KR100592065B1 - Method for preparing valenamine and its hydrochloride - Google Patents

Abstract

The present invention provides the following formula (I) [(1S, 2S, 3S, 4R) -1-amino-5- (hydroxymethyl) cyclohex-5-cene-2,3,4-triol] ( The present invention relates to a method for preparing a valenamine) or a hydrochloride thereof, and to a method for easily preparing a valenamine with high purity by reacting acarbose with alkyl or arylsulfonic acid.

Valeienamine, (1S, 2S, 3S, 4R) -1-amino-5- (hydroxymethyl) cyclohex-5-cene-2,3,4-triol, acarbose, sulfonic acid (sulfonic aicd)

Description

Method of Preparing Valienamine and Its Hydrochloride Salt

The present invention relates to (1S, 2S, 3S, 4R) -1-amino-5- (hydroxymethyl) cyclohex-5-, which is a key intermediate of voglibose, an oral hypoglycemic agent of formula (II). It relates to a new process for preparing sen-2,3,4-triol (valienamine). More specifically, the present invention is to easily prepare a Balinamine or its hydrochloride with high purity by reacting easily obtainable acarbose or acarbose derivatives with alkyl or arylsulfonic acid represented by the following general formula (III). It is about a method.

In the formula (III), R is R ₁ is substituted C _1-12 alkyl, R ₁ is substituted C _3-7 cycloalkyl, R ₁ is _3-7 alkenyl substituted with C, R ₁ is substituted phenyl , R ₁ is substituted naphthyl, or R ₁ is substituted C _3-9 heterocyclic aryl: R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkoxy, C _1-6 acyloxy, C _{1 -6} alkylsulfonyl, C _1-6 alkylthio, C _1-12 alkyl, C _3-7 cycloalkyl, C _3-7 alkenyl, phenyl, naphthyl, or C _3-9 heterocyclicaryl.

The molecular structure of valenamine is very similar to α-D-glucose, and has a strong inhibitory effect on glucosidase. The natural products having a structure similar to the Baliienamine include Salbostatin, acarbose, and valididamycin A. Among them, acarbose is used as a type 2 diabetes drug, and valididamycin A is It is used as an antibiotic for agriculture. In addition, Balienamine can be used as a key intermediate for voglibose, which is drawing attention as a new oral hypoglycemic agent, and it can also be used for the development of new oral hypoglycemic agents based on Balienamine. have.

The conventional technology of commercially preparing ballienamine may be divided into a technique of directly preparing a valenamine through microbial fermentation and a technique of decomposing the derivative of the valenamine into a microorganism or a chemical.

Method of preparing baliamine by decomposing validamycin A using microorganisms Pseudomonas denitrificans or Flavobacterium saccharophilum is described in J. Chem. Soc., Chem. Commun. 746 (1972), J. Antibiot. 28, 298 (1975), J. Antibiot. 33, 1573 (1980), J. Antibiot. 34, 1237 (1981), Japanese Patent 57054593 and the like. However, the method described in this document is a method in which the microorganism fermentation takes a long time and the yield is not high because the method for incubating for a predetermined time after adding to the microbial mixed solution using a validamycin as a substrate or medium. .

A method of producing balienneamine by cultivating soil microorganisms such as Streptomyces hygroscopicus is disclosed in J. Org. Chem. 66, 5066 (2001) and J. Am. Chem. Soc. 123, 2733 (2001). This technique is obtained by separating ballienamine obtained as a by-product through a column in the process of cultivating strapomyces hygroscopicus and obtaining a valididamycin derivative that is used as a fungicide. The purification process is complicated and the yield is low.

A process for preparing a valenamine by degrading the C-N bond of ballidoxyl A with N-bromosuccinimide is described in Chem. Lett. 725 (1989) and J. Chem. Soc., Perkin Trans. 1, 3287 (1991). This method also has a problem in that the purification process is difficult and the yield is low.

