JPH0143741B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is a novel production method that more efficiently leads to optically active tryptophan derivatives than optically active N-phthalylglutamine. Optically active N-phthalyltryptophan and its 5-benzyloxy derivative are compounds useful as intermediates for the synthesis of optically active tryptophan and 5-hydroxytryptophan, which are important as pharmaceuticals. By doing so, optically active tryptophan and optically active 5-hydroxytryptophan can be obtained. Conventionally known methods for chemically synthesizing optically active tryptophans can be roughly divided into methods that start from raw materials with an indole nucleus such as indole aldehyde and gramine, and methods that form an indole ring during synthesis. . However, these conventional methods ultimately synthesize a racemic tryptophan derivative and perform optical resolution physicochemically, chemically, or enzymatically to obtain the desired optically active substance.
This and the opposite optically active form were racemized and recovered.
This method requires extremely complicated operations such as repeated splitting operations, which is a major factor in reducing the yield, and it is difficult to say that either method is industrially advantageous. Therefore, the present inventors conducted intensive research on an industrially advantageous chemical synthesis method for optically active tryptophan derivatives, and filed a patent application (Japanese Patent Application Laid-Open No.
However, as a result of further research, optically active N-phthalylglutamine was used as a raw material, and a new substance, optically active α-
Phthalimide-γ-cyanobutyric acid is reduced to optically active α-phthalimide-γ-formylbutyric acid, and then reacted with phenylhydrazine or 4-substituted phenylhydrazine to perform an indole ring-closing reaction. It was discovered that active N-phthalyl-tryptophan derivatives can be obtained without racemization, and an industrially advantageous method for producing optically active tryptophan derivatives was completed. In the method of the present invention, 1) since the amino protecting group is a phthalyl group, a tryptophan derivative can be obtained without racemization without adding an esterification step. 2) Handling is easy because the intermediate has high solubility in organic solvents. 3) A useful tryptophan derivative can be obtained by subjecting the obtained phthalyltryptophan derivative to a relatively mild treatment such as hydrazine treatment. The chemical formula of the present invention is as follows. In the present invention, optically active N used as a raw material
-Phthalylglutamine is a compound that can be easily produced by a known method from optically active glutamic acid or optically active glutamine, which is industrially produced at low cost. The first step of the present invention is to convert optically active N-phthalylglutamine (I) into optically active α-phthalimide-γ-
Cyanobutyric acid (). The reaction of (I) to () can be obtained by using a general dehydrating agent, but for example, when using acetic anhydride, it is necessary to add well-pulverized (I) to acetic anhydride and heat it for a short time. Therefore, it is easily converted into nitrile ()
It can be done. The acetic anhydride used also serves as a reaction solvent, and is about 2 to 10 times the molar amount, preferably about 5 times the molar amount. The reaction temperature can be any temperature below the boiling point of the solvent, but
Appropriate temperature is around 100℃. Under these conditions 30
