JP3044175B2 - Method for removing allyl group or allyloxycarbonyl group - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to the conversion of allyl esters of carboxylic acids (allyl esters) into the corresponding carboxylic acids.
An improved chemical method for converting an allyloxycarbonyl derivative of an alcohol (allyl carbonate) to the corresponding alcohol or an allyloxycarbonyl derivative of an amine (allyl carbamate) to the corresponding amine. About. The process of the present invention comprises the step of contacting an allyl ester, allyl carbonate or allyl carbamate with a sulfinic acid compound in a reaction inert solvent in the presence of a palladium catalyst.

Accordingly, the present invention relates to the protection of allyl groups when they are used to protect carboxylic acids or when allyloxycarbonyl groups are used to protect alcohols or amines. Useful for removing groups. Furthermore, the process of the present invention can be carried out under mild conditions, so that the carboxylic acid to be treated, alcohol-
Allyl esters, allyl carbonates and allyl carbamates can be deprotected without adversely affecting sensitive functional groups in the amine or amine compound. The method of the present invention is particularly suitable for removing allyl or allyloxycarbonyl protecting groups in the presence of β-lactam groups in natural, biosynthetic, semi-synthetic, and synthetic β-lactam antibiotics. .

[0003]

2. Description of the Related Art Allyl groups are frequently used as protecting groups such as carboxy groups in the synthesis of β-lactam antibiotics. The advantage of using allyl groups in the synthesis of β-lactam antibiotics is described in SW McCombie et al. [J. Org.
Chem., 47, 587 (1982)]. Removal of an allyl group from an allyl ester or the like has been reported in several documents and patent publications.

[0004] Japanese Patent Publication No. 60-9730 (US Patent No. 4)
No. 314942) discloses the reaction of 2-ethylhexanoic acid or an alkali metal salt thereof in the presence of an organic soluble palladium complex catalyst to form an allyl group from an allyl ester, and from an allyl carbonate or an allyl carbamate. A method for removing an allyloxycarbonyl group is disclosed.

JP-A-03-130293 (European Patent Publication No. 410727A1) discloses that an allyl group is formed from a penem compound by a reaction with a cyclic 1,3-diketone such as dimedone or its alkali metal enolate. A method for removal is described. JP 04-41489A
Discloses a similar method using an alkali metal salt of a carboxylic acid having 1 to 4 carbon atoms.

[0006]

However, according to the above-mentioned conventional method, the yield of the final product is not always satisfactory depending on the compound to be treated. For example, in the conventional method, the activity of the catalyst is remarkably reduced when a raw material for crude purification is used, and the yield is reduced when a compound which is unstable under basic conditions for deprotection is treated.

Accordingly, from various compounds having an allyl group, such as allyl ester, allyl carbonate, allyl carbonate, etc., other functional groups which bind the allyl group or the like to the compound to be treated. Without adversely affecting
A method that can be removed with high yield and high chemical selectivity is desired.

[0008]

SUMMARY OF THE INVENTION The present invention provides a process for converting an allyl ester of a carboxylic acid to a carboxylic acid, converting an allyloxycarbonyl derivative of an alcohol to an alcohol, or converting an allyloxycarbonyl derivative of an amine to an amine. In the presence of a palladium catalyst, in a reaction inert solvent,
Disclosed is a method comprising contacting an allyl ester of a carboxylic acid, an allyloxycarbonyl derivative of an alcohol or an allyloxycarbonyl derivative of an amine with a sulfinic acid compound. Hereinafter, the present invention will be described in detail.

The present invention relates to the use of a sulfinic acid compound as a deprotecting agent to remove an allyl group or an allyloxycarbonyl group from an allyl ester, allyl carbonate or allyl carbonate to be treated. It is characterized by. Sulfinic acid compounds that can be used in the present invention include aliphatic, alicyclic, aromatic and heterocyclic sulfinic compounds and salts thereof.

[0010] Preferred sulfinic acid compounds have the general formula: halogen in _{X-SO 2 M ··· (I} ) ( wherein, X is C ₁ ~ ₂₀ alkyl, substituted C ₁ ~ ₂₀ alkyl (substituent is independently nitro , Sulfo, oxo,
Amino, cyano, carboxy, hydroxy or phenyl, a group derived therefrom, a substituted phenyl (the substituents C ₁ ~ ₃ alkyl independently, halogen, nitro, sulfo,
Oxo, amino, cyano, carboxy, hydroxy, acetamido, or groups derived therefrom), furyl, or thienyl; and M is hydrogen,
Which is an alkali metal or ammonium salt residue). "Halogen, nitro, sulfo, oxo, amino, cyano, carboxy or hydroxy-derived group" refers to those readily formed by the reaction of these groups with compounds having reactive groups therewith. (Eg, an ester residue for carboxy, an amide residue for amino, and an ether residue for hydroxy).

[0011] More preferred sulfinic acid compound, in the general formula (I), X is C ₁ ~ ₁₆ alkyl, substituted C ₁ ~ ₁₆
Alkyl (substituents are independently C ₁ -C ₃ alkyl, halogen, nitro, sulfo, oxo, amino, cyano, carboxy, hydroxy or groups derived therefrom), phenyl or substituted phenyl (substituents are independently C ₁
-C ₃ alkyl, halogen, nitro, sulfo, oxo,
Amino, cyano, carboxy, hydroxy, acetamido, or groups derived therefrom), or thiophene, preferably mono- or disubstituted phenyl; and M is hydrogen, an alkali metal, ammonium, or ammonium salt residue. Is a compound. Particularly preferred sulfinic acid compounds are monosubstituted or disubstituted phenylsulfinic acid compounds, wherein in formula (I), X is phenyl or methylphenyl; M is an alkali metal such as lithium, sodium or potassium, or ammonium A compound that is a salt residue (consisting of ammonia, primary amine, secondary amine, tertiary amine, or quaternary ammonium salt residue, etc.).

[0012] Preferred sulfinic acid compounds of the general formula _{(I), C 1 ~ 20} ( preferably C ₁ ~ ₁₀₎ alkyl-substituted sulfinic acid compounds, for example, methyl sulfinic acid, ethyl sulfinic acid, isobutyl sulfinic acid, Octylsulfinic acid, octadecylsulfinic acid and salts thereof are included. The alkyl attached to the sulfinic acid may be substituted with one or two substituents (eg, halogen, hydroxy) as long as they do not interfere with the deprotection reaction. Examples of such compounds include the sodium salt of hydroxymethanesulfinic acid. Among these compounds, the most preferred is the lithium salt of p-toluenesulfinic acid, p-toluenesulfinic acid.
Sodium salt of toluenesulfinic acid, potassium salt of p-toluenesulfinic acid, p-toluenesulfinic acid,
p-Toluenesulfinic acid ammonium salt, benzenesulfinic acid lithium salt, benzenesulfinic acid sodium salt, benzenesulfinic acid potassium salt, benzenesulfinic acid, benzenesulfinic acid tetrabutylammonium salt, p-carboxybenzenesulfinic acid Sodium salt, octylsulfinic acid sodium salt, ethylsulfinic acid sodium salt, 4-chloro-
Sodium salt of 3-nitrobenzenesulfinic acid, 4-
Acetamidobenzenesulfinic acid sodium salt, thiophene-2-sulfinic acid sodium salt, methylsulfinic acid sodium salt, isobutylsulfinic acid sodium salt, hexadecylsulfinic acid sodium salt, hydroxylmethanesulfinic acid sodium salt,
Ammonium p-toluenesulfinate, triethylammonium p-toluenesulfinate, or tetrabutylammonium benzenesulfinate. Among these compounds, more preferred are lithium salt of p-toluenesulfinic acid, sodium salt of p-toluenesulfinic acid, potassium salt of p-toluenesulfinic acid,
p-toluenesulfinic acid, ammonium salt of p-toluenesulfinic acid, lithium salt of benzenesulfinic acid, sodium salt of benzenesulfinic acid, potassium salt of benzenesulfinic acid, benzenesulfinic acid, or ammonium salt of benzenesulfinic acid. The deprotecting agent used in the present invention is an allyl ester to be treated,
For allyl carbonate or allyl carbamate,
0.5 to 5 equivalents, preferably 1.0 to 1.2 equivalents are used.

As used herein, "allyl group or allyloxycarbonyl group" means any group having an allyl structure and which can be removed by the method of the present invention. As used herein, “allyl” refers to an alkyl or substituted alkyl having a carbon-carbon double bond at positions 2 and 3. Examples of the "allyl group" include allyl, methylallyl, crotyl, chloroallyl, cinnamyl and the like. Examples of the "allyloxycarbonyl group" include allyloxycarbonyl, methylallyloxycarbonyl, crotyloxycarbonyl, chloroallyloxycarbonyl, cinnamyloxycarbonyl and the like. A suitable allyl or allyloxycarbonyl group is a carboxyl group,
Used to protect hydroxy or amino groups,
Present in known allyl alcohols or active esters thereof. Suitable allyl alcohols are allyl alcohols
, Halogenated allyl alcohol, methyl allyl alcohol, crotyl alcohol, cinnamyl alcohol, or active esters thereof. Accordingly, preferred compounds which can be treated are allyl esters, allyl carbonates and allyl carbamates wherein the allyl group or allyloxycarbonyl group is derived from allyl alcohol.

