JPH06321952A - Method for removing allyl group - Google Patents

Abstract

PURPOSE:To remove an allyl group of an allyl ester of a penem compound by reacting the allyl ester of a penem compound with a carboxylic acid alkali metal salt in the presence of palladium acetate and a trialkyl phosphite. CONSTITUTION:A compound of formula I [(m) is 0 or 1; R<1> is (substituted)allyl] is reactel with an alkali metal salt of 1-8C carboxylic acid or 1-8C carboxylic acid and an alkali metal salt in the presence of palladium acetate and a trialkyl phosphite in a solvent (e.g. THF) at ambient temperature to provide a compound o formula II (R<2> is alkali metal) by removing the allyl group. The allyl group of allyl ester of the penem compound of formula I can rapidly be removed in high yield using a relatively inexpensive raw material stable in air. The allyl group is used as protective group for carboxyl group, etc., in the synthesis of beta-lactam-based antibiotic.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for removing an allyl group frequently used as a protective group such as a carboxyl group when synthesizing a β-lactam antibiotic.

[0002]

2. Description of the Related Art In the synthesis of β-lactam antibiotics, the method of using an allyl group as a protecting group for a carboxyl group is effective. W. McCombie et al. (J. Org. Chem., 47, 587 (198).
2)), or in JP-A-55-94321 and JP-A-62-61984.

However, the resulting allyl ester compound must remove this allyl group at any stage of the synthesis.

As a method for removing the allyl group,
A palladium complex having triphenylphosphine or triethyl phosphite as a ligand is used as a catalyst and has 5 carbon atoms.
~ 8 carboxylic acid alkali metal salt (for example, sodium 2-ethylhexanoate) as an allyl group acceptor,
Method of reacting at room temperature (J. Org. Chem., 4
7,587 (1982), and JP-A-55-94321.
No.), tetrakis (triphenylphosphine) palladium (0) and tributyltin hydride (JP-A-60-72893), acetylacetone or dimedone in the presence of tetrakis (triphenylphosphine) palladium (0). And the like (Japanese Patent Application Laid-Open No. 62-61984).

[0005]

However, many of these methods use tetrakis (triphenylphosphine) palladium (0), which is relatively expensive and unstable in the air, and has a drawback in terms of economy. In addition, since it has a problem in industrially storing tetrakis (triphenylphosphine) palladium (0), it is not preferable as an industrial production method.

As a method for solving the above-mentioned problem, a method of adding triphenylphosphine or triethyl phosphite to palladium acetate to prepare a corresponding palladium complex in the reaction system and then reacting it is shown. When this method is applied to the compound represented by I),
It was revealed that these reactions are slow and it is difficult to complete the reactions depending on the quality of the allyl ester.

[0007]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned drawbacks, the present inventors have found that an allyl ester of a penem compound is used as an allyl group acceptor with an alkali metal carboxylate as an allyl group acceptor. The inventors have found that the reaction for removing an allyl group can be completed quickly at room temperature by reacting palladium (II) acetate with a catalytic amount of a trialkyl phosphite having an alkyl group having 3 to 8 carbon atoms, and completed the present invention.

That is, the present invention has the general formula (I):

[Chemical 3] (In the formula, m represents 0 or 1, and R ¹ represents an optionally substituted allyl group.) An allyl ester of a penem compound represented by the formula: palladium (II) acetate and carbon of an alkyl group in an organic solvent. In the presence of the number 3-8 trialkyl phosphite,
A general formula (II):

[Chemical 4] (In the formula, R ² represents an alkali metal and m represents the same as described above.) The method of removing an allyl group as a penem compound. In the method of the present invention, palladium acetate and a trialkyl phosphite having an alkyl group having 3 to 8 carbon atoms form a corresponding palladium complex in the reaction system.

In the reaction for removing an allyl group from an allyl ester of a penem compound, the alkyl group has 3 to 8 carbon atoms.
The reaction using a palladium complex having trialkyl phosphite as a ligand is novel, and the reaction for removing the allyl group proceeds faster than known reactions by using these palladium complexes. And complete quickly at room temperature.

The optionally substituted allyl group represented by R ¹ of the allyl ester (I) of the penem compound of the present invention (hereinafter referred to as an allyl ester compound) is, for example, allyl group, allyl alcohol, haloallyl alcohol. , Methylallyl alcohol, crotyl alcohol, lower alkoxy acid derivatives thereof, cinnamyl alcohol, and groups derived from cinnamyl alcohol active ester.

