
[ 1350352-76-9 ]

Reference： [1]Patent: WO2011/141933,2011,A2

14
[ 609-15-4 ]
[ 161798-01-2 ]

Reference： [1]Patent: WO2012/14117,2012,A1
[2]Patent: WO2012/168948,2012,A2

15
[ 161797-99-5 ]
[ 100-97-0 ]
[ 161798-01-2 ]

Yield	Reaction Conditions	Operation in experiment
81.3%		A method for controlling the impurity of non-bupretane intermediate is as follows:To 200L clean and dry reactor into the polyphosphoric acid 120kg,Stirring heated to 40 ~ 50 ,Stir with the sameWas added 20 kg (76.0 mol) of ethyl 2- (4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylate 11 kg (76.3 mol)HMTA (urotropine, chemical name hexamethylenetetramine)The Plus finished,Heating up to 93 ° C,Reaction 3h,(4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylic acid ethyl ester,Stop the reaction.The reaction ends,The reaction solution was added to the ice aqueous solution of dilute acetic acid,Hydrolyzed for 20 minutes,Extracted with ethyl acetate 300 L three times,Combined organic phase,Plus 10kg yuan Ming powder dry,filter,The filtrate was concentrated under reduced pressure to give 210 mg of solvent ethyl acetate.To the concentrate was added 100 kg of water,Stirring crystallization,Centrifugal,dry,To obtain a light yellow non-cloth he intermediate 18.0 kg.Yield 81.3percent.Intermediate 2- (3-formyl-4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylic acid ethyl ester Content 99.4percent, dicarboxylic acid impurity content0.008percent
72.3%	With methanesulfonic acid; at 75℃; for 10h;	Example 2: Synthesis of Ethyl-2-(3-Formyl-4-HvdroxyphenvD-4-Methyl-5-Thiazole CarboxylateHexamethylene tetramine (134 g, 0.971 mol) was added to a solution of ethyl 2-(4- hydroxyphenyl)-4-methyl-5-thiazol carboxylate (100 g, 0.38 mol) in methanesulfonic acid (500 mL) slowly over a period of about 30 minutes. The reaction mixture was heated to about 75°C and stirred for about 10 hours. After completion of reaction, the reaction mixture was cooled to about 30°C and water was added to it. The reaction mixture was further cooled to about 0°C and stirred for about 1 hour. The solid thus obtained was filtered, washed with water and dried to give the title compound. (Yield: 80 g, 72.3percent)
	With trifluoroacetic acid; for 40h;Reflux;	a) Preparation of Ethyl 2-(3-formyl-4-hvdroxyphenyl)-4-methyl-5-thiazolecarboxylate[Compound of formula lO.Ogm of Ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazole carboxylate, [Compound of formula II] and 5.86gm of hexamethylenetetramine was added to 100.0ml of trifluoroacetic acid. Reaction mixture was heated to reflux under stirring for 40 hr. Trifluoroacetic acid was distilled out at 80 +/- 3°C. Residue obtained was cooled to 25°C and slowly added 100 ml of water. Slurry formed was stirred for 2.0hr. Slurry of the product was filtered, washed and dried under vacuum to give 9.6 gm of titled compound.

		Example 2:Preparation of 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester2-(4-Hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (413 gm) was added to trifluoroacetic acid (2065) and then added hexamethyl tetramine (248 gm) at room temperature. The contents were heated to 80 C and maintained for 24 hours. The reaction mass was then cooled to room temperature and mass was poured into child water (5155 ml). The reaction mass was extracted with toluene (2887 ml) and stirred for 10 minutes. Then the layers were separated and the aqueous layer was extracted with toluene. Combined organic layers were dried with sodium sulfate and then concentrated to obtain a residual solid. To the residual solid was added cyclohexane (1250 ml) at room temperature and then heated to reflux for 30 minutes. The reaction mass was then cooled to room temperature and stirred for 1 hour. The solid obtained was collected by filtration and dried to obtain 260 gm of 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5- carboxylic acid ethyl ester.
		4-Hydroxybenzo-thioamide (1.0 mmol), IPA (10 mL) and ethyl-2-chloro acetate (1.1 mmol) was heated to 75°C. After completion of reaction, the mixture was poured into water, filtered and washed with water to neutral pH and recrystallized from IPA to give the compound 1. The ethyl 2-(4-hydroxyphenyl)-4-methyl-thiazole-5-carboxylate 1 (1.0 mmol) after adding PPA (10.0 mmol) was heated to 75°C and then HMTA (2.6 mmol) added at 75°C. After the completion of reaction, the reaction mass was poured onto aqueous acetic acid solution and stirred for a few minutes at RT and the obtained product was filtered and washed with water at RT. The final intermediate ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate 2 was purified by recrystallization from IPA.
	With sulfuric acid; at 60 - 120℃;	In a clean reaction flask,Put 170g polyphosphoric acid,10g sulfuric acid,22.3 g hexamethine tetramethylammonium,38 g of ethyl 2- (4-hydroxyphenyl) -4-methyl-5-thiazolecarboxylate (Formula III)Control the reaction temperature is 60-120 ,The reaction time is 3-10 hours,HPLC detection reaction was complete,234 g of butyl acetate and 126 g of water were added,Stirring, standing, stratification,The organic layer was added 76g of water (can be used for the next batch of application) stirring, standing, delamination,The organic layer was concentrated to dryness to give ethyl 2- (3-carboxyphenyl-4-hydroxyphenyl) -4-methyl-5- thiazolecarboxylate (Formula IV)

