JP5785045B2 - Selective debenzylation method and selective hydrogenation catalyst used therefor - Google Patents

Description

  The present invention relates to a selective debenzylation method and a selective hydrogenation catalyst used therefor. More specifically, for example, a benzyl group which is a protecting group in a compound such as an aromatic halogen or an aromatic ketone is converted to a halogen atom. Furthermore, the present invention relates to a selective debenzylation method and a selective hydrogenation catalyst used therefor, which can be hydrogenated and removed with high efficiency without affecting other functional groups such as ketone groups.

  In a chemical reaction step, if it is not desirable for a functional group in an organic compound to participate in the reaction, it is common practice to protect this functional group with a protecting group and not participate in the reaction. . For example, since a carboxyl group in an organic compound has high reactivity, it is generally protected by a benzyl group. The benzyl group is returned to the original carboxy group after completion of the predetermined reaction. As the debenzylation reaction, a hydrogenation reaction performed using a Pd-supported carbon catalyst in a hydrogen atmosphere is performed. It is general purpose.

  However, the conventionally known hydrogenation reaction has a problem that it affects other functional groups and bonds that are not desired to be hydrogenated, such as breaking the bond between an aromatic ring and a halogen atom in an organic compound. It was. Therefore, a catalytic reaction that can selectively perform only the deprotection reaction has been demanded.

  The present inventors have already used ethylenediamine-modified Pd-supported carbon catalyst (Non-patent Document 1) and diphenyl sulfide-modified Pd-supported carbon catalyst (Patent Document 1) based on the concept of controlling the activity of the Pd-supported carbon catalyst by modification with a poisoning substance. ) Etc. were developed.

  However, even in the above technique, in the hydrogenation of an organic compound containing an aromatic halogen compound having a halogen atom or an aromatic ketone compound having a ketone group, the debenzylation reaction proceeds in the former method using a catalyst, At the same time, there is a problem that the aromatic halogen compound or aromatic ketone compound is decomposed or hydrogenated. In addition, the latter method using a catalyst has a problem that although no functional group of the aromatic halogen compound or the aromatic ketone compound is converted, the debenzylation reaction does not proceed.

Further, as the conventional selective debenzylation reaction, the following technologies of Non-Patent Document 2 and Non-Patent Document 3 are known regarding the debenzylation reaction in the presence of an aromatic halogen. Among them, Non-Patent Document 2 is a debenzylation reaction of benzyl 4-chlorobenzoate by oxidation using cerium ammonium nitrate ((NH ₄ ) ₂ [Ce (NO ₃ ) ₆ ]). Furthermore, there is a problem that the cerium ammonium nitrate, which is as low as about 65% and is used in an amount of 4 times the molar amount of the organic compound, is consumed by the reaction.

On the other hand, in Non-Patent Document 3, nickel chloride (NiCl ₂ ) and sodium borohydride (NaBH ₄ ) are used as catalysts, added to the system, and the produced nickel borate is used in the presence of aromatic halogen. A method for carrying out the debenzylation reaction at is described. The yields of debenzylation of aromatic halogen benzyl 2-chlorobenzoate, benzyl 3-chlorobenzoate and benzyl 4-chlorobenzoate by this method were 83, 89 and 87%, respectively. The NiCl ₂ and NaBH ₄ used are 3 times and 9 times the moles of the organic compound, respectively, and require a large amount of catalyst. Moreover, in order to perform a new reaction, it is necessary to add at least NaBH ₄ among these added reagents every time, and there is a problem that it is difficult to reuse the catalyst and there is a problem in terms of cost. It was not a proper technique.

JP 2007-152199 A

J. Org. Chem., 1998, 63, 7990 Ind.J.Chem., 1986, 25B, 433 Synthesis, 2009, 117, 1127

  The selective hydrogenation and hydrocracking reaction, which hydrogenates only the target group as well as the above debenzylation reaction, hydrogenates only a specific functional group among a plurality of functional groups in an organic compound. It is a very important reaction in the synthesis of pharmaceuticals, agricultural chemicals and their intermediates because it can reduce the synthesis steps.

