JPH02172985A - 1,3-dioxan derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> represents H, (substituted) alkyl or aryl; R<2> represents H or hydroxy-protecting group; Y represents C=O, CHOH, etc.]. EXAMPLE:(2R,6R)-2-Benzyloxymethyl-6-methyl-1,3-dioxan-4-one. USE:A synthetic intermediate for carbopenem based antibiotics. PREPARATION:For example, an (R)-3-hydroxybutyric acid ester expressed by formula II (R<8> represents carboxyl-protecting group) is hydrolyzed by treating with a base to form an (R)-3-hydroxybutyric acid. An aldehyde derivative expressed by formula III (example; benzyloxyacetaldehyde) is then added and reacted therewith in dichloromethane in the presence of pyridinium p- toluenesulfonate, etc., under reflux with heating to afford the compound expressed by formula I.

Description

[Detailed description of the invention] [Industrial application field] The present invention is based on the general formula Methyl-1,3-dioxane derivative.

[In the formula, R1 represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group, or an aryl group, and R1
represents a hydrogen atom or a protecting group for a hydroxyl group, and --
When -1-......- is a single bond, Y represents C-0 or CHOH, and when 222 is a double bond, Y represents 7CH.] 6- methyl - can be taken together with the carbon atom to which it is attached to form a carbonyl group) or can be taken together with the carbon atom to which it is attached to form a carbonyl group. ] The present invention relates to a 4-amido-1,3-dioxane derivative represented by the following.

1, 3 represented by general formulas (1) and (II) of the present invention
-Dioxane derivatives can be prepared, for example, in the general formula C, R1 and R4 represent a hydrogen atom or (R' represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group, or an aryl group, and R8 and R& Represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, and also Rs and Rh
is a bond [in the formula, R? represents a hydrogen atom or a protecting group for a hydroxyl group, and is useful as a raw material for the synthesis of 4-acetoxy-2-azetidinone derivatives.

The 4-acetoxy-2-azetidinone derivative represented by the general formula (Tel) can be used as an important synthetic intermediate for carbapenem antibiotics such as chenamycin, which exhibits excellent antibacterial activity (T,) [asetanl et al., Reteroc.
ycles, IL 463 (1982), ) * [Prior art] Conventionally, methods for synthesizing an optically active 4-acetoxy-2-azetidinone derivative represented by the general formula (Iff) include 1)
Those using 6-amitubenicilanic acid as a starting material (F, D
iNInno et al., J.O.C., 42, 2960 (19
77).

K, Hlral et al., HeterocycLes,
17.2001982), )2) D-allo-
Those starting from threonine (M, 5hioza
kl et al., Tetrahefron, 39.2399 (
1983), )3) Those using L-threonine as a starting material (LMaruyama et al., Bull, Chem.
, Soc, Jpn, 58.3264 (1985)
,) 4) Those using L-aspartic acid as a starting material (P
, J, R51der et al., T@trahedron
Lett, 23.2293 (1982), ) 5)
A method whose key step is the reaction of an erulate obtained using methyl (S) or (R)-3-hydroxybutyrate as a starting material with an imine [Chiba et al., Chem.
, Lett, , 651 (1985), ) 6)
(R) A method whose key step is an addition reaction between a silyl enol ether obtained using methyl-3-hydroxybutyrate as a starting material and chlorosulfonyl isocyanate [Oran et al., JP-A-61-18791 (1986),]? )(S
) - those using ethyl lactate as a starting material (Y, Ito et al., etrahedron Lett, 27.575
1 (1986), ) etc. have been reported.

[Problem that the invention seeks to solve]

However, in both methods, the starting materials or reactants are expensive (Methods 2 and 5), the number of steps is large (Method 1), and there are problems with post-reaction waste disposal such as mercury acetate or lead tetranoate. (methods 1, 3 and 4), and the removal of the protecting group at the 1-position N of 2-azetidinone requires a complicated operation (methods 1, 3 and 4).
Methods 2, 3゜and 7), the stereoselectivity of the reaction is low or the control thereof involves steps that are laborious (methods 4゜5, and 6), and relatively expensive protecting groups are not used in the initial step. The overall manufacturing cost is high due to the introduction of method 6.
) etc., each of which would be extremely difficult to implement industrially (
It has some drawbacks.

As a result of intensive studies to overcome these conventional drawbacks, the present inventors have discovered that aldehydes derived from inexpensive α-oxyacids such as lactic acid are produced more cheaply than by fermentation methods.
A novel 1,3-dioxane derivative obtained using R)-3-hydroxybutyric acid as a starting material achieves the above-mentioned (
The present invention was completed by discovering that the compound is a useful compound for synthesizing the important synthetic intermediate of carbapenem represented by (2).

[Means for solving problems]

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

Human No (Ic) [In the formula, R' is a hydrogen atom, substituted or unsubstituted 11 [
or represents a branched alkyl group or an aryl group, and R
1 represents a protecting group for the carboxyl group.] [First step] In this step, the (R)-3-hydroxybutyric acid ester represented by the general formula (TV) is treated with a base and hydrolyzed to form the formula (V
) The (R)-3-hydroxybutyric acid ester used in the zero reaction, which is the process of producing (R)-3-hydroxybutyric acid represented by
Methyl 3-hydroxybutyrate, (R)-ethyl 3-hydroxybutyrate, (tip→propyl-3-hydroxybutyrate, (
R)-3-hydroxybutyric acid polymer and the like.

Further, as the base, a base that is usually used to hydrolyze 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 alcohol solvents such as methanol, ethanol, propatool, and butanol, ether solvents such as diethyl ether and tetrahydrofuran, and water are used alone or as a mixture. It proceeds smoothly at 20°C to 100°C (see Reference Example 1).

(Second step) This step involves combining (R)-3-hydroxybutyric acid (V) with the formula (
6-methyl-1,3-dioxane-4-, which is a compound of the present invention represented by general formula (fa), is reacted with an aldehyde derivative represented by Vl) in the presence of a catalyst and the resulting water is removed. The substituents bonded to the 2- and 6-positions in the general formula (Ia) obtained in the step 0, which is the step of producing an on derivative, are mainly in the cis configuration, as shown in the formula (Im). It is obtained with high stereoselectivity as a product (D.

