JPH04154758A - Production of 2-azetidinone derivative - Google Patents

Abstract

PURPOSE:To readily and highly stereoselectively obtain the subject compound which is a synthetic raw material for carbapenem compounds useful as an antimicrobial agent in good yield by subjecting a new compound as a raw material to condensation cyclizing reaction and then, as necessary, eliminating protecting groups of OH, etc. CONSTITUTION:Carboxylic acids expressed by formula I (R<2> is protecting group of OH) are made to react with a compound expressed by formula II (R<3> is lower alkyl) to produce a compound expressed by formula III, which is subsequently reacted with a tin(II) triflate in the presence of a base to provide an enolate. The resultant enolate is then reacted with acetaldehyde to afford a compound expressed by formula IV. The OH of the obtained compound expressed by formula IV is subsequently protected to afford a compound expressed by formula V (R<11> is R<2>), which is then allowed to react with a 4-lower alkoxyphenylamine to produce a compound expressed by formula VI (R<4> is R<3>). The protecting group R<2> of the OH is subsequently eliminated therefrom to form a new compound expressed by formula VII which is a raw material. The resultant compound expressed by formula VII is then subjected to condensing reaction and, as necessary, the protecting group of OH or the 4-lower alkoxyphenyl group or both are eliminated to afford the objective compound expressed by formula VIII.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a highly stereoselective method for producing 2-azetidinone derivatives that can be used as raw materials for the synthesis of carbapenem compounds useful as antibacterial agents, and more specifically, the present invention relates to a method for highly stereoselective production of 2-azetidinone derivatives, which can be used as raw materials for the synthesis of carbapenem compounds useful as antibacterial agents. 2 represents a hydrogen atom or a hydroxyl group-protecting group, and 2 represents a hydrogen atom or a 4-lower alkoxyphenyl group. The present invention relates to a highly stereoselective method for producing a compound represented by the following, and intermediates for producing the same.

As a method for producing the 2-azetidinone derivative of formula (1), for example, D. A. Evans et al., TeL
rahedron Letters, Vol, 27.
No. 41.4961-4964 (1986), (3 S) 3 ((IR)
l -tert-butyldimethylsilyloxyethyl)-
A method for synthesizing 2-azetidinone is described. However, in this method, the following formula (
B) via an aldehyde derivative represented by
The azetidinone derivative of the above formula (A) cannot be produced with high stereoselectivity and good yield.

The main object of the present invention is to provide a novel method capable of producing the azetidinone derivative represented by the formula (+) with high stereoselectivity and good yield.

Therefore, according to the present invention, a compound represented by the following formula (■), in which R1+ represents a hydroxyl group-protecting group and R' represents a lower alkyl group, is subjected to a condensation ring-closing reaction, and then, as necessary, In the following formula (1), R1 represents a hydrogen atom or a hydroxyl protecting group, and 2 represents a hydrogen atom or a 4-lower alkoxyphenyl group, and a method for producing a compound represented by these is provided.

The present invention will be explained in more detail below.

In the definition of substituents used herein, the term "lower" means that the group or compound to which this term is attached has 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. .

The "lower alkyl group" may be linear or branched, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ec-butyl, tert-butyl, n-pentyl, Included are impentyl, n-hexyl, isohexyl groups, and the like.

The "lower alkoxy group" is a lower alkyl moiety or a lower alkyloxy group having the above meaning, such as methoxy, ethoxy, n-propoxy, impropoxy, n-
butoxy, imbutoxy, 5ec-butoxy, tert
-Butoxy etc. are exemplified.

A "lower alkoxyphenyl group" is a phenyl group substituted at the ortho-, meta- or para-position with the above lower alkoxy group.

Furthermore, the term "hydroxyl group protecting group" refers to any protecting group generally known in peptide chemistry as a serine hydroxyl protecting group, such as acetyl, benzoyl, methanesulfonyl, p-toluenesulfonyl, etc. or aromatic acyl group; aralkyl group such as benzyl, triphenylmethyl; substituted or unsubstituted benzyloxycarbonyl group such as benzyloxycarbonylzyloxycarbonyl, p-methoxybenzyloxycarbonyl; trimethylsilyl, tert-butyldimethylsilyl, Lert- Examples include silyl groups such as butyldiphenylsilyl group and phenylisopropyldimethylsilyl group.

According to the method of the present invention, the 2-azetidinone represented by the formula (1) is produced by subjecting the compound represented by the following formula (■), in which R11 and R4 are as defined above, to a condensation ring-closing reaction. A derivative is produced.

The condensation ring-closing reaction of the compound represented by formula (■) can be carried out, for example, as follows.

