JP3503451B2 - Process for producing oxazolidine-2-one derivative - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to oxazolidine-2-, which is useful as an intermediate for the synthesis of HIV protease inhibitors.
The present invention relates to a method for producing an on derivative, an intermediate thereof, and a method of producing the intermediate.

[0002]

2. Description of the Related Art Oxazolidin-2-one derivatives are HI
It is known as an important synthetic intermediate for the synthesis of V protease inhibitors. As the method for producing this synthetic intermediate, (a) a method of heterocoupling an aminoaldehyde derivative and formaldehyde using low-valent titanium
(PCT publication: WO95-08530), (b) N-
Method for synthesis using iodocyclocarbamation of (benzyloxycarbonyl) allylamine derivative (T
etrahedron Lett., 25, 5079 (1
992)) and the like.

[0003]

However, these manufacturing methods have the following problems. That is, in the method (a) of heterocoupling the aminoaldehyde derivative and formaldehyde using low-valent titanium, the titanium compound is difficult to handle and an expensive reagent must be used in an equivalent amount. The method (ii) for synthesizing N- (benzyloxycarbonyl) allylamine derivative using iodocyclocarbamation uses expensive reagents and requires a multi-step process.

[0004]

As a result of various investigations by the present inventors in order to solve the above problems, the oxazolidin-2-one derivative was produced by using 3-hydroxy-γ-butyrolactone as a raw material. The inventors have found that it is possible and have completed the present invention. The present invention relates to a method for producing an oxazolidin-2-one derivative useful for the synthesis of an HIV protease inhibitor, a novel intermediate thereof and a method for producing the intermediate. The production process of the oxazolidin-2-one derivative (4) of the present invention is shown below.

[Chemical 25] (In the above formulas, R is an alkyl group having 1 to 6 carbon atoms, 3 to 6
It means a cycloalkyl group, an aralkyl group or a 2-alkenyl group forming a member ring, and R ′ means an amino group, a hydrazino group, a hydroxyamino group or an azido group. )

In the production method of the present invention, 3-hydroxy-γ-butyrolactone of the formula (1) described below is converted to a dianion in the presence of a base and then reacted with an alkylating agent to give the compound represented by the formula (2). A compound is obtained. As the base used, sodium hydride, potassium hydride, n-butyllithium, sec-butyllithium, t-butyllithium, lithium diisopropylamide, lithium 2,2,6,6-
Examples thereof include tetramethylpiperidide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, and the like. The amount of base used is 2 to 4 equivalents relative to the substrate. Examples of the alkylating agent to be used include an alkyl halide having 1 to 6 carbon atoms, a cycloalkyl halide forming a 3 to 6 membered ring, an aralkyl halide, and a 2-alkenyl halide, and specifically, benzyl chloride, allyl chloride, Chloride reagents such as methallyl chloride, methyl chloride, isopropyl chloride, cyclohexyl chloride, benzyl bromide,
Bromide reagents such as allyl bromide, methallyl bromide, methyl bromide, isopropyl bromide and cyclohexyl bromide, and iodide reagents such as benzyl iodide, allyl iodide, methallyl iodide, methyl iodide, isopropyl iodide and cyclohexyl iodide. .
Preferred alkylating agents are benzyl chloride, benzyl bromide, benzyl iodide. The amount used is 1 to 4 equivalents with respect to the substrate.

As the solvent to be used, aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane,
Examples thereof include ether solvents such as 1,2-dimethoxyethane, diglyme, triglyme and diethylene glycol monomethyl ether, halogen solvents such as dichloromethane and 1,2-dichloroethane, and mixed solvents thereof. The reaction temperature is from -100 ° C to the reflux temperature of the solvent, preferably -78 ° C to room temperature. In this reaction, the coexistence of hexamethylphosphoamide, hexamethylphosphoric triamide, 1,3-dimethyl-2-imidazolidinone, tetramethylethylenediamine, etc. promotes the reaction. The addition amount is 1 to 20 equivalents, preferably 2 to 10 equivalents, relative to the substrate.

