JPH072809A - New process for producing aminothiazoleacetic acid derivative - Google Patents

Abstract

PURPOSE:To obtain an aminothiazoleactic acid derivative useful as a synthetic intermediate for pharmaceuticals by using an acetoacetic acid benzyl ester as a starting compound, producing a corresponding new compound through several steps and carrying out hydrogenative decomposition of the ester site of the compound under proper condition, thereby easily debenzylating the compound. CONSTITUTION:A compound of the formula II is produced by the hydrogenative decomposition of the ester site of a new compound of the formula I (R<1> is H or protecting group hydrolyzable with acid or base; R<2> is lower alkyl, lower alkoxy, halogen, nitro or H). The compound is easily debenzylated by this reaction to give the compound of the formula II in high yield without causing the reduction of methoxyimino group. An aminothiazoleacetic acid derivative of the formula II useful as a 7-acylating agent for penicillins or cephalosporins exhibiting excellent antibacterial action can easily be produced in high yield. The process can remarkably contribute to the cost reduction of useful penicillins and cephalosporins and exhibit remarkable effect.

Description

Detailed Description of the Invention

The present invention relates to a novel method for producing an aminothiazoleacetic acid derivative which is a synthetic intermediate for penicillins or cephalosporins having excellent antibacterial activity.

[0002]

BACKGROUND OF THE INVENTION General formula [II]

[Chemical 4] (In the formula, R ¹ represents a protecting group or a hydrogen atom which can be hydrolyzed by an acid or a base.) (Hereinafter, referred to as a compound
Abbreviated as II. ) Is a very useful compound as a synthetic intermediate (an acylating agent at the 6-position or 7-position) of penicillins or cephalosporins showing excellent antibacterial action.
J. Antibiotics, 33 , 1005 (1981), J. Antibiotics, 34 , 160
(1982), JP-B-58-22039, JP-B-58-58353, JP-B-59-41995, JP-B-62-3155, JP-B-62-28152, JP-B-63-8107. Gazette, Japanese Patent Publication Sho 63
The report is made in Japanese Patent No. 8116.

Further, the production method thereof has been reported in detail in J. Antibiotics, 34 , 160 (1982), Japanese Patent Publication No. 58-22039, Japanese Patent Publication No. 63-8107 and the like. However, the compounds described in those known documents
In any of the production methods of II, the lower alkyl ester of compound II is hydrolyzed with a base and then neutralized with an acid to obtain the same. The problem with these conventional production methods is that a base is used for the decomposition of the ester. Therefore, when R ^{1 of} compound II is an acyl group such as an acetyl group or a chloroacetyl group which is easily hydrolyzed by a base, That is, the acyl group may be eliminated at the same time. Also, when hydrolyzed with a base, the product forms a salt with the base used, so after the reaction, neutralization with an acid is required,
Inevitably, it is necessary to separate the neutral salt that is a by-product. Therefore, in the case of industrially producing the compound II, if these problems can be solved, it will greatly contribute to the improvement of the yield of the compound II, the quality improvement and the cost reduction.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above situation, and has the following general formula [II] useful as a synthetic intermediate for penicillins and cephalosporins.

[Chemical 5] (In the formula, R ¹ is the same as above.) An object of the present invention is to provide a process for producing an aminothiazoleacetic acid derivative which does not have the above-mentioned problems.

[0005]

The present invention has the general formula [I]

[Chemical 6] (Wherein R ¹ represents a protecting group or a hydrogen atom which can be hydrolyzed by an acid or a base, and R ² represents a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group or a hydrogen atom). General formula [II] characterized by hydrogenolysis of the ester moiety of

[Chemical 7] (In the formula, R ¹ is the same as the above.) It is an invention of a method for producing a compound. The present invention also provides a compound represented by the general formula [I]

[Chemical 8] (In the formula, R ¹ and R ² are the same as defined above).

That is, the present inventors have conducted extensive studies to achieve the above object, and as a result, instead of the conventional lower alkyl ester of compound II, the following general formula [I] was used.

