JP4895510B2 - Method for producing variolamine - Google Patents

Description

  The present invention relates to a method for producing variolamine having an α-glucosidase inhibitory action and a method for producing voglibose using variolamine obtained by the production method.

  Variolamine, which is an amino sugar, is a compound having an α-glucosidase inhibitory action, and is also an important intermediate of voglibose that also has an α-glucosidase inhibitory action and is used as a diabetes drug.

  As a method for synthesizing variolamine, a method using as a raw material valienamine obtained by fermentation from validamycin, an antibiotic (see Patent Document 1, Non-Patent Document 1 and Non-Patent Document 2), and sugars such as D-glucose As a raw material, a method (see Non-Patent Document 2) and the like are known. The latter method has a problem that it takes a long time for production because the reaction takes multiple steps. In contrast, the method using varienamine as a raw material is characterized in that variolamine can be obtained by a relatively short process.

This method using valienamine as a raw material basically comprises a four-step reaction process shown in the following (a) to (d).
(A) a step of obtaining an acyclic carbamate compound by reacting valenamine with a carbonylating agent;
(B) By reacting the acyclic carbamate compound obtained in the above step with a halogenating agent, the following formula (2)

(In the formula, X is a halogen atom.)
A step of obtaining a halogenated cyclic carbamate compound represented by:
(C) The halogenated cyclic carbamate compound obtained in the above step is reductively dehalogenated to give the following formula (1)

And (d) a step of hydrolyzing the cyclic carbamate compound obtained in the above step to obtain variolamine.

Japanese Patent Publication No. 3-16334 S. Horii, H. Fukase et al. Carbohydrate Research, 140, 185 (1985) Horii, "Takeda Institute Bulletin", 52, 1-15, 1993

  As described above, the method using valienamine as a raw material is an industrially advantageous method compared with the method using saccharides as a raw material, but purification of each intermediate material is complicated and its production efficiency is not necessarily high. . For example, in the step (d), in order to remove impurities such as other organic compounds and salts, and to isolate the target product, after the hydrolysis reaction, the reaction solution is filtered and then the ion exchange resin is used. However, this chromatographic fractionation process takes a long time to operate, requires special equipment, and uses expensive ion exchange resins, so the production cost is high. There was a problem. Furthermore, since the target product has high water solubility, it is difficult to solidify only by chromatographic fractionation, and further, there is a problem that treatment such as lyophilization is necessary.

  Further, in carrying out the step (d), it was necessary to purify the crude product of the cyclic carbamate compound represented by the formula (2) obtained by the reduction reaction in the previous step (c) by activated carbon treatment. . This activated carbon treatment requires not only a long time for preparation, treatment (specifically, treatment liquid to be passed through an activated carbon column) and concentration of the treatment liquid, but also requires special equipment such as a column. Therefore, it is also a factor of cost increase.

  Accordingly, an object of the present invention is to provide a method for efficiently obtaining a target product by simplifying a purification step of an intermediate or a target product in a method for producing variolamine using valienamine as a raw material.

  The present inventors have intensively studied to solve the above problems. As a result, the cyclic carbamate compound crude product represented by the formula (2) obtained in the step (c) and the variolamine crude product obtained in the step (d) were crystallized using a specific crystallization solvent. In such a case, the present inventors have found that these crude bodies can be efficiently purified, and have completed the present invention.

  That is, the present invention provides the following formula (1)

In the method for producing variolamine including the step of hydrolyzing the cyclic carbamate compound represented by formula (2) to obtain valolamine, ethyl acetate and crystallization solvent are used as a crystallization solvent from the crude valolamine obtained in the hydrolysis reaction. The method is characterized in that the highly purified variolamine is obtained by crystallization using a lower alcohol selected from methanol, ethanol and butanol .

  Another aspect of the present invention is a method for producing voglibose, characterized in that voglibose is obtained by reacting variolamine obtained by the production method of the present invention with dihydroxyacetone.

  By using the method for producing variolamine of the present invention, it is possible to produce variolamine more easily and inexpensively.

  In the method for producing variolamine of the present invention, the cyclic carbamate compound represented by the formula (1) (hereinafter, unless otherwise specified, the “cyclic carbamate compound” means the compound represented by the formula (1)). } Is hydrolyzed to obtain variolamine. This step corresponds to the step (d) in the conventional “method for producing variolamine using valienamine as a raw material” described in the background art section.