Reference： [1]Patent: CN106366048,2017,A .Location in patent: Paragraph 0007; 0008; 0009; 0010; 0011; 0012
[2]Patent: WO2012/14117,2012,A1 .Location in patent: Page/Page column 12
[3]Patent: WO2012/131590,2012,A1 .Location in patent: Page/Page column 15; 21-23
[4]Patent: WO2012/168948,2012,A2 .Location in patent: Page/Page column 10-11
[5]Letters in Organic Chemistry,2015,vol. 12,p. 217 - 221
[6]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010
[7]Patent: CN104529935,2017,B .Location in patent: Paragraph 0052

16
[ 25984-63-8 ]
[ 161798-01-2 ]

Reference： [1]Patent: WO2012/14117,2012,A1
[2]Patent: WO2012/168948,2012,A2
[3]Letters in Organic Chemistry,2015,vol. 12,p. 217 - 221
[4]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010
[5]Journal of Photochemistry and Photobiology A: Chemistry,2017,vol. 334,p. 1 - 12
[6]Patent: CN104529935,2017,B

17
[ 161798-01-2 ]
[ 161798-02-3 ]

Yield	Reaction Conditions	Operation in experiment
99%		Example - 2: Preparation of Ethyl-2-(3-cyano-4-hydroxyphenyl)-4-methyl thiozole - 5-carboxylateA mixture of 10. Og of Ethyl-2-(3-formyl-4-hydroxy phenyl)-4-methyl thiozole -5- carboxylate and 2.85 g of hydroxylamine hydrochloride were stirred for 30 minutes in 30 g of Dimethylformamide. To this reaction mixture 3.3 grams of acetyl chloride was added and stirred at 90°C for 2-3 hours. Reaction mass was cooled to room temperature and diluted with 100 ml of water and stir for 2 hours. The reaction mass was filtered and washed with purified water to give 10.0 g of Ethyl-2-(3-cyano-4-hydroxy phenyl)-4- methyl thiozole -5-carboxyltae (yield 99.0percent).
99.0%		Example-2 Preparation of Ethyl-2-(3-cyano-4-hydroxyphenyl)-4-methyl thiozole-5-carboxylate A mixture of 10.0 g of Ethyl-2-(3-formyl-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate and 2.85 g of hydroxylamine hydrochloride were stirred for 30 minutes in 30 g of Dimethylformamide. To this reaction mixture 3.3 grams of acetyl chloride was added and stirred at 90° C. for 2-3 hours. Reaction mass was cooled to room temperature and diluted with 100 ml of water and stir for 2 hours. The reaction mass was filtered and washed with purified water to give 10.0 g of Ethyl-2-(3-cyano-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate (yield 99.0percent).
97.6%	With formic acid; hydroxylamine hydrochloride; sodium acetate; at 100 - 105℃; for 10h;	In a 1 L four-necked flask, 60 g of a non-Bustam aldehyde substrate, 866.7 g of anhydrous formic acid, 17.3 g of hydroxylamine hydrochloride and24g anhydrous sodium acetate, stirring warming. The temperature of T = 100 ~ 105 , heat stirring 10h, the material vacuum distillation to no distillate to get the powdery solid compound . Weighing 86.8g, molar yield 97.6percent, purity (HPLC): 98.9percent, single impurity (HPLC): 0.22percent, total miscellaneous (HPLC): 1.1percent.