[Chemical 9] (In the formula, R ¹ and R ² are the same as above.) If a compound (hereinafter, abbreviated as compound I) is used, it is neutralized by hydrogenolysis without using a means of hydrolysis with a base. The inventors have found that the ester can be decomposed with the above pH, and have completed the present invention. Examples of debenzylation of benzyl esters by hydrogenolysis are Org. Syn., 7 , 263
(1953) and many others, but no example of Compound I targeted by the present invention has been reported. The reason is that (1) a compound containing a sulfur atom in the molecule like Compound I generally deactivates a catalyst used for hydrogenolysis, and Compound I also resists hydrogenolysis, Debenzylation seems to be very difficult. (2) When a compound [IIIa] having a structure similar to that of Compound I as shown in the following formula (in the formula, R ³ and R ⁴ each represent a protecting group for an amino group and a carboxyl group) is catalytically reduced, The glycine derivative [IIIb] in which the oxime group has been reduced is disclosed in Japanese Patent Publication No.
-60345, etc.

[Formula 1]

From this, it is expected that when compound I is also reduced, the methoxyimino group is simultaneously reduced.
Etc. However, the present inventors
As a result of earnestly studying the hydrogenolysis of the compound, surprisingly, when the compound I was also hydrolyzed under appropriate conditions, the methoxyimino group was not reduced and easily debenzylated,
The present invention has been achieved by finding that compound II can be obtained in good yield. Examples of the protecting group hydrolyzable by an acid or a base represented by R ¹ in the general formulas [I] and [II] include a lower acyl group such as acetyl group and propionyl group, a chloroacetyl group, a dichloroacetyl group. , A halogenoacetyl group such as a trichloroacetyl group, a trityl group, a formyl group, and a tert-butoxycarbonyl group. R ² in the general formula [I] is, for example, a lower alkyl group such as a methyl group, an ethyl group, a propyl group or a butyl group (whether linear or branched), a methoxy group, Examples thereof include lower alkoxy groups such as ethoxy group, propoxy group and butoxy group (both linear and branched), halogen atoms such as chlorine atom, bromine atom and iodine atom, nitro group and hydrogen atom.

The starting compound I used in the present invention is compound II
It may be produced according to the production method of the lower ester of compound II described in the various publicly known documents mentioned above, which has been reported. That is, instead of using acetoacetic acid lower alkyl ester as a starting material, a benzyl ester derivative which may have a substituent, for example, benzyl acetoacetate,
Using p-methoxybenzyl acetoacetate, p-nitrobenzyl acetoacetate, p-methylbenzyl acetoacetate, etc., according to the method for producing a lower ester of compound II described in the above-mentioned document or the cited document described therein. This may be manufactured. That is, first, acetoacetic acid benzyl esters synthesized from commercially available or optionally substituted benzyl alcohol and diketene are oxime-ized by a conventional method,
Methylation and halogenation are performed sequentially to obtain the formula [IV]

[Chemical 10] (Wherein, X represents a halogen atom, R ² is the same as above), and then this is reacted with thiourea in the presence of a deoxidizing agent to obtain a raw material in which R ¹ is a hydrogen atom. Compound I is obtained. When this is further reacted with a corresponding protecting group-introducing agent such as chloroacetic acid chloride or chloroacetic anhydride in the presence of a deoxidizing agent, a compound I in which R ¹ is a protecting group hydrolyzable with an acid or a base is obtained. To be

The production method of the present invention is characterized in that the ester moiety of the compound I thus obtained is subjected to hydrogenolysis, and the hydrogenolysis can be divided into two depending on the hydrogen source used. The first method is a method using hydrogen gas as a hydrogen source. The second method is a method using a compound capable of generating hydrogen in the reaction system as a hydrogen source. These two methods will be described in detail below in order. The first method is a method generally called "catalytic reduction", and examples of the catalyst used in the present invention include palladium black, palladium (Pd-C) supported on activated carbon, Raney nickel developed with alkali, platinum oxide and the like. To be In particular, Raney nickel sufficiently developed with an alkali and palladium (Pd-C) supported on activated carbon are preferable because they are fast in reaction, have few side reactions, and are inexpensive. The amount used is usually 5 to 100% (weight ratio) of Compound I, but economically 10 to 50% is particularly preferably used. The catalyst can be reused if it is recovered after the reaction and activated.

