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Chemical Structure| 367-28-2 Chemical Structure| 367-28-2

Structure of 367-28-2

Chemical Structure| 367-28-2

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Product Details of [ 367-28-2 ]

CAS No. :367-28-2
Formula : C6H3FO2
M.W : 126.09
SMILES Code : O=C(C=C1)C=C(F)C1=O
English Name :2-Fluoro-1,4-benzoquinone
MDL No. :MFCD09763691

Safety of [ 367-28-2 ]

Application In Synthesis of [ 367-28-2 ]

* 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.

  • Downstream synthetic route of [ 367-28-2 ]

[ 367-28-2 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 367-28-2 ]
  • [ 121623-97-0 ]
  • [ 2415180-16-2 ]
YieldReaction ConditionsOperation in experiment
40.5% With pyridine; titanium tetrachloride In dichloromethane at -78℃; for 16h; Inert atmosphere; Reflux; 1 Preparation of Formula 1: 21.4g of intermediate (2) and 1.26g of 2-fluorobenzoquinone were added to a 500ml flask. Add 250ml of dichloromethane to dissolve. At -78 ° C, add dropwise 11 ml of titanium tetrachloride, 8.2 ml of pyridine, Under nitrogen gas environment, reflux for 16h. The reaction was stopped by adding ice water. Extraction with dichloromethane and water, and finally passing the column with n-hexane and dichloromethane to obtain 2.1 g (yield 40.5%)
  • 2
  • [ 167683-93-4 ]
  • [ 367-28-2 ]
YieldReaction ConditionsOperation in experiment
90% With methanol; sulfuric acid; water In acetonitrile at 22℃; Electrolysis; Flow reactor;
  • 3
  • [ 367-28-2 ]
  • [ 1255666-48-8 ]
  • [ 141-97-9 ]
  • [ 131747-57-4 ]
  • [ 2776171-15-2 ]
  • [ 2776171-13-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (2-(trifluoromethyl)pyridin-3-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #3: tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate Overall yield = 1 g; Further stages; [0278] Step 5: To a pre-stirred solution of mixture of 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylic acid and 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylic acid (1.0 g, 2.71 mmol) and tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate (0.74 g, 3.25 mmol) in DMF (20 mL) was added DIPEA (1.45 mL, 8.13 mmol) followed by HATU (2.05 g, 5.42 mmol) at 0oC under an argon atmosphere. The RM was allowed to attain RT and stir for 16 h. The reaction progress was monitored by TLC. The RM was diluted with water (100 mL) and the organic compound was extracted with EtOAc (2 x 70 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography over silica using 0-55% EtOAc and pet-ether as an eluent to afford a mixture of tert-butyl 3,3-difluoro-4-(6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carbox- amido)piperidine-1-carboxylate and tert-butyl 3,3-difluoro-4-(7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxamido)piperidine-1-carboxylate (1.0 g, 62%).
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (2-(trifluoromethyl)pyridin-3-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #3: tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate Overall yield = 1 g; Further stages; [0278] Step 5: To a pre-stirred solution of mixture of 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylic acid and 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylic acid (1.0 g, 2.71 mmol) and tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate (0.74 g, 3.25 mmol) in DMF (20 mL) was added DIPEA (1.45 mL, 8.13 mmol) followed by HATU (2.05 g, 5.42 mmol) at 0oC under an argon atmosphere. The RM was allowed to attain RT and stir for 16 h. The reaction progress was monitored by TLC. The RM was diluted with water (100 mL) and the organic compound was extracted with EtOAc (2 x 70 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography over silica using 0-55% EtOAc and pet-ether as an eluent to afford a mixture of tert-butyl 3,3-difluoro-4-(6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carbox- amido)piperidine-1-carboxylate and tert-butyl 3,3-difluoro-4-(7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxamido)piperidine-1-carboxylate (1.0 g, 62%).
  • 4
  • [ 367-28-2 ]
  • [ 1255666-48-8 ]
  • [ 141-97-9 ]
  • [ 131747-57-4 ]
  • [ 2776164-27-1 ]
