JPS63170377A - Highly stereo-selective production of (1r,5r,6s)-2-oxo-6-((1 r)-1-hydroxyethyl)-1-methylcarbapenam-3-carboxylic acid derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound in high stereoselectivity, by reacting an azetidinone compound having a steric configuration corresponding to the objective compound with 3-acylthiazolyl-2-thione, thereby stereoselectively fixing the 4-position of the azetidinone skeleton. CONSTITUTION:The objective compound of formula VII (R<1> is H or R<4>) useful as an intermediate for carbapenem antibiotic substances can be stereoselectively produced by (1) reacting a compound of formula I (R<2> is H, lower alkyl, aryl or aralkyl) with tin (II) triflate in the presence of a base, (2) successively reacting with a compound of formula II (R<3> is H or protective group; L is lower alkanoyloxy, lower alkylsulfonyl or arysulfonyl) to obtain a compound of formula III, (3) reacting the compound with a compound of formula IV (R<4> is protective group) in the presence of imidazole, (4) removing the group R<3> from the reaction product, (5) treating the resultant compound of formula V with an azide compound in the presence of a base, (6) cyclizing the obtained compound of formula VI in the presence of a metal catalyst and, if necessary, (7) removing the group R<4> from the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 1-substituted-2-oxocarbabenam-3=luponic acid derivatives, and more specifically, it is an important synthetic intermediate for carbapenem antibiotics. (IR, 5R, 8S)-2 having the configuration shown in the following formula 1, where R1 represents a hydrogen atom or a carboxy protecting group
-oxo-6-[(IR)-1-hydroxyethyl]-
The present invention relates to a production method in which the configuration of a 1-methylcarbapenam-3-carboxylic acid derivative is controlled with high selectivity.

To date, many carbapenem compounds have been proposed for the purpose of various antibacterial activities. For example, ticonamycin-based carbapenem compounds, represented by imipenem, have been recognized to have excellent antibacterial effects, and there are no actual There are also compounds that are becoming popular as pharmaceuticals.

However, these carbapenem antibiotics that are under development have low resistance to decomposition and inactivation by renal dehydropeptidase when administered in vivo, and therefore, actual products related to imipenem, which are highly effective, are The current situation is that it contains cirasufutin, which is a renal dehydropeptidase (hereinafter abbreviated as DHP) inhibitor.

Recently, various compounds have been proposed as carbapenem antibiotics with improved resistance to DHP, in which an alkyl group, such as a methyl group, is introduced at the 1-position of the carbapenem skeleton. This carbapenem antibiotic basically has a structure represented by the following formula (1), where Ra represents an organic compound residue, and these compounds are represented by the following reaction formula A (IXJ' ( In the formula X1, Rb represents an ester residue, and is produced by the method shown below.

Therefore, the compound represented by the formula ■ is an important starting compound for this series of carhepenem antibiotics, but the stereoselective production method for this compound has not been studied in detail. .

By the way, the initial production of the conventional compound represented by formula ■ was as follows:
For example, it is carried out by the route shown in Reaction Formula B below.

Reaction formula B (tXl In the formula, Rb represents an ester residue, and RC represents a hydroxyl group protecting group.

That is, starting from azetidinonecarboxylic acid represented by formula XI, the hydroxyl group at the 3-position is protected to form a compound represented by formula The compound represented by the formula

In the production method shown by the above reaction formula, especially when introducing a methyl group into the compound of formula XH, the coordination of the methyl group inevitably becomes an α-2β-mixture. Therefore, it has the disadvantage that the yield of β-coordination compounds, which are said to have excellent pharmacological effects, is not good. Furthermore, regarding the azetidinone carboxylic acid represented by formula
Furthermore, the current situation is that it is quite difficult to control the steric configuration during the total synthesis process.

Therefore, the present inventors conducted studies to develop a highly selective production method for the compound represented by the above formula 1, which is said to have a particularly preferable configuration among the compounds represented by the above formula (1). As a result, the present invention was completed.