  The production method of the present invention is not particularly different from the conventional “method for producing variolamine using valienamine as a raw material” except that a crystallization method using a specific solvent is employed as a purification method of the target product.

  For example, the cyclic carbamate compound is a halogenated cyclic carbamate compound represented by the following formula (2), as in the step (c) of the conventional “method for producing valolamine using valienamine as a raw material” {hereinafter, particularly, Unless otherwise specified, the “halogenated cyclic carbamate compound” means a compound represented by the formula (2). } Can be obtained by reductive dehalogenation.

(In the formula, X is a halogen atom.)
The halogenated cyclic carbamate compound is obtained by reacting the product obtained by the steps (a) and (b), that is, valienamine with a carbonylating agent such as benzyloxycarbonyl chloride. A product obtained by obtaining an acyclic carbamate compound such as (benzyloxycarbonyl) varienamine and then reacting the obtained acyclic carbamate compound with a halogenating agent such as bromine or iodine can be used. X in the formula (2) is a halogen atom, and is uniquely determined by the halogenating agent used at this time. Although X in Formula (2) will not be specifically limited if it is a halogen atom, It is preferable that it is a bromine atom from points, such as operativity.

  As described above, in order to obtain a cyclic carbamate compound, the halogenated cyclic carbamate compound may be reductively dehalogenated. In this case, as in the conventional method, the halogenated cyclic carbamate compound and the reductive dehalogenation are also used. What is necessary is just to make it react with an agent.

  As the reductive dehalogenating agent, a metal hydride complex reducing agent such as a borohydride complex or an aluminum hydride metal complex, or an organic tin hydride can be used. In addition, reductive dehalogenation can be performed by allowing a reduction catalyst to act in the presence of hydrogen. Furthermore, reductive dehalogenation can be performed by a method of reacting with sodium or lithium in liquid ammonia, a method of reacting with zinc and hydrochloric acid or acetic acid, an electrolytic reduction method, or the like. Among these methods, it is preferable to employ a method using a reductive dehalogenating agent or a method in which a reduction catalyst is allowed to act in the presence of hydrogen.

Specific examples of compounds that can be suitably used as a reductive dehalogenating agent include borohydride complex reducing agents such as sodium borohydride, potassium borohydride, lithium borohydride, trimethoxyboron hydride. Examples include sodium, lithium triethylborohydride, and sodium cyanoborohydride. In addition, examples of the aluminum hydride metal complex include lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and diethylaluminum sodium hydride. The organic tin _{hydride, (n-C 4 H 9} ) 3 SnH, (n-C 4 H 9) 2 SnH 2, (n-C 3 H 7) 3 SnH, (C 2 H 5) 3 _SnH, Ph 3 _SnH, can be mentioned Ph ₂ SnH 2. Furthermore, palladium carbon, palladium black, Raney nickel, platinum black, platinum dioxide and the like can be used as the reduction catalyst. Among these, from the viewpoint of reaction yield, operability, etc., a method using a metal hydride complex reducing agent such as a boron hydride complex or an aluminum hydride metal complex, and a method using a boron hydride complex reducing agent, among others. Is preferred.

  When dehalogenation is performed using a reductive dehalogenating agent or a reduction catalyst, a halogenated cyclic carbamate compound and a reductive dehalogenating agent or a reduction catalyst may be mixed in a solvent. When using a reduction catalyst, it is necessary to coexist hydrogen by a method such as blowing hydrogen gas into the solution. What is necessary is just to select a reaction solvent and reaction conditions suitably according to the kind of reductive dehalogenating agent or reduction catalyst to be used.

  For example, when using a borohydride complex, the reaction solvent is water; alcohols such as methanol, ethanol, propyl alcohol, butanol; N, N-dimethylformamide, N, N-dimethylacetamide, N-methylacetamide. N-alkyl-substituted amide solvents such as dimethyl sulfoxide; glyme solvents such as methyl cellosolve, dimethyl cellosolve, diethylene glycol dimethyl ether; other polar solvents such as dioxane, tetrahydrofuran, acetonitrile, etc .; mixed solvents thereof; or these polar solvents And a non-polar solvent such as ethyl acetate and toluene can be used. The reaction is usually carried out at room temperature for about 1 hour to 1 day under ice cooling or in some cases at the reflux temperature of the solvent.