  The present invention has been made in view of the above circumstances, and does not decompose or hydrogenate a halogen atom or an acyl group in an aromatic halogen compound or an aromatic ketone compound. It is an object of the present invention to provide a technique for efficiently hydrogenating and debenzylating only a benzyl group, which is a protective group, and a catalyst that can be used for this, without converting functional groups such as.

As a result of intensive studies on debenzylation reactions with aromatic halogen compounds and aromatic ketone compounds, the present inventors have supported palladium as a catalytically active species on a beta zeolite (such as NH ₄ ⁺ type) in an ester solvent. The present inventors have found that by using the prepared catalyst, it is possible to efficiently carry out the debenzylation reaction without decomposing or hydrogenating other functional groups of the above compound, and the present invention has been completed.

（式中、Ａｒは、１またはそれ以上の水素化される可能性のある置換基を有する芳香環式基または複素環式基を、Ｚ_１は、単結合、−ＣＨ_２ＣＨ_２−または−ＣＨ＝ＣＨ−を示し、Ｂｎはベンジル基を示す）
で表されるカルボン酸ベンジルエステルに、エステル系溶媒中、パラジウム成分を担持したβ型ゼオライトの存在下で水素ガスを作用させ、式（II）

（式中、Ａｒは前記した意味を有し、Ｚ_２は、単結合または−ＣＨ_２ＣＨ_２−を示す）
で表されるカルボン酸化合物とすることを特徴とする脱ベンジル化方法を提供するものである。 That is, the present invention relates to the formula (I)

(In the formula, Ar represents an aromatic group or a heterocyclic group having one or more substituents that may be hydrogenated, Z ₁ represents a single bond, —CH ₂ CH ₂ — or — CH = CH-, Bn represents a benzyl group)
Hydrogen gas is allowed to act on the carboxylic acid benzyl ester represented by the formula (II) in the presence of β-type zeolite carrying a palladium component in an ester solvent.

(In the formula, Ar has the above-mentioned meaning, and Z ₂ represents a single bond or —CH ₂ CH ₂ —).
The debenzylation method characterized by making it the carboxylic acid compound represented by these is provided.

  In the present invention, hydrogen gas is allowed to act on the carboxylic acid benzyl ester represented by the formula (I) in the presence of β-type zeolite carrying a palladium component in an ester solvent. A method for producing a carboxylic acid compound represented by II) is provided.

  Furthermore, the present invention provides a selective hydrogenation catalyst comprising a palladium component supported on a β-type zeolite.

  According to the method of the present invention, the benzene ring-halogen atom bond of an aromatic halogen compound and the acyl group of an aromatic ketone compound are protected without cleavage or hydrogenation, and without converting any functional group. It is possible to selectively hydrogenate a benzyl group, which is a group, to produce an aromatic carboxylic acid (II) with high efficiency.

  In addition, the β-type zeolite carrying the palladium component (Pd component) used as a catalyst in the method of the present invention can be recycled, and the reaction using this is a process with less waste and reduced cost. There is also an advantage of becoming.

  In the method of the present invention, as shown by the following formula, the benzyl group of the carboxylic acid benzyl ester (I) represented by the formula (I) is hydrogenated and removed using hydrogen gas, and a carboxylic acid compound having a carboxyl group ( II).

  In the above formula, an aromatic group or heterocyclic group having one or more substituents which may be hydrogenated represented by Ar includes halogen atoms such as chlorine, bromine and iodine, An acyl group having an acyl group such as acetyl group, propionyl group, benzoyl group, naphthoyl group, aromatic group such as phenyl group, naphthyl group, biphenyl group, anthranyl group, pyridyl group, pyrimidyl group, indolyl group, benzimidazolyl group, Examples thereof include heterocyclic groups such as quinolyl group, benzofuranyl group, indanyl group, indenyl group, dibenzofuranyl group, and methylenedioxyphenyl group.