(1) The compound represented by formula (■) is reacted with a hydroxyl group activation reagent in the presence of a base to form a reactive derivative, and (2) the resulting reactive derivative is reacted with a base.

The above step (1) is usually carried out using an ether such as diethyl ether or tetrahydrofuran in an inert organic solvent.
Hydrocarbons such as toluene, xylene, cyclohexane;
Halogenated hydrocarbons such as dichloromethane and chloroform, N,N-dimethylformamide, acetonitrile and the like; particularly, the reaction can be suitably carried out in dichloromethane or tetrahydro-7 run.

Examples of the base used in this reaction include alkali metals such as lithium, sodium, and potassium; alkaline earth metals such as calcium; alkali metal hydrides such as sodium hydride; and alkaline earth metals such as calcium hydride. Metal hydrides; alkali metal hydroxides such as sodium hydride and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; alkali metal alkanoates such as sodium acetate; alkaline earth metal carbonates such as magnesium carbonate and carbonate; e.g. trimethylamine, triethylamine , N,N-diisopropyl-N-ethylamine and other tri(lower)alkylamines:
Pyridine compounds such as N,N-di(lower)alkylaminopyridine such as pyridine, picoline, lutidine, N,N-dimethylpyridine: quinoline; Ni-class alkylmorpholine such as e.g. N-methylmorpholine: e.g. , N-di(lower)alkylbenzylamine such as N-dimethylbenzylamine, etc., and preferably triethylamine, N,N-'; isopropyl-N-ethylamine. etc. can be used. The amount of the base to be used varies depending on the type thereof, but it can generally be in the range of about 1 mol to about 4 mol per 1 mol of the compound represented by formula (■) as a raw material.

In addition, examples of hydroxyl group activation reagents include organic sulfonyl halides such as methanesulfonyl chloride and 4-toluenesulfonyl chloride; acyl halides such as acetyl chloride, and the amount used generally depends on the raw material. The amount can be in the range of about 1 mol to about 4 mol per 1 mol of the compound represented by formula (■).

Although the reaction in this step is not strictly limited, it is usually about -20°C to about 60°C, preferably about 0°C.
This can be carried out by stirring at a temperature of about 30°C to about room temperature for about 30 minutes to about 4 hours.

The reactive derivative obtained by this step can be isolated and purified by conventional purification means, such as extraction or chromatography, depending on the case, although it is not always necessary.

Step (2) can usually be carried out in a solvent arbitrarily selected from the inert solvents exemplified above.
In particular, the reactive derivative of the compound represented by formula (■) obtained above is reacted with a base in a mixed solvent of dichloromethane and dimethylformamide.

The base used in the reaction of this step can be arbitrarily selected from the bases exemplified above, but preferably an alkali metal hydride such as sodium hydride can be used. The amount of base used in this case varies depending on the type of base, but is generally about 1 mole per mole of the reactive derivative obtained in step (1) above, which is the raw material.
It can be used in a range of mol to about 3 mol, preferably about 1.2 mol to about 2.0 mol.

The reaction is usually, but not strictly limited to, about 0
C. to about 40.degree. C., preferably at about room temperature, by stirring for about 30 minutes to about 4 hours.

The compound represented by the formula (I) obtained by this step can be isolated and purified by conventional purification means, such as extraction or chromatography.

Although the reactions in each of the above steps (1) and (2) are not essential, it is desirable to carry out the reactions in an inert atmosphere, for example, in nitrogen gas or argon gas.

Further, the condensation ring-closing reaction of the compound represented by the formula (■) can be carried out using, for example, a condensing agent suitable for the compound represented by the formula (■),
For example, it can also be carried out by applying a suitable amount of a combination of triphenylphosphine and diethyl azodicarpoquinlate.

This reaction can be carried out in an inert organic solvent such as tetrahydrofuran, acetonitrile, dioxane, etc., generally by stirring at about 0°C to about 40°C for about 30 minutes to about 2 hours.

By the above method, the following formula (1-1) In the formula, R11 and R4 are as defined above, A compound represented by can be produced.

The compound represented by the above formula (I-1) can be prepared by removing the hydroxyl protecting group (R") and/or the 4-lower alkoxyphenyl group as required, to form the compound represented by the following formula (I-2) in the formula: , R1 and 2 are as defined above; however, when R1 is a hydroxyl protecting group (R"), Z represents a hydrogen atom.

The elimination reaction of the 4-lower alkoxyphenyl group from the compound represented by formula (Ni 1) can be carried out using an oxidizing agent in a suitable solvent.

Examples of the oxidizing agent used include ceric ammonium nitrate, potassium persulfate, ozone, etc., but ceric ammonium nitrate is preferably used.

