JPS61277690A - Pyridoxamine type pyridinophane compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1>-R<3> are H or acetyl). EXAMPLE:(S)-(-)-14-Hydroxy-15-aminomethyl-2, 8-dithia[9](2, 5)pyridinophaneS, S, S', S'-tetraoxide. USE:A synthetic reagent for optically active amino acids. PREPARATION:A compound expressed by formula II, e.g. (S)-(-)-15- aminomethyl-14-hydroxy-2, 8-dithia[9](2, 5)pyridin-ophane, is reacted with an acylating agent, e.g. acetic anhydride/pyridine, to give a novel compound expressed by formula III, which is then treated with an oxidizing agent, e.g. hydrogen peroxide and, as necessary, deacetylated. When the hydrogen peroxide is used, the reaction is carried out in the presence of a mixed solvent of dioxane and water and a catalyst, e.g. sodium tungstate-acetic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a pyridoxamine-type pyridinophane compound and a method for producing the same.

[Background of the invention]

In living organisms, many chiral compounds are synthesized from achiral precursors by the action of enzymes as asymmetric catalysts. Depending on the enzyme, the progress of the reaction may be carried out by a low-molecular coenzyme, but in all cases it is the role of the enzyme protein to provide an asymmetric reaction field and make the product optically active. If it were possible to design and prepare low-molecular-weight compounds that can perform functions similar to those of enzymes and use them for the asymmetric synthesis of useful substances, it would be possible to overcome the inherent instability of enzymes, the narrowness of optimal reaction conditions, and the strict It is considered to have extremely high utility value as an enzymatic chemical element free from substrate specificity.

By the way, pyridoxamine has α
- It is known that when treated with a keto acid, a transamination reaction of pyridoxamine to the keto acid occurs, producing pyridoxal and an α-amino acid. Although this reaction is noteworthy in the production of amino acids, since the amino acids produced are racemic, it cannot be used as is as a method for producing generally needed optically active amino acids.

Therefore, the present inventors first conducted research on compounds that can directly provide optically active amino acids based on this transamination reaction, and incorporated the basic skeleton of pyridoxamine (pyridine ring, aminomethyl group, phenolic hydroxyl group). optically active pyridoxamine-type pyridinophane compounds (
1) and found that the compound could achieve the above object (see Japanese Patent Publication No. 55-42077).

The present inventors conducted extensive research in order to further improve the optical yield of the transamination reaction using the above compound (1). As a result of analysis of the reaction mechanism, it was concluded that the optical yield of the product could be increased by further increasing the steric hindrance caused by the S atom of compound (1) and its surroundings. Therefore, we synthesized compound (5) in which the S atom of compound (1) was selectively oxidized to sulfone, and discovered that this compound could further improve the optical yield of transamination reaction, and completed the present invention. It's arrived.

[Purpose of the invention]

An object of the present invention is to provide a novel pyridoxamine-type pyridinophane compound and a method for producing the same.

[Structure of the invention]

The present invention is a pyridoxamine-type pyridinophane compound represented by the following formula.

CH2NR'R2 In the formula, R' 1R2 and R3 independently represent a hydrogen atom or an acetyl group. The above compound is, for example, a compound of the formula (1
) The compound (1) represented by CH2N H2 is acetylated to form the formula (2
) It can be synthesized by obtaining a compound (2) represented by the following formula, treating it with an oxidizing agent, and then deacetylating it if necessary.

Specific examples of the above compounds include the following.

014-acetoxy-15(diacetylamino)methyl-2,8-dithiaC9'] (2,5) Pyridinophane s, s, s', s'-tetraoxide [Compound (3)
co014-hydroxy-15(acetylamino)methyl-
2,゛8-dithia[9m (2,5)pyridinophane s, s, s', s'-tetraoxide [compound (4)] 014-hydroxy, -15-aminomethyl-2゜8-
Dithia [9] (2,5) pyridinophane s, s, s
',s'-Tetraoxide [Compound (5)] The starting material (1) for synthesizing the compound of the present invention can be produced, for example, by the method described in Japanese Patent Publication No. 55-42077.