  Further, the method of the present invention basically selectively hydrogenates and removes a benzyl group, but in a general hydrogenation reaction, it is hydrogenated and is expected to be decomposed or structurally changed, for example, a halogen atom. , Substituents such as acetyl group, propionyl group, benzoyl group and naphthoyl group are not affected at all. However, the double bond (—CH═CH—) present in the side chain moiety also hydrogenates.

  The solvent used in the debenzylation reaction of the present invention is an ester solvent, and examples thereof include ethyl acetate and butyl acetate obtained by ester reaction of a lower alcohol and a lower carboxylic acid. This is preferably a high-purity one, but a mixed solvent with a solvent such as methanol, ethanol or isopropanol may be used for the purpose of cost reduction.

  Further, in the debenzylation reaction of the present invention, the β-type zeolite (Pd-supported β-zeolite) carrying the Pd component used as a catalyst has the Pd component as an active metal, and the β-type zeolite is used as a carrier for carrying this Pd. It is what was used. The Pd component may be supported as palladium oxide in addition to Pd as a metal, but is preferably in a metal state in order to exhibit good hydrocracking activity.

On the other hand, the β-type zeolite which is a catalyst carrier is a tetragonal synthetic zeolite represented by a unit cell composition Na _n [Al _n Si _{64 -n} O ₁₂₈ ] · xH ₂ O and is nearly square in the c-axis direction. Zigzag pores with a 12-membered ring (0.55 × 0.55 nm) cross section and linear pores with 12-membered rings (0.76 × 0.64 nm) in the a-axis and b-axis directions . In this β-type zeolite, the above-mentioned pores intersect to form a three-dimensional pore, and there is a large space at the intersection of the pores. Synthetic zeolite is usually obtained as Na-type, but the β-type zeolite used in the present invention is not particularly limited, and β-type zeolite ion-exchanged with at least one of various transition metals and rare earths is used. Although NH ₄ type obtained by ion-exchange of Na type may be used, it is preferable. In order to ion-exchange Na type zeolite to make NH ₄ type zeolite, it may be carried out in a liquid phase by a known method.

  In the Pd-supported β-type zeolite used as a catalyst in the present invention, the amount of the Pd component supported per β-type zeolite is preferably 0.01 to 20 wt% in terms of Pd metal, and preferably 1 to 10 wt%. More preferred. If the amount of the Pd component is too small, the reaction rate becomes slow, and a large amount of catalyst is required to complete the reaction. If the amount of the Pd component is too large, the dispersion of the Pd component is deteriorated and the activity per unit weight of Pd is lowered, so that expensive Pd is used inefficiently.

The method for producing the Pd-supported β-type zeolite used in the present invention is not particularly limited, but examples of the production method include the following methods. That is, palladium acetate is weighed into a flask filled with argon (Ar) as an inert gas and dissolved in methanol. NH ₄ type beta zeolite (Si / Al molar ratio = 25) was added to this solution so that the content of metallic palladium was 5% by mass, and stirred at room temperature under an argon atmosphere until the supernatant became transparent. Continue. The obtained black powder is filtered by suction, washed with methanol and water, and then dried at room temperature under reduced pressure in a desiccator.

  In the debenzylation method of the present invention, hydrogen gas is used as a reducing component. This hydrogen gas is supplied into the mixture of the ester solvent, the Pd-supported β-type zeolite, and the carboxylic acid benzyl ester (I). More specifically, hydrogen gas is supplied by filling the space above the reaction solution in the sealed container with hydrogen.

  In the method of the present invention, the amounts of hydrogen gas, ester solvent and carboxylic acid benzyl ester (I) are not particularly limited, but the supply amount of hydrogen gas selectively hydrogenates the benzyl group of carboxylic acid benzyl ester (I). It is necessary that the amount be more than the theoretical amount necessary for the above, and it is preferable to supply about 1 to 1000 times mol, and generally about 1 to 10 times mol for the theoretical amount. The ester solvent as a solvent is preferably added 0.1 to 100 times by weight with respect to the carboxylic acid benzyl ester (I) as the substrate, and the carboxylic acid benzyl ester (I) is completely dissolved. It is desirable to be in the state.