The reaction solvent varies depending on the type of oxidizing agent used. For example, when using ceric ammonium nitrate as the oxidizing agent, a mixture of water and an organic solvent such as acetonitrile, acetone, tetrahydrofuran, dioxane, dimethylformamide, methanol, or ethanol is used. It is convenient to use a solvent.

The amount of the oxidizing agent used is generally determined by the formula (1-1) that is the raw material.
The amount can be in the range of about 1 mol to about 4 mol per 1 mol of the compound represented by.

The reaction is typically, but not strictly limited to, about -
This can be carried out by stirring at a relatively low temperature of about 20°C to about 0°C for about 5 minutes to about 2 hours.

In addition, when using potassium persulfate as an oxidizing agent,
For example, the reaction can be carried out in a near-neutral phosphate buffer under appropriate temperature conditions.

Further, when using ozone as an oxidizing agent, for example, in an inert solvent such as benzene, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, ethyl acetate, methanol, ethanol, acetone, acetic acid, etc., at about -50°
The reaction can be carried out under temperature conditions of from 50°C to about 50°C. In this case, the amount of ozone used is determined by the formula (1
It is preferable that the amount is in excess of 1 mole of the compound represented by the formula (
A compound represented by I-1) can be obtained. Examples of decomposition methods include thermal decomposition, oxidative decomposition using hydrogen peroxide, and reductive decomposition using dimethyl sulfide, zinc dust, triphenylphosphine, sodium thiosulfate, and the like.

On the other hand, the elimination reaction of the hydroxyl protecting group (R'') from the compound represented by formula (1-1) can be carried out under known deprotecting group reaction conditions such as solvolysis or hydrogenolysis. For example, in a solvent such as methanol, ethanol, tetrahydrofuran, dioxane, etc., in the presence of an acid such as hydrochloric acid, sulfuric acid, or acetic acid, at about 0°C to about 100°C.
This can be carried out by stirring at a temperature of about 30 minutes to about 24 hours.

The compound represented by formula (1) thus obtained has a stereospecific structure in which the carbon atom at the 3-position of the azetidinone ring is S-coordinated and the carbon atom at the 3-position side chain is R-coordinated.

The compound represented by the formula (R) can be further induced into a 4-acetoxy form according to a method known per se, for example, the method of Shitachi et al. [Proceedings of the 58th Spring Annual Meeting of the Chemical Society of Japan, ■, p. This results in 4
-Acetoxy-2-azetidinone derivatives are extremely important synthetic intermediates for stereospecific carbapenem compounds (for example, JP-A-62-77384;
(See Japanese Unexamined Patent Publication No. 62-212388, etc.).

Note that the compound represented by the formula (■) used as a starting material in the above production method is a new compound that has not been described in conventional literature, and can be synthesized, for example, by the method shown in Reaction Formula A below. I can do it.

During the ceremony, R2 represents a hydroxyl protecting group, R3 represents a lower alkyl group, R11 and R4 are as defined above.

Each step of the above reaction formula A will be explained below.

Step (a) comprises combining a carboxylic acid represented by formula (II) or a reactive derivative thereof and (4R)- represented by formula (II[).
This is a step of producing a compound represented by formula (IV) by reacting with a 4-alkyl-substituted thiazolidine-2-thione derivative.

The reaction is carried out by adding a carboxylic acid activation reagent and (4R)-4-alkyl-substituted thiazolidine-2 of formula (1) to the carboxylic acid represented by formula (II) in the presence of a base in an inert solvent such as chloroform or dichloromethane. - It can be carried out by adding a thione derivative and stirring.

The 4-position alkyl group (R3) of the thiazolidine-2-thione derivative used in this reaction is preferably an ethyl group or an isopropyl group. Represented by formula (II[) (
The amount of the 4R)-4-alkyl-substituted thiazolidine-2-thione derivative to be used is not strictly limited, but is generally about 1 mol per mol of the compound represented by formula (II).
It can range from 1 mole to about 2 moles.

In addition, examples of the base include dimethylaminopyridine, pyridine, quinoline, lutidine, triethylamine, sodium hydride, etc. The amount used varies depending on the type of base, but in general, the carboxylic acid that is the raw material It can be in the range of about 0.01 mole to about 0.1 mole per mole.

The carboxylic acid activating reagent is 1-ethyl hydrochloride-
3-(3-dimethylaminopropyl)carbodiimide,
Examples include dicyclohexylcarbodiimide.

The reaction is usually, but not strictly limited to, about 0
C. to about 40.degree. C., preferably about room temperature, by stirring for about 1 hour to about 24 hours.

Moreover, this step can also be carried out by previously converting the carboxylic acid of formula (If) into a reactive derivative and then reacting it with the compound represented by formula (II[).