In addition, L-Quebrachitol (described in Angew, Chem., Int. Ed. Engl. 19, 904 (1980) and Leibigs Ann. Chem. 2180 (1981)) or D-glucose (Angew. Chem. , Int. Ed. Engl. 26, 48 (1987) and Gazz. Chim. Ital. 119, 577 (1989), D-Xylose (J. Antibiot. 53, 430 (2000) ), Cyclohexane derivatives (based on Bull. Chem. Soc. Jpn. 58, 3387 (1985)), (-)-quinic acid ((-)-Quinic Acid) (Helv, Chim, Acta, 68, 989). (1985) and the like have been reported in the synthesis of a Balienamine in a variety of methods, but these methods are all too long and complicated synthesis process has not been put to practical use.

Recently, trifluoroacetic acid (TFA) is used to prepare avalenamine from acarbose or acarbose derivatives and ballidamycin using trifluoroacetic acid (TFA), respectively, described in Korean Patent Laid-Open No. 2004-0002339 and Korean Patent Laid-Open No. 2004-0000751, respectively. have. Specifically, in the method of Korean Patent Laid-Open Publication No. 2004-0002339, an acarbose or an acarbose derivative is reacted with TFA at 2 wt. Purification at gave a Balinenamine in a yield of 50-95%. This method is the best of the above-mentioned preparation methods of Balienamine, but it is necessary to use excessive amounts of TFA that can accumulate in the body and be toxic and have a long decomposition period, and the many by-products present in the reaction solution. In order to remove the problem, it is necessary to carry out two or more ion exchange resins, which are difficult to apply in a mass production process.

Therefore, the present inventors have solved the problems of the above method, and as a result of the research for easier preparation of the valenamine, it is possible to easily obtain acarbose (acarbose) or acarbose derivatives with alkyl or arylsulfonic acid (sulfonic acid) and It was found out that when reacting, it is possible to easily prepare the valenamine or its hydrochloride salt. In addition, when the reaction mixture is washed with a mixed solvent of an alkanol having 4 or more carbon atoms and an organic solvent which is not mixed with water, and crystallized, high-purity valenamine or its hydrochloride without undergoing complicated separation and purification processes such as an ion exchange resin. Figured out that you can get.

The present inventors have studied the manufacturing process of the Republic of Korea Patent Publication No. 2004-0002339, which is known to be the easiest to manufacture among the known methods, in addition to having the disadvantages as described above, the yield of the valenamine It has been found that it appears substantially lower than that described in this publication.

Accordingly, the present inventors searched for a reagent that can more easily degrade the C-N bond of acarbose or acarbose derivatives, and studied a method for easily removing a large amount of by-products contained in the reaction solution.

As a result, the present inventors were unable to obtain valenamine in almost all organic acids except for TFA. However, surprisingly, 1.5 to 2.0 equivalents of alkylene or arylsulfonic acid were effectively prepared, and they were also complicated as ion exchange resins. Instead of uneconomical purification, the washing process using a mixed solvent of alkanol with 4 or more carbon atoms and an organic solvent that does not mix with water has developed a breakthrough method for easily removing by-products.

For TFA used in the prior art Angew. Chem., Int., Int. Ed. Engl., 25, 159 (1986) and J. Org. Chem. While it is known to be used for the decomposition of CN bonds similar to those in the prior art in various organic synthesis as described in 1985, 50, 1239 (1985), etc., in the case of the newly developed alkyl or arylsulfonic acids of the present inventors This is not known at all, which is a very interesting result in the field of organic synthesis.

In the present invention, by using alkyl or aryl sulfonic acid instead of TFA, it is possible to more effectively proceed with the production of the valenamine. By-products can be easily washed by washing the reaction solution with a mixed solvent of alkanol having 4 or more carbon atoms and an organic solvent which is not mixed with water. By removing it, it was possible to prepare the valenamine or its hydrochloride by a purification method easier than the conventional process.

An object of the present invention is (1S, 2S, 3S, 4R) -1-amino-5- (hydroxymethyl) cyclohex-5-sen represented by formula (I), which is a key intermediate of orally hypoglycemic agent, bolibos It is to provide a new method for preparing -2,3,4-triol (valienamine) or hydrochloride thereof.

Another object of the present invention is to provide a method for effectively preparing the valenamine represented by the formula (I) or its hydrochloride salt even with a smaller amount of reagent than the known art.

