JPH0786102B2 - Process for producing optically active 6- (4-imidazolylmethyl) -3-substituted-2,5-piperazinedione - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to an optically active 6- (4-imidazolylmethyl)-
The present invention relates to a method for producing a 3-substituted-2,5-piperazinedione.

Cyclic dipeptides have various physiological activities and are used as antibiotics, plant growth inhibitors and the like.

<Prior Art> Peptides having an imidazole group show weak basicity due to dissociation of the imidazole group in the vicinity of neutrality during synthesis, and therefore, for example, acylation or racemization to an imidazole amino group during coupling is required. The synthetic method is limited because it is liable to occur and the purification after coupling is difficult.

6- (4-imidazolylmethyl) -3-phenyl-2,5
-Piperazinedione is represented by the following reaction formula, in which histidine methyl ester and benzyloxycarbonyl-
It is known to be obtained by reacting with phenylalanine-p-nitrophenyl ester to produce benzyloxycarbonyl-phenylalanyl histidine methyl ester, and then cyclizing. [Makromol. Chem. 183 579-586 (1982) and JP-A-59-116256] It is also known that phenylalanine N-carboxylic acid anhydride obtained by reacting D-phenylalanine with phosgene is reacted with histidine methyl ester, and then cyclized. (JP-A-60-97052) <Problems to be solved by the invention> The former benzyloxycarbonyl-phenylalanine-
The method using p-nitrophenyl ester requires a considerable number of days for production because it has many steps and the total yield is low at 37.4% and the reaction time is long. The latter method using phenylalanine N-carboxylic acid anhydride has a small number of steps and a total yield of 50.4%, which is better than that of the whole company, but the coupling reaction between phenylalanine N-carboxylic acid anhydride and histidine methyl ester is a side effect. -40 ℃ to suppress the reaction
Since it is necessary to carry out at the following low temperature and the yield of this step is low, neither of them can be said to be an industrial method.

In order to solve such a problem, as a result of diligent studies on a method for producing optically active 6- (4-imidazolylmethyl) -3-substituted-2,5-piperazinedione, the 3-position amino of phenylalanine N-carboxylic acid anhydride was obtained. By protecting the group and reacting, the generation of by-products is suppressed, and the yield is improved even if the coupling reaction is carried out from a low temperature of -40 ° C or lower as in the past to an industrially advantageous condition of about room temperature. The present invention has been completed and the present invention has been completed.

<Means for Solving Problems> That is, the present invention provides a compound represented by the general formula (I): The optically active N-carboxyamino acid anhydride represented by and an optically active histidine ester are reacted and then cyclized to give an optically active 6- (4-imidazolylmethyl) -3-substituted-inorganic compound represented by the general formula (II). In the method for producing 2,5-piperazinedione, The present invention is characterized in that the 3-position amino group of an optically active N-carboxyamino acid anhydride (hereinafter referred to as NCA) is protected with a protecting group to react with an optically active histidine ester, and then the protecting group is eliminated and then cyclized. Is a process for producing an optically active 6- (4-imidazolylmethyl) -3-substituted-2,5-piperazinedione.

The optically active 6- (4-imidazolylmethyl)-of the present invention
A method for producing a 3-substituted-2,5-piperazinedione is shown below by a general formula.

R in the formula represents a substituent selected from the group consisting of a lower alkyl group having 1 to 5 carbon atoms, a phenyl group, and an unsubstituted or substituted benzyl group, and more specifically, a benzyl group, p
-Hydroxybenzyl group, p-benzyloxybenzyl group, phenyl group, methyl group, isopropyl group, 2-methylpropyl group, 1-methylpropyl group, alkyloxycarbonylmethyl group, 2-alkyloxycarbonylethyl group, (1 -Methyl-4-imidazolyl) methyl group, (3-methyl-4-imidazolyl) methyl group and the like.

The amino acid anhydride (NCA) of the present invention is obtained by reacting an amino acid with phosgene. The amino acids used are all α-amino acids and their derivatives that can be used in ordinary NCA-forming reactions such as α-amino acids, that is, neutral amino acids, acidic amino acid monoesters, and N-substituted derivatives of basic amino acids. Include phenylalanine, tyrosine, O-benzyltyrosine, α-phenylglycine, alanine, valine, leucine, isoleucine, aspartic acid monoester, glutamic acid monoester,
Examples thereof include 1-methylhistidine, 3-methylhistidine and derivatives thereof.

