JP2010285371A - METHOD FOR PRODUCING beta-D-GLUCOPYRANOSYLAMINE DERIVATIVE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially easy method for inexpensively producing a long-chain (saturated/unsaturated) fatty acid derivative of β-D-glucopyranosylamine. <P>SOLUTION: The long-chain (saturated/unsaturated) fatty acid derivative of the β-D-glucopyranosylamine can be produced without accompanying a complicated step or a long-time step by the production method including a first step of reacting D-glucose with ammonia in water or methanol, and a second step of reacting the product of the first step with a halide of a long-chain (saturated/unsaturated) fatty acid. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a method for producing a β-D-glucopyranosylamine derivative that is important in the fields of pharmaceuticals, agricultural chemicals, cosmetics, functional materials and the like.

  It is disclosed in Non-Patent Document 1 that a derivative in which a long-chain saturated fatty acid is amide-bonded to the amino group of β-D-glucopyranosylamine can be used as a surfactant, and has 12 to 41 carbon atoms. Patent Documents 1 and 2 disclose that a derivative obtained by amide-bonding a long-chain unsaturated fatty acid can be used as a structural unit of a hollow fiber-like organic nanotube. Thus, β-D-glucopyranosylamine is an important compound in the fields of pharmaceuticals, agricultural chemicals, cosmetics, functional materials, etc., but the reported production method has problems to be solved in the industry. It was.

  For example, as a method for preparing β-D-glucopyranosylamine, which is a synthetic intermediate, in Patent Document 1, a large excess of ammonium bicarbonate is gradually added to an approximately 0.1 M glucose aqueous solution at 37 ° C. over 3 to 5 days. However, this method has a problem that the reaction takes a long time and the desalting operation in the post-treatment stage becomes complicated.

  On the other hand, Non-Patent Document 1 discloses that β-D-glucopyranosylamine is produced with high purity when 0.2 M glucose and 0.2 M ammonium hydrogen carbonate are reacted in 16 M ammonia water at 42 ° C. for 36 hours. ing. However, a large amount of water is removed by freeze-drying in order to prevent a decrease in purity in the post-treatment process, and there is a practical problem as an industrial production method. Non-Patent Document 2 discloses a long-chain fatty acid derivative of β-D-glucopyranosylamine using 3-acyl-5-methyl-1,3,4-thiadiazole-2 (3H) -thione as an acylating agent. Although a synthesis example is disclosed, the acylating agent is expensive, and it has not been a production method that can be applied industrially easily.

  That is, a long-chain (saturated / unsaturated) fatty acid amide derivative of β-D-glucopyranosylamine is a useful compound. However, in a conventionally proposed production method, β-D-glucose is an intermediate β The process for producing -D-glucopyranosylamine is troublesome, takes a long time, or requires expensive raw materials, so that a long chain of β-D-glucopyranosylamine (saturated) / Unsaturated) fatty acid derivatives could not be produced industrially at low cost.

JP 2004-224717 A JP 2008-30185 A

Carbohydrate Research, 266 211-219 (1995) Tetrahedron Letters, Vol. 32, no. 12, pp1557-1560 (1991)

  An object of the present invention is to provide an industrially simple and inexpensive method for producing a long-chain (saturated / unsaturated) fatty acid derivative of β-D-glucopyranosylamine.

  As a result of intensive studies on the means for avoiding complicated steps and long-time steps for producing a long-chain (saturated / unsaturated) fatty acid derivative of β-D-glucopyranosylamine, A production method comprising: a first step of reacting D-glucose with ammonia in methanol; and a second step of reacting the product of the first step with a long-chain (saturated / unsaturated) fatty acid halide in a polar solvent. Thus, it has been found that a long-chain (saturated / unsaturated) fatty acid derivative of β-D-glucopyranosylamine can be produced without complicated steps and long steps.

  In the production method of the present invention, a long-chain (saturated / unsaturated) fatty acid derivative of β-D-glucopyranosylamine is industrially produced from D-glucose via β-D-glucopyranosylamine. Compared with the conventional method, a complicated process or a long process can be avoided. As a result, it has the effect that industrially useful β-D-glucopyranosylamine long chain (saturated / unsaturated) fatty acid derivatives can be provided at low cost, and its utility value is high.