Still another object of the present invention is to provide a method for effectively purifying the valenamine represented by the formula (I) or a hydrochloride thereof.

Still another object of the present invention is to provide a method suitable for producing a large amount of the valenamine represented by the formula (I) or a hydrochloride thereof.

The above and other objects of the present invention can be achieved by the present invention described below.

The present invention provides (1S, 2S, 3S, 4R) -1-amino-5- (hydroxymethyl) cyclohex-5-sen- represented by the following general formula (I), which is a key intermediate of orally hypoglycemic agent, bolibos, It relates to a new method for producing 2,3,4-triol (hereinafter referred to as 'valienamine') or its hydrochloride.

In the present invention, the valenamine or its hydrochloride is prepared by reacting acarbose or acarbose derivative of the following general formula (IV) with an alkyl or arylsulfonic acid represented by the general formula (III).

In the formula (III), R is R ₁ is substituted C _1-12 alkyl, R ₁ is substituted C _3-7 cycloalkyl, R ₁ is _3-7 alkenyl substituted with C, R ₁ is substituted phenyl , R ₁ is substituted naphthyl, or R ₁ is substituted C _3-9 heterocyclic aryl: R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkoxy, C _1-6 acyloxy, C _{1 -6} alkylsulfonyl, C _1-6 alkylthio, C _1-12 alkyl, C _3-7 cycloalkyl, C _3-7 alkenyl, phenyl, naphthyl, or C _3-9 heterocyclicaryl.

Preferred embodiments of alkyl or arylsulfonic acids are methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid.

In the production process according to the present invention, by using alkyl or arylsulfonic acid represented by formula (III) instead of TFA used in the existing process, the amount of the reagent used is greatly reduced, and the reaction product is mixed with a mixture of alkanol having 4 or more carbon atoms. It is characterized by facilitating the purification process by washing.

In the present specification, acarbose is interpreted to include an acarbose derivative, and the acarbose derivative refers to a form in which one or two sugars are less than acarbose. It is also contemplated herein that the valenamine includes a variety of salt forms that can be obtained in the preparation process with the valenamine.

In the following, the present invention is described in more detail.

In the present invention, the valenamine represented by the formula (I) is prepared according to the following Scheme 1.

In the formula (III), R is R ₁ is substituted C _1-12 alkyl, R ₁ is substituted C _3-7 cycloalkyl, R ₁ is _3-7 alkenyl substituted with C, R ₁ is substituted phenyl , R ₁ is substituted naphthyl, or R ₁ is substituted C _3-9 heterocyclic aryl: R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkoxy, C _1-6 acyloxy, C _{1 -6} alkylsulfonyl, C _1-6 alkylthio, C _1-12 alkyl, C _3-7 cycloalkyl, C _3-7 alkenyl, phenyl, naphthyl, or C _3-9 heterocyclicaryl.

In a preferred embodiment according to the present invention, the acarbose or acarbose derivative represented by Formula (IV) is dissolved in excess water and then reacted with alkyl or arylsulfonic acid represented by Formula (III) to give valenamine or its hydrochloride. Manufacture. The content of water for dissolving acarbose or acarbose derivatives is not particularly limited, but is preferably 5 to 10 times based on the weight of acarbose.

The amount of alkyl or arylsulfonic acid represented by the general formula (III) used in the reaction is 1.1 to 5.0 times the acarbose represented by the general formula (IV) in an equivalent ratio, preferably 1.3 to 3.0 times, more preferably 1.5 ~ 2.0 times. When the alkyl or arylsulfonic acid used exceeds the above content, the production cost is increased and it is uneconomical. When the above content is below, the yield of the product is lowered or the reaction time is longer.

Reaction temperature is 100-120 degreeC, and reaction time is between 1 hour and 12 hours after the start of reaction.

When hydrochloric acid is added to the reaction solution obtained as a result of the reaction, hydrochloric acid of valenamine is obtained, and the amount of hydrochloric acid added is preferably 2 to 10 ml based on 100 ml of water added to dissolve acarbose.

