JP2007277238A - Method for producing voglibose - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an improved method mass-producing high-purity voglibose in high yield by a simpler process. <P>SOLUTION: A high-purity solid phase perbenzylvoglibose benzenesulfonic acid salt obtained by reacting perbenzylvoglibose with benzenesulfonic acid is subjected to hydrogenation reaction, and debenzylation is efficiently advanced thereby even when a trace amount of palladium catalyst is used in ordinary pressure and voglibose is readily isolated by reacting the resultant voglibose benzenesulfonate with a base. As a result, the high-purity voglibose can be mass-produced in high yield and high purity by using a simple process. The voglibose is an α-glucosidase inhibitor-based therapeutic agent for diabetes mellitus and has an effect of suppressing postprandial elevation of glycemia by blocking decomposition of disaccharide to monosaccharide by suppressing secretion of digestive enzyme in the mucous membrane of the small intestine. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention employs an inosose derivative as a starting material, and includes a 1) reductive amination reaction; 2) a benzenesulfonic acid addition reaction; 3) a deprotection reaction; and 4) a liberation reaction. The present invention relates to a novel method capable of synthesizing voglibose with high yield and high purity.

  Voglibose is an alpha-glucosidase inhibitor-based diabetes treatment that increases postprandial blood glucose by inhibiting digestive enzyme secretion in the small intestinal mucosa and blocking the decomposition of disaccharides into monosaccharides. Has the effect of suppressing In particular, voglibose has an excellent enzyme-inhibiting action and has a relatively high affinity for disaccharide-degrading enzymes. Therefore, the dosage can be dramatically reduced and there are few side effects on the digestive system. It is a useful drug.

Voglibose can be synthesized through various routes. US Pat. No. 4,701,559 discloses a typical synthesis method of valienamine having a chemical structure similar to that of voglibose as shown in the following reaction scheme 1. A process for producing voglibose of Formula 1 via a five-step reaction using (1) as a starting material is disclosed.

  In this method, N-acylation of the amine group of varienamine (1) to produce N-carbamoylvarienamine (2) and the double bond to be halogenated to produce a cyclic (hazalbamate) derivative (3 ) Is further dehalogenated to produce a cyclic carbamate derivative (4), and then variolamine (5) is produced, and finally, through reductive amination reaction from variolamine (5) with dihydroxyacetone. A method for producing voglibose of Formula 1.

  Although there is no problem in the chemical reaction stage of this method, it is unsuitable for mass production because a resin column must be used in the process of separating and obtaining the intermediate product and the final product during the post-reaction process, and the total yield is 6 It is uneconomical because it is very low at%. In particular, the valienamine used as a starting material in the method can be obtained through fermentation of a microorganism such as Streptomyces hygroscopicus, or can be obtained by decomposing validamycin with a microorganism. However, the yield is very low, the purification method is complicated, and there is a problem that it is difficult to secure valienamine as an industrial scale amount.

前記式中、Ｘは−ＳＱであり、Ｑは低級アルキル又は低級アルキレンを意味する。 As another method, U.S. Pat. Nos. 4,898,986 and 5,004,838 use a dialkylthioinosose (6) as a starting material, as shown in the following reaction scheme 2. Discloses a method for producing voglibose of formula 1.

In the above formula, X is -SQ, and Q means lower alkyl or lower alkylene.

In this method, after the reductive amination reaction of the dialkylthioinosose derivative (6), the reaction of removing the dialkylthio group using Raney nickel is sequentially performed to obtain perbenzylboglubose (7). After preparation, the voglibose of formula 1 is prepared by removing the perbenzyl group with Raney nickel under 3.4-4 atm.
However, in order to remove the dialkylthio group, the above method must use expensive Raney nickel three times by weight, and the benzyl group cannot be removed unless it is reacted under a high pressure of 3.5 to 4 atm. There is a problem that a high-pressure reactor has to be provided, and in particular, the overall yield is only 17%.

On the other hand, as a method similar to this, Fukase et al. (Fukase, H et al., J. Org. Chem., 57: 3651-3658, 1992) showed an inosose derivative (8) as shown in the following reaction formula 3. And a method for producing voglibose through a reductive amination reaction and a deprotection reaction.

  In this method, perbenzylboglubose (7) is produced from inosource (8) having no dialkylthio group through a reductive amination reaction, and the perbenzyl group is formed in formic acid using a palladium-black (Pd-black) catalyst. The voglibose of Formula 1 is produced by removing.

