JPH069308A - Production of synthetic capsaicin and its microcapsule agent in the same reactor - Google Patents

Abstract

PURPOSE:To produce a microcapsule agent without harming operators by synthesizing a capsaicin by using a raw material having slight irritation as a starting substance and successively forming microcapsules in the same reactor. CONSTITUTION:A compound of formula I (R is 4-12C alkyl, alkenyl or alkynyl; Hal is halogen) is condensed with vanillylamine or its salt in a mixed solvent of water and an organic solvent in the ratio of 10:1-1:10, preferably 2:1-1:5 at 10-50 deg.C optionally in the presence of an acid binder to give a capsaicin of formula II. Then, in the same reacter, the capsaicin is decolored optionally by adding a reducing agent to the reaction solution, the compound of formula II is dispersed into water and made into microcapsules of oil-in-water type and the capsaicin having strong irritation is sealed in the microcapsules to give the microcapsule agent hardly having initation.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention treats cable coating materials for power, communication, signals, etc., packaging materials, equipment, structures of buildings, trees, etc. to prevent feeding damage and biting damage by animals. The present invention relates to a method for producing capsaicins and microcapsule formulations thereof, which are expected to be used in various fields such as an agent and a patch having a longer lasting effect.

[0002]

2. Description of the Related Art As described above, capsaicins have strong irritation and pungency, and therefore they are extremely difficult not only during synthesis but also during handling, such as taking out, weighing, and packaging after synthesis, during production. Moreover, great care was required when processing various products. For example, it is described in the literature that the synthesis of capsaicins was carried out in a completely closed system (Hiroo Ueda: Fragrance Nos. 129, 41 to 4).
6, October 1980).

[0003]

Although capsaicins have been found to be useful as repellents for animals such as patches and rats, they require extremely careful handling due to their strong irritation. Therefore, in industrial production, a considerable amount of equipment, especially in terms of safety and hygiene, is required, and the operation is inevitably complicated.
In view of such a point, the present invention originates from a raw material with low irritation, is manufactured without giving a worker involved in the production a chance to contact the highly stimulative capsaicins, and is already low in irritation when taken out as a product. The problem was to make it into a pharmaceutical form.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the inventors have produced capsaicins using a raw material having a low stimulative property and directly used the raw materials necessary for microencapsulation in this reaction. The present invention succeeded in producing a microcapsule of a hypoallergenic capsaicin in a single bath without throwing it into a container and directly touching the highly stimulant drug substance of the capsaicin, and reached the present invention. That is, equation (1)

[0005]

[Chemical 3] (In the formula, R represents a C _{4 to} C ₁₂ alkyl group, an alkenyl group or an alkynyl group.) The capsaicins represented by the formula (2)

[0006]

[Chemical 4] (Wherein, R represents C ₄ -C ₁₂ alkyl group, an alkenyl group or an alkynyl group, Hal represents a halogen atom.) Of water and an organic solvent vanillyl amine or a salt thereof of a compound represented by the 10: 1 to 1:10 10 to 50 ° C. in a mixed solvent of 10:
Then, if necessary, a condensation agent is obtained in the presence of an acid binder, and then a reducing agent is optionally added to the reaction solution, and raw materials necessary for microencapsulation such as an encapsulating agent are directly added to the reaction bath. When the oil-in-water microcapsules are added to produce microcapsules of capsaicin type, it is safe for the manufacturing operator and extremely easy to handle.

As the solvent used in the condensation reaction, water and aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, heptane and petroleum benzine, halogenated hydrocarbons such as chloroform and dichloromethane, diethyl ether, Mixtures of ethers such as diisopropyl ether and a solvent such as a phthalic acid ester, an adipic acid ester, a phosphoric acid ester or a maleic acid ester, which is mainly used as a plasticizer for resins, may be mentioned. Is usually 10: 1 to 1:10, and preferably 2: 1 to 1: 5. An acid binder is not required when vanillylamine is used in an amount of 2 equivalents or more based on the compound of formula (2), but when vanillylamine is used in an equivalent amount, 1 equivalent or more of the acid binder is added to the hydrochloride of vanillylamine, odor, etc. When a hydrohalide or other salt is used, the salt is removed and condensed with the compound of formula (2), and in order to complete the reaction, 2 equivalents or more of one or more acid bonds with respect to the salt are used. Need an agent. Examples of acid binders include bases such as alkali metal hydroxides (NaOH, KOH, etc.)
, Alkaline earth metal hydroxides (Ca (OH) ₂ , Mg (OH) _2, etc.),
Alkali metal hydrides (NaH, etc.), Alkali metal alcoholates (NaOC ₂ H _5, etc.), Alkali metal oxides (Na ₂ O, K ₂ O)
Etc.), alkali metal carbonates (K ₂ CO ₃ , Na ₂ CO _3, etc.), sodium amide, triethylamine, N, N-dialkylanilines, aliphatic and aromatic tertiary amines such as pyridine, and the like. Also, silver oxide can be used. Further, it is also possible to use a phase transfer catalyst represented by tetra-n-butylammonium, triethylbenzylammonium chloride or the like. The condensation reaction is usually at room temperature to
It can be carried out at the temperature of the boiling point of the solvent.