By reacting the obtained compound represented by the formula (2) with a nitrogen-based nucleophile by a conventional method, a novel diol represented by the formula (3) is obtained. The nitrogen-based nucleophile used is ammonia gas, aqueous ammonia, liquid ammonia,
Examples thereof include metal azide, hydrazine and hydroxylamine. It is used in 1 equivalent or more with respect to the substrate. When the nitrogen-based nucleophile is ammonia gas, aqueous ammonia, or liquid ammonia, an aprotic polar solvent such as N, N-dimethylformamide or dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme , Triglyme, an ether solvent such as diethylene glycol monomethyl ether, a nitrile solvent such as acetonitrile, a halogen solvent such as dichloromethane and 1,2-dichloroethane, liquid ammonia, an aqueous medium, and a mixed solvent thereof. When the nitrogen-based nucleophile is a metal azide, hydrazine or hydroxylamine,
Examples of the solvent used include aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide,
Tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme, ether solvents such as diethylene glycol monomethyl ether, nitrile solvents such as acetonitrile, dichloromethane,
Halogen-based solvent such as 1,2-dichloroethane, aqueous medium,
And mixed solvents thereof. The reaction temperature is −
From 100 ° C to the reflux temperature of the solvent, preferably -78
C to room temperature. This reaction proceeds even without additives, but the reaction proceeds smoothly by adding an aluminum compound such as trimethylaluminum and triethylaluminum, and a zinc compound such as dimethylzinc and diethylzinc. The addition amount is 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to the substrate.

By subjecting the obtained diol represented by the formula (3) to a rearrangement reaction, an oxazolidin-2-one derivative represented by the formula (4) is obtained. As a reagent used for this rearrangement reaction, when R ′ is an amino group, sodium hypochlorite, sodium hypobromite, iodosobenzene, hydroxytosyloxyiodobenzene, bistrifluoroacetoxyiodobenzene, N-bromosuccinic acid Examples thereof include imide and N-chlorosuccinimide. Preferably, hydroxytosyloxyiodobenzene, bistrifluoroacetoxyiodobenzene, N-
Bromosuccinimide is used. When R'is an azido group, the reaction proceeds by heating in the following solvent. When R'is a hydroxyamino group, the rearrangement reaction proceeds by converting the hydroxyl group into a leaving group. Examples of the reagent converting into a leaving group include aryl or alkylsulfonyl halide compounds such as paratoluenesulfonyl chloride and methanesulfonyl chloride, and acyl halide compounds such as benzoyl chloride and acetyl chloride.

When R'is a hydrazino group, sodium nitrite and the like can be mentioned. The amount of these reagents used is 1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to the substrate. Examples of the solvent used include hydrocarbon solvents such as hexane, benzene and toluene, aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide,
Ester-based solvents such as ethyl acetate and butyl acetate, tetrahydrofuran, ether solvents such as 1,4-dioxane, 1,2-dimethoxyethane, diglyme, triglyme and diethylene glycol monomethyl ether, acetone,
Examples thereof include ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone, nitrile solvents such as acetonitrile, halogen solvents such as dichloromethane and 1,2-dichloroethane, aqueous media, and mixed solvents thereof. In this rearrangement reaction, depending on the conditions, the following formula

[Chemical formula 26] In some cases, a compound represented by the formula (wherein R has the same meaning as described above) can be obtained.

Further, oxazolidine-represented by the formula (4)
The 2-one derivative can also be produced from the compound represented by the formula (3) by another method. The reaction process diagram is as follows.