  This invention makes it essential to include a 1st process (A) and a 2nd process (B). In the first step (A), D-glucose is heated in aqueous ammonia or an ammonia / methanol solution, and then excess ammonia and solvent (water or methanol) are removed to remove the intermediate β-D- A crude product of glucopyranosylamine can be obtained. As the ammonia water, the higher the ammonia concentration, the faster the reaction and the smaller the amount of water to be removed after the reaction is, so the ammonia water of 11N or more is preferable, and the ammonia water of 13N or more is more preferable. That is, a commercially available 25-30 wt% ammonia water can be suitably used. The above N is a unit of concentration commonly used by those skilled in the art as a unit of normality, and means a concentration containing 1 gram equivalent of solute in 1 liter of solution. In the case of ammonia water, the ammonium ion is a monovalent cation, so it has the same meaning as 1 mol / liter concentration.

Even in the case of an ammonia / methanol solution, the higher the ammonia concentration, the faster the reaction, and the smaller the amount of methanol to be removed after the reaction is, the more preferably a solution having a concentration of 6N or more can be used, more preferably 7N or more. Ammonia may be in a state preliminarily dissolved in water or methanol, or after adding D-glucose to water or methanol, it may be injected to the above usable or suitable concentration.
The ammonia water may contain 50% by mass or less of methanol and / or ethanol, and the ammonia / methanol solution may contain 50% by mass or less of water and / or ethanol. In these, it is more preferable to use ammonia water at the point which can make ammonia concentration higher.

  The higher the initial charged concentration of D-glucose in the first step (A), the faster the reaction proceeds, and the smaller the amount of solvent removed after the reaction, the better. When the number of moles (mol) of D-glucose is defined by the amount (mol / L, hereinafter abbreviated as M) divided by the volume (L) of ammonia water or ammonia / methanol solution, the initial concentration of D-glucose is 2-5M is preferable, More preferably, it is 2.5-4.5M.

  Non-Patent Document 1 discloses that in a reaction similar to the first step (A), when the concentration of D-glucose exceeds 0.5 M, di-D-glycosylamine is generated. Although the reaction at a high concentration has been considered unfavorable, the preferred concentration of D-glucose in the present invention is such that a favorable result can be obtained in a concentration region that is significantly higher than the conventionally known concentration. There is an effect that cannot be achieved.

  The reaction in the first step (A) is affected by the reaction temperature. The lower the reaction temperature, the generation of by-products can be suppressed, but the reaction time tends to be longer. If the reaction temperature is increased, the progress of the reaction is accelerated and the reaction time can be shortened. In the present invention, a preferable reaction temperature is 25 to 70 ° C, more preferably 35 to 50 ° C. The preferred reaction time in this case varies depending on various conditions, but is preferably 5 to 50 hours, more preferably 10 to 30 hours.

  According to the first step (A), D-glucose reacts with ammonia to be converted to β-D-glucopyranosylamine. After completion of the reaction, a crude product of β-D-glucopyranosylamine which is an intermediate for obtaining the target product of the present invention can be obtained by removing excess ammonia and solvent. Any method such as transpiration, freeze-drying, or reduced-pressure drying can be used as a method for removing excessive amounts of ammonia and the solvent. However, it is preferable to use reduced-pressure drying, and the lower the temperature, β-D-glucose is preferable. Since decomposition | disassembly of pyranosylamine can be suppressed, while a higher one can remove a solvent faster, Preferably it is -30 degreeC-40 degreeC, More preferably, it is -20 degreeC to 20 degreeC.

  The purity of the crude product of β-D-glucopyranosylamine obtained in the first step (A) varies depending on various condition settings, but is generally 55 to 90% by weight. Other than these, α-glucose, β- Glucose and di-β-D-glucopyranosylamine are included. β-D-glucopyranosylamine can be subjected to the second step (B) of the next step while remaining in the state of a crude product containing these impurities.

  In the second step (B), the crude product of β-glucopyranosylamine obtained in the step (A), D-glucose and a long-chain (saturated / unsaturated) fatty acid halide are reacted, and the formula This is a process for producing a β-D-glucopyranosylamine derivative represented by (1).

