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CN114516831B - Preparation method of miglitol - Google Patents

Preparation method of miglitol Download PDF

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CN114516831B
CN114516831B CN202210073219.9A CN202210073219A CN114516831B CN 114516831 B CN114516831 B CN 114516831B CN 202210073219 A CN202210073219 A CN 202210073219A CN 114516831 B CN114516831 B CN 114516831B
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formula
compound
alkyl
miglitol
substituted benzyl
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CN114516831A (en
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代春光
李运峰
蒲学灿
宋宗生
张利荣
郑志国
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Zhejiang Ausun Pharmaceutical Co Ltd
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Zhejiang Ausun Pharmaceutical Co Ltd
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Priority to KR1020247025376A priority patent/KR20240136356A/en
Priority to JP2024543131A priority patent/JP2025503766A/en
Priority to PCT/CN2022/122535 priority patent/WO2023138099A1/en
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract

The invention relates to a preparation method of miglitol. Specifically, the method takes a compound of the formula VI as a raw material, carries out substitution reaction with ethanolamine after sulfonylation, removes protecting groups, and finally hydrogenates to form miglitol. The method has the advantages of simple steps, mild reaction conditions, high total yield, high product purity and the like, and is very suitable for industrial production.

Description

Preparation method of miglitol
Technical Field
The invention relates to the field of pharmaceutical chemical synthesis. In particular to a preparation method of hypoglycemic medicine miglitol, an intermediate compound thereof and a preparation method thereof.
Background
Miglitol (Miglitol) is bayer patternAntidiabetic drugs are marketed in 1997. The novel intestinal alpha-glucosidase inhibitor is discovered from bacillus broth culture medium, is a parent modification product of 1-deoxynojirimycin, belongs to N-substituted-1-deoxynojirimycin type, and has a structure similar to glucose. The chemical name is (2R, 3R,4R, 5S) -1- (2-hydroxyethyl) -2- (hydroxymethyl) -3,4, 5-piperidinotriol, the melting point is 146 ℃, and the optical rotation [ alpha ]]D 20 ＝-8(C,1,CH 3 OH) of the formula:
as a novel alpha-glucosidase inhibitor, miglitol competitively inhibits alpha-glucosidase, reduces carbohydrate metabolism, reduces carbohydrate absorption in the small intestine, and thereby stabilizes postprandial plasma glucose concentration. The medicine is safe and effective, has good general tolerance, and is a common medicine for treating type II diabetes.
The current miglitol preparation method is mainly divided into two modes of chemical synthesis and chemical-biological enzymatic synthesis.
The first way is chemical synthesis:
methods for synthesizing miglitol based solely on chemical methods are disclosed in document Carbohydrate Research,2016,435,1-6. However, this method has drawbacks such as difficult control of diastereoisomeric impurities and low overall yield.
The literature Yunnan chemical industry, 2010 (2), 14-17 also provides a method for preparing miglitol, and the preparation process is as follows: the method comprises the steps of taking methyl-alpha-D-glucoside as a raw material, carrying out a series of chemical modifications to obtain a lipophilic derivative of a key intermediate 1-deoxynojirimycin, and carrying out a series of substitution reactions to obtain miglitol. However, this method is cumbersome in steps, has a large number of byproducts, and is difficult to purify.
Another way is chemical-biological enzymatic synthesis:
patent CN105968042B discloses a method for preparing intermediate hydroxyethylamino glucose by catalytic hydrogenation of glucose and ethanolamine under high-pressure hydrogen, preparing miglitol crude product by biological oxidation of gluconic acid oxidizing bacteria and catalytic hydrogenation under high-pressure hydrogen, purifying and crystallizing, and refining to obtain the final product. The method has the defects of harsh reaction conditions, high thallus culture cost and bioconversion cost, difficult thallus recycling and the like, so that the commercialized application of the method is limited.
Patent CN101029321A discloses a method for preparing miglitol by taking 1-hydroxyethylamino-1-deoxy-D-sorbitol as a raw material, carrying out fermentation reaction by using a bacterial-containing microcapsule prepared by polymeric ion membrane containing gluconic acid oxidizing bacteria to prepare 1-hydroxyethylamino-1-deoxy-D-sorbitol, carrying out catalytic hydrogenation, refining by resin, and concentrating and crystallizing. The route has the defects of harsh reaction conditions, difficult acquisition of raw materials, complicated reaction steps and the like, and is not beneficial to industrial production.
