JPH0733381B2 - 1,3-dioxane derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] [In the formula, R ¹ represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group or an aryl group, and R ² represents a hydrogen atom or a protective group for a hydroxyl group. Also, Is a single bond, Y represents C = O or CHOH, Is a double bond, Y is A 6-methyl-1,3-dioxane derivative represented by [In the formula, R ^{3 and} R ⁴ are hydrogen atoms or (R ¹ represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group or aryl group, and R ⁵ and R ⁶
Represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group.
R ⁵ and R ⁶ may represent together with the carbon atom to which they are bonded to form a carbonyl group) or may form together with the carbon atom to which they are bonded form a carbonyl group. . ] 4-amide-1,3-
It relates to dioxane derivatives.

The 1,3-dioxane derivatives represented by the general formulas (I) and (II) of the present invention have, for example, the general formula [In the formula, R ⁷ represents a hydrogen atom or a hydroxyl-protecting group. ] It is useful as a raw material for synthesizing a 4-acetoxy-2-azetidinone derivative represented by

The 4-acetoxy-2-azetidinone derivative represented by the general formula (III) can be used as an important synthetic intermediate for carbapenem antibiotics such as thienamycin showing excellent antibacterial activity [T. Kametani et al., Heterocycles, 17 , 463]. (198
2). ].

[Conventional technology]

Conventionally, the synthetic method of the optically active 4-acetoxy-2-azetidinone derivative represented by the general formula (III) is 1) 6
-Using aminopenicillanic acid as a starting material [F. DiNinn
o et al., JOC 42 , 2960 (1977), K. Hirai et al., Heerocycles,
17 , 201 (1982). 2) Using D-allo-threonine as a starting material [M. Shiozaki et al., Tetrahedron, 39 , 2399 (1
983). 3) Using L-threonine as a starting material [H. Maruyama et al., Bull. Chem. Soc. Jpn., 58 , 3264 (198
Five). 4) Using L-aspartic acid as a starting material [PJ Reider et al., Tetrahedron Lett., 23 , 2293 (198
2). 5) Using the reaction of enolate and imine obtained by using methyl (S) or (R) -3-hydroxybutyrate as a starting material as a key step [T. Chiba et al., Chem. Lett., 65
1 (1985). 6) Using the addition reaction of silyl enol ether obtained from methyl (R) -3-hydroxybutyrate as a starting material with chlorosulfonyl isocyanate as a key step [Ohashi et al., JP 61-18791 (1986). ] 7)
Using (S) -ethyl lactate as a starting material [Y. Ito et al., T
etrahedron Lett., 27 , 5751 (1986). ] Etc. have been reported.

[Problems to be solved by the invention]

However, in any of the methods, starting materials or reactants are expensive (methods 2 and 5), the number of steps is large (method 1), and there are problems such as mercury acetate or lead tetraacetate having a problem in waste treatment after reaction. Including an oxidation step with a heavy metal compound (methods 1, 3 and 4), and requiring a complicated operation to remove the protecting group at the 1-N position of 2-azetidinone (method)
2,3, and 7), low stereoselectivity of the reaction or involving a laborious process to control it (methods 4, 5, and 6), and introduction of relatively expensive protecting groups in the initial step. Therefore, there are some drawbacks such as an increase in the total manufacturing cost (method 6), which is very difficult to carry out industrially.

As a result of earnest studies aimed at overcoming these conventional drawbacks, the present inventor has produced aldehydes derived from inexpensive α-oxyacids such as lactic acid and fermentation at a lower cost than fermentation (R) -3-. A novel 1,3-dioxane derivative obtained by using hydroxybutyric acid as a starting material is represented by the general formula (I
The present invention has been completed by finding that it is a useful compound for synthesizing an important synthetic intermediate of carbapenem represented by II).

[Means for solving problems]

The 1,3-dioxane derivatives represented by the general formulas (I) and (II) of the present invention can be produced by the following reaction steps.

[In the formula, R ¹ represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group or an aryl group, and R ⁸ represents a protective group for a carboxyl group. [First Step] In this step, the (R) -3-hydroxybutyric acid ester represented by the general formula (IV) is treated with a base to be hydrolyzed to obtain the compound of the formula (V).
Is a step of producing (R) -3-hydroxybutyric acid. The (R) -3-hydroxybutyric acid ester used in this reaction is industrially easily available (R) -3.
-Methyl hydroxybutyrate, ethyl (R) -3-hydroxybutyrate, propyl (R) -3-hydroxybutyrate, (R)
Examples thereof include -3-hydroxybutyric acid polymer. Further, as the base, a base usually used for hydrolyzing an ester to synthesize a corresponding carboxylic acid can be used, but sodium hydroxide is preferably used. The reaction is carried out in a solvent, and as the solvent, alcohol solvents such as methanol, ethanol, propanol and butanol, ether solvents such as diethyl ether and tetrahydrofuran, and water are used alone or as a mixture. The reaction proceeds smoothly at -20 ° C to 100 ° C (see Reference Example 1).

[Second Step] In this step, (R) -3-hydroxybutyric acid (V) and the aldehyde derivative represented by the general formula (VI) are reacted in the presence of a catalyst to remove water produced, and then the general formula (I 6-methyl-1,3-dioxane-which is a compound of the present invention represented by a)
This is a step of producing a 4-one derivative. As shown in the general formula (Ia), the substituents bonded to the 2-position and the 6-position in the general formula (Ia) obtained in this step are those having a cis configuration as a main product with high stereoselectivity. Obtained (D. Seebac
h, “Modern Synthetic Methods Vol.4” ed by R. Scheffo
ld, Springer-Verlag, Berlin, p. 205 (1986)). Examples of the aldehyde derivative used in this reaction include t-butoxy, benzyloxy, tetrahydropyranyloxy,
Acetaldehyde having an alkoxy group such as methoxymethoxy, methoxyethoxymethoxy, and t-butyldimethylsilyloxy in the α-position, propanal, butanal,
Examples include α-alkoxyalkanals such as pentanal, 3-phenylpropanal, and 4-phenylbutanal, but 2-benzyloxypropanal is preferably used (see Reference Examples 2 to 6). Examples of the catalyst used in this reaction include acids such as p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, boric acid and phosphoric acid, and pyridine salts thereof, and the like. P-toluenesulfonic acid pyridine is preferable. Salt (PPTS) is used. As a dehydration method for carrying out this step, a method by azeotropic distillation with a catalyst is mainly used. Examples of the solvent include hydrocarbon solvents such as benzene, toluene, xylene, pentane, hexane and heptane, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane. Can be illustrated. The reaction proceeds smoothly at 0 to 100 ° C (see Examples 1 and 6).

