Hydrodesulfurization catalyst and method for producing peptide compound

Abstract

Provided is a hydrodesulfurization catalyst with which hydrodesulfurization of a sulfur atom bonded to an aromatic ring contained in a peptide compound can be selectively accelerated.　The hydrodesulfurization catalyst is for accelerating the hydrodesulfurization of a sulfur atom bonded to an aromatic ring contained in a sulfur-containing peptide compound. The hydrodesulfurization catalyst comprises a support and a substance supported thereon, wherein the support is made of an inorganic oxide, the supported substance is either a metal including a transition metal element or an oxide thereof, and the support has an average pore diameter of 30 nm or smaller and a pore volume of 0.50 ml / g or greater.

Description

Hydrodesulfurization catalyst and method for producing peptide compounds

[0001] This invention relates to a hydrogenodesulfurization catalyst and a method for producing peptide compounds.

[0002] Patent Document 1 discloses a method for producing peptide compounds.

[0003] Japanese Patent Publication No. 2022-003092 Japanese Patent Publication No. 2004-33819

[0004] Incidentally, when producing peptide compounds, it is sometimes necessary to perform a hydrogenation desulfurization step of sulfur atoms bonded to aromatic rings. Such a step can be carried out, for example, using a palladium-supported alumina catalyst. However, when this step is carried out using existing catalysts, not only is the hydrogenation desulfurization of sulfur atoms bonded to aromatic rings performed, but hydrogenation desulfurization of alkyl and alkylene groups, or sulfur atoms sandwiched between alkylene groups, also occurs in the peptide compound. Since the latter hydrogenation desulfurization reduces the yield of the target peptide compound, there is a need for a hydrogenation desulfurization catalyst that can promote the former hydrogenation desulfurization while suppressing the latter.

[0005] This invention has been made in view of these circumstances, and provides a hydrogenation desulfurization catalyst that can selectively promote the hydrogenation desulfurization of sulfur atoms bonded to aromatic rings in peptide compounds.

[0006] The present invention provides the following: [1] A hydrogenation desulfurization catalyst that promotes the hydrogenation desulfurization of sulfur atoms bonded to an aromatic ring contained in a sulfur-containing peptide compound, wherein the catalyst is composed of a support supported on a carrier, the carrier is composed of an inorganic oxide, the support is a metal containing a transition metal element or an oxide thereof, and the carrier has an average pore diameter of 30 nm or less and a pore volume of 0.50 ml / g or more. [2] The hydrogenation desulfurization catalyst according to [1], wherein the average pore diameter is 12 nm or less. [3] The hydrogenation desulfurization catalyst according to [1] or [2], wherein the inorganic oxide is composed of an oxide containing at least one element selected from zirconium, cerium, aluminum, silicon, magnesium and titanium. [4] The hydrogenation desulfurization catalyst according to [3], wherein the inorganic oxide is composed of an oxide containing at least one of aluminum and titanium. A hydrogenation desulfurization catalyst according to [5] [4], wherein the inorganic oxide is composed of an oxide containing aluminum and titanium. A hydrogenation desulfurization catalyst according to any one of [6] [1] to [5], wherein the transition metal element includes at least one element selected from Group 8, Group 9, Group 10, Group 11 and Group 12 of the periodic table. A hydrogenation desulfurization catalyst according to [7] [6], wherein the transition metal element includes at least one element selected from iron, cobalt, nickel, copper, ruthenium, rhodium, palladium, zinc, iridium and platinum. A hydrogenation desulfurization catalyst according to any one of [8] [1] to [7], wherein the desulfurization activity value of the hydrogenation desulfurization of the sulfur atom bonded to the aromatic ring contained in the first peptide compound is k Ａ The desulfurization activity value of the hydrogenation desulfurization of the sulfur atom sandwiched between the alkyl group and alkylene group in the second peptide compound is k. Ｂ Therefore, k Ａ / k ＢA hydrogenation desulfurization catalyst wherein the first peptide compound is represented by chemical formula (1), the second peptide compound is represented by chemical formula (2), and the desulfurization activity value is calculated under conditions in which hydrogenation desulfurization is performed at 25°C in a reaction solution obtained by mixing equimolar amounts of the first and second peptide compounds and an amount of the catalyst such that the number of moles of the transition metal element is 10 times the total number of moles of the first and second peptide compounds with a buffer composed of 6M guanidine hydrochloride - 0.1M HEPPS buffer. (In the formula, Ac indicates an acetyl group formed by acetylation of the N-terminus, NH ２ The 'A' part of the amide group formed by amidation at the C-terminus represents the part other than the carbonyl group, while G, A, and L represent glycine, alanine, and leucine residues, respectively. X in the formula represents the structure shown in chemical formula (3). (In the formula, Ac indicates an acetyl group formed by acetylation of the N-terminus, NH ２ The 'x' represents the part of the amide group formed by amidation at the C-terminus, excluding the carbonyl group. G, Y, A, and L represent glycine, tyrosine, alanine, and leucine residues, respectively. X in the formula represents the structure shown in chemical formula (3). (In the formula, *1 and *2 indicate the N-terminal bond and the C-terminal bond, respectively, and *3 indicates the bond to the side chain atom.) [9] A method for producing a peptide compound, comprising a hydrogenation desulfurization step of hydrogenation desulfurizing a sulfur atom bonded to an aromatic ring contained in a sulfur-containing peptide compound, wherein the hydrogenation desulfurization step is carried out in the presence of a hydrogenation desulfurization catalyst described in any one of [1] to [8].