The compound of formula (1) may be colored when vanillylamine of low purity is used as a raw material,
As a result, the product using this microcapsule will be colored and its commercial value will be reduced. Therefore, it is preferable to decolorize by adding a reducing agent such as hydrosulfite, sodium sulfite, and hydrazine directly or by dissolving in water before microencapsulation. The raw material represented by the compound of formula (2) may be purchased as a reagent,
formula

[0009]

[Chemical 5] (Wherein, R C ₄ -C ₁₂ alkyl group, an alkenyl group or alkynyl group.) A condensation in a solvent for example an excess of thionyl like the compound optionally represented by chloride, phosphorus trichloride, tribromide It can be easily obtained by reacting with phosphorus oxide or the like. Therefore, according to the present invention, three steps of producing a compound of the formula (2) by using the compound of the formula (3) as a starting material, then performing a condensation reaction to produce the compound of the formula (1), and finally microcapsulating Can also be done in one bath.

Examples of the capsaicins of the formula (1) of the present invention include N- (4-hydroxy-3-methoxybenzyl) -8-methylnon-trans-6-enamide (capsine) and N- (4-hydroxy-3). -Methoxybenzyl) -8-methylnonanamide (dihydrocapsaicin), N- (4-hydroxy-3-methoxybenzyl)
-7-Methyl octanamide (nordihydrocapsaicin), N- (4-hydroxy-3-methoxybenzyl)
-9-Methyldecanamid (homodihydrocapsaicin), N- (4-hydroxy-3-methoxybenzyl)
Examples thereof include -9-methyldecoutrans-7-enamide (homocapsaicin) and N- (4-hydroxy-3-methoxybenzyl) -nonanamide. After obtaining the crude capsaicins in the solvent in this way, microencapsulation is performed as it is in the reactor, but if necessary, after adding a water-insoluble or sparingly soluble solvent to the reactor and stirring for a while Microcapsulation is performed after adding a purification operation to remove the aqueous layer, or the residue obtained by distilling off the solvent used in the reaction by vacuum distillation etc. before encapsulation is microcapsulated and is irritating. A microcapsule of capsaicins containing almost no irritant is obtained by encapsulating strong capsaicins in capsules.

The reaction vessel used in the present invention has a stirrer whose rotation speed is variable from low speed to high speed in order to carry out synthesis to microencapsulation in one bath, and the contents can be heated by a jacket, throwing heater, etc. It is necessary to have an outlet with a stopper at the bottom. Further, in some cases, vacuum distillation is required, so that a reaction bath capable of vacuum distillation is convenient. In the production of the capsaicin drug substance, when a solvent having a higher specific gravity than water is used and the product is washed with water in the post-treatment, the target substance comes to the lower layer. For this reason, it is desirable to put a storage tank for the object connected to the outlet. Then, after discharging the aqueous layer, the target product may be returned from the storage tank to the reaction kettle again to perform the microencapsulation process. Of course, these series of operations are performed in a closed system. In this encapsulation, it is necessary to thoroughly consider the encapsulation conditions in order to effectively encapsulate most of the capsaicins, and not only one-stage encapsulation but also multi-stage encapsulation in some cases. It can also be manufactured by the method. The average particle size of the microcapsules may be selected in consideration of encapsulation conditions and the like, and the optimum size for the application may be selected. The microencapsulation of the present invention is an interfacial polymerization method in which water-insoluble or sparingly-soluble capsaicins are dispersed in water and a core substance containing capsaicins and a water-insoluble polymer film are described on the surface of the dispersed particles. It depends on a method of forming by an oil-in-water polymerization method such as an in-situ polymerization method or an in-situ polymerization method, but is not limited to these two methods as long as it is an oil-in-water polymerization method.