[Third Step] This step is 6-methyl-1,3-represented by the general formula (Ia).
The dioxan-4-one derivative is treated with a reducing agent to give 6-methyl-1,3-dioxan-4- represented by the general formula (Ib).
An all derivative is produced. Conventionally, a method for producing a lactol by reducing a lactone is known, but up to now, 1,3-dioxane-4- represented by the general formula (Ia) has been known.
No attempt has been made to derive an on-derivative into a 6-methyl-1,3-dioxan-4-ol derivative represented by the general formula (Ib) under the conditions of reduction reaction without ring opening of the dioxane ring. There wasn't. The general formula (I b) generated in this reaction
The steric configuration of the 4-position hydroxyl group therein is a mixture of the (R) -form and the (S) -form, but these are used as a raw material for the next fourth step without separation. As the reducing agent used in this step,
Although any reducing agent usually used in the reduction of lactone to synthesize the corresponding lactol can be used, preferably diisobutylaluminum hydride (DIBAL) or sodium bis (methoxyethoxy) aluminum hydride (Vitride) is used. Used from 1 equivalent to 2 equivalents. This reaction is carried out in a solvent, and as the solvent, any solvent can be used as long as it does not participate in the reduction reaction.
An ether solvent such as diethyl ether or tetrohydrofuran, or a hydrocarbon solvent such as benzene, toluene or xylene is preferably used. Reaction is -80 ℃
It runs smoothly at ~ 20 ° C (see Examples 2 and 7).

[Fourth step] This step is 6-methyl-1,3-represented by the general formula (Ib).
The dioxan-4-ol derivative is dehydrated to give a compound of the general formula (I
6-methyl-2H, 6H, which is a compound of the present invention represented by c)
1, to produce a 1,3-dioxin derivative. Conventionally, a method of removing a hydroxyl group and leading to an olefin is known, but a 6-methyl-1,3-dioxan-4-ol derivative represented by the general formula (Ib) is dehydrated without ring opening. No attempt has been made to produce a 6-methyl-2H, 6H-1,3-dioxin derivative represented by the general formula (Ic).
As the dehydration method, after the hydroxyl group is acylated, it is replaced with a halogen atom such as chlorine or bromine by a method of treating with a halide such as hydrogen chloride or hydrogen bromide, and then a dehydrohalogenation reaction is carried out by a base treatment. There is a method of deriving an olefin or a method of treating with a dehydrating agent in the presence of a base to directly derive an olefin, and the latter method is preferably used. Examples of the dehydrating agent used in the latter method include thionyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl bromide, methanesulfonyl bromide and p-bromide.
-Toluenesulfonyl, phosphorus oxybromide, phosphorus tribromide,
Phosphorus pentabromide or the like is used in an amount of 1 to 1.5 equivalents. As the base, a base that accelerates the elimination reaction is usually used, and trimethylamine, triethylamine, tripropylamine,
Tributylamine, N-ethylpiperidine, pyridine,
Lutidine, collidine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] -7 -Undecene and the like can be exemplified, and triethylamine is preferably used. The base is used in an amount of 1 to 5 equivalents based on the dehydrating agent. This reaction is carried out in a solvent. As the solvent, pyridine, collidine, basic solvents such as lutidine, polar solvents such as dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, dichloromethane, chloroform, carbon tetrachloride. Halogenated hydrocarbon solvents such as benzene, toluene,
Examples thereof include hydrocarbon solvents such as xylene and hexane, and ether solvents such as diethyl ether, dibutyl ether, tetrahydrofuran and dioxane. The reaction is
It runs smoothly between −10 ° C. and 100 ° C. (see Examples 3 and 8).

[Fifth Step] In this step, 6-methyl-2H, 6 represented by the general formula (Ic) is used.
By reacting an H, 1,3-dioxin derivative with chlorosulfonyl isocyanate (CSI) and subsequent reductive post-treatment, a compound of the present invention represented by general formula (IIa) 4
This is a step of producing an -amide-1,3-dioxane derivative. Although a method for producing a 2-azetidinone derivative by addition of an olefin and CSI is known, its yield and stereoselectivity are generally low, and it has been very difficult to carry out industrially (WASzabo, Aldrichimica. Acta, 10 , 23 (197
See 7)).

However, the addition reaction between the 6-methyl-2H, 6H-1,3-dioxin derivative represented by the general formula (Ic) of the present invention and CSI proceeds extremely highly stereoselectively, and the addition of the general formula (IIa It was found that only the stereochemistry shown in () was given. CSI is used in 1 to 2 equivalents, preferably 1.1 equivalents, relative to the substrate. This reaction is carried out in a solvent. Examples of the solvent include hydrocarbon solvents such as hexane, heptane, benzene, toluene and xylene, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane, chloroform and carbon tetrachloride, dimethylformamide and hexa. A polar solvent such as methylphosphoric triamide is used. Reaction is -70 ° C
Proceed smoothly at ~ 50 ℃. Further, as the reducing agent used in the reductive post-treatment after the reaction, lithium aluminum hydride,
Metal hydride compounds such as sodium bis (methoxyethoxy) aluminum hydride, sodium borohydride and diisobutylaluminum hydride, organic sulfur compounds such as thiophenol, methyl mercaptan, ethyl methyl captan, propyl mercaptan, dimethyl sulfide and diethyl sulfide , Lithium sulfite, sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, and other sulfites, lithium thiosulfate, thiosulfates such as sodium thiosulfate, and Raney nickel (see Examples 4 and 9).

[Sixth Step] This step is the 4-amide-1,3-represented by the general formula (IIa).
Deprotection of the hydroxyl-protecting group R ² on the 2-position side chain of the dioxane derivative to produce a 4-amide-1,3-dioxane derivative of the present invention represented by the general formula (II b). Is. Deprotection can be easily performed according to the method usually used as a method for deprotecting a protective group for a hydroxyl group (Protective Groups in Organic Sythesis, John-Wily
& Sons, New York, 1981.) (see Examples 5 and 10).

[Seventh Step] In this step, the hydroxyl group on the 2-position side chain of the 4-amide-1,3-dioxane derivative having a free hydroxyl group represented by the general formula (IIb) is oxidized to give the general formula (II It is intended to produce a 2-acyl-1,3-dioxane derivative which is the compound of the present invention represented by c). As the oxidizing agent, an oxidizing agent that can oxidize a secondary alcohol into a corresponding ketone is used. For example, chromium trioxide, chromic acids such as pyridinium chlorochromate, pyridinium dichromate, dimethyl sulfoxide derivatives and ruthenium compounds produced by oxidizing ruthenium trichloride with periodate in the reaction system, and the like, preferably ruthenium compounds Is used. This reaction is preferably carried out in a solvent, and as the solvent, basic solvents such as pyridine, collidine, and lutidine, dimethyl sulfoxide, N, N-dimethylformamide, N, N-
Polar aprotic solvent such as dimethylacetamide, hexamethylphosphoric triamide, acetonitrile,
Dichloromethane, chloroform, halogenated hydrocarbon solvents such as carbon tetrachloride, benzene, toluene, hydrocarbon solvents such as hexane, acetone, 2-butanone, methyl acetate, ethyl acetate, ketone or ester solvents such as amyl acetate, Examples include protic solvents such as t-butanol and water, and mixed solvents thereof. Reaction is -20
It proceeds smoothly at ℃ ~ 100 ℃ (see Example 11).

