Preparation method for miglitol

Abstract

The present invention relates to a preparation method for miglitol. Specifically, the method of the present invention includes the steps of using the compound of formula VI as raw material, subjecting the compound to sulfonylation, then to substitution reaction with ethanolamine, then removing the protecting group, and finally carrying out hydrogenation cyclization to prepare miglitol. The method of the present invention has the advantages of simple steps, mild reaction conditions, high total yield, high product purity, etc., and is very suitable for industrial production.

Description

[Technical field]

[0001] Technical Field The present invention relates to the field of medicinal chemical synthesis. In particular, the present invention relates to a method for preparing the hypoglycemic drug miglitol, its intermediate compounds and its preparation method. [Background technology]

[0002] background Miglitol is an antidiabetic drug launched by Bayer in 1997. It is a new type of intestinal α-glucosidase inhibitor discovered in Bacillus broth medium. Miglitol is a modified product of 1-deoxynojirimycin, belongs to N-substituted-1-deoxynojirimycin, and has a structure similar to glucose. The chemical name of Miglitol is (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol, with a melting point of 146°C, an optical rotation of [α]D20=-8(C, 1, CH3OH), and its structural formula is as follows:

[0003] [ka]

[0004] As a new type of α-glucosidase inhibitor, miglitol competitively inhibits α-glucosidase, reduces the metabolism of carbohydrate compounds, and reduces the absorption of carbohydrates in the small intestine, thereby stabilizing postprandial plasma glucose concentration. Miglitol is a generally well-tolerated, safe and effective drug, and has become a commonly used drug for the treatment of type II diabetes.

[0005] Currently, there are two main methods for preparing miglitol: chemical synthesis and chemical-biological-enzymatic synthesis.

[0006] The first method is chemical synthesis: Carbohydrate Research, 2016, 435, 1-6 discloses a method for synthesizing miglitol based solely on chemical methods. However, this method has drawbacks such as difficulty in controlling diastereoisomeric impurities and low overall yield.

[0007] [ka]

[0008] Yunnan Chemical Technology, 2010(2), 14-17 also discloses a method for preparing miglitol, the preparation process of which is as follows: methyl-α-D-glucoside is used as raw material, and after a series of chemical modifications, a lipophilic derivative of the key intermediate 1-deoxynojirimycin is obtained, and then miglitol is obtained through a series of substitution reactions. However, this method has complicated steps, produces many by-products, and is difficult to purify.

[0009] [ka]

[0010] Another method is chemical-biological-enzymatic synthesis: Patent CN105968042B discloses a method for preparing miglitol, which uses glucose and ethanolamine as raw materials, and catalytically hydrogenates them under high pressure hydrogen conditions to obtain intermediate hydroxyethylglucose, which is then bio-oxidized by Gluconobacter oxydans, and then catalytically hydrogenates them under high pressure hydrogen conditions to obtain crude miglitol, which is purified and crystallized to obtain the final product. This route has disadvantages such as harsh reaction conditions, high costs for bacterial culture and bioconversion, and difficulties in reusing bacteria, which limit its commercial application.

[0011] [ka]

[0012] Patent application CN101029321A discloses a method for preparing miglitol, which uses 1-hydroxyethylamino-1-deoxy-D-sorbitol as raw material, and uses bacteria-containing microcapsules prepared by coating Gluconobacter oxydans with a polymer ion membrane to carry out a fermentation reaction to obtain 1-hydroxyethylamino-1-deoxy-D-sorbose, which is then catalytically hydrogenated, purified by resin, concentrated and crystallized to obtain miglitol. This route has disadvantages such as harsh reaction conditions, difficult availability of raw materials, and complicated reaction steps, and is not suitable for industrial production.

[0013] [ka]

[0014] Patent application CN107746385A discloses a method for preparing miglitol by using 6-deoxy-6-hydroxyethylamino-α-L-sorbose cell resting liquid as raw material. This method has disadvantages such as harsh reaction conditions, difficult availability of raw materials, complicated reaction steps, etc., and is not suitable for industrial production.