[0007] Through diligent research, the inventors discovered that by using a catalyst having the above structure, the hydrogenation and desulfurization of sulfur atoms bonded to aromatic rings can be selectively promoted, leading to the completion of the present invention.

[0008] The reaction scheme of a model peptide compound having a diTyr structure is shown.

[0009] Embodiments of the present invention will be described below. The various features shown in the embodiments below can be combined with each other. Furthermore, each feature constitutes an independent invention. In addition, elements in the embodiments below that are not defined in the claims are optional and can be omitted. Any number of zeros (for example, one or two) may be added to the end of the numerical values ​​disclosed in the following description. For example, one or two zeros may be added after "1.4" to make it "1.40" or "1.400".

[0010] 1. Background of the Invention In recent years, it has been suggested that certain peptide compounds (hereinafter referred to as "specific peptide compounds") may be causative substances of Parkinson's disease and Alzheimer's disease. These specific peptide compounds are important for advancing research on Parkinson's disease and Alzheimer's disease, and it is desirable to be able to produce them efficiently.

[0011] The specific peptide compound is characterized by having a diTyr structure, and an example of a reaction scheme for a model peptide compound having a diTyr structure is shown in Figure 1. In the reaction scheme in Figure 1, compound 2 is produced by sulfenylation of compound 1, compound 3 is produced by oxidation of compound 2, and compound 4 (model peptide compound) is produced by hydrogenation desulfurization of compound 3 (model peptide compound precursor).

[0012] Compound 3 contains a sulfur atom bonded to an aromatic ring (hereinafter referred to as "first sulfur atom"), and in order to obtain compound 4, it is necessary to hydrogenate compound 3 to remove the first sulfur atom (hydrodesulfurization). This hydrogenation can be carried out, for example, using a commercially available palladium-supported alumina catalyst. On the other hand, compound 3 contains a peptide structure composed of numerous amino acids linked by peptide bonds, and the side chains of this peptide structure contain amino acid residues (e.g., methionine) having an alkyl group and an alkylene group, or a sulfur atom sandwiched between alkylene groups (hereinafter referred to as "second sulfur atom"). The second sulfur atom is also present in compound 4 and should not be removed in hydrogenation. However, hydrogenation using existing catalysts has the problem that the selectivity of the reaction to remove the first sulfur atom is low, so when attempting to remove the first sulfur atom, the second sulfur atom is also easily removed. Therefore, there was a need to develop a catalyst that selectively promotes the hydrogenation of the first sulfur atom (hereinafter referred to as "first hydrogenation") compared to the hydrogenation of the second sulfur atom (hereinafter referred to as "second hydrogenation"), which led to the development of the hydrogenation catalyst of the present invention.

[0013] 2. Hydrodesulfurization Catalyst Next, a hydrogenatesulfurization catalyst according to one embodiment of the present invention will be described. This hydrogenatesulfurization catalyst is configured to promote the hydrogenatesulfurization of a sulfur atom (i.e., a first sulfur atom) bonded to an aromatic ring contained in a sulfur-containing peptide compound. The sulfur-containing peptide compound is a peptide compound containing a first sulfur atom. The first sulfur atom is preferably bonded to an aromatic ring and an alkylene group. The aromatic ring is preferably bonded to the main chain of the peptide compound via an alkylene group. Furthermore, the first sulfur atom is preferably bonded to the main chain of the peptide compound via an alkylene group.

[0014] The sulfur-containing peptide compound may or may not contain an alkyl group and an alkylene group, or a sulfur atom sandwiched between two alkylene groups (i.e., a second sulfur atom). However, the technical significance of using the hydrogenodesulfurization catalyst of the present invention is particularly pronounced when a second sulfur atom is present. Preferably, the second sulfur atom is bonded to the main chain of the peptide compound via an alkylene group.