  When an aluminum hydride metal complex reducing agent is used, the reaction solvent is a glyme solvent such as diethylene glycol dimethyl ether; an ether solvent such as dioxane, diethyl ether, t-butyl methyl ether, tetrahydrofuran; or a mixture thereof. A solvent can be used. Also in this case, the reaction can be carried out under the same conditions as in the method using a borohydride complex reducing agent.

  Moreover, when using organotin hydride, it is preferable to use organic solvents, such as benzene, toluene, xylene, ethyl ether, dioxane, diethylene glycol monoethyl ether, as a reaction solvent. At this time, the reaction can easily proceed by coexisting an initiator of a radical reaction such as an azo compound such as azobisisobutyronitrile or a peroxide such as benzoyl peroxide. The reaction is usually carried out at room temperature for about 1 hour to 1 day under ice cooling or in some cases at the reflux temperature of the solvent.

  When mixing with a reduction catalyst in the presence of hydrogen, the reaction solvent is water; alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; amides such as dimethylformamide; and a mixed solvent thereof. It is done. The reaction is usually carried out at ordinary temperature and normal pressure, but it may be heated or under pressure. The reaction time is usually about 1 to 24 hours.

  After reductive dehalogenation reaction by such a method, a crude product of a cyclic carbamate compound is obtained from the reaction solution. In order to obtain a crude product of a cyclic carbamate compound from the reaction solution (usually, a purity of 50 to 90% by HPLC relative area strength), the reaction solution is neutralized and then filtered as necessary to distill off the solvent. That's fine. The neutralization of the reaction solution is carried out by adding a mineral acid such as hydrochloric acid, sulfuric acid or nitric acid, acetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or other organic carboxylic acid or an aqueous solution thereof. It is carried out by adjusting to 5-9, preferably 6-8. For distilling off the solvent, a known concentration method such as normal pressure concentration, reduced pressure concentration, or freeze-drying can be used.

  The crude product thus obtained is purified to a high purity and becomes a raw material for the method of the present invention. As the purification treatment method, an activated carbon column treatment method and / or a crystallization treatment method can be used, but it is preferable to adopt a crystallization treatment method from the viewpoint of simplicity. In order to use as a raw material of the method of the present invention, it is preferable that the purity of the cyclic carbamate compound (based on HPLC relative area strength) is 90% or more, particularly 98% or more by this purification treatment.

  When the activated carbon column treatment is performed, generally a column tower filled with activated carbon is prepared, a solution in which the crude body is dissolved in an organic solvent is introduced into the column tower, and then a suitable developing solvent is poured to What is necessary is just to fractionate. Although the usage-amount of activated carbon should just be adjusted suitably, generally it is the range of 0.5-20 times of a rough body. Moreover, there is no restriction | limiting in particular as activated carbon to be used, However, The activated carbon for chromatography is preferable. In general, water or an organic solvent can be used as the developing solvent. As the organic solvent, alcohols such as methanol and ethanol, ethers such as diethyl ether and tetrahydrofuran, esters and the like can be used. Further, by selecting a developing solvent, it is possible to elute impurities and then appropriately change the developing solvent to elute the target product.

  Moreover, when performing a crystallization process, it is preferable to use ethyl acetate and a lower alcohol as a crystallization solvent from the reason that a seed crystal is unnecessary and a high purity product is obtained. The amount of the solvent comprising ethyl acetate and lower alcohol may be appropriately adjusted depending on the purity of the crude product, the treatment temperature, etc., but is generally 1 to 10 times the amount of the crude product. The ratio of ethyl acetate / lower alcohol is not particularly limited, but a weight ratio of 1/10 to 10/1 is preferable, and 2/1 to 1/5 is particularly preferable. Examples of the lower alcohol to be used include methanol, ethanol, butanol and the like, and methanol is particularly preferable from the viewpoint of recovery rate, purity and the like. In crystallization, it is preferable to first add a lower alcohol, which is a good solvent, and then add ethyl acetate. The crude product obtained by distilling off the solvent after neutralizing the reaction solution may be crystallized as it is, but it is highly purified by crystallizing a cyclic carbamate compound purified by activated carbon column treatment. A cyclic carbamate compound can be obtained.