  • [ 2776163-03-0 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (2-(trifluoromethyl)pyridin-3-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #3: tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate Overall yield = 87 percent; Overall yield = 0.72 g; Further stages; [0279] Step 6: 4.0 M HCl in dioxane (13.62 mL, 13.62 mmol) was added dropwise to a pre-stirred solution of mixture of tert-butyl 4-(6-chloro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxamido)-3,3-difluoropiperidine-1-carboxylate and tert-butyl 4-(7-chloro-2-methyl-5-((2-(trifluoro-methyl)pyridin-3-yl)methoxy)benzofuran-3-carboxamido)-3,3-difluoropiperidine-1-carboxylate (1.0 g, 1.70 mmol) in DCM (15 mL) at 0°C. The RM was allowed to attain RT and stirred for 6 h. The reaction progress was monitored by TLC. The RM was concentrated under reduced pressure, the residue was basified with sat. NaHCO3 (100 mL) and the organic compound was extracted with 10% MeOH in DCM (3 x 50 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by GRACE flash chromatography using 0-60% acetonitrile and 0.1% FA in water as an eluent to afford a mixture cpd 113 and cpd 176 (0.72 g, 87%). A preparative chiral SFC was performed on the mixture of racemic cpd 113 and racemic cpd 176 to provide cpd 113 - En 1, cpd 113 - En 2, cpd 176 - En 1 and cpd 176 - En 2.
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (2-(trifluoromethyl)pyridin-3-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #3: tert-butyl 4-amino-3,3-difluoropiperidine-1-carboxylate Overall yield = 87 percent; Overall yield = 0.72 g; Further stages; [0279] Step 6: 4.0 M HCl in dioxane (13.62 mL, 13.62 mmol) was added dropwise to a pre-stirred solution of mixture of tert-butyl 4-(6-chloro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxamido)-3,3-difluoropiperidine-1-carboxylate and tert-butyl 4-(7-chloro-2-methyl-5-((2-(trifluoro-methyl)pyridin-3-yl)methoxy)benzofuran-3-carboxamido)-3,3-difluoropiperidine-1-carboxylate (1.0 g, 1.70 mmol) in DCM (15 mL) at 0°C. The RM was allowed to attain RT and stirred for 6 h. The reaction progress was monitored by TLC. The RM was concentrated under reduced pressure, the residue was basified with sat. NaHCO3 (100 mL) and the organic compound was extracted with 10% MeOH in DCM (3 x 50 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by GRACE flash chromatography using 0-60% acetonitrile and 0.1% FA in water as an eluent to afford a mixture cpd 113 and cpd 176 (0.72 g, 87%). A preparative chiral SFC was performed on the mixture of racemic cpd 113 and racemic cpd 176 to provide cpd 113 - En 1, cpd 113 - En 2, cpd 176 - En 1 and cpd 176 - En 2.
  • 5
  • [ 367-28-2 ]
  • [ 141-97-9 ]
  • [ 131747-57-4 ]
  • [ 2776171-07-2 ]
  • [ 2776170-98-8 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (2-(trifluoromethyl)pyridin-3-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; [0276] Step 3: (2-(Trifluoromethyl)pyridin-3-yl)methanol (1.11 g, 6.30 mmol), ADDP (1.48 g, 5.88 mmol) and tri-n-butylphosphine (1.38 mL, 5.88 mmol) were added sequentially to a pre-stirred solution of mixture of ethyl 6-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate and ethyl 7-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate (1.0 g, 4.20 mmol) in THF (30 mL) at RT under argon atmosphere. The RM was stirred for 2 h at the same temperature. The reaction progress was monitored by TLC. The RM was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was sequentially washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel using 0-20% EtOAc in pet-ether as an eluent to afford a mixture of ethyl 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylate and ethyl 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylate (1.1 g, 66%). The crude product was used for further step without purification.
