(2S)-2-methyloxan-4-one

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of a mixture of 2,5-dibromothiophene (1.9 g) and ethyl bromide (2.56 g) in THF (6 ml) was added dropwise to a stirred suspension of magnesium (0.29 g) in diethyl ether (3 ml) and the mixture was warmed gently to promote the formation of a Grignard Reagent. The mixture was heated to 40° C. for 1 hour. The mixture was cooled in an ice-bath and a solution of (2S)-2-methyltetrahydropyran-4-one [European Patent Application No. 0385662 (Example 20 thereof); 0.61 g] in THF (5 ml) was added dropwise. The mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using initially methylene chloride and then increasingly polar mixtures of methylene chloride and diethyl ether as eluent. There was thus obtained, as a less polar isomer, (2S,4R)-4-(5-bromothien-2-yl)-4-hydroxy-2-methyltetrahydropyran (0.248 g, 19%) as an oil, having the 2-methyl and 4-hydroxy groups in a trans-relationship. the mixture was warmed gently The mixture was cooled in an ice-bath to warm to ambient temperature extracted with ethyl acetate The organic phase was washed with water and with brine dried (MgSO4) evaporated The residue was purified by column chromatography increasingly polar mixtures of methylene chloride and diethyl ether as eluent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1,2-dibromoethane (5 g) in diethyl ether (10 ml) was added to a stirred suspension of magnesium (3 g) in diethyl ether (10 ml) to initiate the formation of a Grignard reagent. A mixture of 1,2-dibromoethane (16.7 g) and 3-bromothiophene (4 g) in diethyl ether (30 ml) was added dropwise. The mixture was stirred and heated to reflux for 2 hours. A solution of (2S)-2-methyltetrahydropyran-4-one (2 g) in diethyl ether (5 ml) was added and the mixture was heated to reflux for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 7:3 mixture of petroleum ether and ethyl acetate as eluent. There were thus obtained in turn (2S,4R)-4-hydroxy-2-methyl-4-(3-thienyl)tetrahydropyran (0.685 g, 18.5%) and the corresponding (2S,4S)-isomer (1 g, 32%). was added dropwise heated to reflux for 2 hours the mixture was heated to reflux for 1 hour The mixture was partitioned between ethyl acetate and water The organic phase was dried (MgSO4) evaporated The residue was purified by column chromatography a 7:3 mixture of petroleum ether and ethyl acetate as eluent

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of a mixture of 2,5-dibromothiophene (1.9 g) and ethyl bromide (2.56 g) in THF (6 ml) was added dropwise to a stirred suspension of magnesium (0.29 g) in diethyl ether (3 ml) and the mixture was warmed gently to promote the formation of a Grignard Reagent. The mixture was heated to 40° C. for 1 hour. The mixture was cooled in an ice-bath and a solution of (2S)-2-methyltetrahydropyran-4-one [European Patent Application No. 0385662 (Example 20 thereof); 0.61 g] in THF (5 ml) was added dropwise. The mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using initially methylene chloride and then increasingly polar mixtures of methylene chloride and diethyl ether as eluent. There was thus obtained, as a less polar isomer, (2S,4R)-4-(5-bromothien-2-yl)-4-hydroxy-2-methyltetrahydropyran (0.248 g, 19%) as an oil, having the 2-methyl and 4-hydroxy groups in a trans-relationship. the mixture was warmed gently The mixture was cooled in an ice-bath to warm to ambient temperature extracted with ethyl acetate The organic phase was washed with water and with brine dried (MgSO4) evaporated The residue was purified by column chromatography increasingly polar mixtures of methylene chloride and diethyl ether as eluent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1,2-dibromoethane (5 g) in diethyl ether (10 ml) was added to a stirred suspension of magnesium (3 g) in diethyl ether (10 ml) to initiate the formation of a Grignard reagent. A mixture of 1,2-dibromoethane (16.7 g) and 3-bromothiophene (4 g) in diethyl ether (30 ml) was added dropwise. The mixture was stirred and heated to reflux for 2 hours. A solution of (2S)-2-methyltetrahydropyran-4-one (2 g) in diethyl ether (5 ml) was added and the mixture was heated to reflux for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 7:3 mixture of petroleum ether and ethyl acetate as eluent. There were thus obtained in turn (2S,4R)-4-hydroxy-2-methyl-4-(3-thienyl)tetrahydropyran (0.685 g, 18.5%) and the corresponding (2S,4S)-isomer (1 g, 32%). was added dropwise heated to reflux for 2 hours the mixture was heated to reflux for 1 hour The mixture was partitioned between ethyl acetate and water The organic phase was dried (MgSO4) evaporated The residue was purified by column chromatography a 7:3 mixture of petroleum ether and ethyl acetate as eluent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using an analogous procedure to that described in the portion of Example 6 which is concerned with the preparation of starting materials, 1,3-dibromobenzene was reacted with (2S)-2-methyltetrahydropyran-4-one to give (2S,4R)-4-hydroxy-4-(3-bromophenyl)-2-methyltetrahydropyran in 66% yield as an oil.