[Eighth Step] In this step, the 2-acyl-1,3 represented by the general formula (II c) is used.
By treating the dioxane derivative with a peracid
2-oxo-1,3, a compound of the present invention represented by d)
-A step of producing a dioxane derivative.

As the peracid used in this reaction, peroxides usually used in the Baeyer-Villiger reaction such as m-chloroperbenzoic acid, peracetic acid, pertrifluoroacetic acid, formic acid and perphthalic acid are used. Peracid is used in 1 to 5 equivalents, preferably 4 equivalents of the substrate. Examples of the solvent include hydrocarbon solvents such as benzene, toluene and hexane, ether solvents such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, halogenated hydrocarbon solvents such as dichloromethane, chloroform and carbon tetrachloride. , Ester solvents such as methyl acetate, ethyl acetate and amyl acetate, polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide, and acetic acid, propionic acid, butyric acid, etc. Carboxylic acids are used. The reaction proceeds smoothly at -40 ° C to 50 ° C (see Example 12).

The 2-oxo-1,3-dioxane derivative represented by the formula (II d) synthesized by the above-mentioned production steps is 4-acetoxy-2-azetidinone (III) which is an important synthetic intermediate of carbapenems by the following steps. ) Can be led to.

[In the formula, R ⁷ represents a hydrogen atom or a hydroxyl-protecting group. This step is represented by the formula (II d) obtained in the eighth step 2
A -oxo-1,3-dioxane derivative is reacted with a carboxylic acid derivative to produce a 4-acetoxy-2-azetidinone derivative represented by the general formula (III). Examples of the carboxylic acid derivative used in this reaction include formic acid, acetic acid, propionic acid, butyric acid, and benzoic acid.
In this reaction, as a catalyst, a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt of the carboxylic acid derivative, which corresponds to the carboxylic acid derivative used,
Zinc salt or the like is used. The reaction is carried out without solvent or in a solvent, and as the solvent, N, N-dimethylformamide,
N, N-Dimethylacetamide, hexamethylphosphoric triamide and other polar solvents, methyl acetate, ethyl acetate, amyl acetate and other ester solvents, dichloromethane, chloroform, carbon tetrachloride and other halogenated hydrocarbon solvents, benzene, toluene And aromatic hydrocarbon solvents such as xylene.

The reaction proceeds smoothly at 0 ° C to 100 ° C (see Reference Examples 7 and 9).

The hydroxyl group on the 3-position side chain of the 4-acetoxy-2-azetidinone derivative (III) obtained by the above reaction can be introduced with a protecting group according to a method for protecting a usual hydroxyl group (Protective Groups in Organic Synthesis, John Wi
Lley & Sons, New York, 1981 p.10-86. Reference Examples 8 and 9
See).

Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. The abbreviations have the following meanings.

Ac: acetyl group Ar: aryl group Bn: benzyl group Me: methyl group Ph: phenyl group Reference Example 1 Methyl (R)-(-)-3-hydroxybutyrate 20.2 g (171
180 ml of 1N sodium hydroxide aqueous solution was added to the (mmol) under ice-cooling and allowed to stand at the same temperature for 6 days.
The solvent was distilled off under reduced pressure. Ethanol was added to the obtained residue, the insoluble matter was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure to give (R)-(−)-3-hydroxybutyric acid 15.5 g (yield 87% ) Was obtained as a colorless oil.

bp 130 ° C (1mmHg) ▲ [α] ²⁰ _D ▼ -24.1 ° (C = 4.66, H ₂ O) Reference value [α] _D- 25.2 ° (C = 5, H ₂ O) (D. Seebach, “Modern Sythetic Methods Vol.4 "ed by
R. Scheffold, Spring-Verlag, Berlin, p. 205 (198
6). ) IR (neat) 2800 to 3400br, 1710,1400,1060,942,845cm ^-1 .H-NMR ((CD ₃ ) ₂ SO) δ: 1.91 (3H, d, J = 6.2Hz, CH ₃ ),
2.26 (2H, d, J = 6.4Hz, CH ₂ ), 3.2 to 3.5 (2H, br, otherpro
tons), 3.97 (1H, dq, J = 6.2 and 6.4Hz, C H OH). Mass m / e 105 (M + 1) ⁺ , 89 (M-CH ₃ ) ⁺ , 7160. Reference Example 2 Pyridine 5.1 ml (63.1 mmol), methanol 2.1 ml (51.8 mm
ol) and dichloromethane (100 ml) were mixed with benzyloxyacetyl chloride (5.0 ml, 31.7 mmol) at 0 ° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction solution to separate it,
The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the obtained residue was distilled under reduced pressure to obtain 5.70 g (quantitative yield) of methyl benzyloxyacetate.

bp 120~124 ℃ (1mmHg) H- NMR (CDC1 3) δ: 3.76 (3H, s, OCH 3), 4.11 (2H, s, CH
₂ ), 4.63 (2H, s, CH ₂ ), 7.35 (5H, s, aromatic proton
s). Reference example 3 2.50 g (13.9 mmol) of methyl benzyloxyacetate was dissolved in 45 ml of ether, and 16.0 ml of diisobutylaluminum hydride (1M n-hexane solution) was added at -78 ° C, and the mixture was stirred at the same temperature for 1 hour, and then the insoluble matter was removed by Celite. Filtered. The solvent was distilled off under reduced pressure and the resulting residue was distilled with Cugelol to give benzyloxyacetaldehyde (1.40 g, yield 67%).
%) Was obtained.

bp 130 ° C. (1 mmHg) NMR (CDCl ₃ ) δ: 4.08 (2H, s, CH ₂ ), 4.62 (2H, s, CH ₂ ),
7.35 (5H, s, aromatic protons), 9.72 (1H, s, CHO). Example 1 1.32 g (12.7 mmol) of (R) -3-hydroxybutyric acid and 1.29 g (8.60 mmol) of benzyloxyacetaldehyde are dissolved in 60 ml of dichloromethane, and 350 mg (1.46 mmol) of pyridinium p-toluenesulfonate is added to produce it in a Dean-Starck apparatus. The mixture was heated under reflux for 57 hours while distilling off water. After returning the reaction solution to room temperature, water was added to stop the reaction, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (silica gel; hexane: ethyl acetate = 9: 1 → 7: 1) to obtain (2R, 6R) -2-benzyloxymethyl-6-methyl. -1,3-dioxan-4-one (1.48 g, yield 73%) was obtained.