The hydroxyl group and amino group of compound (1,) are acetylated with an acetylating agent such as acetic anhydride/pyridine to form compound (2).
). This acetyl compound (2) is treated with an oxidizing agent to obtain a disulfone compound (3).

Oxidizing agents include hydrogen peroxide, organic peracids such as perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, performic acid, peroxoacids such as peroxonitric acid, peroxo(-
) phosphoric acid, peroxoniphosphoric acid, peroxo(-)sulfuric acid, peroxonisulfuric acid, etc. can be used.

When using hydrogen peroxide, for example dioxane/
The acetyl compound (2) is dissolved in a water mixed solvent or the like, and an aqueous hydrogen peroxide solution is added dropwise to react in the presence of a small amount of a catalyst such as sodium tungstate and acetic acid. Reaction temperature is 60℃
A temperature of ~90°C and a reaction time of about 3 to 8 hours are appropriate.

When m-chloroperbenzoic acid is used, the acetyl compound (2) is dissolved in, for example, chloroform or ethanol, and a solution of m-chloroperbenzoic acid in the same solvent is added dropwise to react. m-chloroperbenzoic acid was added dropwise at 0°C to 20°C, and after the dropwise addition was completed, the mixture was heated at 20°C to 30°C for about 10 to 30 hours.
Just stir.

When using hydrogen peroxide, the hydroxy-monoacetylamino compound (4) is obtained, and when m-chloroperbenzoic acid/chloroform is used, the pentaoxide compound (6) [14-acetoxy-1
5(Diacetylamino)methyl-2,8 Nidithia [9]
(2,5) Pyridinophane N, S, S, S', S'
-pentoxide] are produced as by-products.

When the thus obtained compound (3) or (4) or a mixture of compounds (3) and (4) is treated with, for example, hydrochloric acid, the deacetylated compound (5) is obtained. Similarly, deacetylation of pentaoxide compound (6) yields compound (7).
[3,4-hydroxy-15-aminomethyl-2,8-
Dithia[9](2,5)pyridinophane N, S, S, S
'.

S'-pentaoxide] is obtained.

The above compounds (2), (3), (4), (5), (6) and (7) synthesized by the method of the present invention are new compounds.

The novel pyridoxamine-type pyridinophane compound (5) of the present invention is important as a reagent for the synthesis of optically active amino acids.

That is, for example, a levorotatory or dextrorotatory pyridoxamine type pyridinophane compound (5) is reacted with α-keto acid sodium salt and zinc perchlorate in dry methanol or acetonitrile at room temperature, and then after acid hydrolysis,
Optically active amino acids can be obtained in good yield by isolating the product by organic solvent extraction and ion exchange chromatography. Furthermore, when the levorotatory pyridoxamine-type pyridinophane compound (5) is used, dextro-rotatory amino acids are predominantly produced, and when the dextro-rotatory pyridoxamine-type pyridinophane compound (5) is used, levorotatory amino acids are predominantly produced. At this time, an optically active pyridoxal-type pyridinophane compound (8) [14-hydroxy-15-formyl-2,8-
Dithia [9(2,5)pyridinophanes, s, s',
s'-tetraoxytoco is produced, which can be recovered in good yield and used again in the production of pyridoxamine-type pyridinophane compound (5).

The present invention will be explained in detail below using examples.

Example 1 2.53 g of (S)-(-)-15-aminomethyl-14-hydroxy-2,8-dithia [9] (2,5) pyridinophane (1) was mixed with 25 ml of pyridine and 25 ml of acetic anhydride.
m1 and heated to 100° C. for 16 hours with stirring. Concentrate as much as possible under reduced pressure at 70°C and add ice water. Extract with ethyl acetate, wash with aqueous sodium bicarbonate solution and water, dry (anhydrous magnesium sulfate), and concentrate. The residue was purified with a silica gel chromatography column (eluent: chloroform-methanol 100:1) to give (S)-(-)-14
-acetoxy-15-(diacetylamino)methyl-2
, 8-dithia[9] (2,5)pyridinophane [compound (S)-(-)-(2)] is obtained.