The trialkyl phosphite used as the catalyst has 3 to 8 carbon atoms which are the same or different in the ester group.
Examples thereof include compounds having a group derived from alcohol, and examples thereof include tributyl phosphite, tripropyl phosphite, tripentyl phosphite, trihexyl phosphite, and trioctyl phosphite.

1 to 8 carbon atoms used as an allyl group acceptor
Examples of the alkali metal salt of carboxylic acid include, for example, acetic acid, propionic acid, butyric acid, sodium salt or potassium salt of hexanoic acid or ethylhexanoic acid,
When using a carboxylic acid having 1 to 8 carbon atoms and an alkali metal salt as an allyl group acceptor, the same carboxylic acids as those exemplified above are used, and the alkali metal salt is the carboxylic acid and a metal. Those that form salts,
Examples thereof include sodium or potassium hydrogen carbonate or carbonate.

In the reaction, first, the allyl group acceptor and the allyl ester compound (I) are mixed in an organic solvent. Water is added as necessary. When water is added, the amount of water added may be 2.5 mol or more per 1 mol of the allyl ester compound (I), but if the amount of water is too large, Since the product is dissolved in water in the post-treatment to reduce the yield, it is preferably about 2.5 to 10 mol.

The amount of the allyl group acceptor used is preferably 1 to 1.5 mol per 1 mol of the allyl ester compound (I).

A catalytic amount of trialkyl phosphite and a catalytic amount of palladium acetate were added to the solution thus prepared,
The reaction is carried out in the range of 10 ° C to the boiling point of the solvent used, preferably 5 ° C to 40 ° C.

The amount of trialkyl phosphite used is preferably 1 mol% to 5 mol% with respect to 1 mol of allyl ester compound (I), but the reaction time can be shortened by further increasing the amount.

The amount of palladium (II) acetate used is 0.5 mol% to 2. mol per 1 mol of the allyl ester compound (I).
5 mol% is sufficient. As a method for adding palladium (II) acetate, the whole amount may be added at the initial stage of the reaction, but if necessary, the addition timing may be divided into two or more times, and a fixed amount may be added at the initial stage of the reaction before the reaction is completed. Alternatively, the remaining amount can be added. By doing so, it is possible to further advance the reaction that has slowed down or stopped progressing during the reaction.

The organic solvent to be used is not particularly limited as long as it can dissolve the allyl ester compound (I) and the catalyst palladium acetate and trialkyl phosphite, for example, alkyl halides such as dichloromethane and chloroform; methyl acetate, Esters such as ethyl acetate; diethyl ether, ethylene glycol dimethyl ether,
Ethers such as tetrahydrofuran and 1,4-dioxane; alcohols such as methanol and ethanol; nitriles such as acetonitrile and propionitrile; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; or benzene, toluene, xylene and the like. Aromatic hydrocarbons may be mentioned, and these may be used alone or in admixture of two or more as necessary.

The penem compound represented by the general formula (II) produced by the reaction is obtained by adding water to an organic solvent,
It usually exists in the form of a hydrate, and when it is poorly soluble in the solvent used, the product precipitates as hydrate crystals. In addition, when water is not added to the organic solvent, crystals generally do not easily precipitate, so that it is possible to precipitate crystals of a hydrate of the target compound by adding water after the reaction.

The crystals of the target compound thus obtained can be further purified by an operation such as recrystallization, if necessary.

[0021]

The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 (1'R, 2 "R, 5R, 6S) -6- (1'-hydro)
Xyethyl) -2- (2 "-tetrahydrofuranyl) pe
Synthesis of nem-3-carboxylic acid sodium salt

[Chemical 5] (1′R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl ester 6.51 g (20
mmol) was dissolved in 30 ml of tetrahydrofuran, 1.8 ml of water and 2.50 g of sodium propionate (26
mmol) and tributyl phosphite 0.25 g (1 mm
ol) was added sequentially with stirring. The solution was cooled to 15 ° C., 0.04 g (0.2 mmol) of palladium acetate was added with stirring, then the temperature was raised to 25 ° C. and the temperature was increased to 1.5.
The reaction was completed by stirring for a period of time. The reaction solution was cooled to -5 ° C, and the crystals obtained by filtering the reaction solution were washed successively with 20 ml of THF cooled to 0 ° C and 12.5 ml of acetone. The crystals obtained were dried under reduced pressure to obtain 6.80 g of white crystals. Measurement by high performance liquid chromatography by the internal standard method was performed to find (1'R, 2 "R,
5R, 6S) -6- (1′-hydroxyethyl) -2-
The purity of the hydrate of the sodium salt of (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid was 98.5%. (Yield: 94%) ¹ H-NMR (CDCl ₃ , δppm) , TMS standard) 1.71 (3H, d, J = 6 Hz), 1.73-2.0
3 (3H, m), 2.18-2.35 (1H, m),
3.67-3.92 (3H, m), 4.05-4.19
(1H, m), 5.38 (1H, d, d, J = 7H
z), 5.46 (1H, s) Examples 2-5 (1'R, 2 "R, 5R, 6S) -6- (1'-hydro)
Xyethyl) -2- (2 "-tetrahydrofuranyl) pe
Synthesis of nem-3-carboxylic acid sodium salt The reaction was carried out in the same procedure as in Example 1 under the conditions shown in Table 1 by changing the type of trialkyl phosphite, and the result was (1′R, 2 ″). R, 5R, 6S) -6- (1'-Hydroxyethyl) -2- (2 "-tetrahydrofuranyl) penem-3-carboxylic acid sodium salt 2.5 hydrate purity and yield are shown in the table below. It was as 1.