Patent CN107746385a discloses a method for preparing miglitol from 6-deoxy-6-hydroxyethylamino-alpha-L-sorbose cell resting solution. The route has the defects of harsh reaction conditions, difficult raw material purchase, complicated reaction steps and the like, and is not beneficial to industrial production.
Patent CN101302549B discloses a method for preparing miglitol (HPLC 99.0%) by screening miglitol producing strains, subjecting a substrate to bioconversion, microfiltration, ultrafiltration, nanofiltration, activated carbon decolorization to obtain a miglitol intermediate, and then subjecting the miglitol intermediate to hydrogenation purification. However, the route has the defects of difficult culture and separation of miglitol production strains, low cyclic utilization, small yield and the like, and restricts the industrialized development of the miglitol production strains.
Patent EP0008031B1 discloses a process for the preparation of miglitol starting from 6-amino-6-deoxy-L-sorbitol by amino protection, microbial oxidation, catalytic hydrogenation and reaction with ethylene oxide. However, in this route, the cost of culturing and biotransformation of the cells is high, and the cells are collected by centrifugation, so that the loss of the cells is large, and the method cannot be applied to industrial mass production.
In the patent CN1328270C, furan ring derivative is used as raw material, and catalyst Rani, 1% -5% Pd/C or Pd-CaCO is used 3 A method for preparing miglitol by catalytic hydrogenation. In this patent, the purity of the miglitol concentrate obtained by this method is only 98.9%, which is far from meeting the requirements of the formulation market, and the patent does not give a synthetic route for reference of its raw materials, which necessarily limits the development of this route.
In summary, the existing synthetic routes are classified into two types, namely, miglitol is prepared by a chemical synthesis method; the other is the preparation of miglitol by microbial fermentation or by chemical synthesis followed by microbial fermentation. However, these two preparation methods have the problems of complicated steps, harsh synthesis conditions, difficult raw material acquisition or difficult product purity adaptation to market requirements, and the like. Therefore, it is necessary to develop a synthesis method for preparing high-quality miglitol by using simple and easily available industrial materials as raw materials through simple and convenient operation steps, so as to meet the requirement of industrialized mass production.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of the existing synthesis method and provide a novel miglitol preparation method which is more beneficial to industrial production.
Specifically, the first aspect of the invention provides a preparation method of miglitol in a formula I, which comprises the following steps:
step (1): deprotecting a compound of formula IV to give a compound of formula III;
step (2): removing protecting groups from the compound of the formula III through acid treatment to obtain a compound of the formula II;
step (3): catalytically hydrogenating the compound of formula II in the presence of a catalyst to obtain a compound of formula I;
wherein R is a hydroxyl protecting group;
alternatively, the compound of formula IV is deprotected directly 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).
In one embodiment, R is selected from C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkylcarbonyl, halo C 1-8 Alkylcarbonyl, benzoyl, C 1-8 Alkyl-substituted benzoyl, halo C 1-8 Alkyl-substituted benzoyl, benzenesulfonyl, C 1-8 Alkyl-substituted benzenesulfonyl, halo C 1-8 Alkyl-substituted benzenesulfonyl, benzyl, C 1-8 Alkyl-substituted benzyl, C 1-8 Alkoxy-substituted benzyl, halogen-substituted benzyl, halogenated C 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 protecting groups, e.g. t-BuMe 2 Si、t-BuPh 2 Si、(i-Pr) 3 Si、Et 3 Si or Me 3 Si。
Preferably, R is selected from C 1-8 Alkyl, C 1-8 Alkylcarbonyl, benzoyl, benzyl, C 1-8 Alkyl-substituted benzyl, C 1-8 Alkoxy-substituted benzyl, halogen-substituted benzyl, methoxymethyl, 2-methoxyethoxymethyl, benzyloxymethyl, tetrahydropyran-2-yl or a silicon protecting group.