[Chemical 27] (In the above formulas, R ¹ and R ² denotes the same or different and each represents a hydrogen atom, an alkyl group or a phenyl group, and R ¹
And R ² may form a cycloalkyl ring via the carbon atom to which they are attached, and R and R ′ have the same meanings as given above. )

That is, a diol represented by the formula (3) is reacted with an acetalizing agent in the presence of an acid catalyst by a conventional method to obtain a compound represented by the formula (6). Examples of acetalizing agents used include ketone-based reagents such as acetone, diethyl ketone, benzophenone, and cyclohexanone, aldehyde reagents such as formaldehyde, acetaldehyde, and benzaldehyde, 2,2-dimethoxypropane, 2,2-
Examples thereof include dialkoxy acetal-based reagents of ketones such as dimethoxypentane and enol-ether-based reagents of ketones such as 2-methoxypropene. Acetone, 2,2-dimethoxypropane and 2-methoxypropane are preferred. Examples of the acid catalyst to be used include organic acids such as paratoluenesulfonic acid, pyridinium paratoluenesulfonate and camphorsulfonic acid, mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and Lewis acids such as boron trifluoride. The amount of the acid catalyst is 0.05 to 0.5 based on the compound represented by the formula (3).
It is 1 equivalent. Examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, halogen solvents such as dichloromethane and 1,2-dichloroethane, aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide, and These mixed solvents etc. are mentioned. Further, the acetalizing agent may be used in excess and may also serve as a solvent.

By subjecting the obtained compound represented by the formula (6) to a rearrangement reaction, an oxazolidin-2-one derivative represented by the formula (4) is obtained. As the reagent used in this rearrangement reaction, when R ′ is an amino group, sodium hypochlorite, sodium hypobromite, iodosobenzene, hydroxytosyloxyiodobenzene, bistrifluoroacetoxyiodobenzene, N-bromosuccinic acid Examples thereof include acid imides and N-chlorosuccinimides, with preference given to hydroxytosyloxyiodobenzene, bistrifluoroacetoxyiodobenzene and N-bromosuccinimide.

When R'is an azido group, the reaction proceeds by heating in the following solvent. When R'is a hydroxyamino group, the rearrangement reaction proceeds by converting the hydroxyl group into a leaving group. As a reagent for converting into a leaving group,
Examples thereof include sulfonyl halide compounds such as paratoluenesulfonyl chloride and methanesulfonyl chloride, and acyl halide compounds such as benzoyl chloride and acetyl chloride. When R'is a hydrazide group, sodium nitrite and the like can be mentioned. The amount used is 1 for the substrate
˜2 equivalents, preferably 1 to 1.5 equivalents. As the solvent used for the above rearrangement or heating reaction, hexane,
Hydrocarbon solvents such as benzene and toluene, aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide, ester solvents such as ethyl acetate and butyl acetate, tetrahydrofuran, 1,4-dioxane and 1,2
-Dimethoxyethane, diglyme, triglyme, ether solvents such as diethylene glycol monomethyl ether, acetone, methyl ethyl ketone, ketone solvents such as methyl isobutyl ketone, nitrile solvents such as acetonitrile, dichloromethane, halogen solvents such as 1,2-dichloroethane, Examples thereof include an aqueous medium, a mixed solvent thereof, and the like. Even in this rearrangement reaction, depending on the conditions, the compound represented by the above formula (5) or the following formula

[Chemical 28] (In the formula, R ¹ and R ² have the same meanings as described above, and R and R ′ have the same meanings as described above.) In some cases, a compound represented by the above can be obtained.

3-hydroxy-γ used as a raw material
-Butyrolactone or an intermediate compound (2) is an optically active compound, an optically active compound (3), and if these raw materials or an intermediate is an optically active compound, an optically active oxazolidin-2-one The derivative (4) can be synthesized. According to the method of the present invention, S-form 3-hydroxy-γ
-If butyrolactone is used, the (2S, 3S) oxazolidin-2-one derivative is preferentially obtained, and the R isomer 3
If 2-hydroxy-γ-butyrolactone is used (2R,
The 3R) oxazolidin-2-one derivative is preferentially obtained. When 3-hydroxy-γ-butyrolactone having a high optical purity is used, a remarkable racemization reaction does not occur during the reaction, and an oxazolidin-2-one derivative having a high optical purity can be synthesized. The same applies to the case of other intermediates.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described below with reference to examples, but the present invention is not limited thereto.

