Preparation method and product of alkyl-substituted diacid compound

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of an alkyl-substituted diacid compound and a product. The preparation method comprises the following steps: with a carboxylic ester compound and halogenated olefin as raw materials, carrying out a reaction in the presence of a non-nucleophilic strong base to obtain an alkene ester compound; hydrolyzing the olefine ester compound under an alkaline condition to obtain an olefine acid compound; and carrying out oxidation reaction on the olefine acid compound under the action of sulfuric acid and potassium permanganate to obtain the alkyl-substituted diacid compound. The synthetic route provided by the invention has the advantages of short steps, simple operation, low preparation cost, easily available raw materials, no need of using an expensive catalyst, high reaction efficiency and no need of using a chromatographic column for separation and purification, and is suitable for industrial application. The alkyl-substituted diacid compound product prepared by the method is high in purity, few in impurities and easy to separate.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation method and product of an alkyl-substituted diacid compound. Background Art

[0002] Alkyl-substituted diacid compounds can be used as important intermediates in the field of drug synthesis. Currently, the synthesis of diacid intermediates reported in the literature is mainly carried out through the following route (Organic Syntheses, 1964, 44, 59-61). Using 2-butanone and ethyl 2-cyanoacetate as raw materials, through the ethyl 2,3-dicyano-3-methylvalerate intermediate, without separating the intermediate, hydrolyzing the cyano group and ester group under the acidic condition provided by hydrochloric acid, and heating to decarboxylate to obtain the compound shown in IA.

[0003]

[0004] This route requires the use of highly toxic reagents potassium cyanide or sodium cyanide, has high requirements for the qualifications of production enterprises, high production safety pressure, high regulatory requirements, and it is difficult to achieve the production of autonomously controllable bulk drugs.

[0005] In view of this, there is a need for a synthesis method of alkyl-substituted diacid compounds that does not require highly toxic reagents and has fewer steps and high yields. Summary of the Invention

[0006] In order to solve the above technical problems, the present invention provides a preparation method and product of an alkyl-substituted diacid compound.

[0007] The present invention provides a synthesis method of an alkyl-substituted diacid compound, which at least includes the following steps:

[0008]

[0009] S1. Using the carboxylic acid ester shown in SM1 and the haloalkene shown in SM2 as raw materials, reacting in the presence of a non-nucleophilic strong base to obtain an enoate compound shown in INT1;

[0010] S2. Hydrolyzing the enoate compound shown in INT1 under alkaline conditions to obtain an enoic acid compound shown in INT2;

[0011] S3. Oxidizing the enoic acid compound shown in INT2 under the action of sulfuric acid and potassium permanganate to obtain an alkyl-substituted diacid compound shown in Formula I;

[0012] Wherein, R1, R2, and R3 each independently selected from C1-C6 alkyl; n is an integer from 1 to 12.

[0013] Optionally, in S1, the non-nucleophilic strong base is selected from lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, trityllithium, tritylsodium, and tritylpotassium.

[0014] Optionally, the reaction in S1 is carried out in an organic solvent, and the organic solvent is selected from one of tetrahydrofuran, methyl tert-butyl ether, diethyl ether, and diisopropyl ether.

[0015] Optionally, in S1, the molar ratio of SM1 to SM2 is 1:0.8 to 1.2.

[0016] Optionally, in S1, the molar ratio of SM1 to the non-nucleophilic strong base is 1:0.8 to 1.2.

[0017] Optionally, in S1, the reaction temperature is -60°C to -10°C.

[0018] Optionally, in S1, the reaction time is 20 to 40 minutes.

[0019] Optionally, the hydrolysis reaction in S2 is carried out in the presence of an alcoholic organic solvent and an aqueous solution of an inorganic base.

[0020] Optionally, in S2, the inorganic base is selected from one of sodium hydroxide and potassium hydroxide.

[0021] Optionally, in S2, the hydrolysis reaction temperature is the reflux temperature.

[0022] Optionally, in S2, the hydrolysis reaction time is 6 to 18 hours.

[0023] Optionally, in S2, the molar ratio of the enoate compound represented by INT1 to the hydroxide ion in the inorganic base is 1:3 to 6.

[0024] Optionally, in S2, the volume ratio of the alcoholic organic solvent to the aqueous solution of the inorganic base is 0.8 to 1.2:0.8 to 1.2.

[0025] Optionally, in S3, the molar ratio of the enoic acid compound represented by INT2 to sulfuric acid is 1:2 to 4, preferably 2.4 to 3.6.

[0026] Optionally, in S3, the molar ratio of the enoic acid compound represented by INT2 to potassium permanganate is 1:2 to 4, preferably 2.4 to 3.6.