  Although the above method has advantages in that the reaction is easier and the yield is higher than the method using dialkylthio-inosose (6) as a starting material, a column using silica gel as the reaction product after the reductive amination reaction. There is an annoyance that must be separated and purified by a chromatographic method. In addition, expensive palladium-black used as a catalyst is highly flammable and extremely dangerous when handled on an industrial scale, and it is uneconomical because it must be added in an amount of 100% by weight or more. is there. Furthermore, after the deprotection reaction, voglibose is obtained in the formate form, so to remove formic acid and obtain a pure base voglibose, Dowex cation resin and Amberlite. Since column chromatography using a resin must be performed continuously, it is not suitable for mass production.

As another method, International Publication No. WO2005 / 030698 discloses reductive deprotection of perbenzylboglubose (7) under the reaction of 5% palladium / carbon and hydrochloric acid as shown in the following reaction formula 4 and its hydrochloride. After producing (9), a method for producing voglibose of Formula 1 by neutralizing with an inorganic base or an organic base is disclosed.

  This method is also uneconomical because expensive palladium / carbon must be added in an amount of 100% by weight during the deprotection reaction. When a large amount of palladium catalyst is used, the reaction is performed when the catalyst is introduced into the reactor. When the mixing ratio of oxygen in the air and the vaporized organic solvent reaches a specific range after filtering the product, there is a risk of fire due to the ignition of the palladium-carbon catalyst. Since the reaction must be performed at a very high pressure, particularly at a high pressure of 3 to 3.5 atm, not only a separate high-pressure reactor is required, but the high-pressure reactor itself cannot be made large and the reaction scale is limited. There is a problem.

In addition, perbenzylboglubose (7) used as a raw material is produced from inosource (8) through a reductive amination reaction in the same manner as in the above reaction formula 3, but the perbenzylbobose (7) obtained after the reductive amination reaction is used. Grubose (7) is oily and has an extremely low purity of only 90% by HPLC. Therefore, if it is subjected to deprotection and neutralization without purification, the final voglibose content is It is obtained in an impure state where the impurity content is less than or exceeds the reference value. In order to avoid this, purification must be carried out, but since it is an oily liquid that is not solid, it is purified through column chromatography, but this method is inefficient in terms of productivity, especially Not suitable for mass production.
Further, since the yield of obtaining the final voglibose from the perbenzyl bogulose (7) is as low as about 54%, it has a disadvantage of being inferior in cost competitiveness.

As a result, the above-described method requires a high-pressure reactor that is limited in capacity, uses a large amount of palladium catalyst with a low overall yield, considerably increases production costs, and low purity of deprotected products. This is a manufacturing method that is not preferable for application to an industrial scale because, for example, a low-quality final product can be obtained.
US Pat. No. 4,701,559 U.S. Pat. No. 4,898,986 US Pat. No. 5,004,838 International Publication No. WO2005 / 030698 Fukase, H et al. , J. et al. Org. Chem. 57: 3651-3658,1992.

  Therefore, the present inventors have intensively studied to solve various problems in the conventional voglibose production method, and as a result, high purity solid phase perbenzyl voglibose benzene sulfonic acid obtained by reacting perbenzyl voglibose with benzene sulfonic acid. If the salt is hydrogenated, debenzylation will proceed efficiently even if a very small amount of palladium catalyst is used at normal pressure, and if the resulting voglibose benzenesulfonate is reacted with a base, voglibose can be easily produced. The present invention was completed by confirming that it can be liberated to produce high-purity voglibose in a high yield.

  Accordingly, an object of the present invention is to provide an improved method capable of mass-producing high-purity voglibose in a high yield by a simpler process.

前記式中、Ｐｈはフェニル基であり、Ｂｎはベンジル基である。 To achieve the above object, the present invention provides: 1) Preparation of perbenzyl voglibose of formula 4 through reductive amination reaction of inosose derivative of formula 5 and 2-amino-1,3-propanediol of formula 6 Stage;
2) adding benzene sulfonic acid to the perbenzyl voglibose to produce perbenzyl voglibose benzene sulfonate of formula 3;
3) deprotecting the perbenzyl voglibose benzene sulfonate to produce voglibose benzene sulfonate of formula 2; and 4) treating the voglibose benzene sulfonate with a base to liberate voglibose. A method for producing voglibose of formula 1 is provided:

In the above formula, Ph is a phenyl group, and Bn is a benzyl group.

  According to the production method of the present invention, voglibose, which is a therapeutic agent for diabetes, can be mass-produced with high yield and high purity by a simple process.

前記式中、Ｐｈ及びＢｎは前記で定義した通りである。

本発明で出発物質として用いられる式５のイノソース誘導体は公知の方法(Ｉｋｅｇａｍｉ, Ｓ ｅｔ ａｌ., Ｏｒｇａｎｉｃ Ｌｅｔｔｅｒｓ ２(４)：４５７〜４６０, ２０００)を用いて容易に製造することができる。 The production method according to the present invention is schematically illustrated as the following reaction scheme 5.

