KR20140054800A - Methods of preparing a 1-deoxy-1-(2-hydroxyethyl amino)-d-glucitol and miglitol - Google Patents

Abstract

The present invention relates to a method for preparing 1-deoxy-1-(2-hydroxyethyl amino)-D-glucitol from D-glucitol by using a borohydride complex as a reducing agent, and to a method for preparing miglitol from the 1-deoxy-1-(2-hydroxyethyl amino)-D-glucitol. The present invention can be usefully applied in the preparation of miglitol which is a therapeutic agent for diabetes.

Description

METHODS OF PREPARING A 1-DEOXY-1- (2-HYDROXYETHYL AMINO) -D-GLUCITOL AND MIGLITOL A process for preparing 1-deoxy- 1- (2- hydroxyethylamino) }

The present invention relates to a process for producing 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol from D-glucitol using a borohydride complex as a reducing agent, - (2-hydroxyethylamino) -D-glucitol. ≪ / RTI >

Miglitol is an α-glucosidase inhibitor developed by Bayer and has been approved by the FDA in 1996 and currently sold under the trade name Glyset for the treatment of type 2 diabetes have.

Industrially, the microglycol production process is the first step to synthesize 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol from glucose and ethanolamine as shown in Scheme 2, Hydroxyethylamino-L-sorboside as a catalyst and a third step of synthesizing miglitol through chemical synthesis ( Advanced Materials Research , 197-198: pp. 55-55 (2011)).

[Reaction Scheme 2]

Previous literature on the manufacture of miglitol ( Tetrahedron Letters , 52: pp.3802-3804 (2011)) is the same as [Reaction Scheme 3].

[Reaction Scheme 3]

According to the above literature, the entire synthesis process requires a complex reaction with the protecting group due to the non-selectivity of the chemical synthesis to the chiral center in the molecule, so that the economical efficiency is low because a large amount of expensive reagent is used. Considering this point, the biotransformation reaction from the above-mentioned 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol to 6-hydroxyethylamino-L-sorbose in the production of miglitol 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol, which is an intermediate required for the bioconversion reaction, can be prepared by reacting palladium There is a hydrogenation reaction using palladium-on-charcoal (EP 0 447 7160).

[Reaction Scheme 4]

According to the method as shown in Reaction Scheme 4, palladium-on-charcoal is used as a catalyst for the hydrogenation reaction with 12N HCl to prepare 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol And the reaction is carried out at a temperature of 60 ± 5 ° C. and a pressure of 4 atm. However, the hydrogenation reaction is difficult to apply industrially because of the explosion risk. Further, there is a problem that the crystallization is difficult and the yield is relatively low due to the change of sugar due to high temperature under acidic conditions.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have succeeded in producing 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol, which is an intermediate required for the production of miglitol, at a high yield. The present inventors have made efforts to develop a novel manufacturing method capable of improving the problems of the risk and the water retention. As a result, it was confirmed that when a borohydride complex is used as a reducing agent in an organic solvent containing ethanolamine, the microleutol intermediate can be produced at a high yield without the risk of explosion of the reaction, thereby completing the present invention.

Accordingly, an object of the present invention is to provide a process for producing 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol.

Another object of the present invention is to provide a method for producing miglitol.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides a process for producing D-glucitol, which comprises reacting D-glucitol with 1-deoxy-1- (2-hydroxy Deoxy-1- (2-hydroxyethylamino) -D-glucitol, characterized in that it is prepared from 1-deoxy-

[Chemical Formula 1]

The present inventors have succeeded in producing 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol, which is an intermediate required for the production of miglitol, at a high yield. The present inventors have made efforts to develop a novel manufacturing method capable of improving the problems of the risk and the water retention. As a result, it was confirmed that when a borohydride complex is used as a reducing agent in an organic solvent containing ethanolamine, the microleutol intermediate can be produced at a high yield without the risk of explosion of the reaction, thereby completing the present invention.