H-NMR (CDCl ₃ ) δ: 1.36 (3H, d, J = 6.2Hz, CH ₃ ), 2.4-
2.7 (2H, m, CH ₂ ), 3.67 (2H, d, J = 4.4Hz, CH ₂ OBn), 3.96
~ 4.4 (1H, m, C ₆ -H), 4.62 (2H, s, CH ₂ Ph), 5.45 (1H,
t, J ＝ 4.4Hz, C ₂ −H), 7.33 (5H, s, aromatic proton
s). Example 2 (2R, 6R) -2-Benzyloxymethyl-6-methyl-
1,3-dioxan-4-one (1.46 g, 6.20 mmol) was dissolved in ether (30 ml), and diisobutylaluminum hydride (1 M n-hexane solution) (7.4 ml) was added at -78 ° C.
It was stirred for 0 minutes. Rochelle salt aqueous solution (6 g /
It was poured into a mixed solution of water (30 ml) and ether (30 ml), and the mixture was stirred until the two layers became transparent, and separated. After washing the organic layer with saturated saline,
It was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (silica gel, hexane: ether = 3: 1 to 1: 1) to obtain (2R, 6R)-
1.19 g (yield 80%) of 2-benzyloxymethyl-6-methyl-1,3-dioxan-4-ol was obtained. This product is 4
Although it is a mixture of (R) -form and (S) -form of hydroxyl group, these were used as a raw material of the following Example 3 as a mixture without separation.

1 H-NMR (CDCl ₃ ) δ: 1.20, 1.26 (3H, d, CH _{3 in} total),
1.6 to 1.8 (2H, m, CH ₂ ), 3.0,3.4 (1H, OH in total), 3.5
~ 3.6 (2H, m, CH ₂ OBn), 3.8 ~ 4.3 (1H, m, C ₆ -H), 4.59
(2H, s, OCH ₂ Ph), 4.7 to 5.0 (1H, m, C ₄ -H), 5.4 (1H, t,
_{C 2 -H), 7.32 (5H} , s, aromatic protons). Example 3 (2R, 6R) -2-Benzyloxymethyl-6-methyl-
1.15 g (4.85 mmol) of 1,3-dioxan-4-ol was dissolved in 15 ml of dichloromethane, and 2.0 ml of triethylamine (14.
3 mmol) and thionyl chloride (0.42 ml, 5.76 mmol) were added, and 0
The mixture was stirred at 0 ° C for 2 hours. After returning to room temperature and further stirring overnight, the reaction solution was diluted with n-hexane, and water was added to stop the reaction. The organic matter was extracted with n-hexane, washed with saturated saline, and dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (silica gel; hexane → hexane: ether = 300: 1 → 50:
Purified in 1), (2R, 6R) -2-benzyloxymethyl-6-methyl-2H, 6H-1,3-dioxin 407 mg (yield 38
%) Was obtained.

_{H-NMR (CDCl 3) δ} : 1.27 (3H, d, J = 6.6Hz, CH 3), 3.60
(2H, d, J = 4.6Hz, CH ₂ OBn), 4.48 to 4.7 (1H, m, C ₆ -H),
4.62 (2H, s, CH ₂ Ph), 4.79 (1H, dd, J = 1.3 and 6.4Hz, C ₅
-H), 5.15 (1H, t , J = 4.7Hz, C 2 -H), 6.48 (1H, dd, J
= 1.4 and 6.3Hz, C ₄ -H), 7.33 (5H, s, aromatic proton
s). Example 4 (2R, 6R) -2-Benzyloxymethyl-6-methyl-2
196 mg (0.892 mmol) of H, 6H-1,3-dioxin was added to toluene 3
Dissolve in ml and chlorosulfonylisocyanate at -50 ℃
78 μ (0.892 mmol) was added, and the mixture was stirred at the same temperature for 2.5 hours. The reaction solution was cooled to −70 ° C., 3 ml of toluene and 0.96 ml of a 1.0 M solution of sodium bis (methoxyethoxy) aluminum hydride in toluene were added, and the temperature was gradually raised to −50 ° C.
The mixture was stirred at the same temperature for 1 hour. The reaction solution was added to a mixed solution of Rochelle salt aqueous solution (3 g / 20 ml) and toluene 20 ml at 0 ° C.,
After stirring for 0 minutes and filtering the insoluble matter, the organic layer was separated.
The organic layer was washed with saturated brine, the solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (silica gel; hexane: ethyl acetate = 4: 1 → 2: 1), (1S, 3R, Five
R, 6R) -8-Aza-3-benzyloxymethyl-5-methyl-2,4-dioxabicyclo [4.2.0] octane-7-
111 mg (47% yield) of on were obtained as colorless crystals.

H-NMR (CDCl ₃ ) δ: 1.42 (3H, d, J = 6.4Hz, CH ₃ ), 2.83
~ 3.0 (1H, m, C H CO), 3.54 (2H, d, J = 4.6Hz, CH ₂ OBn),
4.23 (1H, quint, J = 6.4Hz, CHCH ₃ ), 4.60 (2H, s, CH ₂ P
h), 5.07 (1H, t, J = 4.4Hz, CHCH ₂ OBn), 5.40 (1H, d, J =
4.6Hz, CHNH), 6.2 ~ 6.4 (1H, br, NH), 7.30 (5H, s, aroma
tic protons). Example 5 (1S, 3R, 5R, 6R) -8-aza-3-benzyloxymethyl-5-methyl-2,4-dioxabicyclo [4.2.0] octane-7-one 69.3 mg (0.263 mmol) in ethanol 2 ml 10% palladium carbon (10 mg) and 0.5N hydrochloric acid ethanol solution (1 drop) were added and the mixture was stirred overnight under a hydrogen atmosphere. After filtering the insoluble matter, the solvent was distilled off under reduced pressure (1S, 3R, 5R, 6R).
-8-aza-3-hydroxymethyl-5-methyl-2,4
-Dioxabicyclo [4.2.0] octane-7-one 45.4m
g (quantitative yield) was obtained.