The case of the interfacial polymerization method will be described. The oil-soluble film agent A is dissolved in the synthesized hydrophobic core substance containing capsaicins, water and an auxiliary substance such as a dispersant are added thereto, and the mixture is stirred under predetermined stirring conditions. A system in which a solution of the oil-soluble film agent A is dispersed with a desired particle size is prepared. While stirring this system, an aqueous solution of the water-soluble film agent B was added, and both film agents were reacted at the interface of the dispersed particles to form a polymer film insoluble in both the core substance and water, thereby encapsulating the hydrophobic core substance. To obtain a microcapsule (1 step encapsulation method). In order to obtain a microcapsule containing less free capsaicins, the following multistage encapsulation can be performed. That is, it is difficult to be compatible with water in a system that has been once microencapsulated, and a solution in which the oil-soluble film agent C is dissolved in a solvent having a high solubility for capsaicins is added as it is or after being dispersed in water in advance, under predetermined stirring conditions. And the water-soluble film agent D is reacted under the temperature conditions to form a polymer film again at the interface of the dispersed particles (two-stage encapsulation method). By repeating this operation in multiple stages, the free capsaicins are efficiently incorporated into the solvent that serves as the core substance to produce microcapsules containing very little free capsaicin (multistage encapsulation method). The oil-soluble film agent A used here may be the same as C, and the water-soluble film agent B may be the same as or different from D, and examples thereof include the following.

Examples of the oil-soluble film agent include polyvalent isocyanate, polyvalent carboxylic acid chloride, polyvalent sulfonic acid chloride, etc., such as hexamethylene diisocyanate, trimethylhexamethylene diisocyanate, isophorone diisocyanate, phenylene diisocyanate, toluene diisocyanate, xylylene diisocyanate, Naphthalene diisocyanate, polymethylene polyphenyl isocyanate, sebacic acid dichloride, adipic acid dichloride, azelaic acid dichloride, terephthalic acid dichloride, trimesic acid dichloride, benzenesulfonyl dichloride, etc.On the other hand, as water-soluble film material, polyvalent amine, polyvalent hydroxy compound Etc., such as ethylenediamine, hexamethylenediamine, phenylenediamine, diethylenetri Min, triethylenetetramine,
Examples include piperazine, ethylene glycol, butanediol, hexanediol, polyethylene glycol and the like.

The in situ polymerization method will be described. In situ
In the polymerization method, the membrane material is dissolved in either the hydrophobic core substance containing the active ingredient or the aqueous phase, the hydrophobic core substance is dispersed in the aqueous phase, and both the core substance and the aqueous phase are dispersed at the interface of the dispersed particles. This is a method for producing microcapsules by forming a polymer film insoluble in, and is different from the interfacial polymerization method. In the case of the method of the present invention, after preparing a suspension of microcapsules of capsaicins once synthesized in the aqueous phase by this polymerization method (one-step encapsulation method), the solubility of capsaicins in this system is high. After dispersing a hydrophobic core substance in which the oil-soluble film material E is dissolved in a solvent that is difficult to be compatible with water, or a solvent having high solubility of capsaicins and hardly compatible with water, The water-soluble film material F is added to the system as it is or after being dissolved in water to form a polymer film insoluble in both the core substance and the aqueous phase at the interface of the dispersed particles (two-stage encapsulation method). By repeating this operation in multiple stages, the free active ingredient is efficiently taken into the solvent that serves as the core substance to produce microcapsules with less free capsaicin (multistage encapsulation method). Examples of the film materials E and F include the following. As the oil-soluble film material E, acrylic acid ester, methacrylic acid ester, vinyl acetate, styrene, divinylbenzene,
It is preferable to use a radical-polymerized material such as ethylene dimethacrylate or the like, and as the water-soluble film material F, it is preferable to form a capsule film by a polyaddition reaction of urea / formalin, melamine / formalin, phenol / formalin and the like.

The type and amount of the membrane material used in the method of the present invention are selected depending on the type of the core substance and the purpose of use of the microcapsule. Further, in the method of the present invention, the interfacial polymerization method and the in situ polymerization method may be combined to form a multi-stage encapsulation. Also, when solid microcapsules such as powder are required for some purposes, the produced microcapsules in suspension are dried with a spray dryer or a multi-stage hot air dryer to easily evaporate water and volatilize. When the solvent is contained in a capsule, the solvent can be removed to obtain a dried preparation.