The most distinguishing feature of the present invention is the use of palladium-on-charcoal for hydrogenation reactions which are potentially explosive in the process of preparing 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol But instead the boron hydride complex is used as a reducing agent. The production method of the present invention is shown in the following Reaction Scheme 1.

[Reaction Scheme 1]

As demonstrated in the following examples, the preparation method of the present invention using boron hydride complexes is superior to the conventional process using palladium-on-charcoal, in that 1-deoxy-1- (2-hydroxyethylamino) -D - The yield of the production of glucitol is markedly increased (see Table 1).

According to a preferred embodiment of the present invention, the production yield of 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol according to the production method of the present invention is 70-100% (theoretical yield) , Preferably 70-90%, more preferably 70-85%, still more preferably 70-82%; , More preferably 75 to 100%, even more preferably 75 to 90%, even more preferably 75 to 85%, still more preferably 75 to 82%; , More preferably 80 to 100%, even more preferably 80 to 90%, still more preferably 80 to 85%, still more preferably 80 to 82%.

According to a preferred embodiment of the present invention, the borohydride complex is prepared from the group consisting of sodium borohydride (NaBH ₄ ), sodium borohydride cyanoside (NaCNBH ₃ ) and dimethylaminoborane (BH ₄ N (CH ₃ ) ₂ ) Is selected.

Preferably, the borohydride complex is sodium borohydride or cyanosodium borohydride, more preferably sodium borohydride.

In the production method of the present invention, the amount by which the borohydride complex is used is 1 to 10 equivalents, preferably 2 to 5 equivalents, and more preferably 2 to 3 equivalents, relative to the molar amount of D-glucose.

According to a preferred embodiment of the present invention, the organic solvent includes an ammonium salt.

Preferably, the ammonium salt is ammonium acetate (CH ₃ COONH _4), first ammonium phosphate _{(NH 4 H 2 PO 4)} , the second ammonium phosphate ((NH _{4) 2} HPO _4), ammonium sulfate ((NH _{4) 2} SO ₄ ), ammonium nitrate (NH ₄ NO ₃ ) and ammonium carbonate ((NH ₄ ) ₂ CO ₃ ), more preferably ammonium acetate.

In the production method of the present invention, the amount of the ammonium salt to be used is 1 to 20 equivalents, preferably 3 to 15 equivalents, and more preferably 5 to 10 equivalents, relative to the molar amount of D-glucose.

According to a preferred embodiment of the present invention, the organic solvent may be an alcohol-based solvent such as methyl alcohol, ethyl alcohol, propyl alcohol or isopropyl alcohol; Ester solvents containing ethyl acetate; A haloalkane-based solvent including methylene chloride and chloroform; An ether solvent comprising tetrahydrofuran; A ketone-based solvent comprising acetone and methyl ethyl ketone; Nitrile solvents including acetonitrile and propionitrile; Amide-based solvents including dimethylformamide and dimethylacetamide; A sulfoxide-based solvent containing dimethylsulfoxide; A solvent in which the two or more organic solvents are mixed; Or a solvent in which the organic solvent and water are mixed.

Preferably, the organic solvent is an alcohol-based solvent, and more preferably the alcohol-based solvent is ethyl alcohol.

The volume of the solvent used in the production method of the present invention is 1: 1-20, preferably 1: 1-15, more preferably 1: 1, in terms of volume (ml) to mass (g) of D- 5-10.

According to a preferred embodiment of the present invention, the production process of the present invention proceeds at a lower temperature than the conventional production process using palladium-on-charcoal.

Preferably, the reaction process of the present invention proceeds at a temperature of -20 to 60 占 폚, preferably at a temperature of 0 to 40 占 폚, and more preferably at a temperature of 20 to 40 占 폚.

In the production process of the present invention, the reaction time is from 5 minutes to 24 hours, preferably from 30 minutes to 5 hours, more preferably from 30 minutes to 1 hour.