Example 1 (2S, 3S) -2-benzyl-3-hydroxy-γ-
Synthesis of butyrolactone

[Chemical 29] Under an argon atmosphere, tetrahydrofuran (THF) (30
ml) with diisopropylamine (5.49 ml, 39.18)
mmol), 1.6M n-butyllithium hexane solution
(24.49 ml, 39.18 mmol) was added at 0 ° C., and 1
After stirring for 5 minutes, it was cooled to -78 ° C. afterwards,
(S) -3-Hydroxy-γ-butyrolactone (1 g, 9.
794 mmol) in THF (20 ml) was added, and -7
After stirring at 8 ° C for 30 minutes, benzyl bromide (4.66m
1, 39.18 mmol) and hexamethylsulfoamide (HMPA) (9.8 ml) in THF (20 ml) were added dropwise. After gradually raising the temperature and stirring at about −45 ° C. for 4 hours, saturated ammonium chloride aqueous solution was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated saline, and then with magnesium sulfate. After drying, it was concentrated under reduced pressure. By purifying the residue by silica gel chromatography (2S, 3S)
-2-benzyl-3-hydroxy-γ-butyrolactone
(1.047 g, 55%) was obtained. mp 90.0-91.0 ° C ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.05 (1H, d, J = 309 H
z), 2.81-2.88 (2H, m), 3.18-3.25 (1H, m), 4.01 (1
H, dd, J = 9.8, 4.9 Hz), 4.22 (1H, dd, J = 9.8, 6.1H
z), 4.35-4.40 (1H, m), 7.21-7.38 (5H, m) ¹³ CNMR (100 MHz, CDCl ₃ ) δ: 34.1, 50.0, 71.4, 72.
5, 127.2, 128.9, 129.0,137.2, 177.0 IR (KBr) 3424, 1746 cm ^-1 Optical rotation: [α] _D ^22.5 +18.2 (c = 1.24, CHCl ₃ ).

(2S, 3S) -2-benzyl-3,4-
Synthesis of dihydroxybutyramide

[Chemical 30] After bubbling liquid ammonia into a solution of (2S, 3S) -2-benzyl-3-hydroxy-γ-butyrolactone (500 mg, 2.601 mmol) in anhydrous methylene chloride (8 ml) at -78 ° C for a few minutes. Warm up to room temperature and add trimethylaluminum hexane solution (2.01 ml, 2.
861 mmol) was added. After stirring for 24 hours, 0.1N
A small amount of hydrochloric acid was added to neutralize, filtered through Celite, and concentrated under reduced pressure. By purifying the residue by silica gel chromatography
(2S, 3S) -2-Benzyl-3,4-dihydroxybutyramide (349 mg, 64%) was obtained. mp 103.0-105.0 ° C ¹ H NMR (400 MHz, CD ₃ OD) δ: 2.63 (1H, ddd, J = 11.2,
8.3, 3.7 Hz), 2.83 (1H, dd, J = 13.4, 11.2 Hz), 3.1
2 (1H, dd, J = 13.4, 3.7 Hz), 3.48 (1H, dd, J = 11.5,
7.1 Hz), 3.65 (1H, dd, J = 11.5, 3.4 Hz), 3.74 (1H,
ddd, J = 8.3, 7.1,3.4 Hz), 7.12-7.26 (5H, m) ¹³ CNMR (100 MHz, CD ₃ OD) δ: 36.0, 53.3, 65.5, 74.1,
127.1, 129.3, 130.1, 141.1, 178.5 IR (KBr) 3384, 1648 cm ^-1 Optical rotation: [α] _D ^22.5 -41.2 ° (c = 0.85, CHCl
₃ )