  In the production method of the present invention, the cyclic carbamate compound highly purified as described above is hydrolyzed, more specifically, the target carbamate bond (—O—CO—NH—) is hydrolyzed. Get all amines. This hydrolysis reaction can also be performed by allowing a hydrolysis catalyst to act in the presence of water, as in step (d) in the conventional method. Examples of the hydrolysis catalyst include alkali compounds such as alkoxides composed of alkali metals such as sodium hydroxide, potassium hydroxide and barium hydroxide, hydroxides of alkali metals or alkaline earth metals, sodium methoxide and sodium ethoxide, Alternatively, an acidic compound such as a mineral acid such as hydrochloric acid, sulfuric acid, and nitric acid, an organic carboxylic acid such as acetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid, and methanesulfonic acid can be used. Reaction is usually water; alcohols such as methanol, ethanol, propyl alcohol, butanol; N-alkyl substituted amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylacetamide; dimethyl sulfoxide Glyme solvent such as methyl cellosolve, dimethyl cellosolve, diethylene glycol dimethyl ether; other polar solvent such as dioxane, tetrahydrofuran, acetonitrile, etc .; or a solvent or dispersion medium comprising these mixed solvents. The reaction is usually carried out by stirring for about 1 hour to 1 day in the temperature range of 0 ° C. to the boiling point of the solvent or dispersion medium.

  After completion of the reaction, the reaction solution is neutralized and the pH of the reaction solution is adjusted to 5-9, preferably 6-8, as in the post-treatment after completion of the dehalogenation reaction, and filtered as necessary. Thereafter, the solvent or dispersion medium is distilled off to obtain a crude product of variolamine (usually, purity of 50 to 90% by HPLC relative area strength).

  When an alkaline compound is used as the hydrolysis catalyst, an acid is used as a neutralizing agent when neutralizing the reaction solution. Examples of the acid used at this time include minerals such as hydrochloric acid, sulfuric acid, and nitric acid. Acid; Organic carboxylic acid such as acetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid; or an aqueous solution thereof; or carbonic acid can be used. When carbonic acid is used as the neutralizing agent, carbonic acid prepared at the time of use by blowing carbon dioxide gas or dry ice into water (prepared on the spot) may be used. Moreover, what is necessary is just to use an alkali as a neutralizing agent, when an acid is used as a hydrolysis catalyst. Examples of the neutralizing agent include hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide and barium hydroxide, bicarbonates such as sodium bicarbonate, carbonates such as sodium carbonate and potassium carbonate In addition, alkaline compounds such as alkoxides made of alkali metals such as sodium methoxide and sodium ethoxide, or aqueous solutions thereof can be used.

  According to the production method of the present invention, a highly purified variolamine is obtained by crystallization of the crude variolamine obtained in this manner using ethyl acetate and a lower alcohol as a crystallization solvent. The biggest feature. By adopting such a crystallization method, it is possible to obtain high-purity variolamine in a simpler, cheaper and even shorter time than when a conventional purification method is employed. Furthermore, the feature of this crystallization method is that it is not necessary to use seed crystals.

  The above crystallization treatment is similar to the conventional crystallization method except that ethyl acetate and a lower alcohol are used in combination as the crystallization solvent, and then the composition of the crystallization solvent is changed after dissolving the crude product in the crystallization solvent. Alternatively, the target crystal may be precipitated by changing the liquid temperature or both. In the present invention, from the viewpoint of purification efficiency, it is preferable to dissolve the crude product in a lower alcohol and, if necessary, remove insolubles by filtration, and then add ethyl acetate to precipitate crystals. The temperature at which the crystals are precipitated is preferably −20 to 30 ° C., particularly −5 to 10 ° C. from the viewpoint of the precipitation rate and purity. Further, the amount of the solvent composed of ethyl acetate and lower alcohol used for crystallization may be appropriately adjusted depending on the purity of the crude product, the processing temperature, etc., but is generally 1 to 10 times the amount of the crude product. . The ratio of ethyl acetate / lower alcohol is not particularly limited, but a weight ratio of 1/10 to 10/1 is preferable, and 2/1 to 1/5 is particularly preferable. Examples of the lower alcohol to be used include methanol, ethanol, butanol and the like, and methanol is particularly preferable from the viewpoint of recovery rate, purity and the like.