It is most preferable to obtain the valenamine in the form of hydrochloride since the presently commercialized valenamine is mainly in the form of hydrochloride and the crystallinity of the hydrochloride form is excellent. The Baliienamine can be obtained by treating the obtained crude reaction product containing the Baliniamine hydrochloride or the crystallized Baliienamine hydrochloride with a strong base or passing through an ion exchange resin. The specific process for obtaining the valenamine from the valenamine hydrochloride can be easily carried out by those skilled in the art according to general methods known to those skilled in the art.

Another aspect of the present invention relates to a method for purifying valenamine or a hydrochloride thereof. Since the reaction product comprising the valenamine obtained according to the present invention or its hydrochloride may include by-products, the present invention may be subjected to further purification as necessary. The reaction product is washed with a mixed solvent of an alkanol having 4 or more carbon atoms and an organic solvent that is not mixed with water (also referred to as an 'alkanol mixed solvent') to remove by-products, thereby obtaining high-purity valenamine hydrochloride easily. At this time, the alkanol having 4 or more carbon atoms preferably refers to alkanol having 4 to 5 carbon atoms. Examples of alkanols having 4 or more carbon atoms include 1-butanol, 2-butanol, t-butanol, 1-pentanol, 2-pentanol, 3-pentanol, and the like. In addition, the organic solvent which is not mixed with water includes ethyl acetate, chloroform, methylene chloride and the like.

The mixing ratio of the alkanol having 4 or more carbon atoms and the organic solvent which is not mixed with water is preferably 2: 8 to 8: 2 by volume. The amount of the alkanol mixed solvent to be used is not particularly limited and may be used in excess because it is used to remove by-products and can be adjusted by those skilled in the art as needed.

The alkanol mixed solvent is added to the reaction product containing the valenamine hydrochloride, and the mixture is divided into a water layer and an organic layer. The water layer is separated, and then the water is removed to obtain crystals of the valenamine hydrochloride. If necessary, the water layer may be washed several times with the alkanol mixed solvent described above. The obtained valenamine hydrochloride can be crystallized with an organic solvent such as C1 to C4 alkanol, or C3 to C5 ketone. Preferred examples of the crystallized organic solvent are methanol, ethanol and acetone.

The purification process can be applied not only to the purification of the valenamine or the hydrochloride thereof obtained according to the present invention, but also to the purification method of the valenamine or the hydrochloride thereof obtained according to a known technique. That is, according to the known technique to obtain a valenamine or its hydrochloride, and purified and crystallized by the purification method according to the present invention can obtain a high-purity valenamine or its hydrochloride.

According to the production method of the present invention, the valenamine represented by the formula (I) or its hydrochloride salt can be easily produced in high purity from the acarbose or acarbose derivative represented by the formula (IV). In particular, by-products which may be included in the reaction product are washed with a mixed solvent of an alkanol having at least 4 carbon atoms and an organic solvent which is not mixed with water, and then crystallized in a crystallized organic solvent, if necessary, to purify the valenamine or its hydrochloride. There is a feature that facilitates.

The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of protection defined by the appended claims.

Example

Preparation of Balienamine Hydrochloride

Example 1

20 g (30.98 mmol) of acarbose was dissolved in 150 ml of water, followed by addition of 6.97 g (46.45 mmol) of trifluoromethanesulfonic acid. The reaction solution was heated at 120 ° C. for 3 hours while stirring in an autoclave. After the reaction was completed, the reaction solution was cooled and the insoluble material was removed by filtration through celite. 5 ml of concentrated hydrochloric acid was added to the filtered aqueous solution, 200 ml of a mixed solvent of 2-butanol and ethyl acetate (volume ratio 1: 1) was added thereto, followed by stirring and extraction of the water layer. 50 ml of water was added to the organic layer, followed by extraction. The combined water layers were washed twice with 100 ml of a mixed solvent of 2-butanol and ethyl acetate (volume ratio 1: 1).

1 g of activated carbon was added to the obtained water layer, stirred for 1 hour, filtered through celite to obtain a yellow aqueous solution, and water was removed under reduced pressure to obtain an oily crude product (4.50 g, 68.7%). 10 ml of ethanol was added to the crude oily product and stirred to form a solid. After all the oil phase disappeared and a solid was formed, 30 ml of acetone was added slowly and stirred. The mixture was left under ice cooling for 2 hours and then filtered to obtain 2.75 g (42.0%) of pure valenamine in the form of hydrochloride. The NMR results for the obtained product are as follows.