H-NMR (CDCl ₃ ) δ: 1.41 (3H, d, J = 6.4Hz, CH ₃ ), 1.8-
2.2 (1H, br, OH), 1.9 to 2.1 (1H, m, C H C = O), 3.66 (2
H, d, J = 4.2Hz, CH ₂ ), 4.26 (1H, quint, J = 6.4Hz, C H C
H ₃ ), 4.99 (1H, t, J = 4.3Hz, C H CH ₂ OH), 5.42 (1H, d, J =
4.6Hz, C H NH), 6.3 to 6.6 (1H, br, NH). Reference example 4 (S) -ethyl lactate 10.2 g (86.0 mmol) and pyrrolidine 7.8
After adding 0 ml (93.4 mmol) under ice, the mixture was stirred at room temperature for 3 days. After the excess pyrrolidine and the produced ethanol were distilled off under reduced pressure, the residue was distilled and (S) -N, N-tetramethylene-2-hydroxypropionamide 11.8 g (yield 95
%) As a colorless oil.

bp 108 ° C, (1mmHg) ▲ [α] ²⁰ _D ▼ -49.2 ° (C4.78, CHCl ₃ ) IR (neat) 3450,3000,2900,1637,1440,1387,1345,1133,
1040 cm ⁻¹ .H-NMR (CDCl ₃ ) δ = 1.33 (3H, d, J = 6.6Hz, CH ₃ ), 1.90
(4H, m, NCH ₂ CH ₂ × 2), 3.45 (4H, m, NCH ₂ CH ₂ × 2), 3.73
(1H, d, J = 7.3Hz, OH), 4.29 (1H, dq, J = 7.3 and 6.6Hz, C
HCO). Mass m / e 143 (M ⁺ ), 128 (M-CH ₃ ) ³ , 98 (M-CH ₃ CH
OH). Elemental analysis value Calculated as C ₇ H ₁₃ NO ₂ 0.25H ₂ O C; 56.93, H; 9.21 N; 9.49% Actual value C; 57.00, H; 9.22 N; 9.53% Reference example 5 To a suspension of 2.00 g (83.3 mmol) of sodium hydride in 50 ml of tetrahydrofuran and 25 ml of dimethylformamide, under ice-cooling, (S) -N, N-tetramethylene-2-hydroxypropionamide 9.98 g (67.7 mmol) of tetrahydrofuran was added. 15 ml of solution was added slowly. After vigorously stirring at the same temperature for 4.5 hours, 8.80 ml (76.5 mmol) of benzyl chloride was added. After stirring at the same temperature overnight, 50 ml of water was added to stop the reaction, and about 50 ml of ethyl acetate was added to separate the layers. The organic layer was washed with saturated saline and dried over magnesium sulfate. The crystalline residue obtained by distilling off the solvent under reduced pressure was recrystallized from a mixed solvent of hexane-ether to give (S) -N, N-tetramethylene-2-benzyloxypropionic acid amide 14.1 g.
(Yield 87%) was obtained as colorless crystals. The analytical sample was obtained by recrystallization from dibutyl ether.

Melting point 42-42.5 ° C ▲ [α] ²⁰ _D ▼ -69.9 ° (C = 1.72, CHCl ₃ ) IR (KBr) 3050,3000,2890,1630,1430,1350,1120,730cm
⁻¹ .H-NMR (CDCl ₃ ) δ = 1.42 (3H, d, J = 6.8Hz, CH ₃ ), 1.85
(4H, m, NCH ₂ CH ₂ × 2), 3.50 (4H, m, NCH ₂ CH ₂ × 2), 4.20
(1H, q, J = 6.8Hz, CHCO), 4.41,4.62 (2H, d × 2, J = respectively 11.7Hz, CH ₂ Ph), 7.32 (5H, s, Ph). Mass m / e 234 (M + 1) ⁺ , 127,98. Elemental analysis value Measured value as C ₁₄ H ₁₉ NO ₂ C; 72.07, H; 8.21 N; 6.00% C; 72.06, H; 8.32 N; 5.90% Reference example 6 3.09 g (13.2 mmol) of (S) -N, N-tetramethylene-2-benzyloxypropionic acid amide was dissolved in 40 ml of tetrahydrofuran, and a solution of sodium bis (methoxyethoxy) aluminum hydride in toluene (1.07 mol /
) 9.80 ml (10.5 mmol) was divided into 3 portions and added dropwise over 3 hours. After stirring at the same temperature for 4 hours, ice-cooled 1N hydrochloric acid
The reaction solution was added to 35 ml to stop the reaction, and dichloromethane was added to extract organic substances. The organic layer was washed successively with 1% hydrochloric acid, saturated saline, saturated aqueous sodium hydrogencarbonate and saturated saline, and then dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure is distilled by Kugelrohr (S)
-2-benzyloxypropanal 1.85 g (yield 85%)
Was obtained as a colorless oil.

bp 100 ℃, 1mmHg ▲ [α] ²⁰ _D ▼ -66.8 ° (neat, l = 1) (Reference: [α] ²⁰ -65.85 ° (neat), PGM Muts, and
SSBigelow, J.Org.Chem., 48 , 3489 (1983)) IR (neat) 3470,3050,3000,2950,2900,1740,1458,1378,
1100,700 cm ^-1 .H-NMR (CDCl ₃ ) δ = 1.32 (3H, d, J = 7.0Hz, CH ₃ ), 3.88
(1H, dq, J = 1.8 and 7.0Hz, CHOBn), 4.62 (2H, s, CH ₂ P
h), 7.35 (5H, s, Ph), 9.66 (1H, d, J = 1.8Hz, CHO). Mass m / e 181 (M + H ₂ O) ⁺ , 135 (M-CO) ⁺ . Example 6 (R) -hydroxybutyric acid 3.52 g (33.8 mmol) and (S)-
3.61 g (22.0 mmol) of 2-benzyloxypropanal was dissolved in 100 ml of dichloromethane, 0.829 g (3.30 mmol) of pyridinium p-toluenesulfonate was added, and Dean-St
The mixture was heated under reflux for 48 hours while distilling off water produced by the arck device. After returning the reaction solution to room temperature, water was added to stop the reaction, and dichloromethane was added to separate the layers. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to column chromatography (silica gel; hexane: ethyl acetate = 15: 1).
→ 2: 1) and purified, (2R, 6R) -2- [1- (S) -benzyloxyethyl] -6-methyl-1,3-dioxan-4-one 3.75 g (68% yield) ) Was obtained as colorless crystals.
The analytical sample was obtained by recrystallization from isopropyl ether.