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: n-Butyl-lithium (2.5M in hexane, 57.5 ml) was dropwise added during 30 minutes to a solution of di-isopropylamine (19.3 ml) in THF (180 ml) which had been cooled to -78° C. The mixture was stirred at -78° C. for 1 hour. The reaction vessel was shielded from light and 2-chlorothiazole (15.0 g) was added dropwise during 20 minutes, whilst keeping the temperature of the reaction mixture below -70° C. The mixture was stirred at -78° C. for 1.5 hours. (2S)-2-Methyltetrahydropyran-4-one (12.9 g) was added during 20 minutes. The mixture was stirred and allowed to warm briefly to -25° C. to obtain a homogeneous solution. The mixture was recooled to -70° C. and stirred at that temperature for 1 hour. A 5% aqueous solution of ammonium chloride was added and the mixture was extracted with diethyl ether. The organic solution was washed with brine, dried (MgSO4) and evaporated. There was thus obtained a mixture (29.4 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 1:4. The mixture so obtained was dissolved in diethyl ether (250 ml) and the solution was cooled to 0° C. A concentrated (25% v/v) aqueous solution of sulphuric acid was added and the mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate (750 ml) and neutralised to pH3 by the addition of sodium bicarbonate. The organic solution was washed with brine, dried (MgSO4) and evaporated to give a mixture (26 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 9:1. The material was purified by column chromatography using a 1:1 mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluent. There was thus obtained (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran (21 g, 79%). was added dropwise during 20 minutes the temperature of the reaction mixture below -70° C The mixture was stirred at -78° C. for 1.5 hours The mixture was stirred to warm briefly to -25° C. to obtain a homogeneous solution was recooled to -70° C. stirred at that temperature for 1 hour the mixture was extracted with diethyl ether The organic solution was washed with brine dried (MgSO4) evaporated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: n-Butyl-lithium (2.5M in hexane, 57.5 ml) was dropwise added during 30 minutes to a solution of di-isopropylamine (19.3 ml) in THF (180 ml) which had been cooled to -78° C. The mixture was stirred at -78° C. for 1 hour. The reaction vessel was shielded from light and 2-chlorothiazole (15.0 g) was added dropwise during 20 minutes, whilst keeping the temperature of the reaction mixture below -70° C. The mixture was stirred at -78° C. for 1.5 hours. (2S)-2-Methyltetrahydropyran-4-one (12.9 g) was added during 20 minutes. The mixture was stirred and allowed to warm briefly to -25° C. to obtain a homogeneous solution. The mixture was recooled to -70° C. and stirred at that temperature for 1 hour. A 5% aqueous solution of ammonium chloride was added and the mixture was extracted with diethyl ether. The organic solution was washed with brine, dried (MgSO4) and evaporated. There was thus obtained a mixture (29.4 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 1:4. The mixture so obtained was dissolved in diethyl ether (250 ml) and the solution was cooled to 0° C. A concentrated (25% v/v) aqueous solution of sulphuric acid was added and the mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate (750 ml) and neutralised to pH3 by the addition of sodium bicarbonate. The organic solution was washed with brine, dried (MgSO4) and evaporated to give a mixture (26 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 9:1. The material was purified by column chromatography using a 1:1 mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluent. There was thus obtained (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran (21 g, 79%). was added dropwise during 20 minutes the temperature of the reaction mixture below -70° C The mixture was stirred at -78° C. for 1.5 hours The mixture was stirred to warm briefly to -25° C. to obtain a homogeneous solution was recooled to -70° C. stirred at that temperature for 1 hour the mixture was extracted with diethyl ether The organic solution was washed with brine dried (MgSO4) evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1,2-dibromoethane (5 g) in diethyl ether (10 ml) was added to a stirred suspension of magnesium (3 g) in diethyl ether (10 ml) to initiate the formation of a Grignard reagent. A mixture of 1,2-dibromoethane (16.7 g) and 3-bromothiophene (4 g) in diethyl ether (30 ml) was added dropwise. The mixture was stirred and heated to reflux for 2 hours. A solution of (2S)-2-methyltetrahydropyran-4-one (2 g) in diethyl ether (5 ml) was added and the mixture was heated to reflux for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 7:3 mixture of petroleum ether and ethyl acetate as eluent. There were thus obtained in turn (2S,4R)-4-hydroxy-2-methyl-4-(3-thienyl)tetrahydropyran (0.685 g, 18.5%) and the corresponding (2S,4S)-isomer (1 g, 32%). was added dropwise heated to reflux for 2 hours the mixture was heated to reflux for 1 hour The mixture was partitioned between ethyl acetate and water The organic phase was dried (MgSO4) evaporated The residue was purified by column chromatography a 7:3 mixture of petroleum ether and ethyl acetate as eluent