In the above formula, Ph and Bn are as defined above.

The inosose derivative of formula 5 used as a starting material in the present invention can be easily prepared by using a known method (Ikegami, S et al., Organic Letters 2 (4): 457-460, 2000).

The method of the present invention will be described in detail according to the respective steps as follows.
Step 1) Reductive amination reaction Using an apparatus equipped with a Dean-stark trap, a condensation reaction between an inosose derivative of formula 5 and 2-amino-1,3-propanediol of formula 6 is performed. After preparing a Schiff base, a perbenzylboglibose of Formula 4 is prepared by adding a reducing agent to the same reactor to reduce the Schiff base.
The 2-amino-1,3-propanediol of the formula 6 used for the condensation reaction can be used in an amount of 1 to 5 equivalents, preferably 1.5 to 3 equivalents, relative to the inosose derivative of the formula 5. .

  As a solvent used in the condensation reaction, methanol, ethanol, propanol, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide, dioxane, tetrahydrofuran, ethyl acetate, benzene, toluene or xylene can be used alone or in combination. . In particular, the condensation reaction may be carried out while removing water produced during the reaction by azeotropic distillation using an apparatus having a Dean-Stark trap using a methanol-benzene mixture or methanol-toluene mixture as a solvent. Most preferred. When the reaction is carried out while removing water, there is an advantage that the reaction proceeds smoothly and the production of by-products is reduced. When the condensation reaction at this time is performed at the reflux temperature, a reaction time of 1 to 3 hours is sufficient.

  On the other hand, the generated Schiff base can be reduced using a reducing agent, such as sodium borohydride, potassium borohydride, lithium borohydride, sodium methoxyborohydride, sodium cyanoborohydride, Lithium aluminum hydride, dimethylamine borane and the like can be used, and sodium cyanoborohydride is particularly preferably used.

  The reducing agent can be used in an amount of 1 to 15 equivalents, preferably 2 to 6 equivalents, relative to the inosose derivative of Formula 5.

Examples of the solvent used in the reduction reaction include methanol, ethanol, N, N-dimethylformamide, dioxane, tetrahydrofuran, acetonitrile, and the like, and methanol is particularly preferable.
The reduction reaction is performed at a temperature of 0 to 50 ° C., preferably 10 to 30 ° C. for 1 to 24 hours.

Step 2) Benzenesulfonic acid addition reaction After the reductive amination reaction of Step 1) above, the perbenzyl voglibose of formula 4 obtained through the post-treatment is dissolved in a specific solvent and benzenesulfonic acid is added. Benzyl voglibose precipitates as a solid in solution in the form of the acid addition salt of formula 3. After filtering the produced solid, the perbenzylboglibose benzene sulfonate of Formula 3 and the filtrate obtained as a solid were analyzed using thin film chromatography (TLC) and high performance liquid chromatography (HPLC). It was confirmed that the perbenzyl voglibose benzene sulfonate of formula 3 that was effectively removed through the liquid and detected with a single spot was obtained in a very pure state of over 99% (HPLC area%). .

The method obtained by separation in the form of the benzenesulfonate is simpler, more efficient in separation and more efficient in comparison with the conventional method in which the reaction product is separated and purified through column chromatography after the reductive amination reaction. This method is excellent in terms of purity.
In the reaction, benzenesulfonic acid is used in an amount of 1 to 2 equivalents, preferably 1.05 to 1.5 equivalents, relative to the inosose derivative of Formula 5.

  As the solvent used in the reaction, acetonitrile, dioxane, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, diethyl ether, isopropyl ether, methylene chloride, chloroform, benzene or toluene, or a mixture thereof is particularly preferable. It is preferable to use a mixture of isopropyl ether and acetonitrile.

  When a benzenesulfonic acid addition reaction is carried out after the reductive amination reaction according to the present invention, it is possible to obtain a perbenzyl voglibose benzenesulfonate of formula 3 in a yield of 80 to 85%.

Step 3) Deprotection Reaction The perbenzylboglibose benzene sulfonate of formula 3 obtained in Step 2 above is a tetrabenzyl compound in which four hydroxy groups are protected with a benzyl group, comprising a palladium-based catalyst, For example, a hydrogen reduction reaction is performed using palladium / carbon, palladium acetate, palladium chloride, palladium bromide, palladium iodide, palladium oxide, palladium hydroxide, or the like as a catalyst to remove the benzyl group. Generally, it is not easy to remove all four benzyl groups at one time. However, the perbenzyl voglibose benzene sulfonate of formula 3 according to the present invention is obtained by adding benzene sulfonic acid to a small amount of a palladium-based catalyst, and By carrying out the reaction under hydrogen, the deprotection reaction proceeds very effectively.