More preferably, R is selected from benzyl, C 1-8 Alkyl-substituted benzyl, C 1-8 Alkoxy-substituted benzyl, halogen-substituted benzyl, t-BuMe 2 Si、t-BuPh 2 Si、(i-Pr) 3 Si、Et 3 Si or Me 3 Si。
Most preferably, R is selected from benzyl, C 1-8 Alkyl-substituted benzyl, t-BuMe 2 Si、t-BuPh 2 Si、(i-Pr) 3 Si、Et 3 Si or Me 3 Si。
In the step (1), the dehydroxylation protecting group R may be a protecting group under basic conditions, acidic conditions or catalytic hydrogenation conditions.
When R is C 1-8 Alkylcarbonyl, halo C 1-8 Alkylcarbonyl, benzoyl, C 1-8 Alkyl-substituted benzoyl, benzenesulfonyl or C 1-8 When the phenylsulfonyl group is substituted with an alkyl group, the hydroxy protecting group is removed in the presence of a base, such as an alkali metal hydroxide or carbonate, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate.
When R is C 1-8 Alkyl, C 1-8 alkoxy-C 1-8 Alkyl, benzyloxy-C 1-8 In the case of alkyl, 2-tetrahydropyranyl or silicon protecting groups, the compound of formula IV may be subjected to removal of the hydroxy protecting group in the presence of an acid to give the compound of formula III, which is then subjected to step (2), or the compound of formula IV may be subjected to direct deprotection in the presence of an acid to give the compound of formula II, which is then subjected to step (3).
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.
When R is benzyl, C 1-8 The protecting group may be removed by catalytic hydrogenation when alkyl substituted benzyl or halogen atom substituted benzyl. The catalyst used for the catalytic hydrogenation is selected from Pd/C, pd (OH) 2 、Pd(OAc) 2 、PdCl 2 Pd and Ni, the hydrogen pressure is 0.5-3.0 MPa, and the reaction time is 4-24 hours.
The reaction solvent in the step (1) is alcohol, ester or ether, or a mixture of any two or more of the alcohol, the ester or the ether.
The alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, isoamyl alcohol, cyclohexanol, benzyl alcohol, etc.
The ester is selected from methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate and isopropyl acetate.
The ether is selected from diethyl ether, isopropyl ether, methyl tertiary butyl ether, anisole, tetrahydrofuran, methyl tetrahydrofuran and 1, 4-dioxane.
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.
In step (3), the catalyst is selected from Pd/C, pd (OH) 2 、Pd(OAc) 2 、PdCl 2 Pd or Ni, such as RaNi.
The hydrogen pressure in the step (3) is 0 to 4MPa, preferably 1.0 to 3MPa, and more preferably 2.0 to 2.5MPa.
The reaction temperature in the step (3) is 0-30 ℃ and the reaction time is 4-24 hours.
In a preferred embodiment, said step (3) further comprises obtaining the compound of formula I by means of a cation exchange resin. The cation exchange resin is 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 DOWEX 50X 8-100, 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.
In a further preferred embodiment, said step (3) further comprises, after treatment with the cation exchange resin, crystallization purification of the crude compound of formula I in an organic solvent or a mixture of organic solvent and water. The organic solvent may be selected from methanol, ethanol, n-propanol, isopropanol, or a mixture of two or more thereof.
In a second aspect, the present invention provides a process for the preparation of a compound of formula IV comprising the steps of:
step (4): combining a compound of formula VI with R 1 Cl in the presence of a base to prepare a compound of formula V;
step (5): reacting a compound of formula V with ethanolamine to produce a compound of formula IV;
wherein R is as defined above in the first aspect, and R 1 Is C 1-8 Alkanoyl, C 1-8 Alkylsulfonyl, arylsulfonyl, C 1-8 An alkyl substituted arylsulfonyl, benzoyl or substituted benzoyl group.
Preferably, said R 1 Selected from formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl, methanesulfonyl, ethanesulfonyl, benzenesulfonyl or p-toluenesulfonyl.
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.
In a preferred embodiment, in said step (4), the temperature is controlled at-5 to 30℃and the compound of formula VI is reacted with R in the presence of a base in a low polarity solvent 1 And (3) Cl reaction. After the reaction is finished, the reaction solution can be subjected to simple processAfter the treatment, the reaction of step (5) is directly carried out.
