* 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.
With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 0 - 20℃; Inert atmosphere
Step 2: Ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) To a suspension of ethyl 2-amino-4-trifluoromethyloxazole-5-carboxylate (A-1) (9.8 g) in acetonitrile (100 ml_) at 0 °C was first added copper (II) bromide (11.8 g) then te/t-butylnitrite (13.8 ml_) slowly. The reaction mixture was warmed slowly from 0 °C to RT under a nitrogen atmosphere. After 4 h of stirring at RT, the reaction mixture was concentrated. The residue was suspended in EtOAc (200 ml_), washed with 1 N HCI (3 x 100 ml_), brine (1 x 100 rriL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (eluant: EtOAc and hexanes) to yield ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) as a colorless liquid (9.18 g, 73percent yield). LCMS (ESI) [M+1]+ 288.2
52%
With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 0 - 20℃; for 2.5 h; Inert atmosphere
To a mixture of ethyl 2-amino-4-(trifluoromethyl)oxazole-5-carboxylate (1.8 g, 8.0 mmol, 1 eq) and CuBr2 (2.14 g, 9.6 mmol, 1.2 eq) in dry MeCN (15 mL) was added t- butylnitrite slowly. The reaction mixture was warmed slowly from 0 °C to rt under a nitrogen atmosphere. After stirring at rt for 2.5 h, the mixture was diluted with saturated H4C1 aqueous solution and extracted with EA twice. The combined organic layers were dried and concentrated. The resulting residue was purified by chromatography on a silica gel column to give ethyl 2-bromo-4-(trifluoromethyl)oxazole-5-carboxylate (1.2 g, 52percent) as a colorless oil.
Reference：
[1] Patent: WO2010/59606, 2010, A2, . Location in patent: Page/Page column 159
[2] Patent: WO2018/11628, 2018, A1, . Location in patent: Paragraph 00321
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 23, p. 6410 - 6414
In alpha,alpha,alpha-trifluorotoluene; at 20 - 120℃; for 0.333333h;Microwave irradiation;
Step 3: Ethyl 2-(1-piperidinyl)-4-trifluoromethyloxazole-5-carboxylate (A- 3) To a solution of <strong>[1227934-69-1]ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate</strong> (A-2) (0.85 mL) in alpha,alpha,alpha-trifluorotoluene (10 mL) at RT was added piperidine (1.1 mL). The reaction mixture was heated at 120 0C for 20 min by microwave then cooled to RT and diluted with EtOAc (100 ml_). The organic solution was washed with H2O (2 x 100 ml_), sat. NH4CI (1 x 100 ml_), brine (1 x 100 ml_), dried over Na2SO4, filtered, and concentrated to give ethyl 2-(1 -piperidinyl)-4- trifluoromethyloxazole-5-carboxylate (A-3) as a yellow solid (1.28 g, 88% yield). LCMS (ESI) [M+1]+ 293.2.
With potassium carbonate; In tetrahydrofuran; at 80℃; for 5h;
Step 1 : Ethyl 2-(cyclohexylthio)-4-trif luoromethyloxazole-5-carboxylate (A-8)To compound A-2 (300 mg, 1.04 mmol) in dry THF (8 ml_) was added cyclohexanethiol (242 mg, 2.08 mmol, 0.26 ml_) and potassium carbonate (288 mg, 2.08 mmol). The resulting reaction mixture was heated at 80 0C for 5 h then cooled to RT and concentrated. Water (15 ml_) was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give the product ethyl 2- (cyclohexylthio)-4-trifluoromethyloxazole-5-carboxylate (A-8) as a yellow oil (336 mg, 100% yield). MS (M+1 ): 324.
100%
With potassium carbonate; In tetrahydrofuran; water;
Step 1: ethyl 2-(cyclohexylthio)-4-trifluoromethyloxazole-5-carboxylate (A-36) To compound A-2 (300 mg, 1.04 mmol) in dry THF (8 mL) was added cyclohexanethiol (242 mg, 2.08 mmol, 0.26 mL) and potassium carbonate (288 mg, 2.08 mmol). The resulting reaction mixture was heated at 80 C. for 5 h then cooled to RT and concentrated. Water (15 mL) was added, and the aqueous solution was extracted with CH2Cl2. The combined organic extract was dried (MgSO4), filtered, and concentrated to give the product ethyl 2-(cyclohexylthio)-4-trifluoromethyloxazole-5-carboxylate (A-36) as a yellow oil (336 mg, 100% yield). MS (M+1): 324.