Preferred compounds from which the allyl protecting group can be removed are, for example, allyl esters of penams such as penicillin G and ampicillin; cephalosporanic acid;
(Phenylacetamide) allyl ester of cephems such as deacetoxycephalosporanic acid and cephamycin; allyl ester of carbapenems such as thienamycin; 5R, 6S-6- (1R-hydroxyethyl) -2
Β-lactam allyl esters such as allyl esters of penems such as-(1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid.

[0015] The method of the present invention is particularly applicable to 5R, 6S-6-
(1R-hydroxyethyl) -2- (1R-oxo-3
Allyl ester of (S-thiolanylthio) -2-penem-3-carboxylic acid was converted to 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid. Suitable for conversion to an acid.

Other preferred compounds which can be treated by the method of the present invention include allyl esters of amino acids such as glycine, serine and phenylalanine, and allyl esters of benzoic acid and nalidixic acid.

Further, the allyl carbonates which can be treated by the method of the present invention include, for example, n-octadecano-
Derivatives of alcohols such as 1-menthol, 1-octanol, 2-octanol, 1-adamantanol, N-benzyloxycarbonylserine;
, Derivatives of steroids such as cortisone, testosterone and estradiol; phenols such as 1-naphthol
And derivatives of macrolides such as erythromycin and rosaramycin. Allyl carbamates which can be treated by the method of the present invention include, for example, 1-aminoadamantane, 2-octylamine, ephedrine,
Derivatives of amines such as aniline, p-methoxyaniline, 1-naphthylamine and benzocaine; and derivatives of amino acids such as glycine, phenylalanine and serine.

In the practice of the present invention, the deprotection reaction of the allyl group or allyloxycarbonyl group is carried out in the presence of a palladium catalyst. A preferred palladium catalyst that can be used in the present invention is a palladium compound that easily reacts with an allyl compound to form a π-allyl complex. More preferred palladium catalysts are tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (acetonitrile) palladium (II), dichlorobis (triisopropoxyphosphine) palladium (II)
Having phosphine ligands such as palladium (II) diacetate and the like, and are usually used together with triphenylphosphine or triethylphosphite (Jiro Tsuji, "Transition metals that changed organic synthesis", Chemical Doujin ,
1991). In the conventional method using 2-ethylhexanoic acid sodium salt as a deprotecting agent, triphenylphosphine or a palladium catalyst itself is supplemented during the reaction in order to promote the deprotection reaction or maintain a high catalytic activity. Need to be added. However, in the method of the present invention, since the catalytic activity of the reaction system is high and the reaction rate is high, it is not always necessary to supplementally add such a phosphine compound or a catalyst. The palladium catalyst is used in such an amount as to provide sufficient catalytic activity for the deprotection reaction, and is generally used in an amount of 0.1 to 0.1% based on the allyl ester, allyloxycarbonate or allyloxycarbamate to be treated. 20 mol%, preferably 2 to 7 mol%
Used in amounts.

The deprotection reaction is performed in a suitable solvent. Suitable solvents include, for example, alcohols (eg, methanol, ethanol), hydroxy group-containing solvents such as water; alkyl halide compounds (eg, dichloromethane, chloroform); esters (eg, acetic acid). Methyl, ethyl acetate), ethers (eg, diethyl ether, tetrahydrofuran), nitriles (eg,
Solvents that do not contain a hydroxy group such as acetonitrile, propionitrile), ketones (eg, acetone, methyl ethyl ketone), and aromatic hydrocarbons (eg, benzene, toluene); mixtures thereof. If necessary, a solvent containing no hydroxy group can be used in combination with a hydroxy group-containing solvent. When p-toluenesulfinic acid sodium salt is used, tetrahydrofuran or the like can be used in combination with methanol or water.

The deprotection reaction can be carried out under substantially neutral conditions. Therefore, the method of the present invention is useful in synthesis using raw materials and final compounds that are susceptible to acidic or basic conditions.

The conditions for the deprotection reaction are determined by the type of the compound to be treated, the deprotecting agent used, the catalyst, the solvent and the like. Generally, the deprotection reaction is carried out between -20 ° C and 100 ° C.
° C, preferably at a temperature of 10 ° C to 40 ° C for 1 minute to 18 minutes.
Time, preferably 5 minutes to 6 hours.

Next, a typical example of removing an allyl group or an allyloxycarbonyl group will be described. The following examples are illustrative and do not limit the scope of the invention.

First, the allyl ester, allyl carbonate or allyl carbamate to be treated, and a palladium catalyst are added to a suitable solvent such as tetrahydrofuran or ethyl acetate. A suitable deprotecting agent such as p-toluenesulfinate is dissolved in a suitable solvent such as methanol.
The solution containing the deprotecting agent is added to the mixture containing the compound to be treated and the catalyst. The reaction mixture is stirred at a suitable temperature for a time sufficient for deprotection to complete the reaction.

When the product in the method of the present invention is sparingly soluble in a solvent, the product precipitates as crystals, and the target salt can be collected by filtration. When the product in the method of the present invention hardly precipitates from the obtained reaction mixture, another solvent in which the product is hardly soluble is added and mixed well with the reaction mixture to precipitate crystals. As another method, hydrochloric acid is added to a solution containing the product to precipitate crystals, and the obtained crystals are separated by filtration using a known filtration means.

[0025]

According to the method of the present invention, an allyl group or an allyloxycarbonyl group from an allyl ester, an allyl carbonate or an allyl carbonate is linked to the compound to be treated. Can be removed with a high yield and a high chemical selectivity without adversely affecting the functional group. The method of the present invention, compared to the conventional method using 2-ethylhexanoic acid sodium salt or dimedone, requires a compound which is destabilized under basic conditions of the reaction and requires deprotection of an allyl group or an allyloxycarbonyl group. A wider range of compounds can be processed, including. In addition, the deprotecting agent used in the present invention is generally inexpensive, and can be effectively used for large-scale production using a crudely purified allyl compound as a raw material.

[0026]

The present invention will be described in more detail with reference to the following Examples and Comparative Examples.

Preparation Example 1: The chloroallyl ester or methylpropenyl ester of the penem compound used herein was obtained from WO 88/08845 (Examples 1-1).
It was prepared in a similar manner as described in 1).

Preparation Example 2 2-propenyl 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylate was prepared as follows. Prepared. 5R, 6S-6- (1
R-hydroxyethyl) -2- (1R-oxo-3S-
The sodium salt of thiolanylthio) -2-penem-3-carboxylic acid (3.0 g, 8.08 mmol) was dissolved in N, N-dimethylformamide (25 ml), and allyl bromide (2.93 g, 24.2 mmol) was added. did. The reaction mixture was stirred at room temperature for 15 hours, and then stirred in water (80 m
l). After stirring for another 2 hours, the resulting white solid was filtered off. The filtrate was extracted with methylene chloride (50ml). The obtained extract was washed with water (10 ml), dried over magnesium sulfate, filtered, concentrated, and further washed with ethyl acetate (5 ml) to obtain a white solid. The combined white solids were recrystallized from ethanol (30 ml),
After filtration, a first product of a propenyl ester was obtained. The mother liquor was concentrated, washed with ethyl acetate (2 ml) and dried in vacuo to give a second product. First and second products,
Mix, dry in vacuo and add 2-propenyl (2.17 g) of 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylate. Obtained as a white solid in 69% yield.

Preparation Example 3 2-butenyl 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylate is prepared as follows. Prepared. 5R, 6S-6- (1R
-Hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid sodium salt (1.75 g, 4.71 mmol) was added to N, N-dimethylformamide (5.2 ml). Dissolved and 1-bromo-2-butene (1.91 g, 14.1 mmol) was added. The reaction mixture was stirred at room temperature for 20 hours before being poured into water (50 ml). After stirring for another 30 minutes,
The resulting pale yellow solid was filtered off. The filtrate was extracted with methylene chloride (30ml). The obtained extract was dried over magnesium sulfate, filtered and concentrated, and further washed with ethyl acetate (5 ml) and n-hexane (5 ml) to obtain a pale yellow solid. The combined solids (2.0 g) were recrystallized from ethanol (20 ml), filtered off, dried in vacuo and 5R, 6S-6- (1R-hydroxyethyl) -2.
2-Butenyl- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylate (1.04 g) was obtained as a white solid in 55% yield. The mother liquor was concentrated, washed with ethyl acetate (2 ml) and dried in vacuo to give the butenyl ester (0.24 g) as a second product, 1
Obtained in 3% yield. The first and second products obtained were mixed.

Preparation Example 4: 2-methyl-5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylate
2-Propenyl was prepared as follows. 5R, 6
Sodium salt of S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid (15.7.g, 42.3 mmol)
l) was dissolved in N, N-dimethylformamide (110 ml) and 1-bromo-2-methyl-2-propene (1
(6.3 g, 121 mmol) was added. After the reaction mixture was stirred at room temperature for 19.5 hours,
l). After stirring for an additional hour, the resulting solid was filtered off and washed with water (20 ml). The filtrate was extracted with methylene chloride (70ml). The resulting extract was washed with water (10ml) and brine (10ml), dried over magnesium sulfate, filtered and concentrated. The remaining solid was suspended in water (20 ml) and filtered. The solid obtained is mixed with the solid obtained previously and ethyl acetate (100
ml), stirred for 30 minutes, and filtered. After vacuum drying, 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio)-
2-Methyl-2-propenyl 2-penem-3-carboxylate (13.6 g) was obtained as a white solid in 80% yield.