The low-polarity solvent is selected from dichloromethane, chloroform, diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, methyl tetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane or acetonitrile, or a mixture of two or more thereof.
The simple treatment is that the reaction liquid is washed and extracted to remove salt generated by the reaction.
In a preferred embodiment, in said step (5), the compound of formula V is reacted with ethanolamine in an organic solvent at a controlled temperature of from 40 to 100 ℃. After the reaction is finished, cooling to room temperature, regulating to be alkaline, further cooling and crystallizing, and optionally crystallizing in an organic solvent or a mixture of the organic solvent and water to obtain the compound of the formula IV.
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.
The organic solvent used for the reaction is selected from dichloromethane, chloroform, diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, methyl tetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane, acetonitrile, or a mixture of two or more thereof.
The organic solvent used for crystallization is selected from dichloromethane, chloroform, diethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, methyl tetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane, acetonitrile, or a mixture of two or more thereof.
In a third aspect, the present invention provides a novel intermediate compound of formula IV
Wherein R is selected from C 1-8 Alkyl, halogenated C 1-8 Alkyl group,C 1-8 Alkylcarbonyl, halo C 1-8 Alkylcarbonyl, benzoyl, C 1-8 Alkyl-substituted benzoyl, halo C 1-8 Alkyl-substituted benzoyl, benzenesulfonyl, C 1-8 Alkyl-substituted benzenesulfonyl, halo C 1-8 Alkyl-substituted benzenesulfonyl, benzyl, C 1-8 Alkyl-substituted benzyl, C 1-8 Alkoxy-substituted benzyl, halogen-substituted benzyl, halogenated C 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 protecting groups, e.g. t-BuMe 2 Si、t-BuPh 2 Si、(i-Pr) 3 Si、Et 3 Si or Me 3 Si。
In a fourth aspect, the present invention provides a method for synthesizing miglitol of formula I, wherein the method uses a compound of formula VI as a raw material, and the miglitol is obtained through a reaction of protecting group addition, substitution reaction, deprotection, catalytic hydrogenation to form a ring, and optionally, recrystallization and purification are performed to obtain a final product.
Specifically, the present invention provides a method for synthesizing miglitol of formula I comprising the following steps (4), (5), (1), (2) and (3):
wherein R and R 1 As defined above.
In a preferred embodiment, the conditions of steps (4) and (5) are as described in the second aspect of the invention. In another preferred embodiment, the conditions of steps (1), (2) and (3) are as described in the first aspect of the invention. Alternatively, the compound of formula IV is deprotected directly 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).
In a more preferred embodiment, the conditions of steps (4) and (5) are as described in the second aspect of the invention and the conditions of steps (1), (2) and (3) are as described in the first aspect of the invention, or the compound of formula IV is deprotected directly 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).
Compared with the prior art, the invention has the following advantages:
1. diastereoisomeric impurities produced using the method of the present invention can be effectively controlled to below 0.1%;
2. the method takes the compound of the formula VI as the raw material to prepare the miglitol, and has high yield reaching 48.5-51.5%;
3. the miglitol prepared by the method has the purity reaching 99.9 percent, thereby providing reliable quality assurance for the preparation.
The invention solves the problems of low total yield, difficult control of diastereoisomeric impurities, low product purity and the like in the prior art, and is suitable for industrialized mass production.
Definition:
for purposes of explaining the present specification, the following definitions will be used, and terms used in the singular form may also include the plural, and vice versa, as appropriate. 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.
The term "halogen" or "halo" as used herein refers to F, cl, br or I. Furthermore, the term "halogen substituted" group is intended to include monohalogenated or polyhalogenated groups in which one or more of the same or different halogens replace one or more hydrogens in the group.
The term "alkyl" as used herein refers to a straight or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms. In particular, the alkyl group has 1-10, for example 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, the term "C 1-8 Alkyl "refers to a straight or branched saturated hydrocarbon group having 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-methylpentaneA base, etc.