[0015] [ka]

[0016] Patent CN101302549B discloses a method for preparing miglitol, which includes first selecting a strain that produces miglitol, subjecting the substrate to bioconversion, microfiltration, ultrafiltration, nanofiltration, and activated carbon decolorization to obtain miglitol intermediate, and then hydrogenating and purifying to obtain miglitol (HPLC 99.0%). This route has the disadvantages of difficult cultivation and isolation of miglitol-producing strains, low recycling rate, small yield, etc., which limit the industrial development of this method.

[0017] Patent EP0008031B1 discloses a method for preparing miglitol using 6-amino-6-deoxy-L-sorbitol as raw material through amino protection, microbial oxidation, catalytic hydrogenation, and reaction with ethylene oxide. However, the cost of bacterial cell culture and bioconversion in this route is high, and the bacterial cells are harvested by centrifugation, resulting in a large loss of bacterial cells, making this method unsuitable for large-scale industrial production.

[0018] [ka]

[0019] Patent CN 1328270C discloses a method for preparing miglitol by catalytic hydrogenation of furan ring derivatives as raw materials and using catalysts RaNi, 1%-5% Pd / C or Pd-CaCO3. As described in this patent, the purity of the purified product of miglitol obtained by this method is only 98.9%, which is far from meeting the requirements of the pharmaceutical market. Moreover, this patent does not provide a synthetic route for the raw materials, which inevitably limits the development of this route.

[0020] [ka]

[0021] In summary, the existing synthetic routes can be summarized into two categories: one is the route for preparing miglitol by chemical synthesis; the other is the route for preparing miglitol by microbial fermentation or chemical synthesis followed by microbial fermentation. However, these two types of preparation methods have problems such as complicated steps, harsh synthesis conditions, difficulty in obtaining raw materials, or difficulty in meeting product purity requirements in the market. Therefore, in order to meet the needs of industrial large-scale production, it is necessary to develop a synthetic method for preparing high-quality miglitol using simple and easily available industrial materials as raw materials through simple and easy-to-operate steps. [Prior art documents] [Patent documents]

[0022] [Patent Document 1] Patent CN105968042B [Patent Document 2] Patent application CN101029321A [Patent Document 3] Patent application CN107746385A [Patent Document 4] Patent CN101302549B [Patent Document 5] Patent EP0008031B1 [Patent Document 6] Patent CN 1328270C [Non-patent literature]

[0023] [Non-Patent Document 1] Carbohydrate Research, 2016, 435, 1-6 [Non-Patent Document 2] Yunnan Chemical Technology, 2010(2), 14-17 Summary of the Invention [Problem to be solved by the invention]

[0024] Disclosure of the Invention The technical problem to be solved by the present invention is to overcome the shortcomings of existing synthetic methods and provide a new method for the preparation of Miglitol which is more suitable for industrial production. [Means for solving the problem]

[0025] Specifically, in a first aspect, the present invention relates to a process for the preparation of miglitol of formula I, comprising the following steps:

[0026] [ka] Step (1): removing the protecting group R from a compound of formula IV to obtain a compound of formula III; Step (2): subjecting the compound of formula III to an acid treatment to remove the protecting group, thereby obtaining a compound of formula II; and Step (3): catalytically hydrogenating the compound of formula II in the presence of a catalyst to obtain the compound of formula I; Including, where R is a hydroxyl protecting group; Alternatively, the compound of formula IV is directly deprotected in the presence of an acid as described in step (2) to give the compound of formula II, which is then subjected to step (3). The above method is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] In one embodiment, R is C 1-8 Alkyl, haloC 1-8 Alkyl, C 1-8 Alkylcarbonyl, HaloC 1-8 Alkylcarbonyl, Benzoyl, C 1-8 Alkyl-substituted benzoyl, halo C 1-8 Alkyl-substituted benzoyl, phenylsulfonyl, C 1-8 Alkyl-substituted phenylsulfonyl, haloC 1-8 Alkyl-substituted phenylsulfonyl, benzyl, C 1-8 Alkyl-substituted benzyl, C1-8 Alkoxy-substituted benzyl, halogen-substituted benzyl, haloC 1-8 Alkyl-substituted benzyl, allyl, C 1-8 Alkoxy-C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkoxy-C 1-8 Alkyl, benzyloxy-C 1-8 It is selected from alkyl, tetrahydropyran-2-yl, or silicon-based protecting groups such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si or Me3Si.