The dehydration reaction is completed in minutes to one hour. Note that the nitrile compound () is a new compound and can be isolated as a crystal. Generally, the reaction product is isolated and purified before being used in the next reaction step, but it is also possible to omit the isolation operation and use the reaction solution as it is in the next reaction. The crystal isolation method is to concentrate the reaction solution under reduced pressure, distill off acetic anhydride, add a solvent such as ethyl acetate to dissolve it, add dicyclohexylamine (hereinafter abbreviated as DCHA), and cool it to crystallize the DCHA salt. It precipitates as Optically active N-phthalimide-γ-cyanobutyric acid when recrystallized from methanol
White crystals of DCHA salt, melting point: 176.0-177.5℃, L
Obtain the specific optical rotation [α] ²⁰ _D -23.8° (C=5, MeOH). This DCHA salt is deamined using an ion exchange resin, etc., and the resulting crystals are recrystallized from water to obtain optically active α-phthalimide-γ-cyanobutyric acid (), melting point: 115.0-126.0°C, L-form. A white crystal with a specific optical rotation [α] ²⁰ _D -61.5° (C=1, MeOH) is obtained. The second step of the present invention is to reduce the nitrile () obtained in the first step to form an aldehyde (). That is, by dissolving the nitrile compound () in an organic solvent such as acetic acid or an aqueous solvent and subjecting it to catalytic reduction using a Raney-nickel catalyst in the presence of lead or lead ions, the desired optically active aldehyde compound ( ). As the reaction solvent, organic acids such as formic acid, acetic acid, and butyric acid and their aqueous solvents can be used, and if necessary, water-soluble organic solvents such as alcohol, dioxane, and tetrahydrofuran can be added. The appropriate amount of Raney nickel catalyst to be used is about 10 to 30% by weight based on the nitrile (). Although there are no particular restrictions on the reduction temperature and reduction hydrogen pressure, normal temperature and normal pressure are preferable. As a post-treatment method, after the completion of the reduction, the catalyst is removed, the liquid is extracted with an appropriate organic solvent such as chloroform or ethyl acetate, the organic solvent layer is dried, and the solvent is distilled off to obtain the aldehyde (). obtained as crystals. When this was recrystallized from acetic acid, a new compound, optically active α-phthalimide-γ-formylbutyric acid (), was obtained as white crystals, melting point: 129.0-132.0°C, specific optical rotation of L-form [α] ²⁰ _D -32.0° ( C=1, MeOH) is obtained. The aldehyde compound () may be isolated as a crystal and used in the next reaction, but it is also possible to use the reaction solution as it is in the next reaction without isolation, and from an operational standpoint. This is advantageous. In addition, the aldehyde (2,4-dinitrophenylhydrazone) and phenylhydrazone can also be isolated as crystals, and these hydrazones are all new compounds, and their structural formulas and physical properties are as follows. be.

[Formula] Melting point: 62-71℃ (decomposed) Specific rotation of L-form [α] ²⁰ _D -45.8゜ (C=1, CHCl ₃ )

[Formula] Melting point: 164.0-167.0゜Specific optical rotation of L form [α] ²⁰ _D -49.2゜ (C=2, DMF) The third step of the present invention is to add phenylhydrazone or its 4-substituted product to the aldehyde (). The purpose is to react the indole ring-closing reaction to obtain an optically active tryptophan derivative (). Phenylhydrazine or its 4-substituted product is added to the crystals of the aldehyde () obtained in the second step or the reaction solution, and an acid catalyst such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or a strongly acidic ion exchange resin is added to this. By adding a strong acid and heating, an indole ring closure reaction occurs,
The desired optically active tryptophan derivative is obtained. In addition, hydrazines are not only in free form, but also in
It can likewise be used in the form of mineral salts. The amount of phenylhydrazine added may be at least the equivalent molar amount, but is preferably about 1.0 to 1.5 times the molar amount. The amount of strong acid added is such that the acid concentration of the reaction solution is 0.5N or less, preferably about 0.1N,
