JPS6312499B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel nitrogen-containing monoterpene derivatives, particularly multimers thereof. Conventionally, many studies have been conducted on substances having a pyrindine skeleton, and various synthetic methods have been announced. However, the present inventors synthesized a new nitrogen-containing monoterpene derivative by substituting a nitrogen atom for an oxygen atom in the iridoid skeleton.

The present inventors first applied microorganisms, enzymes, chemical methods, etc. alone or in combination to the iridoid glycoside or its containing substance to form an aglycone, and then treated the iridoid glycoside with a primary amino group-containing substance. (Patent application 130131/1989)
No. 1) and a method for producing colored products using this pigment composition (Japanese Patent Application No. 158842/1982), but as a result of further research, the present inventors newly developed a method for producing colored products using this pigment composition. They found that a primary amino group is incorporated, clarified the mechanism and the structure of the product, and also investigated the use of these reaction products, leading to the completion of the present invention.

The aglycone part of the iridoid from which the sugar has been removed by hydrolysis is highly reactive, and when a compound containing a primary amino group is added to it, the oxygen atom is easily converted to the aglycone part by the nitrogen atom of the primary amino group. Replaced.
That is, it was found that, as an example, a nitrogen-containing six-membered ring as shown in formula [] is formed.

[However, in the formula, R ₁ is a primary amino group-containing compound residue, R ₂ is -CHO, -COOH and -COOR (R is an alkyl group), R ₃ is hydrogen and an alkyl group,
R ₄ is hydrogen, alkyl group, -CH ₂ OH and -CHO
is a group selected from the group consisting of, and R _A is -
a group selected from the group consisting of CHO, -COOH and -COOR; R _B is -CH ₃ , -CH ₂ OH and -CHO;
is a group selected from the group consisting of].

The substituents R ₁ to _{R 4} of the substance represented by the general formula () according to the present invention are the raw material iridoid compounds. (However, R _A and R _B are as defined above) and can be easily substituted depending on the type of primary amine to be incorporated and reaction conditions. The six-membered ring and the adjacent five-membered ring are highly reactive and useful as intermediates for the synthesis of various substances. i.e. especially C ₁ , C ₆ , C ₈
Since the reactivity is high at the positions and the substituents R ₃ and R ₄ on those carbons, it polymerizes into dimers, trimers, etc. at these positions. For example, by blocking oxygen during the reaction, polymerization occurs via the C ₁ , C ₆ , and C ₈ positions and the substituents R ₃ and R ₄ on those carbons, and examples include [ ] [ ] [ ] and [ ] It was found that dimers or trimers as shown in the figure are formed.

(However, if R ₄ in the above formula is alkyl, R′ ₄ represents a group in which only the terminal methyl group has been changed to a methylene group).

On the other hand, depending on the reaction conditions, polymers can be converted into low-molecular substances by bond cleavage, or can be repolymerized. For example, by heating the compound [] while blocking oxygen, the compound [], []
and [ ] are formed.

These substances exhibit a yellow to reddish-orange color, but
By subjecting these to oxidation reactions such as dehydrogenation,
Along with repolymerization, the conjugated system is extended and a substance colored from red to purple is formed. For example, when compounds [] and [] are oxidized in air in aqueous alcohol, blue-purple compounds [] and [] are obtained.

(However, in the above formula, if R ₄ is alkyl, R′ ₄ represents one in which only the terminal methyl group is changed to a methylene group, and R″ ₄ represents one in which only the terminal methyl group is changed to a methine group).

In addition, the reactivity of these series of compounds is largely influenced by the lone pair of nitrogen atoms present in the six-membered heterocycle, and various compounds can be created by controlling the lone pair of electrons. is possible.

That is, in the case of the general formula [ ], R ₁ can be adjusted to any desired form depending on the type of primary amine used, and R ₂ can be adjusted to any desired form depending on the raw materials used. Also R ₃ and
R ₄ can be in the form of hydrogen or an alkyl group by selecting the raw materials used and controlling the reaction conditions, and can also be made into the form of a dimer or trimer by polymerization. On the other hand, it is also possible to obtain various derivatives by chemically changing the produced substances. For example, oxidative polymerization is carried out by oxidation, and a colored substance is produced. Furthermore, various reducing substances can be obtained by selecting the reducing conditions. For example, the substances shown in the following formulas [] and [] can also be obtained by dissolving them in a solvent and performing catalytic reduction.

The colored substance obtained by oxidation has each substituent
Since R ₁ to _{R 4} are different, each color tone and physical and chemical properties are different, and a wide range of applications as dyes and pigments can be considered. Furthermore, by using the above-mentioned reaction, it becomes easy to detect substances containing primary amino groups.

Furthermore, it is possible to analyze the medicinal effects of iridoid substances, use them as blue proteins, and use them as synthetic intermediates. Up to now, various reports have been made regarding the pharmacological effects of pyridine derivatives, and therefore, the nitrogen-containing monoterpene derivative according to the present invention also shows that depending on the primary amine group-containing substance to be reacted and other conditions, the product may The expected pharmacological effects are fully expected.