  The conditions for the selective hydrogenation reaction in the method of the present invention are not particularly limited, but the reaction temperature is preferably 0 to 200 ° C, more preferably 10 to 100 ° C. The hydrogen pressure is preferably 0.01 to 10 MPa, and more preferably 0.1 to 1 MPa. When the reaction temperature is low or the hydrogen partial pressure is low, the progress of the reaction is slow and the conversion of the raw materials does not proceed sufficiently. Further, when the reaction temperature is high or the hydrogen partial pressure is high, sufficient selectivity cannot be obtained.

  Hereinafter, the method of the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.

Reference example 1
The production of a palladium catalyst for selective catalytic reduction was carried out as follows. That is, NH ₄ type beta zeolite (Si / Al molar ratio = 25, manufactured by N.E. Chemcat Co., Ltd.) was prepared. Then, 527 mg (2.35 mmol) of palladium acetate was weighed into a flask filled with argon as an inert gas and dissolved in 50 ml of methanol. To this solution, 5 g of NH ₄ type beta zeolite was added so that the content of metal palladium was 5% by mass, and stirring was continued for 6 days at room temperature under an argon atmosphere until the supernatant became transparent. The resulting black powder was filtered with suction, washed with methanol (twice 30 ml each) and water (twice 30 ml each) in that order, and then dried for 3 days at room temperature under reduced pressure in a desiccator.

Example 1

  123.3 mg (0.5 mmol) of benzyl 4-chlorobenzoate as a substrate and 10.6 mg of 5% Pd / beta zeolite obtained in Reference Example 1 (1 mol% as metal palladium with respect to the substrate) as a reduction catalyst. After taking 1 mL of ethyl acetate and suspending it in a test tube, stab a needle attached with a balloon filled with hydrogen gas into the septum at the top of the test tube, and gas inside the system from another needle stabbed in the septum. The removing operation was repeated three times, and the system was replaced with hydrogen gas, and then the test tube was filled with hydrogen gas.

  Take 123.3 mg (0.5 mmol) of benzyl 4-chlorobenzoate as a substrate and 10.6 mg of 5% Pd / beta zeolite (1 mol% as metal palladium with respect to the substrate) as a reduction catalyst in a test tube. After suspending by adding 1 mL of ethyl acetate, the needle attached with a balloon filled with hydrogen gas was inserted into the septum at the top of the test tube, and the operation of removing the gas from the system from another needle inserted into the septum was repeated three times. After replacing the system with hydrogen gas, the test tube was filled with hydrogen gas.

After vigorously stirring at 60 ° C. for 24 hours, the obtained reaction solution was filtered using a membrane filter (Millipore, Millex-LH, pore size 0.45 μm), and the membrane filter was further washed with ethyl acetate (15 mL). The obtained filtrate was concentrated, and the obtained concentrate was subjected to ¹ H-NMR.

  From the obtained spectrum, the yield of 4-chlorobenzoic acid (benzyl ester was hydrocracked) obtained as a product and the recovery rate of the raw material was calculated. The conversion rate of the raw material was 100%. The yield of 4-chlorobenzoic acid was 100% (77.6 mg).

Example 2

  In Example 1, 136.4 mg (0.5 mmol) of benzyl 4-chlorocinnamate instead of benzyl 4-chlorobenzoate, 21.2 mg of 5% Pd / beta zeolite (2 mol as metal palladium with respect to the substrate) %) Was used, and the reaction, post-reaction treatment and product analysis were carried out in the same manner as in Example 1 except that the reaction was carried out at 40 ° C. for 1.5 hours. As a result, the conversion rate of the raw material was 100%, and 3- (4-chlorophenyl) propionic acid was obtained in a yield of 98% (89.5 mg).