Reactive derivatives of carboxylic acids include, for example, chloroform,
Obtained by reacting the carboxylic acid of formula (n) with a carboxylic acid activation reagent such as ethyl chlorocarbonate or thionyl chloride in the presence of a base such as dimethylaminopyridine, pyridine, or triethylamine in an inert solvent such as dichloromethane. be able to. The amount of the base used in this case can generally be in the range of about 1 mol to about 2 mol per 1 mol of the carboxylic acid starting material. The reactive derivative obtained thereby can be reacted with a compound represented by formula (III) under the same conditions as above to produce a compound represented by formula (TV).

The compound represented by formula (IV) can be isolated by separating and purifying the reaction product by conventional purification means such as extraction and chromatography.

In addition, (4) shown by the formula (III) used in this reaction
R)-4-Alkyl-substituted thiazolidine-2-thione derivatives can be easily obtained by methods known per se, for example by reacting a 2-amino alcohol with carbon disulfide in the presence of a base (see 62-42964
(see publication).

Further, the carboxylic acid represented by formula (II) can be easily produced by a method known per se, for example, by reacting an acrylic acid ester with a suitable alcohol derivative (see Examples below).

Step (b) is a step of subjecting the compound represented by formula (IV) obtained in step (a) above to an aldol reaction to produce a compound represented by formula (V).

Specifically, the reaction can be carried out by, for example, reacting the compound represented by formula (IV) with tin (■) triflate in the presence of a base to form erulate, and then reacting this with acetaldehyde. The enolization reaction is carried out in an inert organic solvent, for example, ethers such as diethyl ether and tetrahydrofuran; toluene, xylene,
Hydrocarbons such as cyclohexane; halogenated hydrocarbons such as dichloromethane and chloroform; particularly, the reaction can be suitably carried out in dichloromethane or tetrahydrofuran.

The reaction temperature is not strictly limited and can be varied widely depending on the starting materials used, but is generally about -100°C to about room temperature, preferably about -100°C.
It can be carried out at relatively low temperatures of 78°C to about 0°C.

The amount of tin(II) triflate to be used relative to the compound represented by formula (IV) is not critical, but it is usually about 1 to about 3 mol, preferably about 3 mol per mol of the compound represented by formula (IV). can be used within the range of 1.5 to 2.5 mol.

The above reaction is advantageously carried out in the presence of a base; bases that can be used include, for example, triethylamine, diisopropylethylamine, l,4-diazabicyclo[2,2
, 2] Tertiary amines such as octane, N-methylmorpholine, N-ethylpiperidine, pyridine, etc.
Among them, triethylamine or N-ethylpiperidine is advantageously used. These bases generally have the formula (IV
) can be used in a proportion of about 1.0 to about 3 mol, preferably 1.5 to 2.5 mol, per mol of the compound represented by formula. The enolization reaction can generally be completed in about 5 minutes to about 4 hours under the above conditions.

Following this enolization reaction, the produced erulate can be directly reacted with acetaldehyde.

The aldol reaction between the erulate and acetaldehyde can generally be carried out at a temperature of from about -100°C to about room temperature, preferably from about -78°C to about 10°C. The amount of acetaldehyde used in this case is not critical and can be changed as appropriate, but usually the compound 1 of formula (IV) used in the enolization reaction is
It is appropriate to use within the range of about 1 to about 5 moles, preferably 1.5 to 3 moles per mole.

Under such conditions, the reaction generally lasts from about 5 minutes to about 5 hours.
More generally, it can be completed in about 5 minutes to about 2 o'clock.

The aforementioned enolization reaction and the aforementioned aldol reaction are preferably, but not necessarily, carried out under an inert atmosphere, for example under a nitrogen gas or argon gas atmosphere.

Finally, the reaction product is treated with water. For example, after the reaction is completed, a weakly acidic to neutral phosphate buffer or organic acid aqueous solution, preferably a phosphate buffer, is added and stirred, and insoluble matter is filtered off. The resulting compound represented by formula (V) can be separated and purified by conventional methods such as extraction, recrystallization, chromatography, etc.

This step is a step of stereoselectively introducing a 1(R)-hydroxyethyl group into the carboxylic acid amide derivative represented by formula (IV), and its selectivity is extremely good.

The carbon atom at the β position of the compound represented by formula (V) obtained in this step has an S coordination, and the carbon atom at the β position has an R coordination. Since this steric coordination is maintained substantially completely in each of the following steps, the compound of formula (■), which is the stereospecific intermediate compound of the present invention, can be obtained in high yield.

Step (c) is a step of protecting the hydroxyl group of the compound represented by formula (V) produced in the first step (b) to produce a compound represented by formula (VI).