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (2-(trifluoromethyl)pyridin-3-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; [0276] Step 3: (2-(Trifluoromethyl)pyridin-3-yl)methanol (1.11 g, 6.30 mmol), ADDP (1.48 g, 5.88 mmol) and tri-n-butylphosphine (1.38 mL, 5.88 mmol) were added sequentially to a pre-stirred solution of mixture of ethyl 6-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate and ethyl 7-fluoro-5-hydroxy-2-methylbenzofuran-3-carboxylate (1.0 g, 4.20 mmol) in THF (30 mL) at RT under argon atmosphere. The RM was stirred for 2 h at the same temperature. The reaction progress was monitored by TLC. The RM was poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was sequentially washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel using 0-20% EtOAc in pet-ether as an eluent to afford a mixture of ethyl 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylate and ethyl 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylate (1.1 g, 66%). The crude product was used for further step without purification.
  • 6
  • [ 367-28-2 ]
  • [ 141-97-9 ]
  • [ 131747-57-4 ]
  • [ 2776171-11-8 ]
  • [ 2776171-09-4 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (2-(trifluoromethyl)pyridin-3-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #3: With water; sodium hydroxide In tetrahydrofuran; methanol at 60℃; for 4h; Overall yield = 99 percent; Overall yield = 1 g; [0277] Step 4: A solution of NaOH (0.44 g, 11.08 mmol) in water (8 mL) was added dropwise to a pre-stirred solution of a mixture of ethyl 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylate and ethyl 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylate (1.1 g, 2.77 mmol) in a mixture of MeOH (15 mL) and THF (7 mL) at RT. The resulting RM was heated to 60oC and maintained for 4 h. The reaction progress was monitored by TLC. The RM was cooled to RT, poured into ice cold water (50 mL) and acidified with 1N HCl to a pH~2. The crude product was extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (50 mL) followed by brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a mixture of 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylic acid and 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylic acid (1.0 g, 99%). This crude product was used for next step without purification
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (2-(trifluoromethyl)pyridin-3-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #3: With water; sodium hydroxide In tetrahydrofuran; methanol at 60℃; for 4h; Overall yield = 99 percent; Overall yield = 1 g; [0277] Step 4: A solution of NaOH (0.44 g, 11.08 mmol) in water (8 mL) was added dropwise to a pre-stirred solution of a mixture of ethyl 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylate and ethyl 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylate (1.1 g, 2.77 mmol) in a mixture of MeOH (15 mL) and THF (7 mL) at RT. The resulting RM was heated to 60oC and maintained for 4 h. The reaction progress was monitored by TLC. The RM was cooled to RT, poured into ice cold water (50 mL) and acidified with 1N HCl to a pH~2. The crude product was extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (50 mL) followed by brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford a mixture of 6-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylic acid and 7-fluoro-2-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)methoxy)benzofuran-3-carboxylic acid (1.0 g, 99%). This crude product was used for next step without purification
  • 7
  • [ 1977-06-6 ]
  • [ 367-28-2 ]
  • [ 141-97-9 ]
  • [ 184698-41-7 ]
  • [ 2776171-41-4 ]
  • [ 2776171-40-3 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (4-methyl-1,3-thiazol-5-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; Stage #3: methyl 4-aminotetrahydro-2H-pyran-4-carboxylate Overall yield = 57 percent; Overall yield = 0.5 g; Further stages; [0295] Step 3: To a pre-stirred solution of a mixture of 6-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxylic acid and 7-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxylic acid (600 mg, 1.86 mmol), and methyl 4-aminotetrahydro-2H-pyran-4-carboxylate (0.356 g, 2.24 mmol) in DMF (10 mL) was added DIPEA (0.96 mL, 5.60 mmol) followed by HATU (1.41 g, 3.72 mmol) at 0oC under an argon atmosphere. The RM was allowed to attain RT and stirred for 16 h. The reaction progress was monitored by TLC. The RM was diluted with water (50 mL) and then the organic compound was extracted with EtOAc (2 x 50 mL), and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel using 0-55% EtOAc and pet ether as an eluent to afford a mixture of methyl 4-(6-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamido) tetrahydro-2H-pyran-4-carboxylate and methyl 4-(7-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamido)tetrahydro-2H-pyran-4-carboxylate (0.5 g, 57%)