The term "halo C" as used herein 1-8 Alkyl "means C as described above 1-8 Alkyl groups in which one or more (e.g., 1, 2, 3,4, or 5) hydrogen atoms are replaced by halogen. It will be appreciated by those skilled in the art that when there is more than one halogen substituent, the halogens may be the same or different and may be located on the same or different carbon atoms. "halo C 1-8 Examples of alkyl "include-CH 2 F、-CHF 2 、-CF 3 、-CCl 3 、-C 2 F 5 、-C 2 Cl 5 、-CH 2 CF 3 、-CH 2 Cl、-CH 2 CH 2 CF 3 or-CF (CF) 3 ) 2 Etc.
The term "alkoxy", alone or in combination with other groups, denotes a group R y -O-, wherein R y Is an alkyl group as described above. "C 1-8 Alkoxy "represents a group R y -O-, wherein R y Is C as described above 1-8 An alkyl group.
"aryl" refers to a monocyclic or fused bicyclic aromatic ring composed of carbon and hydrogen atoms. "C 6-10 Aryl "refers to aryl groups containing 6 to 10 carbon atoms. For example, aryl may be phenyl or naphthyl.
"aralkyl" refers to an alkyl group as described above, such as benzyl, substituted with an aryl group as described above.
"aralkoxy" refers to an alkoxy group as described above, such as benzyloxy, substituted with an aryl group as described above.
"acyl" refers to the group-CO-R x Wherein R is x Are alkyl, aryl or aralkyl groups as described above, such as alkanoyl or aralkanoyl, such as benzoyl.
The aryl groups described above, whether as a group per se or as part of another group, e.g., aralkyl, aralkoxy, acyl, may be optionally substituted with one or more substituents. When said aryl is substituted, said substituent is selected from C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-8 Alkyl, halogen,Aryl and nitro, more preferably methoxy, ethoxy, halogen or phenyl. For example, substituted benzoyl means that the substituent on the benzene ring is selected from C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-8 Benzoyl of alkyl, halogen or aryl.
Detailed Description
The process of the invention is further illustrated by the following examples. It should be understood that the following examples are provided for the purpose of providing a better understanding of the present invention and are not intended to limit the scope of the present invention in any way.
Preparation of Compounds of formula IV
Example 1:
1870g of methylene dichloride and 269g of a compound of formula VI-a are added into a reaction bottle, stirred and cooled to 0-5 ℃, 125g of triethylamine is added, stirred for 10 minutes, 220g of p-toluenesulfonyl chloride is slowly added, after the addition is completed, the temperature is kept for 30 minutes, then the reaction is raised to 25 ℃, the reaction is carried out under the condition of heat preservation, 400g of water is added, stirred for 30 minutes, and the mixture is kept stand for layering. A dichloromethane solution of the compound of formula V-a was obtained and used directly in the next reaction without treatment.
120g of ethanolamine is added into a dichloromethane solution of the compound of the formula V-a, and the mixture is stirred and heated to reflux; after the temperature is raised, controlling the internal temperature to be 90-95 ℃, and preserving the heat for reaction for 5-7 hours; after the reaction is finished, the temperature is reduced to 20-30 ℃; 200g of water is added, a proper amount of 10 percent NaOH is added dropwise, the pH is adjusted to be more than or equal to 12, and the mixture is stirred and reacts for 12 hours at 20-30 ℃; after the reaction, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, and suction filtering; the filter cake is washed by a small amount of purified water; suction filtration and filter cake drying are carried out to obtain 262g of the compound of the formula IV. Yield: 85.4%, purity: 99%. 1 H NMR(600MHz,DMSO-d6)δ7.35(h,J＝5.9Hz,4H),7.32–7.25(m,1H),4.58(q,J＝12.2Hz,2H),4.50(t,J＝5.3Hz,1H),4.33(s,1H),4.15(td,J＝5.4,2.8Hz,1H),4.02(d,J＝2.8Hz,1H),3.63(d,J＝10.7Hz,1H),3.56(d,J＝10.7Hz,1H),3.43(q,J＝5.0Hz,2H),3.34(s,1H),2.84(dd,J＝12.4,5.2Hz,1H),2.74(dd,J＝12.4,5.7Hz,1H),2.58(td,J＝5.6,2.5Hz,2H),1.40(s,3H),1.29(s,3H)； 13 C NMR(151MHz,DMSO)δ138.74,128.72,127.87,127.74,113.49,111.37,85.54,80.27,75.22,73.17,70.93,60.73,52.35,48.20,27.92,26.95。
Example 2:
adding 1870g of dichloromethane and 254g of a compound of formula VI-b into a reaction bottle, stirring and cooling to 0-5 ℃, adding 115g of triethylamine, stirring for 10 minutes, slowly adding 220g of methanesulfonyl chloride, keeping the low temperature for 30 minutes after the addition is completed, heating to 25 ℃, keeping the temperature for reaction until the reaction is completed, adding 400g of water, stirring for 30 minutes, standing and layering. A dichloromethane solution of the compound of formula V-b was obtained and used directly in the next reaction without treatment.