The reaction can be carried out using a hydroxyl group protection method known per se. For example, the above-mentioned "hydroxyl protecting group" may be reacted in the presence of a base in an inert solvent such as dichloromethane or chloroform.
This can be carried out by reacting halides having various substituents as exemplified as .

Examples of the base used include dimethylaminopyridine, pyridine, imidazole, quinoline, lutidine, and triethylamine, with imidazole being preferably used. Further, as the protecting group, silyl groups such as trimethylsilyl and t-butyldimethylsilyl can be particularly preferably used.

The reaction is preferably carried out in an inert gas atmosphere such as nitrogen gas, and at about -20°C to room temperature, preferably about O
This can be done by stirring at 0C for about 1 hour to about 24 hours. The resulting compound represented by formula (IV) can be isolated and purified by conventional purification means such as extraction or chromatography.

Step (d) is a step of producing a compound represented by formula (■) by reacting the compound represented by formula (VD) obtained in step (C) above with 4-lower alkoxyphenylamine.

The reaction is carried out in an inert organic solvent such as those exemplified above, for example,
It can be carried out in dichloromethane or chloroform.

Examples of the 4-lower alkoxyphenylamine used in this reaction include 4-anisidine and 4-ethoxyphenylamine, and the amount used is generally per mole of the compound represented by formula (Vl). The amount may range from about 1 mol to about 3 mol.

The reaction can be carried out by stirring at about 0° C. to about 60° C., preferably at room temperature, for about 30 minutes to about 24 hours, although it is not strictly limited.

The reaction product can be separated and purified by conventional purification means such as extraction or chromatography.
A compound of formula (■) can be isolated.

In step (e), the protecting group represented by R2 of the compound of formula (■) obtained in the above step (cl) is removed to form the compound of formula (■).
) is a process for producing a compound represented by

The protective group elimination reaction can be carried out by a known deprotection reaction such as solvolysis or hydrogenolysis described in connection with step (2) above.

However, the compound represented by formula (■) has a secondary hydroxyl group protected by R1+ and a primary hydroxyl group protected by R2. Therefore, in the deprotecting group reaction of this step,
By selecting conditions that selectively remove only the protecting group of R2, the compound represented by formula (■) can be obtained in high yield.

For example, when the protecting groups R11 and R2 are the same, the protecting group for the primary hydroxyl group can be preferentially removed by carrying out the reaction at a relatively low temperature. Also,
When the protecting groups R11 and R2 are different, the compound represented by formula (■) can be produced in high yield by selecting particularly favorable conditions for removing the protecting group R2.

An example of this is as follows.

For example, when R11 is a tert-butyldimethylsilyl group and R2 is a benzyl group, in order to preferentially remove only the benzyl group of R2, it is necessary to remove the benzyl group in a mixed solvent of methanol and acetic acid under a hydrogen atmosphere. This can be done by reacting palladium on carbon. The reaction temperature in this case may be relatively low, from about 0° C. to room temperature, and the reaction is completed by stirring for about 30 minutes to about 6 hours.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the scope of the present invention is not limited thereto.

In addition, in the following description, the following abbreviations are used.

WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride DAMP: Dimethylaminopyridine DMF:
N,N-dimethylformamide→: tert-butyldimethylsilyl Example 1 3-benzyloxypropionic acid (1) 75 mg of metallic sodium was added to 9.09 g of benzyl alcohol, and the mixture was stirred at room temperature under a nitrogen stream for 30 minutes.

6.5 g of methyl acrylate was added to this solution and stirred under the same conditions overnight. After the reaction is completed, ethyl acetate and saturated ammonium chloride water are added to the reaction solution for extraction, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, 150 ml of ethanol was added to the resulting residue, and 1
Add normal aqueous sodium hydroxide solution and stir at room temperature for 1 hour. After the reaction is completed, the reaction solution is neutralized with 1N hydrochloric acid, and then the solvent is distilled off under reduced pressure. The residue is extracted with ethyl acetate and 1N hydrochloric acid, washed with ice water and saturated brine, and dried over anhydrous sodium sulfate. By distilling off the solvent under reduced pressure, 3-benzyloxypropionic acid (1) 8.29
(60%).

Example 2 (4R)-3-Benzyloxybrovanoyl-4-isopropyl-1,3-thiazolidine-2-thione (2) In a solution of 2.169 3-benzyloxypropionic acid (1) in 50 mQ of methylene chloride (4R) )-isopropylthiazolidine-2-thione 1.939 and WSc 2.42
g and 50 mg of DMAP are added and stirred at room temperature overnight. After the reaction is completed, the reaction solution is washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel chromatography to obtain compound (2) as a yellow oil with a concentration of 3.329 (86%).
)Obtained.