Preparation 5: Cinnamyl 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylate was prepared as follows. . 5R, 6S-6- (1R
-Hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid sodium salt (6.88 g, 18.5 mmol) was dissolved in N, N-dimethylformamide (25 ml). , Cinnamyl bromide (3.65 g, 18.5 mmol) was added. After stirring the reaction mixture at room temperature for 20 hours, it was poured into water (500 ml) and extracted with methylene chloride (500 ml). The obtained extract was washed with water (50 ml) and concentrated. Isopropyl ether (200 m) was added to the residue, and the precipitated solid was separated by filtration. The solid was recrystallized from isopropanol (50 ml), filtered off, dried in vacuo and dried in 5R, 6S-6- (1R-hydroxyethyl) -2.
Cinnamyl- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylate (2.32 g) was obtained as a pale yellow solid in 31% yield.

Preparation Example 6: Sodium alkyl sulfinate was prepared according to the method described in [Synthesis, 584 (1990)]. Other sodium sulfinates were prepared by reacting sulfonyl chloride with sodium sulfite or zinc dust according to conventional methods.

Preparation Example 7: (2S, 5R) -3,3-dimethyl-4,4,7-trioxo-4-thia (VI)-
2-Chloro-2-propenyl 1-azabicyclo [3.2.0] heptane-2-carboxylate was prepared as follows. Sodium penicillanic acid 4,4-dioxide (3.25) in hexamethylphosphoramide (26 ml)
g, 12.7 mmol), 1-bromo-2-chloro-2
-Propene (3.96 g, 25.5 mmol) was stirred at 55 ° C for 18 hours. Ether (300 ml) was added, washed three times with water (50 ml), dried over magnesium sulfate, filtered and concentrated. The obtained residue is treated with methanol (1).
0 ml), and hexane (100 ml) was added to precipitate a solid. After stirring for 15 minutes, the mixture was filtered off, washed with hexane (10 ml) three times, and dried under vacuum (2S, 5
R) -3,3-dimethyl-4,4,7-trioxo-4
-Thia (VI) -1-azabicyclo [3.2.0] heptane-2-carboxylate 2-chloro-2-propenyl (3.36 g) was obtained as a white solid in a yield of 86%.

Preparation Example 8 2-propenyl 7-benzamide-3-acetoxymethyl-3-cepham-4-carboxylate was prepared as follows. Tetrabutylammonium hydrogen sulfate (1.08 g, 3.19 mmol) was dissolved in water (4.6 ml), and the pH was adjusted to 6 using a 5N aqueous sodium hydroxide solution. 7-benzamide-3
-Acetoxymethyl-3-cepham-4-carboxylate (1.00 g, 2.51 mmol) was added and 1
After stirring at room temperature for 2 hours while maintaining the pH at 6.6 using an aqueous solution of N sodium hydroxide, chloroform (4.6 m
1 + 2.3 ml × 2) for three times. Allyl bromide (912 mg, 7.53 mmol) was added to the chloroform extract.
l) was added and the mixture was stirred at 50 ° C for 2 hours. The reaction was poured into ethyl acetate (200 ml), washed three times with water (20 ml), dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography to give 7-benzamide-3-acetoxymethyl-3.
-Cepham-4-carboxylic acid 2-propenyl (905 m
g) as a pale yellow viscous liquid in 87% yield.

Preparation Example 9 N- (p-methoxyphenyl) allyl carbamate was prepared as follows.
-20 ° C p-anididine (1.24 g, 10.1 g)
mmol) and N-ethylmorpholine (2.03 g, 2
0.1 mmol) of dimethylacetamide (25 ml)
Allyl chlorocarbonate (1.45 g, 12.
1 mmol) was added dropwise. After stirring at −20 ° C. for 1 hour, the mixture was warmed to room temperature and poured into water (25 ml). This was extracted with ethyl acetate (250ml). The ethyl acetate extract was washed with water (25ml), dried over sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography to obtain N- (p-methoxyphenyl) allyl carbamate (2.03 g) with a yield of 97%.

Preparation Example 10: 3-O-allyloxycarbonyl-1, 2: 5,6-di-O-isopropylidene-α
-D-Glucofuranose was prepared as follows.
Allyl chloroformate (740 mg, 6.14 mmol)
l) at 0 ° C with 4-N, N-dimethylaminopyridine (750 mg, 6.14 mmol) and 1,2,5,6-
Di-O-isopropylidene-α-D-glucofuranoose (385 mg, 1.48 mmol) in methylene chloride (4
ml) was added dropwise to the solution. After raising the reaction temperature to room temperature and stirring for 3 hours, water (10 ml) was added and ether (85 ml) was added.
ml) extracted. The ether extract was washed with water (10 ml) 2
Washed twice, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel chromatography and dried in vacuo, and as a colorless transparent liquid, 3-O-allyloxycarbonyl-1, 2: 5,6-di-O-isopropylidene-α-D-glucofurano. -Steel (509mg)
Was obtained in quantitative yield.

Example 1: 5R, 6S-6- (1R-H
Droxyethyl) -2- (1R-oxo-3S-thiola
2-Nylthio) -2-penem-3-carboxylic acid 2-chloro-
Removal of 2-chloro-2-propenyl from 2-propenyl, sodium p-toluenesulfinate tetrahydrate (15
5 mg, 0.615 mmol) of methanol (2.3 m
l) The solution was prepared at room temperature by using the 5R, 6S-
6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid 2-chloro-2-propenyl (261 mg, 0.61)
5 mmol) and tetrakis (triphenylphosphine) palladium (41.7 mg, 36.1 μmol) in a suspension of tetrahydrofuran (3.9 ml). The reaction mixture was stirred at room temperature for 105 minutes, and ethyl acetate (12 ml) was added dropwise to precipitate a sodium salt of the target compound. Celite (0.8%) was added to the resulting mixture.
g) was added. After filtration, the precipitate and celite were washed three times with ethyl acetate (3 ml), and the precipitate was washed with water (5 ml).
And washed with water (1.5 ml) three times. The resulting aqueous solution was acidified with an ion exchange resin (manufactured by Mitsubishi Kasei Corporation; trade name: DIAION PK216H), and acetone (7.5 ml) was added. The ion exchange resin is
It was filtered off and washed three times with acetone / water (2: 1, 1.5 ml). The combined filtrate was concentrated at 24 ° C. by evaporating the acetone using an evaporator, and further lyophilized to give a pale yellow powder (209 mg).
% Yield.

Comparative Example 1: The same experiment as in Example 1 was performed except that the following reactants, catalysts and solvents were used. -2-ethylhexanoic acid sodium salt: 20 mg (0.14 mmol)-5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid 2 -Chloro-2-propenyl: 50 mg (0.118 mmol) ・ Palladium diacetate: 5.6 mg (24.9 μmol) ・ Triethyl phosphite: 39 mg (0.234 mmol) ・ Acetone: 10 ml As a result, 5 mg of pale yellow Was obtained in a yield of 13%.

Comparative Example 2: The same experiment as in Example 1 was performed except that the following reactants, catalysts and solvents were used. Dimedone: 16.5 mg (0.118 mmol) 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid 2-chloro-2 -Propenyl: 50 mg (0.118 mmol) Tetrakis (triphenylphosphine) palladium: 5.1 mg (4.4 μmol) Triphenylphosphine: 9.9 mg (70 μmol) Tetrahydrofuran: 5 ml Could not be obtained.

In view of the results of Example 1 and Comparative Examples 1 and 2, it was found that the method of the present invention can significantly improve the yield as compared with the conventional method.

[0041]Example 2: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
From 2-propenyl-3-carboxylate to 2-propenyl
Removal Sodium p-toluenesulfinate tetrahydrate (35
2 mg, 1.41 mmol) of methanol (3.5 m)
l) The solution was prepared at room temperature using the 5R, 6S-
6- (1R-hydroxyethyl) -2- (1R-oxo
-3S-thiolanylthio) -2-penem-3-carboxylic
2-propenyl acid (500 mg, 1.28 mmol) and
And tetrakis (triphenylphosphine) palladium
(104mg, 89.8μmol) containing tetrahydro
Added to a suspension of furan (8.5 ml). Reaction mixture
Was stirred at room temperature for 35 minutes, ethyl acetate (25 ml)
Was added dropwise to precipitate a sodium salt of the target compound. Profit
Celite (1 g) was added to the resulting mixture. Filtered
Thereafter, the precipitate and Celite were washed three times with ethyl acetate (3 ml).
After washing, the precipitate was dissolved in water (5 ml).
ml) three times. The resulting aqueous solution is ion exchanged.
Exchange resin (manufactured by Mitsubishi Kasei Corporation; trade name: DIAION PK2)
16H) and acetone (17 ml) was added.
The ion-exchange resin is filtered off, and acetone / water (2:
(1, 2 ml) three times. The combined filtrate is 20
Evaporating acetone using an evaporator
More concentrated, further freeze-dried, pale yellow powder
(405 mg) was obtained in 90% yield.

