* 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.
(116c) A 2 N aqueous solution of KOH (3.5 mL, 5 eq) was added to ethyl thiazole-2-carboxylate (213 mg, 1.355 mmol) in ethanol (3 mL). After 2 h at room temperature, the mixture was acidified with 2 N HCl (3.5 mL). Upon sitting overnight, a needle crystal was formed, which was collected by filtration to give thiazole-2-carboxylic acid (43.3 mg, 25percent).
Step 3 : Thiazole-2-carboxylic acid; A solution of ethyl thiazole-2-carboxylate (1.46g; 9.29mmol), obtained using a literature method (HeIv. Chim Acta 1945, 28, p. 924), in EtOH (10 ml) was placed in a sealable vessel and treated with KOH (3.07g; 46.4mmol). The vessel was sealed and heated at 120°C for 30min. After cooling, the solution was poured into water (50mL) and the pH adjusted to 4.0 with con. HCl. The now turbid mixture was extracted with iPrOAc (50mL), dried over magnesium sulfate, filtered and evaporated to a brown oil. The oil was dissolved in CH2Cl2 and filtered, then evaporated to afford the title compound as a brown pasty solid.
Step 3: Thiazole-2-carboxylic acid; A solution of ethyl thiazole-2 -carboxylate (1.46g; 9.29mmol), obtained using a literature method (HeIv. Chim Acta 1945, 28, p. 924), in EtOH (10 ml) was placed in a sealable vessel and treated with KOH (3.07g; 46.4mmol). The vessel was sealed and heated at 1200C for 30min. After cooling, the solution was poured into water (5OmL) and the pH adjusted to 4.0 with con. HCl. The now turbid mixture was extracted with iPrOAc (5OmL), dried over magnesium sulfate, filtered and evaporated to a brown oil. The oil was dissolved in CH2Cl2 and filtered, then evaporated to afford the title compound as a brown pasty solid.
Example 226; (R)-N-(2-(l-(4-fluorophenyl)-5-methyl-4,5-dihydro-lH-indazol-5- yl)ethyl)thiazole-2-carboxamide; [00447] (226a) To an ethanol (3 mL) solution of thiazole-2-carboxylic acid ethyl ester (213 mg, 1.355 mmol) was added aqueous KOH (2 M, 3.5 mL). The mixture EPO <DP n="130"/>was stirred at room temperature for 2 h then concentrated, acidified with aqueous HCl (2 M, 3 mL). The resulting white needle crystal (43 mg) was collected from the solution by filtration.
Synthesis of Carboxylic acid 187 as Illustrated in FIG. 29 Ethyl bromopyruvate (1.66 mL, 13.2 mmol, 1 equiv) and thioacetamide (1.05 g, 13.9 mmol, 1.05 equiv) are dissolved in 95percent aqueous ethanol (14 mL, 1 M) and heated at reflux for 5 minutes. Completion of the reaction is indicated by TLC. The reaction mixture is then cooled to room temperature, concentrated in vacuo, suspended in CHCl3 (20 mL) and washed with saturated aqueous NaHCO3 (2*20 mL) and with H2O (20 mL). Drying (MgSO4) and concentration is followed by flash chromatographic purification (silica gel, EtOAc) to yield the corresponding ethyl ester of acid 7 (2.26 g, 100percent). This ester is dissolved in THF-H2O (1:1; 14 mL, 1 M) and submitted to the action of lithium hydroxide (1.66 g, 39.6 mmol, 3.0 equiv). After stirring at room temperature for 45 min TLC indicates the disappearance of starting material. The mixture is poured into H2O (20 mL) and extracted with ether (2*20 mL). Acidification to pH~2 to 3 with aqueous 4 N HCl is followed by extractions with EtOAc (6*20 mL). Drying (MgSO4) and concentration gives pure carboxylic acid 187 (1.36 g, 72percent).
(3) Thiazole ester (4) (470 mg) as produced above (1) is dissolved in dichloromethane (15 ml), mixed with anisole (0.611 ml) and trifluoroacetic acid (1.22 ml), and stirred at 0° C. for 2 hours. After concentrating to dryness, the mixture is triturated in a mixture of ether and hexane (1:1) to give thiazolecarboxylic acid (5) (336 mg).