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (4-methyl-1,3-thiazol-5-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; Stage #3: methyl 4-aminotetrahydro-2H-pyran-4-carboxylate Overall yield = 57 percent; Overall yield = 0.5 g; Further stages; [0295] Step 3: To a pre-stirred solution of a mixture of 6-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxylic acid and 7-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxylic acid (600 mg, 1.86 mmol), and methyl 4-aminotetrahydro-2H-pyran-4-carboxylate (0.356 g, 2.24 mmol) in DMF (10 mL) was added DIPEA (0.96 mL, 5.60 mmol) followed by HATU (1.41 g, 3.72 mmol) at 0oC under an argon atmosphere. The RM was allowed to attain RT and stirred for 16 h. The reaction progress was monitored by TLC. The RM was diluted with water (50 mL) and then the organic compound was extracted with EtOAc (2 x 50 mL), and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography over silica gel using 0-55% EtOAc and pet ether as an eluent to afford a mixture of methyl 4-(6-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamido) tetrahydro-2H-pyran-4-carboxylate and methyl 4-(7-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamido)tetrahydro-2H-pyran-4-carboxylate (0.5 g, 57%)
  • 8
  • [ 1977-06-6 ]
  • [ 367-28-2 ]
  • [ 141-97-9 ]
  • [ 184698-41-7 ]
  • [ 2776164-39-5 ]
  • [ 2776163-21-2 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (4-methyl-1,3-thiazol-5-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; Stage #3: methyl 4-aminotetrahydro-2H-pyran-4-carboxylate Overall yield = 59 percent; Overall yield = 0.28 g; Further stages; [0296] Step 4: NaBH4 (1.02 g , 27.05 mmol) was added portionwise to a pre-stirred solution of a mixture of methyl 4-(6-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamido) tetrahydro-2H-pyran-4-carboxylate and methyl 4-(7-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamido)tetrahydro-2H-pyran-4-carboxylate (0.5 g, 1.08 mmol) in a mixture of MeOH (10 mL) and THF (5 mL) at 0°C. The RM was allowed to attain RT and stirred for 16 h. The reaction progress was monitored by TLC. The RM was diluted with water (50 mL) and the organic compound was extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by GRACE flash chromatography using 0- 60% acetonitrile and 0.1% FA in water as an eluent to afford a mixture of cpd 122 and cpd 182 (0.28 g, 59%). A preparative chiral SFC was performed on a mixture of cpd 111 and 182 to provide cpd 122 and cpd 182.
Stage #1: 2-fluoro-1,4-benzoquinone; ethyl acetoacetate With zinc(II) chloride In toluene Inert atmosphere; Reflux; Dean-Stark; Stage #2: (4-methyl-1,3-thiazol-5-yl)methanol With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; Stage #3: methyl 4-aminotetrahydro-2H-pyran-4-carboxylate Overall yield = 59 percent; Overall yield = 0.28 g; Further stages; [0296] Step 4: NaBH4 (1.02 g , 27.05 mmol) was added portionwise to a pre-stirred solution of a mixture of methyl 4-(6-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamido) tetrahydro-2H-pyran-4-carboxylate and methyl 4-(7-fluoro-2-methyl-5-((4-methylthiazol-5-yl)methoxy)benzofuran-3-carboxamido)tetrahydro-2H-pyran-4-carboxylate (0.5 g, 1.08 mmol) in a mixture of MeOH (10 mL) and THF (5 mL) at 0°C. The RM was allowed to attain RT and stirred for 16 h. The reaction progress was monitored by TLC. The RM was diluted with water (50 mL) and the organic compound was extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by GRACE flash chromatography using 0- 60% acetonitrile and 0.1% FA in water as an eluent to afford a mixture of cpd 122 and cpd 182 (0.28 g, 59%). A preparative chiral SFC was performed on a mixture of cpd 111 and 182 to provide cpd 122 and cpd 182.
 

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