  As the palladium-based catalyst, it is preferable to use 5% -palladium / carbon and 10% -palladium / carbon of Degussa type, and particularly when considering the reaction time and the purity of the reaction product, 10% -palladium. Most preferably, carbon is used.

  The 10% -palladium / carbon may be used in an amount of 2 to 10% by weight based on the perbenzylboglibose benzene sulfonate of formula 3, and the amount is preferably 3 to 5% by weight.

  Thus, the method of the present invention is very low, 2-10% by weight, compared to the conventional method using a palladium / carbon catalyst in an amount of 100% by weight by using benzyl sulfonate of perbenzylboglibose. Even if it is used in an amount, the deprotection reaction can be carried out effectively, so when considering that the palladium catalyst is very expensive, it is an economical production method that can produce voglibose at a low cost. .

In the present invention, it is preferable to carry out the reaction by supplementing benzenesulfonic acid so that the deprotection reaction proceeds at a normal pressure within a shorter time.
In the above, benzenesulfonic acid can be used in an amount of 0.1-3.0 equivalents relative to the perbenzylboglibose benzenesulfonate of formula 3, and can be used in an amount of 0.3-1.5 equivalents. preferable.

  As the reaction solvent, alcohols such as methanol, ethanol, isopropanol, ethylene glycol, 1,2-propanediol or tetrahydrofuran generally used in the deprotection reaction can be used, and in particular, methanol-tetrahydrofuran mixed solvent Is preferably used.

The deprotection reaction is carried out at a temperature of 10 to 50 ° C., preferably 20 to 30 ° C. for 2 to 24 hours. After the reaction, the deprotected voglibose benzenesulfonate of formula 2 is converted into a solid in the reaction solvent. Although dissolved without precipitation, the reaction solution was filtered to remove the palladium-based catalyst, and the filtrate was distilled and concentrated, and immediately used for the next reaction.

Step 4) liberation reaction (neutralization reaction)
In order to obtain the voglibose of formula 1 which is the final object of the present invention, the voglibose benzenesulfonate of formula 2 must be converted to the free-base form, which is why voglibose of formula 2 Benzene sulfonate is reacted with a base.
In the liberation reaction, it is preferable to use an organic base rather than an inorganic base as a base in an organic solvent. Voglibose has many hydroxyl groups and dissolves easily in water, so if neutralized in water, it is difficult to separate voglibose in a pure state. It is difficult to separate the salt and voglibose. However, if the voglibose acid addition salt is dissolved in an organic solvent and an organic base is added, the newly formed neutralized salt is dissolved in the organic solvent, whereas the liberated voglibose of Formula 1 has low solubility in the organic solvent. Therefore, since it precipitates as a solid in an organic solvent, only voglibose can be easily separated with high purity.

As such an organic base, cyclic amine, primary amine, secondary amine or tertiary amine can be used. For example, cyclohexylamine, dicyclohexylamine, diisopropylamine, diisopropylethylamine, 1,5-diazabicyclo [4] , 3,0] non-5-ene (DBN), 1,4-diazabicyclo [2,2,2] octane (Dabco), 1,8-diazabicyclo [5,4,0] undes-7-ene (DBU) Etc.), and diisopropylethylamine is particularly preferable.
The organic base is used in an amount of 1 to 3 equivalents, preferably 1.5 to 2 equivalents, relative to voglibose benzenesulfonate of formula 2.

As the reaction solvent, acetonitrile, dioxane, tetrahydrofuran, methanol, ethanol, isopropanol and the like can be used, and ethanol is particularly preferable.
The voglibose of formula 1 obtained thereby has a very high purity with an area% of 99.9% or more as analyzed by HPLC. In particular, if the perbenzyl voglibose benzene sulfonate of formula 3 is deprotected and neutralized, voglibose of formula 1 can be obtained in a high yield of 80 to 85% in total. Therefore, the method according to the present invention enables mass production of voglibose on an industrial scale as compared with the conventional method separated and purified using a large amount of cation resin, and can be obtained with high purity and high yield. It turns out that this is a very useful method.

  Thus, perbenzyl voglibose benzene sulfonate of formula 3 is prepared using the inosose derivative of formula 5 as a starting material, and the benzyl group is removed to prepare voglibose benzene sulfonate of formula 2; According to the process of the present invention for producing voglibose of formula 1 by reaction with benzyl sulfonate, perbenzyl voglibose can be used with tetrabenzyl with a much smaller amount of palladium catalyst than existing processes. The group can be removed easily and completely under normal pressure hydrogen, especially by reacting voglibose benzenesulfonate with base to produce high purity voglibose in high yield in a simpler process. it can.

  Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples illustrate the present invention, and the content of the present invention is not limited to the following examples.