Example 3

  In Example 1, 126.6 mg (0.5 mmol) of benzyl 4-acetylbenzoate instead of benzyl 4-chlorobenzoate, 21.2 mg of 5% Pd / beta zeolite (2 mol% as metal palladium with respect to the substrate) The reaction, the treatment after the reaction, and the analysis of the product were carried out in the same manner as in Example 1 except that the reaction was carried out at 60 ° C. for 7 hours. As a result, the conversion rate of the raw material was 100%, and 4-acetylbenzoic acid was obtained in a yield of 100% (81.6 mg).

Example 4

  In Example 1, 136.4 mg (0.5 mmol) of benzyl 3-acetylbenzoate instead of benzyl 4-chlorobenzoate was replaced with 42.4 mg of 5% Pd / beta zeolite (4 mol% as metal palladium with respect to the substrate). The reaction, the treatment after the reaction and the analysis of the product were carried out in the same manner as in Example 1 except that the reaction was carried out at 40 ° C. for 22 hours. The conversion rate of the raw material was 100%, and 3-acetylbenzoic acid was obtained with a yield of 95% (77.5 mg).

Comparative Example 1
In Example 1, instead of 5% Pd / beta zeolite, 10.6 mg of 5% Pd / ZSM-5 (NH ₄ type, Si / Al molar ratio = 30) (1 mol% as metallic palladium with respect to the substrate) A hydrogenation reaction of benzyl 4-chlorobenzoate was performed in the same manner as in Example 1 except that it was used, and treatment after the reaction and analysis of the product were performed. As a result, the conversion rate of the raw material was 29%, and 4-chlorobenzoic acid was obtained in a yield of 28% (22.5 mg).

Comparative Example 2
In Example 1, except that methanol was used instead of ethyl acetate as a solvent, a hydrogenation reaction of benzyl 4-chlorobenzoate was performed in the same manner as in Example 1, and the treatment after the reaction and the analysis of the product were performed. . As a result, the conversion rate of the raw material was 100%, and 4-chlorobenzoic acid was obtained with a yield of 68% (22.5 mg). In addition, as a by-product, methyl 4-chlorobenzoate in which the starting benzyl was replaced with methyl was obtained in a yield of 23% (19.6 mg).

Comparative Example 3
In Example 3, instead of 5% Pd / beta zeolite, 21.2 mg of 5% Pd / ZSM-5 (NH ₄ type, Si / Al molar ratio = 30) (2 mol% as metallic palladium with respect to the substrate) The hydrogenation reaction of benzyl 4-acetylbenzoate was carried out in the same manner as in Example 3 except that the reaction was carried out at 60 ° C. for 24 hours, and the treatment after the reaction and the analysis of the product were carried out. As a result, the conversion rate of the raw material was 99.9% or more, and 4-acetylbenzoic acid was obtained in a yield of 72% (58.8 mg). In addition, by-products benzyl 4- (1-hydroxyethyl) benzoate and 4- (1-hydroxyethyl) benzoic acid, in which the acetyl group is hydrogenated, yielded 8% (10.3 mg) and The yield was 20% (16.6 mg).

Comparative Example 4
In Example 3, instead of ethyl acetate as the solvent, methanol was used, and except that the reaction was performed at room temperature for 12 hours, a hydrogenation reaction of benzyl 4-acetylbenzoate was performed in the same manner as in Example 3, and after the reaction Processing and product analysis were performed. As a result, the conversion rate of the raw material was 93%, and 4-acetylbenzoic acid was obtained in a yield of 53% (43.2 mg). In addition, by-products benzyl 4- (1-hydroxyethyl) benzoate and 4- (1-hydroxyethyl) benzoic acid, in which the acetyl group is hydrogenated, yielded 27% (34.6 mg) and The yield was 13% (10.8 mg).

