CN113527167B - Production method of vildagliptin - Google Patents

Production method of vildagliptin Download PDF

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CN113527167B
CN113527167B CN202010297789.7A CN202010297789A CN113527167B CN 113527167 B CN113527167 B CN 113527167B CN 202010297789 A CN202010297789 A CN 202010297789A CN 113527167 B CN113527167 B CN 113527167B
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acetate
compound
formate
solvent
ether
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CN113527167A (en
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杨猛
魏彦君
王建
邢艳平
徐青景
刘希望
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Weizhi Pharmaceutical Co ltd
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Weizhi Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

The invention discloses a production method of vildagliptin, a synthesis method of a vildagliptin intermediate and application of alkali metal bromide as a catalyst in production of vildagliptin or salts, crystal forms, deuterides, tritides and solvates thereof. The vildagliptin produced by the method has high purity and low impurity content, and particularly the disubstituted product has low impurity content, which is beneficial to the quality control of the vildagliptin bulk drug and/or pharmaceutical preparation, and the use of alkali metal bromide such as potassium bromide as a catalyst for reaction is safe and nontoxic, so that the toxic impurity content of the vildagliptin bulk drug and/or pharmaceutical preparation product is controlled at a very low level; moreover, the reaction condition is mild, the operation and control are convenient, the yield is high, the energy consumption is low, the cost is low, and the method is very suitable for industrial production and popularization and application.

Description

Production method of vildagliptin
Technical Field
The invention belongs to the field of medicines, and particularly relates to a method for producing vildagliptin.
Background
Vildagliptin, CAS no: 274901-16-5, which has the structural formula shown in the specification, can effectively reduce blood sugar level, has good tolerance, is suitable for treating type 2 diabetes, can be used in combination with other antidiabetic drugs such as metformin hydrochloride, has wide clinical application and large market demand.
At present, a plurality of methods for preparing or synthesizing vildagliptin are available, wherein one of the common routes is to use (2S) -N-chloroacetyl-2-cyano tetrahydropyrrole and 3-amino-1-adamantanol as raw materials to react under the action of a catalyst to synthesize the vildagliptin, such as: patent applications such as CN 101037409A, CN 105523985A, CN 104744334A, CN 106966947A, CN 104945299A, CN 105153004A, CN 104326961A, CN 105367470A, CN 105085360A all use simple, readily available, relatively inexpensive potassium iodide as a catalyst for the reaction to synthesize vildagliptin. However, studies of CN 103804267A, CN 105712920A and the like also show that the use of potassium iodide as a catalyst for synthesizing vildagliptin is easy to cause the increase of byproducts and/or impurities of the reaction, especially the obvious increase of di-substituted impurities, which not only results in the reduction of the yield of the product, but also greatly increases the difficulty of operation and control because the di-substituted impurities are difficult to separate and purify, thus being very unfavorable for industrialized mass production.
To solve this problem, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, etc. have been used as catalysts, such as: CN 103804267A, CN 105712920A, CN 105367470A, CN 102617434A, CN 105523985A, etc., are all catalysts of this type. However, this method brings about a new technical problem, because the toxicity of the catalyst such as tetrabutylammonium bromide is far greater than that of potassium iodide, and even if the catalyst is classified as genotoxic impurities in the quality standard of some crude drugs, the content level of the catalyst in the crude drugs and/or pharmaceutical preparations needs to be strictly controlled, if the catalyst is slightly improper in control and/or operation, the catalyst is easy to remain in the products, and potential toxicity risks exist, so that the quality of the crude drugs or the pharmaceutical preparations thereof is seriously compromised.
Therefore, although the existing methods for preparing or synthesizing the vildagliptin are more, some of the key technical problems are not solved well up to the present; in view of this, the present invention has been made.
Disclosure of Invention
Aiming at the problems and/or defects existing in the prior art, the invention aims to provide a method for producing vildagliptin, which has the advantages of mild reaction conditions, convenient operation and control, high product purity, high yield, low impurity content and low cost, and is suitable for industrial production.
The technical scheme provided by the invention is as follows:
a method for producing vildagliptin, comprising the following steps:
wherein X is halogen, preferably fluorine, chlorine, bromine or iodine;
i. the compound A and the compound V react under the condition of taking alkali metal bromide as a catalyst with or without inert gas protection to obtain vildagliptin; preferably, the alkali metal bromide is one or more selected from lithium bromide, sodium bromide and potassium bromide.
In any of the above-mentioned modes of production of vildagliptin, the catalyst is used in a catalytic amount, preferably in an amount of 0.01mol to 0.5mol, more preferably 0.05mol to 0.15mol (e.g., 0.1 mol) per mol of the compound A.
In any technical scheme of the vildagliptin production method, the molar ratio of the compound A to the compound V can be 1:0.8-1.5, and/or the reaction temperature can be 40-80 ℃, and/or the reaction is detected to be finished by thin layer chromatography or high performance liquid chromatography; preferably, the molar ratio of compound A to compound V is from 1:1.05 to 1.22 (e.g., 1:1.11, 1:1.15, or 1:1.20, etc.), and/or the reaction temperature is from 50℃to 65 ℃.