In the production method of the present invention, for the isolation and purification of 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol, chromatography using an ion exchanger, silica gel or silylated silica gel, Can be concentrated and then crystallized with a suitable solvent.

Suitable ion exchangers of the present invention include both weakly acidic, strongly acidic, weakly basic and strongly basic forms, and are preferably strongly acidic or strongly basic ion exchangers.

Suitable crystallization solvents of the present invention include ester solvents such as ethyl acetate; Haloalkane-based solvents such as methylene chloride and chloroform; Ether solvents such as tetrahydrofuran; Ketone solvents such as acetone and methyl ethyl ketone; Nitrile solvents such as acetonitrile and propionitrile; Alcohol solvents such as methyl alcohol, ethyl alcohol, propanol and isopropanol; And organic solvents in which two or more of them are mixed.

Preferably, the crystallization solvent is ethyl alcohol. The used volume of the crystallization solvent is from 1.0 to 20 times, preferably from 5 to 10 times by volume (ml) to the weight (g) of D-glucose used.

The progress of the reaction process can be analyzed and measured using means such as thin film chromatography or ELSD (Evaporative Light Scattering Detector).

According to another aspect of the present invention, the present invention provides a process for preparing Miglitol comprising the steps of:

(a) D-glucitol is reacted with 1-deoxy-1- (2-hydroxyethylamino) -D-glucide of the above formula (1) using anhydrous boron complex as an reducing agent in an organic solvent containing ethanolamine Lt; / RTI >

(b) 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol prepared in step (a) was treated with a strain of the genus Gluconobacter or its dormant cells Biotransformation to hydroxyethylamino-L-sorbose; And

(c) synthesizing the biotransformed 6-hydroxyethylamino-L-sorbose in step (b) with miglitol.

Since the method for producing miglitol of the present invention uses the above-described method for producing 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol, the contents common to both of them Its description is omitted in order to avoid excessive complexity.

According to a preferred embodiment of the present invention, step (b) comprises culturing the strain of the genus Gluconobacter or the dormant cell of the microorganism in a culture medium containing 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol Lt; / RTI > culture medium. In this case, 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol may be added before the strain is inoculated into the medium or added after the inoculation of the strain, Or may be added continuously or in divided portions throughout the culturing process. The amount of 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol to be used can be determined experimentally by those skilled in the art. Preferably, the medium for the production of 6-hydroxyethylamino-L-sorbose comprises 10 g / l to 150 g of 1-deoxy-1- (2-hydroxyethylamino) / L, more preferably in a concentration of 10 g / L to 100 g / L, still more preferably in a concentration of 10 g / L to 80 g / L. When the strain is used in the form of a resting cell paste, the culture medium is prepared by dissolving 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol in an amount of 10 to 200 g / By weight, more preferably from 10 g / L to 150 g / L.

The medium used in the production method of the present invention is not limited to 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol but also D-glucitol, nitrogen source, inorganic salt and trace elements, And may include at least one other carbon source. The amount of each ingredient added is preferably selected to maximize the production of 6-hydroxyethylamino-L-sorbose, the amount of which can be determined empirically by one skilled in the art according to various methods known in the art . As a culture condition for maximizing the production of 6-hydroxyethylamino-L-sorbose from 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol, temperature, pH, , Incubation period, etc., can be determined experimentally by those skilled in the art. The choice of specific culture conditions may vary depending on the strain used, dormant cells, media composition, culture size, and other considerations.

According to a preferred embodiment of the present invention, the culture temperature of the strain in the production method of the present invention is 15 to 37 캜, preferably 25 캜. The preferred pH of the culture is in the range of 4.0 to 8.0, preferably in the range of 4.5 to 7.0, and more preferably 5.5 to 6.0.