[0042]Example 3: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thio-luanylthio) -2-pe
From 2-methyl-2-propenyl nem-3-carboxylate
Remove 2-methyl-2-propenyl Sodium p-toluenesulfinate tetrahydrate (15
1 mg, 0.604 mmol) of methanol (2.3 m
l) The solution was prepared at room temperature by using the 5R, 6S-
6- (1R-hydroxyethyl) -2- (1R-oxo
-3S-thiolanylthio) -2-penem-3-carboxylic
2-methyl-2-propenyl acid (244 mg, 0.60
4 mmol) and tetrakis (triphenylphosphine)
) Palladium (48.6 mg, 42.1 μmol)
To a suspension of tetrahydrofuran (3.8 ml) containing
did. The reaction mixture was stirred at room temperature for 130 minutes,
Ethyl (12 ml) was added dropwise and the target compound, sodium
The salt was precipitated. Celite (0.8%) was added to the resulting mixture.
g) was added. After filtration, the precipitate and Celite
The precipitate was washed three times with ethyl (3 ml), and the precipitate was washed with water (5 ml).
And washed three times with water (2 ml). Obtained
Aqueous solution is an ion exchange resin (Mitsubishi Kasei;
Name: DIAION PK216H)
(7.5 ml) was added. The ion exchange resin is
Separately, wash three times with acetone / water (2: 1, 2 ml)
Was. The combined filtrate was heated at 24 ° C using an evaporator.
Concentrate by evaporating acetone and freeze further
Dry to give a pale yellow powder (198 mg) with 94%
Obtained in yield.

[0043]Comparative Example 3: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
2-methyl-2-propenyl-3-carboxylate to 2-
Removes methyl-2-propenyl Methylene chloride (46 ml)
(196 mg, 0.746 mmol), 2-ethyl
Sodium xanate (993 mg, 5.98 mmol
l), 5R, 6S-6- (1R-H) prepared in Preparation Example 1
Droxyethyl) -2- (1R-oxo-3S-thiola
2-Nylthio) -2-penem-3-carboxylic acid 2-methyl-
Suspension of 2-propenyl (2.00 g, 4.98 mmol)
Turbid, tetrakis (triphenylphosphine) palladium
(325 mg, 281 μmol) was added. Para
The indium catalyst was added (79.9 mg, 69 μmo after 30 minutes).
l; 90 minutes later, 40.3 mg, 35 μmol) was added.
Was. The reaction mixture was stirred at room temperature for 2 hours. Water (10
after extraction with water (2.6 ml).
ml). The combined aqueous phases were washed with activated carbon (0.
17g) and filtered. Filter the remaining filter cake with water
(0.8 ml). Activated carbon
(0.17 g) and filtered. The remaining filtration cake
Was washed with water (0.8 ml). 5 combined aqueous solutions
C. and cooled to pH 2.5 by adding concentrated hydrochloric acid.
And stirred at 5 ° C. for 30 minutes. Get
The deposited precipitate was separated by filtration, washed four times with water (1 ml),
Air dry and dry 5R, 6S-6- (1R-hydroxyethyl
) -2- (1R-oxo-3S-thiolanylthio)-
2-penem-3-carboxylic acid was converted to light gray powder (897 m
g) in a yield of 52%.

Considering the results of Example 3 and Comparative Example 3, it can be seen that the method of the present invention can significantly improve the yield as compared with the conventional method even when treating other allyl compounds. Was.

[0045]Example 4: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
Removal of 2-butenyl from 2-butenyl-3-carboxylate Sodium p-toluenesulfinate tetrahydrate (15
5 mg, 0.618 mmol) of methanol (2.1 m
l) The solution was prepared at room temperature by using the 5R, 6S-
6- (1R-hydroxyethyl) -2- (1R-oxo
-3S-thiolanylthio) -2-penem-3-carboxylic
2-butenyl acid (227 mg, 0.562 mmol) and
And tetrakis (triphenylphosphine) palladium
(28.0 mg, 24.2 μmol)
Added to a suspension of lofuran (3.5 ml). Reaction mixing
The material was stirred at room temperature for 35 minutes and ethyl acetate (11 m
l) was added dropwise to precipitate the sodium salt of the target compound.
Was. Celite (0.8 g) was added to the resulting mixture.
After filtration, the precipitate and celite were removed with ethyl acetate (3 m
1), and the precipitate was dissolved in water (5 ml).
The mixture was washed three times with water (2 ml). The resulting aqueous solution
Is an ion exchange resin (manufactured by Mitsubishi Chemical Corporation; trade name: DIAI)
ON PK216H), and acetone (7.5 m)
l) was added. The ion exchange resin is filtered off,
And water (2: 1, 2 ml) three times. Together
The solution is evaporated at 20 ° C using an evaporator.
And then freeze-dried to give a pale
A yellow powder (178 mg) was obtained in 91% yield.

[0046]Example 5: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
-3- Removal of cinnamyl from cinnamyl carboxylate Sodium p-toluenesulfinate tetrahydrate (14
9 mg (0.594 mmol) of methanol (2.3 m
l) The solution was prepared at room temperature by using the 5R, 6S-
6- (1R-hydroxyethyl) -2- (1R-oxo
-3S-thiolanylthio) -2-penem-3-carboxylic
Cinnamyl acid (251 mg, 0.540 mmol) and
Tetrakis (triphenylphosphine) palladium (3
1.2 mg, 27.0 μmol)
Added to the suspension of the run (3.4 ml). Reaction mixture
Was stirred at room temperature for 30 minutes and ethyl acetate (11 ml)
Was added dropwise to precipitate a sodium salt of the target compound. Profit
Celite (0.8 g) was added to the resulting mixture. Filter
After that, the precipitate and Celite were washed with ethyl acetate (3 ml) for 3 hours.
After washing twice, the precipitate was dissolved in water (5 ml).
(2 ml) three times. The resulting aqueous solution is
Exchange resin (manufactured by Mitsubishi Chemical Corporation; trade name: DIAION P)
K216H), and acetone (7.5 ml) was added.
I got it. The ion exchange resin is filtered off, and acetone / water
(2: 1, 2 ml). The combined filtrate is
At 24 ° C., the acetone is evaporated using an evaporator.
And then freeze-dried to give a pale yellow
Powder (177 mg) was obtained in 94% yield.

[0047]Example 6: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
From 2-propenyl-3-carboxylate to 2-propenyl
Removal Sodium p-toluenesulfinate tetrahydrate (1.
06 g, 4.23 mmol) in water (7 ml).
At room temperature, the 5R, 6S-6- (1R-H
Droxyethyl) -2- (1R-oxo-3S-thiola
Nylthio) -2-penem-3-carboxylic acid 2-propeni
(1.54 g, 3.95 mmol) and tetrakis
(Triphenylphosphine) palladium (209 mg,
0.18 mmol) in tetrahydrofuran (20 m
l) was added to the suspension. The reaction mixture is brought to room temperature at 25
Stirred for minutes. Diethyl ether (20 ml) was added.
Later, the resulting mixture was extracted with water (1 ml). Obtained
The extract was treated with activated carbon (0.28 g) and filtered.
Was. The remaining filter cake was washed with water (1.5 ml).
Cool the combined aqueous solutions to 5 ° C. and add concentrated hydrochloric acid
And acidified to pH 2.5 at 5 ° C.
Stir for 30 minutes. 5R, 6S-6- (1R-hydroxy
Ciethyl) -2- (1R-oxo-3S-thiolanylthi
E) The precipitate of 2-penem-3-carboxylic acid is filtered off
And washed with water (1 ml), dried under vacuum and powdered (1.2
0g) was obtained in 87% yield.

[0048]Example 7: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
-2-Carboxylic acid 2-chloro-2-propenyl to 2-
Removes chloro-2-propenyl Tetrahydrofuran (3.37 ml) and water (1.35 ml)
ml) at room temperature with p-carboxybenzenesulfine
Sodium hydrate (118 mg), prepared in Preparation Example 1
5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
2-chloro-2-propenyl-3-carboxylate (200
mg, 0.471 mmol) and tetrakis (trife
Nylphosphine) palladium (28.7 mg, 24.8)
μmol) of the mixture. Bring the reaction mixture to room temperature
For 90 minutes. After adding water (1 ml),
The reaction mixture was diluted with ethyl ether (9 ml + 4.5 ml ×
Extracted 3 times in 2). Cooling the resulting aqueous phase to 5 ° C.
The pH is adjusted to 2.5 by adding concentrated hydrochloric acid.
Acidified and stirred at 5 ° C. for 30 minutes. Obtained precipitate
Is filtered off, washed with water (1 ml × 3), dried in vacuo,
5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
-3-carboxylic acid and 2-chloro-2-propenyl p-ca
Mixtures of ruboxyphenylsulfone in a molar ratio of 4: 3
I got it.