２，３，４，６−テトラ−Ｏ−ベンジル−Ｄ−グルコノ−１，５−ラクトール２０ｇをジメチルスルホキシド１５０ｍｌと無水酢酸３５ｍｌとの混合液に加え、室温で７時間反応させた。反応完了後、水１００ｍｌを加えて、１時間攪拌した後、ジエチルエーテル８０ｍｌを加えて抽出し、有機層を分離した。水層を酢酸エチル６０ｍｌで抽出し、前記の分離した有機層と混合した。この有機層に飽和重炭酸ナトリウム溶液５０ｍｌを加えて１時間室温で攪拌した後、ＮａＣｌ飽和溶液でさらに洗浄してから有機層を分離し、無水硫酸マグネシウムで乾燥させた。ろ過して得たろ液を減圧下で蒸留して淡黄色オイル状の標題化合物２０．０ｇ(収率：１００％)を得た。
Ｒ_ｆ＝０．６(ｎ−ヘキサン／酢酸エチル、２：１、ｖ／ｖ)
¹H-NMR (300MHz, CDCl₃ δ): 3.69〜3.73 (m, 2H), 4.13 (d, J=6.5Hz, 1H), 4.47〜4.74 (m, 8H), 5.0 (d, J=11.4Hz, 1H), 7.19〜7.38 (m, 20H) Production Example 1
Production of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone

20 g of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactol was added to a mixed solution of 150 ml of dimethyl sulfoxide and 35 ml of acetic anhydride and reacted at room temperature for 7 hours. After completion of the reaction, 100 ml of water was added and stirred for 1 hour, followed by extraction with 80 ml of diethyl ether, and the organic layer was separated. The aqueous layer was extracted with 60 ml of ethyl acetate and mixed with the separated organic layer. To this organic layer, 50 ml of saturated sodium bicarbonate solution was added and stirred for 1 hour at room temperature. After further washing with a saturated NaCl solution, the organic layer was separated and dried over anhydrous magnesium sulfate. The filtrate obtained by filtration was distilled under reduced pressure to obtain 20.0 g (yield: 100%) of the title compound as a pale yellow oil.
R _f = 0.6 (n-hexane / ethyl acetate, 2: 1, v / v)
¹ H-NMR (300MHz, CDCl ₃ δ): 3.69 ~ 3.73 (m, 2H), 4.13 (d, J = 6.5Hz, 1H), 4.47 ~ 4.74 (m, 8H), 5.0 (d, J = 11.4Hz , 1H), 7.19-7.38 (m, 20H)

前記製造例１で製造された２，３，４，６−テトラ−Ｏ−ベンジル−Ｄ−グルコノ−１，５−ラクトン２０ｇをトルエン１００ｍｌに加えてネオペンチルグリコール５．６ｇを徐々に滴加した後、１時間室温で攪拌した。メトキシトリメチルシラン２５．５ｍｌを徐々に滴加し、トリメチルシリルトリフルオロメタンスルホネート０．７ｍｌを加えた後、４０〜４５℃を維持しながら５時間攪拌した。反応が終わった後、氷水を加えて冷却させ、トリエチルアミンを滴加してｐＨを７に調整した。トルエンを減圧下で除去し、残渣を塩化メチレン１００ｍｌに溶解して水１２０ｍｌで洗浄した後、有機層を無水硫酸マグネシウムで乾燥させた。ろ過して得たろ液を減圧下で蒸留し、析出した固体にメタノール１５０ｍｌ−水５０ｍｌを洗浄し、再結晶させた後、ろ過してから熱風乾燥して白色固体状の標題化合物１９．１ｇ(収率：８３％)を得た。
Ｒ_ｆ＝０．５(ｎ−ヘキサン／酢酸エチル、３：１、ｖ／ｖ)
¹H-NMR (300MHz, CDCl₃ δ): 0.76 (s, 3H), 3.38 (dd, J=2.4, 10.2Hz, 1H), 3.40 (dd, J=2.4, 10.2Hz, 1H), 3.53〜3.76 (m, 6H), 3.87 (t, J=9.2Hz, 1H), 4.06 (d, J=10.7Hz, 1H), 4.51 (d, J=11.0Hz, 1H), 4.55 (d, J=12.2Hz, 1H), 4.63 (d, J=12.2Hz, 1H), 4.74 (d, J=11.0Hz, 1H), 4.76 (d, J=11.3Hz, 1H), 4.83 (d, J=11.0Hz, 1H), 4.95 (d, J=11.0Hz, 1H), 5.02 (d, J=11.3Hz, 1H), 7.14〜7.40 (m, 20H) Production Example 2
Preparation of 2,3,4,6-tetra-O-benzyl-5,5-dimethylspiro [1,5] -anhydro-D-glucitol-1,2- [1,3] dioxane