[0028] Preferably, R is C 1-8 Alkyl, C 1-8 Alkylcarbonyl, benzoyl, benzyl, C 1-8 Alkyl-substituted benzyl, C 1-8 It is selected from alkoxy-substituted benzyl, halogen-substituted benzyl, methoxymethyl, 2-methoxyethoxymethyl, benzyloxymethyl, tetrahydropyran-2-yl, or a silicon-based protecting group.

[0029] More preferably, R is benzyl, C 1-8 Alkyl-substituted benzyl, C 1-8 It is selected from alkoxy-substituted benzyl, halogen-substituted benzyl, t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si or Me3Si.

[0030] Most preferably, R is benzyl, C 1-8 Alkyl substituted benzyl, selected from t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si or Me3Si.

[0031] In step (1), the hydroxyl protecting group R can be deprotected under basic conditions, acidic conditions or catalytic hydrogenation conditions.

[0032] R is C 1-8 Alkylcarbonyl, HaloC 1-8 Alkylcarbonyl, Benzoyl, C 1-8Alkyl-substituted benzoyl, phenylsulfonyl or C 1-8 In the case of alkyl-substituted phenylsulfonyl, the hydroxyl protecting group is deprotected in the presence of a base, such as an alkali metal hydroxide or carbonate, for example lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

[0033] R is C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl, benzyloxy-C 1-8 If the protecting group is an alkyl, 2-tetrahydropyranyl or silicon-based protecting group, the hydroxyl protecting group of the compound of formula IV can be deprotected in the presence of an acid to give a compound of formula III, which is then subjected to step (2); alternatively, the compound of formula IV can be directly deprotected in the presence of an acid to give a compound of formula II, which is then subjected to step (3).

[0034] The acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, or trifluoroacetic acid, or a mixture of two or more thereof.

[0035] R is benzyl, C 1-8 In the case of alkyl-substituted benzyl or halogen-substituted benzyl, the protecting group can be removed by catalytic hydrogenation. The catalyst used for catalytic hydrogenation is selected from Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd and Ni, the hydrogen pressure is 0.5-3.0 MPa, and the reaction time is 4-24 hours.

[0036] The reaction solvent in step (1) is an alcohol, an ester or an ether, or a mixture of any two or more of these.

[0037] The alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, isopentanol, cyclohexanol, benzyl alcohol, and the like.

[0038] The esters are selected from methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate, isopropyl acetate.

[0039] The ethers are selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, anisole, tetrahydrofuran, methyltetrahydrofuran and 1,4-dioxane.

[0040] In step (2), the acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, or trifluoroacetic acid, or a mixture of two or more thereof.

[0041] In step (3), the catalyst is selected from Pd / C, Pd(OH)2, Pd(OAc)2, PdCl2, Pd or Ni, such as RaNi.

[0042] The hydrogen pressure in step (3) is 0 to 4 MPa, preferably 1.0 to 3 MPa, and more preferably 2.0 to 2.5 MPa.

[0043] The reaction temperature in step (3) is 0 to 30° C., and the reaction time is 4 to 24 hours.

[0044] In a preferred embodiment, the step (3) further comprises obtaining the compound of formula I by passing through a cation exchange resin, the cation exchange resin being selected from strong acid cation exchange resin D001, strong acid cation exchange resin HD-8, strong acid cation exchange resin JK006, strong acid cation exchange resin JK001, strong acid cation exchange resin DOWEX50x8-100, cation exchange resin CG50, strong acid cation exchange resin HZ002, strong acid cation exchange resin HZ016, strong acid cation exchange resin C145, strong acid cation exchange resin C150, or strong acid cation exchange resin C160.