The long chain (saturated / unsaturated) fatty acid halide used in the present invention is a halide of a long chain fatty acid having a total carbon number of 12 to 22, and the carboxyl group of the saturated and / or unsaturated long chain fatty acid is converted to an acid. It is derived from a halide. Preferred as halogen are bromine and chlorine, which are highly reactive, and more preferred is inexpensive chlorine.
Specific examples of long-chain saturated fatty acid halides include lauric acid chloride, tridecanoic acid chloride, myristic acid chloride, tetradecanoic acid chloride, palmitic acid chloride, stearic acid chloride, behenyl acid chloride, 2- Examples thereof include methyl octadecanoic acid chloride. Specific examples of long-chain unsaturated fatty acid halides include myristoleic acid chloride, palmitoleic acid chloride, oleic acid chloride, elaidic acid chloride, linoleic acid chloride, γ-linolenic acid chloride, arachidonic acid chloride Etc. are exemplified. Among these, lauric acid chloride, myristic acid chloride, palmitic acid chloride, stearic acid chloride, and oleic acid chloride are preferable, considering the availability of raw materials and the stability of the compound. Is oleic acid chloride.

  These long chain (saturated / unsaturated) fatty acid halides can be used in combination with a plurality of different types. Moreover, since natural fats and oils are often used as starting materials, a mixture of several types of saturated and unsaturated fatty acid halides may be commercially available. Such a mixture can also be suitably used as long as the object of the present invention is not impaired.

  The charging ratio of β-D-glucopyranosylamine and long-chain (saturated / unsaturated) fatty acid halide in the second step (B) is not particularly limited, but considering the yield and cost, In terms of cost, it is preferable to react β-D-glucopyranosylamine with a long-chain (saturated / unsaturated) fatty acid halide in a range from a stoichiometric amount to a small excess amount. Specifically, when 0.5 to 2.5 moles of long-chain (saturated / unsaturated) fatty acid halide is reacted with 1 mole of β-D-glucopyranosylamine, the total cost is minimized. It is preferable because it can be adjusted to 1.0 to 2.0 mol.

  The above reaction is carried out in a reaction medium. The reaction solvent is preferably a polar solvent, specifically methanol, ethanol, 2-propanol, N, N-dimethylformamide (DMF) or the like, and more preferably methanol. The reaction of the present invention can be carried out even if the polar solvent contains 50% by weight or less, preferably 30% by weight or less of water. Further, it may contain an amount of a non-polar solvent that does not separate into two layers.

The preferred amount of the reaction solvent depends on the amount of D-glucose used in the first step (A), and it is preferable to use 2 to 15 ml of the reaction solvent with respect to 1 g of D-glucose. When the amount of the reaction solvent used is too small, the progress of the reaction becomes insufficient, and when it is too large, the cost increases.
When a reaction solvent is used, the reaction solution after the reaction contains a reaction product β-D-glucopyranosylamine long chain (saturated / unsaturated) fatty acid derivative, unreacted β-D-glucopyranosy. A mixture containing ruamine and a long-chain (saturated / unsaturated) fatty acid halide, a reaction solvent, hydrochloric acid and a salt thereof as a by-product.

  Moreover, a basic substance can coexist as a scavenger of the acid by-produced in the second step. Basic substances in this case include sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium bicarbonate, trisodium citrate, sodium phosphate and other alkali metal compounds, trimethylamine, triethylamine, N, N-diisopropylethylamine, pyridine. , 2,6-lutidine, N, N-dimethylaminopyridine, and tertiary amines such as 1,8-diazabicyclo [5.4.0] undecene-7 are exemplified, and triethylamine is preferable in consideration of reactivity and cost. The addition amount of the basic substance is preferably from 0.5 mol to 2.0 mol, more preferably from 1.0 mol to 1 mol, relative to 1 mol of the long chain (saturated / unsaturated) fatty acid chloride. .5 moles.

  The lower the reaction temperature in the second step (B), the generation of by-products can be suppressed, but the reaction time tends to be longer. If the reaction temperature is increased, the progress of the reaction is accelerated and the reaction time is increased. It's short. In the present invention, the preferred reaction temperature in the second step is −5 to 35 ° C., more preferably 0 to 25 ° C. The preferred reaction time in this case varies depending on various conditions, but is preferably 5 minutes to 50 hours, more preferably 10 minutes to 10 hours.

From the reaction solution obtained in the second step, a long chain (saturated / unsaturated) of β-D-glucopyranosylamine is obtained by conventional methods such as solvent extraction, solvent washing, recrystallization, activated carbon treatment, and various chromatography. The fatty acid derivative can be obtained by separation and purification, and the obtained long-chain (saturated / unsaturated) fatty acid derivative of β-D-glucopyranosylamine can be used for various applications.