Therefore, according to the present invention, it has a configuration represented by the following formula 1, in which R1 is a hydrogen atom or a carboxy protecting group (IR,5R,EiS)-
2-oxo-6-[(IR)-1-hydroxyethyl]
- A method for producing a 1-methylcarpamine 3-carboxylic acid derivative, the method comprising the following steps: (a) The following formula TI In the formula, R2 is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group. 3-acyl- represented by
A 1,3-thiazolidine-2-thione compound is reacted with tin (■) triflate in the presence of a base, followed by the following formula m. Reacting with an azetidinone compound represented by the following formula representing a lower alkylsulfonyl group or an arylsulfonyl group to obtain a compound represented by the following formula: (b) The obtained compound represented by 2 is treated in the presence of imidazole, A compound represented by the following formula V, in which R3 and R4 are as defined above, is reacted with a magnesium malonate compound represented by the following formula (% formula %), in which R4 represents a carboxy protecting group. Obtained: (C) The resulting compound represented by formula V was subjected to an elimination reaction of the protecting group R3 to obtain a compound represented by the following formula (1) where R4 is as defined above: (d ) The resulting compound represented by the formula (1) is then treated with an azide compound in the presence of a base to obtain a diazo compound represented by the following formula (1), in which R4 is as defined above: (e) obtained For the diazo compound represented by the formula ■,
It consists of carrying out a cyclization reaction in the presence of a metal catalyst and optionally removing the carboxy protecting group R4, thereby making it possible to produce a compound having the configuration represented by Formula 1 in a highly selective and controlled manner. can.

The present invention also particularly relates to (3S,4R)-3 of the formula
-[(IR)-1-hydroxyethyl]-4-[(IR
)-1-Methyl-3-poxy-2-oxyprovir]-azetidin-2-one derivative, and a method for producing the same with highly selective configuration control, the method comprising the step ( It consists of a), (b) and (C).

The uninvented feature is to select as a starting compound a compound represented by formula G that already retains the desired configuration, and to react that compound with 3-acylthiazolidine-2-1,000 ion represented by formula II. The 4th position of the azetidinone skeleton is fixed stereoselectively to create a compound represented by the formula ■, and from this compound - an important intermediate of the formula ■
The desired compound (IJ5R,BS)-2-oxo-13-[(I
R)-1-hydroxyethyl]-1-methylcarbapenam-3-carboxylic acid derivative.

A method for producing carbapenem compounds while retaining these specific configurations has not been studied in the past. Therefore, the present invention provides a novel highly stereoselective method for producing the compound represented by formula 1. It is.

As used herein, the term "lower" refers to 1 to 7 carbon atoms, preferably 1 to 7 carbon atoms, preferably 1
~4 pieces.

The "lower alkyl group" may be linear or branched and preferably have 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, 5ec-butyl,
tert-butyl, n-pentyl, inpentyl, n-
Included are hexyl, monoxyl groups, and the like.

Examples of the "carboxyl protecting group" include ester residues, such as methyl, ethyl, n-propyl, isopropyl, n-1i
Lower alkyl ester residues such as so-1sec-1tert-butyl, n-hexyl ester; benzyl, p-
Aralkyl ester residues such as nitrobenzyl, 0-nitrobenzyl, P-methoxybenzyl; lower aliphatic acyloxymethyl residues such as acetoxymethyl, propionyloxymethyl, n-1iso-, butyryloxymethyl, pivaloyloxymethyl, etc. Examples include groups.

The "aryl group" may be monocyclic or polycyclic, and may further have one or more lower alkyl groups on the ring, such as phenyl, tolyl, xylyl, α- Included are naphthyl, β-naphthyl, biphenylyl groups, and the like.

"Aralkyl group" is an aryl-substituted alkyl group in which the alkyl group is the above-mentioned lower alkyl group and the aryl group has the above meaning, and specifically, it includes benzyl, phenethyl, α-methylbenzyl, phenylpropyl, and naphthylmethyl groups. etc. can be exemplified.

Furthermore, examples of "hydroxyl protecting groups" include silyl groups such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenyl-tert-butylsilyl; benzyloxycarbonyl group; p-nitrobenzyloxycarbonyl, 0-nitrobenzyloxycarbonyl and other commonly used hydroxyl group-protecting groups.

In addition, a "lower alkanoyloxy group" is a lower alkyl -C-O- group in which the lower alkyl moiety has the above meaning, examples include acetoxy, propionyloxy, butyryloxy groups, etc., and an "arylsulfonyl group" An aryl-5O2- group in which the aryl moiety has the above meaning, and includes, for example, benzenesulfonyl, tolylsulfonyl, naphthylsulfonyl groups, etc., and a "lower alkylsulfonyl group" refers to a lower alkyl group in which the lower alkyl moiety has the above meaning. -5O2- group, specifically methanesulfonyl, ethanesulfonyl,
Examples include propanesulfonyl groups.