¹ H NMR (300 MHz, D ₂ O) δ = 3.58 (1H, ABq, J _1-2 = 10.0 Hz, J _1-6 = 7.4 Hz), 3.84 (1H, ABq, J _2-1 = 9,91 Hz, J _2-3 = 4.42 Hz), 3.95 (1H, dd, J _3-2 = 4.86 Hz, J _3-4 = 6.1 Hz), 4.01 (1H, d, J _4-3 = 6.6 Hz), 4.08 (2H , bs, H7), 5.63 (1H, m, H6)

Example 2

20 g (30.98 mmol) of acarbose was dissolved in 150 ml of water, followed by addition of 9.29 g (61.90 mmol) of trifluoromethanesulfonic acid. The reaction solution was heated at 120 ° C. for 1.5 hours while stirring in an autoclave. After the reaction was completed, the reaction solution was cooled and the insoluble material was removed by filtration through celite. 5 ml of concentrated hydrochloric acid was added to the filtered aqueous solution, 200 ml of a mixed solvent of 2-butanol and ethyl acetate (volume ratio 1: 1) was added thereto, followed by stirring and extraction of the water layer. 50 ml of water was added to the organic layer, followed by extraction. The combined water layers were washed twice with 100 ml of a mixed solvent of 2-butanol and ethyl acetate (volume ratio 1: 1).

1 g of activated carbon was added to the obtained water layer, stirred for 1 hour, filtered through celite to obtain a yellow aqueous solution, and water was removed under reduced pressure to obtain an oily crude product (4.63 g, 70.6%). 5 ml of ethanol was added to the crude oily product and stirred to form a solid. After all the oil phase disappeared and a solid was formed, 40 ml of acetone was added slowly and stirred. The mixture was left under ice cooling for 2 hours and then filtered to obtain 2.94 g (44.9%) of pure valenamine in the form of hydrochloride. The NMR results for the obtained product are as follows.

¹ H NMR (300 MHz, D ₂ O) δ = 3.58 (1H, ABq, J _1-2 = 10.0 Hz, J _1-6 = 7.4 Hz), 3.84 (1H, ABq, J _2-1 = 9,91 Hz, J _2-3 = 4.42 Hz), 3.95 (1H, dd, J _3-2 = 4.86 Hz, J _3-4 = 6.1 Hz), 4.01 (1H, d, J _4-3 = 6.6 Hz), 4.08 (2H , bs, H7), 5.63 (1H, m, H6)

Example 3

20 g (30.98 mmol) of acarbose was dissolved in 150 ml of water, followed by addition of 4.46 g (46.40 mmol) of methanesulfonic acid. The reaction solution was heated at 120 ° C. for 3 hours while stirring in an autoclave. After the reaction was completed, the reaction solution was cooled and the insoluble material was removed by filtration through celite. 5 ml of concentrated hydrochloric acid was added to the filtered aqueous solution, 200 ml of a mixed solvent of 2-butanol and ethyl acetate (volume ratio 1: 1) was added thereto, followed by stirring and extraction of the water layer. 50 ml of water was added to the organic layer, followed by extraction. The combined water layers were washed twice with 100 ml of a mixed solvent of 2-butanol and ethyl acetate (volume ratio 1: 1).

1 g of activated carbon was added to the obtained water layer, stirred for 1 hour, filtered through celite to obtain a yellow aqueous solution, and water was removed under reduced pressure to obtain an oily crude product (5.02 g, 76.6%). 15 ml of methanol was added to the crude oily product and stirred to form a solid. After all the oil phase disappeared and a solid was formed, 40 ml of acetone was added slowly and stirred. The mixture was left under ice cooling for 2 hours and filtered to obtain 2.24 g (34.2%) of pure valenamine in the form of hydrochloride. The NMR results for the obtained product are as follows.