20 g of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone produced in Production Example 1 was added to 100 ml of toluene, and 5.6 g of neopentyl glycol was gradually added dropwise. Thereafter, the mixture was stirred at room temperature for 1 hour. 25.5 ml of methoxytrimethylsilane was gradually added dropwise, 0.7 ml of trimethylsilyl trifluoromethanesulfonate was added, and the mixture was stirred for 5 hours while maintaining 40 to 45 ° C. After the reaction was completed, ice water was added and cooled, and triethylamine was added dropwise to adjust the pH to 7. Toluene was removed under reduced pressure, the residue was dissolved in 100 ml of methylene chloride and washed with 120 ml of water, and then the organic layer was dried over anhydrous magnesium sulfate. The filtrate obtained by filtration was distilled under reduced pressure, and the precipitated solid was washed with 150 ml of methanol-50 ml of water, recrystallized, filtered, and then dried with hot air to give 19.1 g of the title compound as a white solid ( Yield: 83%).
R _f = 0.5 (n-hexane / ethyl acetate, 3: 1, v / v)
¹ H-NMR (300MHz, CDCl ₃ δ): 0.76 (s, 3H), 3.38 (dd, J = 2.4, 10.2Hz, 1H), 3.40 (dd, J = 2.4, 10.2Hz, 1H), 3.53 to 3.76 (m, 6H), 3.87 (t, J = 9.2Hz, 1H), 4.06 (d, J = 10.7Hz, 1H), 4.51 (d, J = 11.0Hz, 1H), 4.55 (d, J = 12.2Hz , 1H), 4.63 (d, J = 12.2Hz, 1H), 4.74 (d, J = 11.0Hz, 1H), 4.76 (d, J = 11.3Hz, 1H), 4.83 (d, J = 11.0Hz, 1H ), 4.95 (d, J = 11.0Hz, 1H), 5.02 (d, J = 11.3Hz, 1H), 7.14-7.40 (m, 20H)

Production Example 3
Production of inosose derivative (formula 5)

<Step 1> Methyl addition reaction 417 ml of 2M trimethylaluminum in toluene was placed in a reaction vessel and heated to 60 ° C., and then 2,3,4,6-tetra-O-benzyl-5, obtained in Production Example 2 was used. A solution prepared by dissolving 100 g of 5-dimethylspiro [1,5] -anhydro-D-glucitol-1,2- [1,3] dioxane in 200 ml of toluene was gradually added dropwise, and the reaction mixture was brought into and out of 90 ° C. Heated and stirred for 2 hours. After completion of the reaction, 600 ml of toluene was added to lower the temperature to 5 to 10 ° C., and then 600 ml of water was gradually added dropwise, followed by stirring for 1 hour. The free organic layer was separated, and the aqueous layer was extracted twice with 300 ml of diethyl ether and then mixed with the organic layer. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate obtained was distilled under reduced pressure to obtain a pale yellow oily residue.

<Step 2> Oxidation reaction 1.2 L of diketyl sulfoxide and 300 ml of acetic anhydride were added to the pale yellow oily residue obtained in the methyl addition reaction in Step 1, and the mixture was stirred overnight at room temperature. 1 L of water was added in an ice bath, 2 L of diethyl ether was added, and the mixture was stirred at room temperature for 2 hours to separate the organic layer. The separated organic layer was washed three times with 1 L of saturated sodium bicarbonate solution and once with 1 L of saturated NaCl solution, dried over anhydrous magnesium sulfate and filtered, and then the filtrate was distilled under reduced pressure to give a yellow oil. Of residue was obtained.

<Step 3> Cyclization reaction 1 L of tetrahydrofuran and 150 ml of water were added to the residue obtained in the oxidation reaction of Step 2 above and stirred, and then 22.4 g of zinc chloride was added and refluxed for 3 hours. After refluxing, the temperature was lowered to room temperature and 1 L of water was slowly added dropwise. The organic layer separated by extraction with 1 L of diethyl ether was washed twice with 1 L of saturated sodium bicarbonate solution and once with 1 L of saturated NaCl solution, then dried over anhydrous magnesium sulfate, filtered, and then the solvent was removed under reduced pressure. Was removed. The residue was dissolved in 150 ml of chloroform and crystallized while gradually adding 200 ml of n-hexane. The produced solid was filtered and dried with hot air to obtain 44.2 g (yield: 50%) of the title compound as a fine white solid.
_Rf = 0.35 (n-hexane / ethyl acetate, 2: 1, v / v)
¹ H-NMR (300MHz, CDCl ₃ δ): 2.45 (dd, J = 3.0, 15.0Hz, 2H), 2.85 (s, 1H), 3.17 (d, J = 9.0Hz, 1H), 3.55 (d, J = 9.0Hz, 1H), 4.06 (d, J = 9.0Hz, 2H), 4.15 (d, J = 9.0Hz, 1H), 4.44 (d, J = 10.0Hz, 2H), 4.55 (d, J = 12.0 Hz, 1H), 4.77 (d, J = 12.0Hz, 2H), 4.95 to 5.03 (m, 3H), 7.08 to 7.42 (m, 20H)
Example 1