As mentioned above, new uses can be easily developed by using this derivative.

Example (Reference example) A mixture of 452 mg of genipin and 201 mg of methylamine hydrochloride was dissolved in 40 ml of Matsukurbain's buffer (PH7.2):ethanol (1:1), and after stirring for 1 hour at room temperature in an open system. The solvent is removed under reduced pressure. The residue was extracted with benzene, and the benzene extract was washed with water, dehydrated, and the solvent was distilled off under reduced pressure to obtain 300 mg of a red syrupy residue. This residue was dissolved in 30 ml of benzene and extracted with 30 ml of 1N hydrochloric acid.Furthermore, 50 ml of 1N NaOH was added to this hydrochloric acid solution and extracted again with benzene. The benzene extract was washed with water, dehydrated, and the solvent was distilled off under reduced pressure to form a red syrupy residue.
Obtained 150mg. This residue was separated and purified by chromatography on a Sephadex LH20 (trade name) column using methanol as the developing solvent to obtain red needle-shaped crystals.
Got 30 mg.

This compound has the structural formula: Its properties are as follows.

mP (melting point): 125℃; PMR (proton NMR measurement diagram): see Figure 1-1; IR (infrared absorption diagram): see Figure 1:-2; UV (ultraviolet absorption diagram): see Figure 1- See 3; MAS (mass spectrometry main peak value): 203.

Example (Reference example) A mixture of 904 mg of genipin and 268 mg of methylamine hydrochloride was dissolved in 60 ml of Matsukurbain's buffer (PH 7.2):ethanol (1:1) and dissolved at 60 to 70 ml in a nitrogen stream.
After heating at °C for 2 hours, the solvent was distilled off under reduced pressure. The residue was extracted with chloroform, the extract was washed with water, dehydrated, and the solvent was distilled off under reduced pressure to obtain 400 mg of a red, syrupy residue. This residue was subjected to chromatography on a silica gel column using chloroform as a developing solvent. The chloroform eluates were combined and concentrated. 200 mg of the resulting residue was separated and purified by chromatography on a Sephadex LH20 column using methanol as a developing solvent to obtain 50 mg of red needles.

This compound has the structural formula: Its properties are as follows.

mP: 138℃; PMR: See Figure 2-1; CMR (C ¹³ nuclear magnetic resonance measurement): See Figure 2-2; IR: See Figure 2-3; UV: See Figure 2-4; MAS: 217.

Example: A mixture of 904 mg of genipin and 268 mg of methylamine hydrochloride was treated in the same manner as in the example and treated with Cephadex.
Separation and purification by chromatography was performed on an LH20 column using methanol as a developing solvent to obtain 40 mg of a red oily compound.

This compound has the structural formula: Its properties are as follows.

PMR: See Figure 3-1; IR: See Figure 3-2; MAS: 410.

Example (Reference example) A mixture of 900 mg of genipin and 450 mg of ethylamine hydrochloride was treated in the same manner as in the example to obtain 60 mg of red needle crystals.

This compound has the structural formula: Its properties are as follows.

PMR: See Figure 4-1 MAS: 231.

Example (Reference example) A mixture of 904 mg of genipin and 350 mg of glycine methyl ester hydrochloride was treated in the same manner as in the example to obtain 70 mg of a red oily compound.

This compound has the structural formula: Its properties are as follows.

PMR: See Figure 5-1; IR: See Figure 5-2; UV: See Figure 5-3; MAS: 275.

Example (Reference example) A mixture of 452 mg of genipin and 200 mg of aniline was treated in the same manner as in the example to obtain 30 mg of a yellow oily compound.

This compound has the structural formula: Its properties are as follows.

PMR: See Figure 6-1.

Example (Reference example) A mixture of 452 mg of genipin and 0.5 ml of 30% aqueous ammonia was treated in the same manner as in the example, and 80 mg of the compound in the form of colorless needles was obtained by the same purification method.

This compound has the structural formula: Its properties are as follows.

PMR: See Figure 7-1.

Example: A mixture of 452 mg of genipin and 134 mg of methylamine hydrochloride was dissolved in a mixture of 30 ml of Matsukulbane's buffer (PH 6.0) and ethanol (2:1) and heated at 60 to 70°C for 15 minutes while passing air through it. After that, the solvent was distilled off under reduced pressure, and the residue was extracted with chloroform.
After washing the chloroform extract with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 300 mg of a red syrupy residue. This residue was subjected to chromatography on a silica gel column using ether-methanol as a developing solvent. Ether:methanol = 85:15 The eluate was fractionated and the oily compound 80
I got mg.

This compound has the structural formula: Its properties are as follows.

PMR: See Figure 8-1; CMR: See Figure 8 2; IR: See Figure 8-3; UV: See Figure 8-4.