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Using an analogous procedure to that described in the portion of Example 6 which is concerned with the preparation of starting materials, 1,3-dibromobenzene was reacted with (2S)-2-methyltetrahydropyran-4-one to give (2S,4R)-4-hydroxy-4-(3-bromophenyl)-2-methyltetrahydropyran in 66% yield as an oil.

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of a mixture of 2,5-dibromothiophene (1.9 g) and ethyl bromide (2.56 g) in THF (6 ml) was added dropwise to a stirred suspension of magnesium (0.29 g) in diethyl ether (3 ml) and the mixture was warmed gently to promote the formation of a Grignard Reagent. The mixture was heated to 40° C. for 1 hour. The mixture was cooled in an ice-bath and a solution of (2S)-2-methyltetrahydropyran-4-one [European Patent Application No. 0385662 (Example 20 thereof); 0.61 g] in THF (5 ml) was added dropwise. The mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated. The residue vas purified by column chromatography using initially methylene chloride and then increasingly polar mixtures of methylene chloride and diethyl ether as eluent. There was thus obtained, as a less polar isomer, (2S,4R)-4-(5-bromothien-2-yl)-4-hydroxy-2-methyltetrahydropyran (0.248 g, 19%) as an oil, having the 2-methyl and 4-hydroxy groups in a trans-relationship. the mixture was warmed gently The mixture was cooled in an ice-bath to warm to ambient temperature extracted with ethyl acetate The organic phase was washed with water and with brine dried (MgSO4) evaporated The residue vas purified by column chromatography increasingly polar mixtures of methylene chloride and diethyl ether as eluent

反応条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of a mixture of 2,5-dibromothiophene (1.9 g) and ethyl bromide (2.56 g) in THF (6 ml) was added dropwise to a stirred suspension of magnesium (0.29 g) in diethyl ether (3 ml) and the mixture was warmed gently to promote the formation of a Grignard Reagent. The mixture was heated to 40° C. for 1 hour. The mixture was cooled in an ice-bath and a solution of (2S)-2-methyltetrahydropyran-4-one [European Patent Application No. 0385662 (Example 20 thereof); 0.61 g] in THF (5 ml) was added dropwise. The mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography using initially methylene chloride and then increasingly polar mixtures of methylene chloride and diethyl ether as eluent. There was thus obtained, as a less polar isomer, (2S,4R)-4-(5-bromothien-2-yl)-4-hydroxy-2-methyltetrahydropyran (0.248 g, 19%) as an oil, having the 2-methyl and 4-hydroxy groups in a trans-relationship. the mixture was warmed gently The mixture was cooled in an ice-bath to warm to ambient temperature extracted with ethyl acetate The organic phase was washed with water and with brine dried (MgSO4) evaporated The residue was purified by column chromatography increasingly polar mixtures of methylene chloride and diethyl ether as eluent

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of (methoxymethyl)triphenyl phosphine chloride (32 g) in anhydrous THF (160 ml), cooled to −10° C., was added dropwise sodium bis(trimethylsilyl) amide (46.7 ml of 2M solution in THF). The reaction mixture was stirred for 1 hour and then a solution of (2S)-2-methyltetrahydro-4H-pyran-4-one (7.1 g) in anhydrous THF (20 ml) was added over 5 minutes. The resulting mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with water (50 ml) and extracted with diethyl ether (3×100 ml). The organics were dried and evaporated to dryness. The resulting gum was treated with diethyl ether and filtered. The organics were evaporated to dryness and the resulting residue was purified by chromatography on silica eluting with ethyl acetate/isohexane (1:9) to give the title compound (˜1:1 E/Z mixture of isomers) as an oil. Yield 6.22 g. NMR CDCl3 1.1 (dd, 3H), 1.45-2.1 (m, 3H), 2.4-2.55 (m, 1H), 3.2 (m, 2H), 3.4 (s, 3H), 3.85 (m, 1H) 5.7 (m, 1H). to warm to room temperature stirred for 3 hours The reaction was quenched with water (50 ml) extracted with diethyl ether (3×100 ml) The organics were dried evaporated to dryness The resulting gum was treated with diethyl ether filtered The organics were evaporated to dryness the resulting residue was purified by chromatography on silica eluting with ethyl acetate/isohexane (1:9)