The NCA reaction is carried out by suspending the amino acid in an appropriate solvent,
This is carried out by passing phosgene until the reaction solution becomes transparent. As the NCA-forming reaction solvent, any solvent that does not substantially interfere with the phosgenation reaction or does not react with the produced NCA can be used. Usually, aliphatic and aromatic hydrocarbons, halogenated hydrocarbons can be used. And nitrates, nitrated hydrocarbons, nitrites, ketones, carboxylic acid esters or ethers, and mixtures thereof. Specifically, acetonitrile, dioxane, ethyl acetate, tetrahydrofuran, toluene, chlorobenzene and the like are used.

The NCA-forming reaction temperature can be appropriately selected depending on the reactivity of the amino acid, but is usually in the range of about 0 to 150 ° C.

The amount of phosgene to be communicated may be 1 equivalent or more with respect to the amino acid, but about 2 equivalents or more, preferably 2 to 5 equivalents is preferable for completion of the reaction.

The blowing time of phosgene may be appropriately selected depending on the reactivity of the amino acid, and usually the blowing time is about 0.5 to 5 hours.
It is desirable to keep the reaction conditions as they are for the completion of the NCA reaction even after the blowing. The aging time is usually about
It is about 0.5 to 10 hours.

The perfect group for protecting the 3-amino group of NCA of the present invention is to reduce the nucleophilicity of the amino group and consequently suppress side reactions such as polymerization of NCA, and the following optically active stidine. Those that can be removed under mild conditions that do not induce racemization of the protected dipeptide ester formed by the coupling reaction with the ester are preferable, and 2-nitrophenylsulfenyl group (hereinafter referred to as N _ps group) 3-nitro -3
_{-Pyridinesulfenyl} group (hereinafter referred to as _Npys group) and the like are used.

The introduction of a protecting group to the amino group at the 3-position was carried out by using NCA and N _ps -Cl in the solvent.
_{Alternatively, Npys-} Cl is dissolved, and a base such as triethylamine, N-methylmorpholine or pyridine is _added dropwise to this solution. More than an equivalent amount of base is needed to trap the HCl that is normally produced.

The solvent used in this reaction is not particularly limited, and NC
The same solvent as in the A-formation reaction can be used. After the NCA reaction,
The reaction solution obtained by distilling off excess phosgene under normal pressure or reduced pressure can be used as it is.

The reaction temperature is preferably a low temperature of 50 ° C. or lower in order to prevent racemization at the 4-position.

3 represented by the above general formula (I) produced by this reaction
The optically active NCA with the protected amino group can be filtered off the amine hydrochloride without separation from the reaction solution, and the filtrate can be directly used for the coupling reaction with the next optically active histidine ester, or if necessary. After distilling off the solvent, the product can be used after being purified by recrystallization, column chromatography or the like.

The optically active histidine ester used in the present invention can be obtained as a hydrochloride by suspending optically active histidine and an alcohol in a solvent and then esterifying by suspending dry hydrogen chloride.

The type of ester is not particularly limited as long as it can inactivate the carboxyl group of histidine to prevent side reactions in the coupling reaction and has high solubility in an organic solvent. Specifically, methyl ester, ethyl ester, benzyl ester, tert-butyl ester, phenacyl ester, trichloroethyl ester, p-nitrobenzyl ester, diphenylmethyl ester, benzhydryl ester, p-methoxybenzyl ester, 4-picolyl ester. , Cyclohexyl ester and the like.

Optically active NCA in which the amino group at the 3-position of general formula (I) is protected
And the optically active histidine ester are coupled in a solvent at a temperature of about 0 to 50 ° C for several hours.

In the coupling reaction, the histidine ester needs to be in a hydrochloric acid-free state. For this reason, an equivalent amount or more of amine is added to the reaction system to neutralize it, and the reaction with NCA is performed. Alternatively, the optically active histidine ester may be neutralized with an amine in a coupling reaction solvent in advance before being subjected to the coupling reaction to remove the produced amine hydrochloride.

The amount of the protected optically active NCA used is 1 equivalent or more with respect to the histidine ester in order to complete the reaction, usually about 1
Used in the range of up to 2 equivalents.

The solvent used in this reaction is not particularly limited and is usually an aliphatic or aromatic hydrocarbon, a halogenated hydrocarbon, a nitrated hydrocarbon, a nitrile, a ketone, a carboxylic acid ester, an ether. Classes and mixtures thereof can be used. Specific examples include chloroform, tetrahydrofuran, ethyl acetate, acetonitrile, methylene chloride and the like. Protected optically active NC
The solvent used for obtaining A can be used as it is.

The coupling reaction is carried out at about 0 to 50 ° C, and it is not particularly limited as long as it does not induce racemization of the protected dipeptide ester. There is no need to lower it further.

The reaction is usually completed within 5 hours. In the reaction, the optically active histidine ester as a raw material is traced by thin layer chromatography or high performance liquid chromatography, and the time point at which the optically active histidine ester disappears can be regarded as the reaction end point.

