* 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.
Stage #1: With water; sodium hydroxide In 1,4-dioxane at 20℃; for 1 h; Stage #2: With hydrogenchloride In 1,4-dioxane; water
b) 2-Methyl-thiazole-5-carboxylic acid To a stirred solution of 2-methyl-thiazole-5-carboxylic acid ethyl ester (1.3 g, 8.0 mmol) in dioxane (12 mL) at room temperature was added NaOH (2N, 12 mL). After 1 h the reaction mixture was neutralized with HCl (IN, 12 mL), then filtered and the collected solid dried in vacuo to give the title compound (758 mg, 70percent) as an off white solid. MS: m/e = 142.0 [M-H]".
41%
With lithium hydroxide monohydrate; water In tetrahydrofuran at 20℃; for 16 h;
To a stirred solution of compound 97 (41 g, 239.76 mmol) in THF: H2O (7: 1, 400 mL) was added lithium hydroxide monohydrate (29.49 g, 719.29 mmol) at room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and acidified with 2 N HCl to pH~2 and extracted using EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford compound 98 (14 g, 41percent) as an off-white solid. TLC: 20percent EtOAc/ hexanes (Rf: 0.1); 1H NMR (DMSO-d6, 400 MHz): δ 13.29 (br.s, 1H), 8.16 (s, 1H), 2.69 (s, 3H); LCMS Calculated for C5H5NO2S: 143.00; Observed: 144.1 (M+1)+.
14 g
With water; sodium hydroxide In tetrahydrofuran at 0 - 20℃; for 2.16 h;
To a 0° C. solution of ethyl 2-methyl-thiazole-5-carboxylate (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3*100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g).
14 g
With water; sodium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 2.16667 h;
To a 0°C. solution of ethyl 2-methyl-thiazole-5-carboxylate (15 g, 88 mmol) in tetrahydrofuran (50 ml) was added aqueous sodium hydroxide solution (5 N, 50ml) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3x100 ml). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14g).
14 g
With water; sodium hydroxide In tetrahydrofuran at 0℃; for 2.16667 h;
To a 0° C. solution of ethyl 2-methyl-thiazole-5-carboxylate (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3×100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g).
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 44, p. 14639 - 14649
[2] Patent: WO2010/127974, 2010, A1, . Location in patent: Page/Page column 43; 44
[3] Patent: WO2018/160878, 2018, A1, . Location in patent: Page/Page column 279
[4] Chemische Berichte, 1940, vol. 73, p. 1240,1252
[5] Australian Journal of Chemistry, 2004, vol. 57, # 6, p. 599 - 604
[6] Patent: US2009/131431, 2009, A1, . Location in patent: Page/Page column 142
[7] Patent: US2010/240903, 2010, A1, . Location in patent: Page/Page column 14
[8] Patent: WO2007/36733, 2007, A1, . Location in patent: Page/Page column 212
[9] Journal of Chemical Research, 2011, vol. 35, # 5, p. 313 - 316
[10] Patent: US2014/113855, 2014, A1, . Location in patent: Paragraph 0279; 0288; 0289
[11] Patent: US2018/78532, 2018, A1, . Location in patent: Paragraph 0233; 0238
[12] Patent: US2018/161279, 2018, A1, . Location in patent: Paragraph 0474-0475
3
[ 62-55-5 ]
[ 33142-21-1 ]
[ 79836-78-5 ]
Yield
Reaction Conditions
Operation in experiment
47%
for 4 h; Reflux; Inert atmosphere
Example 72- [2-(5-Methyl-3-phenyl-isoxazol-4-yl)-ethyl] -thiazole-5-carboxylic acid isopropyl- amidea) 2-Methyl-thiazole-5-carboxylic acid ethyl esterTo a stirred solution of ethyl 2-chloro-2-formyl acetate (5.0 g, 33 mmol) in benzene (50 mL) at reflux under argon was added thioamide (2.5 g, 33 mmol). After 4 h the reaction mixture was cooled, diluted with water (50 mL) and neutralized to pH 7 with a saturated solution of sodium hydro gencarbonate. The reaction mixture was extracted with ethyl acetate then the combined extracts were washed with water and brine, then dried, filtered and concentrated in vacuo. Purification by chromatography (silica, 0 to 50percent ethyl acetate in heptane) gave the title compound (2.68 g, 47percent) as a yellow liquid. MS: m/e = 172.0 [M+H]+.