5eebach+”Modern 5ynthstlc
Methods Vol, 4'ed byR, 5c
heffold+ Sprlnger-Verlag,
BerlIn+p, 205 (1986)) The aldehyde derivatives used in this reaction include alkoxy groups such as t-butoxy, benzyloxy, tetrahydropyranyloxy, methoxymethoxy, methoxyethoxymethoxy, and 1-butyldimethylsilyloxy. Examples include α-alkoxy alkanals having acetaldehyde, propanal, butanal, pentanal, 3-phenylpropanal, and 4-phenylbutanal in the position, but 2-benzyloxypropanal is preferably used (reference Examples 2 to 6) Catalysts used in the reaction include acids such as p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, boric acid, and phosphoric acid, or their pyridine salts, but preferably , p-) As a dehydration method for carrying out the zero step using pyridine salt of luenesulfonate (PPTS), a method using azeotropic vaporization with a catalyst is mainly used. As a solvent, benzene, toluene,
Examples include hydrocarbon solvents such as xylene, pentane, hexane, and heptane, ether solvents such as diethyl ether and tetrahydrofuran, and halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane. 10 (l (see Examples 1 and 6)).

[Third step] In this step, 6-methyl-1, represented by -M formula (Ia),
A 6-methyl-1,3-dioxan-4-ol derivative represented by general formula (Ib) is produced by treating a 3-dioxan-4-one m conductor with a reducing agent. Conventionally, methods for producing lactol by reducing lactones have been known, but until now - 1,3-dioxan-4-one derivatives represented by maximum (Ia) were subjected to ring-opening of the dioxane ring under reducing reaction conditions. No attempt has been made to derive a 6-methyl-1,3-dioxan-4-ol derivative represented by the general formula Nb) without the following. Note that the steric configuration of the 4-position hydroxyl group in the general formula Nb) produced in this reaction is a mixture of (R) and (S), but these are used as a raw material for the next 4th step without being separated. As the reducing agent used in this step, any reducing agent that is normally used when reducing a lactone to synthesize the corresponding lactol can be used, but diisobutylaluminum hydride (
DIBAL) or sodium bis(methoxyethoxy)aluminum hydride (Vltrlda) in an amount of 1 to 2 equivalents is carried out in a solvent, and the solvent is usually any solvent that does not participate in the reduction reaction. You can also use
Preferably, an ether solvent such as diethyl ether or tetrahydrofuran, or a hydrocarbon solvent such as benzene, toluene or xylene is used.
˜20 t” (see Examples 2 and 7).

[Fourth step] This step is a 6-methyl- represented by general formula 9 (Ib).
A 6-methyl-2H,6H-1,3-dioxin derivative, which is a compound of the present invention represented by the general formula (IC), is produced by dehydrating a 1,3-dioxan-4-ol derivative. Conventionally, the hydroxyl group was removed and converted into an olefin (
Although the method is known, the 6-methyl-1,3-dioxan-4-ol derivative represented by -Cheng (Ib) is dehydrated without ring opening to obtain 6-methyl-1,3-dioxan-4-ol derivative represented by general formula (Ic). -Methyl-
No attempt has been made to produce 28,6H-1,3-dioxin derivatives. The dehydration method is to acylate the hydroxyl group, then replace it with a halogen atom such as chlorine or bromine by treating with a halide such as hydrogen chloride or hydrogen bromide, and then perform a dehydrohalogenation reaction by treating with a base. There is a method of deriving it into an olefin, or a method of directly deriving it into an olefin by treating it with a dehydrating agent in the presence of a base, and the latter method is preferably used. Dehydrating agents used in the latter method include thionyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl bromide, J
Methanesulfonyl L, p-)luenesulfonyl bromide, phosphorus oxybromide, phosphorus tribromide, phosphorus pentabromide, etc.
1.5 equivalents are used. As the base, a base that promotes the elimination reaction is usually used, such as trimethylamine, triethylamine, tripropylamine, tributylamine,
N-ethylpiperidine, pyridine, lutidine, collidine, 1,5-diazabiscif'Q (4,3,01)7-5
Examples include 7.1.4-diazabicyclo(2,2,2)octane, 1,8-diazabicyclo(5,4,0)-7-undecene, and triethylamine is preferably used. The base is used in an amount of 1 to 5 equivalents relative to the dehydrating agent.The reaction is carried out in a solvent. Examples of solvents include basic solvents such as pyridine, collidine, and lutidine, polar solvents such as dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, and hexamethylphosphoric triamide, dichloromethane, chloroform,
Examples of 0 reactions include halogenated hydrocarbon solvents such as tJ, hydrocarbon solvents such as benzene, toluene, xylene, and hexane, and ether solvents such as diethyl ether, dibutyl ether, tetrahydrofuran, and dioxane. -to'c~!00°C (see Examples 3 and 8).

[Fifth step] This step is a process in which 6-methyl-2 represented by -fulfillment (I c)
By reaction of H,6H-1,3-dioxin derivatives with chlorosulfonyl isocyanate (C3) and subsequent (reductive work-up), 4-amide-1, which is a compound of the present invention represented by -achievement (na) , 3-dioxane derivative.

Although a method for producing 2-azetidinone derivatives by addition of an olefin and C3I is known, the yield and stereoselectivity for -M are low (and it has been difficult to implement it industrially). W, A, 5zabo.

Aldrlchlmlca Acta, 10.23(1
977)).

However, the addition reaction between the 6-methyl-2H,6H-1,3-dioxin derivative represented by the general formula (IC) and C31 of the present invention proceeds with extremely high stereoselectivity, and -achievement (n
It was found that only the stereochemistry shown in a) was obtained. C3I is used in an amount of 1 to 2 equivalents relative to the substrate, but preferably 6 reactions in which 1.1 equivalents are used are carried out in a solvent. Examples of the i-medium 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, The reaction using a polar solvent such as hexamethylphosphoric triamide proceeds smoothly at -70°C to 50°C. Further, as the reducing side used in the reductive post-treatment after the reaction, metal hydride compounds such as lithium aluminum hydride, sodium bis(methoxyethoxy)aluminum hydride, sodium borohydride, diisobutylaluminum hydride,
Organic sulfur compounds such as thiophenol, methyl mercaptan, ethyl mercaptan, propyl mercaptan, dimethyl sulfide, diethyl sulfide, sulfites such as lithium sulfite, sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, lithium thiosulfate, thiosulfate thiosulfates such as sodium and Raney nickel (Examples 4 and 9).
).

[Sixth Step] This step consists of forming a 4-amide represented by the general formula (Tla) to 1.
Protecting group R for the hydroxyl group on the 2-position side chain of the 3-dioxane derivative
1 is deprotected to produce a 4-amido-1,3-dioxane derivative, which is the compound of the present invention represented by (II b). Deprotection can be carried out according to the method normally used for deprotecting hydroxyl-protecting groups (Protective Groups
n Organic 5ythes1a, John-1
1i1y & 5oz.