Ca IH-227,7° (CHCl3, C1,3
7) IR: 1690 cm-' NMR (δ, CDCl: 0-95 (3H, d,
J=6.8Hz), 1.04(3H,d, J=6.8H
z), 2.37 (IH, qd, J=6.8°13.2H
z), 3.00 (IH, dd,, hl, 1.1l-4H
z), 3.43-3.59 (3H, m), 3.70-3
．． 92 (2H, m), 4.54 (2H, s), 5.1 (
h5.18(LH,m), 7.33C5H,s) Example 3 (4R)-3-[(2S,3R)-3-hydroxy-2
-(Benzyloxymethyl)butanoyl]-4-isopropyl-1,3-thiazolidine-2-thione (3) Tin (■) triflate (SnCOTflz) 11
．． 4.2 mQ of N-ethylpiperidine and a solution of 3 g of compound (1) in 20 ml of methylene chloride were added to a solution of 61 g of methylene chloride in 23 ml, and the mixture was heated at -78°C for 30 minutes in a nitrogen stream.
After stirring for 1 minute, a solution of an excess amount of acetaldehyde in 3 mQ of methylene chloride was added at -78°C, and the mixture was stirred at the same temperature for 30 minutes. After the reaction is completed, 0.1N phosphate buffer is added and the mixture is filtered through Celite, and the three solutions are washed successively with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel chromatography to obtain compound (3) as a yellow oil with a yield of 2.889 (84%).
Obtained.

[σ1 -302,4° (CHC]3, C1,91)
IR: 3450.1690 am-'NIJR(δ,
CDC13): 0.98 (3H, d, J-6,8
Hz), 1.05 (3H, d, J□6.8Hz), 1
．． 26 (3H, d, J=6.5Hz), 2.36 (I
H, qd, J=6.8.13.6Hz), 2.93(
IH, dd.

J=1.0.1l-4Hz), 3.07(IH,d,
19) 1z), 3.27 (IH, dd, J=7.7.
11.4Hz), 3.78 (IH, dd, J=5.2
．． 9.2Hz), 3.91 (IH, dd, J=8.4
．． 9.2Hz), 4.26-4.33 (IH, m), 4
．． 43 (IH, d, J=12.4Hz), 4.52 (
IH, d, J=12.4Hz), 4.98-5.04
(IH, m), 5.08-5.17 (LH, m), 7.
27-7.37 (5H, m) Example 4 (4R) 3 [(2S, 3R) 3-ter
t-Butyldimethylsilyloxy-2-(benzyloxymethyl)butameyl]-4-isogropyl-1゜3~thiazolidine-2-thione (4) 1. imidazole was added to a solution of 2.6 g of tert-butyldimethylchlorosilane in 14 mQ of methylene chloride. After adding 179 and stirring at 0°C in a nitrogen stream for 1 hour, compound (3)
A 2.8 By methylene chloride solution (8.5 ml) is added and stirred under the same conditions overnight. After the reaction is completed, the reaction solution is washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel chromatography to obtain compound (4) as a yellow oil with a concentration of 3.42
9 (91%).

Ca ]ff 247-1' (CHCIs, C
1,1) IR: 1690 cm-' NMR (δ, CDCl: 0.01 (3H, s
), 0-03 (3H, s), 0.88 (9H, s), 0
．． 98 (3H, d, 6.8Hz), 1.05 (3H,
d, J=6.8Hz), 1.29(3H,d,
J=6.1Hz), 2.36(LH,qd, J=6
．． 8. 13.6Hz), 2.87 (LH, aa.

1.0.11.4Hz), 3.16(IH, dd, J
=7.7.11.4Hz), 3.83-3.87(2H
, m), 4.22-4.34 (IH, m), 4.47 (
2H, s), 4.92-5.09 (2H, m), 7.2
8-7.34 (5H, m) Example 5 (2S, 3R) -3-tert-butyldimethylylyloxy-2-(benzyloxymethyl)-N-
(4-methoxyphenyl)butyric acid amide (5) compound (4
) 920 mg of p-aningine was added to a solution of 3.0 g of methylene chloride in 20 mff, and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel chromatography to obtain compound (5) as white crystals.
．． 76g (quantitative).