35%
With magnesium sulfate In ethanol for 24 h; Inert atmosphere; Reflux
To a stirred solution of ethyl 2-chloro-3-oxopropanoate 61 (26 g, 173.33 mmol) in ethanol (200 mL) under argon atmosphere were added ethanethioamide 62 (10 g, 133.33 mmol), dry magnesium sulfate (10 g) at RT and heated to reflux for 24 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo, diluted with EtOAc (500 mL). The combined organic extracts were washed with saturated sodium bicarbonatesolution (2 x 200 mL), brine (200 mL), dried over sodium sulfate, filtered and concentrated invacuo to obtain the crude. The crude was purified through flash column chromatography using6percent EtOAc/ hexanes to afford compound 63 (8 g, 35percent) as brown syrup. TLC: 25percent EtOAc/hexanes (Rf: 0.7); ‘H-NMR (DMSO-d6, 500 MHz): ö 8.24 (s, 1H), 4.27 (q, J = 7.2 Hz, 2H),2.70 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).
33%
With magnesium sulfate In ethanol at 80℃; for 16 h; Inert atmosphere
To a stirring solution of compound 96 (110 g, 733.33 mmol) in ethanol (1.2 L) under Ar atmosphere were added ethanethioamide (54.99 g, 733.33 mmol) and anhydrous magnesium sulfate (55 mg, 454.66 mmol) at room temperature, followed by heating to 80 oC for 16 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and extracted using EtOAc. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10percent EtOAc/hexanes to afford compound 97 (41 g, 33percent) as thick syrup. TLC: 20percent EtOAc/ hexanes (Rf: 0.3); 1H NMR (400 MHz, DMSO-d6): δ 8.26 (s, 1H), 4.29 (q, J = 7.2 Hz, 2H), 2.71 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H); LCMS Calculated for C7H9NO2S: 171.04; Observed: 172.1 (M+1)+.
Reference：
[1] Journal of the American Chemical Society, 1982, vol. 104, # 16, p. 4461 - 4465
[2] Patent: WO2010/127974, 2010, A1, . Location in patent: Page/Page column 43
[3] Patent: WO2018/53157, 2018, A1, . Location in patent: Page/Page column 108; 109
[4] Patent: WO2018/160878, 2018, A1, . Location in patent: Page/Page column 278-279
[5] Journal of Chemical Research, 2011, vol. 35, # 5, p. 313 - 316
[6] Patent: WO2013/177668, 2013, A1, . Location in patent: Page/Page column 55-56
[7] Patent: WO2014/5217, 2014, A1, . Location in patent: Page/Page column 23; 24
[8] Patent: WO2014/29007, 2014, A1, . Location in patent: Page/Page column 22; 23
[9] Chemical Communications, 2014, vol. 50, # 77, p. 11358 - 11361
[10] Patent: US2015/191473, 2015, A1, . Location in patent: Paragraph 0171
b) 2-Methyl-thiazole-5-carboxylic acid To a stirred solution of <strong>[79836-78-5]2-methyl-thiazole-5-carboxylic acid ethyl ester</strong> (1.3 g, 8.0 mmol) in dioxane (12 mL) at room temperature was added NaOH (2N, 12 mL). After 1 h the reaction mixture was neutralized with HCl (IN, 12 mL), then filtered and the collected solid dried in vacuo to give the title compound (758 mg, 70percent) as an off white solid. MS: m/e = 142.0 [M-H]".
41%
With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 20℃; for 16h;
To a stirred solution of compound 97 (41 g, 239.76 mmol) in THF: H2O (7: 1, 400 mL) was added lithium hydroxide monohydrate (29.49 g, 719.29 mmol) at room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and acidified with 2 N HCl to pH~2 and extracted using EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford compound 98 (14 g, 41percent) as an off-white solid. TLC: 20percent EtOAc/ hexanes (Rf: 0.1); 1H NMR (DMSO-d6, 400 MHz): delta 13.29 (br.s, 1H), 8.16 (s, 1H), 2.69 (s, 3H); LCMS Calculated for C5H5NO2S: 143.00; Observed: 144.1 (M+1)+.