Ne11York, 1981. (See Examples 5 and 10).

[Step 7] This step oxidizes the hydroxyl group on the 2-position side chain of the 4-amido-1,3-dioxane derivative having a free hydroxyl group represented by -achievement <nb> to obtain the general formula ( A 2-acyl-1,3-dioxane derivative, which is a compound of the present invention represented by I[e), is produced.

As the oxidizing agent, an oxidizing agent that can oxidize alcohol to the corresponding ketone is used. For example, chromic acids such as chromium dioxide, pyridinium chlorochromate, and pyridinium dichromate, dimethyl sulfoxide derivatives, and ruthenium trichloride are used in the reaction system. The reaction in which a luteme compound produced by oxidation with periodine MM is used is preferably carried out in a solvent, and examples of the solvent include basic solvents such as pyridine, collidine, and lutidine, dimethyl sulfoxide, N,N-dimethylformamide, etc. ,N.

Polar aprotic solvents such as N-dimethylacetamide, hexamethylphosphoric triamide, and acetonitrile, halogenated hydrocarbon solvents such as dichloromethane, chloroform, and carbon tetrachloride, hydrocarbon solvents such as benzene, toluene, and hexane, and acetone. , 2-butanone,
Ketone or ester solvents such as methyl acetate, ethyl acetate, and amyl acetate, protic solvents such as t-butanol and water, and mixed solvents thereof can be used as examples. See Example 11).

[Eighth Step] Examples include ruthenium compounds, and preferably ruthenium compounds.This step is preferably performed using 2-acyl-1,3
- By treating the dioxane derivative with peracid, the formula (n
2-oxo-1, which is a compound of the present invention represented by d)
, 3-dioxane derivative.

The filtration acids used in this reaction include m-chloroperbenzoic acid, peracetic acid, pertrifluoroacetic acid, performic acid, and perphthalic acid. A peroxide used in the ger reaction is used. The peracid is used in an amount of 1 to 5 equivalents of the substrate, preferably 4 equivalents. As a solvent,
Hydrocarbon solvents such as benzene, toluene, hexane, etc.
diethyl ether, tetrahydrofuran, dioxane,
1. Ether solvents such as 2-dimethoxyethane, halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, ester solvents such as methyl acetate, ethyl acetate, amyl acetate, N,N-dimethylformamide, N , N-dimethylacetamide, polar solvents such as hexamethylphosphoric triamide, and acetic acid, propionic acid, r! A carboxylic acid such as a acid is used0
The reaction proceeds smoothly at -40°C to 50°C (Example 12)
reference).

The 2-oxo-1,3-dioxane derivative represented by formula (II d) synthesized by the above manufacturing process can be synthesized by the following process to produce 4-oxo-1,3-dioxane derivative, which is an important synthetic intermediate for carbapenems.
It can be induced into acetoxy-2-azetidinone (m).

[In the formula, Ht represents a hydrogen atom or a protecting group for a hydroxyl group.] In this step, the 2-oxo-1,3-dioxane derivative represented by the formula (II (1)) obtained in the eighth step is The carboxylic acid derivatives used in the reaction include formic acid, acetic acid, propionic acid, Catalysts for the zero-reaction, such as butyric acid and benzoic acid, include lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, zinc salts, etc. of the carboxylic acid FA conductor, depending on the carboxylic # derivative used. The reaction is carried out without a solvent or in a solvent, and solvents include polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, methyl acetate, ethyl acetate, Examples include ester solvents such as amyl acetate, halogen hydrocarbon solvents such as dichloromethane, chloroform, and carbon tetrachloride, and aromatic hydrocarbon solvents such as benzene, toluene, and xylene.

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

A protecting group can be introduced into the hydroxyl group on the 3-position side of the 4-acetoxy-2-azetidinone derivative (III) obtained in the above reaction according to a conventional method for protecting a hydroxyl group (f'roLectlve Groups lnO
rganic 5yntheaiss John Wl
lley & 5on3゜New Work, 1981
p, 10-86. (See Reference Examples 8 and 9).

The present invention will be described in detail below with reference to Examples and Reference Examples, but the present invention is not limited thereto.The meanings of the abbreviations are as follows.

80: Acetyl group Ar+ 7-lyl group Bn8 Benzyl group Me: Methyl group Phl Phenyl group Reference example 1 (R)-(-)-3-hydroxybutyrate methyl 20.2g
(171 mmo I) was added with 180 ml of IN sodium hydroxide aqueous solution under ice cooling, and after being left at the same temperature for 6 days,
180 ml of IN hydrochloric acid was added, and the solvent was distilled off under reduced pressure. After adding ethanol to the obtained residue and filtering out insoluble materials, the solvent was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure to obtain (R)-
(-)-3-hydroxybutyrofi 15.5g (yield 87%)
) was obtained as a colorless oil.

bp 130℃ (l Tsurufig) [α), ”-24,1' (C-4,66, Hg
0) Literature value [α) m -25,2° (c-5, Hg
o) (D, 5eebach, '''Modern 5y
thetlc Methods Vol, 4'ad b
y R, 5cheffol! , Spring-Verl
ag, BerlIn.

p, 205 (1986),) IR (neat) 2800-3400br.

1710, 1400. 1060.942°845
am-'3.2~3.5<2H,br, otherprot
ons), 3.97 (IH, dQ.

J-6,2 and 6.4Hz, CHOH).

Mass m10 105 (M+1)'(M
-CHI)'', 71.60° Reference Example 2 5.0 ml of benzyloxyacetyl chloride was added to a mixed solution of 5.1 ml of pyridine (63.1 mmo 1), 2.1 ml of methanol (51.8 fnmo 1) and 100 ml of dichloromethane at 0°C. (31,7 mmo
1) was added and stirred overnight at room temperature. Water was added to the reaction solution to separate the layers, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was distilled under reduced pressure to obtain methyl benzyloxyacetate5.
70 g (quantitative yield) was obtained.

bp 12Q~124℃ (1 crane Hg) H-NMR (C
DCI δ: 3.76 (3H, s.

0CHs), 4.11 (2H,s, CHg).

4.63 (2H,s, CH,), 7.35 (5H,s
, aromatlc protons).