In the present invention, for the production of 6-hydroxyethylamino-L-sorbose, a cell extract of a strain of the genus Gluconobacter or a cell extract of a dormant cell of the microorganism may be used. The method for producing 6-hydroxyethylamino-L-sorbose using a cell extract comprises the steps of (a) culturing a cell extract of a strain of the genus Gluconobacter or a cell extract of dormant cells of the microorganism in a 1-deoxy-1- (2- 0.0 > hydroxyethylamino) -D-glucitol; < / RTI > And (b) recovering 6-hydroxyethylamino-L-sorbose.

Preferably, the strain of the genus Gluconobacter is Gluconobacter oxydans, more preferably Gluconobacter oxydans CKDBM 0901. The gluconobacter oxydans CKDBM 0901 was found to be resistant to 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol and 1-deoxy-1- (2-hydroxyethylamino) As a strain having an ability to bioconvert D-glucitol to 6-hydroxyethylamino-L-sorbose at a high yield, it was deposited on September 21, 2012 in the Korean Collection for Type Cultures , ≪ / RTI > KCTC) with deposit number KCTC 12282BP. The Gluconobacter oxydans CKDBM 0901 is disclosed in detail in Korean Patent Application No. 10-2012-0112395, which is incorporated herein by reference.

In step (c) of the present invention, the biotransformed 6-hydroxyethylamino-L-sorbose is synthesized as miglitol. The microgolide is an α-glucosidase inhibitor as (2R, 3R, 4R, 5S) -1- (2-hydroxyethyl) -2- (hydroxymethyl) piperidine- It is a treatment for diabetes.

Methods for preparing miglitol using 6-hydroxyethylamino-L-sorbose are described in U.S. Patent Nos. 5,602,013, 5,610,039, 5,916,748 and 6,552,176, The patent literature is incorporated herein by reference.

According to a preferred embodiment of the present invention, the method of synthesizing miglitol using 6-hydroxyethylamino-L-sorbose obtained in step (b) includes 6-hydroxyethylamino-L-sorbose Is filtered, treated with activated charcoal to remove pigments, and transferred to a hydrogenation reactor to perform microglial synthesis. As the catalyst for the hydrogenation reaction, palladium-on-charcoal is preferably used, and the reaction is carried out at a temperature and pressure suitable for the reaction, followed by filtration to remove the catalyst. In order to purify the microgolide from the filtrate, it is adsorbed on the resin, followed by elution and concentration, followed by crystallization and recrystallization, followed by drying to obtain microgitol having high purity in the form of a white powder.

The features and advantages of the present invention are summarized as follows:

(i) The present invention provides a method for producing 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol from D-glucitol using a borohydride complex as a reducing agent, -Deoxy-1- (2-hydroxyethylamino) -D-glucitol by biotransformation.

(ii) The production process of the present invention can be carried out by using a borohydride complex instead of palladium-on-charcoal in the presence of 1-deoxy-1- (2-hydroxyethylamino) D-glucitol can be produced.

(iii) Therefore, the present invention can be usefully used for the production of diabetes mellitol, which is a therapeutic agent for diabetes.

1 shows NMR results for 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol prepared according to the method of the present invention.
2 is an ELSD (Evaporative Light Scattering Detector) result for 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol prepared according to the method of the present invention.
3 is a Mass result for 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol prepared according to the method of the present invention.
FIG. 4 shows spectra of an analyte prepared according to the method of the present invention by infrared spectroscopy. FIG.
Figure 5 shows the NMR results for miglitol prepared according to the method of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Example 1. Preparation of 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol

Preparation using sodium borohydride (Preparation Example 1)

In a 2 liter volumetric flask, 1,000 ml of ethyl alcohol in which 214 g of ammonium acetate was dissolved and 100 g of D-glucose were added, and the mixture was cooled to about 5 캜. Then, 35 g of ethanolamine was added thereto, and 63 g of sodium borohydride (NaBH ₄ ) was added slowly at a temperature of 5-10 ° C, then the temperature was gradually raised to room temperature, stirred for 60 minutes and then the reaction was terminated. 50 ml of 5% hydrochloric acid was added to the reaction solution, stirred at room temperature for 10 minutes, and allowed to stand. The resulting reaction solution was adsorbed on a strongly acidic NAC-4 cation exchanger and then washed with purified water, followed by elution with 30% ammonia water and methyl alcohol eluent and concentration. The resulting fractions were concentrated in vacuo, and the residue was crystallized from ethyl alcohol, filtered and dried to obtain 102 g (82% of theory) of 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol (Purity: 99.9%).