As the reaction solvent, water, water-soluble solvents such as alcohol, dioxane acetate, and tetrahydrofuran, and mixed solvents thereof can be used. The reaction temperature can be carried out at any temperature below the boiling point of the reaction solvent, but from 60 to
Approximately 100℃ is desirable. This reaction process is divided into two steps. First, the reaction between the aldehyde () and the phenylhydrazines is completed, and the phenylhydrazone derivative is isolated. After that, the next indole ring-closing reaction is carried out to obtain the desired product. It is also possible to use an optically active tryptophan derivative (). The reaction product thus obtained is extracted with an organic solvent such as ethyl acetate or chloroform, and after drying the organic solvent layer, the desired optically active N-phthalyltryptophan derivative is obtained by subjecting it to an appropriate treatment. Obtained in good yield. In addition, in the method of the present invention, if L-N-phthaliglutamine is used as a raw material, all L-N-
It becomes a phthalyltryptophan derivative, and also D-N
-If phthalylglutamine is used as a raw material, all of the products will be DN-phthalyltryptophan derivatives. As described above, the method of the present invention is a method for synthetically producing an optically active tryptophan derivative using optically active glutamic acid or optically active phthalylglutamine, which is easily obtained from optically active glutamine, as a raw material, and which is inexpensive and easily available. This method does not require optical resolution, which was considered essential in conventional known methods, and is a new and useful method for producing tryptophans. Next, examples of the present invention will be described. Example 1 L-α-phthalimide-γ-cyanobutyric acid ()
Synthesis of 27.6 g (0.1 mol) of well-pulverized phthalyl-L-glutamine was added as crystals to 50 ml of acetic anhydride heated to 100°C, stirred at the same temperature for 1 hour, and concentrated under reduced pressure. When AcoEt was added to the residue and the solution was cooled, crystals were precipitated, so this was removed, and dicyclohexylamine was added to the solution and cooled, resulting in 29.4 g of L-α-
A dicyclohexylamine salt of phthalimido-γ-cyanobutyric acid is obtained. Recrystallization from MeOH gives white feather crystals with a yield of 66.9% and a melting point of 176.0-177.5°C, [α] ²⁰ _D -23.8° (C=5, MeOH). Elemental analysis value (%) C H N Calculated value 68.31 7.57 9.56 Analysis value 68.31 7.45 9.60 L-α-phthalimide-γ-cyanobutyric acid dicyclohexylamine salt 29.4 was dissolved in 300 ml of 75% MeOH, 1R120H type resin was added and left for 1 hour. . After removing the resin, the residue was concentrated to dryness to obtain 17.3 g of L-α-phthalimido-γ-cyanobutyric acid. Yield 66.9%,
When recrystallized from water, melting point: 115-126.0℃, [α]
²⁰ _D -61.5° (C=1, MeOH) white crystals are obtained. Elemental analysis value (%) C H N Calculated value 60.47 3.90 10.85 Analysis value 60.19 4.17 10.69 Example 2 (i) Synthesis of L-α-phthalimide-γ-formylbutyric acid () L-α-phthalimide-γ-cyanobutyric acid
Dissolve 25.8g (0.1mol) in 500ml of 25% AcOH,
Added 6g of Raney Nickel poisoned with 3% lead,
Catalytic reduction at room temperature and normal pressure. After absorbing 2.4% of hydrogen gas, reduction stopped and the catalyst left. liquid
Extracted with _CHCl3 . After drying ₃ layers of CHCl _{and 4} MgSO
After distilling off CHCl ₃ , an acetic acid solution containing 21.8 g of L-α-phthalimido-γ-formylbutyric acid is obtained. Yield: 83.5% Ether-n-hexane is added to crystallize. Melting point when recrystallized from acetic acid;
129.0~132.0℃, [α] ²⁰ _D -32.0゜(C=1,
Obtain white crystals of MeOH). Elemental analysis value (%) C H N Calculated value 59.77 3.86 5.36 Analytical value 59.59 4.32 5.40 (ii) Isolation of 2,4-dinitrophenylhydrazone L-α-phthalimide-γ-cyanobutyric acid