Methyl benzyloxyacetate 2.50 g (13.9m
mol) to ether 45m! 16.0 ml of diisobutylaluminum hydride (IM n-hexane solution) was added at -78°C, and after stirring at the same temperature for 1 hour,
Insoluble matter was filtered through Celite. The residue obtained by evaporating the solvent under reduced pressure was distilled using Kugelol to obtain 1.40 g (yield: 67%) of benzyloxyacetaldehyde.

bp　100℃(1 crane Hg) NMR (CDC1s) δ: 4.08 (2H, s.

CH,), 4.62 <2H,s, CHm).

7.35 (5H,s, aromat 1cproto
ns), 9.72 (IH, l.

CHO).

Reference example 3 (R)-3-hydroxy acid #1.32g (12,7
mmol) and benzyloxyacetaldehyde 1.29
g (8,60 mmo +) in dichloromethane 60 m
350 μm (1,46 mmof) of pyridinium p-toluenesulfonate was added to Dean-3.
The reaction solution was heated under reflux for 57 hours while distilling off the water produced using a tarck apparatus, and then returned to room temperature, water was added to stop the reaction, and the solution was extracted with dichloromethane. Saturate the organic layer
After washing with water and saturated saline, it was dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (silica gel; hexane: ethyl acetate-9).
:1→7:l) to give (2R,6R)-2-benzyloxymethyl-6-methyl-1,3-dioxane-4
-one 1.48g (yield 7υ0) was obtained.

H-NMR (CDCIs) δ: 1.36 (3Hd, J=
6.2Hz, CHs), 2.4-2.7 (2H, m, C
HJl 3.67 (2H, d.

J=4.4H2ICHgOBn), 3.96-4.4
(I H, m, Cm-H), 4.62 (2
H,s, DanH1Ph), 5.45 (IH.

t, J-4,4Hz, Cm H), 7.
33 (5H,s, aromat 1cpro
tons).

Example 2 1.46 g (2R,6R)-2-benzyloxymethyl-6-methyl 1,3-dioxan-4-one (6,20
mmol) in 30 ml of ether, 7.4 ml of diisobutylaluminum hydride (LM in n-hexane solution) was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. The mixture was poured into a mixture of 30 ml of water and 30 ml of ether, stirred until the two layers became transparent, and then separated. The organic layer was washed with saturated brine and then dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (silica gel, hexane; ether - 3:1 to 1:1) (2R, 5R
)-2-benzyloxymethyl-6-methyl-1,3-
1.19 g (yield: 80%) of dioxan-4-ol was obtained. This product is a mixture of the (R)-isomer and (S)-isomer of the 4-position hydroxyl group, but these remain as a mixture without being separated. This was used as a raw material for Example 3 below.

H-NMR (CDCIs) δ: 1.20.1.26 (
A total of 31 (, d, CHD, 1.6 to 1.8 (2H,
m, CH,), 3.0.3.4 (total l H, O
H), 3.5-3.6 <2) T, m.

CHtOBn), 3.8-4.3 (IH, m.

Cb H), 4.59 (2H, 3, OCH YuPh)
, 4.7-5.0 (I H, m, C4H).

5.4 (LH, to cl l(), 7.3
2 (5H, s, aromatic protons).

Example 3 1.15 g (2R,6R)-2-benzyloxymethyl-6-methyl-1,3-dioxan-4-ol (4
, 85 mmol) was dissolved in 15 ml of dichloromethane, and 2.0 ml (14.3 mmol 1) of triethylamine was dissolved in 15 ml of dichloromethane.
and 0.42 ml (5.76 mmol 1) of thionyl chloride were added thereto, and the mixture was stirred at 40°C for 2 hours. Return to room temperature and add 1 more
After stirring overnight, the reaction solution was diluted with 1-hexane, and water was added to stop the reaction. Extract the organic matter with n-hexane,
After washing with saturated saline, it was 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-3
00:1→511) to give (2R,6R)-2-
benzyloxymethyl-6-methyl-28,6H-1,
407 ml of 3-dioxin (yield 3B%) was obtained.

H-NMR (CDCIs) δ+ 1.27 (3H.

d, J” 6.6Hz, CHs), 3.60
(2H.

d, J-4,6Hidandan*0Bn), 4.48~4.
7 (IH, m, CM-H), 4.62 (2H.

s, CHmPh), 4.79 (IH, dd.

J-1,3 and 6.4Hz, C5-H), 5.15(I
H, t, J-4,7Hz, Cm-H).

6.48 (IH, dd, J-1,4 and 6.3Hz.

Ca-H), 7.33 (5H, s.

aromatic protons).

υ (2R,6R)-2-benzyloxymethyl-6-methyl-2H,6H-1,3-dioxin 196wg (0
,892mmo 1) in 3ml of toluene, -5
Chlorosulfonyl isocyanate 78 μJ (0
, 892 mmol) and stirred at the same temperature for 2.5 hours.
．． Add 0.96 ml of a 0M toluene solution of sodium bis(methoxyethoxy)aluminum hydride, gradually raise the temperature to -50°C, stir at the same temperature for 1 hour, and add Rochelle's salt aqueous solution (3 g/ml) at 0°C. The mixture was added to a mixed solution of 20 ml) and 20 ml of toluene, stirred for 30 minutes, and after filtering out unnatural substances, the organic layer was separated. After washing the organic layer with saturated brine, the solvent was distilled off under reduced pressure and the resulting residue was subjected to column chromatography (silica gel; hexane: ethyl acetate).
4=1→2:1) and purified by (Is, 3R, 5R, 6R
)-8-aza-3-benzyloxymethyl-5-methyl-2,4-dioxabicyclo(4,2,0)octane-
7-one 111■ (yield 47%) was obtained as colorless crystals.

H-NMR (CDCIs) δ: 1.42 (3H.

d, J=6.4Hz, CHs), 2.83-3.0(I
H, m, (: and Co), 3.54 (2H, d.

J"4.6Hz, -q"110Bn), 4.23
(IH, qunt, J-6,4Hz, two groups CH,)-
4,60 (2H, S, CH meaning Ph).

5.07 (IH, t, J-4, 4Hz, Dandan CH warehouse 0
Bn), 5.40 (IH, d, J-4, 6Hz, two-base NH), 6.2-6.4 (IH.

br, NH), 7.30 (5H, s.

aromatLe protons).

(Is,3R,SR,5R)-8-aza-3-benzyloxymethyl-5-methyl-2,4-dioxanebicyclo(4,2,0)octan-7-one 69.3g (0
, 263 mmo 1) in 2 ml of ethanol, 1
10 ml of 0% palladium carbon and 1 drop of 0.5N hydrochloric acid-tanol solution 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 (is, 3R, 5R
,6R)-8-aza-3-hydroxymethyl-5-methyl-2,4-dioxabicyclo(4,2,0)octan-7-one (45.4 µm (quantitative yield)) was obtained.