Ethyl 2-methyl-1,3-thiazole-5-carboxylate [e.g. available from Interchim S.A.] (61 mg) in ethanol (1 ml) was treated with aqueous sodium hydroxide (2M, 0.706 ml). The clear solution was stirred at room temperature for 18 h and then treated with aqueous hydrochloric acid (2M, 0.54 ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1 ml) and treated at 20° C. with oxalyl chloride (0.032 ml) and DMF (1 drop). The mixture was stirred at room temperature for 30 mins and was then added dropwise to a solution of Intermediate 16 (98 mg) in anhydrous acetonitrile (2 ml). DIPEA (0.064 ml) was added and the solution stirred at room temperature for 20 h. The mixture was diluted with dichloromethane (15 ml), washed with dilute aqueous sodium chloride (2.x.15 ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2 g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87 mg). LCMS showed MH+=429; TRET=1.94 min.
Synthesis of (E) To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3*100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g).
Example 311 N-[1,6-diethyI-4-(tetrahydro-2H-pyran-4-yIamino)-1H- pyrazoIo[3,4-b]pyridin-5-yl]methyl}-2-methyI-1,3-thiazole-5-carboxamideEthyl 2-methyl-1 ,3-thiazole-5-carboxylate [e.g. available from lnterchim S.A.] (61 mg) in ethanol (1ml) was treated with aqueous sodium hydroxide (2M, 0.706ml). The clear solution was stirred at room temperature for 18h and then treated with aqueous hydrochloric acid (2M, 0.54ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1ml) and treated at 20°C with oxalyl chloride (0.032ml) and DMF (1 drop). The mixture was stirred at room temperature for 30mins and was then added dropwise to a solution of Intermediate 16 (98mg) in anhydrous acetonitrile (2ml). DIPEA (0.064ml) was added and the solution stirred at room temperature for 2Oh. The mixture was diluted with dichloromethane (15ml), washed with dilute aqueous sodium chloride (2 x 15ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87mg). LCMS showed MH+ =
14 g
With water; sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 2.16h;
To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3*100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g).
14 g
With water; sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 2.16667h;
To a 0°C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 ml) was added aqueous sodium hydroxide solution (5 N, 50ml) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3x100 ml). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14g).
14 g
With water; sodium hydroxide; In tetrahydrofuran; at 0℃; for 2.16667h;
To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3×100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g).
With hydrazine; In ethanol; for 12h;Heating / reflux;
Preparation 9: 2-methyl-1,3-thiazole-5-carbohydrazide; EPO <DP n="44"/>The title compound was prepared in analogy to the method described in Preparation 4 starting from ethyl 2-methyl-1 ,3-thiazole-5-carboxylate (0.5g) and used without further purification. Ethanol was used instead of methanol. MS (mlz): 158.1 [MH]+.
2-bromomethylthiazole-5-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;
Reference Example 18 Ethyl 2-bromomethyl-5-thiazolecarboxylate A solution of ethyl 2-methyl-5-thiazole carboxylate [S. H Mashragui, P. M. Keehn, JACS 104 4461-4465 (1982)] (4.73 g, 27.68 mmol) in carbon tetrachloride (30 ml) was treated with N-bromosuccinimide (4.92 g, 27.64 mmol) and benzoyl peroxide (0.03 g). The reaction mixture was heated to reflux under a strong light for 11/4 hours. The reaction was allowed to cool to ambient temperature and filtered. The filtrate was evaporated and subjected to chromatography (CH2 Cl2) to give the title product (1.16 g, 17percent). NMR (200 MH2,DMSO-d6): delta8.4 (s, 1H), 5.06 (s, 2H), 4.33 (g, 2H), 1.3 (t, 3H).
13%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 21h;
N-bromosuccinimide (2.58 g, 14.5 mmol) and AIBN (158 mg, 0.965 mmol) were added to a stirred solution of <strong>[79836-78-5]2-methyl-5-(carboethoxy)thiazole</strong> (1.65 g, 9.65 mmol) in CCl4 (40 mL). The mixture was stirred at 80° C. for 5 h, an additional portion of AIBN (158 mg, 0.965 mmol) was added and the resulting mixture was stirred for another 16 h at 80° C. The mixture was cooled, filtered thru celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel using CH2Cl2/hexane as an eluent to give compound 13 (1.09 g, 13percent) gas a dark-red oil: MS (ES): 250 (MH+).