4-{2-[1-methyl-4-(1-methyl-4-(4-amino-2-pyrrolecarboxamido)-2-pyrrolecarboxamido)-2-pyrrolecarboxamido]ethyl}morpholine dihydrochloride[ No CAS ]
4-{2-[1-methyl-4-(1-methyl-4-(1-methyl-4-(thiazole-2-carboxamido)-2-pyrrolecarboxamido)-2-pyrrolecarboxamido)-2-pyrrolecarboxamido]ethyl}morpholine[ No CAS ]
cloridrato del 2-amino-2-isobutirrilacetacetato di etile[ No CAS ]
[ 910476-37-8 ]
Yield
Reaction Conditions
Operation in experiment
60%
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0℃;Molecular sieve;
Compound 1 (3 mmol), compound 2 (3 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (3.3 mmol) and N,N-dimethylpyridine (DMAP) (0.3 mmol) were mixed with a molecular sieve, and the resulted mixture was cooled in ice bath (0° C.). Then DMF and pyridine (4.5 mmol) were added in turn. The progress of reaction was tracked by TLC. After the reaction was completed, the reactant was diluted with water and extracted with EtOAc. The solvent was removed completely by concentration. Then compound 3 was obtained through column chromatograph (yield 60percent). Subsequently, compound 3 (0.3 mmol) was mixed with ammonium acetate (NH4OAc) (15 mmol) and sodium acetate (NaOAc) (30 mmol) and heated to 130° C., and the progress of reaction was tracked by TLC. Then the reactant was cooled to room temperature, and diluted with water, extracted with ethyl acetate. The solvent was removed completely by concentration. Then compound 4i (Wang279-1) was obtained by separation through column chromatograph with petroleum ether/ethyl acetate (volume ratio 1:1) (yield 31percent).
60%
With pyridine; dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0℃;Molecular sieve;
Compound 1 (3mmol), compound 2 (3mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (3.3mmol) and N,N-dimethyl pyridine (DMAP) (0.3mmol) were mixed with a molecular sieve, and the resulted mixture was cooled in ice bath (0°C). Then DMF and pyridine (4.5mmol) were added in turn. The progress of reaction was tracked by TLC. After the reaction was completed, the reactant was diluted with water and extracted with EtOAc. The solvent was removed completely by concentration. Then compound 3 was obtained through column chromatograph (yield 60percent). Subsequently, compound 3 (0.3mmol) was mixed with ammonium acetate (NH4OAc) (15mmol) and sodium acetate (NaOAc) (30mmol) and heated to 130°C, and the progress of reaction was tracked by TLC. Then the reactant was cooled to room temperature, and diluted with water, extracted with ethyl acetate. The solvent was removed completely by concentration. Then compound 4i (Wang279-1) was obtained by separation through column chromatograph with petroleum ether/ ethyl acetate (volume ratio 1:1) (yield 31percent).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0℃;
Benzoic aldehyde (25 mmol) was added to the 25percent ammonia water solution (20 mL) containing potassium cyanide (KCN) (30 mmol) and ammonium chloride (37.5 mmol). The resulted mixture was stirred for 56 hours, and the reaction was tracked by TLC. The reactant was extracted with dichloromethane. Then the extract was dried over magnesium sulphate (MgSO4), and the solvent was concentrated to obtain compound 9 (2.9 g, yield 90percent). Compound 9 (6 mmol) was mixed with EDC (7.8 mmol), DMAP (0.6 mmol) and thiazole-2-formic acid (6 mmol). The resulted mixture was cooled under ice bath (0° C.), subsequently DMF was added thereto (15 mL). The progress of reaction was tracked by TLC. After the reaction was completed, the reactant was diluted with water, and extracted with ethyl acetate. The solvent was removed completely by concentration, and compound 10 was obtained by separation through column chromatograph (0.76 g, yield 50). Compound 10 (3.1 mmol) was mixed with triphenylphosphine (Ph3P) (7.75 mmol) and carbon tetrachloride (CCl4) (7.75 mmol), and the resulted mixture was dissolved in acetonitrile (20 mL). The reaction was conducted at 45° C. and tracked by TLC. After the reaction was completed, the solvent was removed by concentration, and compound 11 (Wang261) (yield 60percent) was obtained by separation through column chromatograph with petroleum ether/ethyl acetate (volume ratio 5:1). The following compounds were synthesized by the same method:
50%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0℃;
Benzoic aldehyde (25mmol) was added to the 25percent ammonia water solution (20mL) containing potassium cyanide (KCN) (30mmol) and ammonium chloride (37.5mmol). The resulted mixture was stirred for 56 hours, and the reaction was tracked by TLC. The reactant was extracted with dichloromethane. Then the extract was dried over magnesium sulphate (MgSO4), and the solvent was concentrated to obtain compound 9 (2.9g, yield 90percent). Compound 9 (6mmol) was mixed with EDC (7.8mmol), DMAP (0.6mmol) and thiazole-2-formic acid (6mmol). The resulted mixture was cooled under ice bath (0°C), subsequently DMF was added thereto (15mL). The progress of reaction was tracked by TLC. After the reaction was completed, the reactant was diluted with water, and extracted with ethyl acetate. The solvent was removed completely by concentration, and compound 10 was obtained by separation through column chromatograph (0.76g, yield 50). Compound 10 (3.1mmol) was mixed with triphenylphosphine (Ph3P) (7.75mmol) and carbon tetrachloride (CCl4) (7.75mmol), and the resulted mixture was dissolved in acetonitrile (20mL). The reaction was conducted at 45°C and tracked by TLC. After the reaction was completed, the solvent was removed by concentration, and compound 11 (Wang261) (yield 60percent) was obtained by separation through column chromatograph with petroleum ether/ ethyl acetate (volume ratio 5:1).
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