85.9%	With formic acid; hydroxylamine hydrochloride; sodium formate; at 100℃; for 8h;	Example 3: Synthesis of ethyl-2-(3-cyano-4-hvdroxyphenvn-4-methyl-5-thiazole carboxylateHydroxylamine hydrochloride (35.82 g, 0.515 mol) and sodium formate (46.73 g, 0.687 mol) were added to a solution of ethyl-2-(3-formyl-4-hydroxyphenyl)-4-methyl-5- thiazole carboxylate (100 g, 0.343 mol) in formic acid (anhydrous, 300 mL) and the reaction mixture was heated to a temperature of about 100°C for about 8 hours. After completion of reaction, the reaction mixture was cooled to about 40°C and water was added to it. The reaction mixture was cooled to about 25°C and stirred for about 1 hour. The solid obtained was filtered, washed with water and dried. The solid was then dissolved in acetone at about 50°C and water was added slowly over a period of about 30 minutes. The mixture was cooled to about 25°C and again stirred for about 1 hour. The solid thus obtained was filtered, washed with acetone:water (1 :1) mixture and dried to obtain the title product. (Yield: 85 g, 85.9percent)
42.6%	With ammonia; iodine; In tetrahydrofuran; water; at 25 - 30℃;	In a 50 mL round-bottomed flask charge under stirring 0.5g (1.72 mmol) of ethyl 2-(3-formyl-4- hydroxyphenyl)-4-methylthiazole-5-carboxylate in 8.6 mL THF, at 25-30 °C. Add 10.3 mL (544.94 mmol) 25percent aqueous ammonia, under stirring at 25-30 °C. Add 480 mg (1.89 mmol) iodine (I2) to the reaction mass, stir the reaction mixture at 25-30 °C for 15-30 min. Check the progress of the reaction by TLC (cyclohexane: ethyl acetate 1 :1). Starting material is consumed. Add 8.6 mL 5percent w/v aqueous thiosulfate and 40 mL ethyl acetate at the reaction mass, separate organic layer and extract aqueous layer twice with 40 mL ethyl acetate. Combine organic layers, dry over anhydrous sodium sulfate, filter off and concentrate to dryness. Purification of the residue with column chromatography (cyclohexane: ethyl acetate 3: 1) afforded 0.213 g of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (Formula Ilia). Yield : 42.6percent.

Reference： [1]Patent: WO2012/66561,2012,A1 .Location in patent: Page/Page column 8
[2]Patent: US2013/303780,2013,A1 .Location in patent: Paragraph 0043
[3]Patent: CN106187940,2016,A .Location in patent: Paragraph 0016; 0049
[4]Patent: WO2012/14117,2012,A1 .Location in patent: Page/Page column 12
[5]Patent: WO2015/18507,2015,A2 .Location in patent: Page/Page column 14
[6]Letters in Organic Chemistry,2015,vol. 12,p. 217 - 221
[7]Journal of Chemical Research,2018,vol. 42,p. 547 - 551

18
[ 78-77-3 ]
[ 161798-01-2 ]
[ 160844-75-7 ]

Yield	Reaction Conditions	Operation in experiment
84%		Example - 1: Preparation of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyI thiozole -5-carboxylateA mixture of 10. Og of Ethyl -2-(3-formyl-4-hydroxy phenyl)-4-methyl thiozole -5- carboxylate and 2.85 g of hydroxylamine hydrochloride were stirred for 30 minutes in 40 g of Dimethyl sulfoxide. To this reaction mixture 3.3 grams of acetyl chloride was added and stirred at 70 -80°C for 2-3 hours. Reaction mass was cooled to room temperature and to this 19 g of potassium carbonate and 19 g of isobutyl bromide was added successively. The reaction mass was stirred for 5 hours at 70-80°C. Reaction mass was diluted with 200 ml of purified water. The reaction mass was filtered and washed with purified water to give 10.0 g of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole -5-carboxyltae (yield 84.0percent)
84.0%		Example-1 Preparation of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole-5-carboxylate A mixture of 10.0 g of Ethyl-2-(3-formyl-4-hydroxy phenyl)-4-methyl thiozole-5-carboxylate and 2.85 g of hydroxylamine hydrochloride were stirred for 30 minutes in 40 g of Dimethyl sulfoxide. To this reaction mixture 3.3 grams of acetyl chloride was added and stirred at 70-80° C. for 2-3 hours. Reaction mass was cooled to room temperature and to this 19 g of potassium carbonate and 19 g of isobutyl bromide was added successively. The reaction mass was stirred for 5 hours at 70-80° C. Reaction mass was diluted with 200 ml of purified water. The reaction mass was filtered and washed with purified water to give 10.0 g of Ethyl-2-(3-cyano-4-isobutoxy phenyl)-4-methyl thiozole-5-carboxylate (yield 84.0percent)

Reference： [1]Patent: WO2012/66561,2012,A1 .Location in patent: Page/Page column 8
[2]Patent: US2013/303780,2013,A1 .Location in patent: Paragraph 0042