In any of the above-described modes of carrying out the vildagliptin production methods, the reaction of step i may be carried out in the presence of an alkaline substance and/or an organic solvent;
preferably, the alkaline substance is selected from one or more of inorganic alkali, alkaline inorganic salt and organic amine, more preferably alkaline inorganic salt and organic amine, the molar ratio of the alkaline inorganic salt to the organic amine can be 1:0.3-0.4, and/or the organic solvent can be selected from one or more of nitrile solvent, hydrocarbon solvent, halogenated hydrocarbon solvent, alcohol solvent, ether solvent and ester solvent;
more preferably, the method further comprises the steps of,
the inorganic base (including hydroxide of alkali metal) is selected from one or more than two of lithium hydroxide, sodium hydroxide and potassium hydroxide, and/or the alkaline inorganic salt (including alkali metal carbonate and/or alkali metal bicarbonate) is selected from one or more than two of lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate and potassium bicarbonate, and/or the organic amine is selected from one or more than two of ethylamine, diethylamine, triethylamine, diisopropylethylamine, hydroxyethyl ethylenediamine, N-methylmorpholine, formamide, N-methylformamide, N-dimethylformamide, N-diethylformamide, acetamide, N-methylacetamide, N-dimethylacetamide, N-methylpropionamide and caprolactam;
and/or the nitrile solvent is selected from one or more than two of acetonitrile, propionitrile, butyronitrile, succinonitrile, valeronitrile, benzonitrile and benzyl cyanide;
and/or the hydrocarbon solvent is selected from one or more than two of aliphatic hydrocarbon, cycloparaffin and unsaturated hydrocarbon;
and/or the halogenated hydrocarbon solvent is selected from one or more than two of chloromethane, dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene, trichloroethylene, tetrachloroethylene, chloropropane, dichloropropane, chlorobutane, chlorobenzene, dichlorobenzene, bromomethane, bromoethane, bromopropane, bromobenzene and dibromobenzene;
and/or the alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, n-amyl alcohol, isoamyl alcohol, propylene glycol, butanediol, glycerol and benzyl alcohol;
and/or the ether solvent is selected from one or more than two of diethyl ether, propyl ether, butyl ether, amyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl furan, dioxolane, dioxane, ethylene oxide, propylene oxide, anisole, diphenyl ether, tetrahydropyran and epichlorohydrin;
and/or the ester solvent is selected from one or more than two of methyl formate, ethyl formate, propyl formate, isopropyl formate, butyl formate, isobutyl formate, pentyl formate, isopentyl formate, benzyl formate, hexyl formate, trimethyl orthoformate, methyl acetate, ethyl acetate, vinyl acetate, propyl acetate, isopropyl acetate, allyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, methyl isoamyl acetate, cyclohexyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, methyl acrylate, methyl methacrylate, ethyl methacrylate, methyl butyrate, ethyl butyrate and propyl butyrate;
and/or the number of the groups of groups,
preferably, the amount of the basic substance is 0.8 to 2.5mol per mol of the compound A, and/or the amount of the organic solvent is 0.5 to 5.0kg per mol of the compound A; more preferably, the basic substance is used in an amount of 1.2mol to 2.0mol (e.g., 1.65 mol) per mol of the compound A, and/or the organic solvent is used in an amount of 1kg to 5.0kg (e.g., 1.4 kg) per mol of the compound A.
In any of the above-mentioned methods for producing vildagliptin, after the catalytic reaction is completed, step ii, or step ii and step iii are performed;
ii. Concentrating after the step i is finished, adding water, acidifying, extracting, taking a water phase, adding an organic solvent, alkalizing, extracting, taking an organic phase, concentrating, recrystallizing, separating out solids, filtering and drying to obtain the finished product;
iii, after the step ii is finished, adding water, acidifying, extracting, taking a water phase, adding an organic solvent, alkalizing, extracting, taking an organic phase, concentrating, recrystallizing, separating out a solid, filtering, and drying to obtain the compound;
preferably, in step ii and/or iii, the pH is adjusted to 4.0 to 6.0 by acidification and/or 8.0 to 10.0 by alkalization;
and/or the number of the groups of groups,
preferably, in step ii and/or iii, the acidification is performed using an inorganic acid, preferably one or more selected from hydrochloric acid, sulfuric acid and nitric acid, and/or the alkalization is performed using an alkaline substance, preferably an inorganic base and/or an alkaline inorganic salt, wherein the definition of the inorganic base and the alkaline inorganic salt is as described above, and/or the organic solvent is one or more selected from hydrocarbon solvent, halogenated hydrocarbon solvent, ether solvent and ester solvent, wherein the definition of the hydrocarbon solvent, halogenated hydrocarbon solvent, ether solvent and ester solvent is as described above, and/or the recrystallization is performed using an alcohol solvent and/or an ester solvent, preferably the definition of the alcohol solvent and/or the ester solvent is as described above;
and/or the number of the groups of groups,
preferably, in step ii and/or iii, the temperature at which solids are precipitated is from 5℃to 15 ℃.
In any one of the above-mentioned methods for producing vildagliptin, the method for producing compound a is further included, and the synthetic steps are as follows:
wherein X is as defined above and Y is halogen, preferably fluorine, chlorine, bromine or iodine;
(1) the compound I and the compound C react with or without inert gas protection to obtain a compound B;
(2) dehydrating the compound B obtained in the step (1) by a dehydrating agent to obtain a compound A;
preferably, the method comprises the steps of,
in the step (1), the amount of the compound C is 0.8mol or more, more preferably 1.02mol or more, still more preferably 1.02mol to 1.2mol, and/or the temperature of the reaction is-5 ℃ or less, more preferably-10 ℃ or less, still more preferably-25 ℃ to-10 ℃, and/or the reaction is detected by thin layer chromatography or high performance liquid chromatography per mol of the compound I;
and/or the number of the groups of groups,
in the step (2), the dehydrating agent is selected from one or more of trifluoroacetic anhydride, phosphorus oxychloride, phosphorus pentoxide and cyanuric chloride, and/or the dehydrating agent is used in an amount of 0.8mol or more, more preferably 1.02mol or more, still more preferably 1.02mol to 1.2mol, per mol of the compound I, and/or the reaction temperature is 15 ℃ or less, more preferably 0 ℃ or less, still more preferably-20 ℃ to 0 ℃, and/or the reaction is detected by thin layer chromatography or high performance liquid chromatography.
In any one of the above-mentioned methods for producing vildagliptin, in the step (1) and/or (2), the reaction is carried out in the presence of an alkaline substance and/or an organic solvent;
preferably, the basic substance and/or the organic solvent are as defined above;
and/or the number of the groups of groups,
preferably, in step (1), the amount of the basic substance is 0.8 to 2.5mol per mol of the compound I, and/or the amount of the organic solvent is 0.5 to 5.0kg per mol of the compound I; more preferably, the basic substance is used in an amount of 1.05mol to 1.5mol (e.g., 1.2 mol) per mol of the compound I, and/or the organic solvent is used in an amount of 1kg to 5.0kg (e.g., 3.0 kg) per mol of the compound I;
and/or the number of the groups of groups,
preferably, in the step (2), the amount of the alkaline substance is 1.2 to 5mol per mol of the dehydrating agent, and/or the amount of the organic solvent is 0.5 to 5.0kg per mol of the dehydrating agent; preferably, the basic substance is used in an amount of 1.5 to 2.5mol (e.g., 1.9 mol) per mol of the dehydrating agent, and/or the organic solvent is used in an amount of 1kg to 5.0kg (e.g., 3.0 kg) per mol of the dehydrating agent.
In any of the above-mentioned methods for producing vildagliptin, the synthesis of the compound a may further comprise step (3):
(3) and (3) after the step (2) is finished, adding water, extracting, taking an organic phase, concentrating, recrystallizing, separating out solids, filtering and drying.
Preferably, after the step (2) is completed, adding water, extracting, taking an organic phase, washing with water, then washing with sodium bicarbonate or potassium bicarbonate aqueous solution, sodium chloride or potassium chloride aqueous solution, concentrating, recrystallizing, separating out solids, filtering, and drying;
and/or the number of the groups of groups,
preferably, the recrystallization is carried out using a halogenated hydrocarbon solvent and/or an ether solvent, preferably, the halogenated hydrocarbon solvent and/or the ether solvent are as defined above;
and/or the number of the groups of groups,
preferably, the temperature of the precipitated solid is 0-10 ℃;
more preferably, the concentration of the sodium bicarbonate or potassium bicarbonate aqueous solution is 7wt% ± 2wt%, and/or the concentration of the sodium chloride or potassium chloride aqueous solution is 25wt% ± 5wt%;
and/or the number of the groups of groups,
more preferably, when the recrystallization is performed using a halogenated hydrocarbon solvent and an ether solvent, the mass ratio of the halogenated hydrocarbon solvent to the ether solvent is 1:2 to 10, still more preferably 1:5 to 6.
The invention also provides a production method of the compound A, and the production method of the compound A is as described above.
The invention also provides the application of the alkali metal bromide as a catalyst in the production of vildagliptin or salts, crystal forms, deuterated matters, tritiated matters and solvates thereof; preferably, the alkali metal bromide is selected from one or more than two of lithium bromide, sodium bromide and/or potassium bromide;
in any of the above-described applications, the catalyzed reaction is as follows:
wherein X is halogen, preferably fluorine, chlorine, bromine or iodine.
Preferably, in any of the above embodiments of the use, the amount of catalyst is as described above.
Preferably, in any of the above embodiments of the application, the process steps and/or process conditions of the catalytic reaction are as described above.
The above preferred conditions may be combined to obtain preferred embodiments of the present invention without departing from the general knowledge in the art.
The beneficial effects of the invention are as follows:
(1) The vildagliptin produced by the method has high purity and low impurity content, and especially the disubstituted product has low impurity content, thereby being beneficial to the quality control of the vildagliptin bulk drug and/or pharmaceutical preparation;
(2) The method uses bromides such as potassium bromide and the like as a reaction catalyst, is safe and nontoxic, and is beneficial to controlling the toxic impurity content of the vildagliptin bulk drug and/or the pharmaceutical preparation product at a very low level;
(3) The method has the advantages of mild reaction conditions, convenient operation and control, high yield, low energy consumption and low cost, and is very suitable for industrialized production and popularization and application.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The invention is illustrated in further detail by way of examples which follow, but are not intended to limit the scope of the invention to the examples.
In the present invention, the specific conditions are not specified, and the reagent or the apparatus is carried out according to the conventional conditions or the conditions recommended by the manufacturer, and the reagent or the apparatus is not specified by the manufacturer, and can be obtained by purchasing commercial products or preparing the reagent or the apparatus by a known method.
In connection with the definition of terms used in the present invention, unless otherwise indicated, the initial definition provided by the terms herein applies to the term throughout; to the extent that terms are not specifically defined herein, they should be given meanings that would be able to be given to those skilled in the art in light of the disclosure and/or the context.
For example, classification and/or interpretation of solvents can be found in the handbook of solvents, edited by Cheng Nenglin (4 th edition, beijing: chemical industry Press).
Some of the schemes and examples below may omit details of common reactions, separation techniques, and analytical procedures, and some may omit secondary products from chemical reactions. In addition, in some cases, the reaction intermediates may be used in subsequent steps without isolation and/or purification.
In general, the chemical transformations described in the specification may be performed using substantially stoichiometric reactants, although some reactions may benefit from using an excess of one or more reactants. Any description of stoichiometry, temperature, pH, etc., herein, whether or not the term "range" is explicitly used, is intended to include the endpoints as shown.
Example 1
1. Synthesis of vildagliptin intermediate (Compound IV)
A process for the production of vildagliptin intermediate (compound IV) comprising the steps of:
(1) under the protection of inert gas (nitrogen in the embodiment), the compound I (L-prolylamide) (S) -pyrrosidine-2-carboxamide with the purity more than or equal to 96 percent), the compound II (chloroacetyl chloride ) and alkaline substances (one or more than two of inorganic alkali, alkaline inorganic salt and organic amine can be used for neutralizing hydrogen chloride generated in the reaction process), the triethylamine is selected in the embodiment to react in an organic solvent (dichloromethane is selected in the embodiment), the reaction is basically complete by thin-layer chromatography detection (the residual amount of the compound I is less than or equal to 5 percent and the embodiment is controlled to be less than or equal to 2 percent), and then the reaction is directly used for the next reaction;
wherein, the molar ratio of the compound I to the compound II is 1:0.8-1.5 (for example, 1:1.05), the molar ratio of the compound I to the alkaline substance is 1:0.8-2.0 (for example, 1:1.2), the dosage of the organic solvent can be properly adjusted according to the actual situation, for example, the dosage of the organic solvent is 0.5 kg-5.0 kg (for example, 3.0 kg) per mol of the compound I; in this step of this example, the amounts of compound I, compound II and basic substance (triethylamine) were 1.31mol, 1.38mol and 1.58mol, respectively, and the amount of the organic solvent (methylene chloride) was 3.98kg;
(2) continuously adding a dehydrating agent (such as trifluoroacetic anhydride, phosphorus oxychloride, phosphorus pentoxide, cyanuric chloride and the like) and an organic solvent (such as N, N-dimethylformamide) solution of an alkaline substance (such as methylene chloride) into the reaction liquid obtained in the previous step under the protection of inert gas (such as nitrogen in the embodiment), carrying out reaction at the temperature of-20 ℃ to 0 ℃, detecting the reaction basically completely by thin-layer chromatography (the residual amount of the compound III is less than or equal to 5 percent, controlling the residual amount of the compound III to be less than or equal to 2 percent in the embodiment), and carrying out the next post-treatment;
wherein, the molar ratio of the compound I to the dehydrating agent is 1:0.8-1.5 (for example, 1:1.05), the molar ratio of the dehydrating agent to the alkaline substance is 1:1.5-2.5 (for example, 1:1.9), the dosage of the supplementary organic solvent can be properly adjusted according to the actual situation, for example, the dosage of the supplementary organic solvent is 0.1 kg-1.0 kg (for example, 0.2 kg) per mole of the dehydrating agent; in this step of this example, the amount of the dehydrating agent (phosphorus oxychloride) was 1.38mol, the amount of the basic substance (N, N-dimethylformamide) was 2.63mol, and the amount of the supplemental organic solvent (methylene chloride) was 0.28kg;
(3) adding a proper amount of purified water (0.45 kg is selected in the embodiment) into the reaction solution obtained in the previous step, stirring, standing, separating, taking an organic phase, extracting the aqueous phase by using methylene dichloride (0.4 kg), merging the organic phases, washing 3 times by using water, then washing by using 7wt% of sodium bicarbonate aqueous solution and 25wt% of sodium chloride aqueous solution (the dosage is 0.5 kg-0.6 kg respectively), taking the organic phase, carrying out reduced pressure distillation (the vacuum degree is less than or equal to-0.08 MPa, the control temperature is 10 ℃ to 40 ℃, for example, 20 ℃ and 25 ℃ and 30 ℃ and the like, the embodiment is 25 ℃ to no fraction, adding 0.12kg of methylene dichloride and 0.67kg of methyl tert-butyl ether, heating to 40 ℃ to 60 ℃ (50 ℃ in the embodiment), stirring and dissolving completely, then slowly cooling to 0 ℃ to 10 ℃ (for example, 1 ℃ and 2 ℃ and 5 ℃ in the embodiment), separating out solid, filtering, drying, and obtaining 0.136kg of compound IV (Chinese name, (2S) -N-chloroacetyl-2-cyanopyrrolidine, 1- (2-bromocrine) -2-cyanopyrrolidine (2-35% of which is yellow, the purity is calculated as a standard, and the yellow compound is 62-35.35% of brown solid, and the yellow compound is detected by CAS (60% and 60% of the standard purity is calculated by using the method).
2. Production of vildagliptin (Compound VI) products
A process for the production of vildagliptin (compound VI) products comprising the steps of:
i. under the protection of inert gas (nitrogen in the embodiment), the compound IV, the compound V (3-amino-1-adamantanol, the purity of (3R, 5R, 7S) -3-aminoadamantan-1-ol is more than or equal to 98 percent), a catalyst (potassium bromide is selected in the embodiment) and an alkaline substance (which is used for neutralizing hydrogen chloride generated in the reaction process, one or more of inorganic base, alkaline inorganic salt and organic amine are selected in the embodiment), the compound IV, the compound V (3-amino-1-adamantanol) and the alkaline substance are reacted in an organic solvent at the temperature of 50-55 ℃, and after the detection of the reaction is basically complete (the residual amount of the compound IV is less than or equal to 5 percent, the control of the embodiment is less than or equal to 2 percent), the reaction is filtered, and a filter cake is washed by methylene dichloride to obtain filtrate;
wherein the molar ratio of the compound IV to the compound V is 1:1.05-1.22 (e.g. 1:1.2), the molar ratio of the compound IV to the alkaline substance is 1:0.8-2.0 (e.g. 1:1.65), the catalyst is used in a catalytic amount, for example, the catalyst is used in an amount of 0.01-0.5 mol per mol of the compound IV, the organic solvent is used in an amount which can be properly adjusted according to the actual situation, for example, the organic solvent is used in an amount of 0.5-5.0 kg (e.g. 1.36 kg) per mol of the compound IV;
specifically, 0.58mol of compound IV, 0.7mol of compound V and 0.06mol of catalyst (potassium bromide) are uniformly mixed with alkaline substances (0.7 mol of potassium carbonate and 0.26mol of N, N-dimethylformamide) and organic solvents (0.79 kg of acetonitrile) for reaction;
ii. The filtrate obtained in the last step is distilled under reduced pressure (vacuum degree is less than or equal to-0.08 MPa, temperature is controlled at 30 ℃ to 50 ℃, for example, 35 ℃ and 40 ℃ are adopted in the embodiment), 40 ℃ is selected until distillate is not generated, then the distillate is cooled to 10 ℃ to 25 ℃, 0.45kg of purified water is added, pH value is regulated to 4.0 to 6.0 (for example, 4.5, 4.7, 5.0, 5.5 and the like, temperature is controlled at 10 ℃ to 25 ℃, pH value is regulated to 5.0 in the embodiment), then 0.53kg of dichloromethane is added, stirring, standing, liquid separation, the upper aqueous phase is taken, then 0.93kg of dichloromethane is added, pH value is regulated to 8.0 to 10.0 (for example, 8.5, 9.0, 9.5 and the like by sodium carbonate, pH value is regulated to 9.0 in the embodiment), stirring, standing and liquid separation are carried out, extracting lower organic phase with dichloromethane (0.26 kg×2), mixing organic phases, adding 0.13kg anhydrous sodium sulfate, filtering, washing the filter cake with dichloromethane (0.26 kg), vacuum distilling the filtrate (vacuum degree is less than or equal to-0.08 MPa, controlling temperature at 10-40deg.C, such as 20deg.C, 25deg.C, 30deg.C, etc.), continuously vacuum distilling until no distillate is generated, adding 0.18kg ethyl acetate, adding 0.90kg ethyl acetate, inert gas (nitrogen gas is selected in this example), heating to 40-60deg.C, stirring for 1.0-3.0 h to completely dissolve, slowly cooling to 5-15deg.C, precipitating solid, filtering, washing with ethyl acetate, drying to obtain 0.15kg crude vildagliptin (compound VI), white powdery solid, the yield is 85.2 percent based on the calculation of the compound IV, the content of the disubstituted product (impurity) is 0.55 percent by HPLC detection, and the total impurity content is less than or equal to 2.0 percent;
iii, mixing the crude vildagliptin product with purified water at a mass ratio of 1:1-10 (0.1 kg of the crude vildagliptin product is selected in the embodiment and 0.3kg of the purified water), regulating the pH value to 4.0-6.0 by dilute hydrochloric acid (the control temperature is 10-25 ℃, the pH value is 5.0 is selected in the embodiment), adding 0.4kg of dichloromethane, stirring, standing, separating liquid, taking an upper aqueous phase, then adding 0.53kg of dichloromethane, regulating the pH value to 8.0-10.0 by sodium carbonate (the control temperature is 10-25 ℃, the pH value is 9.0 in the embodiment), stirring, standing, separating liquid, taking a lower organic phase, extracting the upper aqueous phase by dichloromethane (0.2 kg multiplied by 2), combining the organic phase, adding 0.085kg of anhydrous sodium sulfate, filtering, washing a filter cake by dichloromethane (0.2 kg), distilling the filtrate under reduced pressure (vacuum degree is less than or equal to-0.08 MPa, temperature is controlled between 10 ℃ and 40 ℃) until a small amount of liquid (about 300 mL) remains, then adding 0.4kg of isopropanol, heating to 40 ℃ to 50 ℃ to dissolve the isopropanol completely, distilling under reduced pressure until a small amount of liquid (about 300 mL) remains, then adding 0.4kg of isopropanol, repeating the steps once, distilling under reduced pressure until a small amount of liquid (about 300 mL) remains, then adding 0.32kg of ethyl acetate, stirring to dissolve, distilling under reduced pressure until a small amount of liquid (about 300 mL), then adding 0.32kg of ethyl acetate, repeating the steps once, distilling under reduced pressure until a small amount of liquid (about 300 mL) remains, adding 0.32kg of ethyl acetate, protecting with inert gas (nitrogen is selected in the embodiment), heating to 40 ℃ to 50 ℃, stirring for 1.0h to 3.0h to dissolve completely, then slowly cooling to 5-15 ℃, precipitating solid, filtering, washing with ethyl acetate, drying (vacuum degree is less than or equal to-0.08 MPa, temperature is controlled at 45-55 ℃), obtaining 0.095kg of vildagliptin product, yield is 95%, white powdery solid, purity of the product is 99.53% through infrared spectrum IR confirmation and HPLC detection, content of disubstituted product (impurity) is less than 0.02% (not detected), and total impurity content is less than or equal to 0.5%.
Examples 2 to 4
The same matters as in example 1 were not repeated, except that in step (1), the addition amount of compound II was changed in such a manner that the molar ratio of compound I to compound II was 1:1.0, 1:1.1, 1:1.2, respectively; the test result shows that when the molar quantity of the compound II is more than 1.02 times of that of the compound I, the reaction is complete, the production effect is good, the yield and purity of the vildagliptin product are basically equivalent to those of the example 1, the content of the disubstituted product (impurities) and the total impurities is low, and the requirements of quality standards (the content of the impurities of the disubstituted product is less than or equal to 0.15 percent and the content of the total impurities is less than or equal to 1.0 percent) are met.
Examples 5 and 6
The same contents as in example 1 are not repeated, except that in step (1), the reaction temperature is changed to-80 to-25 ℃ and-8 to-5 ℃ respectively; the results show that the yield and purity of the vildagliptin product are basically equivalent to those of example 1 when the reaction temperature is-80 ℃ to-25 ℃, the content of the disubstituted product (impurities) and the total impurities is low, the requirements of quality standards (the content of the impurities of the disubstituted product is less than or equal to 0.15 percent and the content of the total impurities is less than or equal to 1.0 percent) are met, and the total impurity content in the vildagliptin product is increased by 2.26 percent when the reaction temperature is-8 ℃ to-5 ℃.
Examples 7 and 8
The same contents as those of example 1 are not repeated, except that in the step (2), the reaction temperature is changed to-80 to-20 ℃ and 0.5 to 15 ℃ respectively; the results show that the yield and purity of the vildagliptin product are basically equivalent to those of the example 1 when the reaction temperature is between-80 ℃ and-20 ℃, the content of the disubstituted product (impurities) and the total impurities is low, the requirements of quality standards (the content of the impurities of the disubstituted product is less than or equal to 0.15 percent and the content of the total impurities is less than or equal to 1.0 percent) are met, and the total impurity content in the vildagliptin product is increased by 2.65 percent when the reaction temperature is between 0.5 ℃ and 15 ℃.
Examples 9 to 11
The same procedure as in example 1 was not repeated, except that in step (3), the recrystallization solvents (0.12 kg of methylene chloride and 0.67kg of methyl tert-butyl ether) were changed to isobutanol/n-heptane, respectively, in the same amounts, and the mass ratios were changed to 1:0.5, 1:4.5 and 1:15, respectively; the results show that the yield and purity of the vildagliptin product are not greatly influenced, the content of the disubstituted product (impurities) and the total impurities is low, and the requirements of quality standards (the content of the disubstituted product impurities is less than or equal to 0.15 percent and the total impurity content is less than or equal to 1.0 percent) are met.
Example 12
The same contents as in example 1 are not repeated, except that in step i, the catalyst (potassium bromide) is changed to potassium iodide; the test result shows that the yield of the vildagliptin product is obviously reduced to 64.5% of the original yield, and the content of the disubstituted product (impurity) in the product is increased to more than 1.95%.
Examples 13 to 16
The same procedure as in example 1 is not repeated, except that in step i, the amount of compound V added is varied in accordance with the molar ratio of compound IV to compound V of 1:1.05, 1:1.1, 1:1.15, 1:1.35, respectively; the test results show that when the molar ratio is 1:1.35, the content of the disubstituted product (impurity) in the product is increased to more than 3.54%, and when the molar ratio is other than the molar ratio, the yield and the purity of the product are similar to those of the product in the embodiment 1, the content of the disubstituted product (impurity) and the total impurity is low, and the requirements of quality standards (the content of the disubstituted product impurity is less than or equal to 0.15% and the total impurity content is less than or equal to 1.0%) are met.
Examples 17 and 18
The same contents as in example 1 were not repeated except that in step i, the reaction temperature was changed to 60℃and 65℃respectively; the results show that the yield and purity of the product compared with example 1 are basically equivalent to those of example 1, the content of the disubstituted product (impurities) and the total impurities is low, and the requirements of quality standards (the content of the disubstituted product impurities is less than or equal to 0.15 percent and the total impurity content is less than or equal to 1.0 percent) are met.
Example 19
According to the same proportion and process conditions as those of the embodiment 1 or other optimized embodiments, the amplification production is carried out, for example, 5 times, 10 times, 20 times, etc.; the results show that the product quality is close to that of the product in the example 1, the content of the disubstituted product (impurities) and the total impurities is low, the requirements of quality standards (the content of the disubstituted product impurities is less than or equal to 0.15 percent and the total impurity content is less than or equal to 1.0 percent) are met, and the production stability is high.
The results show that the method for producing the vildagliptin is mild in reaction conditions, convenient to operate and/or control, high in product purity, low in impurity content, favorable for controlling the product quality of the vildagliptin bulk drug and/or the pharmaceutical preparation, high in yield, low in energy consumption and low in cost, and is very suitable for industrial production and popularization and application.

Claims (31)

1. A method for producing vildagliptin, comprising the steps of:
wherein X is halogen;
i. under the protection of inert gas or not, the compound A and the compound V react under the condition of taking potassium bromide as a catalyst and in the presence of alkaline substances and organic solvents to obtain vildagliptin;
wherein the molar ratio of the compound A to the compound V is 1:1.05-1.22;
the amount of potassium bromide used is 0.1mol per mole of compound a;
the alkaline substances are potassium carbonate and DMF, and the molar ratio of the potassium carbonate to the DMF is 1:0.3-0.4;
the amount of the basic substance to be used is 1.65mol per mol of the compound A;
the organic solvent is acetonitrile.
2. The process according to claim 1, wherein X is fluorine, chlorine, bromine or iodine.
3. The process according to claim 1, wherein in step i the reaction temperature is 40 to 80 ℃ and/or the reaction is detected by thin layer chromatography or high performance liquid chromatography.
4. A production process according to claim 3, wherein in step i the temperature of the reaction is 50 ℃ to 65 ℃.
5. The method according to claim 1, wherein,
the amount of the organic solvent is 0.5kg to 5.0kg per mole of the compound A.
6. The process according to claim 5, wherein the amount of the organic solvent is 1kg to 5.0kg per mol of the compound A.
7. The method of claim 1, wherein step ii, or steps ii and iii, is performed after the catalytic reaction is completed:
ii. Concentrating after the step i is finished, adding water, acidifying, extracting, taking a water phase, adding an organic solvent, alkalizing, extracting, taking an organic phase, concentrating, recrystallizing, separating out solids, filtering and drying to obtain the finished product;
and iii, after the step ii is finished, adding water, acidifying, extracting, taking a water phase, adding an organic solvent, alkalizing, extracting, taking an organic phase, concentrating, recrystallizing, separating out a solid, filtering, and drying.
8. The process according to claim 7, wherein in step ii and/or iii, the pH is adjusted to 4.0 to 6.0 by acidification and/or the pH is adjusted to 8.0 to 10.0 by alkalization.
9. The process according to claim 8, wherein in step ii and/or iii, acidification is carried out with mineral acid;
and/or, in step ii and/or iii, alkalization is carried out using an alkaline substance.
10. The production method according to claim 9, wherein in step ii and/or iii, the inorganic acid is selected from one or two or more of hydrochloric acid, sulfuric acid and nitric acid;
and/or, in step ii and/or iii, the alkaline substance is an inorganic base and/or an alkaline inorganic salt; the inorganic base is selected from one or more than two of lithium hydroxide, sodium hydroxide and potassium hydroxide; the alkaline inorganic salt is selected from one or more than two of lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate and potassium bicarbonate.
11. The production method according to claim 7, wherein in step ii and/or iii, the organic solvent is one or more of hydrocarbon solvents, halogenated hydrocarbon solvents, ether solvents and ester solvents;
the hydrocarbon solvent is one or more than two of aliphatic hydrocarbon, cycloparaffin and unsaturated hydrocarbon;
the halogenated hydrocarbon solvent is selected from one or more than two of methane chloride, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene, trichloroethylene, tetrachloroethylene, chloropropane, dichloropropane, chlorobutane, chlorobenzene, dichlorobenzene, bromomethane, bromoethane, bromopropane, bromobenzene and dibromobenzene;
the ether solvent is one or more selected from diethyl ether, propyl ether, butyl ether, amyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl furan, dioxolane, dioxane, ethylene oxide, propylene oxide, anisole, diphenyl ether, tetrahydropyran and epichlorohydrin;
the ester solvent is selected from one or more of methyl formate, ethyl formate, propyl formate, isopropyl formate, butyl formate, isobutyl formate, pentyl formate, isopentyl formate, benzyl formate, hexyl formate, trimethyl orthoformate, methyl acetate, ethyl acetate, vinyl acetate, propyl acetate, isopropyl acetate, allyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, methyl isoamyl acetate, cyclohexyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, methyl acrylate, methyl methacrylate, ethyl methacrylate, methyl butyrate, ethyl butyrate and propyl butyrate.
12. The process according to claim 7, wherein in step ii and/or iii, the recrystallization is carried out using an alcohol solvent and/or an ester solvent.
13. The method according to claim 12, wherein in step ii and/or iii, the alcoholic solvent is one or more selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-pentanol, isopentanol, propylene glycol, butylene glycol, glycerol and benzyl alcohol;
in the step ii and/or iii, the ester solvent is selected from one or more of methyl formate, ethyl formate, propyl formate, isopropyl formate, butyl formate, isobutyl formate, pentyl formate, isopentyl formate, benzyl formate, hexyl formate, trimethyl orthoformate, methyl acetate, ethyl acetate, vinyl acetate, propyl acetate, isopropyl acetate, allyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, amyl acetate, isopentyl acetate, hexyl acetate, methyl isoamyl acetate, cyclohexyl acetate, methylcyclohexyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, methyl acrylate, methyl methacrylate, ethyl methacrylate, methyl butyrate, ethyl butyrate and propyl butyrate.
14. The process according to claim 7, wherein in step ii and/or iii, the temperature of the precipitated solid is 5℃to 15 ℃.
15. The production method according to any one of claims 1 to 14, further comprising a production method of compound a, the synthetic steps of which are as follows:
wherein X is as defined in claim 1 and Y is halogen;
(1) the compound I and the compound C react with or without inert gas protection to obtain a compound B;
(2) and (3) dehydrating the compound B obtained in the step (1) by a dehydrating agent to obtain a compound A.
16. The method of claim 15, wherein Y is fluorine, chlorine, bromine or iodine.
17. The production method according to claim 15, wherein in the step (1), the compound C is used in an amount of 0.8mol or more per mol of the compound I;
and/or, in the step (1), the temperature of the reaction is lower than or equal to-5 ℃;
and/or, in the step (1), detecting that the reaction is completed by thin layer chromatography or high performance liquid chromatography;
and/or in the step (2), the dehydrating agent is selected from one or more than two of trifluoroacetic anhydride, phosphorus oxychloride, phosphorus pentoxide and cyanuric chloride;
and/or, in the step (2), the amount of the dehydrating agent is 0.8mol or more per mol of the compound I;
and/or, in the step (2), the temperature of the reaction is less than or equal to 15 ℃;
and/or, in the step (2), detecting the completion of the reaction by thin layer chromatography or high performance liquid chromatography.
18. The production method according to claim 17, wherein in the step (1), the compound C is used in an amount of 1.02mol or more per mol of the compound I;
and/or, in the step (1), the temperature of the reaction is less than or equal to-10 ℃;
and/or, in the step (2), the amount of the dehydrating agent is 1.02mol or more per mol of the compound I;
and/or, in the step (2), the temperature of the reaction is less than or equal to 0 ℃.
19. The production method according to claim 17, wherein in step (1), the compound C is used in an amount of 1.02mol to 1.2mol per mol of the compound I;
and/or, in the step (1), the reaction temperature is-25 ℃ to-10 ℃;
and/or, in the step (2), the amount of the dehydrating agent is 1.02mol to 1.2mol per mol of the compound I;
and/or, in the step (2), the reaction temperature is-20-0 ℃.
20. The process according to claim 15, wherein in step (1) and/or (2), the reaction is carried out in the presence of an alkaline substance and/or an organic solvent.
21. The production method according to claim 20, wherein the alkaline substance is one or more selected from the group consisting of an inorganic base, an alkaline inorganic salt and an organic amine;
and/or the organic solvent is selected from one or more than two of nitrile solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, alcohol solvents, ether solvents and ester solvents.
22. The production method according to claim 21, wherein the alkaline substance is an alkaline inorganic salt or an organic amine;
and/or the nitrile solvent is selected from one or more than two of acetonitrile, propionitrile, butyronitrile, succinonitrile, valeronitrile, benzonitrile and benzyl cyanide;
and/or the hydrocarbon solvent is selected from one or more than two of aliphatic hydrocarbon, cycloparaffin and unsaturated hydrocarbon;
and/or the halogenated hydrocarbon solvent is selected from one or more than two of chloromethane, dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene, trichloroethylene, tetrachloroethylene, chloropropane, dichloropropane, chlorobutane, chlorobenzene, dichlorobenzene, bromomethane, bromoethane, bromopropane, bromobenzene and dibromobenzene;
and/or the alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tertiary butanol, n-amyl alcohol, isoamyl alcohol, propylene glycol, butanediol, glycerol and benzyl alcohol;
and/or the ether solvent is selected from one or more than two of diethyl ether, propyl ether, butyl ether, amyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl furan, dioxolane, dioxane, ethylene oxide, propylene oxide, anisole, diphenyl ether, tetrahydropyran and epichlorohydrin;
and/or the ester solvent is selected from one or more of methyl formate, ethyl formate, propyl formate, isopropyl formate, butyl formate, isobutyl formate, pentyl formate, isopentyl formate, benzyl formate, hexyl formate, trimethyl orthoformate, methyl acetate, ethyl acetate, vinyl acetate, propyl acetate, isopropyl acetate, allyl acetate, butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, methyl isoamyl acetate, cyclohexyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, methyl acrylate, methyl methacrylate, ethyl methacrylate, methyl butyrate, ethyl butyrate and propyl butyrate.
23. The production method according to claim 21, wherein the inorganic base is one or more selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide;
and/or the alkaline inorganic salt is selected from one or more than two of lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate and potassium bicarbonate;
and/or the organic amine is selected from one or more than two of ethylamine, diethylamine, triethylamine, diisopropylethylamine, hydroxyethyl ethylenediamine, N-methylmorpholine, formamide, N-methylformamide, N-dimethylformamide, N-diethylformamide, acetamide, N-methylacetamide, N-dimethylacetamide, N-methylpropionamide and caprolactam.
24. The process according to claim 20, wherein in the step (1), the basic substance is used in an amount of 0.8mol to 2.5mol per mol of the compound I,
and/or, in the step (1), the amount of the organic solvent is 0.5kg to 5.0kg per mol of the compound I;
and/or, in the step (2), the amount of the alkaline substance is 1.2mol to 5mol per mol of the dehydrating agent;
and/or, in the step (2), the amount of the organic solvent is 0.5kg to 5.0kg per mole of the dehydrating agent.
25. The production method according to claim 24, wherein in the step (1), the basic substance is used in an amount of 1.05mol to 1.5mol per mol of the compound I;
and/or, in the step (1), the amount of the organic solvent is 1kg to 5.0kg per mol of the compound I;
and/or, in the step (2), the amount of the alkaline substance is 1.5mol to 2.5mol per mol of the dehydrating agent;
and/or, in the step (2), the amount of the organic solvent is 1kg to 5.0kg per mole of the dehydrating agent.
26. The production method according to claim 15, wherein the synthesis of compound a further comprises step (3):
(3) and (3) after the step (2) is finished, adding water, extracting, taking an organic phase, concentrating, recrystallizing, separating out solids, filtering and drying.
27. The method of claim 26, wherein the step (3) comprises the steps of: after the step (2) is finished, adding water, extracting, taking an organic phase, washing with water, then washing with sodium bicarbonate or potassium bicarbonate aqueous solution, sodium chloride or potassium chloride aqueous solution, concentrating, recrystallizing, separating out solid, filtering, and drying.
28. The production method according to claim 27, wherein recrystallization is performed using a halogenated hydrocarbon-based solvent and/or an ether-based solvent;
and/or the temperature of the precipitated solid is 0-10 ℃;
and/or the concentration of the sodium bicarbonate or potassium bicarbonate aqueous solution is 7wt% ±2wt%;
and/or the concentration of the sodium chloride or potassium chloride aqueous solution is 25wt% + -5 wt%.
29. The process according to claim 28, wherein the halogenated hydrocarbon solvent is one or more selected from the group consisting of monochloromethane, dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethylene, trichloroethylene, tetrachloroethylene, chloropropane, dichloropropane, chlorobutane, chlorobenzene, dichlorobenzene, bromomethane, bromoethane, bromopropane, bromobenzene and dibromobenzene;
and/or the ether solvent is selected from one or more than two of diethyl ether, propyl ether, butyl ether, amyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl furan, dioxolane, dioxane, ethylene oxide, propylene oxide, anisole, diphenyl ether, tetrahydropyran and epichlorohydrin.
30. The production method according to claim 28, wherein when the recrystallization is performed using a halogenated hydrocarbon solvent and an ether solvent, the mass ratio of the halogenated hydrocarbon solvent to the ether solvent is 1:2 to 10.
31. The production method according to claim 28, wherein when the recrystallization is performed using a halogenated hydrocarbon solvent and an ether solvent, the mass ratio of the halogenated hydrocarbon solvent to the ether solvent is 1:5 to 6.
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