[0049]Example 8: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
-2-Carboxylic acid 2-chloro-2-propenyl to 2-
Removes chloro-2-propenyl Octyl sulfinic acid sodium salt (98.8 mg,
0.492 mmol) in methanol (1.6 ml)
At room temperature, 5R, 6S-6- (1) prepared in Preparation Example 1
R-hydroxyethyl) -2- (1R-oxo-3S-
Thiolanylthio) -2-penem-3-carboxylic acid 2-c
Loro-2-propenyl (200 mg, 0.470 mmol
l) and tetrakis (triphenylphosphine) para
Teto containing indium (29.9mg, 25.9μmol)
Added to a suspension of lahydrofuran (3.2 ml). Anti
The reaction mixture was stirred at room temperature for 4.5 hours, and ethyl acetate was added.
(8 ml) was added dropwise to precipitate the sodium salt of the target compound.
I let it. Celite (0.4 g) was added to the obtained mixture.
Was. After filtration, the precipitate and Celite were separated from ethyl acetate (2
ml), and the precipitate is dissolved in water (2 ml).
Further, it was washed with water (1 ml). The resulting aqueous solution is
Ion exchange resin (manufactured by Mitsubishi Kasei Corporation; trade name: DIAION)
 PK216H), and acetone (5 ml) was added.
I got it. The ion exchange resin is filtered off, and acetone / water
(5: 1, 1 ml). The combined filtrate is 20
Evaporating acetone with an evaporator at ℃
And then freeze-dried to give a pale yellow powder
(135 mg) was obtained in 82% yield.

[0050]Example 9: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
-2-Carboxylic acid 2-chloro-2-propenyl to 2-
Removes chloro-2-propenyl Ethyl sulfinic acid sodium salt (57.3 mg,
0.493 mmol) in methanol (1.6 ml)
At room temperature, 5R, 6S-6- (1) prepared in Preparation Example 1
R-hydroxyethyl) -2- (1R-oxo-3S-
Thiolanylthio) -2-penem-3-carboxylic acid 2-c
Loro-2-propenyl (200 mg, 0.470 mmol
l) and tetrakis (triphenylphosphine) paradi
(28.9mg, 25.0μmol)
Added to a suspension of hydrofuran (3.2 ml). reaction
The mixture was stirred at room temperature for 6.5 hours and ethyl acetate (8
ml) was added dropwise to precipitate the sodium salt of the target compound.
Was. Celite (0.45 g) was added to the obtained mixture.
Was. After filtration, the precipitate and Celite were separated from ethyl acetate (2
ml), and the precipitate is dissolved in water (2 ml).
Further, it was washed with water (1 ml). The resulting aqueous solution is
Ion exchange resin (manufactured by Mitsubishi Kasei Corporation; trade name: DIAION)
 PK216H), and acetone (5 ml) was added.
I got it. The ion exchange resin is filtered off, and acetone / water
(2: 1, 1 ml). The combined filtrate is 20
Evaporating acetone with an evaporator at ℃
And then freeze-dried to give a pale yellow powder
(149 mg) was obtained in 91% yield.

[0051]Example 10: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
-2-Carboxylic acid 2-chloro-2-propenyl to 2-
Removal of chloro-2-propenyl group 5R, 6S-6- (1R-hydroxy) prepared in Preparation Example 1
Ciethyl) -2- (1R-oxo-3S-thiolanylthi
E) 2-Penem-3-carboxylic acid 2-chloro-2-p
Lopenyl (7.82 g, 18.4 mmol), Triphe
Nylphosphine (723 mg, 2.76 mmol) and
Tetrakis (triphenylphosphine) palladium
(1.06 g, 0.92 mmol) in methylene chloride (1
96 ml) and benzenesulfinic acid (2.8)
7g, 20.2 mmol) was added at room temperature. Reaction mixing
The product was stirred at room temperature for 1 hour,
The crystals were filtered and washed three times with methylene chloride (7 ml).
And vacuum dried. 96% of white powder (6.19 g)
In a yield of

Comparative Example 4: 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid 2-chloro-
2-propenyl (16.9 g, 39.9 mmol), triphenylphosphine (1.46 g, 5.57 mmol)
l), sodium 2-ethylhexanoate (8.08 g,
48.6 mmol) were suspended in methylene chloride (365 ml). Tetrakis (triphenylphosphine) palladium (2.48 g, 2.14 mmol) was added at 20 ° C. After stirring at 20 ° C. for 2 hours, the brown reaction solution was
The mixture was cooled to ゜ 5 ° C. and extracted by adding water (86.5 ml). It was extracted once more with water (22 ml). The aqueous extracts were combined, cooled to 0-5 ° C, and concentrated hydrochloric acid to pH 5.2.
I made it. It was treated with activated carbon (1.46 g) and filtered, and the remaining filter cake was washed with water (6.7 ml). Again, the same activated carbon treatment was performed. The combined filtrate and washings were cooled to 5 ° C, brought to pH 2.5 with concentrated hydrochloric acid and stirred at 5 ° C for 1 hour. The precipitate was collected by filtration, washed five times with water (8 ml) and twice with acetone (6.6 ml), and dried under reduced pressure at room temperature. Pale gray-white powder (10.6
g) was obtained in a yield of 76%.

Comparative Example 5: The same experiment as in Example 10 was performed except that the following reactants, catalysts and solvents were used. 16.5 mg (0.118 mmol) of dimedone 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid 2-chloro-2- Propenyl 50 mg (0.118 mmol) tetrakis (triphenylphosphine) palladium 5.1 mg (4.4 μmol) triphenylphosphine 9.9 mg (70 μmol) tetrahydrofuran 5 ml As a result, the target compound was not obtained at all. Considering the results of Example 10 and Comparative Examples 4 and 5, it was found that the method of the present invention can significantly improve the yield as compared with the conventional method.

[0054]Example 11: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
-2-Carboxylic acid 2-chloro-2-propenyl to 2-
Removal of chloro-2-propenyl group Sodium benzenesulfinate (99.0 mg, 0.1%
494 mmol) in a methanol solution (1.6 ml).
5R, 6S-6- (1R-hydroxy prepared in Preparation Example 1
Ethyl) -2- (1R-oxo-3S-thiolanylthi
E) 2-Penem-3-carboxylic acid 2-chloro-2-p
Lopenyl (203mg, 0.479mmol) and tet
Lakis (triphenylphosphine) palladium (32.
Tetrahydrofuran containing 6 mg, 28.3 μmol)
(3.2 ml) at room temperature. Reaction mixture
After stirring at room temperature for 3.6 hours, a palladium catalyst (10 m
g, 8.7 μmol). 6.5 hours later, acetic acid
Ethyl (8 ml) was added dropwise, and the sodium salt of the target compound was added.
Was precipitated. Celite (0.6 g) was added to the obtained mixture.
Was added. After filtration, the precipitate and celite were washed with ethyl acetate.
(2 ml), and the precipitate was dissolved in water (2 ml).
Thaw, wash with acetone / water (1: 1, 3 ml)
Was. The obtained aqueous solution is used as an ion exchange resin (Mitsubishi Kasei Corporation)
Manufactured by DIAIONPK216H).
Seton (5 ml) was added. The ion exchange resin is filtered off
And washed with acetone / water (2: 1, 1 ml). Match
The filtrate was washed with acetone at 20 ° C using an evaporator.
And then freeze-dried to give
A brown powder (157 mg) was obtained in 94% yield.

Example 12: 5R, 6S using lithium p-toluenesulfinate
-6- (1R-hydroxyethyl) -2- (1R-oxo
So-3S-thiolanylthio) -2-penem-3-carbo
2-chloro-2-propenyl acid to 2-chloro-2-
Removing propenyl p- toluenesulfonic lithium fin acid (64.6 mg,
0.398 mmol) prepared in Preparation Example 1
2-chloro-2-propenyl-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylate (140 mg, 0.3
30 mmol) and tetrakis (triphenylphosphine) palladium (27.4 mg, 23.7 μmol)
And tetrahydrofuran-methanol (5: 3, 3.
3 ml) at room temperature. The reaction mixture was stirred at room temperature for 60 minutes, and ethyl acetate (6.6 ml) was added dropwise.
The sodium salt of the target compound was precipitated. Celite (0.6 g) was added to the resulting mixture. After filtration, the precipitate and celite were washed three times with ethyl acetate (1.5 ml), the precipitate was dissolved in water (2 ml), and further dissolved in water (1 ml).
And washed three times. The obtained aqueous solution is ion-exchanged with resin (manufactured by Mitsubishi Kasei; DIAION PK216H).
And acetone (5 ml) was added. The ion exchange resin was filtered off and washed three times with acetone / water (2: 1, 1 ml). The combined filtrate was evaporated using an evaporator.
Concentrated by evaporating the acetone at ゜ C and further lyophilized to give a pale yellow powder (109 mg) in 94% yield.