Next, a dispersant for dispersing the hydrophobic core substance in the aqueous phase is essential as an auxiliary agent used in the encapsulation of Mackuro. Specifically, gum arabic and sodium alginate are used. , Natural saccharides such as locust bean gum and xanthan sun gum, semi-synthetic polysaccharides such as carboxymethyl cellulose and methyl cellulose, synthetic polymers such as polyvinyl alcohol, etc., or suspensions at the time of microencapsulation of two or more species. It is usually 0.01 to 10.0%, preferably 0.1 to 3.
Use 0%. If necessary, polyoxyethylene alkyl ether, polyoxyethylene alkyl allyl ether, alkylphenyl condensate ether, polyoxyethylene alkyl ester, polyoxyethylene alkylamino ether, polyoxyethylene alkylamide, polyoxyethylene polyoxypropylene. One or more surfactants such as block polymers, polyoxyethylene vegetable oil ethers, sorbitan fatty acid esters and polyoxyethylene sorbitan fatty acid esters are usually used in an amount of 10% or less, preferably 3% or less. Also,
When a capsaicin is dissolved in a solvent to form a capsule core substance, for example, butyl ether, ethers such as ethyl vinyl ether, heptane, aliphatic such as xylene,
Aromatic hydrocarbons, halogenated hydrocarbons such as dichloromethane and trichloroethane, mineral oils such as machine oils, vegetable oils, phthalates, adipates, phosphates, maleates, low molecular weight epoxy compounds, etc. 1 such as solvents mainly used as plasticizers for resins
One or more solvents are used. As other auxiliaries, antifungal agents, specific gravity adjusting agents and, depending on the active ingredients, decomposition inhibitors, pH adjusting agents and the like can be added to the core substance and / or the aqueous phase.

[0017]

Industrial Applicability As a result of the production of capsaicins according to the present invention, capsaicins having a strong stimulating property even in a small amount are synthesized from raw materials having almost no irritating property, and microcapsules containing very few free capsaicins in the same bath. It was possible to obtain a drug product which is safe and easy to handle with less irritation without being directly touched by the workers involved in the process.

[0018]

The present invention will be described below with reference to examples (parts represent parts by weight). Example 1 58.27 g of 4-hydroxy-3-methoxybenzylamine hydrochloride (content 97.63%) and 225 m of water under a nitrogen atmosphere.
l and 210 ml of toluene are put into a reactor having a three-one motor with a variable rotation speed and a discharge port with a stopper at the bottom and stirred. 2% of 30% potassium carbonate aqueous solution
Add 16 g and stir. Further, 54.81 g of n-nonanoic acid chloride (content 96.7%) is added dropwise at 10 to 15 ° C over 1 hour. The reaction is completed by raising the reaction temperature to 45 ° C. and further stirring for 2 hours. The initial water of the reaction is allowed to stand for liquid separation from the bottom of the reactor, subsequently 120 ml of 10% sodium carbonate aqueous solution is added for washing, and liquid separation is carried out in the same manner as the initial water. Then, it is washed with 120 ml of a 5% aqueous sodium hydrosulfite solution and separated.
Then, it is washed with 120 ml of a 1% hydrochloric acid aqueous solution and separated. Further, it is washed with 120 ml of water and separated. Then, the solvent is almost completely removed by distillation under reduced pressure to give N- (4-hydroxy-3-).
Methoxybenzyl) -nonanamide crude product 89.67
g can be obtained. (A very small amount was collected and the purity of the product was determined by high performance liquid chromatography (hereinafter referred to as HPLC) to be 96.2%, and the pure yield from the amine compound was 98.0%.)

Further, 643 g of dioctyl phthalate and 86 g of Millionate MR-400 (manufactured by Nippon Polyurethane Co.)
1% polyvinyl alcohol aqueous solution 2
Add 600g, dispersion temperature 25 ℃, rotation speed 650rp
m for 10 minutes and dispersed to prepare an O / W type emulsion. On the other hand, 22 g each of ethylenediamine and diethylenetriamine were dissolved in 820 g of water and added dropwise to the above emulsion while stirring at a rotation speed of 250 rpm, and the reaction was continued at 60 ° C. for 3 hours to suspend microcapsules of polyurea film in water (average). A particle size of 49 μm) was prepared, dried with a spray drier to remove water, and a microcapsule containing 10% nonyl acid vanillyl amide was obtained.