Adding 120g of ethanolamine into the dichloromethane solution of the compound of the formula V-b, stirring, heating and preserving heat for reaction for 5-7 hours; after the reaction is finished, the temperature is reduced to be lower than 20 ℃; 200g of water is added, a proper amount of 10 percent NaOH is added dropwise, the pH is adjusted to be more than or equal to 12, and the mixture is stirred and reacts for 12 hours at 20-30 ℃; after the reaction, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, and suction filtering; the filter cake is washed by a small amount of purified water; suction filtration and filter cake drying are carried out to obtain 227.6g of the compound of the formula IV-b. Yield: 78.1%, purity: 98.5%.
Preparation of Compounds of formula III
Example 3:
240g of the compound of formula IV-a is added into an autoclave, 1440mL of methanol is added into the autoclave, 36g of 10% palladium/carbon is added into the autoclave, nitrogen is replaced, hydrogen is replaced, stirring is carried out, the temperature is raised to 50 ℃ at the inner temperature, the hydrogen pressure is 0.9-1.0 MPa, the temperature is kept for 4 hours, the reaction is carried out under pressure filtration, and the filtrate is concentrated under reduced pressure, thus 175.2g of the compound of formula III is obtained. Yield: 98.0%. 1 H NMR(600MHz,DMSO-d6)δ4.46–3.78(m,6H),3.60–3.32(m,4H),2.84(dd,J＝12.4,5.2Hz,1H),2.75(dd,J＝12.6,5.8Hz,1H),2.59(s,2H),1.34(d,J＝59.4Hz,6H)； 13 C NMR(151MHz,DMSO)δ114.60,111.12,85.25,80.06,75.21,62.43,60.59,52.26,48.18,27.95,27.10。
Preparation of Compounds of formula I
Example 4:
adding 175.2g of the compound of the formula III into a reaction bottle, dropwise adding 200g of concentrated hydrochloric acid, controlling the internal temperature to be 20-40 ℃ until the reaction is finished, and adding 60g of sodium hydroxide to regulate alkali to obtain an aqueous solution of the compound of the formula II. Transferring the aqueous solution of the compound of the formula II into a high-pressure reaction kettle, adding 20g (wet weight, water content 60%) of 10% palladium/carbon into the high-pressure reaction kettle, replacing nitrogen and hydrogen for 3 times respectively, and controlling the pressure of the hydrogen to be 1.0-3.0 MPa. After the reaction is finished, filtering, and recycling and reusing the filter cake catalyst. And (3) loading the filtrate on a cation exchange resin column, after all materials are loaded on the column, dissociating the materials by using purified water and ammonia water, collecting ammonia hydrolysis liquid, and concentrating under reduced pressure under the condition of controlling the external temperature to be 60-65 ℃. After concentrating, adding absolute ethanol for crystallization, stirring for 2 hours at 50-55 ℃, slowly cooling to-5-0 ℃ for crystallization for 2 hours, and carrying out suction filtration. The filter cake was dried to give 117.2g of crude miglitol. Yield: 85.0%.
117.2g miglitol crude product, purified water and ethanol are added into a reaction bottle, stirred and heated to 50-55 ℃, 10g active carbon is added for decolorization after 1 hour, and suction filtration is carried out after 1 hour. The filter cake was rinsed with hot absolute ethanol, the filtrates were combined and stirred at 50-55 ℃ for 2 hours. Slowly cooling to 25 ℃ for crystallization for 2 hours, cooling to-5-0 ℃ for stirring crystallization for 3-5 hours. Suction filtration and filter cake drying are carried out to obtain 105.6g of miglitol. Yield: 90.1%, purity: 99.9%.