  According to the production method of the present invention, even if the crude product obtained by distilling off the solvent after neutralizing the reaction solution after completion of the hydrolysis reaction (also referred to as primary crude product) is crystallized as it is, for example, By the HPLC analysis method, it is possible to obtain a highly pure variolamine having a relative area intensity of 95% or more, preferably 98% or more. As such an HPLC analysis method, for example, a post-column fluorescence derivatization method using a taurine / periodic acid reagent can be used. In this method, a fluorescent substance produced by adding a taurine / periodic acid reagent continuously to the column eluate and reacting at 100 ° C. may be detected. As the column, for example, Asahi Pack NH2P-50-4E (manufactured by Showa Denko KK) can be used.

  Further, as another embodiment of the present invention, a variolamine having higher purity can be obtained by adopting an embodiment in which the secondary crude product obtained by purifying the primary crude product is similarly crystallized. You can also. Even in this case, the time and labor required to obtain a high-purity product of the same degree are greatly reduced as compared with the case where other purification methods are employed.

  Of course, an activated carbon column treatment method and / or an ion exchange resin treatment method may be employed as a purification method for further purification of the secondary crude product.

  In the activated carbon column treatment, the secondary crude solution is introduced into the column tower packed with activated carbon, and then a suitable developing solvent is flowed in the same manner as described in the method for purifying the crude product of the cyclic carbamate compound. This is done by fractionating the object. At this time, although the usage-amount of activated carbon should just be adjusted suitably, generally it is the range of 0.5-20 times of a rough body. Moreover, although there is no restriction | limiting in particular as activated carbon to be used, It is preferable to use activated carbon for chromatography. In general, water or an organic solvent can be used as the developing solvent. As the organic solvent for dissolving the secondary crude product, alcohols such as methanol and ethanol, ethers such as diethyl ether and tetrahydrofuran, esters and the like can be used. Further, by selecting a developing solvent, it is possible to elute impurities and then appropriately change the developing solvent to elute the target product.

  In the ion exchange resin treatment, a cation exchange resin such as a strong acid resin or a weak acid resin and / or an anion exchange resin such as a strong basic resin or a weak basic resin is brought into contact with a crude solution to remove ionic impurities, etc. remove. The above contact can be performed by a batch method or a column method, but the column method is preferably employed from the viewpoint that impurities can be removed by fractionation. As the ion exchange resin species, the cation exchange resin is preferably an ammonium salt type weakly acidic resin, and the anion exchange resin is preferably an OH type strong base type resin.

  The variolamine obtained by the production method of the present invention can be suitably used as a raw material for voglibose. In order to produce voglibose using the variolamine obtained by the production method of the present invention, it may be synthesized by reducing a Schiff base obtained by reacting variolamine and dihydroxyacetone. Hereinafter, this method will be described.

  First, valolamine and dihydroxyacetone are reacted to obtain a Schiff base. Reaction is usually water; alcohols such as methanol, ethanol, propyl alcohol, butanol; N-alkyl substituted amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylacetamide; dimethyl sulfoxide Glyme solvent such as methyl cellosolve, dimethyl cellosolve, diethylene glycol dimethyl ether; other polar solvent such as dioxane, tetrahydrofuran, acetonitrile, etc .; or a solvent or mixed solvent composed of these mixed solvents. The reaction is usually carried out by stirring for about 10 minutes to 1 day in the temperature range of 0 ° C. to the boiling point of the solvent or mixed solvent. In order to accelerate the progress of the reaction, it is also useful to use a catalyst such as distillation of water or Lewis acid.

  The reduction reaction of the formed Schiff base can be performed by known methods such as various metal hydride complex reducing agents and catalytic reduction. Among these, it is preferable to use a metal hydride complex reducing agent for ease of handling. Specific examples of compounds that can be suitably used as the reducing agent include borohydride complex reducing agents such as sodium borohydride, potassium borohydride, lithium borohydride, sodium trimethoxyborohydride, hydrogenated Examples include lithium triethylboron and sodium cyanoborohydride. In addition, examples of the aluminum hydride metal complex include lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and diethylaluminum sodium hydride. The reaction is usually carried out by stirring for about 10 minutes to 1 day in the temperature range of 0 ° C. to the boiling point of the solvent or mixed solvent.

  The Schiff base synthesis reaction and the subsequent reduction reaction may be performed simultaneously as a single reaction, or may be performed continuously in the same vessel. Further, the obtained Schiff base is taken out, and then the reduction reaction is performed. It may be performed in two stages.