  The results of Examples 1 to 4 and Comparative Examples 1 to 4 are collectively shown in Table 1.

  According to the method of the present invention, the benzene ring-halogen atom bond of an aromatic halogen compound and the acyl group of an aromatic ketone compound are protected without cleavage or hydrogenation, and without converting any functional group. It is possible to selectively hydrogenate the benzyl group, which is a group, to produce an aromatic carboxylic acid with high efficiency.

  Therefore, the method of the present invention can be used very advantageously in a reaction in which the carboxyl group needs to be protected with a benzyl group, and is useful for improving the yield and economic efficiency in the production of chemical substances.

Claims (11)

Formula (I)

(In the formula, Ar represents an aromatic or heterocyclic group having a substituent selected from the group consisting of chlorine and acetyl group , Z ₁ represents a single bond, —CH ₂ CH ₂ — or —CH═CH— And Bn represents a benzyl group)
Hydrogen gas is allowed to act on the carboxylic acid benzyl ester represented by the formula (II) in the presence of β-type zeolite carrying a palladium component in an ester solvent.

(In the formula, Ar has the above-mentioned meaning, and Z ₂ represents a single bond or —CH ₂ CH ₂ —).
A debenzylation method characterized by comprising a carboxylic acid compound represented by the formula:   The debenzylation method according to claim 1, wherein the ester solvent is ethyl acetate, propyl acetate, n-butyl acetate, isobutyl acetate, or γ-butyrolactone.   3. The debenzylation method according to claim 1, wherein the β-type zeolite carrying a palladium component is a β-type zeolite carrying metal palladium or a β-type zeolite carrying metal palladium and palladium oxide. The debenzylation method according to any one of claims 1 to 3, wherein the β-type zeolite is NH ₄ type β-type zeolite. Formula (I)

(In the formula, Ar represents an aromatic or heterocyclic group having a substituent selected from the group consisting of chlorine and acetyl group , Z ₁ represents a single bond, —CH ₂ CH ₂ — or —CH═CH— And Bn represents a benzyl group)
A hydrogen gas is allowed to act on the carboxylic acid benzyl ester represented by the formula (II) in the presence of a β-type zeolite carrying a palladium component in an ester solvent.

(In the formula, Ar has the above-mentioned meaning, and Z ₂ represents a single bond or —CH ₂ CH ₂ —).
The manufacturing method of the carboxylic acid compound represented by these.   The method for producing a carboxylic acid compound according to claim 5, wherein the ester solvent is ethyl acetate, propyl acetate, n-butyl acetate, isobutyl acetate, or γ-butyrolactone.   The method for producing a carboxylic acid compound according to claim 5 or 6, wherein the β-type zeolite supporting a palladium component is β-type zeolite supporting metal palladium or β-type zeolite supporting metal palladium and palladium oxide. The method for producing a carboxylic acid compound according to any one of claims 5 to 7, wherein the β-type zeolite is NH ₄ -type β-type zeolite. A selective hydrogenation catalyst comprising a palladium component supported on a β-type zeolite, comprising a compound of formula (I )

(In the formula, Ar represents an aromatic or heterocyclic group having a substituent selected from the group consisting of chlorine and acetyl group, Z ₁ represents a single bond, —CH ₂ CH ₂ — or —CH═CH— And Bn represents a benzyl group )
A hydrogen gas in an ester solvent is allowed to act on the carboxylic acid benzyl ester represented by formula (II )

(In the formula, Ar has the above-mentioned meaning, and Z ₂ represents a single bond or —CH ₂ CH ₂ — ).
The selective hydrogenation catalyst for debenzylation reaction made into the carboxylic acid compound represented by these .   The selective hydrogenation catalyst according to claim 9, wherein the β-type zeolite supporting a palladium component is a β-type zeolite supporting metal palladium or a β-type zeolite supporting metal palladium and palladium oxide. The selective hydrogenation catalyst according to claim 9 or 10, wherein the β-type zeolite is an NH ₄ -type β-type zeolite.