[a] U +8.7° (CHCI3, C2, 16)
IR: 3320.1660.1510 cm-'NI
JR (δ, CDCh) 20, 02 (6H, s), 0-
80 (9H, s), 1.06 (3H, d, J=6.3
Hz), 2.61-2.68 (IH, m), 3.51 (
LH, dd, J-6,9,9,9Hz), 3.65(
3H, s), 3.81 (IH, dd, J=5.9.9
．． 9Hz), (120 (LH, m), 4.37 (IH,
d, J=11.9Hz), 4.48(IH, d, J
= 11.9Hz), 6.71 (2H, d, J = 8.9
Hz), 7.20 (5H, s), 7.24 (2H, d,
J=8.9Hz), 8.33 (IH, brs) Example 6 (2S,3R)-3-tert-butyldimethylsilyloxy-2-hydroxymethyl-N-(4-methoxyphenyl)butyric acid amide (6 ) Compound (5) 1.0 g methanol-acetic acid (4:l) l
Add 10% palladium on carbon (50% water content) to the OmQ mixture.
00+ng was added, and the mixture was heated at room temperature under hydrogen flow (4 atm).
Shake for an hour. After the reaction is complete, palladium on carbon is filtered off through Celite. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 725 mg (91%) of compound (6) as white crystals.

m, p,: 111°C IR (KBr): 3370.1660.1560 c
m-'NMR (δ, CDCl5): 0-01 (3H
, s), 0.03 (3H, s), 0.79 (9H, s)
, 1.13 (3H, d, J=6-3Hz), 1.53
(IH, brs), 2.49-2.54 (IH, m),
3.33 (IH, dd.

J=3.6.8.9Hz), 3.65(3H,s), 3
．． 89-3.93 (IH, m), 4.08-4.17 (
IH, m), 6.73 (2H, a, J=8.9Hz)
, 7.29 (2H, d, J=8.9Hz), 8.7
7(IH, brs) Example 7 (2S, 3R) -3-tert-butyldimethylsilyloxy-2-methanesulfonyloxymethyl-N-
(4-methoxyphenyl)butyric acid amide (7) compound (6
) Add 0.4 mff of methanesulfonyl chloride and 0.71 mQ of triethylamine to a 900 mg solution of 12 mff of tetrahydrofuran, stir at O'C in a nitrogen stream for 30 minutes, and then stir at room temperature for 1 hour.

After the reaction is completed, ethyl acetate and saturated aqueous anquinia chloride are added to the reaction solution for extraction, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 11 g (quantitative) of Compound (7) as a colorless oil.

[σ]ぢ +10.4° (CHC1,,c O,98
)IR: 1650.1350.1170 cm-'N
MR (δ, CDCl5): 0.01 (3H, s),
0.02 (3H, S), 0.80 (9H, s), 1.0
8 (3H, d, J=5.9Hz), 2.8O-2-8
6 (IH, m), 2.90 (3H, s), 3.64 (3
H, s), 4.03-4.12 (IH, m), Cl47
4.21 (IH, m), 4.45-4.51 (LH, m
), 6.71 (2H, d, J=8.9Hz), 7.2
1 (2H, d, J=8.9Hz), 8.15 (IH,
brs) Example 8 (3S) -3-((l R) -1-tert-butyldimethylsilyloxyethyl)-1-(4-methoxyphenyl)-2-azetidinone (8) Sodium hydride (55% oily ) To a suspension of 120 mg of methylene chloride-DMF (4: 1) in 30 mL of methylene chloride-DMF (4: 1) was added 1.09 of compound (7) in methylene chloride-DMF (4: 1).
) A 20mff mixture was added dropwise over 30 minutes, and the mixture was stirred for 1.5 hours at room temperature in a nitrogen stream. After the reaction was completed, the reaction solution was sequentially washed with saturated aqueous ammonia chloride, water, and saturated brine, and then
Dry with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 776 mg (quantitative) of compound (8) as white crystals.

[σ1 deterioration -58,2° (CHC1,,c 1.25
)IR: 1750.1515 cm-'NMR(δ,
CDCl5): 0.01 (3H, s), 0.02 (
3H, s), 0.75 (9H, s), 1.21 (3H,
d, J=6.3Hz), 3.20-3.25(IH,
m), 3.51-3.61 (2H, m), 3.75 (3
H, s), 4.22-4.30 (LH, m), 6.82
(2H, d, J=8.9Hz), 7.25 (2B,
d, J=8.9Hz) Example 9 (3S) 3 ((l R) l -tert
-butyldimethylsilyloxyethyl)-2-azetidinone compound (8) 300mg acetonitrile 5.6mQ
To the solution, 9 ml of an aqueous solution of 1.47 g of ceric ammonium nitrate was added dropwise at -15° C. over 2 minutes, and the mixture was stirred for 20 minutes under the same conditions. After the reaction is complete, ethyl acetate is added to the reaction solution, which is washed successively with water, 10% sodium sulfite solution, 5% sodium carbonate solution, water, and saturated ammonium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel chromatography to obtain the compound (
8) was obtained as white crystals in an amount of 137 mg (67%).