[0015] The molecular weight of the sulfur-containing peptide compound is not particularly limited and is, for example, 500 to 20,000, preferably 1,000 to 10,000. Specifically, this molecular weight is, for example, 500, 1,000, 1,500, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 15,000, 20,000, and may be within the range between any two of the values exemplified herein.

[0016] The hydrodesulfurization catalyst of the present embodiment is composed of a carrier having a supported substance supported thereon. The carrier is composed of an inorganic oxide, the supported substance is a metal containing a transition metal element or an oxide thereof, and the carrier has an average pore diameter of 30 nm or less and a pore volume of 0.50 ml / g or more. The average pore diameter and the pore volume can be measured by the nitrogen gas adsorption method.

[0017] As shown in the examples and comparative examples described later, the hydrodesulfurization catalyst having such a configuration has a significantly higher reaction rate of the first hydrodesulfurization than the reaction rate of the second hydrodesulfurization, and thus has excellent reaction selectivity of the first hydrodesulfurization with respect to the second hydrodesulfurization (hereinafter, also simply referred to as "reaction selectivity"), and can increase the yield of a desired peptide compound (e.g., the model peptide compound shown by Compound 4 in FIG. 1).

[0018] The average pore diameter of the carrier is preferably 12 nm or less. In this case, the reaction selectivity is particularly excellent. This average pore diameter is, for example, 1 to 30 nm, preferably 5 to 12 nm. Specifically, this average pore diameter is, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 nm, and may be within the range between any two of the values exemplified herein or any value below.

[0019] The pore volume is preferably 0.60 ml / g or more, and more preferably 0.70 ml / g or more. In this case, the reaction selectivity is particularly excellent. This pore volume is, for example, 0.50 to 2.0 ml / g, preferably 0.60 to 1.5 ml / g, and more preferably 0.70 to 1.2 ml / g. Specifically, this pore volume is, for example, 0.50, 0.60, 0.70, 0.80, 0.90, 1.00, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0 ml / g, and may be in the range between any two of the values ​​exemplified here, or greater than or equal to either of them.

[0020] The inorganic oxide constituting the support is preferably composed of an oxide containing at least one element selected from zirconium, cerium, aluminum, silicon, magnesium, and titanium (hereinafter referred to as the "inorganic element group"). Oxides containing such elements can form a porous structure particularly stably and easily constitute a support having the above-mentioned average pore diameter and pore volume. Furthermore, they facilitate the stable support of the material being carried.

[0021] The inorganic oxide may be an oxide containing one of the elements included in the inorganic element group, or it may be an oxide containing two or more elements. Furthermore, the inorganic oxide is preferably composed of an oxide containing at least one of aluminum and titanium, and more preferably composed of an oxide containing aluminum and titanium. The inorganic oxide is preferably alumina or titania, or a composite oxide of alumina and titania. The carrier preferably has a core-shell structure having a core composed of a first inorganic oxide and a shell composed of a second inorganic oxide. The first and second inorganic oxides are each oxides containing at least one element selected from the inorganic element group described above. The first inorganic oxide preferably contains aluminum, and more preferably alumina. The second inorganic oxide preferably contains titanium, and more preferably titania.

[0022] The transition metal element preferably includes at least one element selected from Groups 8, 9, 10, 11, and 12 of the periodic table, and more preferably includes at least one element selected from iron, cobalt, nickel, copper, ruthenium, rhodium, palladium, zinc, iridium, and platinum. These elements are particularly desirable as supports for the hydrogenodesulfurization catalyst of this embodiment because they exhibit particularly excellent desulfurization activity. The support is preferably in a metallic state, but may be an oxide as long as it exhibits desulfurization activity. Furthermore, the transition metal element preferably includes at least one element selected from nickel, palladium, and platinum. Nickel, palladium, and platinum are all Group 10 elements, and are thought to produce similar effects to palladium, whose effects have been demonstrated in the examples. The support is preferably metallic nickel, palladium, or platinum, and more preferably metallic palladium.

[0023] The shape of the carrier is not particularly limited. The shape of the carrier may be, for example, powder, bulk, or honeycomb, and from the viewpoint of ease of handling, it is preferably powder. When the carrier is powder, its average particle diameter is preferably 1 to 100 μm, more preferably 2 to 30 μm, and even more preferably 5 to 20 μm. Specifically, this average particle diameter may be, for example, 1, 2, 5, 10, 15, 20, 25, 30, 50, or 100 μm, and may be in the range between any two of the values ​​exemplified herein. In this specification, "average particle diameter" means the particle size at 50% of the volume integrated value in the particle size distribution determined by laser diffraction-scattering method. When the carrier is in bulk form (molded product), the sphere equivalent diameter having the same outer surface area as the outer surface area of ​​the carrier is preferably, for example, 0.05 to 0.5 inches, specifically, for example, 0.05, 0.1, 0.2, 0.3, 0.4, and 0.5 inches, and may be in the range between any two of the values ​​exemplified here.