  As the purification treatment after the reaction, an ion exchange resin treatment is suitable. Ionic impurities and the like can be removed by bringing a crude solution into contact with a cation exchange resin such as a strong acid resin and a weak acid resin and / or an anion exchange resin such as a strong basic resin and a weak basic resin. The above contact can be performed by a batch method or a column method, but the column method is preferably employed from the viewpoint that impurities can be removed by fractionation. As the ion exchange resin species, the cation exchange resin is preferably an ammonium salt type weakly acidic resin, and the anion exchange resin is preferably an OH type strong base type resin.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

Purity analysis method:
The purity analysis of variolamine was performed by a post-column fluorescence derivatization method using a taurine / periodic acid reagent. A fluorophore produced was detected by continuously adding taurine / sodium periodate reagent to the column eluate and reacting at 100 ° C. Asahi Pack NH2P-50-4E was used as the column, and a buffer in which 20 mM sodium phosphate buffer (pH 6.50) and acetonitrile were mixed at a ratio (volume ratio) of 1: 2 was used as the developing solvent. The analysis was performed at a flow rate of 0.6 ml / min and a development time of 1 hour. Purity was calculated by relative area intensity (100% area) in HPLC analysis.

Example 1
Compound of the following structure {Compound wherein X is bromine in the above formula (2) (molecular weight 298.1)}

Reductive dehalogenation was performed by slowly adding 17.2 g of sodium borohydride to a solution at 5 ° C. in which 6.5 g (21.7 mmol) was dissolved in 77 g of ion-exchanged water under ice-cooling and allowing to stand for 4 hours. It was. Thereafter, the temperature of the solution was raised to room temperature, and then 2.6 g of acetic acid was added for neutralization, followed by concentration under reduced pressure to obtain 26 g of a crude solution of a cyclic carbamate compound.

After adding 30 g of methanol to 13 g of the obtained crude liquid and removing insolubles by filtration, 30 g of ethyl acetate was added and crystallization was performed by stirring at 25 ° C. for 3 hours. The precipitate was collected by filtration and dried to obtain 1.85 g of a white solid. The obtained white solid was confirmed by ¹ H-NMR analysis to be a cyclic carbamate compound represented by the formula (1) (molecular weight 219.2, yield 78%). Further, when the purity was examined by HPLC, it was confirmed that the purity was 95%.

A solution of 3.7 g (16.9 mmol) of the cyclic carbamate compound thus obtained in 100 g of ion-exchanged water was heated to 35 ° C., and 26.6 g of barium hydroxide octahydrate was added. The mixture was heated to 80 ° C. and stirred for 5 hours for hydrolysis. After cooling the reaction solution, carbon dioxide gas was bubbled for 5 hours to neutralize the reaction solution, and the neutralized reaction solution was filtered. By concentrating the back solution, 3.9 g of a variolamine crude product was obtained. After adding 25 g of methanol to 1.95 g of the obtained crude product and filtering insoluble matter, 50 g of ethyl acetate was added, and the mixture was stirred at 25 ° C. for 3 hours for crystallization. The precipitate was collected by filtration and dried to obtain 1.32 g (yield 81%) of a white solid. ^{From the 1} H-NMR analysis, it was confirmed that the obtained white solid was variolamine. It was also confirmed by HPLC that the variolamine had a purity of 98%.

Example 2
The following purification treatment was performed using 13 g of the cyclic carbamate compound crude liquid obtained in Example 1. That is, the crude liquid was put into a column tower packed with 2.2 g of activated carbon for chromatography, and 125 ml of ion-exchanged water was passed therethrough. Subsequently, 210 ml of 50% aqueous methanol solution was passed through, and the resulting fraction solution was concentrated to 5 ml. When the HPLC purity at this point was confirmed, the purity was 60%. A precipitate was produced by adding 5 ml of methanol to the solution and then cooling. The precipitate was filtered off and dried to obtain 1.73 g of white solid (cyclic carbamate compound) (yield 73%). As a result of HPLC analysis, the purity of the obtained cyclic carbamate compound was 99%.