19
[ 161798-01-2 ]
C₁₆H₁₆NO₄S^(1-)*K⁽¹⁺⁾ [ No CAS ]

Reference： [1]Patent: WO2012/131590,2012,A1

20
[ 161798-01-2 ]
ethyl 2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate [ No CAS ]

Reference： [1]Letters in Organic Chemistry,2015,vol. 12,p. 217 - 221

21
[ 161798-01-2 ]
2-[3-cyano-4-(3-hydroxy-2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid [ No CAS ]

Reference： [1]Letters in Organic Chemistry,2015,vol. 12,p. 217 - 221

22
[ 161798-01-2 ]
ethyl 2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylate [ No CAS ]

Reference： [1]Letters in Organic Chemistry,2015,vol. 12,p. 217 - 221

23
[ 161798-01-2 ]
2-[3-cyano-4-(2-hydroxy-2-methylpropoxy)phenyl]-4-methylthiazole-5-carboxylic acid [ No CAS ]

Reference： [1]Letters in Organic Chemistry,2015,vol. 12,p. 217 - 221

24
[ 161798-01-2 ]
3-{2-cyano-4-[5-(ethoxycarbonyl)-4-methylthiazol-2-yl]phenoxy}-2-methylpropanoic acid [ No CAS ]

Reference： [1]Letters in Organic Chemistry,2015,vol. 12,p. 217 - 221

25
[ 161798-01-2 ]
2-[4-(2-carboxypropoxy)-3-cyanophenyl]-4-methylthiazole-5-carboxylic acid [ No CAS ]

Reference： [1]Letters in Organic Chemistry,2015,vol. 12,p. 217 - 221

26
C₈H₁₁ClO₄ [ No CAS ]
[ 161798-01-2 ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010

27
[ 161798-01-2 ]
[ 74-95-3 ]
C₁₅H₁₄BrNO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 75℃;	General procedure: Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate 2 (1.0 mmol), dimethyl formamide (4 mL) as a solvent media and potassium carbonate (1.05 mmol)was taken in RBF and heated to 75°C for 15 to 20 min and then dibromoethane (2.0 mmol) solution in dimethylformamide (1 mL) was added and reaction continued for 4-5 hr. The completion of reaction was checked by TLC. Heating was stopped after the completion of reaction and reaction mixture was gradually cooled to RT. It was filtered and washed with dimethyl formamide (1 mL). The reaction mass was collected and poured onto water (20 mL), stirred for 30 min, filtered and washed with water. The product ethyl 2-(4-(2-bromoethoxy)-3-formylphenyl)-4-methylthiazole-5-carboxylate 5 was purified by recrystallization from IPA at RT.

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010

28
[ 161798-01-2 ]
[ 106-93-4 ]
ethyl 2-(4-(2-bromoethoxy)-3-formylphenyl)-4-methylthiazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 75℃;	Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate 2 (1.0 mmol), dimethyl formamide (4 mL) as a solvent media and potassium carbonate (1.05 mmol)was taken in RBF and heated to 75°C for 15 to 20 min and then dibromoethane (2.0 mmol) solution in dimethylformamide (1 mL) was added and reaction continued for 4-5 hr. The completion of reaction was checked by TLC. Heating was stopped after the completion of reaction and reaction mixture was gradually cooled to RT. It was filtered and washed with dimethyl formamide (1 mL). The reaction mass was collected and poured onto water (20 mL), stirred for 30 min, filtered and washed with water. The product ethyl 2-(4-(2-bromoethoxy)-3-formylphenyl)-4-methylthiazole-5-carboxylate 5 was purified by recrystallization from IPA at RT.

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010

29
[ 161798-01-2 ]
ethyl 2-(3-formyl-4-((5-(4-hydroxy-2-oxo-2H-chromen-3-yl)pentyl)oxy)phenyl)-4-methylthiazole-5-carboxylate [ No CAS ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010

30
[ 161798-01-2 ]
ethyl 2-(3-formyl-4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methoxy)phenyl)-4-methylthiazole-5-carboxylate [ No CAS ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010

31
[ 161798-01-2 ]
ethyl 2-(3-formyl-4-(2-(4-hydroxy-2-oxo-2H-chromen-3-yl)ethoxy)phenyl)-4-methylthiazole-5-carboxylate [ No CAS ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010

32
[ 161798-01-2 ]
ethyl 2-(3-formyl-4-(3-(4-hydroxy-2-oxo-2H-chromen-3-yl)propoxy)phenyl)-4-methylthiazole-5-carboxylate [ No CAS ]