[0024] The amount of the support is preferably 30% by mass or less, with the hydrogenodesulfurization catalyst being 100% by mass. This amount is, for example, 0.1 to 30% by mass, preferably 2 to 10% by mass, and specifically, for example, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, and 30% by mass, and may be in the range between any two of the values ​​exemplified here, or less than or equal to either of them.

[0025] 3. First and Second Peptide Compounds for Catalyst Evaluation Next, the first and second peptide compounds for catalyst evaluation will be described. The model peptide compound precursor described in "1. Background of the Invention" has both first and second sulfur atoms, making it difficult to use for evaluating the reaction selectivity of catalysts. Therefore, a first peptide compound having a first sulfur atom and a second peptide compound having a second sulfur atom are used to evaluate the reaction selectivity of catalysts.

[0026] The first peptide compound is represented by chemical formula (1), and the second peptide compound is represented by chemical formula (2). The first and second peptide compounds undergo hydrogenation desulfurization to obtain the structures shown in chemical formulas (4) and (5), respectively. Since the first and second peptide compounds have similar molecular weights and types of amino acid residues constituting the peptide compounds, the reaction selectivity of the first and second hydrogenation desulfurization can be evaluated by comparing the reaction rates of hydrogenation desulfurization of the first peptide compound and the hydrogenation desulfurization of the second peptide compound. The molecular weight of the first peptide compound is 621.71, and the molecular weight of the second peptide compound is 651.78.

[0027] Chemical formulas (1) to (4) have an N-terminus on the left and a C-terminus on the right. The N-terminus has an acetyl group formed by acetylation of the N-terminus. The C-terminus has an amide group (-C(O)-NH) formed by amidation of the C-terminus. ２ ) is provided.

[0028] (In the formula, Ac indicates an acetyl group formed by acetylation of the N-terminus, NH ２represents a site other than the carbonyl group among the amide groups formed by amidation of the C-terminus, and G, A, and L each represent a glycine residue, an alanine residue, and a leucine residue. X in the formula represents a structure represented by chemical formula (3).

[0029] (In the formula, Ac represents an acetyl group formed by acetylation of the N-terminus, and NH ２ represents a site other than the carbonyl group among the amide groups formed by amidation of the C-terminus, and G, Y, A, and L each represent a glycine residue, a tyrosine residue, an alanine residue, and a leucine residue. X in the formula represents a structure represented by chemical formula (3).

[0030] (In the formula, *1 and *2 each represent a bonding portion on the N-terminal side and a bonding portion on the C-terminal side, and *3 represents a bonding portion with an atom in the side chain.)

[0031] (In the formula, Ac represents an acetyl group formed by acetylation of the N-terminus, and NH ２ represents a site other than the carbonyl group among the amide groups formed by amidation of the C-terminus, and G, A, and L each represent a glycine residue, an alanine residue, and a leucine residue. X in the formula represents a structure represented by chemical formula (3).

[0032] (In the formula, Ac represents an acetyl group formed by acetylation of the N-terminus, and NH ２ represents a site other than the carbonyl group among the amide groups formed by amidation of the C-terminus, and G, Y, A, and L each represent a glycine residue, a tyrosine residue, an alanine residue, and a leucine residue. X in the formula represents a structure represented by chemical formula (3).

[0033] 4. k Ａ / k Ｂ The hydrodesulfurization catalyst of the present embodiment uses the desulfurization activity value of the hydrogenation desulfurization of the sulfur atom bonded to the aromatic ring contained in the first peptide compound as k Ａ and uses the desulfurization activity value of the hydrogenation desulfurization of the sulfur atom sandwiched between the alkyl group and the alkylene group contained in the second peptide compound as k ＢTherefore, k Ａ / k Ｂ The value is 10.0 or higher. The desulfurization activity value is calculated under conditions where hydrogenation desulfurization is performed at 25°C in a reaction solution obtained by mixing equimolar amounts of the first and second peptide compounds and the catalyst in an amount such that the number of moles of the transition metal element is 10 times the total number of moles of the first and second peptide compounds in a buffer solution composed of 6M guanidine hydrochloride - 0.1M HEPPS buffer solution. The concentrations of the first and second peptide compounds in the reaction solution are each 1 mM.