H-NMR (CDC1dδ+ 1.41 (3H.

d, J=6.4Hz, CH,), 1.8-2.2 (IH
, br, OH), 1.9-2.1 (1B.

m, CHC-0), 3.66 (2H,d, J-4,2
H2, CHt), 4.26 (IH.

quint, J=6.4Hz, CdanCHs).

4.99 (IH, t, J-4, 3Hz, C
HCHlOH), 5.42 (1)1. d, J-
4,6H3CHN)(), 6.3~6.6(I
H.

br, NH).

Reference example 4 (S)-ethyl lactate 10.2g (86.0mmo 1
) with pyrrolidine? , 80m1 (93,4mmo 1)
was added under ice-cooling, and then stirred at room temperature for 3 days. After removing excess pyrrolidine and the produced ethanol under reduced pressure, the residue was distilled to obtain 11.8 g (yield: 95 U6) of (S)-N,N-tetramethylene-2-hydroxypropionic acid amide as a colorless oil. obtained as.

bp 10B℃, (1■Hg) [α)” -49,2' (C4,78,0HCIs
)IR(nsat)3450.30G0.2900゜1
637.1440, 1387.1345°1133.1
04104O'H-NMR (CDC11) δ-1,33 (3o, d.

J=6.6H2, CHs), 1.90 (4B.

m, NCH*CHx2), C45 (4H.

m, Ndan Jyu CHmX2), 3.73 (IH.

d, J thin'1.3kix, OH), 4.29
(IH.

aq, J-7,3 and 6.6Hz, CHCO).

Mass m/e 143 (M”), 128 (M
-C1(s)”, 9 B (M-CHsCHOH).

Elemental analysis value: CyH+sNO proverb: Calculated value as 0.25HgO: C, 56,93, HS 9.21 8 i 9
．． 49% actual value C; 57.00. H; 9.22
N; 9.53H Reference Example 5 Sodium hydride 2.00 g (83.3 mmol
) of tetrahydrofuran 50ml and dimethylformamide 25ml! to a suspension of (S)-N under ice cooling.

A solution of 9.98 g (67.7 mmol) of N-tetramethylene-2-hydroxypropionic acid amide in 15 ml of tetrahydrofuran was slowly added. 4. At the same temperature.
After stirring vigorously for 5 hours, 8.80 ml of benzyl chloride
<76.5 mmol 1) was added. After stirring at the same temperature for 71 nights, 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 brine and then 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
14.1 g (yield: 87%) of -tetramethylene-2-benzyloxypropionic acid amide was obtained as colorless crystals.

The sample for analysis was obtained by recrystallization from dibutyl ether.

Melting point 42-42.5℃ [α] -66,9” (C-1,72,CHCt
s) IR (KBr) 3050°3000.2890°1
63G, 1430, 1350.1120°730cm-
1 H-NMR (CD C1s) δ-1,42 (3H, a.

J=6.8Hz, CH, 1.85 (4H.

m, NCH*CH;X2), 3.50 (4H.

m, NCHCHmx2), 4.20 (IH.

q, J=6.8Hz, CHCO), 4.41°4.62
(2H, dx2.J - 11.7Hz, CHz respectively
Ph), 7.32 (5H, s, Ph).

Mass m/s 234 (M+1)'127.
98° Elemental analysis value Cla HI 4 N Ot Calculated value C; 72.07. H; 8.21 N i 6.
00%Ci 72.06. H; 8.32
N S 5.90% Reference Example 6 (S)-N,N-tetramethylene-2-benzyloxypropionic acid amide (3.09 g (13°2 mmof)) was dissolved in 40 ml of tetrahydrofuran and diluted with bis(methoxyethoxy)aluminum hydride under water cooling. Sodium dissolved in toluene NIE (1,07mo 1 /j) 9.80ml
(10.5 mmol 1) was divided into 3 portions and added dropwise over 3 hours. After stirring at the same temperature for 4 hours, ice-cooling I
The reaction solution was added to 35 ml of N hydrochloric acid to stop the reaction, and dichloromethane was added to extract the organic matter. Organic layer, 1%
It was washed successively with hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was distilled using a Kugelrohr to obtain (S)-2-benzyloxypropanal (1.85%).
g (yield 85% g) was obtained as a colorless oil.

bp 100℃, 1fi! Ig [α]” −66,8” (neat, Jml) (literature value; [α)” −65,85° (neat).

P, G, M, 1luts, and S, 5. Bigel
ow, J, Org, Cheg+,.

3489 (1983)) IR (neat) 3470, 3050.3000゜29
50.2900.1?40.1458゜1378.11
00.700 cm-' H-NMR (CDCIs) δ-1,32 (3M, d.

J=7.0Hz, CHs), 3.88 (IH.

dq, Jml, 8 and 7.0) f z, CHOB n
).

4.62 (2H,s, CH proverb Ph), 7.
35 (5H, s, Ph), 9.66 (lH, d.

J-1,8Hz, CHO).

Msss m/s 181 (M+HtO)'135
(M-Co)” (R)-hydroxybutyric acid 3.52 g (33.8 mm
ol) and (S)-2-benzyloxypropanal3.
61 g (22. After the reaction solution was heated under reflux for an hour and returned to room temperature, water was added to stop the reaction, and dichloromethane was added to separate the solution. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over magnesium sulfate. The residue obtained by distilling off solvent # under reduced pressure was purified by column chromatography (silica gel; hexitine:ethyl acetate -15+1-2:1) to obtain (2R,6R)-2-(1-(S)-base). 7ji) Lt
[oxyethyl]-6-methyl-1,3-dioxane-4
3.75 g (yield 68%) of -one was obtained as colorless crystals. The sample for analysis was obtained by recrystallization from isopropyl ether.

Melting point 74.5-75.0°C (ff)%” -51,4° (C-1,21,CHC
l,) IR (KBr) 3000.2880.1750°173G, 1340.1258.1110°980,
690 cm-' H-NMR (CDCII) δ: 1.24 (3H, d
.

J=6.5Hz, Hs C) (OB n).

1.35 (3H, d, J-6, 2Hz, OH YuCHC
Hx), 2.41 (IH, dd, J dew 1O07 and 17.8Hz, C5-Hax).