A solution obtained by dissolving 1.73 g of the obtained cyclic carbamate compound in 50 g of ion-exchanged water was heated to 35 ° C., 12.6 g of barium hydroxide octahydrate was added, and the mixture was heated to 80 ° C. Hydrolysis was carried out by reacting for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature and then neutralized by bubbling carbon dioxide gas for 5 hours. The neutralized reaction liquid was filtered, and then the filtrate was concentrated to obtain 1.9 g of a crude liquid. Crystallization was performed by adding 22 g of methanol to 1.9 g of this crude liquid and uniformly dissolving it, followed by 44 g of ethyl acetate and stirring at 25 ° C. for 4 hours. The precipitate was collected by filtration and dried to obtain 1.2 g of white solid (yield 76%). ^{From the 1} H-NMR analysis, it was confirmed that the white solid was variolamine. The purity was confirmed by HPLC analysis to be 99%.

Comparative Example 1
The crude variolamine 1.95 g obtained in Example 1 was treated with an ion exchange resin in the following manner. That is, a column filled with 45 ml of weakly acidic resin (Mitsubishi Chemical WK40, NH4 type) pretreated by passing 1N ammonia water and further ion-exchanged water was filled with the crude liquid, and then 40 ml of water was passed. Subsequently, 350 ml of dilute aqueous ammonia was passed through and 250 ml of the elution fraction was concentrated to obtain a 5 ml solution. Thereafter, the obtained liquid was applied to a column packed with 50 ml of a strongly basic resin (Dowex 1 × 2, OH type) pretreated by passing 1N NaOH and further ion-exchanged water, and then passed 90 ml of water. As a result, 4 ml of an elution fraction containing bariolamine was obtained. The obtained fraction was concentrated to a solution of about 2 ml. In this solution, no crystal deposition was observed even at 5 ° C. The solution was freeze-dried to obtain 1.30 g of a white solid (yield 75%). When the purity of the obtained white solid (variolamine) was confirmed by HPLC, the purity was 98%.

Comparative Example 2
An elution fraction containing variolamine obtained by carrying out the same two-stage ion-exchange resin treatment as in Comparative Example 2 using 1.95 g of the crude variolamine obtained by the same method as in Example 1. About 2 ml was dissolved by adding 10 ml of methanol at room temperature. In this solution, no precipitation of crystals was observed even at 0 ° C.

Example 3
Dissolve 4.0 g of valolamine obtained in Example 1 in dimethylformamide, add 13.1 g of dihydroxyacetone, 3.0 ml of 2N hydrochloric acid, and 5.5 g of sodium cyanoborohydride, and then at 70 ° C. for 24 hours. Stir with heating. Dimethylformamide was distilled off from the reaction solution, and the resulting residue was dissolved in 200 g of water. The aqueous solution was acidified with 2N hydrochloric acid, stirred for 1 hour under ice-cooling, neutralized, then subjected to column chromatography (500 ml) of Dowex 50w × 8 (H type, manufactured by Dow Chemical Co.), washed with water, 0. Elution was performed with 5N aqueous ammonia. The eluate was concentrated under reduced pressure, and Amberlite CG-50 (NH4 type, Organo) was then subjected to column chromatography on the concentrated solution and then about 20 ml of the concentrated solution. The water-eluting component was concentrated under reduced pressure, and then lyophilized to obtain 3.2 g of voglibose as a white powder. The chemical structure of the compound was confirmed by ¹ H-NMR.

Claims (3)

Following formula (1)

In the method for producing variolamine including the step of hydrolyzing the cyclic carbamate compound represented by formula (2) to obtain valolamine, ethyl acetate and crystallization solvent are used as a crystallization solvent from the crude valolamine obtained in the hydrolysis reaction. The method described above is characterized in that a highly purified variolamine is obtained by crystallization using a lower alcohol selected from methanol, ethanol and butanol . Following formula (2)

(In the formula, X is a halogen atom.)
A reductive dehalogenation of the halogenated cyclic carbamate compound represented by formula (1) to obtain a crude product of the cyclic carbamate compound represented by the formula (1), and ethyl acetate as a crystallization solvent from the crude product obtained in the step. and, methanol, ethanol, the method of claim 1 by crystallization using a lower alcohol selected from butanol, further comprising the step of obtaining a highly purified ring-like carbamate compound. 3. A process for producing voglibose, characterized in that voglibose is obtained by reacting variolamine obtained by the method according to claim 1 with dihydroxyacetone.