[0034] k Ａ / k Ｂ The larger the value, the more selectively the desired reaction, first hydrogenation desulfurization, is carried out, and therefore it can be said that the catalyst has desirable properties.

[0035] Desulfurization activity value k Ａ ,k Ｂ This can be calculated based on the following formula (1). If C = 0, the desulfurization activity value cannot be calculated, so if the measured concentration after t minutes is 0, for convenience, we assume that C is 0.1% of the initial concentration, and the desulfurization activity value k Ａ ,k Ｂ Calculate (lnC ０ -lnC) / t (1) (wherein t is the reaction time (minutes), and k Ａ When calculating C ０ and C are the initial concentration and the concentration after t minutes of the first peptide compound, respectively, and k Ｂ When calculating C ０ (And C are the initial concentration and the concentration of the second peptide compound after t minutes, respectively.)

[0036] The reaction time t is k Ａ ,k Ｂ It can be set to any time that can be calculated, for example, 5 minutes, 10 minutes, 15 minutes, 60 minutes, etc. Ａ / k ＢIt is preferable that the reaction time t is 10.0 or higher at any reaction time t, but it may be 10.0 or higher at any reaction time t. The reaction time t is preferably in the range of 1 to 60 minutes, and more preferably in the range of 5 to 15 minutes. Furthermore, it is preferable that the reaction time t is within the range in which the hydrogenation desulfurization of the first peptide compound is not completed. After the hydrogenation desulfurization of the first peptide compound is completed, only the hydrogenation desulfurization of the second peptide compound will proceed, so k Ａ / k Ｂ This is because the value of may appear smaller and may not accurately reflect the actual reaction rate ratio. Also, regardless of whether the reaction time t is 5 minutes, 10 minutes, 15 minutes, or 60 minutes, k Ａ / k Ｂ It is preferable that k is 10.0 or higher, but in one, two, or three of the reaction times t of 5 minutes, 10 minutes, 15 minutes, and 60 minutes, Ａ / k Ｂ It may be 10.0 or higher.

[0037] k Ａ / k Ｂ The larger the value, the better; 15.0 or higher is preferred, and 20.0 or higher is even more preferred. Ａ / k Ｂ There is no specific upper limit, but for example, it is 1,000. Ａ / k Ｂ For example, these could be 10.0, 15.0, 20.0, 25.0, 30.0, 35.0, 40.0, 45.0, 50.0, 55.0, 60.0, 65.0, 70.0, 75.0, 80.0, 85.0, 90.0, 95.0, 100, 200, 500, 1,000, or any range between any two of the numbers exemplified here.

[0038] The conversion rate of the first peptide compound from the start of the reaction to the time elapsed t minutes is, for example, 10 to 100%. The conversion rate (%) can be calculated based on the following formula (2). ((Initial concentration C) ０ (Concentration C after t minutes) / Initial concentration C ０ ) × 100 (2)

[0039] The conversion rate is, for example, 10 to 100%, specifically, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99.9, and 100%, and may be within the range of any two of the values ​​exemplified here.

[0040] k Ａ / k Ｂ It is preferable that the conversion rate is 10.0 or higher within any range of conversion rates, but it may be 10.0 or higher at any conversion rate. The arbitrary conversion rate is preferably within the range of 10 to 99.9%. After the conversion rate reaches 100%, only the hydrogenation desulfurization of the second peptide compound will proceed, so k Ａ / k Ｂ This is because the value may appear smaller than it actually is, and may not accurately reflect the ratio of the actual reaction rates. Specifically, the conversion rate may be, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, or 99.9%, and may also be within a range between any two of the values ​​exemplified here.

[0041] 5. Method for Manufacturing Hydrodesulfurization Catalyst The hydrogendesulfurization catalyst of this embodiment can be manufactured by supporting a support composed of a metal containing a transition metal element or an oxide thereof on an inorganic oxide constituting a carrier. In one example, the support can be supported on the carrier by an impregnation method. In one example, the impregnation method can be carried out by impregnating the carrier with an aqueous solution containing the metal element constituting the support and then calcining the impregnated material. If the support is a metal, a reducing gas such as hydrogen gas can be used as needed to convert the oxide state of the support to a metallic state.

[0042] The inorganic oxide is preferably synthesized by the pH swing method. By synthesizing it by the pH swing method, porous and homogeneous inorganic oxide particles (for example, needle-shaped in the case of alumina) can be obtained. Furthermore, by controlling the synthesis conditions, inorganic oxides with a desired pore size can be obtained.