[Properties of compound (S)-(-)-(2)] mp 14
'? -8℃ Yield 3.18g (87%) [α
o" 42.6 ° (C0,384,
CHCt, )UVma, (C)IC13) 289n
m (C4,OX 10')IR1780 (ester)
, 1710.1690 cm-' (7 mido) Example 2 3.08 g of compound (S)-(-)-(2) was dissolved in a mixture of 60 ml of dioxane and 30 ml of water, and about 5 ml of sodium tungstate dihydrate was dissolved. Add 50 μl of acetic acid and heat to 60-65°C, and add 30% hydrogen peroxide aqueous solution 3.
．． 80-85 after dropping 8ml over 30 minutes while stirring
Heat to ℃ for 6 hours. After cooling, add 5% hydrogen sulfite) I
Excess hydrogen peroxide is decomposed by adding an aqueous solution of hydrogen peroxide, and extracted with chloroform. After drying (anhydrous magnesium sulfate), concentrate and perform silica gel column chromatography. (S)-(-)-14- with chloroform-methanol (50:1)
Acedoxy-15-(diacetylamino)methyl-2,
8-dithia[9] (2,5)pyridinophane s, s
, s', s'-tetraoxide [compound (S)-(-)
-(3)], then (S)-(-)-15-(acetylamino)methyl-14-hydroxy-2,8-dithia[9
] (2,5) pyridinophane s, s, s', s'-
Tetraoxide, [compound (S)-(-)-(4)] is eluted.

[Properties of compound (S)-(-)-(3)] mp 20
4-5°C Yield 1.19. g (33%) [α co,
” -78° (C0,363, CHCl3
)UVmax (CHCl3) 282nm Cε
4.2 X 103) 1, R1790 (ester), 1
710.1690cm-' (amide) [Properties of compound (S)-(-)-(4)] mp 26
6-7°C (decomposition) Yield 0.89 g (30%) [α]. ”-168° (C0,321, pyridine) I
R3400 (amide), 1650C[O-' (amide) Example 3 1.15 g of compound (S)-(-)-(3) was added to a mixture of 10 ml of ethanol, 5 ml of water, and 5 ml of concentrated hydrochloric acid, and refluxed for 3 hours. do. After treatment with activated carbon and concentration, and adding ethanol to the residue, 15-aminomethyl-14-hydroxy-2,8-dithia[9(2°5)pyridinophanes]
, s, s', s'-tetraoxide [compound (S)-(
-)-(5)] monohydrochloride is precipitated.

[Properties of monohydrochloride of compound (S)-(-)-(5)] mp>280°C Yield 0.80g (74%).

[α]. 2'-317° (Co, 293, H2O)
UV'+aax (H2O) 333nm (E
3.7 X 10'), 301 nm (C4, lX10
3), 2'55nm (C3,7x103) Monohydrochloride of compound (S) -(-)-(5) 0,7
1? g was dissolved in 15 ml of water, 0.164 g of sodium hydrogen carbonate was added as a solid, stirred at room temperature for 30 minutes, and the precipitate of compound (S)-(-)-(5) was filtered off.

[Properties of compound (S> -(-)-(5))] mp196
-9℃ decomposition Yield 0.613 g (96%) [α], +9-352° (C0,241, pyridine)
UV, <Dioxane) 300 nm (C2,9x Example 4 10 ml of ethanol. Add 0.85 g of compound (S)-(-)-(4) to 5 ml of water and 5 ml of concentrated hydrochloric acid and reflux for 3 hours. Below The treatment was carried out in the same manner as in Example 3, and the compound (]
-(-) -(5) is obtained. Yield: 0.71 g (85%) Example 5 Racemic form of compound (1) 10. OOg to pyridine 10
Example 1
The same treatment as above is carried out to quantitatively obtain the racemate of compound (2).