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃;Inert atmosphere;
Step 2: Ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) To a suspension of ethyl 2-amino-4-trifluoromethyloxazole-5-carboxylate (A-1) (9.8 g) in acetonitrile (100 ml_) at 0 C was first added copper (II) bromide (11.8 g) then te/t-butylnitrite (13.8 ml_) slowly. The reaction mixture was warmed slowly from 0 C to RT under a nitrogen atmosphere. After 4 h of stirring at RT, the reaction mixture was concentrated. The residue was suspended in EtOAc (200 ml_), washed with 1 N HCI (3 x 100 ml_), brine (1 x 100 rriL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (eluant: EtOAc and hexanes) to yield ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) as a colorless liquid (9.18 g, 73% yield). LCMS (ESI) [M+1]+ 288.2
52%
With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃; for 2.5h;Inert atmosphere;
To a mixture of ethyl 2-amino-4-(trifluoromethyl)oxazole-5-carboxylate (1.8 g, 8.0 mmol, 1 eq) and CuBr2 (2.14 g, 9.6 mmol, 1.2 eq) in dry MeCN (15 mL) was added t- butylnitrite slowly. The reaction mixture was warmed slowly from 0 C to rt under a nitrogen atmosphere. After stirring at rt for 2.5 h, the mixture was diluted with saturated H4C1 aqueous solution and extracted with EA twice. The combined organic layers were dried and concentrated. The resulting residue was purified by chromatography on a silica gel column to give ethyl 2-bromo-4-(trifluoromethyl)oxazole-5-carboxylate (1.2 g, 52%) as a colorless oil.
Step 1 : Ethyl 2-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5- carboxylate (A-28)NaH (0.060 mg, 1.5 mmol) (60 %) was added to a solution of 2-oxopyrrolidine (0.13 g, 1.5 mmol) in DMF (5.0 mL) at - 78 0C followed by stirring for 15 mins at - 78 C. Then <strong>[1227934-69-1]ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate</strong> A-2 (0.29 g, 1.0 mmol) was added. The reaction mixture was stirred for 3 h while the temperature was slowly warmed to RT. The reaction mixture was purified by chromatography on a Prep Gilson HPLC to yield ethyl 2-(2-oxopyrrolidin-1- yl)-4-(trifluoromethyl)oxazole-5-carboxylate (A-28) as a white solid (0.15 g, 34% yield). 1H NMR (500 MHz, CDCI3) delta 4.44 (m, 2H), 4.09 (t, 2H, J = 7.0 Hz), 2.69 (t, 2H1 J = 8.2 Hz), 2.28 (m, 2H), 2.42 (t, 3H, J = 7.3 Hz).
Step 1 : 2-Bromo-4-trifluoromethyloxazole-5-carboxylic acid (A-25)LiOH-H2O (0.64 g, 15.25 mmol) was added to a solution of ethyl 2-bromo-4- trifluoromethyloxazole-5-carboxylate (A-2) (3.50 g, 12.2 mmol) in THF/H2O (20/5 m L) at 0 0C followed by stirring for 3 h at 0 0C. The reaction mixture was diluted with EtOAc/H2O (25/25 mL) and neutralized with 1 M HCI (16 mL) at 0 0C. The organic phase was separated, dried over MgSO4, filtered, and concentrated. The product was dried in vacuo to yield 2-bromo-4- trifluoromethyloxazole-5-carboxylic acid (A-25) as a white solid (2.80 g, 88% yield).;
2-(3,5-dimethylpiperid in-1-yl)-4-trifluoromethyloxazole-5-carboxylic Acid (A-17) Intermediate A-17 was prepared by the general procedure for intermediate A-4, by using A-2 and 3,5-dimethylpiperidine as starting materials. MS (M+1): 293.
2-(3,4-dihydroisoquinolin-2(1H)-yl)-4-trifluoromethyloxazole-5-carboxylic Acid (A-21) Intermediate A-21 was prepared by the general procedure for intermediate A-4, by using A-2 and 1,2,3,4-tetrahydroisoquinoline as starting materials. MS (M+1): 313.
2-(3-hydroxypiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic Acid (A-26) Intermediate A-26 was prepared by the general procedure for intermediate A-4, by using A-2 and 3-hydroxypiperidine as starting materials. MS (M+1): 281.