¹ H NMR (300 MHz, D ₂ O) δ = 3.58 (1H, ABq, J _1-2 = 10.0 Hz, J _1-6 = 7.4 Hz), 3.84 (1H, ABq, J _2-1 = 9,91 Hz, J _2-3 = 4.42 Hz), 3.95 (1H, dd, J _3-2 = 4.86 Hz, J _3-4 = 6.1 Hz), 4.01 (1H, d, J _4-3 = 6.6 Hz), 4.08 (2H , bs, H7), 5.63 (1H, m, H6)

Example 4

20 g (30.98 mmol) of acarbose was dissolved in 150 ml of water, followed by addition of 8.84 g (46.47 mmol) of p-toluenesulfonic acid monohydrate. The reaction solution was heated at 120 ° C. for 3 hours while stirring in an autoclave. After the reaction was completed, the reaction solution was cooled and the insoluble material was removed by filtration through celite. 5 ml of concentrated hydrochloric acid was added to the filtered aqueous solution, 200 ml of a mixed solvent of 2-butanol and ethyl acetate (volume ratio 1: 1) was added thereto, followed by stirring and extraction of the water layer. 50 ml of water was added to the organic layer, followed by extraction. The combined water layers were washed twice with 100 ml of a mixed solvent of 2-butanol and ethyl acetate (volume ratio 1: 1).

1 g of activated carbon was added to the obtained water layer, stirred for 1 hour, filtered through celite to obtain a yellow aqueous solution, and water was removed under reduced pressure to obtain an oily crude product (5.12 g, 78.1%). 10 ml of ethanol was added to the crude oily product and stirred to form a solid. After the oil phase disappeared and a solid was formed, 50 ml of acetone was slowly added thereto and stirred. The mixture was left under ice cooling for 2 hours and then filtered to obtain 2.95 g (45.0%) of pure valenamine in the form of hydrochloride. The NMR results for the obtained product are as follows.

¹ H NMR (300 MHz, D ₂ O) δ = 3.58 (1H, ABq, J _1-2 = 10.0 Hz, J _1-6 = 7.4 Hz), 3.84 (1H, ABq, J _2-1 = 9,91 Hz, J _2-3 = 4.42 Hz), 3.95 (1H, dd, J _3-2 = 4.86 Hz, J _3-4 = 6.1 Hz), 4.01 (1H, d, J _4-3 = 6.6 Hz), 4.08 (2H , bs, H7), 5.63 (1H, m, H6)

Example 5

20 g (30.98 mmol) of acarbose was dissolved in 150 ml of water, followed by addition of 11.78 g (61.93 mmol) of p-toluenesulfonic acid monohydrate. The reaction solution was heated at 120 ° C. for 1.5 hours while stirring in an autoclave. After the reaction was completed, the reaction solution was cooled and the insoluble material was removed by filtration through celite. 5 ml of concentrated hydrochloric acid was added to the filtered aqueous solution, 200 ml of a mixed solvent of 2-butanol and ethyl acetate (volume ratio 1: 1) was added thereto, followed by stirring and extraction of the water layer. 50 ml of water was added to the organic layer, followed by extraction. The combined water layers were washed twice with 100 ml of a mixed solvent of 2-butanol and ethyl acetate (volume ratio 1: 1).

1 g of activated carbon was added to the obtained water layer, stirred for 1 hour, filtered through celite to obtain a yellow aqueous solution, and water was removed under reduced pressure to obtain an oily crude product (5.25 g, 80.1%). 10 ml of ethanol was added to the crude oily product and stirred to form a solid. After the oil phase disappeared and a solid was formed, 50 ml of acetone was slowly added thereto and stirred. The mixture was left under ice cooling for 2 hours and then filtered to obtain 3.16 g (48.2%) of pure valenamine in the form of hydrochloride. The NMR results for the obtained product are as follows.