Melting point 74.5-75.0 ° C ▲ [α] ²⁰ _D ▼ -51.4 ° (C = 1.21, CHCl ₃ ) IR (KBr) 3000,2880,1750,1730,1340,1258,1110,980,69
0 cm ^-1 .H-NMR (CDCl ₃ ) δ: 1.24 (3H, d, J = 6.5Hz, CH ₃ CHOB
n), 1.35 (3H, d, J = 6.2Hz, CH ₃ CHCH ₂ ), 2.41 (1H, dd, J =
10.7 and _{17.8Hz, C 5 -Hax), 2.69} (1H, dd, J = 4.3 and 17.
8Hz, C ₅ −Heq), 3.68 (1H, dq, J = 3.8 and 6.5Hz, C H OB
n), 4.04 (1H, ddq, J = 4.3 and 6.2 and 10.7Hz, C ₆ -H),
4.67 (2H, s, CH ₂ Ph), 5.29 (1H, d, J = 3.8Hz, C ₂ -H), 7.
28 to 7.38 (5H, m, aronatic protons). Mass m / e 251 (M + 1) ⁺ , 163,144 (M-OCH ₂ Ph) ⁺ , 1
35,91. Elemental analysis value C ₁₄ H ₁₈ O ₄ calculated value C; 67.18, H; 7.25% Analytical value C; 67.15, H; 7.17% Example 7 (2R, 6R) -2- [1- (S) -Benzyloxyethyl] -6-methyl-1,3-dioxan-4-one 2.21 g
Dissolve (8.81 mmol) in 50 ml of ether, and diisobutylaluminum hydride (1M n-hexane solution) at -60 ° C 1
0.5 ml (10.5 mmol) was added, and the mixture was stirred at the same temperature for 30 minutes. Add the reaction mixture under ice cooling to a mixture of Rochelle salt aqueous solution (10 g / 40 ml) and 40 ml of ether, stir until the two layers become transparent,
The layers were separated. The organic layer was washed with saturated brine and dried over magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel; hexane: ether = 4: 1 → 3: 1) to obtain (2R, 6R) -2- [1-
(S) -Benzyloxyethyl] -6-methyl-1,3-
2.14 g (96% yield) of dioxan-4-ol was obtained as a colorless oil. The product stereochemistry of the hydroxyl group at 4-position than H-NMR data (R) - body and (S) - a mixture of the body, the generation ratio, for example, from the area ratio of C ₂ -H (R) (δ4 .Five
7): (S) (δ3.52) = 1: 1.13 was revealed, but these were used as a raw material in the following Example 8 as a mixture without separation.

IR (neat) 3300 to 3500br, 2980, 2950, 2890, 1445, 1370, 11
00,700 cm ^-1 .H-NMR (CDCl ₃ ) δ: 1.20 (3H × 0.53, d, J = 6.4 Hz, CH ₃ CH
OBn (A)) 1.21 (3H × 0.53, d, J = 6.3Hz, C ₆ -CH
₃ (A)) 1.22 (3H x 0.47, d, J = 6.5Hz, CH ₃ CHOBn
(B)) 1.26 (3H × 0.47, d, J = 6.2Hz, C 6 -CH 3 (B))
1.34 (1H × 0.47, ddd, J = 9.6, 11.3 and 12.8Hz, C ₅ −Hax
(B)), 1.63 (1H x 0.53, ddd, J = 1.2, 3.0 and 13.3Hz, C
_5- Heq (A)), 1.70 (1H x 0.53, dddd, J = 2.0, 3.4, 11.3
And _{13.3Hz, C 5 -Hax (A)} ), 1.81 (1H, × 0.47, ddd, J =
2.3, 2.4 and _{12.8Hz, C 5 -Heq (B)} ), 2.89 (1H × 0.53, d
d, J = 2.0 and 2.3Hz, OH (A)), 3.24 (1H, × 0.47, d, J =
6.7Hz, OH (B), 3.52 (1H x 0.53, dq, J = 4.7 and 6.4H
z, C H OBn (A)), 3.60 (1H × 0.47, dq, J = 4.7 and 6.4H
z, C H OBn (B), 3.73 (1H × 0.47, ddq, J = 2.3, 6.2 and 1
_{1.3Hz, C 6 -H (B)} ), 4.22 (1H × 0.53, ddq, J = 3.0,6.2
And 11.3Hz, C ₆ -H (A)), 4.57 (1H × 0.47, d, J = 4.6H
z, C ₂ -H (B)), 4.66 (2H × 0.53, s, CH ₂ Ph (A)), 4.
67 (2H x 0.47, s, CH ₂ Ph (B)), 4.91 (1H x 0.47, ddd, J
= 2.4, 6.7 and 9.6 Hz, C ₄ -H (B)), 5.14 (1H × 0.53,
_{d, J = 4.7Hz, C 2} -H (A)), 5.42 (1H × 0.53, ddd, J = 1.
2,2.3 and 3.4Hz, C ₄ -H (A), 7.3 ~ 7.4 (5H, m, aroma
tic protons). However, the proton marked with (A) is a signal of 4S-form, and the proton marked with (B) is a signal of 4R-form.

Mass m / e 195,146,135,107,91. Example 8 (2R, 6R) -2- [1- (S) -Benzyloxyethyl] -6-methyl-1,3-dioxan-4-ol 7.63 g
Dissolve (30.2 mmol) in 100 ml of dichloromethane, and under ice cooling,
12.6 ml (90.4 mmol) triethylamine and thionyl chloride 2.
6 ml (35.3 mmol) was added and the mixture was stirred at 40 ° C. for 2 hours. After returning the reaction solution to room temperature, it was diluted with ether and water was added to stop the reaction. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (silica gel; hexane → hexane: ether 50: 1) to give (2R, 6R) -2- [1- (S) -benzyloxyethyl. ] -6-Methyl-2H, 6H-1,3-dioxin 4.93 g
(70% yield) was obtained as a yellow oil.

▲ [α] ²⁰ _D ▼ -51.9 ° (C = 1.22, CHCl ₃ ) IR (naet) 2990,2870,1640,1450,1312,1220,730,695cm
⁻¹ .H-NMR (CDCl ₃ ) δ: 1.23 (3H, d, J = 6.4Hz, CH ₃ CHOBn),
1.26 (3H, d, J = 6.4Hz, CH ₃ CHCH ₂ ), 3.62 (1H, dq, J = 4.4
And 6.4 Hz, C H OBn), 4.52 (1H, dq, J = 1.3 and 6.4 Hz, C ₆
-H), 4.67 (2H, s , CH 2 Ph), 4.78 (1H, dd, J = 1.3 and 6.
_{4Hz, C 5 -H), 4.93} (1H, d, J = 4.6Hz, C 2 -H), 6.50 (1
H, (dd, J = 1.5 and 6.4Hz, C ₄ -H), 7.32 (5H, s, aromati
c protons). ^{Mass m / e 234 (M +} ), 143 (M-CH 2 Ph) +, 135,91. Example 9 (2R, 6R) -2- [1- (S) -benzyloxyethyl] -6-methyl-2H, 6H-1,3-dioxin 2.80 g (12.
(0 mmol) was dissolved in 30 ml of toluene, 1.15 ml (13.2 mmol) of chlorosulfonylisocyanate was added at -60 ° C, and the mixture was stirred at the same temperature for 3 hours. 7.2 ml of a toluene solution of sodium bis (methoxyethoxy) aluminum was added, the temperature was gradually raised, and the mixture was stirred at -50 ° C for 1 hour. The reaction solution was transferred to a mixture solution of ice-cooled Rochelle salt aqueous solution (60 g / 200 ml) and 100 ml of toluene, and stirred at the same temperature for 30 minutes. The insoluble material was filtered, the organic layer was separated, and washed with saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography (Silygel; hexane: ethyl acetate = 5: 1 → 1: 1) to obtain (1S, 3R, 5R, 6R) -8-
Aza-3- [1- (S) -benzyloxyethyl] -5
-Methyl-2,4-dioxabicyclo [4.2.0] octane-
7-one (1.85 g, yield 56%) was obtained as colorless crystals. The analytical sample was obtained by recrystallization from a mixed solution of ethyl acetate-n-hexane.