[0027] Optionally, in S3, potassium permanganate can be added continuously or in batches as solid potassium permanganate or by dropping a potassium permanganate solution. Optionally, when adding solid potassium permanganate continuously or in batches, the concentration of sulfuric acid is 1 - 2 mol / L; when dropping a potassium permanganate solution, the concentration of sulfuric acid is 12 - 18 mol / L. Optionally, in S3, when adding potassium permanganate, the reaction temperature in the reaction system is controlled at 20°C - 60°C, preferably 30°C - 50°C.

[0028] Optionally, after the oxidation reaction in S3, a post-treatment step is further included, including: filtering the reaction product, washing the obtained filtrate with organic solvent A and extracting with organic solvent B to obtain an organic phase; washing the organic phase with saturated sodium chloride solution and drying to obtain a crude product. Optionally, organic solvent A is one or more of n-heptane, n-hexane, or petroleum ether; organic solvent B is one or more of ethyl acetate, n-butanol, or n-pentanol.

[0029] The present invention also relates to an alkyl-substituted diacid compound product obtained by the above synthesis method.

[0030] The technical solution provided by the embodiments of the present invention has the following advantages compared with the prior art:

[0031] The synthesis route of the alkyl-substituted diacid compound proposed by the present invention has short steps, simple operation, low preparation cost, easily available raw materials, does not require the use of highly toxic reagents and expensive catalysts, does not require special reaction conditions such as high pressure, and has high reaction efficiency. It does not require the use of a chromatography column for separation and purification, and is suitable for industrial application.

[0032] The alkyl-substituted diacid compound product prepared by the present invention has high purity, few impurities and is easy to separate, and can be used as a raw material for drug synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 1H-NMR spectrum of the compound shown in IA 1 1H-NMR spectrum. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0034] In order to more clearly understand the above objects, features and advantages of the present invention, the solution of the present invention will be further described below. It should be noted that, without conflict, the embodiments of the present invention and the features in the embodiments can be combined with each other.

[0035] Many specific details are set forth in the following description in order to fully understand the present invention, but the present invention can also be implemented in other ways different from those described herein; obviously, the embodiments in the specification are only a part of the embodiments of the present invention, rather than all of the embodiments.

[0036] The abbreviations used in this application are as follows:

[0037] EA: Ethyl acetate;

[0038] THF: Tetrahydrofuran;

[0039] 1 H-NMR: Proton nuclear magnetic resonance.

[0040] In this article, C1-C6 alkyl refers to a straight-chain or branched-chain alkyl group with 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.

[0041] An embodiment of the present invention provides a method for synthesizing an alkyl-substituted diacid compound. The synthesis route adopted is shown in the following formula:

[0042]

[0043] S1. Using the carboxylic acid ester shown as SM1 and the haloalkene shown as SM2 as raw materials, reacting in the presence of a non-nucleophilic strong base to obtain an enoate compound shown as INT1;

[0044] S2. Hydrolyzing the enoate compound shown as INT1 under alkaline conditions to obtain an enoic acid compound shown as INT2;

[0045] S3. Oxidizing the enoic acid compound shown as INT2 under the action of sulfuric acid and potassium permanganate to obtain an alkyl-substituted diacid compound shown as Formula I;

[0046] Among them, R1, R2, and R3 each independently selected from C1-C6 alkyl; n is an integer from 1 to 12, and X represents a halogen.

[0047] The raw materials required for the synthesis route of the embodiment of the present invention are easily available, without the need to use highly toxic reagents and precious metal catalysts. The intermediate products are easy to purify and do not require the use of a chromatography column for purification, which is particularly suitable for the industrial production of pharmaceutical intermediate raw materials. Using potassium permanganate as a catalyst for the oxidation reaction has the advantages of low cost and high reaction efficiency.

[0048] As an improvement of the embodiment of the present invention, R1 and R2 each independently selected from C1-C3 alkyl.

[0049] As an improvement of the embodiment of the present invention, R1 and R2 each independently selected from methyl, ethyl or propyl. Among them, propyl includes n-propyl or isopropyl.

[0050] As an improvement of the embodiment of the present invention, R3 is selected from C1-C6 alkyl, further optionally selected from C1-C3 alkyl, such as methyl, ethyl or propyl. Among them, propyl includes n-propyl or isopropyl.

[0051] As an improvement of an embodiment of the present invention, X is selected from F, Cl, Br, and I.

[0052] As an improvement of an embodiment of the present invention, n is an integer from 1 to 6.

[0053] As an improvement of an embodiment of the present invention, R1 is methyl, R2 and R3 are both ethyl, X is Br, and n = 1.

[0054] As an improvement of an embodiment of the present invention, in S1, the non-nucleophilic strong base is selected from lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, trityllithium, tritylsodium, and tritylpotassium. The reaction temperature can be -60°C to -10°C.

[0055] As a specific embodiment, when the non-nucleophilic strong base is lithium diisopropylamide, the reaction temperature can be -25°C to -10°C, and further can be -20°C to -10°C. Among them, lithium diisopropylamide is stored in a mixed solvent of THF and n-hexane, and the volume ratio of THF to n-hexane can be 12:25.