Next, the highly stereoselective production method of the present invention will be explained in more detail by explaining each step.

In step (a), an N-acyl-1,3-thiazolidine-2-thousone derivative of formula (1) is treated with tin(II) in the presence of a base.
4 to form a two-route, which is then reacted with a compound of formula (2) to form azetidine-2 (2).
- N-acyl-1,3-thiazolidine-2- of formula (1) above -
The enolization reaction using tin (II) reflate of thione derivatives is usually carried out in a solvent inert to the reaction, such as ethers such as diethyl ether and tetrahydrofuran; hydrocarbons such as toluene, xylene, and cyclohexane; dichloromethane, chloroform, etc. The reaction can be suitably carried out in halogenated hydrocarbons, particularly in 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.
Relatively low temperatures of 78°C to about 0°C are used.

The amount of tin(II) triflate used relative to the compound of formula II is not critical, but typically about 1 to about 2 moles of tin(■) triflate, preferably 1 to about 2 moles, per mole of the compound of formula II. It can be used in a proportion of 1.5 moles.

The above enolization reaction is carried out under basic conditions, and examples of bases that can be used include triethylamine, diisopropylethylamine, 1,4-diazabicyclo[2,
Examples include tertiary amines such as 2,21 octane, N-methylmorpholine, N-ethylpiperidine, and pyridine.
Among them, N-ethylpiperidine is advantageously used. These bases generally range from about 1.0 to 1.0 per mole of compound of formula II.
It can be used in a proportion of about 3 equivalents, preferably 1.0 to 2.0 equivalents.

The enolization reaction can generally be completed in about 5 minutes to about 4 hours, thereby yielding erulate.

Following this enolization reaction, the resulting erulate can be directly reacted with the compound of the formula m.

The alkylation reaction between the erulate and the compound of formula (1) 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 the compound of formula (II) to be used in this case is not critical and can be changed as appropriate, but is usually about 0.5 to about 5 mol, preferably about 5 mol per mol of the compound of formula II used in the enolization reaction. It is appropriate to use it in a proportion of 0.5 to 2 moles.

Under such conditions, the reaction can generally be completed in about 5 minutes to about 5 hours, more generally about 5 minutes to about 2 hours.

The enolization reaction and the alkylation reaction described above are preferably, but not necessarily, carried out under an inert atmosphere, such as a nitrogen gas or argon gas atmosphere.

Finally, the reaction product is treated with water. For example, after the reaction is completed, a phosphate buffer solution with a pH of around 7 is added, stirred, and insoluble materials are removed by a furnace.
It can be separated and purified by recrystallization, chromatography, etc.

This step (b) involves reacting the azetidin-2-one derivative represented by the formula (1) produced in the step (a) with a magnesium malonate compound represented by the formula (R300CH2CO2)2Mg in the presence of imidazole; This is a process for obtaining a compound represented by formula V.

The reaction is preferably carried out in an inert organic solvent, such as ether solvents such as ether, tetrahydrofuran, and disoxane; hydrocarbon solvents such as toluene, xylene, and cyclohexane; and halogenated hydrocarbon solvents such as dichloromethane and chloroform. ; Acetonitrile and the like can be mentioned, but acetonitrile is particularly preferably used.

The reaction temperature is not strictly limited and can be varied widely depending on the starting materials used, but generally a relatively low temperature of about 0°C to about 100°C, preferably around room temperature, is used. Ru.

The amount of the magnesium malonate compound used is approximately equimolar to the compound of formula (1), and the reaction is completed in about 50 hours, preferably about 20 hours.

In addition, examples of the magnesium malonate compound to be used include paranitrobenzylmagnesium malonate, benzylmagnesium malonate, methylmagnesium malonate, etc. Among them, it is preferable to use paranitrobenzylmagnesium malonate. .