Melting point 103.0 to 103.5 ° C [α] ²⁰ _D ▼ -30.9 ° (C = 1.15, CHCl ₃ ) IR (KBr) 3200,1760,1715,1380,1158,1118,980,695c
^{. m -1 H-NMR (CDCl} 3) δ: 1.21 (3H, d, J = 6.5Hz, C H 3 CHOB
n), 1.43 (3H, d, J = 6.3Hz, C H ₃ CH), 2.92 (1H, ddd, J =
4.2, 4.6 and 6.3Hz, C H C = O), 3.56 (1H, dq, J = 4.2 and 6.5Hz, C H OBn), 4.22 (1H, quint, J = 6.3Hz, C H CH ₃ ),
_{4.65 (2H, s, CH 2} Ph), 4.86 (1H, d, J = 4.2Hz, C H CHOBn),
5.43 (1H, d, J = 4.6Hz, C H NH), 6.15 (1H, br, NH), 7.26
~ 7.36 (5H, m, aromatic protons). Mass m / e 278 (M + 1) ⁺ , 232,204,171 (M-OCH ₂ P
h) ⁺ . Elemental analysis value measured as C ₁₅ H ₁₉ NO ₄ C; 64.97 H; 6.91 N; 5.05%. Analytical value C; 64.95 H; 6.99 N; 4.99%. Example 10 (1S, 3R, 5R, 6R) -8-Aza-3- [1- (S) -benzyloxyethyl] -5-methyl-2,4-dioxabicyclo [4.2.0] octane-7-one 1.32 g (4.75 mmol) was dissolved in ethanol (7 ml), 20% palladium hydroxide-carbon (90 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. After filtering the insoluble matter, the solvent was distilled off under reduced pressure (1S, 3R, 5R, 6R)-
8-Aza-3- [1- (S) -hydroxyethyl] -5
-Methyl-2,4-dioxabicyclo [4.2.0] octane-
0.887 g (quantitative yield) of 7-one was obtained as colorless crystals.
The analytical sample was obtained by recrystallization from a mixed solution of ethyl acetate-n-hexane.

Melting point 91.5-92.0 ° C ▲ [α] ²⁰ _D ▼ + 17.8 ° (C = 1.08, CHCl ₃ ) IR (KBr) 3450,3350,3300,1758,1380,1105,995,700c
^{. m -1 H-NMR (CDCl} 3) δ: 1.22 (3H, d, J = 6.6Hz, C H 3 CHOH),
1.43 (3H, d, J = 6.2Hz, C H ₃ CH), 2.08 (1H, d, J = 4.6Hz, O
H), 2.92 (1H, ddd, J = 4.2, 4.6 and 6.4Hz, CHC = O), 3.7
~ 3.9 (1H, m, C H OH), 4.24 (1H, quint, J = 6.4Hz, CH ₃ C
H ), 4.72 (1H, d, J = 4.6Hz, C H CHOH), 5.45 (1H, d, J =
4.6Hz, C H NH), 6.16~6.28 (1H, br, NH) Mass m / e 188 (M + 1) +, 142 (M-CH 3 CHOH) +, 126,
98. Elemental analysis value calculated as C ₈ H ₁₃ NO ₄ C; 51.33 H; 7.00 N; 7.48%. Analytical value C; 51.20 H; 7.12 N; 7.43%. Example 11 (1S, 3R, 5R, 6R) -8-Aza-3- [1- (S) -hydroxyethyl] -5-methyl-2,4-dioxabicyclo [4.2.0] octane-7-one 887 mg ( 4.74 mmol) is dissolved in a mixed solution of 10 ml of carbon tetrachloride, 10 ml of acetonitrile and 15 ml of water, and 1.66 g (7.28 mmol) of periodate dihydrate and 19.7 mg (0.087 mmol) of ruthenium (III) chloride hydrate are added. 1
Stir for hours. Dichloromethane was added to the reaction solution to extract organic matter, and the aqueous layer was extracted with a mixed solvent of chloroform-ethanol 3: 1. The organic layers were combined and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography (silica gel, dichloromethane: acetone = 1: 0 to 9: 1) to obtain (1S, 3R, 5R, 6R) -8-aza-3-. Acetyl-5-methyl-2,4-dioxabicyclo [4.2.0] octane-7-one (776 mg, yield 88%) was obtained as colorless crystals. The analytical sample was obtained by recrystallization from a mixed solution of ethyl acetate-n-hexane.

Melting point 86.5-87.0 ° C [α] ²⁰ _D ▼ + 16.9 ° (C = 1.14, CHCl ₃ ) IR (KBr) 3200,3000,1750,1735,1140,740 cm ⁻¹ .H-NMR (CDCl ₃ ) δ : 1.48 (3H, d, J = 6.4Hz, CH ₃ CH), 2.2
6 (3H, s, CH ₃ C = O), 3.00 (1H, ddd, J = 4.2 and 4.4 and
6.4Hz, C H C = O) , 4.32 (1H, quint, J = 6.4Hz, C H C
H ₃ ), 5.06 (1H, s, C H COCH ₃ ), 5.48 (1H, d, J = 4.4Hz, CH
N), 6.3-6.6 (1H, br, NH). Mass m / e 186 (M + 1) ⁺ , 142 (M-CH ₃ CPO) ⁺ , 98.6
9. Elemental analysis value calculated as C ₈ H ₁₁ NO ₄ C; 51.89 H; 5.99 N; 7.56%. Analytical value C; 51.65 H; 5.98 N; 7.40%. Example 12 (1S, 3R, 5R, 6R) -8-aza-3-acetyl-5-methyl-2,4-dioxabicyclo [4.2.0] octane-7-one 32.4 mg (0.175 mmol) was added to ethyl acetate 0.5 ml. Dissolved in m
-Chloroperbenzoic acid (150.7 mg, 0.70 mmol) was added and the mixture was stirred for 10 minutes. The solvent was distilled off under reduced pressure and the obtained residue was purified by column chromatography (silica gel; dichloromethane: acetone = 1: 0 to 9: 1) to give (1S, 5R, 6R) -8-aza-.
5-Methyl-2,4-dioxabicyclo [4.2.0] octane-3,7-dione (8.6 mg, yield 31%) was obtained as colorless crystals. The analytical sample was obtained by recrystallization from 1,2-dichloroethane.