[0045] In a further preferred embodiment, the step (3) further comprises purifying the crude compound of formula I after treatment with a cation exchange resin by crystallization from an organic solvent or a mixture of an organic solvent and water, the organic solvent may be selected from methanol, ethanol, n-propanol, isopropanol, or a mixture of two or more thereof.

[0046] In a second aspect, the present invention provides a method for the preparation of a compound of formula IV, comprising the following steps:

[0047] [ka] Step (4): reacting the compound of formula VI with R1Cl in the presence of a base to prepare a compound of formula V; Step (5): reacting the compound of formula V with ethanolamine to prepare a compound of formula IV; Including, where R is as defined above for the first aspect and R1 is C 1-8 Alkanoyl, C 1-8 Alkyl sulfonyl, aryl sulfonyl, C 1-8 alkyl substituted arylsulfonyl, benzoyl or substituted benzoyl; The above method is provided.

[0048] Preferably, R1 is selected from formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl, methanesulfonyl, ethanesulfonyl, phenylsulfonyl, or p-toluenesulfonyl.

[0049] Preferably, the base is selected from inorganic or organic bases, such as alkali metal hydroxides or carbonates or bicarbonates, for example sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, ethylenediamine, diisopropylethylenediamine, diisopropylamine, piperidine, morpholine, pyridine or 2-methylpyridine.

[0050] In a preferred embodiment, in step (4), the temperature is controlled at -5 to 30°C, and the compound of formula VI is reacted with R1Cl in the presence of a base in a low polarity solvent. After the reaction is completed, the reaction solution can be directly subjected to the reaction in step (5) after simple treatment.

[0051] The low polarity solvent is selected from dichloromethane, chloroform, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane or acetonitrile, or a mixture of two or more thereof.

[0052] A simple treatment is to extract the reaction solution by washing with water to remove salts produced by the reaction.

[0053] In a preferred embodiment, in step (5), the temperature is controlled at 40-100° C., and the compound of formula V is reacted with ethanolamine in an organic solvent. After the reaction is completed, the reaction mixture is cooled to room temperature, adjusted to alkaline, and further cooled to crystallize, and optionally crystallized in an organic solvent or a mixture of an organic solvent and water to obtain the compound of formula IV.

[0054] The base is selected from inorganic or organic bases, such as alkali metal hydroxides or carbonates or bicarbonates, for example sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide.

[0055] The organic solvent used in the reaction is selected from dichloromethane, trichloromethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane, acetonitrile or a mixture of two or more thereof.

[0056] The organic solvent used for crystallization is selected from dichloromethane, chloroform, diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane, acetonitrile or a mixture of two or more thereof.

[0057] In a third aspect, the present invention provides a compound of formula IV:

[0058] [ka] (Wherein, R is C 1-8 Alkyl, haloC 1-8 Alkyl, C 1-8 Alkylcarbonyl, HaloC 1-8 Alkylcarbonyl, Benzoyl, C 1-8 Alkyl-substituted benzoyl, halo C 1-8 Alkyl-substituted benzoyl, phenylsulfonyl, C 1-8 Alkyl-substituted phenylsulfonyl, haloC 1-8 Alkyl-substituted phenylsulfonyl, benzyl, C 1-8 Alkyl-substituted benzyl, C 1-8 Alkoxy-substituted benzyl, halogen-substituted benzyl, haloC 1-8 Alkyl-substituted benzyl, allyl, C 1-8 Alkoxy-C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkoxy-C 1-8 Alkyl, benzyloxy-C 1-8 alkyl, tetrahydropyran-2-yl, or silicon-based protecting groups, such as t-BuMe2Si, t-BuPh2Si, (i-Pr)3Si, Et3Si, or Me3Si. The present invention provides a novel intermediate compound of the formula:

[0059] In a fourth aspect, the present invention provides a method for synthesizing Miglitol of formula I, which uses a compound of formula VI as a raw material and obtains Miglitol through reactions of protecting group addition, substitution, protecting group removal, and catalytic hydrogenation cyclization, and optionally further purifies it through recrystallization to obtain the final product.