[0043] In this invention, the "pH swing method" refers to a synthesis method in which the pH of an inorganic oxide synthesis solution is changed between the acidic and alkaline sides, causing the inorganic oxide to swing between the dissolution and precipitation regions and grow uniformly to the desired particle size. In the pH swing method, inorganic oxide particles with the desired pore structure and specific surface area can be obtained by appropriately controlling various conditions such as the number of swings, synthesis temperature, pH of the acidic and alkaline sides and holding time, raw material concentration, and the presence or absence of additives such as particle growth regulators. Therefore, in this invention, there are no restrictions on the various conditions during the synthesis of the inorganic oxide by the pH swing method, and they can be appropriately selected according to the purpose.

[0044] Furthermore, if the carrier has a core-shell structure, the carrier can be formed by first forming the core by the pH swing method, and then forming the shell by a precipitation and layering process. In the precipitation and layering process, a raw material solution for forming the shell and a pH adjusting agent are supplied in the presence of the core, and the second inorganic oxide is precipitated and layered on the surface of the core in a pH range between the isoelectric point of the second inorganic oxide constituting the shell and the isoelectric point of the first inorganic oxide constituting the core.

[0045] The isoelectric point is a value unique to each substance, and the charge on the surface of particles suspended in a liquid switches between positive and negative at a pH value corresponding to this point. More specifically, the charge becomes negative on the alkaline side and positive on the acidic side, with the isoelectric point as the boundary. In the pH swing method described above, the pH is changed across this isoelectric point, causing repeated crystal growth and partial dissolution, resulting in the growth of homogeneous crystals.

[0046] For example, if the first inorganic oxide constituting the core is alumina and the second inorganic oxide constituting the shell is titania, the isoelectric point of alumina is 9.0 and the isoelectric point of titania is 6.0. Therefore, the raw material solution and pH adjusting agent are supplied to adjust the pH of the reaction solution between 6.0 and 9.0. As a result, the surface charge of each becomes positive for alumina because the pH is lower than its isoelectric point, and negative for titania because the pH is higher than its isoelectric point, and a titania layer is well formed on the surface of the alumina.

[0047] The carrier of this embodiment can also be manufactured by referring to the method disclosed in Patent Document 2.

[0048] 6. Method for Producing Peptide Compounds The method for producing peptide compounds according to one embodiment of the present invention comprises a hydrogenation desulfurization step in which sulfur atoms bonded to aromatic rings in a sulfur-containing peptide compound are hydrogenated. This hydrogenation desulfurization step is carried out in the presence of the hydrogenation desulfurization catalyst described above. As described above, the hydrogenation desulfurization catalyst of this embodiment can selectively promote first hydrogenation desulfurization, so by using this catalyst, it is possible to produce a desired peptide compound in high yield. Hydrogenation desulfurization can be carried out, in one example, by contacting a sulfur-containing peptide compound with an aqueous solution containing the hydrogenation desulfurization catalyst described above and hydrogen gas. Hydrogen gas can be obtained, in one example, by electrolysis of the aqueous solution. In this case, the catalyst can be applied to the electrode that generates hydrogen gas in the electrolysis of the aqueous solution. In this case, since the generated hydrogen gas immediately comes into contact with the hydrogenation desulfurization catalyst, hydrogenation desulfurization can be carried out efficiently.

[0049] The present invention will be described in more detail below with reference to examples. In the following description, "parts" or "%" refers to mass unless otherwise specified.

[0050] 1. Production of Hydrodesulfurization Catalyst 1-1. Example 1 - Production of the support Alumina-titania composite support was produced according to the following method.

[0051] [pH Swing Process] Alumina hydrogel (inorganic oxide) was prepared as a nucleus as follows. First, solution A was prepared by adding 2075 g of water to 925 g of aluminum nitrate. Next, solution B was prepared by adding 2440 g of water to 560 g of sodium aluminate. 2.5 liters of water were added to a 15 liter enamel container and heated to 60°C while stirring. 180 g of solution A was added to the enamel container and held for 5 minutes. At this time, the pH of the synthesized solution was 2.5.

[0052] Next, 200 g of solution B was added to the enamel container, and the pH of the synthesis solution was adjusted to 9.0 and held for 5 minutes. Then, 180 g of solution A was added, the pH was adjusted to 2.5 and held for 5 minutes, and then 180 g of solution B was added again, the pH was adjusted to 9.0 and held for 5 minutes. This procedure was repeated six times to prepare a dispersion of alumina hydrogel.