<Stage 1>
(1S)-(1 (OH), 2,4,5 / 1,3) -2,3,4-tri-O-benzyl-5-[[2-hydroxy-1- (hydroxymethyl) ethyl] amino Preparation of 1-C-[(benzyloxy) -methyl] -1,2,3,4-cyclohexanetetrol benzene sulfonate (perbenzyl voglibose benzene sulfonate, formula 3)

(1-1)
Production of perbenzylbogrubose (Formula 4) 20 g of the inosource derivative obtained in Production Example 3 was added to 400 ml of a methanol-toluene (1: 1 v / v) mixture, and 7.5 g of serinol was gradually added dropwise. The mixture was stirred for 1 hour under reflux, and reacted while removing the reaction water generated during the condensation reaction using an apparatus equipped with a Dean-stark trap. After the reaction, the methanol-toluene mixture was removed under reduced pressure, and 400 ml of ethyl acetate and 200 ml of water were added to the residue to separate the organic layer. The separated organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was distilled under reduced pressure to obtain a pale yellow oily residue. 1 L of methanol was added to the residue, and the mixture was stirred overnight while adding 13.6 g of sodium borohydride in 1 / 3-minute portions at 1 hour intervals. After the reaction was completed, 400 ml of ethyl acetate and 200 ml of water were added to the residue obtained by removing methanol under reduced pressure, and the organic layer was separated. The separated organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was distilled under reduced pressure to obtain a pale yellow oily residue.

(1-2)
Production of perbenzyl voglibose benzenesulfonate (formula 3)
To the residue obtained in (1-1), 200 ml of acetonitrile-isopropyl ether (1: 1 v / v) was added, 6.0 g of benzenesulfonic acid was added, and the mixture was stirred at room temperature for 2 hours. After gradually adding 100 ml of isopropyl ether and stirring at room temperature for 2 hours, the precipitated crystals were filtered. The filtered crystals were washed with 80 ml of acetonitrile-isopropyl ether (1: 2, v / v) and dried with hot air to obtain 23.6 g of the title compound as a white solid (yield: 83%).
R _f = 0.2 (methylene chloride / methanol, 20: 1, v / v)
¹ H-NMR (300MHz, CDCl ₃ δ): 1.75 (d, J = 15.0Hz, 1H), 2.22 (d, J = 15.5Hz, 1H), 3.45 ~ 3.51 (m, 3H), 3.54 (brd s, 1H), 3.85 to 4.16 (m, 7H), 4.27 (d, J = 9.0Hz, 1H), 4.41 to 4.54 (m, 3H), 4.63 (d, J = 10.5Hz, 1H), 4.75 (d, J = 10.5Hz, 2H), 7.07 ~ 7.30 (m, 23H), 7.79 (d, J = 10Hz, 2H)

前記実施例１で得たペルベンジルボグリボースベンゼンスルホン酸塩１０ｇをテトラヒドロフラン−メタノール(１：１、ｖ／ｖ)１００ｍｌに溶解し、１０％−パラジウム／炭素(ｄｅｇｕｓｓａ)０．３ｇ及びベンゼンスルホン酸２．０ｇを加えた後、常圧の水素気流中で室温を維持しながら１２時間攪拌した後、反応混合液をセライトを通してろ過した。得られたろ液をテトラヒドロフラン−メタノール(１：１、ｖ／ｖ)２０ｍｌで洗浄し、ジイソプロピルアミン９．１ｍｌを加えた後、室温で２時間攪拌した。析出した結晶をメタノール３０ｍｌで洗浄し、乾燥して白色の標題化合物２．８６ｇ(収率：８４％)を得た。
Ｒ_ｆ＝０．３(イソプロパノール／酢酸／水、５：１：１、ｖ／ｖ)
¹H-NMR (300MHz, D₂O δ): 1.45 (dd, J=2.7, 15.0Hz, 1H), 2.01 (dd, J=3.1, 15.0Hz, 1H), 2.81 (m, 1H), 3.34 (dt, J=2.7, 3.1, 4.0Hz, 1H), 3.37 (d, J=9.0Hz, 1H), 3.45 (s, 1/2H), 3.54 (s, 1/2H), 3.58〜3.65 (m, 5H), 3.76 (t, J=9.2, 9.6Hz, 1H) <Stage 2>
(1S)-(1 (OH), 2,4,5 / 1,3) -5-[[2-hydroxy-1- (hydroxymethyl) ethyl] amino] -1-C- [hydroxymethyl] -1 , 2,3,4-Cyclohexanetetrol (Voglibose, Formula 1)