Melting point 127 to 127.5 ° C ▲ [α] ²⁰ _D ▼ -140.2 ° (C = 1.02, AcOEt). IR (KBr) 3270,3200,1775,1740,1400,1200,1080,1000,6
00cm ^-1 .H-NMR (CDCl ₃ ) δ: 1.55 (3H, d, J = 7.1Hz, CH ₃ ), 3.50
(1H, ddd, J = 1.7,2.3 and 4.4Hz, CHC = O), 4.92 (1H, d
q, J = 1.7 and 7.1Hz, CH ₃ CH), 5.80 (1H, d, J = 4.4Hz, CH
N), 6.7-7.0 (1H, br, NH). Mass m / e 158 (M + 1) ⁺ , 113 (M-CO ₂ ) ⁺ , 98,69. Elemental analysis value C ₆ H ₇ NO ₄ calculated value C; 45.87 H; 4.49 N; 8.91%. Analytical value C; 45.79 H; 4.36 N; 8.90%. Reference example 7 (1S, 5R, 6R) -8-aza-5-methyl-2,4-dioxabicyclo [4.2.0] octane-3,7-dione 41.7 mg (0.26
6mmol) in 0.5ml of acetic acid, sodium acetate 25.1mg
(0.306 mmol) was added and the mixture was stirred at 40 ° C overnight. The solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (silica gel; hexane: ethyl acetate = 4: 6 → 3: 7) to give (3R, 4R) -3- [1- (R)- Hydroxyethyl]
-4-acetoxy-2-azetidinone 36.8 mg (yield 80
%) As colorless crystals. The analytical sample was obtained by recrystallization from ethyl acetate.

Melting point 113-114 ° C ▲ [α] ²⁰ _D ▼ + 78.0 ° (Cp1.07, MeOH). CR (KBr) 3500,3250,3000,1750,1725,1241,991,699c
m ^-1 .H-NMR (CDCl ₃ ) δ: 1.35 (3H, d, J = 6.4Hz, CH ₃ ), 2.10
(1H, d, J = 3.5Hz, OH), 2.12 (3H, s, O = CCH ₃ ), 3.22 (1
H, dd, J = 1.3 and 5.9Hz, CHC = O), 4.19 (1H, m, CHOH),
5.81-6.3 to 6.6 (1H, br, NH). Mass m / e 174 (M + 1) ⁺ , 130 (M-CH ₃ C = O) ⁺ , 11
5,87. Elemental analysis value Calculated as C ₇ H ₁₁ NO ₄ C; 48.55 H; 6.40 N; 8.09% Analytical value C; 48.42 H; 6.39 N; 8.00% Reference Example 8 (3R, 4R) -3- [1- (R) -hydroxyethyl]-
4-acetoxy-2-azetidinone 0.347 g (2.01 mmol)
Is dissolved in 4.0 ml of dimethylformamide and imidazole is added.
0.324g (4.76mmol) and t-butyldimethylchlorosilane
0.333 g (2.21 mmol) was added and the mixture was stirred at room temperature overnight. 8 ml of water
Was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with water, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by column chromatography (silica gel; dichloromethane: ethyl acetate = 9: 1) to obtain (3R, 4R) -3- [1-
(R) -t-butyldimethylsilyloxyethyl] -4
0.525 g (yield 89%) of -acetoxy-2-azetidinone was obtained as a colorless solid.

The analytical data of this product were in agreement with those of Reference Example 9 below.

Reference example 9 (1S, 5R, 6R) -8-Aza-5-methyl-2,4-dioxabicyclo [4.2.0] octane-3,7-dione 12.6 mg (0.08
0 mmol) was dissolved in 0.2 ml of acetic acid and 46 mg of potassium acetate (0.47
(mmol) and stirred for 4 hours, the solvent was evaporated under reduced pressure. This was made into a dimethylformamide solution without purification, and 50 mg (0.73 mmol) of imidazole and 240 mg (1.60 mmol) of t-butyldimethylchlorosilane were added.
Stir overnight. Water was added to the reaction solution to stop the reaction, the organic matter was extracted with ethyl acetate, and the organic layer was washed with saturated brine.
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the obtained residue was subjected to column chromatography (silica gel;
Purify with hexane: ethyl acetate = 4: 1) to obtain (3R, 4R)-
3- [1- (R)-(t-butyldimethylsilyloxy) ethyl] -4-acetoxy-2-azetidinone 22.4
mg (yield 97%) was obtained as colorless crystals. The analytical sample was obtained by recrystallization from cyclohexane.

Melting point 107-107.5 ° C [α] ²⁰ _D ▼ + 45.1 ° (C = 1.07, CHCl ₃ ). (Reference value; melting point 108 to 109 ° C. [α] ²⁵ _D + 47.8 ° (C = 0.56, CHCl ₃ ). Y. Ito, T. Kawabata, S. Terashima, TL, 47 , 5751 (198
6). ) IR (KBr) 3200,2950,2930,2850,1780,1740,1377,1227,1
^{. 035,832,772cm -1 H-HMR (CDCl} 3) δ: 0.07 (6H, s, (CH 3) 2 Si), 0.87 (9
_{H, s, (CH 3)} 3 C), 1.25 (3H, d, J = 6.4Hz, CH 3 CH), 2.10
(3H, s, CH ₃ C = O), 3.18 (1H, dd, J = 1.3 and 3.7Hz, C H
C = O), 4.22 (1H, m, CHCH ₃ ), 5.84 (1H, d, J = 1.3Hz, CH
N), 6.4 to 6.5 (1H, br, NH).

Claims (2)

[Claims] 1. A general formula [In the formula, R ¹ represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group or an aryl group, and R ² represents a hydrogen atom or a hydroxyl group-protecting group. Also, Is a single bond, Y represents C = O or CHOH, Is a double bond, Y is A 6-methyl-1,3-dioxane derivative represented by: 2. General formula [In the formula, R ³ and R ⁴ are hydrogen atoms or (R ¹ represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group or aryl group, and R ⁵ and R ⁶ represent a hydrogen atom, a hydroxyl group, or a protected hydroxyl group. R ⁵ and R ⁶ Can form a carbonyl group together with the bonded carbon atom) or can form a carbonyl group together with the bonded carbon atom. ] The 1,3-dioxane derivative represented by these.