2.69 (IH, dd, J-4, 3 and 17.8Hz
, Cs Heq), 3.68 (IH.

dq, J-3,8 and 6.5Hz, Cdan OB n)
+4.04 (IH, ddq, J 4.3 and 6.2 and 10.7Hz, C1-H), 4.67 (2H, s, HwP h), 5.29 (l H.

d, J=3.8Hz, Cm-H), 7.28-7.38
<5H, m, aronatic protons
).

Mass m/a 251 (M+1)”,
163°144 (M-OCHIPh)”, 135
゜91゜Elemental analysis (JL Calculated value as Cl 4 H + a Oa C; 67.18.H: 7.25% analysis ([C
:67.15. H near, 17% Example 7 (2RS 6R)-2-(1-(S)-benzyloxyethyl)-6-methyl-1,3-dioxan-4-one 2.21 g (8,81 mmo 1) the ether 5
Diisobutylaluminum hydride (IM n-hexane solution) 10.5rn 1 dissolved in 9ml at -60°C
(10.5 mmol 1) was added and stirred at the same temperature for 30 minutes. After cooling with water, cool the reaction solution with Rochelle salt aqueous solution (10 g/4
The mixture was added to a mixture of 0 ml) and 40 ml of ether, stirred until the two layers became transparent, and separated. The incubator layer was washed with saturated saline and dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (silica gel; hexane:ether-4jl-3+1) to obtain (2R,6R)-2-(1-(S)-benzyloxyethyl). 2.14 g (yield 96%) of -6-methyl-1,3-dioxan-4-ol was obtained as a colorless oily substance.
Based on H-NMR data, the stereochemistry of the 4-position hydroxyl group of this product is (
It is a mixture of R) and (S), and the production ratio is:
For example, from the integral ratio of C* −H (R) (64,57)
: (S)(63,52)-121,13, but these were used as a mixture as a raw material in the following Example 8 without being separated.

IR (neat) 3300-3500br.

2980.2950.2890.1445°1370.
1100.700es-' HNMR (CDC1s) δ: 1.20 (3HxO
,53,d,J-6,4Hz.

CHsCHOBn(A))1.21 (3HxO,5
3゜d, J-6, 3H3CI-CH5(A)) 1.22
(3HX0.47.d, J-6,5Hz.

CHCHOBn(B)) 1.26 (3Hx0.47
゜d, J-6,2Hz+ C1-CI(s(B))1
．． 34 (IHxO, 47, ddd, J-9, 6゜1
1.3 and 12.8Hz, Ca-Ha! (B)).

1.63 (IHXo, 53°ddd, J-1,2°3.0 and 13.3Hz, C5-Heq (^)).

1.70 (IHxo, 53.addd,,)-2,
0゜3.4.11.3 and 13.3Hz, C, -Hax
(A)), 1.81 (IH, Xo, 47°dd
d, J-2,3,2,4 and i2.8Hz.

C5-Heq(B)), 2.89 (IHXo, 53
゜dd, J-2,0 and 2.3Hz, 0H(A)).

3.24 (IH, Xo, 47.d, J-6,7Hz
, 0H(B)), 3.52 (IHxo, 53゜dq, J-4,7 and 6.4H2, CHOBn(^))
.

3.60 (IHxO,47,dq, J=4.7 and 6.4Hz, CHOBn(B)), 3.73 (IH
XO, 47, ddq, J-2, 3, 6, 2 and 11.3
Hz, CI-H (B)), 4.22 (I HX
O, 53° ddq, J-3, 0, 6, 2 and 11.3
Hz.

Ca-H(A)), 4.57 (IHxo, 47.
d, J=4.6Hz, Ct-H(B)), 4.
66 (2HX0.53.a, CHmPh(A)).

4.67 (2Hx0.47.s, CHmPh(
B)).

4.91 (IHxO, 47, ddd, J-2, 4° 6.7 and 9.6H2, C4-H (B)), 5.14 (
IHXo, 53. d, J-4,7Hz.

cm-H(^)), 5.42 (IHxo, 53
゜ddd, J-1, 2, 2, 3 and 3.4Hz.

Ca-H(A)), 7.3-7.4 (5H, m
.

aromatlc protons).

However, the protons marked with (^) indicate that 4S is a single signal, and the protons marked with (b) indicate that 4R is a single signal.

Mass m/e 195.146,135° Example 8 (2R,6R)-2-(1-(S)-benzyloxyethyl]-6-methyl-1,3-dioxan-4-ol 7.63 g ( 30.2 mmol 1) was dissolved in 100 ml of dichloromethane, and 12.3 mmol of triethylamine was dissolved under water cooling.
6 ml (90,4 mmo 1) and thionyl chloride 2
．． Add 6ml (35.3mmo 1) and incubate at 40℃ for 2 hours.
After stirring the reaction solution for an hour and returning it 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 bicarbonate and saturated brine, and then dried over magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (silica gel; hexane-hexane:ether 50:1) to obtain (2R,6R)-2-[1
-(S)-benzyloxyethyl]-6-methyl-2H
, 6H-1,3-dioxin 4.93 g (yield 70 u6)
) was obtained as a yellow oil.

[α)” -51,9” (C dazzle 1.22.C
HCII) IR (mast) 299G, 287
0. 1640°1450, 1312. 1220.
730°695cm-')1-NMR (CD CIs) δ: 1.23
(3H, d.

J-6, 4Hz, 1LLCHOBn).

1.26 (3H, d, J-6,4Hz, C
HiCHCHg), 3.62 (IH,dq,
J-4,4 and 6.4HICdan0Bn), 4.52(
l) i, dq, J-1,3 and 6.4H! IC, -H)
, 4.67 (2H,s, CHmPh).

4.78 (IH, dd, J-1, 3 and 6.4H2,
Cs H), 4.93 (IH, d.

J=4.6Hz, Ct-H), 6.50 (IH
.

(dd, J-1, 5 and 6', 4H2, Ca-H).

7.32 (5H,s, aromat 1cp
rotons).