Step (C) is a step of removing the protecting group for the hydroxyl group represented by R3 in the compound of formula (1) obtained in step (b). For example, R3 is a triorganosilyl group such as t-butyldimethylsilyl group. Removal of a protecting group that is a group of formula V
Acidic hydrolysis of the compound in a solvent such as methanol, ethanol, tetrahydrofuran, dioxane, etc. in the presence of an acid such as hydrochloric acid, sulfuric acid, acetic acid, etc. at a temperature of 0 to 100°C for 0.5 to 18 hours. This can be implemented by (The above-mentioned "triorganosilyl group" more preferably includes a silyl group substituted with an organic group independently selected from a lower alkyl group, a phenyl group, and a phenylalkyl group.) Through this step, the desired formula The compound represented by can be obtained quantitatively.

Step (d) is to treat the compound represented by formula (1) obtained in step (C) with an azide compound in the same inert organic solvent as described in step (b) in the presence of a base to obtain the desired product. An azide compound of formula (2) is obtained.

Examples of the azide compounds used include p-rupoxybenzenesulfonyl azide, toluenesulfonyl azide, methanesulfonyl azide, dodecylbenzenesulfonyl azide, and bases include triethylamine, pyridine, diethylamine, etc. The following bases can be exemplified.

The reaction is preferably carried out in acetonitrile in the presence of triethylamine by adding P-h luenesulfonyl azide,
This can be carried out by treating at 0 to 100°C, preferably at room temperature, for 1 to 50 hours, and thereby the desired diazo compound of formula (1) can be obtained in high yield.

Step (e) is a step in which the diazo compound of formula (1) obtained in step (d) is cyclized to give the target compound of formula I of the present invention. The step preferably comprises a compound of formula (1), for example,
Bis(acetylacetona)) in an inert solvent such as benzene, toluene, tetrahydrofuran, cyclohexane, ethyl acetate, dichloromethane, etc., preferably in toluene, at a temperature of 25 to 110 °C for 1 to 5 hours.
Cu (U), CuSO4, m powder, Rh2 ('0CO
CH3) a, rhodium octanoate or Pd(Q
It is carried out by treatment in the presence of a metal catalyst such as a metal carboxylate compound such as C:0GH3)a. On the other hand, as another method, the above cyclization step can also be carried out by preparing the compound of formula (1) in a solvent such as benzene, diethyl ether, etc. at a temperature of 0 to 250°C for 0.5 to 2 hours using a Pyrex filter (the wavelength is (larger than 300nm)
This can be carried out by irradiating light through.

Further, in the resulting compound of formula 1, the deprotection of the compound in which R1 has a carboxyl protecting group can be easily removed in the next desired step, and a compound in which R1 is a hydrogen atom can be obtained.

According to the method of the present invention described above, the 1st position of the carbapenem skeleton is substituted with a methyl group with an R configuration, the 5th and 6th positions are substituted with an R and S configuration, respectively, and the 6th position is a hydroxyethyl group. The compound represented by formula 1 having a specific configuration in which the hydroxyl group has an R configuration can be produced with high stereoselectivity, which is particularly advantageous considering that conventional methods could only produce racemic forms. It can be said that it is a manufacturing method.

The (IR)i of the present invention thus produced is represented by the formula
-2-oxocarbapenem-3-carboxylic acid derivatives can be converted into (IR)-1-substituted rubabenem-3-carboxylic acid derivatives having a mercapto substitution at the 2-position, which has excellent antibacterial activity. can.

The present invention will be further explained below with reference to Examples, but the scope of the present invention is not limited thereto.

Note that symbols in the examples have the following meanings.

Ac niacetyl, Et + ethyl PNE + varanitrobenzyl Example 1 m + 21 tin trifle) 3.712 g was dissolved in 101 g of anhydrous tetrahydrofuran under a nitrogen gas stream, and after cooling to 0 °C, 1.31 g of toethylpiperidine and the compound (2 )1
．． A solution of 2 g of anhydrous tetrahydrofuran in 7 ml was added, and the mixture was stirred at the same temperature for 2 hours. Then compound (1) 1.42
Add 2 ml of anhydrous tetrahydrofuran solution of g and stir for a while. After the reaction is complete, add chloroform 1001,
Wash with 10% citric acid aqueous solution, dry the organic layer with MgSO4, and evaporate the solvent. The residue was purified by silica gel chromatography (eluent: n-hexane-ethyl acetate = 2 to 1:1), and compound (3) was obtained as a yellow solid at 1.83%
g (97%) was obtained.