[0053] [Precipitation and Lamination Process] 2000 parts of the obtained alumina hydrogel dispersion are kept at 60°C, and colloidal silica (SiO₂ ２ 1.8 parts of a particle growth regulator (containing 8%) were added, and hydrochloric acid (pH adjuster) was added to chemically and / or microscopically integrate the alumina and titania, adjusting the pH to 7.5 so that it is between the isoelectric points of titania and alumina. 97.7 parts of 37.9% titanium tetrachloride solution and 14% aqueous ammonia (pH adjuster) were simultaneously added to adjust the pH to 7.5, and the mixture was reacted for 5 minutes while maintaining the temperature at 60°C. The resulting reaction product was washed with water, filtered, molded, and dried at 120°C for 3 hours.

[0054] [Casturing Process] The product from the precipitation and layering process was placed in an oven and calcined at 500°C for 3 hours to obtain the aluminatitania composite support of Example 1.

[0055] - Supporting the Supported Material The alumina-titania composite carrier obtained by the above method was crushed into a powder using a mortar and pestle. The average particle size of this powder was measured using a laser diffraction / scattering particle size distribution analyzer (LA-950, manufactured by Horiba, Ltd.) and was found to be 10 μm.

[0056] Approximately 10 g of this powder was introduced into a rotary evaporator flask, and then the necessary amount of palladium nitrate solution was added. After that, it was impregnated under reduced pressure, dried, and then calcined. Subsequently, a reduction treatment was carried out under a reducing gas atmosphere to obtain a hydrogenation desulfurization catalyst with 5% by mass of palladium supported on a carrier.

[0057] 1-2. Example 2 An alumina support was obtained in the same manner as in Example 1, except that a precipitation and stacking step was omitted and a calcination step was performed on the product of the pH swing step. Palladium was supported on this alumina support in the same manner as in Example 1 to obtain a hydrogenation desulfurization catalyst.

[0058] 1-3. Example 3 A titania support was obtained by the method shown below. Palladium was supported on this titania support in the same manner as in Example 1 to obtain a hydrogenation desulfurization catalyst.

[0059] When 1100 parts of water were kept at 60°C and 12.5 parts of the same colloidal silica (particle growth regulator) as in Example 1 were added, the pH was 7.5. When 330 parts of a 37.9% titanium tetrachloride solution were added, the pH became 1.5. Further addition of 14% aqueous ammonia (pH adjuster) brought the pH back to 7.5 (one pH swing). This pH swing operation was repeated six times, adjusting the amount added to match the pH value, to prepare a dispersion of titania hydrogel.

[0060] The obtained titania hydrogel dispersion was washed with water, filtered, molded, and dried at 120°C for 3 hours. The filtered titania hydrogel was then calcined in the same manner as in Example 1 to obtain a titania support. 1-4. Comparative Example 1 In Comparative Example 1, commercially available TCI Palladium 5% on Aluminum (P2238) was used.

[0061] 2. Measurement of Average Pore Diameter and Pore Volume The average pore diameter and pore volume were measured for the catalysts of the examples and comparative examples. The results are shown in Table 1.

[0062] The equipment and measurement conditions used for the measurement are as follows: Equipment name: Specific surface area and pore size distribution analyzer (BELSORP-miniII) Manufacturer: Microtrac-Bell Co., Ltd. Gas used: N ２ Adsorption temperature: 77K Pretreatment conditions: Vacuum: 300℃ 3 hours Analysis program: BET, BJH

[0063] 3. Evaluation of Hydrogenated Desulfurization Reaction A predetermined amount of 6M guanidine hydrochloride-0.1M HEPPS buffer solution, prepared with guanidine hydrochloride and HEPPS, was added to the flask to adjust the pH to 6.7. Then, the starting materials were prepared by adding the first peptide compound and the second peptide compound to the flask so that the total number of moles of sulfur contained in each compound was 0.2 μmol (each with a molar concentration of 1 mM). Next, the catalysts of the examples and comparative examples were added to the flask, and after attaching argon gas and hydrogen gas lines to the flask, the air inside the flask was purged with argon gas. The catalyst was added so that the number of moles of palladium was 10 times the total number of moles of the first and second peptide compounds.

[0064] Subsequently, the gas line was switched to hydrogen, and after introducing hydrogen gas, the cocks on the inlet and outlet gas lines were closed. The reaction was then completed by maintaining the mixture at room temperature under atmospheric pressure and in a sealed state while stirring with a stirring bar.