Mass m/e 234 (M”),
143(M-C)i-rich Ph)", 135.91°(2R,5R)-2-(1-(S)-benzyloxyethyl]-6-methyl-2H,6H-1,3-dioxin2 .80g (12,0mmo 1) toluene 30
After adding 1.15 rnl (IL 2 mmol) of chlorosulfonyl isocyanate at -60°C and stirring at the same temperature for 3 hours, the reaction solution was cooled to -70°C and mixed with 60 ml of toluene and 2M hydrogen. Toluene solution of sodium bis(methoxyethoxy)aluminum chloride7.
2 ml was added, the temperature was gradually raised, and the reaction mixture was stirred for 1 hour at -50°C.
00ml) and toluene (100ml), and stirred at the same temperature for 30 minutes. Insoluble matter was filtered, and the organic layer was separated and washed with saturated brine. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was subjected to column chromatography (silica gel; hexane: ethyl acetate W5:
1→1:1) to produce (13,3R,5R,6R)
-8-aza-3-(1-(S)-benzyloxyethyl-5-methyl-2,4-dioxabicyclo(4,2,
0) 1.85 g (yield 56%) of octan-7'-one was obtained as colorless crystals. The sample for analysis was obtained by recrystallization from a mixed solution of ethyl acetate and n-hexane.

Melting point 103.0-103.5°C [α); -30,9° (C-1,15, CHCl5
)IR(KBr)32G0.1760,1715°13
80.1158.1118.980゜695cs-' H-NMR (CDCIs) δ + 1.21 (3
H,d.

J-6,5Hz, CHsCHOBn) 1.43 (
3H, d, J-6, 3Hz.

CHsCH), 2.92 (11(, ddd.

J-4, 2, 4, 6 and 6.3Hz, CHC-0).

3.56 (IH, dq, J 4.2 and 6.5H3C
HOBn), 4.22 (IH.

qu lnt, J=6.3Hz, CHCHs).

4.65 (2) Summer, s, CH*Ph), 4.86 (IH
, d, J=4.2Hz, CHCHOBn).

5.43 (1) 1. d, J-4,6Hz.

C) INH), 6.15 (IH, br, NH)
.

7.26-7.36 (5H, m.

aroma L lc proLona).

Mass m/e 278 (N+1)”,
232°204, 171 (M-OCHmP
h) "Elemental analysis value C+ s H+ *N Calculated value as Oa CB64.97 H; 6.9i N+5.
05%.

Analysis value C: 64.95 Hi 6.99 Ni
4.99M.

Example 10 (Is, 3R, 5R, 6R)-8-aza-3-(1-(
S)-benzyloxyethyl-5-methyl-2,4-
Dioxabicyclo(4,2,0)octan-7-one 1
．． 32g (4.75mmo 1) in 7ml of ethanol
90 μm of 20% palladium hydroxide on carbon 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 to obtain (Is, 3R, 5R, 6R)-
8-aza-3-(1-(S)-hydroxyethyl]-5
-Methyl-2,4-dioxabicyclo(4,2,0)octan-7-one 0.887 g (quantitative yield) was obtained as colorless crystals. The sample for analysis was ethyl acetate-n-
Obtained by recrystallization from a hexane mixture.

Melting point 91.5-92.0℃ [α]■+17,8° (C-1,08, CHCl,)I
R (KBr) 3450.3350.3300゜1?58
, 1380.1105,995°700cm-' H-NMR (CDC1i) δF 1.22 (3H, d
.

J'=6.6Hz, CHsCHOH).

1.43 (3H, d, J=6.2Hz.

Cdan 5CH), 2.08 (IH, d, J-4, 6Hz
, 0) I), 2.92 (IH, ddd.

J-4,2,4,6 and 6.4H3CHC-0).

3.7-3.9 (IH, m, C and OH), 4.24 (
IH, qunt, J = 6.4Hz.

CH3Cdan), 4.12 (LH,d, J-4,6H3
CHCHO) (), 5.45 (IH.

d, J-4,6Hz, C and NH), 6.16-6.28
(I H, b r, N) () Ma s s m/
e 188 (M+ 1)'', 142 (M-CHs
CHOH)''', 126.9B.

Elemental analysis value Cs HIs N Calculated value as Oa C1
51,33H; 7.00 N, 7.48%.

Analysis value C151,20H; 7.12 Ni'1.43
%.

(1-(S)-hydroxyethyl-5-methyl-2,
4-Dioxabicyclo[4,2,0]octan-7-one 887* (4,74 mmo I) was dissolved in carbon tetrachloride 10
m1. Dissolve in a mixture of 1Qml of acetonitrile and 15ml of water to obtain 1.66g of periodic acid dihydrate ('1.2
8mmo L) and ruthenium(III) chloride hydrate 19
．． 7* (0,087 mmo 1) was added and stirred for 1 hour. Dichloromethane was added to the reaction mixture to extract the organic matter, and the aqueous layer was further extracted with a mixed solvent of chloroform-ethanol 3:1. The organic layers were combined and sulfuric acid was added. Dry with magnesium. The residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (silica gel, dichloromethane:acetone-1:0-9:l) to give (Is, 3R, 5R).

6R)-8-aza-3-acetyl-5-methyl-2,4
-Dioxabicyclo(4,2,0)octan-7-one 776 cm (yield: 8B%) was obtained as colorless crystals. The sample for analysis was obtained by recrystallization from a mixed solution of ethyl acetate and n-hexane.

Melting point 86.5-87.0℃ [α] Mushroom・+16.9@(C-1,14,CHCl
Small) I R (KB r) 3200. 3000.17
50゜1735.1140.740aII-'H-NM
R(CDCIs) δ2 1.48 (3H, d.

J=6.4Hz, CHsCH), 2.26(3H, a
, CHs C=O) ,3,00(IH,dd
d, J-4,2 and 4.4 and 6.4H! , C and C-0
), 4.32 (IH.

qulnt, J-6, 4Hz, CdanCHt).

5.06 (IH,s, CHCOCHs) 15.48
(IH, d, J-4, 4H2, CHN).

6.3-6.6 (IH, br, NH).

Mass m/s 186 (M+1)”,
142 (M-CHsC-0)", 9B, 69° Elemental analysis value Calculated value as C whisper HIIN Oa C751,8
9Hi5.99N; 7.56%.

Analysis ft1c i 51.65 H; 5.98
N: 7.40%.

(Is, 3R, SR, 6R)-8-aza-3-acetyl-5-methyl-2,4-dioxabicyclo(4,2,0
) Octane-7-one 32.4■ (0,175 mmo
1) was dissolved in 0.5 ml of ethyl acetate, 150.7 cm (0.70 mmol) of m-chloroperbenzoic acid was added, and the mixture was stirred for 10 minutes. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (silica gel; dichloromethane:acetone - 1:0 to 9:1) to obtain (Is, 5R, 6
R)-8-aza-5-methyl-2,4-dioxabicyclo(4,2,0)octa:z-3+7-dione 8.45
sv (yield 31%) was obtained as colorless crystals. The sample for analysis was obtained by recrystallization from 1,2-dichloroethane.