With N-Bromosuccinimide; (E)-3,3'-(diazene-1,2-diyl)bis(2-methylpropanenitrile); In 2-Methylpentane; ethyl acetate;
i 2-Bromomethyl-5-thiazolecarboxylic acid, ethyl ester 2-Methyl-5-thiazolecarboxylic acid ethyl ester (3.9 g) (J. Am. Chem. Soc. 1982, 104, 4461), N-bromosuccinimide (4.1 g) and catalytic azoisobutyronitrile in ethyl acetate (150 ml) was heated at reflux and under a 500 W halogen lamp for 16 hours. The solution was washed with water, dried (MgSO4) and evaporated. Purification was by chromatography eluding with 50percent ethyl acetate in isohexane. Yield 1.5 g. MS: GC-MS: 249/251 (M+)
Under nitrogen atmosphere, to a solution of ethyl 2-chloroformylpropionate in acetone (250 mL) was added thioacetamide (7.74 g), and the mixture was stirred at 56° C. for 6 hours, and stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=12.5/1-->10/1) to give ethyl 2-methyl-1,3-thiazole-5-carboxylate (5.74 g, 32percent). 1H NMR (CDCl3, 400 MHz) delta 8.24 (s, 1H), 4.35 (q, 2H, J=7.1 Hz), 2.75 (s, 3H), 1.37 (t, 3H, J=7.1 Hz).
32%
In acetone;
Under nitrogen atmosphere, to a solution of ethyl 2-chloroformylpropionate in acetone (250 mL) was added thioacetamide (7.74 g), and the mixture was stirred at 56°C for 6 hours, and stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate = 12.5/1 --> 10/1) to give ethyl 2-methyl-1,3-thiazole-5-carboxylate (5.74 g, 32 percent). 1H NMR (CDCl3, 400MHz) delta 8.24 (s, 1H), 4.35 (q, 2H, J=7.1Hz), 2.75 (s, 3H), 1.37 (t, 3H, J=7.1Hz).
2-(N-t-butoxycarbonylamino)methyl-5-ethoxycarbonylthiazole[ No CAS ]
[ 79836-78-5 ]
Yield
Reaction Conditions
Operation in experiment
With trifluoroacetic acid; In dichloromethane; water; sodium hydrogencarbonate; Ethyl oxalyl chloride;
a) 2-(ethoxalylamino)methyl-5-ethoxycarbonylthiazole A 13 ml potion of trifluoroacetic acid was added to 4.00 g of 2-(N-t-butoxycarbonylamino)methyl-5-ethoxycarbonylthiazole under ice-cooling, and the mixture was then stirred at the same temperature for 1 hour. Then, the solvent was concentrated and evaporated under reduced pressure, and 15 ml of dichloromethane and 5 ml of an aqueous saturated sodium hydrogencarbonate solution were then added. In addition, powdery sodium hydrogencarbonate was added until a neutral state was attained. To the solution, 10 ml of dichloromethane in which 32 ml of ethyl chloroglyoxylate was dissolved was added dropwise over 10 minutes, while the reaction solution was maintained in the neutral state by adding sodium hydrogencarbonate and water. The solution was extracted with dichloromethane (10 ml*5), and the extract was washed with water (20 ml). The organic layer was dried over anhydrous magnesium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by a silica gel column chromatograph to obtain 3.65 g of 2-(ethoxalylamino)methyl-5-ethoxycarbonylthiazole. NMR (CDCl3) delta: 1.41 (6H, m), 4.40 (4H, m), 4.87 (2H, d, J=6.4 Hz), 7.85 (1H, br.s), 8.16 (1H, s) MS (ESI): 287 (M+ +H)
A. Ethyl 2-Methylthiazole-5-carboxylate Using the procedure of Example 1O but replacing thioformamide with thioacetamide provided the crude desired compound.
23
[ 79836-78-5 ]
[ 87967-95-1 ]
[ 1254970-03-0 ]
Yield
Reaction Conditions
Operation in experiment
19%
With acetic anhydride; acetic acid; at 120℃; for 144h;
Example 632- [(E)-2-(5-Methyl-3-phenyl-isoxazol-4-yl)-vinyl] -thiazole-5-carboxylic acid (tetra- hydro-pyran-4-yl)-amidea) 2-[(E)-2-(5-Methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid ethyl ester2-Methyl-thiazole-5-carboxylic acid ethyl ester (547 mg, 2.92 mmol) was dissolved in acetic anhydride (0.15 mL, 15.5 mmol) and acetic acid (0.04 mL, 2.54 mmol) then 5-methyl-3- phenyl-4-isoxazolecarbaldehyde (500 mg, 2.92 mmol) was added and the reaction mixture warmed to 1200C. After 6 days, the reaction mixture was cooled to room temperature then diluted with water and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 0 to 30 percent ethyl acetate in heptane) to give the title compound (191 mg, 19percent) as an off-white solid after trituration with isopropylether. MS: m/e = 341.3 [M+H]+.
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