10 g of perbenzylboglibose benzenesulfonate obtained in Example 1 was dissolved in 100 ml of tetrahydrofuran-methanol (1: 1, v / v), 0.3 g of 10% palladium / carbon (degussa) and benzenesulfonic acid 2 After adding 0.0 g, the mixture was stirred for 12 hours while maintaining room temperature in a hydrogen stream under normal pressure, and then the reaction mixture was filtered through celite. The obtained filtrate was washed with 20 ml of tetrahydrofuran-methanol (1: 1, v / v), 9.1 ml of diisopropylamine was added, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were washed with 30 ml of methanol and dried to obtain 2.86 g of white title compound (yield: 84%).
R _f = 0.3 (isopropanol / acetic acid / water, 5: 1: 1, v / v)
¹ H-NMR (300MHz, D ₂ O δ): 1.45 (dd, J = 2.7, 15.0Hz, 1H), 2.01 (dd, J = 3.1, 15.0Hz, 1H), 2.81 (m, 1H), 3.34 ( dt, J = 2.7, 3.1, 4.0Hz, 1H), 3.37 (d, J = 9.0Hz, 1H), 3.45 (s, 1 / 2H), 3.54 (s, 1 / 2H), 3.58 to 3.65 (m, 5H), 3.76 (t, J = 9.2, 9.6Hz, 1H)

The purity of voglibose produced as described above was analyzed by HPLC (column: Asahipak NH2P-50 4E (manufactured by Shodex), eluent: acetonitrile / pH 6.5 sodium phosphate buffer mixture (63:37)). The content was measured using a potentiometric method, but 0.4 g of voglibose was precisely measured, dissolved in 80 ml of glacial acetic acid, titrated with 0.1N perchloric acid, and then corresponding to 1 ml of 0.1N-perchloric acid. The content was determined by the procedure for calculating the amount (mg) of voglibose as follows.
HPLC purity: 99.97% (area%)
Content: 99.4%
Melting point (mp): 165-166 ° C

Example 2
The same procedure as in Example 1 was performed except that ethanol was used in place of tetrahydrofuran-methanol in Step 2 of Example 1 to obtain voglibose having a purity of 99.94% in a yield of 82%.

  The method for producing voglibose according to the present invention uses a benzenesulfonate salt of perbenzylboglibose, thereby producing a voglibose production method using perbenzylboglibose hydrochloride (eg, International Publication No. WO2005 / 030698, yield: 54%). Compared to this, voglibose can be produced with remarkably superior purity and yield.

Claims (9)

1) preparing a perbenzylvoglibose of formula 4 through a reductive amination reaction of an inosose derivative of formula 5 with 2-amino-1,3-propanediol of formula 6;
2) adding benzene sulfonic acid to the perbenzyl voglibose to produce perbenzyl voglibose benzene sulfonate of formula 3;
3) deprotecting the benzyl group of the perbenzyl voglibose benzene sulfonate to produce voglibose benzene sulfonate of formula 2; and 4) treating the voglibose benzene sulfonate with a base to liberate voglibose. A process for producing voglibose of formula 1 comprising steps:

In the above formula, Ph is a phenyl group, and Bn is a benzyl group.   The method according to claim 1, wherein in step 2), benzenesulfonic acid is used in an amount of 1 to 2 equivalents with respect to the inosose derivative of formula 5.   The method according to claim 1, wherein in step 3), the deprotection reaction is performed using a palladium catalyst and benzenesulfonic acid in the presence of hydrogen at normal pressure.   4. The process according to claim 3, wherein the palladium catalyst is a degussa type 10% palladium / carbon.   The method according to claim 4, wherein the 10% -palladium / carbon is used in an amount of 3 to 5% by weight based on the perbenzylboglibose benzenesulfonate of formula 3.   The said benzenesulfonic acid is used in the quantity of 0.1-3.0 equivalent with respect to the perbenzyl voglibose benzenesulfonate of Formula 3, The manufacturing method of Claim 3 characterized by the above-mentioned.   The production method according to claim 6, wherein the benzenesulfonic acid is used in an amount of 0.3 to 1.5 equivalents with respect to the perbenzylboglibose benzenesulfonate of formula 3.   In step 4), the base is cyclohexylamine, dicyclohexylamine, diisopropylamine, diisopropylethylamine, 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), 1,4-diazabicyclo [2,2, 2) The production method according to claim 1, wherein the production method is selected from the group consisting of octane (Dabco) and 1,8-diazabicyclo [5,4,0] undes-7-ene (DBU).   The method according to claim 8, wherein the base is diisopropylethylamine.