2-(cyclohexyl(methyl)amino)-4-trifluoromethyloxazole-5-carboxylic Acid (A-34) Intermediate A-34 was prepared by the general procedure for intermediate A-4, by using A-2 and N-methylcyclohexylamine as starting materials. MS (M+1): 293.
2-(3,3-dimethylpiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic Acid (A-18) Intermediate A-18 was prepared by the general procedure for intermediate A-4, by using A-2 and 3,3-dimethylpiperidine as starting materials. MS (M+1): 293.
Step 1: Ethyl 2-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxylate (A-30) NaH (0.060 mg, 1.5 mmol) (60%) was added to a solution of 2-oxopyrrolidine (0.13 g, 1.5 mmol) in DMF (5.0 mL) at -78 C. followed by stirring for 15 mins at -78 C. Then <strong>[1227934-69-1]ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate</strong> A-2 (0.29 g, 1.0 mmol) was added. The reaction mixture was stirred for 3 h while the temperature was slowly warmed to RT. The reaction mixture was purified by chromatography on a Prep Gilson HPLC to yield ethyl 2-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)oxazole-5-carboxylate (A-30) as a white solid (0.15 g, 34% yield). 1H NMR (500 MHz, CDCl3) delta 4.44 (m, 2H), 4.09 (t, 2H, J=7.0 Hz), 2.69 (t, 2H, J=8.2 Hz), 2.28 (m, 2H), 2.42 (t, 3H, J=7.3 Hz).
2-(3-(trifluoromethyl)piperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic Acid (A-24) Intermediate A-24 was prepared by the general procedure for intermediate A-4, by using A-2 and 3-(trifluoromethyl)piperidine as starting materials. MS (M+1): 333.
2-(3-methoxypiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic Acid (A-27) Intermediate A-27 was prepared by the general procedure for intermediate A-4, by using A-2 and 3-methoxypiperidine as starting materials. MS (M+1): 295.
2-(3-fluoropiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic Acid (A-25) Intermediate A-25 was prepared by the general procedure for intermediate A-4, by using A-2 and 3-fluoropiperidine hydrochloride as starting materials with N,N-diisopropylethylamine. MS (M+1): 283.
2-(4-phenylpiperidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic Acid (A-22) Intermediate A-22 was prepared by the general procedure for intermediate A-4, by using A-2 and 4-phenylpiperidine as starting materials. MS (M+1): 341.
2-(cyclopentyl(methyl)amino)-4-trifluoromethyloxazole-5-carboxylic Acid (A-35) Intermediate A-35 was prepared by the general procedure for intermediate A-4, by using A-2 and N-methylcyclopentylamine as starting materials. MS (M+1): 279.
2-(3-methoxypyrrolidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic Acid (A-29) Intermediate A-29 was prepared by the general procedure for intermediate A-4, by using A-2 and 3-methoxypyrrolidine hydrochloride as starting materials with N,N-diisopropylethylamine. MS (M+1): 281.
2-(1,4-oxazepan-4-yl)-4-(trifluoromethyl)oxazole-5-carboxylic Acid (A-15) Intermediate A-15 was prepared by the general procedure for intermediate A-4, by using A-2 and homomorpholine hydrochloride as starting materials. LCMS (ESI) calcd for [M+1]+ 281.1. found 281.2.
2-(3-methylpyrrolidin-1-yl)-4-trifluoromethyloxazole-5-carboxylic Acid (A-28) Intermediate A-28 was prepared by the general procedure for intermediate A-4, by using A-2 and 3-methylpyrrolidine hydrochloride as starting materials with N,N-diisopropylethylamine. MS (M+1): 265.
ethyl 4-(trifluoromethyl)-2-(trimethylstannyl)oxazole-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); In toluene; at 100℃; for 16h;Inert atmosphere;
A mixture of <strong>[1227934-69-1]ethyl 2-bromo-4-(trifluoromethyl)oxazole-5-carboxylate</strong> (500 mg, 1.74 mmol, 1 eq), Me6Sn2 (626 mg, 3.48 mmol, 2 eq) and Pd(PPh3)4 (100 mg, 0.087 mmol, 0.05 eq) in toluene (10 mL) was heated at 100 C under nitrogen atmosphere for 16 h. After cooling to rt, the mixture was concentrated and the resulting residue was directly used in the next step.
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