NMR (δ, C:DCh): 0.0? (8)1. s)
, 0.88 (9H, s) , 1.21 (38, d)
, 1.28 (3H, d) , 3.30 (IH, d
d), 3.2El (2H.

t), 3.94 (IH, dd), 4.55 (2
H, t), 8.24 (IH, bs).

Example 2 fil f41 +51 tin triflae) 57. After dissolving Og in 1134 ml of anhydrous tetrahydrofuran under a nitrogen gas stream and cooling it to 0°C, 19.9 ml of N-ethylpiperidine and 21.71 g of compound (4) were dissolved in 12 ml of anhydrous tetrahydrofuran.
3ml of the solution was added and stirred at the same temperature for 1.5 hours. Then, a solution of 1.42 g of compound (1) in 123 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred for 1 hour. After the reaction is complete,
Add chloroform, wash with 10% aqueous citric acid solution and brine, dry the organic layer over MgSO4, and evaporate the solvent. The residue was made viscous by silica gel chromatography (eluent: n-hexane-ethyl acetate = 2:l), and the melting point was 85.
Compound (4) as a yellow solid at 5-86.5°C
．． 57g (98%) was obtained.

NMR (6, CDCh): 0.0? (EiH,s),
0.90 (3H, s), 1.00 (3H, t),
1.23 (3H, d), 1.28 (3H, d)
, 2.90(I)l, dd) , 3.50(IH,
dd), 8.10 (IH, bs).

[α]25=+233.9° (C=0.77, C
HCh) Compound (5) obtained in Example 2 To a solution of 30.88 g of anhydrous acetonitrile 7401, imidazole 12
．． 13 g was added thereto, and the mixture was stirred for 5.5 hours at room temperature under a nitrogen gas stream.

Then Mg(02GCH2C02PNB) 253.39
g and stirred overnight at 60°C.
The mixture was condensed under reduced pressure to up to 1 sl, 1 portion of ethyl acetate was added, and the organic layer was washed successively with an aqueous IN-MCI solution, a 5% aqueous NaHCO3 solution, and brine, and dried over MgSO4. The solvent was distilled off, and the residue was purified by column chromatography using 800 g of silica gel to obtain compound (8) 3 as a colorless oil.
7.47g was obtained.

NMR (δ, CDCh): 0.0B (13H, s),
0.87 (9H, s), 1.18 (3H, d
), 1.20 (3M, d), 3.83 (2
H,s), 5.27 (2H.

s), 5.92 (IH, bs), ? ,5Et,
8.24 (4H aromatic ring proton).

Motoichi was used in the following Example 4 without further purification.

Example 4 To a solution of 37.47 g of compound (8) obtained in Example 3 in methanol 3921, 19.8 ml of C-HCl was added,
The reaction solution was stirred at room temperature for 1.5 hours, then the reaction solution was
Concentrate under reduced pressure to ml, add ethyl acetate 8001, water,
It was washed with brine and dried over MgSO4. The solvent was distilled off under reduced pressure to obtain Compound (7) as a colorless oil.

NMR (δ, Cl5C13): 1.25 (3H, d)
, 1.30 (3H, d) , 2.90 (2H, o+
), 3.85(2H,s), 3.83(IH,
m), 4.15 (IH.

m), 5.27 (2H, s), 8.03 (IH,
bs), 7.55, 8.27 (4) 1 aromatic ring proton).

Next, the above compound (7) was dissolved as it was in 408 ml of anhydrous acetonitrile, 13.8 ml of dodecylbenzenesulfonyl azide was added, the mixture was stirred at room temperature for 20 minutes, and the solvent was distilled off. The residue was subjected to column chromatography using 800 g of silica gel (eluent: chloroform-acetone = = 2+
1), compound (8) was purified as a colorless oil 2
1.57 g (8 as total yield of Examples 2, 3 and 4)
8.4%).

IR(CHCh)cm-': 2+50, 175
0, 1720, 185ONMR (δ, CDC13)
:1.23(3H,d), 1.30(3H,d)
, 2.92 (IH, m), 3.50-4.30 (
3)1. m), 5.38 (2H, s), 8.40 (
IH, bs), ? , 57, 8.30 (4H, aromatic ring proton) [α121 = -41,8° (C = 3.t, CH
2Cl2) Example 5 21.57 g of compound (8) obtained in Example 4 was dissolved in 134 ml of ethyl acetate, and rhodium octanoate 0.0
65 g was added and stirred at 80°C for 0.5 hour. The solvent was then distilled off and dried to obtain compound (9) as a solid.