¹ H NMR (300 MHz, D ₂ O) δ = 3.58 (1H, ABq, J _1-2 = 10.0 Hz, J _1-6 = 7.4 Hz), 3.84 (1H, ABq, J _2-1 = 9,91 Hz, J _2-3 = 4.42 Hz), 3.95 (1H, dd, J _3-2 = 4.86 Hz, J _3-4 = 6.1 Hz), 4.01 (1H, d, J _4-3 = 6.6 Hz), 4.08 (2H , bs, H7), 5.63 (1H, m, H6)

The present invention has the effect of providing a method for easily preparing high-purity valenamine or a hydrochloride thereof, which is a key intermediate of orally glyco lowering agent, bolibos, by reacting acarbose or acarbose derivatives with alkyl or arylsulfonic acid. In the prior art related to the preparation of the valenamine, the amount of reagents used is large, and the ion exchange resin is used to purify the reaction product, but the separation and purification using the ion exchange resin is difficult to apply to the actual mass process. have. However, the present invention uses alkyl or arylsulfonic acid instead of trifluoroacetic acid, which is used in the conventional process, to drastically reduce the amount of reagent used and to mix the reaction solution with an alkanol having 4 or more carbon atoms and an organic solvent that does not mix with water. It has the advantage that it can be easily purified by crystallization in an organic solvent after washing.

Simple modifications and variations of the present invention can be readily understood by those skilled in the art, and all such variations or modifications can be considered to be included within the scope of the present invention.

Claims (6)

A process for producing a valenamine represented by formula (I) or a hydrochloride thereof by reacting acarbose or acarbose derivative represented by formula (IV) with alkyl or arylsulfonic acid represented by formula (III).

In the formula (III), R is R ₁ is substituted C _1-12 alkyl, R ₁ is substituted C _3-7 cycloalkyl, R ₁ is _3-7 alkenyl substituted with C, R ₁ is substituted phenyl , R ₁ is substituted naphthyl, or R ₁ is substituted C _3-9 heterocyclic aryl: R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkoxy, C _1-6 acyloxy, C _{1 -6} alkylsulfonyl, C _1-6 alkylthio, C _1-12 alkyl, C _3-7 cycloalkyl, C _3-7 alkenyl, phenyl, naphthyl, or C _3-9 heterocyclicaryl. The method of claim 1, wherein the alkyl or arylsulfonic acid represented by the formula (III) is methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. According to claim 1, wherein the content ratio of acarbose or acarbose derivatives with alkyl or arylsulfonic acid is 1: 1.1 to 5.0 in an equivalent ratio, and the acarbose or acarbose derivatives with alkyl or arylsulfonic acid are reacted at 100 to 120 ° C. for 1 to 12 hours. A process for producing a balienamine or a hydrochloride thereof. The acarbose or acarbose derivative represented by the formula (IV) is reacted with an alkyl or arylsulfonic acid represented by the formula (III), and the reaction product is washed with a mixed solvent of alkanol having 4 or more carbon atoms and an organic solvent which does not mix with water. A crystallization method of baliamine or hydrochloride thereof comprising the step of crystallizing with one or more organic solvents selected from methanol, ethanol or acetone.

In the formula (III), R is R ₁ is substituted C _1-12 alkyl, R ₁ is substituted C _3-7 cycloalkyl, R ₁ is _3-7 alkenyl substituted with C, R ₁ is substituted phenyl , R ₁ is substituted naphthyl, or R ₁ is substituted C _3-9 heterocyclic aryl: R ₁ is hydrogen, halogen, hydroxy, C _1-6 alkoxy, C _1-6 acyloxy, C _{1 -6} alkylsulfonyl, C _1-6 alkylthio, C _1-12 alkyl, C _3-7 cycloalkyl, C _3-7 alkenyl, phenyl, naphthyl, or C _3-9 heterocyclicaryl. Balinene consisting of a step of washing the aqueous solution of ballienamine hydrochloride with a mixed solvent of alkanol having 4 or more carbon atoms and an organic solvent not mixed with water, and crystallizing with one or more organic solvents selected from methanol, ethanol or acetone Method for purifying amine or its hydrochloride. The alkanol having 4 or more carbon atoms is 2-butanol, and the organic solvent which is not mixed with water is ethyl acetate, chloroform, or methylene chloride, and has 4 or more carbon atoms. The mixing ratio of the non-mixing organic solvent is 2: 8 to 8: 2 by volume ratio of the purification method of the valenamine or its hydrochloride.