Synthesis of (4S, 5S) -4-benzyl-5-hydroxymethyloxazolidin-2-one Bistrifluoroacetoxyiodobenzene in a mixed solvent of acetonitrile (0.31 ml) and water (0.31 ml).
(133 mg, 0.308 mmol) was dissolved, followed by (2
S, 3S) -2-Benzyl-3,4-dihydroxybutyramide (43 mg, 0.205 mmol) was added, the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the residue by silica gel chromatography
(4S, 5S) -4-Benzyl-5-hydroxymethyloxazolidin-2-one (28 mg, 65%) was obtained. mp 158.0-159.0 ° C ¹ H NMR (400 MHz, CD ₃ OD) δ: 2.79 (1H, dd, J = 13.7,
10.0 Hz), 3.01 (1H, dd, J = 13.7, 4.6 Hz), 3.84-3.86
(2H, m), 4.24 (1H, ddd, J = 10.0, 8.1, 4.6 Hz), 4.6
9 (1H, ddd, J = 8.1, 5.9, 4.6 Hz), 7.20-7.37 (5H, m) ¹³ CNMR (100 MHz, CD ₃ OD) δ: 37.0, 57.2, 61.0, 81.
2, 127.8, 129.8, 130.1, 139.0, 161.4 IR (KBr) 3348, 3264, 1728 cm ^-1 Optical rotation: [α] _D ^22.5 -67.2 ° (c = 1.33, CHCl ₃ ).

Example 2 Synthesis of (2S, 3S) -2-benzyl-3,4-dihydroxybutylhydrazide

[Chemical 31] (2S, 3S) -2-benzyl-3-obtained in Example 1
Hydroxy-γ-butyrolactone (147 mg, 0.76)
5 mmol of 1,2-dimethoxyethane (DME) (2 ml)
Hydrazine monohydrate (0.055 ml,
1.148 mmol) was added. After stirring for 6 hours, the solvent was evaporated, and the residue was purified by silica gel chromatography to obtain (2S, 3S) -2-benzyl-3,4-dihydroxybutylhydrazide (122 mg, 71%). mp 137.2-142.5 ° C ¹ H NMR (400 MHz, CD ₃ OD) δ: 2.51 (1H, ddd, J = 11.6,
8.6, 3.6 Hz), 2.83 (1H, dd, J = 13.5, 11.6 Hz), 3.1
2 (1H, dd, J = 13.5, 3.6 Hz), 3.48 (1H, dd, J = 11.5,
7.1 Hz), 3.58 (1H, dd, J = 11.5, 2.9 Hz), 3.74 (1H,
ddd, J = 8.6, 7.1,2.9 Hz), 7.10-7.25 (5H, m) ¹³ CNMR (100 MHz, CD ₃ OD) δ: 36.0, 52.2, 65.4, 74.
0, 127.0, 129.1, 129.8,140.8, 174.2 IR (KBr) 3496, 3316, 1624 cm ^-1 Optical rotation: [α] _D ²⁰ -68.7 ° (c = 1, MeOH)

Synthesis of (4S, 5S) -4-benzyl-5-hydroxymethyloxazolidin-2-one

[Chemical 32] DM (2S, 3S) -2-benzyl-3,4-dihydroxybutylhydrazide (50 mg, 0.223 mmol) was added to DM.
It was dissolved in a mixed solvent of E (1 ml) and water (1 ml), cooled to 0 ° C., and sodium nitrite (23 mg, 0.334 mmo).
1), followed by 2N aqueous hydrochloric acid solution (0.05 ml). 1
After heating to 00 ° C. and reacting for 4 hours, it was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the residue by silica gel chromatography (4S, 5S) -4
-Benzyl-5-hydroxymethyloxazolidine-2
-On (22 mg, 48%) was obtained.