[0060] Specifically, the present invention provides a method for synthesizing miglitol of formula I, comprising the following steps (4), (5), (1), (2) and (3):

[0061] [ka] wherein R and R1 are as defined above; The above method is provided.

[0062] In a preferred embodiment, the conditions for steps (4) and (5) are as described in the second aspect of the invention. In another preferred embodiment, the conditions for steps (1), (2) and (3) are as described in the first aspect of the invention. Alternatively, the compound of formula IV is directly deprotected in the presence of an acid as described in step (2) to give the compound of formula II, which is then subjected to step (3).

[0063] In a more preferred embodiment, the conditions for steps (4) and (5) are as described in the second aspect of the invention and the conditions for steps (1), (2) and (3) are as described in the first aspect of the invention, or the compound of formula IV is directly deprotected in the presence of an acid as described in step (2) to give the compound of formula II, which is then subjected to step (3).

[0064] Compared with the prior art, the present invention has the following advantages: 1. The diastereoisomeric impurities produced by the method of the present invention can be effectively controlled to less than 0.1%; 2. The process for preparing miglitol by using the compound of formula VI as the raw material of the present invention has a high yield, reaching 48.5-51.5%; 3. The purity of Miglitol prepared by the method of the present invention can reach 99.9%, thereby providing reliable preparation quality assurance.

[0065] The present invention overcomes the problems of the prior art such as low overall yield, difficulty in controlling diastereoisomeric impurities, and low product purity, and is suitable for industrial large-scale production.

[0066] definition For the purpose of interpreting the specification, the following definitions will be used, and where appropriate, terms used in the singular will also include the plural and vice versa. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0067] As used herein, the term "halogen" or "halo" refers to F, Cl, Br, or I. Furthermore, the term "halogen substituted" group is intended to encompass mono- or poly-halogenated groups, in which one or more hydrogens in the group are replaced with one or more of the same or different halogens.

[0068] The term "alkyl" as used herein refers to a straight or branched chain saturated hydrocarbon group consisting of carbon and hydrogen atoms. Specifically, an alkyl group has 1 to 10, e.g., 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, as used herein, "C 1-8 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having from 1 to 8 carbon atoms, examples of which are methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, and the like.

[0069] As used herein, "haloC" refers to 1-8 The term "alkyl" refers to any of the above C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C30, C41, C52, C63, C74, C75, C86, C97, C98, C99, C100, C111, C121, C132, C142, C153, C163, C174, C185, C196, C197, C198, C215, C199, C226, C232, C246, C352, C362, C372, C382, C392, C493, C494, C495, 1-8 It is understood by those skilled in the art that when two or more halogen substituents are present, the halogens may be the same or different and may be located on the same or different carbon atoms. 1-8 Examples of "alkyl" include -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, -CH2CH2CF3 or -CF(CF3)2, and the like.

[0070] The term "alkoxy", alone or in combination with other groups, refers to the group R, where R is alkyl as defined above. y -O-. 1-8 "Alkoxy" is a group R y -O-, where R y is the above C 1-8 It is an alkyl.

[0071] The term "aryl" refers to a monocyclic or fused bicyclic aromatic ring consisting of carbon and hydrogen atoms. 6-10 "Aryl" refers to an aryl group containing 6 to 10 carbon atoms. For example, aryl can be phenyl or naphthyl.

[0072] The term "aralkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above, such as benzyl.

[0073] The term "aralkoxy" refers to an alkoxy group as defined above substituted with an aryl group as defined above, such as benzyloxy.

[0074] The term "acyl" means R x is a group -CO-R, which is alkyl, aryl or aralkyl as defined above, for example alkanoyl or aralkanoyl, for example benzoyl. x Refers to...