Example 2 Using the same container as in Example 1, under a nitrogen atmosphere, 4-hydroxy-3-methoxybenzylamine hydrochloride (content 97.6) was used.
3%) 58.27 g, water 180 ml, cyclohexane 21
Add 0 ml and stir. 162 g of 40% potassium carbonate aqueous solution is added thereto and stirred. Furthermore, 8-methylnon-trans-6-enoic acid chloride (content 95.5%) 63.6
8 g is added dropwise at 20 to 25 ° C. over 1 hour. Temperature 3
The reaction is completed by raising the temperature to 5 ° C. and stirring for 3 hours.
The initial water of the reaction is allowed to stand still for liquid separation from the bottom of the reactor, followed by washing with 120 ml of a 3% sodium sulfite aqueous solution for liquid separation. Then 1%
Wash with 120 ml of hydrochloric acid aqueous solution and separate. 120 ml of water
Wash and separate with. Then, the solvent is almost completely removed by distillation under reduced pressure to obtain 97.24 g of a crude product of (E) -N (4-hydroxy-3-methoxybenzyl) -8-methylnon-6-enamide. (The purity of this product is HPLC
Is 95.7%, and the net yield is 97.1% from the amine compound.
Becomes )

Further, 630 g of dioctyl adipate was added, to which was added 1950 g of a 3% aqueous solution of styrene maleic anhydride resin prepared with a small amount of sodium hydroxide and having a pH of 4.5, and the dispersion liquid was rotated at 85 ° C. and rotated. Number fifty
The mixture was treated at 0 rpm for 30 minutes to prepare an O / W type emulsion. On the other hand, 480 g of a 50% aqueous solution of an aqueous solution of melamine formalin prepolymer “SUMIREZ RESIN 613” (trade name, manufactured by Sumitomo Chemical Co., Ltd.) was added to the above emulsion at a rotation speed of 3
The mixture was added dropwise with stirring at 00 rpm, and stirring was continued at 70 ° C. for 3 hours to prepare microcapsules of melamine resin film suspended in water. The particle size of this microcapsule is 5 μm
94% was in the range of 100 μm, and the average particle size was 25 μm. This is dried with a spray dryer, and (E)-
N- (4-hydroxy-3-methoxybenzyl) -8-
A microcapsule containing methylnon-6-enamide was obtained.

Test Example 1 Synthesis of powdered microcapsules of Examples 1 and 2 and N- (4-hydroxy-3-methoxybenzyl) -nonanamide before microencapsulation synthesized by the same method as in Examples 1 and 2. And (E) -N- (4-hydroxy-3-methoxybenzyl) -8-methylnon-6
After adding 0.2% of the end amide compound as an active ingredient to vinyl compound SE-24 (manufactured by Mitsui Toatsu Chemicals, Inc.),
A polyvinyl chloride sheet with a thickness of 1 mm was prepared by heating and mixing with a hot rolling roll machine (NS-105 (J) W type manufactured by Nishimura Koki Co., Ltd.) at 180 ° C for 10 minutes, and the polyvinyl chloride sheet was bitten by a rat. The effect of preventing harm was examined and tested. The untreated section is a sheet made of vinyl compound only. Test method Cut each sheet into 75 × 150 mm, fold in two, put two solid samples for rats, and staple on three sides,
Use as a test sample. This sample was placed in a breeding cage in which three rats having a body weight of about 300 g were placed and allowed to stand overnight, and the sheet-damaged area of the rat was examined. 1 sample for each cage
Three cages were put in each and tested. result

[0023]

The microcapsule preparations of Examples 1 and 2 had little irritation and were easy to handle during the work such as weighing, mixing, etc. and sheeting with high heat. It had a strong irritating effect even with a slight touch on the hand, and the intense pungency remained forever. In addition, it had a strong irritating odor during processing and was extremely difficult to handle. The sheets of the microcapsule preparations of Examples 1 and 2 were better in preventing bite damage to rats. From the above results, the usefulness of the production method of the present invention was confirmed.

Claims (1)

[Claims] 1. The formula: (Wherein R represents a C _{4 to} C ₁₂ alkyl group, alkenyl group or alkynyl group), and capsaicin having a strong stimulating property is represented by the formula: (Wherein R represents a C ₄ -C ₁₂ alkyl group, an alkenyl group or an alkynyl group, and Hal represents a halogen atom), vanillylamine or a salt thereof is mixed with water and an organic solvent in a ratio of 10: 1 to 1: 1. 10 to 50 in a mixed solvent of 10:
After optionally condensing at 0 ° C. in the presence of an acid binder, a reducing agent is optionally added to the reaction solution, and then dispersed in water as it is in the reaction bath to obtain an oil-in-water type solution. A method for producing the same bath of capsaicins and microcapsules thereof, which comprises performing microencapsulation.