Example 5:
227.6g of the compound of the formula IV-b is added into a reaction bottle, 300g of concentrated hydrochloric acid is added dropwise, the internal temperature is controlled to be 20-40 ℃ until the reaction is finished, 60g of sodium hydroxide is added for alkali adjustment, and the compound of the formula II is obtained after the alkali adjustment. Transferring the aqueous solution of the compound of the formula II into a high-pressure reaction kettle, adding 20g (wet weight, water content 60%) of 10% palladium/carbon into the high-pressure reaction kettle, replacing nitrogen and hydrogen for 3 times respectively, and controlling the pressure of the hydrogen to be 1.0-3.0 MPa. After the reaction is finished, filtering, and recycling and reusing the filter cake catalyst. And (3) loading the filtrate on a cation exchange resin column, after all materials are loaded on the column, dissociating the materials by using purified water and ammonia water, collecting ammonia hydrolysis liquid, and concentrating under reduced pressure under the condition of controlling the external temperature to be 60-65 ℃. After concentrating, adding absolute ethanol for crystallization, stirring for 2 hours at 50-55 ℃, slowly cooling to-5-0 ℃ for crystallization for 2 hours, and carrying out suction filtration. And drying the filter cake to obtain 100g of miglitol crude product.
100g of miglitol crude product, purified water and ethanol are added into a reaction bottle, stirred and heated to 50-55 ℃, 10g of active carbon is added for decolorization after 1 hour, and suction filtration is carried out after 1 hour. The filter cake was rinsed with hot absolute ethanol, the filtrates were combined and stirred at 50-55 ℃ for 2 hours. Slowly cooling to 25 ℃ for crystallization for 2 hours, cooling to-5-0 ℃ for stirring crystallization for 3-5 hours. Suction filtering and filter cake drying to obtain 78-83 g miglitol. The overall yield of miglitol from the compound of formula VI-b is 42.5-45.3%, purity: 99.9%.

Claims (7)

1. Compounds of formula IV
Wherein R is selected from benzyl, C 1-8 Alkyl-substituted benzyl, C 1-8 Alkoxy-substituted benzyl, halogen-substituted benzyl and halogenated C 1-8 Alkyl substituted benzyl.
2. A process for the preparation of a compound of formula IV comprising the steps of:
step (4): combining a compound of formula VI with R 1 Cl in the presence of a base to prepare a compound of formula V;
step (5): reacting a compound of formula V with ethanolamine to produce a compound of formula IV;
wherein R is as defined in claim 1, and R 1 Is C 1-8 Alkylsulfonyl, arylsulfonyl, C 1-8 An alkyl substituted arylsulfonyl group.
3. The method of claim 2, wherein R 1 Selected from methanesulfonyl, ethanesulfonyl, benzenesulfonyl or p-toluenesulfonyl.
4. The process according to claim 2, wherein the base in step (4) is selected from inorganic or organic bases.
5. The process according to claim 2 or 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.
6. A process for the preparation of a compound of formula I comprising the steps of:
step (4): combining a compound of formula VI with R 1 Cl in the presence of a base to prepare a compound of formula V;
step (5): reacting a compound of formula V with ethanolamine to produce a compound of formula IV;
step (1): deprotecting a compound of formula IV to give a compound of formula III;
step (2): removing protecting groups from the compound of the formula III through acid treatment to obtain a compound of the formula II; and
step (3): catalytically hydrogenating the compound of formula II in the presence of a catalyst to obtain a compound of formula I;
alternatively, the compound of formula IV is deprotected directly in the presence of the acid described in step (2) to give a compound of formula II, followed by step (3);
wherein R is selected from benzyl, C 1-8 Alkyl-substituted benzyl, C 1-8 Alkoxy-substituted benzyl, halogen-substituted benzyl and halogenated C 1-8 Alkyl-substituted benzyl;
and R is 1 Selected from C 1-8 Alkylsulfonyl, arylsulfonyl, C 1-8 An alkyl substituted arylsulfonyl group.
7. The method of claim 6, wherein R 1 Selected from methanesulfonyl, ethanesulfonyl, benzenesulfonyl or p-toluenesulfonyl.
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