The reaction solvent is a solvent which does not particularly participate in the catalytic reduction reaction, and may be any solvent which can dissolve the compound I. For example, alcohols such as methanol, ethanol and propanol, acetone, and mettle ethyl ketone. Such as ketones, hydrocarbons such as benzene and toluene, halogen solvents such as methylene chloride and ethylene chloride, ester solvents such as ethyl acetate, cyclic ether solvents such as dioxane and tetrahydrofuran, acetonitrile and propionitrile, etc. Examples thereof include nitrile solvents, amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide, and mixed solvents of these solvents and water. Of these, ester-based, cyclic ether-based, and amide-based aprotic solvents are particularly preferably used because they have few side reactions and can give a desired product of high quality. On the other hand, in the case of a protic solvent such as alcohols, good results may not be obtained depending on the catalyst to be combined, so that sufficient caution should be taken when setting the conditions.

The reaction temperature may be appropriately selected in consideration of the catalyst, the solvent, the hydrogen pressure, etc., and may be any temperature from room temperature to around the boiling point of the solvent, but especially from room temperature to around 50 ° C. The hydrogen pressure may be appropriately selected depending on the catalyst, the solvent, or the state of progress of the reaction, but usually, the atmospheric pressure to about 100 kg / cm ² and preferably about 20 to 50 kg / cm ² are selected. After the reaction, the produced compound II can be taken out from the reaction system without neutralization unlike the alkaline hydrolysis. That is, after catalytic reduction, the catalyst is removed by filtration and the mother liquor is concentrated to obtain the target compound II as a crude product. If necessary, this crude product is purified by recrystallization or column chromatography,
You can get a refined product. As described above, in the conventional alkali hydrolysis method, since the product forms a neutralized salt with the alkali used, it was necessary to make it free with hydrochloric acid or the like. Since it is obtained in the form of, the neutralization is not necessary, the operation is simple, and it has excellent characteristics such as cost reduction and burden of waste liquid treatment.

The second method is a method called "Catalytic Transfer Hydrogenation" in which hydrogen is decomposed by using a compound serving as a hydrogen source instead of the hydrogen gas used in the first method. As the catalyst to be used, those shown in the first method can be similarly used, and the amount used is the same as that in the first method. Examples of the compound serving as a hydrogen source include formic acid, ammonium formate, cyclohexene, cyclohexadiene, and the like. Particularly, cyclohexene, cyclohexadiene and the like are more preferable because they can keep the reaction system neutral. The amount used may be equimolar or more to the compound I, but is usually used in a large excess. In addition, hydrazine hydrate, sodium borohydride, and the like, which are typically mentioned as typical compounds that can serve as a hydrogen source, cannot be used for the purpose of the present invention. As the reaction solvent, all of the solvents shown in the first method can be used, but in the second method, alcohol-based solvents give good results with few side reactions. The reaction can be carried out in a wide range from room temperature to around the boiling point of the solvent, but usually heating is often done to accelerate the reaction, and the reaction under reflux is particularly preferable. In the case of the second method, unlike the case of the first method, it goes without saying that the reaction is carried out at normal pressure. The removal of the product is exactly the same as in the first method. still,
Compound I can of course be debenzylated by alkaline hydrolysis and does not narrow the means of deprotection. In this respect as well, it can be said that the compound I according to the present invention is obviously superior as a starting compound for the compound II as compared with conventional alkyl esters.

Further, the compounds I and II include geometric isomers [Ia] represented by the following formula.

[Chemical 11] And [IIa]

[Chemical 12] (In the formula, R ¹ and R ² are the same as described above). For the sake of convenience, only the structure having the methoxyimino group at the syn position has been described above, but it goes without saying that the method of the present invention can be applied to the case where the methoxyimino group is at the anti position as described above. Moreover, since the method of the present invention does not affect the methoxyimino group at all, the methoxyimino group is not converted from syn to anti during hydrogenolysis. Hereinafter, examples and experimental examples will be shown in order to describe the present invention more specifically, but the present invention is not limited by these examples and experimental examples.

Example 1: Synthesis of benzyl α-methoxyiminoaminothiazole acetate An aqueous solution containing 6.4 g of sodium acetate and 6.0 g of thiourea.
Benzyl methoxyiminobromoacetoacetate 22.
100 ml of a methanol solution containing 4 g was added dropwise at room temperature, and 1
The mixture was stirred and reacted for a time. After the reaction, dilute the reaction solution with water,
It was extracted with ethyl acetate. 10% Hydrochloric acid was added to the extracted layer, the mixture was stirred for 30 minutes, and the precipitated crystals were collected by filtration to obtain the hydrochloride salt of compound I. This hydrochloride is neutralized with 10% sodium hydroxide and extracted with ethyl acetate. The extracted layer is washed with water, dried and concentrated under reduced pressure to α
-Methoxyiminoaminothiazole benzyl acetate crystal 1
I got 2.0g. Yield 58.0%. mp.108.4-109.8 ° C. NMR (CDCl ₃ ): δ7.50-7.30 (5H, m, Ar- H ), 6.57 (1H, s, th
iazole5- H ), 5.38 (2H, s, PhC H ₂ ), 5.21 (2H, s, N H ₂ ), 4.01 (3
H, s, OC H ₃ )