Examples of the production method of the present invention will be described below to further clarify the present invention, but the present invention is not limited to these.
<Example 1>
D-(+)-glucose (10.0 g, 55.5 mmol) and 25% aqueous ammonia (13.0 ml) manufactured by Wako Pure Chemical Industries, Ltd. are placed in a thick glass container, sealed, and stirred to obtain D-(+) -Glucose was dissolved. The reaction vessel was warmed to 40 ° C. After 24 hours, it was opened and the contents were transferred to an eggplant type flask. Next, it was connected to a vacuum pump on a 5 ° C. water bath, and ammonia water was removed under reduced pressure. After 6 hours, the flask contents were dried and scraped to obtain a crude product (10.7 g) of β-D-glucopyranosylamine. ^{According to 1} H-NMR analysis, this crude product was found to have a molar fraction of β-D-glucopyranosylamine 84%, α-glucose 3%, β-glucose 6%, and di-β-D-glucopyranosy. It was confirmed that the mixture was composed of 6% ruamine.
In the first step of Example 1, since the amount of ammonia water used was small, excess ammonia water after the reaction could be easily removed even at a low temperature.

  Methanol (80 ml) was added to the obtained crude product, and dissolved by stirring at room temperature. Next, when it was ice-cooled, a partially crystalline compound was precipitated from the solution. At the same temperature, oleic acid chloride (11.0 ml, 33.3 mmol) manufactured by Sigma-Aldrich was dropped over 5 minutes, and then triethylamine (9.80 ml, 70.3 mmol) was dropped over 5 minutes. Furthermore, at the same temperature, oleic acid chloride (11.0 ml, 33.3 mmol) was added dropwise over 5 minutes, and then the temperature was raised to room temperature. After continuing stirring for 3 hours, the reaction mixture was concentrated under reduced pressure.

  Tetrahydrofuran (80 ml) and saturated brine (60 ml) were added to the concentrated residue for partitioning, and the aqueous layer was discarded. Next, the organic layer was washed with a mixed solution of 33% aqueous citric acid solution (30 g) and saturated brine (60 ml), and the organic layer was recovered. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain pale yellow crystalline β-D-glucopyranosylamine oleic acid derivative (14.4 g).

[Test example]
After processing the oleic acid derivative of β-D-glucopyranosylamine obtained in Example 1 by the method described in Patent Document 2, it was confirmed by observation with an electron microscope that hollow fiber organic nanotubes could be produced. did.

<Example 2>
Place D-(+)-glucose (10.0 g, 55.5 mmol), 7N ammonia / methanol (18.5 ml) and a rotor from Wako Pure Chemical Industries, Ltd. into a thick glass container, and seal the container. And stirred with a magnetic stirrer. After 24 hours, it was opened and the contents were transferred to an eggplant type flask. Next, it connected to the vacuum pump on a 20 degreeC water bath, and removed ammonia / methanol under pressure reduction. The flask contents were dried after 3 hours, and scraped off to obtain a crude product (10.6 g) of β-D-glucopyranosylamine. ^{According to 1} H-NMR analysis, the crude product was found to have a molar fraction of 56% β-D-glucopyranosylamine, 13% α-glucose, 20% β-glucose, and di-β-D-glucopyranosin. It was confirmed that the mixture was composed of 11% ruamine.

  Methanol (50 ml) was added to the obtained crude product and dissolved by stirring at room temperature. Next, when it was ice-cooled, a partially crystalline compound was precipitated from the solution. Oleic acid chloride (7.00 ml, 21.2 mmol) manufactured by Wako Pure Chemical Industries, Ltd. was added dropwise at the same temperature over 5 minutes, and then triethylamine (6.30 ml, 45.2 mmol) was added dropwise over 5 minutes. Furthermore, at the same temperature, oleic acid chloride (7.00 ml, 21.2 mmol) was added dropwise over 5 minutes, and then the temperature was raised to room temperature. After continuing stirring for 3 hours, the reaction mixture was concentrated under reduced pressure.

  Tetrahydrofuran (80 ml) and saturated brine (60 ml) were added to the concentrated residue for partitioning, and the aqueous layer was discarded. Next, the organic layer was washed with a mixed solution of 33% aqueous citric acid solution (30 g) and saturated brine (60 ml), and the organic layer was recovered. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain pale brown crystalline β-D-glucopyranosylamine oleic acid derivative (11.0 g).