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010

33
[ 161798-01-2 ]
[ 109-64-8 ]
C₁₇H₁₈BrNO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 75℃;	General procedure: Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate 2 (1.0 mmol), dimethyl formamide (4 mL) as a solvent media and potassium carbonate (1.05 mmol)was taken in RBF and heated to 75°C for 15 to 20 min and then dibromoethane (2.0 mmol) solution in dimethylformamide (1 mL) was added and reaction continued for 4-5 hr. The completion of reaction was checked by TLC. Heating was stopped after the completion of reaction and reaction mixture was gradually cooled to RT. It was filtered and washed with dimethyl formamide (1 mL). The reaction mass was collected and poured onto water (20 mL), stirred for 30 min, filtered and washed with water. The product ethyl 2-(4-(2-bromoethoxy)-3-formylphenyl)-4-methylthiazole-5-carboxylate 5 was purified by recrystallization from IPA at RT.

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010

34
[ 110-52-1 ]
[ 161798-01-2 ]
C₁₈H₂₀BrNO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 75℃;	General procedure: Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate 2 (1.0 mmol), dimethyl formamide (4 mL) as a solvent media and potassium carbonate (1.05 mmol)was taken in RBF and heated to 75°C for 15 to 20 min and then dibromoethane (2.0 mmol) solution in dimethylformamide (1 mL) was added and reaction continued for 4-5 hr. The completion of reaction was checked by TLC. Heating was stopped after the completion of reaction and reaction mixture was gradually cooled to RT. It was filtered and washed with dimethyl formamide (1 mL). The reaction mass was collected and poured onto water (20 mL), stirred for 30 min, filtered and washed with water. The product ethyl 2-(4-(2-bromoethoxy)-3-formylphenyl)-4-methylthiazole-5-carboxylate 5 was purified by recrystallization from IPA at RT.

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010

35
[ 111-24-0 ]
[ 161798-01-2 ]
C₁₉H₂₂BrNO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 75℃;	General procedure: Ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate 2 (1.0 mmol), dimethyl formamide (4 mL) as a solvent media and potassium carbonate (1.05 mmol)was taken in RBF and heated to 75°C for 15 to 20 min and then dibromoethane (2.0 mmol) solution in dimethylformamide (1 mL) was added and reaction continued for 4-5 hr. The completion of reaction was checked by TLC. Heating was stopped after the completion of reaction and reaction mixture was gradually cooled to RT. It was filtered and washed with dimethyl formamide (1 mL). The reaction mass was collected and poured onto water (20 mL), stirred for 30 min, filtered and washed with water. The product ethyl 2-(4-(2-bromoethoxy)-3-formylphenyl)-4-methylthiazole-5-carboxylate 5 was purified by recrystallization from IPA at RT.

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2015,vol. 54B,p. 1005 - 1010

36
[ 161798-01-2 ]
[ 141-97-9 ]
ethyl 2-(3-acetyl-2-oxo-2H-chromen-6-yl)-4-methylthiazole-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With piperidine; In ethanol; at 0 - 5℃;	A mixture of <strong>[161798-01-2]ethyl 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate</strong> (1) (0.1 mol) and ethyl acetoacetate (2) (0.12 mol) were dissolved in ethanol and cooled at 0-5 °C. Piperidine (1 mL) was added drop wise to this mixture while stirring. The reaction mixture left overnight, resulting in the formation of yellow colored solid. Purification by recrystallization from ethanol to afford analytically pure product.

Reference： [1]Synthetic Communications,2015,vol. 45,p. 588 - 595

37
[ 1809-19-4 ]
[ 161798-01-2 ]
C₂₂H₃₂NO₇PS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With N,N'-dimethylpiperazine; In tetrahydrofuran; at 60℃; for 3h;	Synthesis of dibutyl (5-(5-ethyl-4-methylthiazol-2-yl)-2-hydroxyphenyl) (hydroxy) methyl phosphonate (3a). Amixture of febuxostat aldehyde (0.002 mole), dibutylphosphite(0.002 mole), and 1, 4-dimethylpiperazine (0.002 mole) wasrefluxed for 3 h in tetrahydrofuran (THF) (20 mL) at 60°C.The progress of the reaction was monitored by TLC analysis.After completion of the reaction, as indicated by TLC (silicagel) using hexane and ethyl acetate (3:1) as a mobile phase, thesolvent was removed in a rota-evaporator and the crude productobtained was purified by column chromatography on silica gel(60?120 mesh) using hexane and ethyl acetate (3:1) as an eluentto afford the analytically pure 3a. Analogously, the compounds3b?d were prepared by adopting the above procedure.