[0075] The aryl groups described above may be optionally substituted with one or more substituents, either by themselves or as part of another group, such as aralkyl, aralkoxy, and acyl. When the aryl group is substituted, the substituents may be any of the following: 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-8 More preferably, the substituted benzoyl is selected from alkyl, halogen, aryl, and nitro, more preferably methoxy, ethoxy, halogen, or phenyl. For example, the substituted benzoyl is 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-8 It refers to a benzoyl having substituents on the phenyl ring selected from alkyl, halo, or aryl.

[0076] Detailed Description The method of the present invention is further illustrated by the following examples. It should be understood that the following examples are provided solely for the purpose of enabling a better understanding of the invention, and are not intended to limit the scope of the invention in any manner. EXAMPLES

[0077] Preparation of Compounds of Formula IV Example 1:

[0078] [ka] 1870 g of dichloromethane and 269 g of compound of formula VI-a were added to a reaction bottle, stirred and cooled to 0-5°C, 125 g of triethylamine was added, stirred for 10 minutes, and 220 g of p-toluenesulfonyl chloride was added slowly. After the addition was complete, the reaction was held at low temperature for 30 minutes, then warmed to 25°C to maintain the reaction temperature, 400 g of water was added and stirred for 30 minutes, then allowed to settle and the layers were separated. A solution of compound of formula Va in dichloromethane was obtained and used in the next reaction without further treatment.

[0079] Add 120g of ethanolamine to the above dichloromethane solution of the compound of formula Va, stir and heat the mixture to reflux, control the internal temperature at 90-95 ℃, and maintain the reaction temperature for 5-7 hours; After the reaction is completed, cool the mixture to an internal temperature of 20-30 ℃; Add 200g of water, then add 10% NaOH (appropriate amount) dropwise to adjust pH ≧ 12, and react at a temperature of 20-30 ℃ with stirring for 12 hours; After the reaction is completed, cool the mixture to 0-5 ℃, stir for 2 hours to crystallize, filter by suction, wash the filter cake with a small amount of purified water, filter by suction, and dry the filter cake to obtain 262g of the compound of formula IV. Yield: 85.4%, purity: 99%. 1 H NMR (600 MHz, DMSO-d6) δ 7.35 (h, J = 5.9 Hz, 4H), 7.32 - 7.25 (m, 1H), 4.58 (q, J = 12.2 Hz, 2H), 4.50 (t, J = 5.3 Hz, 1H), 4.33 (s, 1H), 4.15 (td, J = 5.4, 2.8 Hz, 1H), 4.02 (d, J = 2.8 Hz, 1H), 3.63 (d, J = 10.7 Hz, 1H), 3.56 (d, J = 10.7 Hz, 1H), 3.43 (q, J = 5.0 Hz, 2H), 3.34 (s, 1H), 2.84 (dd, J = 12.4, 5.2 Hz, 1H), 2.74 (dd, J = 12.4, 5.7 Hz, 1H), 2.58 (td, J = 5.6, 2.5 Hz, 2H), 1.40 (s, 3H), 1.29 (s, 3H); 13 C NMR (151 MHz, DMSO) δ 138.74, 128.72, 127.87, 127.74, 113.49, 111.37, 85.54, 80.27, 75.22, 73.17, 70.93, 60.73, 52.35, 48.20, 27.92, 26.95.

[0080] Example 2:

[0081] [ka] 1870 g of dichloromethane and 254 g of compound of formula VI-b were added to a reaction bottle, stirred and cooled to 0-5°C, 115 g of triethylamine was added, stirred for 10 minutes, and 220 g of methanesulfonyl chloride was added slowly. After the addition was complete, the reaction was held at low temperature for 30 minutes, then warmed to 25°C and held at temperature until the reaction was complete. 400 g of water was added and stirred for 30 minutes, then allowed to settle and the layers were separated. A solution of compound of formula Vb in dichloromethane was obtained and used in the next reaction without further treatment.