Melting point 127-127.5℃ (α)”-140,2@ (C=1.02.Ac0Et
).

IR(KBr)3270,3200.1775°174
0.14G0.1200.1080゜1000.600
cm-' 1(-NMR(CDCIs) δ: 1.55 (3H,
d.

J=7.1Hz, CHs), 3.50 (1M.

ddd, J-1, 7, 2, 3 and 4.4Hz, CHC-
O), 4.92 <IH,dq, J=1.7 and "1.lHz, CHsCIS, 5.80(IH,d,
J=4.4Hz, DandanN), 6.7~7.0 (IH
,br,NH).

Mass m/e 158 (M+1)”C
M-Cog)”, 98.69゜Elemental analysis value
C&H? Calculated value C as N Oa; 45.87
H: 4.4g N: 8°91%.

Analysis value C; 45.79 H; 4.36 N; 8.9
0%.

Reference example 7 (Is, 5R, 6R) 28-aza-5-methyl-2,4
-dioxabicyclo(4,2,0)octane-3,7-
Dione 41.7cm (0,266mmol 1) was mixed with acetic acid 0.
Dissolve in 5ml of sodium acetate 25.1q (0.30ml)
6 mm o 1) was added thereto, and the mixture was stirred at 40°C overnight.

The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (silica gel; hexane:ethyl acetate -4:6→
(3R,4R)-3-(1-(R)
-Hydroxyethylgo-4-acetoxy-2-azetidinone (36.8 µm (yield: 809A)) was obtained as colorless crystals. The sample for analysis was obtained by recrystallization from ethyl acetate.

Melting point 113-114℃ [α)”+78.0° (C-1,07, M e OH
).

IR (KBr) 3500, 3250.3000°175
0.1725,1241.991699aa-' H-NMR (CDCIs) δ: 1.35 (3H,
d.

J=6.4Hz, CHx), 2.10 (IH.

d, J=3.5Hz, OH), 2.12 (3H.

s, 0=CCHs), 3.22 (IH, dd.

J-1, 3 and 5.9Hz, CHC-0).

4.19 (IH, m, double 0) 1), 5.816.3
~6.6 (IH,br,NH).

Mass m/e 174 (M+1)''
, 130 (M-CH snow C=O)", 1 15
．． 87゜Elemental analysis value C? Calculated value as H+ + N Oa C148,55H; 6.40 N; 8.09
% analysis value C: 48.42 H, 6,39Ni8.00
% Reference Example 8 (3R,4R)-3-(1-(R)-Hydroxyethylgo 4-acetoxy-2-azetidinone 0.347 g
(2,01 mmol 1) in dimethylformamide 4.
Dissolve in 0ml, imidazole 0.324g (4,7
6mmo 1) and t-butyldi)9-ylchlorosilane 0
．． Add 333 g (2.21 mmol) and stir at room temperature.
Stirred overnight. The reaction was stopped by adding 8 ml of water and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine, and then dried over magnesium sulfate. The residue obtained by distilling off the Tl medium under reduced pressure was purified by column chromatography (silica gel; dichloromethane = ethyl acetate - 9:1) to obtain (3R14R)-3-(1-(R)-t-butyldimethylsilyl). 0.525 g (yield: 89%) of oxyethyl]-4-acetoxy-2-azetidinone was obtained as a colorless solid.

The analytical data for the main island matched that of Reference Example 9 below.

Reference Example 9 (13,SR,6R)-8-aza-5-methyl-2,4
-dioxabicyclo(4,2,0)octane-3,7-
Dione 12.6m (0,080mmo 1) was mixed with acetic acid 0
．． Dissolve in 2 ml of potassium acetate 46* (0.47 mm
After stirring for 4 hours, the solvent was distilled off under reduced pressure. Do not purify this product (make it a dimethylformamide solution and add 50 g of imidazole (0.73 mmol 1
) and t-butyldimethyltalolosilane 240w (1
, 60 mmol 1) was added and stirred overnight. Water was added to stop the reaction, organic matter was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying with magnesium sulfate, the solvent was distilled off under reduced pressure and the resulting residue was subjected to column chromatography (silica gel; hexane: ethyl acetate-4
:1) to give (3R,4R)-3-(1-(R)
-(t-butyldimethylsilyloxy)ethyl)-4
-acetoxy-2-7zetidinone 22.4■ (yield 97
%) was obtained as colorless crystals. The sample for analysis was obtained by recrystallization from cyclohexane.

Melting point 107~107.5℃ (&) ”・+45.1” (C-1,07, CMC
I.

(Literature value; melting point 108-109℃ (α) atmosphere'+47.8" (C-0,56, CHCl
5).

Y, Ito+T Javabata+S, Tarashi
ma, T. L., 4e, 5751 (1986)
,”) I R(KB r) 32 G 0. 2950.
2930°2850, 1780. 1740. 13
7? .

1227, 1G35. 832. 772am-'H
-NMR (CDCIs) δ: 0.0? (6H,s
.

(CHs) ms l), 0.87 (9H, a.

(CH snow) sc), 1.25 (3H, a,
J-6,4Hz, CHsCH), 2.10
(3H, a.

CHsC=O), 3.18 (IH, dd,
J-1, 3 and 3.7H! , C and C-0), 4.22
(IH, m, two-group CHs), ri, 84 (IH9d
* J −1-3Hz + two groups N), 6.4 to 6.
5<IH, br, NH).

Procedural amendment (voluntary) December 1989

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R^1 represents a hydrogen atom, a substituted or unsubstituted linear or branched alkyl group, or an aryl group, and R
^1 represents a hydrogen atom or a protecting group for a hydroxyl group, and ▲
There are mathematical formulas, chemical formulas, tables, etc. When ▼ is a single bond, Y
There are ▲mathematical formulas, chemical formulas, tables, etc.▼or ▲mathematical formulas,
There are chemical formulas, tables, etc. ▼ represents, and when ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ is a double bond, Y represents ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼. ] A 6-methyl-1,3-dioxane derivative represented by: (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R^3 and R^4 are hydrogen atoms or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1 is a hydrogen atom , represents a substituted or unsubstituted linear or branched alkyl group or aryl group, R^5 and R^6 represent a hydrogen atom, a hydroxyl group, or a protected hydroxyl group. R^5 and R^6 are a bond ) or can be taken together with a bonded carbon atom to form a carbonyl group. ] A 1,3-dioxane derivative represented by: