WO2023138099A1 - Preparation method for miglittol - Google Patents

Preparation method for miglittol Download PDF

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WO2023138099A1
WO2023138099A1 PCT/CN2022/122535 CN2022122535W WO2023138099A1 WO 2023138099 A1 WO2023138099 A1 WO 2023138099A1 CN 2022122535 W CN2022122535 W CN 2022122535W WO 2023138099 A1 WO2023138099 A1 WO 2023138099A1
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compound
formula
alkyl
halogenated
benzoyl
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PCT/CN2022/122535
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French (fr)
Chinese (zh)
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WO2023138099A8 (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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浙江奥翔药业股份有限公司
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Priority to KR1020247025376A priority Critical patent/KR20240136356A/en
Publication of WO2023138099A1 publication Critical patent/WO2023138099A1/en
Publication of WO2023138099A8 publication Critical patent/WO2023138099A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the field of medicinal chemical synthesis. Specifically, the present invention relates to a preparation method of the hypoglycemic drug Miglitol, an intermediate compound thereof and a preparation method.
  • Miglitol is an antidiabetic drug launched by Bayer in 1997. It is a new type of intestinal ⁇ -glucosidase inhibitor discovered from the bacillus broth medium. It is the parent modified product of 1-deoxynojirimycin, which belongs to the N-substituted-1-deoxynojirimycin type, and its structure is similar to glucose.
  • Miglitol can competitively inhibit ⁇ -glucosidase, reduce the metabolism of carbohydrate compounds, reduce the absorption of carbohydrates in the small intestine, thereby stabilizing the plasma glucose concentration after meals.
  • the drug is safe, effective, and generally well tolerated, and has become a commonly used drug for the treatment of type II diabetes.
  • the preparation methods of miglitol are mainly divided into chemical synthesis and chemical-biological enzymatic synthesis.
  • the document Yunnan Chemical Industry, 2010 (2), 14-17 also provides a method for preparing miglitol.
  • the preparation process is as follows: using methyl- ⁇ -D-glucoside as a raw material, through 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.
  • this method has cumbersome steps, many by-products and difficult purification.
  • Patent CN105968042B discloses that glucose and ethanolamine are used as raw materials to carry out catalytic hydrogenation under high-pressure hydrogen conditions to prepare the intermediate hydroxyethylglucosamine, and then undergo biological oxidation by gluconic acid oxidizing bacteria, and then catalytic hydrogenation under high-pressure hydrogen conditions to prepare crude miglitol, which is then purified and crystallized to obtain the final product.
  • This route has disadvantages such as harsh reaction conditions, high cost of cell culture and biotransformation, and difficult recycling of cells, which limits its commercial application.
  • Patent CN101029321A discloses a method of using 1-hydroxyethylamino-1-deoxy-D-sorbitol as a raw material, and using a polymeric ion membrane to contain gluconic acid oxidizing bacteria-containing microcapsules for fermentation reaction to obtain 1-hydroxyethylamino-1-deoxy-D-sorbose, followed by catalytic hydrogenation, resin refining, concentration and crystallization to obtain miglitol.
  • This route has disadvantages such as harsh reaction conditions, difficult acquisition of raw materials, cumbersome reaction steps, etc., which is unfavorable for industrialized production.
  • Patent CN107746385A discloses a method for preparing miglitol by using 6-deoxy-6-hydroxyethylamino- ⁇ -L-sorbose cell resting fluid as raw material. This route has disadvantages such as harsh reaction conditions, difficult procurement of raw materials, cumbersome reaction steps, etc., which is unfavorable for industrialized production.
  • Patent CN101302549B discloses a method for first screening out miglitol-producing strains, subjecting substrates to biotransformation, microfiltration, ultrafiltration, nanofiltration, and activated carbon decolorization to obtain miglitol intermediates, and then preparing miglitol (HPLC99.0%) by hydrogenation purification.
  • this route has the disadvantages of difficult cultivation and isolation of miglitol-producing strains, low recycling rate, and low yield, which restricts its industrialization development.
  • Announced in the patent EP0008031B1 take 6-amino-6-deoxy-L-sorbitol as raw material, the method for preparing Miglitol through amino protection, microbial oxidation, catalytic hydrogenation, and reaction with ethylene oxide.
  • the cost of bacterial cell culture and biotransformation in this route is relatively high, and the bacterial cells are collected by centrifugation, resulting in a large loss of bacterial cells, which cannot be adapted to large-scale industrial production.
  • Patent CN1328270C discloses a method for preparing miglitol by catalytic hydrogenation of furan ring derivatives using catalyst RaNi, 1% to 5% Pd/C or Pd- CaCO3 .
  • the purity of the refined product of miglitol produced by this method is only 98.9%, which is far from meeting the requirements of the preparation market.
  • this patent does not provide a synthetic route for its raw materials for reference, which inevitably limits the development of this route.
  • the existing synthetic routes can be summarized into two categories, one is the preparation of miglitol by chemical synthesis; the other is the preparation of miglitol by microbial fermentation or chemical synthesis followed by microbial fermentation.
  • these two types of preparation methods have problems such as cumbersome steps, harsh synthesis conditions, difficulty in obtaining raw materials or difficulty in meeting market requirements in product purity. Therefore, it is necessary to develop a synthetic method for preparing high-quality miglitol by using simple and easy-to-obtain industrial materials as raw materials through simple and convenient steps, so as to meet the needs of industrialized large-scale production.
  • the technical problem to be solved by the present invention is to overcome the shortcomings of the existing synthesis methods and provide a new preparation method of miglitol that is more conducive to industrial production.
  • the first aspect of the present invention provides a method for preparing Miglitol of formula I, comprising the following steps:
  • Step (1) deprotecting the compound of formula IV to obtain the compound of formula III;
  • Step (2) deprotecting the compound of formula III through acid treatment to obtain the compound of formula II;
  • Step (3) Catalytic hydrogenation of the compound of formula II in the presence of a catalyst to obtain the compound of formula I;
  • R is a hydroxyl protecting group
  • step (3) the compound of formula IV is directly deprotected in the presence of the acid described in step (2) to obtain the compound of formula II, and then step (3) is performed.
  • said R is selected from C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkylcarbonyl, halogenated C 1-8 Alkylcarbonyl, benzoyl, C 1-8 Alkyl substituted benzoyl, halogenated C 1-8 Alkyl substituted benzoyl, benzenesulfonyl, C 1-8 Alkyl substituted benzenesulfonyl, halogenated C 1-8 Alkyl substituted benzenesulfonyl, benzyl, C 1-8 Alkyl substituted benzyl, C 1-8 Alkoxy substituted benzyl, halogen atom 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, tetra
  • 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 atom substituted benzyl, methoxymethyl, 2-methoxyethoxymethyl, benzyloxymethyl, tetrahydropyran-2-yl or silicon protecting group.
  • R is selected from benzyl, C 1-8 alkyl substituted benzyl, C 1-8 alkoxy substituted benzyl, halogen atom substituted benzyl, t-BuMe 2 Si, t-BuPh 2 Si, (i-Pr) 3 Si, Et 3 Si or Me 3 Si.
  • 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.
  • the dehydroxyl protecting group R can be deprotected under basic conditions, acidic conditions or catalytic hydrogenation conditions.
  • R is C 1-8 alkylcarbonyl, halogenated C 1-8 alkylcarbonyl, benzoyl, C 1-8 alkyl substituted benzoyl, benzenesulfonyl or C 1-8 alkyl substituted benzenesulfonyl
  • a base such as an alkali metal hydroxide or carbonate, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
  • the compound of formula IV can remove the hydroxyl protecting group in the presence of acid to obtain the compound of formula III, and then proceed to step (2), or the compound of formula IV can directly remove the protecting group in the presence of acid to prepare the compound of formula II, and then proceed 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.
  • catalytic hydrogenation can remove the protecting group.
  • 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 used is 0.5-3.0 MPa, and the reaction time is 4-24 hours.
  • the reaction solvent in step (1) is alcohol, ester or ether, or a mixture of any two or more thereof.
  • the alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, isoamyl alcohol, cyclohexanol, benzyl alcohol and the like.
  • Described ester is selected from methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate, isopropyl acetate.
  • the ether is selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, anisole, tetrahydrofuran, methyl tetrahydrofuran, and 1,4-dioxane.
  • 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.
  • 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 step (3) is 0-4MPa, preferably 1.0-3MPa, more preferably 2.0-2.5MPa.
  • the reaction temperature in step (3) is 0-30° C., and the reaction time is 4-24 hours.
  • the step (3) further includes obtaining the compound of formula I through 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 DOWEX50 ⁇ 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 C 150, or strongly acidic cation exchange resin C160.
  • the step (3) further includes crystallizing and purifying the crude compound of formula I in an organic solvent or a mixture of an organic solvent and water after being treated with a cation exchange resin.
  • the organic solvent can be selected from methanol, ethanol, n-propanol, isopropanol, or a mixture of two or more thereof.
  • the second aspect of the present invention provides the preparation method of the compound of formula IV, comprising the following steps:
  • Step (4) reacting the compound of formula VI with R 1 Cl in the presence of a base to prepare the compound of formula V;
  • Step (5) reacting the compound of formula V with ethanolamine to prepare the compound of formula IV;
  • R is as defined above in the first aspect, and R is C 1-8 alkanoyl, C 1-8 alkylsulfonyl, arylsulfonyl, C 1-8 alkyl substituted arylsulfonyl, benzoyl or substituted benzoyl.
  • said R 1 is selected from formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl, methanesulfonyl, ethylsulfonyl, benzenesulfonyl or p-toluenesulfonyl.
  • the base is selected from inorganic bases or organic bases, such as alkali metal hydroxides or carbonates or bicarbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, ethylenediamine, diisopropylethylenediamine, diisopropylamine, piperidine, morpholine, pyridine or 2-picoline.
  • inorganic bases or organic bases such as alkali metal hydroxides or carbonates or bicarbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, ethylenediamine, diisopropylethylenediamine, diisopropylamine, piperidine, morpholine, pyridine or 2-picoline.
  • the temperature is controlled at -5-30° C., and the compound of formula VI is reacted with R 1 Cl in a low-polarity solvent in the presence of a base.
  • the reaction solution can be directly processed in step (5) after simple treatment.
  • the low polarity solvent is selected from dichloromethane, chloroform, diethyl ether, isopropyl ether, methyl tert-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 solution is washed and extracted with water to remove the salt produced by the reaction.
  • 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, cool down to room temperature, adjust to alkalinity, further cool down and crystallize, and optionally crystallize in an organic solvent or a mixture of an organic solvent and water to obtain the compound of formula IV.
  • the base is selected from inorganic bases or organic bases, such as alkali metal hydroxides or carbonates or bicarbonates, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert-butoxide.
  • alkali metal hydroxides or carbonates or bicarbonates such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert-butoxide.
  • the organic solvent used for the reaction is selected from dichloromethane, chloroform, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, 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 tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane, acetonitrile, or a mixture of two or more thereof.
  • the present invention provides a novel intermediate compound of formula IV
  • R is selected from C 1-8 Alkyl, halogenated C 1-8 Alkyl, C 1-8 Alkylcarbonyl, halogenated C 1-8 Alkylcarbonyl, benzoyl, C 1-8 Alkyl substituted benzoyl, halogenated C 1-8 Alkyl substituted benzoyl, benzenesulfonyl, C 1-8 Alkyl substituted benzenesulfonyl, halogenated C 1-8 Alkyl substituted benzenesulfonyl, benzyl, C 1-8 Alkyl substituted benzyl, C 1-8 Alkoxy substituted benzyl, halogen atom 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
  • the present invention provides a method for synthesizing miglitol of formula I.
  • the method uses the compound of formula VI as a raw material to obtain miglitol through the reaction of adding a protecting group, substitution reaction, deprotecting group, and catalytic hydrogenation to form a ring, and optionally recrystallization and purification to obtain the final product.
  • the present invention provides a method for synthesizing Miglitol of formula I, which comprises the following steps (4), (5), (1), (2) and (3):
  • R and R 1 are as defined above.
  • the conditions of steps (4) and (5) are as described in the second aspect of the present invention.
  • the conditions of steps (1), (2) and (3) are as described in the first aspect of the present invention.
  • the compound of formula IV is directly deprotected in the presence of the acid described in step (2) to obtain the compound of formula II, and then step (3) is performed.
  • steps (4) and (5) are as described in the second aspect of the present invention, and the conditions of steps (1), (2) and (3) are as described in the first aspect of the present invention, or the compound of formula IV is directly deprotected in the presence of the acid described in step (2) to obtain the compound of formula II, and then step (3) is performed.
  • the present invention has the following advantages:
  • the diastereomeric impurities produced by the method of the present invention can be effectively controlled and controlled below 0.1%;
  • the present invention uses the compound of formula VI as a raw material to prepare miglitol with a high yield, reaching 48.5% to 51.5%;
  • the purity of the miglitol prepared by the method of the present invention reaches 99.9%, thereby providing reliable quality assurance for the preparation.
  • the invention overcomes the problems of low total yield, difficult control of diastereomer impurities, low product purity and the like in the prior art, and is therefore suitable for large-scale industrial production.
  • halogen or halo as used herein refers to F, Cl, Br or I.
  • 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.
  • alkyl refers to a linear or branched saturated hydrocarbon group composed of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1-10, eg 1-8, 1-6, 1-5, 1-4, 1-3 or 1-2 carbon atoms.
  • C 1-8 alkyl refers to a linear 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-methylpentyl and the like.
  • halogenated C 1-8 alkyl refers to the above-mentioned C 1-8 alkyl, wherein one or more (eg 1, 2, 3, 4 or 5) hydrogen atoms are replaced by halogen. It should be understood 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.
  • halogenated C 1-8 alkyl examples 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 and the like.
  • alkoxy denotes the group Ry - O-, wherein Ry is alkyl as defined above.
  • C 1-8 alkoxy refers to the group R y —O—, wherein R y is a C 1-8 alkyl group as described above.
  • Aryl refers to a monocyclic or fused bicyclic aromatic ring composed of carbon atoms and hydrogen atoms.
  • C 6-10 aryl means an aryl group containing 6-10 carbon atoms.
  • aryl can be phenyl or naphthyl.
  • Alkyl means an alkyl group as described above substituted with an aryl group as described above, eg benzyl.
  • Alkoxy means an alkoxy group as described above substituted with an aryl group as described above, eg benzyloxy.
  • Acyl refers to the group -CO- Rx , wherein Rx is alkyl, aryl or aralkyl as described above, for example alkanoyl or aralkanoyl, for example benzoyl.
  • the aryl group mentioned above can be optionally substituted by one or more substituents.
  • the substituent is selected from C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-8 alkyl, halogen, aryl and nitro, more preferably methoxy, ethoxy, halogen or phenyl.
  • a substituted benzoyl refers to a benzoyl group in which the substituent on the benzene ring is selected from C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-8 alkyl, halogen or aryl.

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Abstract

The present invention relates to a preparation method for miglitol. Specifically, the method of the present invention comprises: using a compound represented by formula VI as a raw material, subjecting the raw material to sulfonylation and then to a substitution reaction with ethanolamine, then removing a protecting group, and finally carrying out hydrogenation and 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 and the like, and is very suitable for industrial production.

Description

一种米格列醇的制备方法A kind of preparation method of Miglitol 技术领域technical field
本发明涉及药物化学合成领域。具体而言，本发明涉及降糖药物米格列醇的制备方法、其中间体化合物以及制备方法。The invention relates to the field of medicinal chemical synthesis. Specifically, the present invention relates to a preparation method of the hypoglycemic drug Miglitol, an intermediate compound thereof and a preparation method.
背景技术Background technique
米格列醇(Miglitol)是拜耳公司于1997年上市的抗糖尿病药物。它是从杆菌肉汤培养基中发现的一种新型肠道α-葡萄糖苷酶抑制剂，是1-脱氧野尻霉素的母体修饰产物，属于N-取代-1-脱氧野尻霉素类型，结构与葡萄糖相似。化学名为(2R,3R,4R,5S)-1-(2-羟乙基)-2-(羟甲基)-3,4,5-哌啶三醇，熔点146℃，旋光度[α]D 20＝-8(C,1,CH 3OH)，结构式如下： Miglitol is an antidiabetic drug launched by Bayer in 1997. It is a new type of intestinal α-glucosidase inhibitor discovered from the bacillus broth medium. It is the parent modified product of 1-deoxynojirimycin, which belongs to the N-substituted-1-deoxynojirimycin type, and its structure is similar to glucose. The chemical name is (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)-3,4,5-piperidinetriol, the melting point is 146°C, the optical rotation is [α]D 20 =-8(C,1,CH 3 OH), and the structural formula is as follows:
Figure PCTCN2022122535-appb-000001
Figure PCTCN2022122535-appb-000001
作为一种新型α-葡糖苷酶抑制剂，米格列醇能竞争性抑制α-葡糖苷酶，减少糖类化合物的代谢，降低糖类在小肠的吸收，从而稳定餐后血浆葡萄糖浓度。该药物安全有效，且一般耐受性良好，已成为治疗Ⅱ型糖尿病的常用药物。As a new type of α-glucosidase inhibitor, Miglitol can competitively inhibit α-glucosidase, reduce the metabolism of carbohydrate compounds, reduce the absorption of carbohydrates in the small intestine, thereby stabilizing the plasma glucose concentration after meals. The drug is safe, effective, and generally well tolerated, and has become a commonly used drug for the treatment of type Ⅱ diabetes.
目前米格列醇的制备方法主要分为化学合成和化学-生物酶促合成两种方式。At present, the preparation methods of miglitol are mainly divided into chemical synthesis and chemical-biological enzymatic synthesis.
第一种方式是化学合成：The first way is chemical synthesis:
文献Carbohydrate Research,2016,435,1-6中公布了仅基于化学方法合成米格列醇的方法。但是，该方法存在非对映异构体杂质难以控制，且总收率低等弊端。The literature Carbohydrate Research, 2016, 435, 1-6 discloses a method for synthesizing miglitol based only on chemical methods. However, this method has disadvantages such as difficult control of diastereomer impurities and low overall yield.
Figure PCTCN2022122535-appb-000002
Figure PCTCN2022122535-appb-000002
文献云南化工,2010(2),14-17中也给出了一种制备米格列醇的方法，制备过程如下：以甲基-α-D-葡萄糖苷为原料，经过一系列的化学修饰，得到关键中间体1-脱氧野尻霉素的亲脂衍生物，再经一系列取代反应得到米格列醇。然而，此方法步骤繁琐，副产物多，纯化较困难。The document Yunnan Chemical Industry, 2010 (2), 14-17 also provides a method for preparing miglitol. The preparation process is as follows: using methyl-α-D-glucoside as a raw material, through 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 cumbersome steps, many by-products and difficult purification.
Figure PCTCN2022122535-appb-000003
Figure PCTCN2022122535-appb-000003
另一种方式是化学-生物酶促合成：Another way is chemical-biological enzymatic synthesis:
专利CN105968042B中公布了以葡萄糖和乙醇胺为原料，在高压氢气条件下进行催化氢化，制备中间体羟乙氨基葡萄糖，然后通过葡糖酸氧化菌生物氧化，再在氢气高压条件下催化氢化，制备米格列醇粗品，然后经提纯、结晶精制，得到最终产品的方法。该路线存在反应条件苛刻，菌体培养成本和生物转化成本较高，菌体不易回收利用等缺点，因此限制了其商业化应用。Patent CN105968042B discloses that glucose and ethanolamine are used as raw materials to carry out catalytic hydrogenation under high-pressure hydrogen conditions to prepare the intermediate hydroxyethylglucosamine, and then undergo biological oxidation by gluconic acid oxidizing bacteria, and then catalytic hydrogenation under high-pressure hydrogen conditions to prepare crude miglitol, which is then purified and crystallized to obtain the final product. This route has disadvantages such as harsh reaction conditions, high cost of cell culture and biotransformation, and difficult recycling of cells, which limits its commercial application.
Figure PCTCN2022122535-appb-000004
Figure PCTCN2022122535-appb-000004
专利CN101029321A中公布了以1-羟乙氨基-1-脱氧-D-山梨醇为原料，用聚合离子膜包含葡萄糖酸氧化菌制成的含菌微囊进行发酵反应，制得1-羟乙氨基-1-脱氧-D-山梨糖，再经催化加氢，过树脂精制后浓缩结晶制得米格列醇的方法。该路线存在反应条件苛刻，原料不易获得，反应步骤繁琐等弊端，不利于工业化生产。Patent CN101029321A discloses a method of using 1-hydroxyethylamino-1-deoxy-D-sorbitol as a raw material, and using a polymeric ion membrane to contain gluconic acid oxidizing bacteria-containing microcapsules for fermentation reaction to obtain 1-hydroxyethylamino-1-deoxy-D-sorbose, followed by catalytic hydrogenation, resin refining, concentration and crystallization to obtain miglitol. This route has disadvantages such as harsh reaction conditions, difficult acquisition of raw materials, cumbersome reaction steps, etc., which is unfavorable for industrialized production.
Figure PCTCN2022122535-appb-000005
Figure PCTCN2022122535-appb-000005
专利CN107746385A中公布了以6-脱氧-6-羟乙基氨基-α-L-山梨糖细胞静息液为原料制备米格列醇的方法。该路线存在反应条件苛刻，原料不易采购，反应步骤繁琐等弊端，不利于工业化生产。Patent CN107746385A discloses a method for preparing miglitol by using 6-deoxy-6-hydroxyethylamino-α-L-sorbose cell resting fluid as raw material. This route has disadvantages such as harsh reaction conditions, difficult procurement of raw materials, cumbersome reaction steps, etc., which is unfavorable for industrialized production.
Figure PCTCN2022122535-appb-000006
Figure PCTCN2022122535-appb-000006
专利CN101302549B公布了先通过筛选出米格列醇生产菌株，将底物进行生物转化、微滤、超滤、纳滤、活性炭脱色得到米格列醇中间体，再通过氢化纯化制备米格列醇(HPLC99.0％)的方法。但该路线存在米格列醇生产菌株培养分离困难，循环利用不高，产量小等缺点，制约了其工业化的发展。Patent CN101302549B discloses a method for first screening out miglitol-producing strains, subjecting substrates to biotransformation, microfiltration, ultrafiltration, nanofiltration, and activated carbon decolorization to obtain miglitol intermediates, and then preparing miglitol (HPLC99.0%) by hydrogenation purification. However, this route has the disadvantages of difficult cultivation and isolation of miglitol-producing strains, low recycling rate, and low yield, which restricts its industrialization development.
专利EP0008031B1中公布了以6-氨基-6-脱氧-L-山梨醇为原料，经氨基保护、微生物氧 化、催化加氢、与环氧乙烷反应来制备米格列醇的方法。但是，该路线中菌体培养成本及生物转化成本较高，用离心方法收集菌体，菌体损失大，无法适应工业化大生产。Announced in the patent EP0008031B1 take 6-amino-6-deoxy-L-sorbitol as raw material, the method for preparing Miglitol through amino protection, microbial oxidation, catalytic hydrogenation, and reaction with ethylene oxide. However, the cost of bacterial cell culture and biotransformation in this route is relatively high, and the bacterial cells are collected by centrifugation, resulting in a large loss of bacterial cells, which cannot be adapted to large-scale industrial production.
Figure PCTCN2022122535-appb-000007
Figure PCTCN2022122535-appb-000007
专利CN1328270C中公布了以呋喃环衍生物为原料，使用催化剂RaNi、1％～5％Pd/C或Pd-CaCO 3催化氢化制备米格列醇的方法。在该专利中，该方法制得的米格列醇精制品纯度只有98.9％，远不能满足制剂市场的要求，而且，该专利并未给出其原料可供参考的合成路线，这必然限制了该路线的发展。 Patent CN1328270C discloses a method for preparing miglitol by catalytic hydrogenation of furan ring derivatives using catalyst RaNi, 1% to 5% Pd/C or Pd- CaCO3 . In this patent, the purity of the refined product of miglitol produced by this method is only 98.9%, which is far from meeting the requirements of the preparation market. Moreover, this patent does not provide a synthetic route for its raw materials for reference, which inevitably limits the development of this route.
Figure PCTCN2022122535-appb-000008
Figure PCTCN2022122535-appb-000008
综上所述，现有的合成路线归纳起来分为两类，一类是通过化学合成方法制备米格列醇；另一类是通过微生物发酵或先化学合成后微生物发酵制备米格列醇。但是，这两类制备方法存在步骤繁琐，合成条件苛刻，原料获取困难或者产品纯度难以适应市场要求等问题。因此，需要开发一种以简单易得的工业物料为原料，经过简单的、操作方便的步骤，制备高质量的米格列醇的合成方法，从而满足工业化大规模生产的需求。In summary, the existing synthetic routes can be summarized into two categories, one is the preparation of miglitol by chemical synthesis; the other is the preparation of miglitol by microbial fermentation or chemical synthesis followed by microbial fermentation. However, these two types of preparation methods have problems such as cumbersome steps, harsh synthesis conditions, difficulty in obtaining raw materials or difficulty in meeting market requirements in product purity. Therefore, it is necessary to develop a synthetic method for preparing high-quality miglitol by using simple and easy-to-obtain industrial materials as raw materials through simple and convenient steps, so as to meet the needs of industrialized large-scale production.
发明内容Contents of the invention
本发明所要解决的技术问题在于克服现有合成方法的不足之处，提供更有利于工业化生产的新的米格列醇制备方法。The technical problem to be solved by the present invention is to overcome the shortcomings of the existing synthesis methods and provide a new preparation method of miglitol that is more conducive to industrial production.
具体而言，本发明第一方面提供了一种式I的米格列醇的制备方法，包括以下步骤：Specifically, the first aspect of the present invention provides a method for preparing Miglitol of formula I, comprising the following steps:
Figure PCTCN2022122535-appb-000009
Figure PCTCN2022122535-appb-000009
步骤(1)：将式IV化合物脱保护基R，得到式III化合物；Step (1): deprotecting the compound of formula IV to obtain the compound of formula III;
步骤(2)：将式III化合物经酸处理脱保护基，得到式II化合物；Step (2): deprotecting the compound of formula III through acid treatment to obtain the compound of formula II;
步骤(3)：将式II化合物在催化剂存在下催化氢化，得到式I化合物；Step (3): Catalytic hydrogenation of the compound of formula II in the presence of a catalyst to obtain the compound of formula I;
其中，R为羟基保护基；Wherein, R is a hydroxyl protecting group;
或者，将式IV化合物直接在步骤(2)所述的酸存在下脱保护基，得到式II化合物，然后进行步骤(3)。Alternatively, the compound of formula IV is directly deprotected in the presence of the acid described in step (2) to obtain the compound of formula II, and then step (3) is performed.
在一个实施方案中，所述的R选自C 1-8烷基、卤代C 1-8烷基、C 1-8烷基羰基、卤代C 1-8烷基羰基、苯甲酰基、C 1-8烷基取代的苯甲酰基、卤代C 1-8烷基取代的苯甲酰基、苯磺酰基、C 1-8烷基取代的苯磺酰基、卤代C 1-8烷基取代的苯磺酰基、苄基、C 1-8烷基取代的苄基、C 1-8烷氧基取代的苄基、卤素原子取代的苄基、卤代C 1-8烷基取代的苄基、烯丙基、C 1-8烷氧基-C 1-8烷基、C 1-8烷氧基-C 1-8烷氧基-C 1-8烷基、苄氧基-C 1-8烷基、四氢吡喃-2-基、或硅保护基，例如t-BuMe 2Si、t-BuPh 2Si、(i-Pr) 3Si、Et 3Si或Me 3Si。 In one embodiment, said R is selected from C 1-8Alkyl, halogenated C 1-8Alkyl, C 1-8Alkylcarbonyl, halogenated C 1-8Alkylcarbonyl, benzoyl, C 1-8Alkyl substituted benzoyl, halogenated C 1-8Alkyl substituted benzoyl, benzenesulfonyl, C 1-8Alkyl substituted benzenesulfonyl, halogenated C 1-8Alkyl substituted benzenesulfonyl, benzyl, C 1-8Alkyl substituted benzyl, C 1-8Alkoxy substituted benzyl, halogen atom substituted benzyl, halogenated C 1-8Alkyl substituted benzyl, allyl, C 1-8Alkoxy-C 1-8Alkyl, C 1-8Alkoxy-C 1-8Alkoxy-C 1-8Alkyl, benzyloxy-C 1-8Alkyl, tetrahydropyran-2-yl, or silicon protecting groups such as t-BuMe 2Si, t-BuPh 2Si, (i-Pr) 3Si, Et 3Si or Me 3Si.
优选的，R选自C 1-8烷基、C 1-8烷基羰基、苯甲酰基、苄基、C 1-8烷基取代的苄基、C 1-8烷氧基取代的苄基、卤素原子取代的苄基、甲氧基甲基、2-甲氧基乙氧基甲基、苄氧基甲基、四氢吡喃-2-基或硅保护基。 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 atom substituted benzyl, methoxymethyl, 2-methoxyethoxymethyl, benzyloxymethyl, tetrahydropyran-2-yl or silicon protecting group.
更优选的，R选自苄基、C 1-8烷基取代的苄基、C 1-8烷氧基取代的苄基、卤素原子取代的苄基、t-BuMe 2Si、t-BuPh 2Si、(i-Pr) 3Si、Et 3Si或Me 3Si。 More preferably, R is selected from benzyl, C 1-8 alkyl substituted benzyl, C 1-8 alkoxy substituted benzyl, halogen atom substituted benzyl, t-BuMe 2 Si, t-BuPh 2 Si, (i-Pr) 3 Si, Et 3 Si or Me 3 Si.
最优选的，R选自苄基、C 1-8烷基取代的苄基、t-BuMe 2Si、t-BuPh 2Si、(i-Pr) 3Si、Et 3Si或Me 3Si。 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.
在所述的步骤(1)中，脱羟基保护基R可以是在碱性条件下、酸性条件下或催化氢化条件下脱保护基。In the step (1), the dehydroxyl protecting group R can be deprotected under basic conditions, acidic conditions or catalytic hydrogenation conditions.
当R为C 1-8烷基羰基、卤代C 1-8烷基羰基、苯甲酰基、C 1-8烷基取代的苯甲酰基、苯磺酰基或C 1-8烷基取代的苯磺酰基时，在碱存在下，例如碱金属氢氧化物或碳酸盐，例如氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠或碳酸钾的存在下，脱除羟基保护基。 When R is C 1-8 alkylcarbonyl, halogenated C 1-8 alkylcarbonyl, benzoyl, C 1-8 alkyl substituted benzoyl, benzenesulfonyl or C 1-8 alkyl substituted benzenesulfonyl, the hydroxy protecting group is removed in the presence of a base, such as an alkali metal hydroxide or carbonate, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.
当R为C 1-8烷基、C 1-8烷氧基-C 1-8烷基、苄氧基-C 1-8烷基、2-四氢吡喃基或硅保护基时，式IV化合物可在酸存在下脱除羟基保护基得到式III化合物，然后进行步骤(2)，或者式IV化合物可以直接在酸存在下脱保护基制备式II化合物，然后进行步骤(3)。 When R is C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl, benzyloxy-C 1-8 alkyl, 2-tetrahydropyranyl or silicon protecting group, the compound of formula IV can remove the hydroxyl protecting group in the presence of acid to obtain the compound of formula III, and then proceed to step (2), or the compound of formula IV can directly remove the protecting group in the presence of acid to prepare the compound of formula II, and then proceed to step (3).
所述的酸选自盐酸、氢溴酸、氢碘酸、硫酸、磷酸、甲酸、乙酸或三氟乙酸，或其两种及两种以上的混合物。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.
当R为苄基、C 1-8烷基取代的苄基或卤素原子取代的苄基时，催化氢化可脱除保护基。 催化氢化所用的催化剂选自Pd/C、Pd(OH) 2、Pd(OAc) 2、PdCl 2、Pd、Ni，所用的氢气压力为0.5～3.0MPa，反应时间为4～24小时。 When R is benzyl, C 1-8 alkyl substituted benzyl or halogen atom substituted benzyl, catalytic hydrogenation can remove the protecting group. 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 used is 0.5-3.0 MPa, and the reaction time is 4-24 hours.
步骤(1)的反应溶剂为醇、酯或醚，或其任何两种或两种以上的混合物。The reaction solvent in step (1) is alcohol, ester or ether, or a mixture of any two or more thereof.
所述醇选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、仲丁醇、叔丁醇、正戊醇、异戊醇、环己醇、苯甲醇等。The alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, isoamyl alcohol, cyclohexanol, benzyl alcohol and the like.
所述的酯选自甲酸甲酯、甲酸乙酯、甲酸异丙酯、乙酸甲酯、乙酸乙酯、乙酸异丙酯。Described ester is selected from methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate, isopropyl acetate.
所述的醚选自乙醚、异丙醚、甲基叔丁基醚、苯甲醚、四氢呋喃、甲基四氢呋喃、1,4-二噁烷。The ether is selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, anisole, tetrahydrofuran, methyl tetrahydrofuran, and 1,4-dioxane.
在步骤(2)中，所述的酸选自盐酸、氢溴酸、氢碘酸、硫酸、磷酸、甲酸、乙酸或三氟乙酸，或其两种及两种以上的混合物。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.
在步骤(3)中，所述的催化剂选自Pd/C、Pd(OH) 2、Pd(OAc) 2、PdCl 2、Pd或Ni，例如RaNi。 In step (3), the catalyst is selected from Pd/C, Pd(OH) 2 , Pd(OAc) 2 , PdCl 2 , Pd or Ni, such as RaNi.
步骤(3)所述的氢气压力为0～4MPa，优选1.0～3MPa，更优选2.0～2.5MPa。The hydrogen pressure in step (3) is 0-4MPa, preferably 1.0-3MPa, more preferably 2.0-2.5MPa.
步骤(3)所述的反应温度为0～30℃，反应时间4～24小时。The reaction temperature in step (3) is 0-30° C., and the reaction time is 4-24 hours.
在一个优选的实施方案中，所述的步骤(3)还包括通过阳离子交换树脂得到式I化合物。所述的阳离子交换树脂选自强酸性阳离子交换树脂D001、强酸性阳离子交换树脂HD-8、强酸性阳离子交换树脂JK006、强酸性阳离子交换树脂JK001、强酸性阳离子交换树脂DOWEX50×8-100、阳离子交换树脂CG50、强酸性阳离子交换树脂HZ002、强酸性阳离子交换树脂HZ016、强酸性阳离子交换树脂C145、强酸性阳离子交换树脂C150、或强酸性阳离子交换树脂C160。In a preferred embodiment, the step (3) further includes obtaining the compound of formula I through 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 DOWEX50×8-100, 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 C 150, or strongly acidic cation exchange resin C160.
在进一步优选的实施方案中，所述的步骤(3)还包括在通过阳离子交换树脂处理后，将式I化合物粗品在有机溶剂或有机溶剂与水的混合物中结晶纯化。所述的有机溶剂可以选自甲醇、乙醇、正丙醇、异丙醇，或它们的两种或两种以上的混合物。In a further preferred embodiment, the step (3) further includes crystallizing and purifying the crude compound of formula I in an organic solvent or a mixture of an organic solvent and water after being treated with a cation exchange resin. The organic solvent can be selected from methanol, ethanol, n-propanol, isopropanol, or a mixture of two or more thereof.
本发明第二方面提供了式IV化合物的制备方法，包括如下步骤：The second aspect of the present invention provides the preparation method of the compound of formula IV, comprising the following steps:
Figure PCTCN2022122535-appb-000010
Figure PCTCN2022122535-appb-000010
步骤(4)：将式VI化合物与R 1Cl在碱存在下反应制备式V化合物； Step (4): reacting the compound of formula VI with R 1 Cl in the presence of a base to prepare the compound of formula V;
步骤(5)：将式V化合物与乙醇胺反应制备式IV化合物；Step (5): reacting the compound of formula V with ethanolamine to prepare the compound of formula IV;
其中R如上文第一方面所定义，且R 1为C 1-8烷酰基、C 1-8烷基磺酰基、芳基磺酰基、C 1-8烷基取代的芳基磺酰基、苯甲酰基或取代的苯甲酰基。 wherein R is as defined above in the first aspect, and R is C 1-8 alkanoyl, C 1-8 alkylsulfonyl, arylsulfonyl, C 1-8 alkyl substituted arylsulfonyl, benzoyl or substituted benzoyl.
优选的，所述的R 1选自甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、苯甲酰基、甲磺酰基、乙磺酰基、苯磺酰基或对甲苯磺酰基。 Preferably, said R 1 is selected from formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl, methanesulfonyl, ethylsulfonyl, benzenesulfonyl or p-toluenesulfonyl.
优选的，所述的碱选自无机碱或有机碱，例如碱金属氢氧化物或碳酸盐或碳酸氢盐，例如碳酸钠、碳酸钾、碳酸氢钠、三乙胺、乙二胺、二异丙基乙二胺、二异丙胺、哌啶、吗啉、吡啶或2-甲基吡啶。Preferably, the base is selected from inorganic bases or organic bases, such as alkali metal hydroxides or carbonates or bicarbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, ethylenediamine, diisopropylethylenediamine, diisopropylamine, piperidine, morpholine, pyridine or 2-picoline.
在一个优选的实施方案中，在所述的步骤(4)中，控制温度-5～30℃，式VI化合物在碱存在下，在低极性溶剂中与R 1Cl反应。反应完毕后，反应溶液可经过简单处理后，直接进行步骤(5)反应。 In a preferred embodiment, in the step (4), the temperature is controlled at -5-30° C., and the compound of formula VI is reacted with R 1 Cl in a low-polarity solvent in the presence of a base. After the reaction is completed, the reaction solution can be directly processed in step (5) after simple treatment.
所述的低极性溶剂选自二氯甲烷、三氯甲烷、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、甲基四氢呋喃、甲苯、氯苯、己烷、正己烷、环己烷、正庚烷或乙腈，或其两种及两种以上的混合物。The low polarity solvent is selected from dichloromethane, chloroform, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane or acetonitrile, or a mixture of two or more thereof.
所述的简单处理为反应液经过水洗萃取，除去反应产生的盐。The simple treatment is that the reaction solution is washed and extracted with water to remove the salt produced by the reaction.
在一个优选的实施方案中，在所述的步骤(5)中，控制温度40～100℃，式V化合物在有机溶剂中与乙醇胺反应。反应完毕后，降至室温，调至碱性，进一步降温析晶，任选地在有机溶剂或有机溶剂与水的混合物中结晶后得到式IV化合物。In a preferred embodiment, in the 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, cool down to room temperature, adjust to alkalinity, further cool down and crystallize, and optionally crystallize in an organic solvent or a mixture of an organic solvent and water to obtain the compound of formula IV.
所述的碱选自无机碱或有机碱，例如碱金属氢氧化物或碳酸盐或碳酸氢盐，例如氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸氢钠、甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾。The base is selected from inorganic bases or organic bases, such as alkali metal hydroxides or carbonates or bicarbonates, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium tert-butoxide.
所述的用于反应的有机溶剂选自二氯甲烷、三氯甲烷、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、甲基四氢呋喃、甲苯、氯苯、己烷、正己烷、环己烷、正庚烷、乙腈，或其两种及两种以上的混合物。The organic solvent used for the reaction is selected from dichloromethane, chloroform, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane, acetonitrile, or a mixture of two or more thereof.
所述的用于结晶的有机溶剂选自二氯甲烷、三氯甲烷、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、甲基四氢呋喃、甲苯、氯苯、己烷、正己烷、环己烷、正庚烷、乙腈，或其两种及两种以上的混合物。The organic solvent used for crystallization is selected from dichloromethane, chloroform, diethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane, acetonitrile, or a mixture of two or more thereof.
第三方面，本发明提供了一种新的中间体式IV化合物In a third aspect, the present invention provides a novel intermediate compound of formula IV
Figure PCTCN2022122535-appb-000011
Figure PCTCN2022122535-appb-000011
其中R选自C 1-8烷基、卤代C 1-8烷基、C 1-8烷基羰基、卤代C 1-8烷基羰基、苯甲酰基、C 1-8烷基取代的苯甲酰基、卤代C 1-8烷基取代的苯甲酰基、苯磺酰基、C 1-8烷基取代的苯磺酰基、卤代C 1-8烷基取代的苯磺酰基、苄基、C 1-8烷基取代的苄基、C 1-8烷氧基取代的苄基、卤素原子取代的苄基、卤代C 1-8烷基取代的苄基、烯丙基、C 1-8烷氧基-C 1-8烷基、C 1-8烷氧基-C 1-8烷氧基-C 1-8烷基、苄氧基-C 1-8烷基、四氢吡喃-2-基、或硅保护基，例如t-BuMe 2Si、t-BuPh 2Si、(i-Pr) 3Si、Et 3Si或Me 3Si。 where R is selected from C 1-8Alkyl, halogenated C 1-8Alkyl, C 1-8Alkylcarbonyl, halogenated C 1-8Alkylcarbonyl, benzoyl, C 1-8Alkyl substituted benzoyl, halogenated C 1-8Alkyl substituted benzoyl, benzenesulfonyl, C 1-8Alkyl substituted benzenesulfonyl, halogenated C 1-8Alkyl substituted benzenesulfonyl, benzyl, C 1-8Alkyl substituted benzyl, C 1-8Alkoxy substituted benzyl, halogen atom substituted benzyl, halogenated C 1-8Alkyl substituted benzyl, allyl, C 1-8Alkoxy-C 1-8Alkyl, C 1-8Alkoxy-C 1-8Alkoxy-C 1-8Alkyl, benzyloxy-C 1-8Alkyl, tetrahydropyran-2-yl, or silicon protecting groups such as t-BuMe 2Si, t-BuPh 2Si, (i-Pr) 3Si, Et 3Si or Me 3Si.
第四方面，本发明提供了一种合成式I的米格列醇的方法，该方法以式VI化合物为原料，经过上保护基、取代反应、脱保护基、催化氢化成环的反应得到米格列醇，任选地再经重结晶纯化得到最终成品。In the fourth aspect, the present invention provides a method for synthesizing miglitol of formula I. The method uses the compound of formula VI as a raw material to obtain miglitol through the reaction of adding a protecting group, substitution reaction, deprotecting group, and catalytic hydrogenation to form a ring, and optionally recrystallization and purification to obtain the final product.
具体而言，本发明提供一种合成式I的米格列醇的方法，其包括以下步骤(4)、(5)、(1)、(2)和(3)：Specifically, the present invention provides a method for synthesizing Miglitol of formula I, which comprises the following steps (4), (5), (1), (2) and (3):
Figure PCTCN2022122535-appb-000012
Figure PCTCN2022122535-appb-000012
其中，R和R 1如上文所定义。 Wherein, R and R 1 are as defined above.
在一个优选的实施方案中，步骤(4)和(5)的条件如本发明第二方面所述。在另一个优选的实施方案中，步骤(1)、(2)和(3)的条件如本发明第一方面所述。或者，将式IV化合物直接在步骤(2)所述的酸存在下脱保护基，得到式II化合物，然后进行步骤(3)。In a preferred embodiment, the conditions of steps (4) and (5) are as described in the second aspect of the present invention. In another preferred embodiment, the conditions of steps (1), (2) and (3) are as described in the first aspect of the present invention. Alternatively, the compound of formula IV is directly deprotected in the presence of the acid described in step (2) to obtain the compound of formula II, and then step (3) is performed.
在一个更优选的实施方案中，步骤(4)和(5)的条件如本发明第二方面所述，且步骤(1)、(2)和(3)的条件如本发明第一方面所述，或者将式IV化合物直接在步骤(2)所述的酸存在下脱保护基，得到式II化合物，然后进行步骤(3)。In a more preferred embodiment, the conditions of steps (4) and (5) are as described in the second aspect of the present invention, and the conditions of steps (1), (2) and (3) are as described in the first aspect of the present invention, or the compound of formula IV is directly deprotected in the presence of the acid described in step (2) to obtain the compound of formula II, and then step (3) is performed.
本发明相对于现有技术，具有以下优势：Compared with the prior art, the present invention has the following advantages:
1.使用本发明方法产生的非对映异构体杂质可以得到有效控制，控制在0.1％以下；1. The diastereomeric impurities produced by the method of the present invention can be effectively controlled and controlled below 0.1%;
2.本发明以式VI化合物为原料制备米格列醇的收率高，达到48.5～51.5％；2. The present invention uses the compound of formula VI as a raw material to prepare miglitol with a high yield, reaching 48.5% to 51.5%;
3.使用本发明方法制备的米格列醇，纯度达到99.9％，从而为制剂提供可靠的质量保证。3. The purity of the miglitol prepared by the method of the present invention reaches 99.9%, thereby providing reliable quality assurance for the preparation.
本发明克服了现有技术的总收率低、非对映异构体杂质难控制、产品纯度低等问题，因此适合于工业化大规模生产。The invention overcomes the problems of low total yield, difficult control of diastereomer impurities, low product purity and the like in the prior art, and is therefore suitable for large-scale industrial production.
定义：definition:
为了解释本说明书，将使用以下定义，并且只要适当，以单数形式使用的术语也可以包括复数，并且反之亦然。要理解，本文所用的术语仅是为了描述具体的实施方案，并且不意欲是限制性的。In order to explain this specification, the following definitions will be used, and whenever appropriate, terms used in the singular may 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.
本文所用的术语“卤素”或“卤代”是指F、Cl、Br或I。此外，术语“卤素取代的”基团旨在包括单卤代或多卤代基团，其中一个或多个相同或不同的卤素取代该基团中的一个或多个氢。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.
本文所用的术语“烷基”指由碳原子和氢原子组成的直链或支链的饱和烃基团。具体地，烷基具有1-10个，例如1至8个、1至6个、1至5个、1至4个、1至3个或1至2个碳原子。例如，如本文中所使用，术语“C 1-8烷基”指具有1至8个碳原子的直链或支链的饱和烃基团，其实例例如甲基、乙基、丙基(包括正丙基和异丙基)、丁基(包括正丁基、异丁基、仲丁基或叔丁基)、戊基(包括正戊基、异戊基、新戊基)、正己基、2-甲基戊基等。 The term "alkyl" as used herein refers to a linear or branched saturated hydrocarbon group composed of carbon atoms and hydrogen atoms. Specifically, the alkyl group has 1-10, eg 1-8, 1-6, 1-5, 1-4, 1-3 or 1-2 carbon atoms. For example, as used herein, the term "C 1-8 alkyl" refers to a linear 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-methylpentyl and the like.
本文所用的术语“卤代C 1-8烷基”指上文所述的C 1-8烷基，其中一个或多个(例如1、2、3、4或5个)氢原子被卤素代替。本领域技术人员应当理解，当卤素取代基多于一个时，卤素可以相同或不同，并且可以位于相同或不同的碳原子上。“卤代C 1-8烷基”的实例包括-CH 2F、-CHF 2、-CF 3、-CCl 3、-C 2F 5、-C 2Cl 5、-CH 2CF 3、-CH 2Cl、-CH 2CH 2CF 3或-CF(CF 3) 2等。 The term "halogenated C 1-8 alkyl" as used herein refers to the above-mentioned C 1-8 alkyl, wherein one or more (eg 1, 2, 3, 4 or 5) hydrogen atoms are replaced by halogen. It should be understood 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. Examples of "halogenated C 1-8 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 and the like.
单独或与其他基团组合的术语“烷氧基”表示基团R y-O-，其中R y是如上所述的烷基。“C 1-8烷氧基”表示基团R y-O-，其中R y是如上所述的C 1-8烷基。 The term "alkoxy", alone or in combination with other groups, denotes the group Ry - O-, wherein Ry is alkyl as defined above. "C 1-8 alkoxy" refers to the group R y —O—, wherein R y is a C 1-8 alkyl group as described above.
“芳基”是指由碳原子和氢原子组成的单环或稠合双环的芳香环。“C 6-10芳基”是指含有6-10个碳原子的芳基。例如，芳基可以是苯基或萘基。 "Aryl" refers to a monocyclic or fused bicyclic aromatic ring composed of carbon atoms and hydrogen atoms. "C 6-10 aryl" means an aryl group containing 6-10 carbon atoms. For example, aryl can be phenyl or naphthyl.
“芳烷基”是指被如上所述的芳基取代的如上所述的烷基，例如苄基。"Aralkyl" means an alkyl group as described above substituted with an aryl group as described above, eg benzyl.
“芳烷氧基”是指被如上所述的芳基取代的如上所述的烷氧基，例如苄氧基。"Aralkoxy" means an alkoxy group as described above substituted with an aryl group as described above, eg benzyloxy.
“酰基”是指基团-CO-R x，其中R x为如上所述的烷基、芳基或芳烷基，例如烷酰基或芳烷酰基，例如苯甲酰基。 "Acyl" refers to the group -CO- Rx , wherein Rx is alkyl, aryl or aralkyl as described above, for example alkanoyl or aralkanoyl, for example benzoyl.
以上所述的芳基，无论是作为基团本身，还是作为其它基团例如芳烷基、芳烷氧基、酰基的一部分，均可以任选地被一个或多个取代基所取代。当所述的芳基被取代时，所述取代基选自C 1-6烷基、C 1-6烷氧基、卤代C 1-8烷基、卤素、芳基和硝基，更优选甲氧基、乙氧基、卤素或苯基。例如，取代的苯甲酰基是指苯环上的取代基选自C 1-6烷基、C 1-6烷氧基、卤代C 1-8烷基、卤素或芳基的苯甲酰基。 The aryl group mentioned above, whether as the group itself or as a part of other groups such as aralkyl, aralkoxy, acyl, can be optionally substituted by one or more substituents. When the aryl is substituted, the substituent is selected from C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-8 alkyl, halogen, aryl and nitro, more preferably methoxy, ethoxy, halogen or phenyl. For example, a substituted benzoyl refers to a benzoyl group in which the substituent on the benzene ring is selected from C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-8 alkyl, halogen or aryl.
具体实施方式Detailed ways
通过以下实施例对本发明的方法进行进一步的说明。应当理解，提供以下实施例的目的仅仅是为了能够更好的理解本发明，而不是以任何方式限定本发明的范围。The method of the present invention is further illustrated by the following examples. It should be understood that the purpose of providing the following examples is only for better understanding of the present invention, rather than limiting the scope of the present invention in any way.
式IV化合物的制备The preparation of formula IV compound
实施例1：Example 1:
Figure PCTCN2022122535-appb-000013
Figure PCTCN2022122535-appb-000013
向反应瓶中加入1870g二氯甲烷，269g式VI-a化合物，搅拌并降温至0～5℃，加入125g三乙胺，搅拌10分钟，缓慢加入220g对甲苯磺酰氯，加毕，保持低温反应30分钟后升温至25℃，再保温反应，加入400g水搅拌30分钟，静置分层。得到式V-a化合物的二氯甲烷溶液，不经处理直接用于下一步反应。Add 1870g of dichloromethane and 269g of the compound of formula VI-a to the reaction flask, stir and lower the temperature to 0-5°C, add 125g of triethylamine, stir for 10 minutes, slowly add 220g of p-toluenesulfonyl chloride, after the addition is complete, keep the reaction at low temperature for 30 minutes, then raise the temperature to 25°C, then heat the reaction, add 400g of water and stir for 30 minutes, and let it stand for stratification. The dichloromethane solution of the compound of formula V-a was obtained, which was directly used in the next reaction without treatment.
向上述式V-a化合物的二氯甲烷溶液中，加入120g乙醇胺，搅拌升温至回流；升温毕，控制内温90～95℃，保温反应5～7小时；反应毕，降温至内温20～30℃；加入200g水，再滴加适量10％NaOH，调pH≥12，在20～30℃下搅拌反应12小时；反应毕，降温至0～5℃，搅拌析晶2小时，抽滤；滤饼用少量纯化水泡洗；抽滤，滤饼烘干得到式IV化合物262g。收率：85.4％，纯度：99％。 1H 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)； 13C 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。 Add 120g of ethanolamine to the dichloromethane solution of the above-mentioned compound of formula Va, stir and heat up to reflux; after the temperature is raised, control the internal temperature to 90-95°C, and keep the temperature for 5-7 hours; after the reaction, cool down to the internal temperature of 20-30°C; add 200g of water, then add an appropriate amount of 10% NaOH dropwise, adjust the pH to ≥ 12, and stir for 12 hours at 20-30°C; The filter cake was soaked and washed with a small amount of purified water; suction filtration, and the filter cake was dried to obtain 262g of the compound of 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。
实施例2：Example 2:
Figure PCTCN2022122535-appb-000014
Figure PCTCN2022122535-appb-000014
向反应瓶中加入1870g二氯甲烷，254g式VI-b化合物，搅拌并降温至0～5℃，加入115g三乙胺，搅拌10分钟，缓慢加入220g甲磺酰氯，加毕，保持低温反应30分钟后升温至25℃，再保温反应至完毕，加入400g水搅拌30分钟，静置分层。得到式V-b化合物的二氯甲烷溶液，不经处理直接用于下一步反应。Add 1870g of dichloromethane and 254g of the compound of formula VI-b to the reaction flask, stir and cool down to 0-5°C, add 115g of triethylamine, stir for 10 minutes, slowly add 220g of methanesulfonyl chloride, after the addition is complete, keep the reaction at low temperature for 30 minutes and then raise the temperature to 25°C, then keep warm until the reaction is complete, add 400g of water and stir for 30 minutes, and let stand to separate layers. The dichloromethane solution of the compound of formula V-b was obtained, which was directly used in the next reaction without treatment.
向上述式V-b化合物的二氯甲烷溶液中，加入120g乙醇胺，搅拌升温保温反应5～7小时；反应毕，降温至内温低于20℃；加入200g水，再滴加适量10％NaOH，调pH≥12，在20～30℃下搅拌反应12小时；反应毕，降温至0～5℃，搅拌析晶2小时，抽滤；滤饼用少量纯化水泡洗；抽滤，滤饼烘干得到式IV-b化合物227.6g。收率：78.1％，纯度：98.5％。Add 120 g of ethanolamine to the dichloromethane solution of the compound of formula V-b above, stir and raise the temperature and keep it warm for 5 to 7 hours; after the reaction, cool down to an internal temperature lower than 20°C; add 200g of water, then add an appropriate amount of 10% NaOH dropwise, adjust the pH to ≥12, and stir and react at 20 to 30°C for 12 hours; -b compound 227.6 g. Yield: 78.1%, purity: 98.5%.
式III化合物的制备The preparation of formula III compound
实施例3：Example 3:
Figure PCTCN2022122535-appb-000015
Figure PCTCN2022122535-appb-000015
向高压釜中加入240g式IV-a化合物，1440mL甲醇，将36g 10％钯/碳加入高压釜，氮气置换，氢气置换，搅拌升温至内温50℃，氢气压力0.9～1.0MPa，保温反应4小时，压滤，滤液减压浓缩，得到175.2g式III化合物。收率：98.0％。 1H 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)； 13C 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。 Add 240g of the compound of formula IV-a and 1440mL of methanol into the autoclave, add 36g of 10% palladium/carbon into the autoclave, replace with nitrogen and hydrogen, stir and heat up to an internal temperature of 50°C, and the pressure of hydrogen is 0.9-1.0MPa, keep the reaction for 4 hours, press filter, and concentrate the filtrate under reduced pressure to obtain 175.2g of the compound of formula III. 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。
式I化合物的制备The preparation of formula I compound
实施例4：Example 4:
Figure PCTCN2022122535-appb-000016
Figure PCTCN2022122535-appb-000016
向反应瓶中加入175.2g上述式III化合物，滴加200g浓盐酸，控制内温20～40℃至反应毕，加入60g氢氧化钠调碱，得到式II化合物水溶液。将式II化合物水溶液转移至高压反应釜中，向高压反应釜中加入10％钯/碳20g(湿重，水分60％)，氮气、氢气各置换3次，控制氢气压力为1.0～3.0MPa。反应毕，过滤，滤饼催化剂回收套用。滤液上阳离子交换树脂柱，待物料全部上柱完毕，再用纯化水、氨水解离，收集氨水解离液并在控制外温60～65℃条件下进行减压浓缩。浓缩毕，加入无水乙醇结晶，于50～55℃搅拌2小时，缓慢降温至-5～0℃析晶2小时，抽滤。滤饼烘干得到117.2g米格列醇粗品。收率：85.0％。Add 175.2g of the above-mentioned compound of formula III to the reaction flask, add dropwise 200g of concentrated hydrochloric acid, control the internal temperature at 20-40°C until the reaction is complete, add 60g of sodium hydroxide to adjust the base, and obtain an aqueous solution of the compound of formula II. The aqueous solution of the compound of formula II was transferred to an autoclave, and 10% palladium/carbon 20g (wet weight, moisture 60%) was added to the autoclave, nitrogen and hydrogen were replaced 3 times, and the hydrogen pressure was controlled to be 1.0-3.0MPa. After the reaction is completed, filter and recover the filter cake catalyst for mechanical use. The filtrate is put on the cation exchange resin column. After all the materials are loaded on the column, they are dissociated with purified water and ammonia water, and the ammonia water dissociation liquid is collected and concentrated under reduced pressure under the condition of controlling the external temperature of 60-65°C. After concentration, add anhydrous ethanol to crystallize, stir at 50-55°C for 2 hours, slowly cool down to -5-0°C to crystallize for 2 hours, and filter with suction. The filter cake was dried to obtain 117.2 g of crude Miglitol. Yield: 85.0%.
向反应瓶中加入117.2g米格列醇粗品、纯化水和乙醇，搅拌升温至50～55℃，1小时后加入10g活性炭脱色，1小时后抽滤。滤饼用热的无水乙醇淋洗，合并滤液并于50～55℃搅拌2小时。缓慢降温至25℃析晶2小时，降温至-5～0℃搅拌析晶3～5小时。抽滤，滤饼烘干，得到105.6g米格列醇。收率：90.1％，纯度：99.9％。Add 117.2g of crude Miglitol, purified water and ethanol to the reaction flask, stir and heat up to 50-55°C, add 10g of activated carbon for decolorization after 1 hour, and filter with suction after 1 hour. The filter cake was rinsed with hot absolute ethanol, and the filtrates were combined and stirred at 50-55°C for 2 hours. Slowly lower the temperature to 25°C for crystallization for 2 hours, then lower the temperature to -5-0°C and stir for 3-5 hours for crystallization. Suction filtration and drying of the filter cake yielded 105.6 g of Miglitol. Yield: 90.1%, purity: 99.9%.
实施例5：Example 5:
Figure PCTCN2022122535-appb-000017
Figure PCTCN2022122535-appb-000017
向反应瓶中加入227.6g上述式IV-b化合物，滴加300g浓盐酸，控制内温20～40℃至反应毕，加入60g氢氧化钠调碱，调节毕，得到式II化合物水溶液。将式II化合物水溶液转移至高压反应釜中，向高压反应釜中加入10％钯/碳20g(湿重，水分60％)，氮气、氢气各置 换3次，控制氢气压力为1.0～3.0MPa。反应毕，过滤，滤饼催化剂回收套用。滤液上阳离子交换树脂柱，待物料全部上柱完毕，再用纯化水、氨水解离，收集氨水解离液并在控制外温60～65℃条件下进行减压浓缩。浓缩毕，加入无水乙醇结晶，于50～55℃搅拌2小时，缓慢降温至-5～0℃析晶2小时，抽滤。滤饼烘干得到100g米格列醇粗品。Add 227.6g of the above-mentioned compound of formula IV-b to the reaction bottle, add dropwise 300g of concentrated hydrochloric acid, control the internal temperature at 20-40°C until the reaction is complete, add 60g of sodium hydroxide to adjust the base, and after the adjustment is complete, an aqueous solution of the compound of formula II is obtained. The aqueous solution of the compound of formula II was transferred to the autoclave, and 10% palladium/carbon 20g (wet weight, moisture 60%) was added to the autoclave, nitrogen and hydrogen were replaced 3 times, and the hydrogen pressure was controlled to be 1.0-3.0MPa. After the reaction is completed, filter and recover the filter cake catalyst for mechanical use. The filtrate is put on the cation exchange resin column. After all the materials are loaded on the column, they are dissociated with purified water and ammonia water, and the ammonia water dissociation liquid is collected and concentrated under reduced pressure under the condition of controlling the external temperature of 60-65°C. After concentration, add anhydrous ethanol to crystallize, stir at 50-55°C for 2 hours, slowly cool down to -5-0°C to crystallize for 2 hours, and filter with suction. The filter cake was dried to obtain 100 g of crude Miglitol.
向反应瓶中加入100g米格列醇粗品、纯化水和乙醇，搅拌升温至50～55℃，1小时后加入10g活性炭脱色，1小时后抽滤。滤饼用热的无水乙醇淋洗，合并滤液并于50～55℃搅拌2小时。缓慢降温至25℃析晶2小时，降温至-5～0℃搅拌析晶3～5小时。抽滤，滤饼烘干，得到78～83g米格列醇。从式VI-b化合物制备米格列醇的总收率为42.5～45.3％，纯度：99.9％。Add 100g of crude Miglitol, purified water and ethanol to the reaction flask, stir and heat up to 50-55°C, add 10g of activated carbon for decolorization after 1 hour, and filter with suction after 1 hour. The filter cake was rinsed with hot absolute ethanol, and the filtrates were combined and stirred at 50-55°C for 2 hours. Slowly lower the temperature to 25°C for crystallization for 2 hours, then lower the temperature to -5-0°C and stir for 3-5 hours for crystallization. Suction filtration and drying of the filter cake yielded 78-83 g 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 (11)

  1. 式I化合物的制备方法，包括以下步骤：The preparation method of formula I compound, comprises the following steps:
    Figure PCTCN2022122535-appb-100001
    Figure PCTCN2022122535-appb-100001
    步骤(1)：将式IV化合物脱保护基R，得到式III化合物；Step (1): deprotecting the compound of formula IV to obtain the compound of formula III;
    步骤(2)：将式III化合物经酸处理脱保护基，得到式II化合物；Step (2): deprotecting the compound of formula III through acid treatment to obtain the compound of formula II;
    步骤(3)：将式II化合物在催化剂存在下催化氢化，得到式I化合物；Step (3): Catalytic hydrogenation of the compound of formula II in the presence of a catalyst to obtain the compound of formula I;
    其中，R为羟基保护基；Wherein, R is a hydroxyl protecting group;
    或者，将式IV化合物直接在步骤(2)所述的酸存在下脱保护基，得到式II化合物，然后进行步骤(3)。Alternatively, the compound of formula IV is directly deprotected in the presence of the acid described in step (2) to obtain the compound of formula II, and then step (3) is performed.
  2. 根据权利要求1所述的方法，其中R选自C 1-8烷基、卤代C 1-8烷基、C 1-8烷基羰基、卤代C 1-8烷基羰基、苯甲酰基、C 1-8烷基取代的苯甲酰基、卤代C 1-8烷基取代的苯甲酰基、苯磺酰基、C 1-8烷基取代的苯磺酰基、卤代C 1-8烷基取代的苯磺酰基、苄基、C 1-8烷基取代的苄基、C 1-8烷氧基取代的苄基、卤素原子取代的苄基、卤代C 1-8烷基取代的苄基、烯丙基、C 1-8烷氧基-C 1-8烷基、C 1-8烷氧基-C 1-8烷氧基-C 1-8烷基、苄氧基-C 1-8烷基、四氢吡喃-2-基、或硅保护基，例如t-BuMe 2Si、t-BuPh 2Si、(i-Pr) 3Si、Et 3Si或Me 3Si。 The method according to claim 1, wherein R is selected from C 1-8Alkyl, halogenated C 1-8Alkyl, C 1-8Alkylcarbonyl, halogenated C 1-8Alkylcarbonyl, benzoyl, C 1-8Alkyl substituted benzoyl, halogenated C 1-8Alkyl substituted benzoyl, benzenesulfonyl, C 1-8Alkyl substituted benzenesulfonyl, halogenated C 1-8Alkyl substituted benzenesulfonyl, benzyl, C 1-8Alkyl substituted benzyl, C 1-8Alkoxy substituted benzyl, halogen atom substituted benzyl, halogenated C 1-8Alkyl substituted benzyl, allyl, C 1-8Alkoxy-C 1-8Alkyl, C 1-8Alkoxy-C 1-8Alkoxy-C 1-8Alkyl, benzyloxy-C 1-8Alkyl, tetrahydropyran-2-yl, or silicon protecting groups such as t-BuMe 2Si, t-BuPh 2Si, (i-Pr) 3Si, Et 3Si or Me 3Si.
  3. 根据权利要求1-2任一项所述的方法，其中R选自C 1-8烷基、C 1-8烷基羰基、苯甲酰基、苄基、C 1-8烷基取代的苄基、C 1-8烷氧基取代的苄基、卤素原子取代的苄基、四氢吡喃-2-基、或硅保护基，例如t-BuMe 2Si、t-BuPh 2Si、(i-Pr) 3Si、Et 3Si或Me 3Si。 The method according to any one of claims 1-2, wherein 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 atom substituted benzyl, tetrahydropyran-2-yl, or silicon protecting groups, such as t-BuMe 2 Si , t-BuPh 2 Si, (i-Pr) 3 Si, Et 3 Si or Me 3 Si.
  4. 根据权利要求1-3任一项所述的方法，其中步骤(2)所述的酸选自盐酸、氢溴酸、氢碘酸、硫酸、磷酸、甲酸、乙酸、或三氟乙酸、或其两种及两种以上的混合物。The method according to any one of claims 1-3, wherein the acid described in step (2) 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.
  5. 根据权利要求1-4任一项所述的方法，其中步骤(3)所述的催化剂选自Pd/C、Pd(OH) 2、Pd(OAc) 2、PdCl 2、Pd或Ni，例如RaNi。 The method according to any one of claims 1-4, wherein the catalyst in step (3) is selected from Pd/C, Pd(OH) 2 , Pd(OAc) 2 , PdCl 2 , Pd or Ni, such as RaNi.
  6. 根据权利要求1-5所述的方法，其中在步骤(1)中通过催化氢化脱除保护基R，其中所用的催化剂选自Pd/C、Pd(OH) 2、Pd(OAc) 2、PdCl 2、Pd、Ni，例如RaNi。 The method according to claims 1-5, wherein in step (1) the protective group R is removed by catalytic hydrogenation, wherein the catalyst used is selected from Pd/C, Pd(OH) 2 , Pd(OAc) 2 , PdCl 2 , Pd, Ni, such as RaNi.
  7. 式IV化合物的制备方法，包括如下步骤：The preparation method of formula IV compound, comprises the steps:
    Figure PCTCN2022122535-appb-100002
    Figure PCTCN2022122535-appb-100002
    步骤(4)：将式VI化合物与R 1Cl在碱存在下反应制备式V化合物； Step (4): reacting the compound of formula VI with R 1 Cl in the presence of a base to prepare the compound of formula V;
    步骤(5)：将式V化合物与乙醇胺反应制备式IV化合物；Step (5): reacting the compound of formula V with ethanolamine to prepare the compound of formula IV;
    其中R如权利要求1-3任一项所定义，且R 1为C 1-8烷酰基、C 1-8烷基磺酰基、芳基磺酰基、C 1-8烷基取代的芳基磺酰基、苯甲酰基或取代的苯甲酰基。 Wherein R is as defined in any one of claims 1-3, and R is C 1-8 alkanoyl, C 1-8 alkylsulfonyl, arylsulfonyl, C 1-8 alkyl substituted arylsulfonyl, benzoyl or substituted benzoyl.
  8. 根据权利要求7所述的方法，其中R 1选自甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、苯甲酰基、甲磺酰基、乙磺酰基、苯磺酰基或对甲苯磺酰基。 The method according to claim 7, wherein R is selected from formyl, acetyl, propionyl, butyryl, isobutyryl, benzoyl, methanesulfonyl, ethylsulfonyl, benzenesulfonyl or p-toluenesulfonyl.
  9. 根据权利要求7或8所述的方法，其中步骤(4)所述的碱选自无机碱或有机碱，例如碱金属氢氧化物或碳酸盐或碳酸氢盐，例如碳酸钠、碳酸钾、碳酸氢钠、三乙胺、乙二胺、二异丙基乙二胺、二异丙胺、哌啶、吗啉、吡啶或2-甲基吡啶。The method according to claim 7 or 8, wherein the alkali described in step (4) is selected from inorganic bases or organic bases, such as alkali metal hydroxides or carbonates or bicarbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, ethylenediamine, diisopropylethylenediamine, diisopropylamine, piperidine, morpholine, pyridine or 2-picoline.
  10. 式IV化合物Formula IV compound
    Figure PCTCN2022122535-appb-100003
    Figure PCTCN2022122535-appb-100003
    其中R选自C 1-8烷基、卤代C 1-8烷基、C 1-8烷基羰基、卤代C 1-8烷基羰基、苯甲酰基、C 1-8烷基取代的苯甲酰基、卤代C 1-8烷基取代的苯甲酰基、苯磺酰基、C 1-8烷基取代的苯磺酰基、卤代C 1-8烷基取代的苯磺酰基、苄基、C 1-8烷基取代的苄基、C 1-8烷氧基取代的苄基、卤素原子取代的苄基、卤代C 1-8烷基取代的苄基、烯丙基、C 1-8烷氧基-C 1-8烷基、C 1-8烷氧基-C 1-8烷氧基-C 1-8烷基、苄氧基-C 1-8烷基、四氢吡喃-2-基、或硅保护基，例如t-BuMe 2Si、t-BuPh 2Si、(i-Pr) 3Si、Et 3Si或Me 3Si。 where R is selected from C 1-8Alkyl, halogenated C 1-8Alkyl, C 1-8Alkylcarbonyl, halogenated C 1-8Alkylcarbonyl, benzoyl, C 1-8Alkyl substituted benzoyl, halogenated C 1-8Alkyl substituted benzoyl, benzenesulfonyl, C 1-8Alkyl substituted benzenesulfonyl, halogenated C 1-8Alkyl substituted benzenesulfonyl, benzyl, C 1-8Alkyl substituted benzyl, C 1-8Alkoxy substituted benzyl, halogen atom substituted benzyl, halogenated C 1-8Alkyl substituted benzyl, allyl, C 1-8Alkoxy-C 1-8Alkyl, C 1-8Alkoxy-C 1-8Alkoxy-C 1-8Alkyl, benzyloxy-C 1-8Alkyl, tetrahydropyran-2-yl, or silicon protecting groups such as t-BuMe 2Si, t-BuPh 2Si, (i-Pr) 3Si, Et 3Si or Me 3Si.
  11. 式I化合物的制备方法，包括以下步骤：The preparation method of formula I compound, comprises the following steps:
    Figure PCTCN2022122535-appb-100004
    Figure PCTCN2022122535-appb-100004
    Figure PCTCN2022122535-appb-100005
    Figure PCTCN2022122535-appb-100005
    步骤(4)：将式VI化合物与R 1Cl在碱存在下反应制备式V化合物； Step (4): reacting the compound of formula VI with R 1 Cl in the presence of a base to prepare the compound of formula V;
    步骤(5)：将式V化合物与乙醇胺反应制备式IV化合物；Step (5): reacting the compound of formula V with ethanolamine to prepare the compound of formula IV;
    步骤(1)：将式IV化合物脱保护基R，得到式III化合物；Step (1): deprotecting the compound of formula IV to obtain the compound of formula III;
    步骤(2)：将式III化合物经酸处理脱保护基，得到式II化合物；和Step (2): deprotecting the compound of formula III through acid treatment to obtain the compound of formula II; and
    步骤(3)：将式II化合物在催化剂存在下催化氢化，得到式I化合物；Step (3): Catalytic hydrogenation of the compound of formula II in the presence of a catalyst to obtain the compound of formula I;
    或者，将式IV化合物直接在步骤(2)所述的酸存在下脱保护基，得到式II化合物，然后进行步骤(3)；Alternatively, the compound of formula IV is directly deprotected in the presence of the acid described in step (2) to obtain the compound of formula II, and then step (3);
    其中R选自C 1-8烷基、卤代C 1-8烷基、C 1-8烷基羰基、卤代C 1-8烷基羰基、苯甲酰基、C 1-8烷基取代的苯甲酰基、卤代C 1-8烷基取代的苯甲酰基、苯磺酰基、C 1-8烷基取代的苯磺酰基、卤代C 1-8烷基取代的苯磺酰基、苄基、C 1-8烷基取代的苄基、C 1-8烷氧基取代的苄基、卤素原子取代的苄基、卤代C 1-8烷基取代的苄基、烯丙基、C 1-8烷氧基-C 1-8烷基、C 1-8烷氧基-C 1-8烷氧基-C 1-8烷基、苄氧基-C 1-8烷基、四氢吡喃-2-基、或硅保护基，例如t-BuMe 2Si、t-BuPh 2Si、(i-Pr) 3Si、Et 3Si或Me 3Si； where R is selected from C 1-8Alkyl, halogenated C 1-8Alkyl, C 1-8Alkylcarbonyl, halogenated C 1-8Alkylcarbonyl, benzoyl, C 1-8Alkyl substituted benzoyl, halogenated C 1-8Alkyl substituted benzoyl, benzenesulfonyl, C 1-8Alkyl substituted benzenesulfonyl, halogenated C 1-8Alkyl substituted benzenesulfonyl, benzyl, C 1-8Alkyl substituted benzyl, C 1-8Alkoxy substituted benzyl, halogen atom substituted benzyl, halogenated C 1-8Alkyl substituted benzyl, allyl, C 1-8Alkoxy-C 1-8Alkyl, C 1-8Alkoxy-C 1-8Alkoxy-C 1-8Alkyl, benzyloxy-C 1-8Alkyl, tetrahydropyran-2-yl, or silicon protecting groups such as t-BuMe 2Si, t-BuPh 2Si, (i-Pr) 3Si, Et 3Si or Me 3Si;
    且R 1为C 1-8烷酰基、C 1-8烷基磺酰基、芳基磺酰基、C 1-8烷基取代的芳基磺酰基、苯甲酰基或取代的苯甲酰基。 And R 1 is C 1-8 alkanoyl, C 1-8 alkylsulfonyl, arylsulfonyl, C 1-8 alkyl substituted arylsulfonyl, benzoyl or substituted benzoyl.
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