[0023]

[Table 1] Example 6 (1'R, 2 "R, 5R, 6S) -6- (1'-hydro
Xyethyl) -2- (2 "-tetrahydrofuranyl) pe
Synthesis of nem-3-carboxylic acid sodium salt (1′R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl 3.25 g of ester (10
mmol) dissolved in 10 ml of methyl isobutyl ketone, 0.9 ml of water, 1.80 g of sodium hexanoate.
(13 mmol) and tributyl phosphite 0.125 g
(0.5 mmol) was added sequentially with stirring. 1 solution
After cooling to 5 ° C., 22.5 mg (0.1 m of palladium acetate)
(mol) was added under stirring, the temperature was raised to 25 ° C., and the mixture was stirred at the same temperature for 1 hour. After stirring, tributyl phosphite was added.
125 g (0.5 mmol) and palladium acetate 22.5
mg (0.1 mmol) was added again, and the mixture was further stirred at the same temperature for 5.5 hours. After cooling the reaction solution to -5 ° C,
The crystals obtained by filtering the reaction solution were cooled to 0 ° C in THF.
It was washed successively with 5 ml and 3 ml of acetone. The crystals obtained were dried under reduced pressure to obtain 3.37 g of white crystals. Measurement by high performance liquid chromatography by the internal standard method showed that (1'R, 2 "R, 5R, 6S) -6-
The purity of the hydrate of the sodium salt of (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid was 96.2%. (Yield: 9
2%)

[0024]

INDUSTRIAL APPLICABILITY The method of the present invention is capable of removing the allyl group of the allyl ester of a penem compound rapidly with a high yield by using a relatively inexpensive raw material which is stable in air, and is industrially very effective. Is.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location // A61K 31/43 ADZ 9454-4C C07B 61/00 300 C07D 499/00 Z (72) Inventor Yukiyuki Iiyoshi 950 Fujisawa, Nakago-mura, Nakakubiki-gun, Niigata Inside Nihongi Plant, Soda Co., Ltd. (72) Inventor Makoto Toyooka 950 Fujisawa, Nakago-mura, Nakakubiki-gun, Niigata Prefecture In Nihongi Plant, Japan Soda Co., Ltd. (72) Masaji Ishiguro 1-1 1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka Prefecture Suntory Ltd. Biomedical Research Institute (72) Inventor Takashi Nakatsuka 1-1-1 Wakayamadai, Shimamoto-cho Mishima-gun Osaka Prefecture Suntory Ltd.

Claims (5)

[Claims] 1. A compound represented by the general formula (I): (In the formula, m represents 0 or 1, and R ¹ represents an optionally substituted allyl group.) The allene ester compound of the penem compound represented by the formula ( ¹ ) was treated with palladium (II) acetate and an alkyl group in an organic solvent. In the presence of trialkyl phosphite having 3 to 8 carbon atoms and reacting with an alkali metal salt of a carboxylic acid having 1 to 8 carbon atoms or a carboxylic acid having 1 to 8 carbon atoms and an alkali metal salt, : [Chemical 2] (In the formula, R ² represents an alkali metal and m represents the same as above.) A method for removing an allyl group, which is a penem compound. 2. The method according to claim 1, wherein R ¹ is an allyl group, a haloallyl group, a methylallyl group, a crotyl group or a cinnamyl group. 3. The method according to claim 1, wherein the carboxylic acid is propionic acid, butyric acid, hexanoic acid or ethylhexanoic acid. 4. The method according to claim 1, wherein the alkali metal salt of carboxylic acid is a sodium salt or a potassium salt. 5. The method of claim 1, wherein the trialkyl phosphite is tributyl phosphite.