After completion of the reaction, the produced amine hydrochloride is filtered off, and the filtrate is concentrated to give pale yellow protected dipeptide ester crystals.

Removal of the protecting group from the protected optically active dipeptide ester needs to be appropriately selected depending on the type of the protecting group. In the case of N _ps group and N _pys group, 2 equivalent or more of 2M hydrogen chloride solution is added at room temperature. By stirring for 2 hours.
Use a 2M hydrogen chloride solution prepared by blowing dry hydrogen chloride into a solvent such as methanol or dioxane in advance.

After completion of the reaction, the mixture is evaporated to dryness under reduced pressure to remove excess hydrogen chloride and the solvent, and then repeatedly washed with ether until the crystals become white to obtain dipeptide ester hydrochloride.

Quantitatively by concentrating the ether filter wash under reduced pressure
N _ps -Cl or N _pys -Cl can be recovered. The recovered N _ps -Cl or N _pys -Cl can be reused as it is.

The obtained optically active dipeptide ester hydrochloride is treated with a base to give a free ester, which is then subjected to a cyclization reaction.

The cyclization reaction is carried out by refluxing an alcohol solution of a hydrochloric acid-free optically active dipeptide ester to obtain the desired optically active 6- (4-imidazolylmethyl) -3-substituted-2,5 represented by the general formula (II). -Piperazindione can be obtained. The reflux is conducted for about 0.5-10 hours.

The end point of the cyclization reaction can be determined by thin layer chromatography or high performance liquid chromatography when the starting dipeptide ester disappears.

After completion of the reaction, the reaction solution was concentrated under reduced pressure, added to ether for crystallization, filtered, and dried under reduced pressure to obtain optically active 6- (4-imidazolylmethyl) cyclodipeptide.
White crystals of -3-substituted 2,5-piperazinedione are obtained.

<Effects of the Invention> By protecting the amino group at the 3-position of the optically active N-carboxyamino acid anhydride and then performing a coupling reaction with an optically active histidine ester, it is possible to perform NCA without causing a reaction at an extremely low temperature as in the conventional case. The total yield from
The yield is 70% or more, the purity is 90% or more,
Among them, optically active 6- (4-imidazolylmethyl) -3-substituted-2,5-piperazinedione having an optical purity of 99% or more can be obtained.

<Examples> Hereinafter, the present invention will be described in more detail with reference to Examples.
The invention is not limited to these examples.

Reference Example 1 Production of D-histidine methyl ester dihydrochloride 41.93 g of D-histidine hydrochloride (monohydrate) and 458 g of dry methyl alcohol were placed in a one-necked flask equipped with a thermometer, a condenser and a blowing tube. Was charged. When dry hydrogen chloride was passed through this with stirring, heat was generated, the suspended white crystals of histidine were once dissolved, and immediately white crystals of histidine ester were precipitated. Bubbling was continued at 50 to 60 ° C. until hydrogen chloride was saturated, then ice-cooled and left overnight at room temperature. White crystals of the ester were collected by filtration and washed with dry diethyl ether to obtain 48.4 g of D-histidine-methyl ester dihydrochloride (D-HIS.OME.2HCl).

Melting point 201 to 203 ° C. Optical rotation [α] _D ²⁵ + 9.0 ° (C = 2, H ₂ O) Reference Example 2 D-phenylalanine N-carboxylic acid anhydride (D-PHE
Production of NCA) A four-necked flask equipped with a thermometer, a condenser and a blowing tube was charged with 16.5 g of D-phenylalanine and 175 g of dry tetrahydrofuran (THF). This was passed through 33.0 g of phosgene below 10 ° C. After the completion of blowing, the temperature was raised to 40 ° C. and stirring was continued for 1 hour, and the white crystals of phenylalanine were completely dissolved. Excess phosgene was distilled off under reduced pressure at a liquid temperature of 40 ° C. or lower to obtain a THF solution of D-PHENCA. Partial concentration and separation were performed, and the yield and physical property values were determined.

100% mp 89 to 90.5 ° C. Optical rotation Yield [α] ^{_{D 25 + 99.97 ° (C =}} 2, CHCl 3) Example 1 D-N- (2-nitrophenyl sulfenyl) phenylalanine N- carboxylic acid anhydride Production of ( _Nps- D-PHE NCA) In a four-necked flask equipped with a thermometer, a condenser and a dropping funnel, 19.1 g of a THF solution of D-PHE NCA produced in Reference Example 2 and O-nitrophenylsulfenyl chloride. (N _ps ‐Cl)
1.90 g was charged and cooled with ice water.

Add 10 ml of IM dry THF solution of triethylamine (TEA) to this.
After dropping for 30 minutes, stirring was continued for 30 minutes at the same temperature.