[0082] Add 120g of ethanolamine to the above compound of formula Vb in dichloromethane solution, stir and heat the mixture, and maintain the reaction temperature for 5-7 hours. After the reaction is completed, cool the mixture to an internal temperature below 20 ℃, add 200g of water, and then add 10% NaOH (appropriate amount) dropwise to adjust pH ≧ 12, and react at a temperature of 20-30 ℃ with stirring for 12 hours. After the reaction is completed, cool the mixture to 0-5 ℃, stir for 2 hours to crystallize, filter by suction, wash the filter cake with a small amount of purified water, filter by suction, and dry the filter cake to obtain 227.6g of compound of formula IV-b. Yield: 78.1%, purity: 98.5%.

[0083] Preparation of Compounds of Formula III Example 3:

[0084] [ka] 240g of the compound of formula IV-a, 1440mL of methanol and 36g of 10% palladium / carbon were added to an autoclave, the atmosphere was replaced with nitrogen, then the atmosphere was replaced with hydrogen, the mixture was stirred under hydrogen pressure of 0.9-1.0MPa and heated to an internal temperature of 50°C, and the reaction temperature was maintained for 4 hours. The reaction mixture was filtered by suction, and the filtrate was concentrated under reduced pressure to obtain 175.2g of the compound of formula III. Yield: 98.0%. 1H NMR (600 MHz, DMSO-d6) δ 4.46 - 3.78 (m, 6H), 3.60 - 3.32 (m, 4H), 2.84 (dd, J = 12.4, 5.2 Hz, 1H), 2.75 (dd, J = 12.6, 5.8 Hz, 1H), 2.59 (s, 2H), 1.34 (d, J = 59.4 Hz, 6H); 13 C NMR (151 MHz, DMSO) δ 114.60, 111.12, 85.25, 80.06, 75.21, 62.43, 60.59, 52.26, 48.18, 27.95, 27.10.

[0085] Preparation of Compounds of Formula I Example 4:

[0086] [ka] 175.2g of the compound of formula III was added to the reaction bottle, 200g of concentrated hydrochloric acid was added dropwise, and the internal temperature was controlled at 20-40 ° C until the reaction was completed, and 60g of sodium hydroxide was added to make the mixture alkaline, and an aqueous solution of the compound of formula II was obtained. The aqueous solution of the compound of formula II was transferred to an autoclave, and 20g of 10% palladium / carbon (wet weight, water content is 60%) was added, and the atmosphere was replaced with nitrogen and hydrogen three times each, and the hydrogen pressure was controlled at 1.0-3.0 MPa. After the reaction was completed, the mixture was filtered, and the filter cake catalyst was collected and reused. The filtrate was loaded into a cation exchange resin column, and after all the materials were loaded into the column, it was dissociated with purified water and ammonia water. The ammonia water dissociation liquid was collected and concentrated under reduced pressure while controlling the external temperature at 60-65 ° C. After concentration, absolute ethanol was added to the residue to crystallize, the mixture was stirred at 50-55°C for 2 hours, slowly cooled to -5-0°C to crystallize for 2 hours, and then filtered under suction. The filter cake was dried to obtain 117.2g of crude miglitol. Yield: 85.0%.

[0087] In a reaction bottle, 117.2 g of miglitol crude product, purified water and ethanol were added, the mixture was stirred and heated to 50-55°C, after 1 hour, 10 g of activated carbon was added for decolorization, and then filtered by suction after 1 hour. The filter cake was rinsed with warm absolute ethanol, the filtrates were combined and stirred at 50-55°C for 2 hours. The solution was slowly cooled to 25°C and crystallized for 2 hours, then cooled to -5-0°C and stirred for 3-5 hours for crystallization, and then filtered by suction. The filter cake was dried to obtain 105.6 g of miglitol. Yield: 90.1%, purity: 99.9%.