^{1 H NMR (400 MHz, D2O} ) δ 3.92-3.87 (m, 1H, H-3), 3.83-3.80 (dd, 1H, H-1 '), 3.72-3.74 (m, 1H, H-2), H-4 and H-4), 3.65-3.61 (m, 2H, H-4 and H-6), 2.82-2.64 (m, 4H, H- , H-9, H-10); MS (ESI) m / z calcd for [C ₈ H ₁₉ NO ₆ ] 225.12, obsd 225.12.

Preparation using sodium cyanoborohydride (Preparation Example 2)

In a 2-liter flask, 1,000 ml of ethyl alcohol and 214 g of ammonium acetate (CH ₃ COONH ₄ ) were dissolved, and 100 g of D-glucose was added, followed by cooling to about 5 캜. 35 g of ethanolamine was added thereto, and 103 g of sodium cyanoborohydride (NaCNBH ₃ ) was added slowly at a temperature of 5-10 ° C, then the temperature was gradually raised to room temperature, stirred for 60 minutes, and the reaction was terminated. 50 ml of 5% hydrochloric acid was added to the reaction solution, stirred at room temperature for 10 minutes, and allowed to stand. The resulting reaction solution was adsorbed on a strongly acidic NAC-4 cation exchanger and then washed with purified water, followed by elution with 30% ammonia water and methyl alcohol eluent and concentration. The resulting fractions were concentrated in vacuo, and the resulting residue was crystallized from ethyl alcohol, filtered and dried to give 100 g (80% of theory) of 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol (Purity: 99.7%).

Preparation using palladium (comparative example)

1000 mL of ethyl alcohol and 100 g of D-glucose were placed in a 2 L hydrogenation reactor (PARR Instrument Co. USA, 5100 Reactor), and then 35 g of ethanolamine and 30 g of 4% palladium-on-charcoal were charged, The pressure was adjusted to 6 bar and the mixture was stirred at 60 DEG C for 24 hours. After the reaction was completed, filtration was carried out. After filtration, the catalyst was washed with 50 ml of ethyl alcohol, and the filtrate was concentrated in vacuo. The obtained residue was crystallized from ethyl alcohol, filtered and dried to obtain 1-deoxy-1- (2-hydroxyethylamino ) -D-glucitol (theoretical yield 64%) (purity: 99.5%).

Comparison result

Table 1 shows the results of Production Example 1, Production Example 2 and Comparative Example of 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol described above. NMR, ELSD and Mass results of 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol prepared according to the preparation examples of the present invention are shown in FIGS.

Reaction conditions yield water Manufacturing Example 1 Sodium borohydride 82% 99.9% Manufacturing Example 2 Sodium borohydride 80% 99.7% Comparative Example Palladium 64% 99.5%

As shown in Table 1, the process of the present invention was much better than the conventional process using palladium in yield (Table 1). In addition, the production method of the present invention can produce 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol in an industrially high yield without passing through a hydrogenation reaction step, It has an advantage that it can produce.

Example  2. Preparation of 6-hydroxyethylamino-L- Sorbos  production

Deoxy-1- (2-hydroxyethylamino) propylthioacetate prepared in Example 1, which contained 5 g / l of magnesium sulfate, 5 g / l of potassium phosphate monobasic and 5 g / ) -D-glucitol was prepared in a GSYN medium containing 10 g / l, 50 g / l, 100 g / l, 150 g / l and 200 g / l, Followed by sterilization at 121 ° C for 30 minutes. 1.5 g of resting cell paste of Gluconobacter oxydans CKDBM0901 (Deposit No. KCTC 12282BP) was added to the flask prepared above, and 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol at 25 < 0 > C and 220 rpm for 96 hours.