IR((:HCl2)cm-': 2950, 2
925, 1880, 183ONMR (δ, CDC1
3): 1.22 (3H, d, J = 8.0L (z)),
1.37 (3H, d, J = 6.0t(z)),
2.40 (IH, bs), 2.83 (IH, q, J
-8゜0t(z)), 3.28(IH, d, d)
, 4.00-4.50 (2H, m) , 4.75 (
IH,s), 5.28 and 5.39(2H,ABq
, J=12Hz), ? , 58, 8.24 (4H, aromatic ring proton).

(Volunteer to write procedural amendments) March 17, 1985 Commissioner of the Patent Office Kuro 1) Akio Yu 1, Indication of the case 1986 Patent Application No. 315444 2, Name of the invention (IR, 5R, 6S>-2-oxo -6-[(IR)-
1-Hydroxyethyl-1-methylcarbapenam-3-
Highly stereoselective production method of carboxylic acid derivatives 3, relationship with the case of the person making the amendment Patent applicant name
Japan Redery Co., Ltd.4, Agent address: 1 person outside 1-9-15 Akasaka, Minato-ku, Tokyo 107 5, Date of procedural amendment order: None6, “Claims j” column of the specification to be amended Column 7 of "Detailed Description of the Invention", Contents of Amendment (1) The statement in 1. Scope of Claims of the specification is corrected as shown in the attached sheet.

(2) On page 9, line 5 of the specification, "Chikonamai" is corrected to "Chenamai".

(3) On page 16, line 9 of the same [ ” A certain thing " υ I am corrected.

(4) Paragraph 26j' (in the third line from the bottom): ``Azide compound'' is corrected to ``rNoazo compound''.

(5) Same page 35, line 2 chives (゛Azide 13.8m1J
The statement is corrected to read ``36.31 g of azide and 13.8 ml of triethylamine.

(6) On page 36, lines 7, 8, and 9, the words r't(z)J are corrected to [HzJ.

Above 2, Claim No. 11 In the formula, R1 represents a hydrogen atom or a carboxy protecting group, and has the configuration (IR, 5R, 8S)-2
-oxo-8-[(IR)-1-hydroxyethyl1-
In the method for producing a 1-methylcarbapenam-3-carboxylic acid derivative, 3-acyl-
A 1,3-thiazolidine-2-thione compound is reacted with tin (■) triflate in the presence of a base, followed by the following formula (■), where R3 represents a hydroxyl protecting group, L is a lower alkanoyloxy group, Representing a lower alkylsulfonyl group or an arylsulfonyl group, is reacted with an azetidinone compound represented by the following formula,
R2 and R3 are as defined above to obtain a compound represented by: (b) The resulting compound represented by the formula React with a magnesium malonate compound represented by to obtain a compound represented by the following formula V: (C) The resulting compound represented by the formula A compound represented by the following formula ■, in which R4 is as defined above, is obtained: (d) The resulting compound represented by the formula ■ is then treated with an azide compound in the presence of a base to obtain a compound represented by the following formula ■. (e) The resulting diazo compound represented by the formula (■) is subjected to a cyclization reaction in the presence of a metal catalyst, and optionally carboxy-protected. A highly selective method for producing a carboxylic acid derivative having the steric configuration represented by the above formula 1, which comprises removing the group R4.

2. (3S, 4R)-3-[(IR)-1- having the configuration shown by the following formula (1), where R4 represents a carboxy protecting group
hydroxyethyl]-4-[(IR)-1-methyl-3
-carboxy-2-ogisoprovir]-azetidine-2
-one derivative.

3. (3S, 4R)-3-[(IR)-1-, which has the configuration shown by the following formula (3), where R4 represents a carboxy protecting group.
hydroxyethyl]-4-[(IR)-1-methyl-3
-carboxy-2-oxoprobyl]-azetidine-2
In the method for producing an -one derivative, (a) 3-acyl- represented by the following formula TI where R2 represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group.
A 1,3-thiazolidine-2-thione compound is reacted with tin (■) triflate in the presence of a base, followed by the following formula (■), where R3 represents a hydroxyl protecting group, and L represents a lower alkanoyloxy group. , representing a lower alkylsulfonyl group or an arylsulfonyl group, to obtain a compound represented by the following formula: (b) The resulting compound represented by Reacting with a magnesium malonate compound of the formula V, in which R4 represents a carboxy protecting group, yields a compound of the following formula V, where R3 and R4 are as defined above: (C) A highly selective method for producing a compound having the steric configuration represented by the formula (2) above, which comprises subjecting the resulting compound represented by the formula V to an elimination reaction of the protecting group R3.