  Next, methanol (150 ml) was added to the obtained light brown crystalline β-D-glucopyranosylamine oleic acid derivative (11.0 g) and dissolved at 55 ° C. Powdered activated carbon (1.1 g) was added and stirred at the same temperature. After 30 minutes, the activated carbon was removed by suction filtration using Celite 545 (trade name, one of diatomaceous earth) at the same temperature. The filtrate was concentrated under reduced pressure to obtain colorless crystalline β-D-glucopyranosylamine oleic acid derivative (9.18 g).

<Example 3>
D-(+)-glucose (10.0 g, 55.5 mmol) and 25% aqueous ammonia (280 ml) manufactured by Wako Pure Chemical Industries, Ltd. are placed in a thick glass container, sealed, and stirred to obtain D-(+)- Glucose was dissolved. The reaction vessel was warmed to 40 ° C. After 24 hours, it was opened and the contents were transferred to an eggplant type flask. Next, ammonia water was removed under reduced pressure using a rotary evaporator connected to a vacuum pump on a 40 ° C. water bath. After 8 hours, the flask contents were dried and scraped to obtain a crude product (11.4 g) of β-D-glucopyranosylamine. ^{According to 1} H-NMR analysis, this crude product was found to have a molar fraction of β-D-glucopyranosylamine 55%, α-glucose 15%, β-glucose 21%, and di-β-D-glucopyranosin. It was confirmed that the mixture was composed of 9% ruamine.
In the first step of Example 3, the amount of ammonia water used was large, and the water bath was set to 40 ° C. in order to prevent excessive removal of the ammonia water after the reaction from taking too long.

  Methanol (80 ml) was added to the obtained crude product, and dissolved by stirring at room temperature. Next, when it was ice-cooled, a partially crystalline compound was precipitated from the solution. At the same temperature, oleic acid chloride (9.10 ml, 27.5 mmol) manufactured by Sigma-Aldrich was added dropwise over 5 minutes, and then triethylamine (8.00 ml, 57.4 mmol) was added dropwise over 5 minutes. Furthermore, at the same temperature, oleic acid chloride (9.10 ml, 27.5 mmol) was added dropwise over 5 minutes, and then the temperature was raised to room temperature. After continuing stirring for 3 hours, the reaction mixture was concentrated under reduced pressure.

  Tetrahydrofuran (80 ml) and saturated brine (60 ml) were added to the concentrated residue for partitioning, and the aqueous layer was discarded. Next, the organic layer was washed with a mixed solution of 33% aqueous citric acid solution (30 g) and saturated brine (60 ml), and the organic layer was recovered. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain pale yellow crystalline β-D-glucopyranosylamine oleic acid derivative (8.1 g).

In Example 3 in which the concentration of D-glucose in the first step was low, distillation of ammonia water took a long time at a high temperature, resulting in a slightly inferior yield of the obtained β-D-glucopyranosylamine. It was. The reason is probably not because ammonia content was vaporized first while ammonia water was distilled off over a long period of time at a high temperature, and β-D-glucopyranosylamine once produced was hydrolyzed. I think. However, there was no effect on the second step, and the final product could be obtained.

  The production method of the present invention can be suitably used as an inexpensive method for producing a long-chain fatty acid derivative of β-D-glucopyranosylamine.

Claims (4)

First step (A) A step of reacting D-glucose with ammonia in water or a methanol solvent, and then removing excess ammonia and the solvent to obtain a crude product of β-glucopyranosylamine.
Second step (B) A step of reacting the crude product of β-glucopyranosylamine obtained in the step (A) with a long chain (saturated / unsaturated) fatty acid halide in a reaction solvent.
For producing a long-chain (saturated / unsaturated) fatty acid derivative of β-D-glucopyranosylamine represented by the following formula (1):

[R in Formula (1) represents a hydrocarbon group having 11 to 21 carbon atoms. ]
The long-chain (saturated / unsaturated) fatty acid derivative of β-D-glucopyranosylamine according to claim 1, wherein the initial concentration of D-glucose in the first step (A) is in the range of 2 to 5 mol / liter concentration. Production method.
The addition amount of the long chain (saturated / unsaturated) fatty acid halide in the second step (B) is 0.5 to 2.5 mol with respect to 1 mol of the D-glucose. Of β-D-glucopyranosylamine long chain (saturated / unsaturated) fatty acid derivative.
In the second step (B), 1.0 to 1.5 mol of basic substance is added to 1 mol of long-chain (saturated / unsaturated) fatty acid halide, A method for producing a long-chain (saturated / unsaturated) fatty acid derivative of β-D-glucopyranosylamine.