Example 3. Synthesis of miglitol from 6-hydroxyethylamino-L-sorbose

In Example 2, 300 ml of a culture solution obtained by conducting the conversion culture using CKDBM0901 dormant cell paste and 100 g / l of 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol was dissolved in 50 ml of 6 ) Was filtered, treated with activated carbon to remove yellow pigment, and transferred to a hydrogenation reactor (PARR Instrument Co. USA, 5100 Reactor) to carry out microglial synthesis. 10% palladium-on-charcoal was used as a catalyst for the hydrogenation reaction, and the reaction was carried out at 25 ° C and 10 atm for 5 hours, followed by filtration to remove the catalyst. The filtrate was analyzed by the NMR method, and as a result, it was confirmed that miglitol was synthesized from 6-hydroxyethylamino-L-sorbose.

Example 4. Preparation and material identification of miglitol samples

In order to obtain miglitol from the reaction filtrate obtained in Example 3, the filtrate was adsorbed on strongly acidic cation resin (Dowex 50 × 2-200), eluted with methanol and 30% aqueous ammonia solution, and concentrated. The concentrate was dried by crystallization and recrystallization using methanol, and then analyzed by gas chromatography. As a result, it was confirmed that miglitol having a purity of 99.6% was produced in 62% yield from 6-hydroxyethylamino-L-sorbos Respectively.

As a result of structural analysis by IR and NMR of the sample prepared as described above, it was confirmed that it was identical to the molecular structure of miglitol (FIGS. 4 and 5).

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (9)

1-deoxy-1- (2-hydroxyethylamino) -D-glucitol having the following formula (1) using anhydrous boron complex as an reducing agent in an organic solvent containing ethanolamine Deoxy-1- (2-hydroxyethylamino) -D-glucitol.
[Chemical Formula 1]

The method of claim 1, wherein the borohydride complex is selected from the group consisting of sodium borohydride (NaBH ₄ ), sodium cyanoborohydride (NaCNBH ₃ ), and dimethylaminoborane (BH ₄ N (CH ₃ ) ₂ ) .
The method according to claim 1, wherein the borohydride complex is used in an amount of 1 to 10 equivalents based on the molar amount of D-glucose.
The method of claim 1, wherein the organic solvent further comprises an ammonium salt.
5. The method according to claim 4, wherein the ammonium salt is used in an amount of 5 to 10 equivalents based on the molar amount of D-glucose.
The method according to claim 4, wherein the ammonium salt is selected from the group consisting of ammonium acetate (CH ₃ COONH ₄ ), ammonium monophosphate (NH ₄ H ₂ PO ₄ ), ammonium diphosphate ((NH ₄ ) ₂ HPO ₄ ) ₄ ) ₂ SO ₄ ), ammonium nitrate (NH ₄ NO ₃ ) and ammonium carbonate ((NH ₄ ) ₂ CO ₃ ).
The method according to claim 1, wherein the organic solvent is an alcohol-based solvent.
The process according to claim 1, wherein the process is carried out at a temperature of from 0 to 40 ° C.
A process for producing miglitol comprising the steps of:
(a) 1-deoxy-1- (2-hydroxyethylamino) -D-glucosyl chloride of the following formula 1 is prepared by reacting D-glucitol with a borohydride complex as an reducing agent in an organic solvent containing ethanolamine Lt; / RTI >
[Chemical Formula 1]

(b) 1-deoxy-1- (2-hydroxyethylamino) -D-glucitol prepared in step (a) was treated with a strain of the genus Gluconobacter or its dormant cells Biotransformation to hydroxyethylamino-L-sorbose; And
(c) synthesizing the biotransformed 6-hydroxyethylamino-L-sorbose in step (b) with miglitol.

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