Reduction was carried out in the same manner as in (i) using 2.58 g (0.01 mol), 50 ml of 25% acetic acid, and 0.6 g of 3% lead-poisoned Raney nickel. Contains 2N hydrochloric acid 400
3.71g of L-α-phthalimide when added to ml
γ-formylbutyric acid-2,4-dinitrophenylhydrazone is obtained. Yield 84.1%, methanol-
Melting point when recrystallized from water: 164.0-167.0℃;
α] ²⁰ _D -49.2° (C=2, DMF) yellow crystals are obtained. Elemental analysis value (%) C H N Calculated value 51.71 3.43 15.87 Analytical value 51.51 3.50 15.71 (iii) Isolation of phenylhydrazone L-α-phthalimide-γ-cyanobutyric acid
2.58 g (0.01 mol) 50 ml of 25% acetic acid 0.6 g of 3% lead-poisoned Raney nickel was used for reduction in the same manner as in (i), and the catalyst-removed solution was dissolved in 15 ml of an aqueous solution containing 1.45 g of phenylhydrazine hydrochloride. In addition,
Extracted with _CHCl3 . After drying the CHCl ₃ layer with MgSO ₄ and concentrating to dryness, 2.40 g of L-α-phthalimide
Phenylhydrazone γ-formylbutyrate is obtained as an amorphous powder. Yield 68.3%, melting point: 62-71
°C (decomposition), [α] ²⁰ _D -45.8° (C = 1, CHCl ₃ ) Elemental analysis value (%) C H N Calculated value 64.95 4.88 11.96 Analysis value 64.10 4.77 12.03 Example 3 N-phthalyl-L-tryptophan Synthesis (i) Synthesis from L-α-phthalimide-γ-formylbutyric acid Phenylhydrazine hydrochloride 1.74g (0.012 mol)
L-α-phthalimide-γ-formylbutyric acid obtained in Example 2 in 50 ml of 0.2N hydrochloric acid methanol containing
Add an acetic acid solution containing 2.61 g (0.01 mol) and heat under reflux for 1 hour. After that, methanol was distilled off and extracted with ethyl acetate. The ethyl acetate layer was dried with _MgSO4 and then concentrated. Benzene:methanol=9:1
The mixture was subjected to column chromatography using silica gel as a solvent, and the distilled portion of the target product was concentrated to dryness to obtain 2.50 g of N-phthalyl-L-tryptophan. Yield 48.5%, melting point: 65~
70℃, [α] ²⁰ _D −263.0° (C=1, MeOH) Elemental analysis value (%) C H N Calculated value 68.26 4.22 8.38 Analysis value 67.88 4.01 8.27 (ii) Synthesis from phenylhydrazone In Example 2 Obtained L-α-phthalimide-γ-
3.51 g (0.01 mol) of phenylhydrazone formylbutyrate is heated under reflux for 1 hour in 100 ml of 0.1 hydrochloric acid.
Extract the reaction solution with ethyl acetate. Thereafter, the same treatment as in (i) is carried out to obtain 2.34 g of N-phthalyl-L-tryptophan. Yield 70.1%. Example 4 Synthesis of 5-benzyloxy-N-phthalyl-L-tryptophan 4-benzyloxyphenylhydrazine hydrochloride
An acetic acid solution containing 2.61 g (0.01 mol) of L-α-phthalimido-γ-formylbutyric acid obtained in Example 2 was added to 100 ml of methanol containing 3.01 g (0.012 mol), and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated to dryness, made into an ethyl acetate solution, the insoluble matter was removed, and the ethyl acetate layer was concentrated to dryness. The residue was subjected to column chromatography using silica gel using benzene:methanol=9:1 as a solvent, and the distilled portion of the target product was concentrated to dryness to give 2.48 g of 5-benzyloxy-N-phthalyl-
Obtain L-tryptophan. Yield 56.3%, melting point;
72-76℃, [α] ²⁰ _D -187.0゜ (C=1, MeOH) Elemental analysis value (%) C H N Calculated value 70.90 4.58 6.36 Analysis value 70.28 4.55 6.25

Claims (1)

[Claims] 1 Using optically active N-phthalylglutamine as a raw material, it is subjected to a dehydration reaction to form optically active α-phthalimide-γ-cyanobutyric acid, and then reduced to optically active α-phthalimide-γ-formylbutyric acid, and further 1. A method for producing an optically active tryptophan derivative, which comprises reacting with phenylhydrazine or 4-substituted phenylhydrazine to perform an indole ring closure reaction.