Example 3 Synthesis of (4S, 5S) -4-benzyl-5-hydroxymethyloxazolidin-2-one

[Chemical 33] (2S, 3S) -2-benzyl-3-obtained in Example 1
Hydroxy-γ-butyrolactone (147 mg, 0.76)
A 50% aqueous solution of hydroxylamine was added to a solution of 5 mmol of DME (2 ml) at room temperature. After stirring for 3 hours, the solvent was distilled off to obtain a crude product of (2S, 3S) -2-benzyl-3,4-dihydroxybutylhydroxamic acid. Subsequently, the crude product was dissolved in acrylonitrile (1 ml),
After cooling to ℃, triethylamine (0.11 ml, 0.79)
mmol), paratoluenesulfonyl chloride (75 m
g, 0.395 mmol) was added. After warming to room temperature and stirring for 1 hour, the solvent was distilled off and ethyl acetate and water were added for extraction. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the residue by silica gel chromatography, (4S, 5S) -4-benzyl-
5-Hydroxymethyloxazolidin-2-one (39
Yield mg, 47% (two steps).

Example 4 Synthesis of (2S, 3S) -2-methyl-3-hydroxy-γ-butyrolactone

[Chemical 34] Diisopropylamine (5.49 ml, 39.18 mmol), 1.6 M n in THF (30 ml) under argon atmosphere.
-Butyl lithium hexane solution (24.49 ml, 39.
18 mmol) at 0 ° C. and stirred for 15 minutes,
Cooled to 78 ° C. Then, (S) -3-hydroxy-
TH of γ-butyrolactone (1 g, 9.794 mmol)
A solution of F (20 ml) was added, and the mixture was stirred at -78 ° C for 30 minutes, and then a solution of methyl iodide (2.44 ml, 39.18 mmol) and HMPA (9.8 ml) in THF (20 ml) was added dropwise. After gradually raising the temperature and stirring at about −45 ° C. for 4 hours, a saturated aqueous solution of ammonium chloride was added at the same temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated saline, and then with magnesium sulfate. After drying, it was concentrated under reduced pressure. By purifying the residue by silica gel chromatography (2S, 3S)-
2-methyl-3-hydroxy-γ-butyrolactone (0.
591 g, 52%) was obtained.

Synthesis of (2S, 3S) -2-methyl-3,4-dihydroxybutyramide

[Chemical 35] After bubbling liquid ammonia into a solution of (2S, 3S) -2-methyl-3-hydroxy-γ-butyrolactone (591 mg, 5.093 mmol) in anhydrous methylene chloride (15 ml) at −78 ° C. for a few minutes. Warm up to room temperature and add trimethylaluminum hexane solution (3.9 ml, 5.6
02 mmol) was added. After stirring for 24 hours, a small amount of 0.1N hydrochloric acid was added to neutralize, filtered through Celite, and concentrated under reduced pressure. By purifying the residue by silica gel chromatography
(2S, 3S) -2-Methyl-3,4-dihydroxybutyramide (407 mg, 60%) was obtained.

Synthesis of (4S, 5S) -4-methyl-5-hydroxymethyloxazolidin-2-one

[Chemical 36] Bistrifluoroacetoxyiodobenzene (97 ml) in a mixed solvent of acetonitrile (1.5 ml) and water (1.5 ml).
3 mg, 2.253 mmol) was dissolved, followed by (2S,
3S) -2-Methyl-3,4-dihydroxybutyramide
(200 mg, 1.502 mmol) was added, the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the residue by silica gel chromatography (4S,
5S) -4-Methyl-5-hydroxymethyloxazolidin-2-one (112 mg, 57%) was obtained.

Example 5 Synthesis of (2S, 3S) -2-allyl-3-hydroxy-γ-butyrolactone

[Chemical 37] Diisopropylamine (5.49 ml, 39.18 mmol), 1.6 M n in THF (30 ml) under argon atmosphere.
-Butyl lithium hexane solution (24.49 ml, 39.
18 mmol) at 0 ° C. and stirred for 15 minutes,
Cooled to 78 ° C. Then, (S) -3-hydroxy-
TH of γ-butyrolactone (1 g, 9.794 mmol)
After adding a solution of F (20 ml) and stirring at −78 ° C. for 30 minutes, a solution of allyl chloride (3.2 ml, 39.18 mmol) and HMPA (9.8 ml) in THF (20 ml) was added dropwise. After gradually raising the temperature and stirring at about −45 ° C. for 4 hours, a saturated aqueous solution of ammonium chloride was added at the same temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated saline, and then with magnesium sulfate. After drying, it was concentrated under reduced pressure. By purifying the residue by silica gel chromatography (2S, 3S)-
2-methyl-3-hydroxy-γ-butyrolactone (0.
807 g, 58%) was obtained.