[0056]Example 13: Sodium 4-chloro-3-nitrobenzenesulfinate
5R, 6S-6- (1R-hydroxyethyl
) -2- (1R-oxo-3S-thiolanylthio)-
2-Penem-3-carboxylic acid 2-chloro-2-propeni
To remove 2-chloro-2-propenyl group from Tetrahydrofuran-methanol (5: 3, 3.9 m
l) was prepared in Preparation Example 1 using 5R, 6S-6- (1R-H
Droxyethyl) -2- (1R-oxo-3S-thiola
2-Nylthio) -2-penem-3-carboxylic acid 2-chloro-
2-propenyl (165 mg, 0.389 mmol),
Sodium 4-chloro-3-nitrobenzenesulfinate
(106 mg, 0.433 mmol), tetrakis
(Triphenylphosphine) palladium (29.5m
g, 25.5 μmol), triphenylphosphine (2
(9.7 mg, 0.113 mmol) at room temperature.
The reaction mixture was stirred at room temperature for 130 minutes and ethyl acetate (8
ml) was added dropwise to precipitate the sodium salt of the target compound.
Was. Celite (0.6 g) was added to the resulting mixture.
After filtration, the precipitate and celite were removed from ethyl acetate (2 m
l) 3 times, and the precipitate is dissolved in water (1.5 ml).
Then, it was washed three times with water (1.0 ml). Water obtained
Ion exchange resin (Mitsubishi Kasei; DIA)
ION PK216H) and acetone (6m
l) was added. The ion exchange resin is separated by filtration, and acetone / water
(2: 1, 1.0 ml). Combined filtrate
The acetone was evaporated at 21 ° C. using an evaporator.
And freeze-dried to give a pale yellow
Powder (98.2 mg) was obtained in 72% yield.

Example 14: Using sodium 4-acetamidobenzenesulfinate
5R, 6S-6- (1R-hydroxyethyl) -2
-(1R-oxo-3S-thiolanylthio) -2-pene
2-chloro-2-propenyl mu-3-carboxylate to 2
-Chloro -2-propenyl group was removed. Tetrahydrofuran (3.3 ml) and methanol (2.0 ml) were added to sodium 4-acetamidobenzenesulfinate (139 mg, 0.626 mmol), 5R, 6S- prepared in Preparation Example 1. 6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylate 2-chloro-2-propenyl (226 mg, 0.534 mmol) and tetrakis (triphenylphosphine) Palladium (35.
5 mg, 30.7 μmol) at room temperature. The reaction mixture was stirred at room temperature for 60 minutes, and ethyl acetate (11 ml) was added dropwise to precipitate a sodium salt of the target compound. Celite (0.8 g) was added to the resulting mixture. After filtration, the precipitate and celite were washed three times with ethyl acetate (1.5 ml), the precipitate was dissolved in water (3 ml), and further washed three times with water (1.5 ml). The obtained aqueous solution was converted to an ion exchange resin (manufactured by Mitsubishi Kasei Co.,
IAION PK216H), and acetone (7.5 ml) was added. The ion exchange resin was filtered off and washed three times with acetone / water (2: 1, 1.5 ml). The combined filtrate was concentrated by evaporation of the acetone at 19 ° C. using an evaporator and further lyophilized to give a pale yellow powder (176 mg) in 94% yield.

[0058]Example 15: 5 using sodium thiophene-2-sulfinate
R, 6S-6- (1R-hydroxyethyl) -2- (1
R-oxo-3S-thiolanylthio) -2-penem-3
-2-chloro-2-propenyl carboxylate to 2-chloro
(B) removing 2-propenyl group Tetrahydrofuran-methanol (5: 3, 2.0 m
l) was prepared in Preparation Example 1 using 5R, 6S-6- (1R-H
Droxyethyl) -2- (1R-oxo-3S-thiola
2-Nylthio) -2-penem-3-carboxylic acid 2-chloro-
2-propenyl (85.4 mg, 0.201 mmol
l), sodium thiophene-2-sulfinate (4
0.1 mg, 0.236 mmol), tetrakis (tri
Phenylphosphine) palladium (16.9 mg, 1
4.6 μmol) at room temperature. Bring the reaction mixture to room temperature
And stirred for 150 minutes, and ethyl acetate (4 ml) was added dropwise.
The sodium salt of the target compound was precipitated. The resulting mixture
Celite (0.4 g) was added to the material. After filtration, precipitation
The product and Celite were washed three times with ethyl acetate (1 ml),
The precipitate was dissolved in water (1.0 ml).
Washed 3 times in 1). The resulting aqueous solution is ion-exchanged
Fat (manufactured by Mitsubishi Kasei Corporation; trade name: DIAION PK216)
H), and acetone (3 ml) was added. ion
The exchange resin was filtered off, and acetone / water (2: 1, 1.0 m
Washed 3 times in 1). Evaporate the combined filtrate.
By evaporating acetone at 21 ° C using
And freeze-dried to give a pale yellow powder (67.6 m
g) was obtained with a 96% yield.

Example 16: 5R, 6S-6 using sodium methylsulfinate
-(1R-hydroxyethyl) -2- (1R-oxo-
3S-thiolanylthio) -2-penem-3-carboxylic acid
2-chloro-2-propenyl to 2-chloro-2-pro
After removing the phenyl group, tetrahydrofuran (3.2 ml) was added to tetrakis (triphenylphosphine) palladium (32.6 mg, 22.6 mg).
8.3 μmol) and 5R, 6S- prepared in Preparation Example 1.
2-chloro-2-propenyl 6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylate (200 mg, 0.47
1 mmol) at room temperature. Sodium methylsulfinate (50.5mg, 0.494mmol)
(1.6 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 2 hours and ethyl acetate (8 ml)
Was added dropwise to precipitate a sodium salt of the target compound. Celite (0.6 g) was added to the resulting mixture. After filtration, the precipitate and celite were removed with ethyl acetate (2 ml).
After washing twice, the precipitate was dissolved in water (2 ml).
ml). The obtained aqueous solution is ion-exchanged with resin (manufactured by Mitsubishi Kasei; DIAION PK216H).
And acetone (5 ml) was added. The ion exchange resin was filtered off and washed three times with acetone / water (5: 1, 2 ml). The combined filtrate was concentrated by evaporating the acetone using an evaporator, and further lyophilized to give a pale brown powder (141 mg) in 86% yield.

Example 17: 5R, 6S using sodium isobutylsulfinate
-6- (1R-hydroxyethyl) -2- (1R-oxo
So-3S-thiolanylthio) -2-penem-3-carbo
2-chloro-2-propenyl acid to 2-chloro-2-
Removing propenyl isobutyl benzenesulphinate (71.3 mg,
0.494 mmol) in methanol solution (1.6 ml)
Was prepared in Preparation Example 1 as 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid 2-chloro-2-
Propenyl (200 mg, 0.471 mmol) and tetrakis (triphenylphosphine) palladium (3
A suspension of 2.6 mg (28.3 μmol) in tetrahydrofuran (3.2 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 6.3 hours. Ethyl acetate (8m
l) was added dropwise to precipitate the sodium salt of the target compound. Celite (0.6 g) was added to the resulting mixture.
After filtration, the precipitate and celite were removed from ethyl acetate (2 m
After washing twice with 1), the precipitate was dissolved in water (2 ml) and further washed with water (1 ml). The obtained aqueous solution was ion-exchanged with a resin (manufactured by Mitsubishi Kasei; DIAION PK2).
16H) and acetone (5 ml) was added. The ion exchange resin was filtered off, and acetone / water (5: 1, 1
ml). The combined filtrate was concentrated by evaporating the acetone using an evaporator at 20 ° C. and freeze-dried to give a pale brown powder (148 mg).
Was obtained in 90% yield.

Example 18: 5R, 6 using sodium hexadecylsulfinate
S-6- (1R-hydroxyethyl) -2- (1R-O
Oxo-3S-thiolanylthio) -2-penem-3-cal
2-chloro-2-propenyl borate to 2-chloro-2
- removal of the propenyl group hexadecyl benzenesulphinate (176 mg,
0.564 mmol), 5R, 6S prepared in Preparation Example 1
2-Chloro-2-propenyl -2- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylate (219 mg, 0.5
To a mixture containing 16 mmol) and tetrakis (triphenylphosphine) palladium (38.0 mg, 33 μmol) was added tetrahydrofuran (3.5 ml) and methanol (2.5 ml). 5. Bring the reaction mixture to room temperature.
Stir for 4 hours. Ethyl acetate (10 ml) was added dropwise to precipitate the sodium salt of the target compound. Celite (0.7 g) was added to the resulting mixture. After filtration, the precipitate and celite were washed twice with ethyl acetate (2 ml), the precipitate was dissolved in water (2 ml), and further washed with water (1 ml). The obtained aqueous solution was acidified with an ion exchange resin (manufactured by Mitsubishi Kasei Corporation; trade name: DIAION PK216H),
Acetone (5 ml) was added. The ion exchange resin was filtered off and washed with acetone / water (5: 1, 2 ml). The combined filtrate was concentrated by evaporating the acetone using an evaporator at 20 ° C. and further lyophilized to give a pale yellow powder (144 mg) in 80% yield.