Example (Reference Example) 100 mg of the compound obtained in Example was dissolved in 30 ml of 50% methanol aqueous solution, heated at 60 to 70°C for 2 hours in a nitrogen stream, and then the solvent was distilled off under reduced pressure. The residue was extracted with chloroform, the chloroform extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 80 mg of a red syrupy residue. This residue was purified by chromatography on a silica gel column using chloroform as a developing solvent. The chloroform eluates were combined and concentrated. 60 mg of the resulting residue was separated and purified by chromatography on a Sephadex LH20 column using methanol as a developing solvent to obtain 15 mg of red needles. This substance is mixed, PMR,
As a result of comparison of IR and UV spectra, the compound obtained in the example, that is, the structural formula: It was confirmed that it was the same substance as the one.

Example: A mixture of 904 mg of genipin and 268 mg of methylamine hydrochloride was dissolved in 60 ml of Matsukurbain's buffer (PH7.2):ethanol (1:1) for 40 to 50 minutes in a nitrogen stream.
After stirring at °C for 1 hour, the solvent was distilled off under reduced pressure. The residue was extracted with chloroform, and the chloroform extract was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting red syrupy residue was purified by chromatography on a silica gel column using chloroform as a developing solvent. The chloroform eluates were combined and concentrated under reduced pressure. 250 mg of the resulting residue was chromatographed on a Sephadex LH20 column using methanol as a developing solvent. The eluate was concentrated under reduced pressure, and the resulting residue was purified by chromatography on an activated alumina (activity) column using chloroform as a developing solvent.
Red-orange oily compound 70 from chloroform eluate
I got mg.

This compound has the structural formula: Its properties are as follows.

PMR: See Figure 9-1; IR: See Figure 9-2; UV: See Figure 9-3; MAS: 404.

EXAMPLE
After standing for 24 hours, the mixture was concentrated under reduced pressure to obtain 70 mg of a blue-purple syrupy residue. This residue was purified by chromatography on an activated alumina (activity) column using chloroform as a developing solvent. Chloroform:
30 mg of a blue-purple syrupy compound was obtained from the methanol=90:10 eluate.

This compound has the structural formula: Its properties are as follows.

PMR: See Figure 10-1; IR: See Figure 10-2; UV: See Figure 10-3; VIS: (Visible absorption spectrum measurement): See Figure 10-4 Example XII Obtained by Example 100 mg of the obtained compound was dissolved in 30 ml of 50% aqueous methanol solution, heated in the air at 60 to 70°C for 2 hours, and then concentrated under reduced pressure to obtain 90 mg of a purple syrupy residue. This residue was purified by chromatography on an activated alumina (activity) column using chloroform as a developing solvent. Chloroform: methanol =
30 mg of a purple syrupy compound was obtained from the 95:5 eluate.

This compound has the structural formula: Its properties are as follows.

PMR: See Figure 11-1; IR: See Figure 11-2; UV: See Figure 11-3; VIS: See Figure 11-4; MAS: 402.

Example (Reference example) 50 mg of the compound obtained in the example was added to 10 ml of ethanol.
catalytic reduction was carried out over a platinum catalyst at room temperature for 19 hours under hydrogen flow. After separating the catalyst from the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was purified by chromatography on a silica gel column using chloroform as a developing solvent to obtain a colorless syrupy reduced product.
I got mg.

This compound has the structural formula: Its properties are as follows.

PMR: See Figure 12-1; IR: See Figure 12-2; MAS: 223.

[Brief explanation of the drawing]

The attached drawings show various properties of the novel nitrogen-containing monopentene derivative of the present invention, and Figures 1-1, 2 and 3 show the PMR, IR and
Figure 2 -1, -2, -3 and -4 show the PMR, CMR, IR and UV of the body obtained in the example.
Figure 3-1 and -2 show the body obtained in the example.
Figure 4-1 shows the PMR of the body obtained in the example, Figure 5-1, -2 and -3 show the PMR, IR and UV of the body obtained in the example. Figure 6-1 shows the PMR of the body obtained in the example, and Figure 7-
1 is the PMR of the body obtained in the example, Figure 8-1,
-2, -3 and -4 are the bodies obtained in the example.
PMR, CMR, IR and UV, Figure 9-1,-2
and -3 is the PMR, IR and
UV, Figure 10 -1, -2, -3 and -4 are examples
PMR, IR, UV and VIS of the body obtained in XI,
Figure 1-1, -2, -3 and -4 show the PMR, IR, UV and VIS of the body obtained in Example XII, and Figure 12 -1 and -2 show the PMR, IR, UV and VIS of the body obtained in Example PMR and IR are shown respectively.

Claims (1)

[Claims] 1. General formula or [In the formula, R ₁ is -CH ₃ ; R ₂ is -COOCH ₃ ; R ₃ is -H; R ₄ is a group selected from the group consisting of -CH ₃ or -CH ₂ OH] A dimer or trimer of a nitrogen-containing monoterpene derivative.