[0088] Example 5:

[0089] [ka] 227.6g of the compound of formula IV-b was added to the reaction bottle, 300g of concentrated hydrochloric acid was added dropwise, the internal temperature was controlled at 20-40 ° C until the reaction was completed, and 60g of sodium hydroxide was added to make the mixture alkaline, obtaining an aqueous solution of the compound of formula II. The aqueous solution of the compound of formula II was transferred to an autoclave, 20g of 10% palladium / carbon (wet weight, water content is 60%) was added, and the atmosphere was replaced with nitrogen and hydrogen three times each, and the hydrogen pressure was controlled at 1.0-3.0 MPa. After the reaction was completed, the mixture was filtered, and the filter cake catalyst was collected and reused. The filtrate was loaded into a cation exchange resin column, and after all the materials were loaded into the column, it was dissociated with purified water and ammonia water. The ammonia water dissociation liquid was collected and concentrated under reduced pressure while controlling the external temperature at 60-65 ° C. After concentration, absolute ethanol was added to the residue to crystallize, the mixture was stirred at 50-55°C for 2 hours, slowly cooled to -5-0°C to crystallize for 2 hours, and then filtered under suction. The filter cake was dried to obtain 100g of crude miglitol product.

[0090] 100g of miglitol crude product, purified water and ethanol were added to a reaction bottle, the mixture was stirred and heated to 50-55°C, after 1 hour, 10g of activated carbon was added for decolorization, and then filtered under suction after 1 hour. The filter cake was rinsed with warm anhydrous ethanol, the filtrates were combined and stirred at 50-55°C for 2 hours. The solution was slowly cooled to 25°C for crystallization for 2 hours, then cooled to -5-0°C, stirred for crystallization for 3-5 hours, and then filtered under suction. The filter cake was dried to obtain 78-83g of miglitol. The total yield of miglitol prepared from the compound of formula VI-b is 42.5-45.3%, and the purity is 99.9%.

Claims

1. Formula IV: 【Chemical 1】 wherein R is selected from benzyl, C 1-8 alkyl-substituted benzyl, C 1-8 alkoxy-substituted benzyl, halogen-substituted benzyl, and haloC 1-8 alkyl-substituted benzyl. Compound.

2. A process for the preparation of a compound of formula IV comprising the steps of: 【Chemistry 2】 Step (4): The compound of formula VI is reacted with R 1 Cl to prepare a compound of formula V; Step (5): reacting the compound of formula V with ethanolamine to prepare a compound of formula IV; Including, where R is as defined in claim 1 and R 1 is C 1-8 alkylsulfonyl, arylsulfonyl, or C 1-8 alkyl-substituted arylsulfonyl.

3. R 1 3. The method of claim 2, wherein is selected from methanesulfonyl, ethanesulfonyl, phenylsulfonyl, or p-toluenesulfonyl.

4. 3. The method of claim 2, wherein the base in step (4) is selected from an inorganic base or an organic base.

5. The method of claim 4, wherein the base in step (4) is selected from an alkali metal hydroxide or carbonate or bicarbonate.

6. The method of claim 4, wherein the base in step (4) is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, ethylenediamine, diisopropylethylenediamine, diisopropylamine, piperidine, morpholine, pyridine, or 2-methylpyridine.

7. A process for the preparation of a compound of formula I comprising the steps of: 【Chemistry 3】 【change】 Step (4): The compound of formula VI is reacted with R 1 Cl to prepare a compound of formula V; Step (5): reacting the compound of formula V with ethanolamine to prepare a compound of formula IV; Step (1): Removing the protecting group R from a compound of formula IV to obtain a compound of formula III; Step (2): subjecting the compound of formula III to acid treatment to remove the protecting group, thereby obtaining a compound of formula II; and Step (3): catalytically hydrogenating the compound of formula II in the presence of a catalyst to obtain the compound of formula I; Including, Alternatively, the compound of formula IV can be directly deprotected in the presence of an acid as described in step (2) to give a compound of formula II, which is then subjected to step (3), where R is benzyl, C 1-8 Alkyl-substituted benzyl, C 1-8 selected from alkoxy-substituted benzyl, halogen-substituted benzyl, and haloC 1-8 alkyl-substituted benzyl; R 1 is C 1-8 alkylsulfonyl, arylsulfonyl, or C 1-8 alkyl-substituted arylsulfonyl; The method.

8. The method of claim 7, wherein R 1 is selected from methanesulfonyl, ethanesulfonyl, phenylsulfonyl, or p-toluenesulfonyl.

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