[0062]Example 19: 5 using sodium hydroxymethanesulfinate
R, 6S-6- (1R-hydroxyethyl) -2- (1
R-oxo-3S-thiolanylthio) -2-penem-3
-2-chloro-2-propenyl carboxylate to 2-chloro
(B) removing 2-propenyl group Sodium hydroxymethanesulfinate (61.9m
g, 0.402 mmol) from 5R prepared in Preparation Example 1,
6S-6- (1R-hydroxyethyl) -2- (1R-
Oxo-3S-thiolanylthio) -2-penem-3-ca
2-chloro-2-propenyl rubonic acid (142 mg,
0.335 mmol) and tetrakis (triphenylpho
Sphine) palladium (24.3 mg, 21.0 μmo)
l) containing tetrahydrofuran-methanol (5: 3,
(3.3 ml) at room temperature. Chamber the reaction mixture
The mixture was stirred at room temperature for 80 minutes, and ethyl acetate (6.6 ml) was added dropwise.
Then, the sodium salt of the target compound was precipitated. Got
Celite (0.6 g) was added to the mixture. After filtration,
Precipitate and celite are washed three times with ethyl acetate (1.5 ml)
After washing, the precipitate was dissolved in water (2 ml).
Washed 3 times in 1). The resulting aqueous solution is ion-exchanged
Fat (manufactured by Mitsubishi Kasei Corporation; trade name: DIAION PK216)
H) and acetone (5 ml) was added. ion
The exchange resin is filtered off and washed with acetone / water (2: 1, 1 ml).
Washed three times. The combined filtrate was evaporated using an evaporator.
Concentrate by evaporating the acetone at 20 ° C.
And freeze-dried to give pale yellow powder (94.5 mg) as 8
Obtained in 6% yield.

Example 20: 5R using ammonium p-toluenesulfinate
6S-6- (1R-hydroxyethyl) -2- (1R-
Oxo-3S-thiolanylthio) -2-penem-3-ca
2-chloro-2-propenyl rubnate to 2-chloro-
The 2-propenyl group was removed and p-toluenesulfinic acid (53.1 mg, 0.340
mmol) was dissolved in chloroform (1 ml), 25% aqueous ammonia (0.5 ml) was added at room temperature, and the mixture was vigorously stirred and concentrated under reduced pressure to obtain a white solid. Preparation Example 1
5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio)-
2-Penem-3-carboxylic acid 2-chloro-2-propenyl (132 mg, 0.311 mmol) was added and dissolved in methylene chloride (3.1 ml). Tetrakis (triphenylphosphine) palladium (25.0 mg, 22μ)
mol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours, extracted by adding water (1 ml), and further extracted twice with water (1.5 ml). The water extracts were combined, treated with activated carbon and filtered, and the filtrate was adjusted to pH 2 with concentrated hydrochloric acid. The precipitate was filtered, washed twice with water (0.5 ml) and dried in vacuo at room temperature. A white powder (51.9 mg) was obtained in 48% yield.

Example 21: Using triethylammonium p-toluenesulfinate
5R, 6S-6- (1R-hydroxyethyl) -2
-(1R-oxo-3S-thiolanylthio) -2-pene
2-chloro-2-propenyl mu-3-carboxylate to 2
Removal of -chloro -2-propenyl group 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid 2-prepared in Preparation Example 1 Chloro-2-propenyl (77.5 mg, 0.183 mmol), p-
Toluenesulfinic acid (32.4 mg, 0.207 mm
ol), triethylamine (21.0 mg, 0.207
mmol) in methylene chloride (1.8 ml),
Tetrakis (triphenylphosphine) palladium (1
(4.5 mg, 12.5 μmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, extracted by adding water (1.8 ml), and further extracted twice with water (0.9 ml).
The water extracts were combined, treated with activated carbon and filtered, and the filtrate was adjusted to pH 2 with concentrated hydrochloric acid. The precipitate was collected by filtration and water (0.5 m
1), and dried under vacuum at room temperature. A pale off-white powder (32.4 mg) was obtained in 51% yield.

Example 22: Using tetrabutylammonium benzenesulfinate
5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
-2-Carboxylic acid 2-chloro-2-propenyl to 2-
The chloro-2-propenyl group was removed, and methylene chloride (7.0 ml) was added to tetrabutylammonium benzenesulfinate (300 mg, 0.81 mmol).
l), 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid 2-chloro- prepared in Preparation Example 1
To a mixture of 2-propenyl (300 mg, 0.707 mmol) and tetrakis (triphenylphosphine) palladium (49 mg, 42.4 μmol) at room temperature. The reaction mixture was stirred at room temperature for 25 minutes and water (1.5 m
l) and extracted, and extracted twice more (1.0 ml X
2) I did. The combined aqueous layer was cooled to 5 ° C., acidified to pH 2.5 by adding 1N hydrochloric acid, and stirred at 5 ° C. for 30 minutes. The obtained precipitate was separated by filtration, washed with cold water (2 ml), and dried under vacuum. A white powder (173 mg) was obtained in 70% yield.

[0066]Example 23: (2S, 5R) -3,3-dimethyl-4,4,7-tri
Oxo-4-thia (VI) -1-azabicyclo [3.
2.0] Heptane-2-carboxylic acid 2-chloro-2-p
Removal of 2-chloro-2-propenyl group from lophenyl Tetrahydrofuran-methanol (5: 3, 10.5m
l) was prepared in Preparation Example 7 (2S, 5R) -3,3-di
Methyl-4,4,7-trioxo-4-thia (VI)-
1-azabicyclo [3.2.0] heptane-2-carbo
2-chloro-2-propenyl acid (323 mg, 1.0
5 mmol), sodium p-toluenesulfinate
(289 mg, 1.15 mmol), tetrakis (tri
Phenylphosphine) palladium (68.0 mg, 5
8.8 μmol) at room temperature. Bring the reaction mixture to room temperature
For 60 minutes. Precipitation of sodium salt of target compound
did. Ethyl acetate (21 ml) and Celite (2
g) was added. After filtration, the precipitate and Celite
After washing with ethyl (4 ml) three times, the precipitate was washed with water (5 ml).
And washed three times with water (2.0 ml). Get
Ion exchange resin (Mitsubishi Kasei; trade name)
DIAION PK216H). Ion exchange
The exchanged resin is filtered off and washed with acetone / water (2: 1, 3 ml).
Washed twice. The combined filtrate was evaporated using an evaporator.
Concentrate by evaporating the acetone at 1 ° C, and further
Lyophilized to give a white powder (242 mg) in 99% yield.
Rate obtained.

Example 24: 7-Benzamide-3-acetoxymethyl-3-cepha
2-propenyl to 2-propenyl
The group was removed and sodium p-toluenesulfinate (218 mg,
0.871 mmol) in methanol solution (3.0 ml)
Was prepared in Preparation Example 8 and 2-propenyl 7-benzamide-3-acetoxymethyl-3-cepham-4-carboxylate (330 mg, 0.792 mmol), tetrakis (triphenylphosphine) palladium (54.9 m)
g, 47.5 μmol) in a tetrahydrofuran solution (5.0 ml) at room temperature. The reaction mixture was stirred at room temperature for 60 minutes. The sodium salt of the target compound precipitated. After adding ethyl acetate (16 ml) and stirring for 30 minutes, the precipitate was collected by filtration and washed three times with ethyl acetate (2 ml). The obtained filtrate was vacuum-dried at room temperature to give 7-benzamide-3-acetoxymethyl-3-cepham-4-.
The carboxylic acid sodium salt (253 mg) was obtained as a white powder in 80% yield.

Example 25: From N- (p-methoxyphenyl) allyl carbamate
Remove allyloxycarbonyl group p-toluenesulfinic acid (64.3 mg, 0.411
mmol) and N- (p-methoxyphenyl) allyl carbamate prepared in Preparation Example 9 (77.6 mg, 0.37
Tetrakis (triphenylphosphine) palladium (30.4 mmol) in methylene chloride solution (3.7 ml).
(3 mg, 26.2 μmol). The reaction mixture was stirred at room temperature for 40 minutes. The reaction solution was subjected to silica gel chromatography to obtain p-anididine (36.3 m
g) was obtained in 79% yield.

Example 26: 3-O-allyloxycarbonyl-1, 2: 5,6-di-
From O-isopropylidene-α-D-glucofuranoose
Removal of allyloxycarbonyl group 3-O-allyloxycarbonyl-prepared in Preparation Example 10
1,2: 5,6-di-O-isopropylidene-α-D-
Glucofuranose (115 mg, 0.334 mmol)
And methylene chloride solution (3.3 ml) of tetrakis (triphenylphosphine) palladium (27.0 mg, 23.4 μmol) in toluenesulfinic acid (59.3 m).
g, 0.380 mmol). After the reaction mixture was stirred at room temperature for 30 minutes, triethylamine (6.8 m
g, 67 μmol) and purified by silica gel chromatography to give a white solid of 1, 2: 5, 6
-Di-O-isopropylidene-α-D-glucofurano-
(85.6 mg) in 98% yield.