[Properties of racemic form of compound (2)] m, p, 127-8°C Yield: 14.37 g Example 6 Racemic form 2. of compound (2) was added to 100 ml of chloroform.
OOg is dissolved and a solution of 7.50 g (7.5 equivalents based on 85% content) of m-chloroperbenzoic acid in 75 ml of chloroform is added with stirring over a period of 1 hour at 5-10° C., water-cooled. A precipitate separates out during the process. After stirring at the same temperature for 1 hour, the mixture was stirred at room temperature overnight to completely dissolve the precipitate. Excess m-chloroperbenzoic acid is decomposed with a 5% aqueous solution of hydrogen sulfite, and an aqueous sodium bicarbonate solution is added to extract the chloroform layer. The chloroform layer is washed with water, dried and concentrated. The residue is purified on a silica gel column [eluent chloroform-ethanol (100:1):I.

The racemate of compound (3) elutes first, then 14-
Acetoxy-15(diacetylamino)methyl-2,8
-dithia[9] (2,5)pyridinophane N, S,
The racemic form of S,S',S'-pentaoxide (6) is eluted.

[Properties of racemic compound (3)] ml 202-4°C Yield 0.95 g (41%) [
Properties of racemic compound (6)] mp 201-2°C (decomposition) Yield 0.97 g (41%
) UVma, 1(C)IC13) 287nm (εI
L, 9
0 g was dissolved, and a mixture of 7.5 g of m-chloroperbenzoic acid and 75 ml of ethanol was added over 1 hour at around 15° C. with stirring. A precipitate was deposited during the dropwise addition, and the precipitate hardly dissolved even after stirring overnight at room temperature. Excess m-chloroperbenzoic acid is decomposed with an aqueous sodium bisulfite solution, and extracted with a chloroform-aqueous sodium bicarbonate solution. Wash the chloroform with water, dry and concentrate. The residue was purified using a silica gel column and the eluent was chloroform-methanol 100:
1) Obtain the racemic compound (3).

Yield 1.71 g (74%) Example 8 1.92 g of racemic compound (6) was dissolved in 20 g of ethanol.
ml, 3 ml with stirring in 10 ml of water and 10 ml of concentrated hydrochloric acid.
Reflux for an hour. Treat with activated carbon and concentrate.

Add water and adjust pH to 3 with sodium hydroxide aqueous solution to 15
-aminomethyl-14-hydroxy-2,8-dithia [
9 pieces (2,5) pyridinophane N, S.

The racemic form of s, s', s'--pentaoxide (7) is precipitated and filtered off.

[Properties of racemic compound (7)] mp>280°C Yield 1.38g (97%) LIV,
, (IM HCI) 327nm (E4.8
10″), 276nm (ε9.Oxl 03), 24
0 nm (ε23.7×103) Example 9 The racemic form of compound (3) is treated in the same manner as in Example 3 to obtain the racemic form of compound (5) and its monohydrochloride.

[Properties of racemic compound (5)/HCI 3180℃
It gradually melts from the vicinity and begins to decompose around 190℃, ~
Decomposition ends at 212°C.

Yield: 80% [Properties of racemic compound (5) 3: Dissolution begins gradually at around 150°C, decomposition begins at around 175°C, and decomposition ends at 202°C.

Yield: Almost 100%

Claims (3)

[Claims] (1) A pyridoxamine-type pyridinophane compound represented by the following general formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R^1, R^2 and R^3 independently represent a hydrogen atom or an acetyl group. (2) Formula (1) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (1) By acetylating the compound (1) represented by formula (2) ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼(2) The compound (2) represented by the following general formula is obtained, which is treated with an oxidizing agent and then deacetylated if necessary. A method for producing a pyridoxamine-type pyridinophane compound. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ In the above formula, R^1, R^2 and R^3 independently represent a hydrogen atom or an acetyl group. (3) The method according to claim 2, wherein the oxidizing agent is hydrogen peroxide or a peracid.