Example 2: Synthesis of benzyl α-methoxyiminochloroacetylaminothiazoleacetate 7.0 g of benzyl α-methoxyiminoaminothiazoleacetate obtained in Example 1 was dissolved in 70 ml of N, N-dimethylacetamide and cooled with ice. Then, 2.3 ml of chloroacetyl chloride was added dropwise, and the mixture was stirred and reacted at room temperature for 1 hour. After the reaction, the reaction solution was diluted with water, extracted with ethyl acetate, the extract layer was washed with water, dried and concentrated under reduced pressure to obtain 8.6 g of crystals of benzyl α-methoxyiminochloroacetylaminothiazoleacetate.
Yield 97.3%. mp.84.8-88.3 ° C. NMR (CDCl ₃ ): δ9.80 (1H, br, N H ), 7.50-7.30 (5H, m, Ar-
H ), 7.08 (1H, s, thiazole5- H ), 5.41 (2H, s, PhC H ₂ ), 4.28 (2
H, s, ClC H ₂ ), 4.05 (3H, s, OC H ₃ )

Experimental Example 1: Catalytic reduction of benzyl α-methoxyiminochloroacetylaminothiazoleacetate 1 g of benzyl α-methoxyiminochloroacetylaminothiazoleacetate was dissolved in 60 ml of each solvent shown in Table 1 to obtain 10% Pd-
C 200 mg was added, and the mixture was stirred and reacted at a hydrogen pressure of ² Kg / cm ² at room temperature for 2 hours, and α-methoxyiminochloroacetylaminothiazoleacetic acid (target compound) and α-
Methoxyiminochloracetylaminothiazole benzyl acetate (raw material) was analyzed by a TLC scanner (Shimadzu CS-820 type). The results are shown in Table 1.

[Table 1] As is clear from Table 1, in the case of the Pd-C catalyst, the use of ethanol as a solvent produces a large amount of by-products.

Experimental Example 2: Catalytic reduction of benzyl α-methoxyiminochloroacetylaminothiazoleacetate 3.7 g of benzyl α-methoxyiminochloroacetylaminothiazoleacetate was dissolved in 100 ml of ethyl acetate to prepare 10% Pd.
After adding 200 mg of -C and stirring at room temperature for 2 hours under the hydrogen pressure shown in Table 2, the reaction solution was analyzed in the same manner as in Experimental Example 1. The results are shown in Table 2.

[Table 2] As is clear from Table 2, it is understood that the yield of a material having a low reaction rate is improved by increasing the hydrogen pressure.

Example 3: Synthesis of α-methoxyiminochloroacetylaminothiazoleacetic acid 3.7 g of benzyl α-methoxyiminochloroacetylaminothiazoleacetate was dissolved in 100 ml of ethyl acetate to prepare 10% Pd.
-C 750 mg was added, and the mixture was stirred and reacted at a hydrogen pressure of 20 Kg / cm ² at room temperature for 4 hours. After the reaction, 100m methanol in the reaction solution
l was added, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was crystallized with 20 ml of water-containing acetone to obtain 2.3 g of α-methoxyiminochloroacetylaminothiazoleacetic acid. yield
82%. NMR (DMSO-d ₆ ): δ 12.81 (1H, br, N H ), 7.92 (1H, s, COO
H ), 7.39 (1H, s, thiazole5- H ), 4.27 (2H, s, ClC H ₂ ), 4.02 (3
H, s, OC H ₃ )

Example 4: Synthesis of α-methoxyiminochloroacetylaminothiazoleacetic acid 3.7 g of benzyl α-methoxyiminochloroacetylaminothiazoleacetate was dissolved in 20 ml of N, N-dimethylacetamide, and 750 mg of 10% Pd-C was added. Then, the mixture was stirred and reacted at a hydrogen pressure of 20 Kg / cm ² at room temperature for 6 hours. After the reaction, the catalyst was filtered off from the reaction solution, 100 ml of water was added to the filtrate, and the precipitated crystals were collected by filtration to obtain 2.1 g of α-methoxyiminochloroacetylaminothiazoleacetic acid. Yield 76%.