The formed TEA hydrochloride was filtered off, and the filtrate was concentrated to give N _ps −
3.26 g of D-PHE NCA was obtained.

Yield 95% Melting point 151-153 ° C Optical rotation [α] _D ²⁵ -52.4 ° (C = 2, THF) DN- (2-nitrophenylsulfenyl) phenylalanyl-D-histidine methyl ester (N _ps -DP
HE-D-HIS / OME) production D-PHE NCA in a four-necked flask equipped with a thermometer and a condenser.
4.21 g, dry ethyl acetate 40 g and N _ps -Cl 3.79 g were charged and cooled with ice water. Add triethylamine (TEA) IM dry T
After 10 ml of the HF solution was added dropwise over 30 minutes, stirring was continued at the same temperature for 30 minutes.

The produced N _ps -D-PHE NCA was not isolated, but was _added to the reaction solution to prepare D-HIS.OME.2HCl (5.33 g) and chloroform 7
0 g and TEA 16.25 g were added and the reaction was carried out at room temperature for 2 hours. Next, after filtering off the TEA hydrochloride precipitated by the addition of THF, was obtained by concentration of the filtrate the crude _{N ps -D-PHE-D-} HIS · OME.

Dissolve this in 50 g of chloroform and add 5% citric acid, 5%
Aqueous sodium bicarbonate solution, washed successively with water, to give the _{N ps -D-PHE-D-} HIS · OME8.59g The chloroform layer was concentrated under reduced pressure.

Yield 83% Melting point 93-95 ° C Optical rotation [α] _D ²⁵ -15.4 ° (C = 1, THF) D-phenylalanyl-D-histidine methyl ester dihydrochloride (PHE-D-HIS OME 2HCl) Production N _ps -D-PHE-D-HIS.OME8.59g and 2N hydrogen chloride in dioxane solution 91.5g were placed in an eggplant-shaped flask and stirred at room temperature for 2 hours.

As a result of tracking the reaction by liquid chromatography, the raw material peak disappeared completely in 2 hours.

After completion of the reaction, excess hydrogen chloride and the solvent were distilled off under reduced pressure at 40 ° C., and the remaining pale yellow solid was washed with diethyl ether until it became white to obtain 6.77 g of D-PHE-D-HIS.OME.2HCl. It was As a result of elemental analysis (Cl 18.2%), the crystal was dihydrochloride.

Yield 95% Optical rotation [α] _D ²⁵ + 2.3 ° (C = 2, AcOH) Further, the ether washing liquid was concentrated under reduced pressure to recover 3.79 g of N _ps -Cl. (Recovery rate 100%) 3- (R) -benzyl-6- (R)-(4-imidazolylmethyl) -2,5-piperazinedione (cyclo-D-PHE
-D-HIS) D-PHE-D-HIS.OME.2HCl 2.80 g prepared above and dry THF 65 g in a four-necked flask equipped with a thermometer and a condenser.
Then, 4.93 g of dried TEA was charged, and the mixture was stirred at room temperature for 1 hour.
The formed TEA hydrochloride was filtered off under reduced pressure, and the filtrate was concentrated. Dissolve the residue in 100 g of dry methyl alcohol,
Heated to reflux for hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and diethyl ether was added thereto. The white crystals that have precipitated are collected by filtration,
Wash with ether and Cyclo-D-PHE-D-HIS 1.42g
Got

92.8% purity as a result of analysis by liquid chromatography
Met. The total yield from D-PHE NCA was 78.9%.

Melting point 243.5 to 244 ° C. Optical rotation [α] _D ²⁵ + 66.8 ° (C = 2, AcOH) Examples 2 to 8 Reference examples 1 and 2 and Example 1 using the amino acids or their derivatives shown in Table 1. Various optically active 6-
Imidazolylmethyl) -3-substituted-2,5-piperazinedione was prepared.

Claims (2)

[Claims] 1. A general formula (I) The optically active N-carboxyamino acid anhydride represented by and an optically active histidine ester are reacted and then cyclized to give an optically active 6- (4-imidazolylmethyl) -3-substituted-inorganic compound represented by the general formula (II). In the method for producing 2,5-piperazinedione, An optically active 6- (characterized in that the 3-position amino group of an optically active N-carboxyamino acid anhydride is protected with a protecting group to react with an optically active histidine ester, and then the protecting group is eliminated and cyclized. 4-imidazolylmethyl) -3
-Process for producing substituted-2,5-piperazinedione. 2. The optically active 6- (4-imidazolylmethyl) -3 according to claim 1, wherein the protecting group is a 2-nitrophenylsulfenyl group or a 3-nitro-2-pyridinesulfenyl group. -Process for producing substituted-2,5-piperazinedione.