Synthesis of (2S, 3S) -2-allyl-3,4-dihydroxybutyramide

[Chemical 38] To a solution of (2S, 3S) -2-allyl-3-hydroxy-γ-butyrolactone (19) (807 mg, 5.681 mmol) in anhydrous methylene chloride (15 ml) was added liquid ammonia at -78 ° C for 2-3 minutes. After blowing, the temperature was raised to room temperature and trimethylaluminum hexane solution (4.4 ml,
6.249 mmol) was added. After stirring for 24 hours, 0.
A small amount of 1N hydrochloric acid was added to neutralize, filtered through Celite, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (2S, 3S) -2-allyl-3,4-dihydroxybutyramide (561 mg, 62%).

Synthesis of (4S, 5S) -4-allyl-5-hydroxymethyloxazolidin-2-one

[Chemical Formula 39] Bistrifluoroacetoxyiodobenzene (1.46 g, in a mixed solvent of acetonitrile (3 ml) and water (3 ml))
3.38 mmol), followed by (2S, 3S) -2-
Allyl-3,4-dihydroxybutyramide (561m
g, 3.522 mmol) and stirred at room temperature for 5 hours,
It was concentrated under reduced pressure. Add saturated aqueous sodium hydrogen carbonate solution,
The mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the residue by silica gel chromatography (4S, 5S) -4-
Allyl-5-hydroxymethyloxazolidin-2-one (288 mg, 52%) was obtained.

─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shigeo Katsumura 12-10 Hiraisanso, Takarazuka-shi, Hyogo (56) References International publication 95/08530 (WO, A1) (58) Fields investigated (Int.Cl. ⁷ , DB name) C07D 263/24 C07D 307/32 C07D 317/26 C07M 7/00 CA (STN) CASREACT (STN) REGISTRY (STN)

Claims (23)