[0065] Subsequently, the gas line was switched to argon, and the inside of the flask was replaced with argon gas. After standing, the supernatant of the liquid product and catalyst at the bottom of the flask was separated and analyzed using reverse-phase HPLC (column: COSMOSIL 5C). １８ AR-II (4.6 × 250 mm), flow rate: 1 mL / min, 220 nm detection, HPLC gradient condition: 0.1% (v / v) TFA (trifluoroacetic acid) in MeCN (acetonitrile) - 0.1% (v / v) TFA in H ２ The supernatant was analyzed using O (5:95–45:55, 30 min).

[0066] Table 2 shows the results obtained by changing the reaction time and catalyst as shown in Table 2. The reaction time is the time it takes to maintain the flask at room temperature while stirring with a stirring bar under atmospheric pressure and in a sealed state after introducing hydrogen gas into the flask. As shown in Table 2, when using the catalysts of Examples 1 to 3, k was obtained regardless of the reaction time. Ａ / k Ｂ While the value is 10.0 or higher, when the catalyst of Comparative Example 1 is used, regardless of the reaction time, k Ａ / k ＢThe value was less than 10.0. This result indicates that the catalyst of the embodiment of the present invention can selectively promote the hydrogenation and desulfurization of sulfur bonded to aromatic rings.

[0067]

Claims

1. A hydrogenodesulfurization catalyst that promotes the hydrogenodesulfurization of sulfur atoms bonded to aromatic rings in a sulfur-containing peptide compound, wherein the catalyst is composed of a support supported on a carrier, the carrier is composed of an inorganic oxide, the support is a metal containing a transition metal element or an oxide thereof, and the carrier has an average pore diameter of 30 nm or less and a pore volume of 0.50 ml / g or more.

2. A hydrogenodesulfurization catalyst according to claim 1, wherein the average pore size is 12 nm or less.

3. A hydrogenodesulfurization catalyst according to claim 1, wherein the inorganic oxide is composed of an oxide containing at least one element selected from zirconium, cerium, aluminum, silicon, magnesium, and titanium.

4. A hydrogenodesulfurization catalyst according to claim 3, wherein the inorganic oxide is composed of an oxide containing at least one of aluminum and titanium.

5. A hydrogenodesulfurization catalyst according to claim 4, wherein the inorganic oxide is composed of an oxide containing aluminum and titanium.

6. A hydrogenodesulfurization catalyst according to claim 1, wherein the transition metal element comprises at least one element selected from Group 8, Group 9, Group 10, Group 11 and Group 12 of the periodic table.

7. A hydrogenodesulfurization catalyst according to claim 6, wherein the transition metal element comprises at least one element selected from iron, cobalt, nickel, copper, ruthenium, rhodium, palladium, zinc, iridium, and platinum.

8. A hydrogenation desulfurization catalyst according to claim 1, wherein the desulfurization activity value of the hydrogenation desulfurization of the sulfur atom bonded to the aromatic ring contained in the first peptide compound is k Ａ The desulfurization activity value of the hydrogenation desulfurization of the sulfur atom sandwiched between the alkyl group and alkylene group in the second peptide compound is k. Ｂ Therefore, k Ａ / k Ｂ The hydrogenation catalyst is characterized in that the value is 10.0 or greater, the first peptide compound is represented by chemical formula (1), the second peptide compound is represented by chemical formula (2), and the desulfurization activity value is calculated under conditions in which hydrogenation desulfurization is performed at 25°C in a reaction solution obtained by mixing equimolar amounts of the first and second peptide compounds and the catalyst in an amount such that the number of moles of the transition metal element is 10 times the total number of moles of the first and second peptide compounds with a buffer composed of 6M guanidine hydrochloride - 0.1M HEPPS buffer. (In the formula, Ac indicates an acetyl group formed by acetylation of the N-terminus, NH ２ The 'A' part of the amide group formed by amidation at the C-terminus represents the part other than the carbonyl group, while G, A, and L represent glycine, alanine, and leucine residues, respectively. X in the formula represents the structure shown in chemical formula (3). (In the formula, Ac indicates an acetyl group formed by acetylation of the N-terminus, NH ２ The 'x' represents the part of the amide group formed by amidation at the C-terminus, excluding the carbonyl group. G, Y, A, and L represent glycine, tyrosine, alanine, and leucine residues, respectively. X in the formula represents the structure shown in chemical formula (3). (In the formula, *1 and *2 indicate the N-terminal and C-terminal bonds, respectively, and *3 indicates the bonds to the side chain atoms.) 9. A method for producing a peptide compound, comprising a hydrogenation desulfurization step of hydrogenating a sulfur atom bonded to an aromatic ring in a sulfur-containing peptide compound, wherein the hydrogenation desulfurization step is carried out in the presence of a hydrogenation desulfurization catalyst according to any one of claims 1 to 8.

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