[0070]Example 27: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
-2-Carboxylic acid 2-chloro-2-propenyl to 2-
Removal of chloro-2-propenyl group Palladium diacetate (20.5 mg, 91.3 μm
ol) was prepared in Preparation Example 1 as 5R, 6S-6- (1R-
Hydroxyethyl) -2- (1R-oxo-3S-thio
Ranylthio) -2-penem-3-carboxylic acid 2-chloro
-2-propenyl (182 mg, 0.430 mmol
l), sodium p-toluenesulfinate (126 m
g, 0.502 mmol) and triethyl phosphite
(52.6 mg, 0.317 mmol)
A solution of drofuran-methanol (5: 3, 4.5 ml)
At room temperature. Stir the reaction mixture at room temperature for 80 minutes
Then, ethyl acetate (9 ml) was added dropwise, and the target compound
The lithium salt was precipitated. Celite in the resulting mixture
(0.7 g) was added. After filtration, precipitate and selenium
The precipitate was washed three times with ethyl acetate (2 ml), and the precipitate was washed with water.
(2.5 ml) and further with water (1.5 ml) three times
Washed. The obtained aqueous solution is ion-exchange resin (Mitsubishi Chemical
Acidification with DIAION PK216H (manufactured by Seisakusho)
Then, acetone (6 ml) was added. Filter the ion exchange resin
Separately, wash three times with acetone / water (2: 1, 1.5 ml)
did. The combined filtrate was evaporated at 20 ° C using an evaporator.
Concentrate by evaporating acetone in and freeze
Dry pale yellow powder (121 mg) in 80% yield
I got it.

Comparative Example 6: Palladium diacetate (2
0.8R, 92.6 µmol) of 5R, 6S-6- (1R-hydroxyethyl) -2-prepared in Preparation Example 1.
(1R-oxo-3S-thiolanylthio) -2-penem-3-carboxylic acid 2-chloro-2-propenyl (191
mg, 0.451 mmol), sodium 2-ethylexanoate (105 mg, 0.630 mmol) and triethyl phosphite (52.4 mg, 0.316 mmol)
l) containing tetrahydrofuran-methanol (5: 3,
(4.5 ml) at room temperature. The reaction mixture was stirred at room temperature for 6 hours, and ethyl acetate (9 ml) was added dropwise to precipitate a sodium salt of the target compound. Celite (0.7 g) was added to the resulting mixture. After filtration, the precipitate and celite were washed three times with ethyl acetate (2 ml), and the precipitate was dissolved in water (2.5 ml).
Washed 3 times in 1). The obtained aqueous solution was converted to an ion exchange resin (manufactured by Mitsubishi Chemical Corporation; trade name: DIAION PK216).
H) and acidified with acetone (6 ml). The ion-exchange resin was filtered off, and acetone / water (2: 1, 1.5 m
Washed 3 times in 1). The combined filtrate was concentrated by evaporating the acetone at 20 ° C. using an evaporator and further freeze-dried to give a pale yellow powder (67.9 m
g) was obtained in a 45% yield. Example 27 and Comparative Example 6
In view of the above results, it was found that the method of the present invention can significantly improve the yield as compared with the conventional method even when treating with another palladium catalyst.

[0072]Example 28: 5R, 6S-6- (1R-hydroxyethyl) -2-
(1R-oxo-3S-thiolanylthio) -2-penem
-2-Carboxylic acid 2-chloro-2-propenyl to 2-
Removal of chloro-2-propenyl group Tetrahydrofuran-methanol (5: 3, 5.6 m
l) and triethyl phosphite (38.3 mg, 0.1 g).
230R) was prepared as 5R, 6S-6 prepared in Preparation Example 1.
-(1R-hydroxyethyl) -2- (1R-oxo-
3S-thiolanylthio) -2-penem-3-carboxylic acid
2-chloro-2-propenyl (237 mg, 0.558
mmol), sodium p-toluenesulfinate (1
55 mg, 0.621 mmol), dichlorobis (ace
Tonitrile) palladium (19.9 mg, 13.7 μm
ol) at room temperature. Stir the reaction mixture at room temperature overnight
Then, ethyl acetate (11 ml) was added dropwise, and the target compound
The thorium salt was precipitated. Celite in the resulting mixture
(0.8 g) was added. After filtration, precipitate and selenium
The precipitate was washed three times with ethyl acetate (2 ml), and the precipitate was washed with water.
(3.0 ml) and further 3 times with water (2.0 ml)
Washed. The obtained aqueous solution is ion-exchange resin (Mitsubishi Chemical
Acidification with DIAION PK216H (manufactured by Seisakusho)
Then, acetone (7.5 ml) was added. Ion exchange resin
Are filtered off and three times with acetone / water (2: 1, 1.5 ml)
Washed. The combined filtrate was evaporated using an evaporator.
Concentrate by evaporating the acetone at ゜ C and further
Lyophilize a pale yellow powder (166 mg) to 85%
Obtained in yield.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI C07D 499/87 C07B 61/00 300 499/897 C07D 499/00 N 501/04 A C07H 9/04 // C07B 61/00 300 (56) References JP-A-6-220054 (JP, A) JP-A-55-94321 (JP, A) JP-A-61-286331 (JP, A) JP-A-3-130293 (JP, A) Kaihei 4-41489 (JP, A) Table 8-8-508986 (JP, A) TETRAHEDRON LETTE RS (1993), 34 (26), pages 4189-4192 TETRAHEDRON LETTE RS (1987), 28 (38), pages 4371-4372 (58) Field surveyed (Int.Cl. ⁷ , DB name) C07B 51/00 B01J 31/02 103 C07D 499/00-499/82 C07D 501/00-501/62 C07B 61/00 300 CA (STN) REGIS RY (STN)

Claims (13)

(57) [Claims] 1. A method for converting an allyl ester of a carboxylic acid into a carboxylic acid, converting an allyloxycarbonyl derivative of an alcohol into an alcohol, or converting an allyloxycarbonyl derivative of an amine into an amine, wherein the palladium catalyst is used. A method comprising contacting an allyl ester of a carboxylic acid, an allyloxycarbonyl derivative of an alcohol or an allyloxycarbonyl derivative of an amine with a sulfinic acid compound in a reaction inert solvent. Wherein said sulfinic acid compound has the general formula: halogen in _{X-SO 2 M ··· (I} ) ( wherein, X is C ₁ ~ ₂₀ alkyl, substituted C ₁ ~ ₂₀ alkyl (substituents are independently Nitro, sulfo, oxo, amino, cyano, carboxy, hydroxy or a group derived therefrom, phenyl, substituted phenyl (substituents are independently C 1-3 alkyl, halogen, nitro, sulfo,
Oxo, amino, cyano, carboxy, hydroxy, acetamido, or a group derived therefrom), furyl, or thienyl; and M is a hydrogen, alkali metal or ammonium salt residue). The method of claim 1. 3. The method according to claim 1, wherein the palladium catalyst is a palladium compound which can easily form a π-allyl complex by reacting with the allyl compound. 4. The palladium catalyst is tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (acetonitrile) palladium (II), dichlorobis (triisopropoxyphosphine) palladium (II). ) Or palladium (II) diacetate;
The method of claim 3. 5. The method of claim 2 wherein X is phenyl or methylphenyl; and M is hydrogen, lithium, sodium, potassium, or ammonium. 6. The sulfinic acid compound may be a lithium salt of p-toluenesulfinic acid, a sodium salt of p-toluenesulfinic acid, a potassium salt of p-toluenesulfinic acid, p-toluenesulfinic acid, or p-toluenesulfinic acid. Ammonium salt, lithium salt of benzenesulfinic acid, sodium salt of benzenesulfinic acid, potassium salt of benzenesulfinic acid, benzenesulfinic acid, tetrabutylammonium salt of benzenesulfinic acid, p
-Sodium salt of carboxybenzenesulfinic acid, sodium salt of octylsulfinic acid, sodium salt of ethylsulfinic acid, sodium salt of 4-chloro-3-nitrobenzenesulfinic acid, sodium salt of 4-acetamidobenzenesulfinic acid, thiophene-2- Sulfinic acid sodium salt, methylsulfinic acid sodium salt, isobutylsulfinic acid sodium salt, hexadecylsulfinic acid sodium salt, hydroxylmethanesulfinic acid sodium salt, ammonium p-toluenesulfinate, triethylammonium p-toluenesulfinate Or tetrabutylammonium benzenesulfinate. 7. The sulfinic acid compound may be a lithium salt of p-toluenesulfinic acid, a sodium salt of p-toluenesulfinic acid, a potassium salt of p-toluenesulfinic acid, p-toluenesulfinic acid, or p-toluenesulfinic acid. An ammonium salt, a lithium salt of benzenesulfinic acid, a sodium salt of benzenesulfinic acid, a potassium salt of benzenesulfinic acid, benzenesulfinic acid, and an ammonium salt of benzenesulfinic acid.
The described method. 8. The method according to claim 1, wherein the solvent is selected from alcohols, halogenated alkyl compounds, esters, ethers, nitriles, ketones, aromatic hydrocarbons, water and mixtures thereof. The described method. 9. The method according to claim 1, wherein the reaction is carried out at a temperature between -20.degree. 10. The method according to claim 8, wherein the reaction is carried out at a temperature of 10 ° C. to 40 ° C. 11. The method according to claim 1, wherein the allyl ester of a carboxylic acid is converted into a carboxylic acid, wherein the carboxylic acid is a β-lactam compound. 12. The method of claim 10, wherein said carboxylic acid is a penum, cephem, carbapenem or penem compound. (13) 5R, 6S-6- (1R-hydroxyethyl) -2- (1R-oxo-3S-thiolanylthio)
Allyl ester of 2-penem-3-carboxylic acid is
R, 6S-6- (1R-hydroxyethyl) -2- (1
R-oxo-3S-thiolanylthio) -2-penem-3
2. The process according to claim 1, wherein the conversion is to a carboxylic acid.