(57) [Claims] 1. The following formula: (In the formula, R means an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group forming a 3 to 6 membered ring, an aralkyl group or a 2-alkenyl group, and R ′ is an amino group, a hydrazino group,
It means a hydroxyamino group or an azido group. ) The compound represented by the formula (1) is subjected to a rearrangement reaction. (In the formula, R means the same as the above.) A method for producing an oxazolidin-2-one derivative. 2. The following formula: (In the formula, R and R ′ have the same meanings as described above.) The compound represented by the following formula: (In the formula, R ¹ and R ² are the same or different and each is a hydrogen atom,
It means an alkyl group or a phenyl group, or R ¹ and R ² may form a cycloalkyl ring via the carbon atom to which they are attached, and R and R ′ have the same meanings as above. ), And then subjecting this compound (6) to a rearrangement reaction. (In the formula, R means the same as the above.) A method for producing an oxazolidin-2-one derivative. 3. The following formula: (In the formula, R means the same as the above.) The compound represented by the following formula: (Wherein R and R ′ have the same meanings as described above), and the compound (3) is subjected to a rearrangement reaction. (In the formula, R means the same as the above.) A method for producing an oxazolidin-2-one derivative. 4. The following formula: (In the formula, R means the same as the above.) The compound represented by the following formula: (Wherein R and R ′ have the same meanings as described above), and then the compound (3) is acetalized to obtain a compound represented by the following formula: (Wherein R, R′R ¹ and R ² have the same meanings as described above), and the compound (6)
Is subjected to a rearrangement reaction, the following formula: (In the formula, R means the same as the above.) A method for producing an oxazolidin-2-one derivative. 5. 3-hydroxy-γ-butyrolactone is reacted with an alkylating agent in the presence of a base to give the following formula: (Wherein R has the same meaning as described above), and then the compound (2) is reacted with a nitrogen-based nucleophile to obtain a compound represented by the following formula: (Wherein R and R ′ have the same meanings as described above), and the compound (3) is subjected to a rearrangement reaction. (In the formula, R means the same as the above.) A method for producing an oxazolidin-2-one derivative. 6. 3-hydroxy-γ-butyrolactone is reacted with an alkylating agent in the presence of a base to give the following formula: (Wherein R has the same meaning as described above), and the compound (2) is reacted with a nitrogen-based nucleophile to obtain a compound represented by the following formula: (Wherein R and R ′ have the same meanings as described above), and the compound (3) is acetalized to obtain a compound represented by the following formula: (Wherein R, R′R ¹ and R ² have the same meanings as described above), and the compound (6)
Is subjected to a rearrangement reaction, the following formula: (In the formula, R means the same as the above.) A method for producing an oxazolidin-2-one derivative. 7. The following formula: (In the formula, R means an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group forming a 3 to 6 membered ring, an aralkyl group or a 2-alkenyl group, and R ′ is an amino group, a hydrazino group,
It means a hydroxyamino group or an azido group. ) The compound represented by this. 8. The following formula: (Wherein R has the same meaning as described above) and a nitrogen-based nucleophile is reacted with the compound represented by the following formula: (In the formula, R and R ′ have the same meanings as described above.) A method for producing a compound represented by the formula. 9. 3-hydroxy-γ-butyrolactone is reacted with an alkylating agent in the presence of a base to give the following formula: (Wherein R has the same meaning as described above), and the compound (2) is reacted with a nitrogen-based nucleophile. (In the formula, R and R ′ have the same meanings as described above.) A method for producing a compound represented by the formula. 10. An optically active oxazolidin-2-one derivative is produced from an optically active raw material.
A method for producing the derivative described. 11. The method for producing a (2S, 3S) -oxazolidin-2-one derivative according to claim 5, wherein (S) -3-hydroxy-γ-butyrolactone is used. 12. The method for producing a (2R, 3R) -oxazolidin-2-one derivative according to claim 5, wherein (R) -3-hydroxy-γ-butyrolactone is used. 13. The oxazolidine-2 according to claim 5, wherein the alkylating agent is an alkyl halide having 1 to 6 carbon atoms, a cycloalkyl halide forming a 3 to 6 membered ring, an aralkyl halide or a 2-alkenyl halide. -A method for producing an on derivative. 14. The nitrogen-based nucleophile is ammonia, metal azide, hydrazine or hydroxylamine.
7. The method for producing an oxazolidin-2-one derivative according to item 6. 15. In the formula (3), when R ′ is an amino group, the rearrangement reagent is sodium hypochlorite, sodium hypobromite, iodosobenzene, hydroxytosyloxyiodobenzene, bistrifluoroacetoxyiodobenzene. , N-bromosuccinimide or N-chlorosuccinimide, The manufacturing method of the oxazolidin-2-one derivative of Claims 1-6. 16. The compound of formula (3), wherein R ′ is a hydrazino group, the rearrangement reagent is sodium nitrite.
7. The method for producing the oxazolidin-2-one derivative according to any one of claims 1 to 6. 17. The oxazolidin-2-one derivative according to claim 1, wherein the rearrangement reagent when R ′ is a hydroxyamino group in formula (3) is an alkylsulfonyl halide, an arylsulfonyl halide or an acyl halide. Manufacturing method. 18. 2-Benzyl-3,4-dihydroxybutyramide. 19. The conformation is (2S, 3S) or (2R,
3R) 2-benzyl-3,4-dihydroxybutyramide. 20. 2-Benzyl-3,4-dihydroxybutylhydrazide. 21. The configuration is (2S, 3S) or (2R,
3R) 2-benzyl-3,4-dihydroxybutylhydrazide. 22. 2-Benzyl-3,4-dihydroxybutylhydroxamic acid. 23. The conformation is (2S, 3S) or (2R,
3R) 2-benzyl-3,4-dihydroxybutyl hydroxamic acid.