Claims (1)

[Claims] 1. The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) In the formula, R^1 represents a hydrogen atom or a carboxy protecting group, and has a stereochemistry represented by (1R , 5R, 6S)-2
-oxo-6-[(1R)-1-hydroxyethyl]-
In the method for producing 1-methylcarbapenam-3-carboxylic acid derivatives, (a) the following formula II ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) In the formula, R^2 is a hydrogen atom or a lower alkyl group , representing an aryl group or an aralkyl group, is reacted with tin(II) triflate in the presence of a base, followed by the following formula III ▲Math. , chemical formulas, tables, etc.▼ (III) In the formula, R^3 represents a hydroxyl protecting group, and L represents a lower alkanoyloxy group, a lower alkylsulfonyl group, or an arylsulfonyl group. Then, a compound represented by the following formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ (IV) where R^2 and R^3 are as defined above, is obtained: (b) With the resulting formula IV: The compound shown is reacted with a magnesium malonate compound of the following formula Mg(OOCCH_2COOR^4)_2 where R^4 represents a carboxy protecting group in the presence of imidazole to form the following formula V ▲Math. There are chemical formulas, tables, etc. ▼(V) In the formula, R^3 and R^4 are as defined above, to obtain a compound represented by: (c) The resulting compound represented by formula V is treated with a protecting group. R^3
By subjecting to the elimination reaction of A compound represented by formula VI is treated with an azide compound in the presence of a base to obtain the following formula VII ▲ Numerical formula, chemical formula, table, etc. ▼ (VII) where R^4 is as defined above, Obtain a diazo compound represented by: (e) For the obtained diazo compound represented by formula VII,
A highly selective method for producing a carboxylic acid derivative having the steric configuration represented by the above formula I, which comprises carrying out a cyclization reaction in the presence of a metal catalyst and optionally removing the carboxy protecting group R^4. 2. The following formula VI ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ (VI) In the formula, R^4 represents a carboxy protecting group, and has the configuration shown by (3S, 4R)-3-[(1R) -1
-hydroxyethyl]-4-[(1R)-1-methyl-
3-carboxy-2-oxopropyl]-azetidine-
2-one derivative. 3. The following formula VI ▲There are numerical formulas, chemical formulas, tables, etc.▼ (VI) In the formula, R^4 represents a carboxy protecting group, and has the configuration shown by (3S, 4R)-3-[(1R) -1
-hydroxyethyl]-4-[(1R)-1-methyl-
3-carboxy-2-oxopropyl]-azetidine-
In the method for producing a 2-one derivative, (a) the following formula II ▲ Numerical formula, chemical formula, table, etc. ▼ (II) In the formula, R^2 is a hydrogen atom, a lower alkyl group, an aryl group, or an aralkyl group. The 3-acyl-1,3-thiazolidine-2-thione compound represented by is reacted with tin(II) triflate in the presence of a base, followed by the following formula III ▲Mathematical formulas, chemical formulas, tables, etc. ▼(III) In the formula, R^3 represents a protecting group for a hydroxyl group, and L represents a lower alkanoyloxy group, a lower alkylsulfonyl group, or an arylsulfonyl group. There are chemical formulas, tables, etc. ▼ (IV) In the formula, R^2 and R^3 are as defined above. Obtain the compound represented by: (b) The resulting compound represented by formula IV is treated with imidazole. In the presence of Mg(OOCCH_2COOR^4)_2, where R^4 represents a carboxy protecting group, it is reacted with a magnesium malonate compound represented by the following formula V ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (V) In the formula, R^3 and R^4 are as defined above to obtain a compound represented by: (c) The resulting compound represented by formula V is protected by a protecting group R^3
1. A highly selective method for producing a compound having the configuration represented by the formula VI, which comprises subjecting the compound to an elimination reaction.