Example 5: Synthesis of α-methoxyiminochloroacetylaminothiazoleacetic acid 3.7 g of benzyl α-methoxyiminochloroacetylaminothiazoleacetate was dissolved in 50 ml of ethanol, 1.5 g of Raney nickel was added, and hydrogen pressure of 1 Kg / cm ² was applied. The mixture was stirred and reacted at room temperature for 4 hours. After the reaction, the catalyst was removed from the reaction solution by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was crystallized with 60 ml of water-containing acetone to obtain 2.2 g of α-methoxyiminochloroacetylaminothiazoleacetic acid. Yield 79%. From the results of this example, it was found that there is no problem even with an ethanol solvent in the case of Raney nickel catalyst.

Example 6: Synthesis of α-methoxyiminochloroacetylaminothiazoleacetic acid 1.8 g of benzyl α-methoxyiminochloroacetylaminothiazoleacetate was dissolved in 8 ml of ethanol, 4 ml of cyclohexene and 150 mg of 10% Pd-C were added, The mixture was heated and refluxed for 10 hours. After the reaction, the reaction solution was cooled, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was recrystallized from 10 ml of water-containing acetone to obtain 1.0 g of α-methoxyiminochloroacetylaminothiazoleacetic acid. Yield 74%.

Example 7: Synthesis of α-methoxyiminoaminothiazoleacetic acid benzyl α-methoxyiminoaminothiazoleacetate 2.0 g
Was dissolved in 100 ml of ethyl acetate, 500 mg of 10% Pd-C was added, and the mixture was stirred and reacted at a hydrogen pressure of 20 kg / cm ² at room temperature for 4 hours. After the reaction, 100 ml of methanol was added to the reaction solution, the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was recrystallized from 20 ml of water-containing methanol to obtain 1.3 g of α-methoxyiminoaminothiazoleacetic acid. Yield 72% NMR (DMSO-d ₆ ): δ7.82 (1H, s, COO H ), 6.73 (2H, br, N H
₂ ), 6.73 (1H, s, thiazole5- H ), 3.95 (3H, s, OC H ₃ )

[0023]

INDUSTRIAL APPLICABILITY The present invention easily and easily collects the aminothiazoleacetic acid derivative represented by the above general formula [II] which is useful as an acylating agent at the 7-position of penicillins and cephalosporins having excellent antibacterial activity. It provides a method for efficient production and has a remarkable effect in that it greatly contributes to the price reduction of useful penicillins and cephalosporins.

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[Procedure amendment]

[Submission date] August 25, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0007

[Correction method] Change

[Correction content]

From this, it is expected that when compound I is also reduced, the methoxyimino group is simultaneously reduced.
Etc. However, the present inventors
As a result of earnestly studying the hydrogenolysis of the compound, surprisingly, when the compound I was also hydrolyzed under appropriate conditions, the methoxyimino group was not reduced and easily debenzylated,
The present invention has been achieved by finding that compound II can be obtained in good yield. Among the protecting groups hydrolyzable by an acid or a base represented by R ¹ in the general formulas [I] and [II], the protecting group hydrolyzable by an acid is, for example, an acetyl group or a propionyl group. Lower acyl group, trityl group, formyl group,
tert-butoxycarbonyl group and the like, and examples of the protective group hydrolyzable by a base include a chloroacetyl group,
Examples thereof include halogenoacetyl groups such as dichloroacetyl group and trichloroacetyl group. R ² in the general formula [I] is, for example, a lower alkyl group such as a methyl group, an ethyl group, a propyl group or a butyl group (whether linear or branched), a methoxy group, Examples thereof include lower alkoxy groups such as ethoxy group, propoxy group and butoxy group (both linear and branched), halogen atoms such as chlorine atom, bromine atom and iodine atom, nitro group and hydrogen atom.

Claims (2)

[Claims] 1. A compound represented by the general formula [I]: (Wherein R ¹ represents a protecting group or a hydrogen atom which can be hydrolyzed by an acid or a base, and R ² represents a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group or a hydrogen atom). Of the general formula [II], which is characterized by hydrogenolysis of the ester moiety of (Wherein R ¹ is the same as above). 2. A compound represented by the general formula [I]: (In the formula, R ¹ and R ² are the same as the above).