[σJ 汀 −74,1° (CHCl s, C1,73
) IR: 1750 cm-,' NMR (δ, CDCl5): 0.02 (6H, s)
, 0.80 (9H, s), 1.12 (3H, d, J=
6.3Hz), 3.12-3.29 (3H, to), 4
．． 09-4.18 (II, m), 5.84 (IL
brs) Procedural Letter (Spontaneous) April 6, 1991 Director General of the Patent Office Satoshi Uematsu 3, Person making the amendment Relationship with the case Patent applicant name Nippon Ledery Co., Ltd. 4, Agent 〒107 6, Subject of Amendment 7, Contents of the Amendment As shown in the attached sheet (1) The claims of the present application (page 1, line 5 of the specification to page 5, line 7) are corrected as shown in the attached sheet.

(2) On page 1, line 5-1 of the specification, "r tert-butyldimethylsilyl" is corrected to "j tert-butyldimethyl".

(3) In the third line from the bottom of page 35, “(SnCOTf1
4) Correct J to r 5n(OTf)z)J.

(4) The chemical structural formula (4) on page 37, line 6 is corrected as follows.

(5) Chemical structural formulas (4) and (5) on the last line of page 38
) is corrected as follows.

□” (6) Chemical structural formula (5) and (
6) is corrected as follows.

” (7) Chemical structural formula (6) and (
7) is corrected as follows.

(8) Chemical structural formulas (7) and (8) on page 42, line 14 are corrected as follows.

(9) Chemical structural formulas (8) and (9) on page 44, line 1 are corrected as follows.

” (Attachment) [Claims] r 1. A compound represented by the following formula (■) in which R'' represents a hydroxyl group-protecting group and R4 represents a lower alkyl group is subjected to a condensation ring-closing reaction, and then, if necessary, the hydroxyl group is removed from the resulting compound. In the following formula (1), which is characterized by eliminating a protecting group and/or a 4-lower alkoxyphenyl group, 8 represents a hydrogen atom or a hydroxyl group protecting group, and 2 represents a hydrogen atom or a 4-lower alkoxyphenyl group. A method for producing a compound represented by the following, which represents a quinphenyl group.

2. The following formula (■) During the ceremony, R'' represents a hydroxyl protecting group, R4 represents a lower alkyl group, The compound shown in

3, (a) The following formula (II) R20,A, /CO□H(I[) In the formula, R2 represents a hydroxyl group-protecting group. [) In the formula, R3 represents a lower alkyl group, and (b) the resulting compound is reacted with the following formula (TV), where R2 and R3 are as defined above. , reacted with U tin (II) triflate in the presence of a base to give erulate, and then reacted with acetaldehyde to obtain (c) the following formula (V), where R2 and R3 are as defined above, Protecting the hydroxyl group of the compound represented by (d) the following formula (Vl) obtained, where R'' represents a hydroxyl group-protecting group, and R2 and R3 are as defined above, the compound represented by 4 - Reacting with lower alkoxyphenylamine, (e) Obtaining the following formula (■) In the formula, R4 represents a lower alkyl group, and R11 and R2 are as defined above. A method for producing a compound of formula (■) according to claim 2, characterized in that R2 is eliminated.

Claims (1)

[Claims] 1. The following formula (VIII) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (VIII) In the formula, R^1^1 represents a hydroxyl group protecting group, and R^4 represents a lower alkyl group. A compound represented by the following formula ( I ) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) In the formula, R^1 represents a hydrogen atom or a protecting group for a hydroxyl group, and Z represents a hydrogen atom or a 4-lower alkoxyphenyl group. Production method. 2. The following formula (VIII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIII) In the formula, R^1^1 represents a hydroxyl group protecting group, and R^4 represents a lower alkyl group. . 3. (a) Formula (II) below ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (II) In the formula, R^2 represents a protecting group for the hydroxyl group. Formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) In the formula, R^3 represents a lower alkyl group. React with the compound shown by (b) The following formula (IV) obtained ▲ Formula , chemical formulas, tables, etc. ▼ (IV) In the formula, R^2 and R^3 are as defined above. A compound represented by is reacted with tin (II) triflate in the presence of a base. The resulting enolate is reacted with acetaldehyde, and (c) the following formula (V) is obtained. Protect the hydroxyl group of a compound represented by (d) and obtain the following formula (VI) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) In the formula, R^1^1 represents a protecting group for the hydroxyl group. , R^2 and R^3 are as defined above, react the compound represented by with 4-lower alkoxyphenylamine, and (e) obtain the following formula (VII) ▲ Numerical formula, chemical formula, table, etc. ▼(VII) In the formula, R^4 represents a lower alkyl group, R^1^1 and R^2 are as defined above, and the hydroxyl protecting group R^2 is removed from the compound represented by The formula (V
III) Method for producing the compound.