[0056] As an improvement of an embodiment of the present invention, the reaction in S1 is carried out in an organic solvent, and the organic solvent is selected from one of tetrahydrofuran, methyl tert-butyl ether, diethyl ether, and diisopropyl ether.

[0057] As an improvement of an embodiment of the present invention, in S1, the molar ratio of SM1 to SM2 is 1:0.8 to 1.2; further, it can be 1:1.0 to 1.2. For example, the reaction can be carried out at ratios such as 1:0.9, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, etc.

[0058] As an improvement of an embodiment of the present invention, in S1, the molar ratio of SM1 to the non-nucleophilic strong base is 1:0.8 to 1.2; further, it can be 1:1.0 to 1.2, and further can be 1:1.05 to 1.15. For example, the reaction can be carried out at ratios such as 1:0.9, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, etc.

[0059] As an improvement of an embodiment of the present invention, in S1, the reaction time can be 20 to 40 minutes.

[0060] As an improvement of an embodiment of the present invention, in S1, the non-nucleophilic strong base placed in the organic solvent, SM1 dissolved in the organic solvent, and SM2 dissolved in the organic solvent are added in sequence; at the same time, ensure that the reaction temperature during the raw material addition process is within the range of -60°C to -10°C to control the reaction process.

[0061] As an improvement of an embodiment of the present invention, in S1, a non-nucleophilic strong base placed in an organic solvent is first added, and then SM1 dissolved in the organic solvent is added. After the addition, the reaction temperature is maintained within the range of -60°C to -10°C for a period of time, such as 20 to 40 minutes, and specifically 30 minutes can be adopted to ensure the full progress of the reaction. Then SM2 dissolved in the organic solvent is added, and the reaction temperature is maintained within the range of -60°C to -10°C for reaction for 20 to 40 minutes, and specifically 30 minutes can be adopted.

[0062] As an improvement of an embodiment of the present invention, in S1, after the reaction is completed, an inorganic acid is added to adjust the pH to 5 to 6 to end the reaction, and dilute hydrochloric acid can be specifically adopted. At the same time, ensure that the temperature during the dropping process is not higher than 5°C, for example, within the range of -10°C to 5°C, to reduce the occurrence of side reactions.

[0063] The present invention also proposes a specific implementation manner of S1: Under anhydrous and anaerobic conditions, a non-nucleophilic strong base placed in an organic solvent is added, cooled to -60°C to -10°C, and SM1 dissolved in a dry organic solvent is added dropwise. During the dropping process, the temperature is maintained at -60°C to -10°C. After the addition, this temperature is maintained for 20 to 30 minutes; SM2 dissolved in a dry organic solvent is added dropwise. During the dropping process, the temperature is maintained at -60°C to -10°C. After the addition, this temperature is maintained for 25 to 35 minutes; dilute hydrochloric acid is added dropwise to adjust the pH to 5 to 6 to terminate the reaction, and the temperature is maintained at -10°C to 5°C during the dropping process.

[0064] As an improvement of an embodiment of the present invention, after the reaction in S1, there is also a post-treatment step, which specifically includes: discarding the aqueous phase of the reaction solution, washing, drying, and concentrating the organic phase to obtain a product for the next reaction.

[0065] Further preferably, the post-treatment step is: discarding the aqueous phase of the reaction solution, washing the organic phase successively with dilute hydrochloric acid, saturated NaHCO3 aqueous solution, and saturated NaCl aqueous solution, drying, filtering, and washing the filter cake with an organic solvent, preferably washing 2 to 4 times. The product is obtained after concentration. The organic solvent used for washing the filter cake can be at least one of dichloromethane, ethyl acetate, chloroform, and dichloroethane. Concentration can be carried out by reduced pressure concentration at 40°C to 50°C.

[0066] As a specific implementation manner of the post-treatment step of S1: Discard the aqueous phase of the reaction solution, wash the organic phase with 1mol / L hydrochloric acid, saturated NaHCO3 aqueous solution, and saturated NaCl aqueous solution respectively, dry with anhydrous Na2SO4, filter, and wash the filter cake with dichloromethane twice. Combine the filtrates and concentrate by reduced pressure at 42°C to 45°C to obtain the product.

[0067] As an improvement of the embodiment of the present invention, an alcohol organic solvent and an inorganic base aqueous solution are added to the reaction system in S2 for reaction, and the alcohol organic solvent can promote the reaction. Specifically, the alcohol organic solvent can be methanol, ethanol, isopropanol, etc., and the inorganic base can be selected from one of sodium hydroxide and potassium hydroxide.

[0068] As an improvement of the embodiment of the present invention, in S2, the hydrolysis temperature is the reflux temperature, and the hydrolysis time can be 8 to 14 hours, specifically, it can be 9 hours, 10 hours, 11 hours or 12 hours.

[0069] As an improvement of the embodiment of the present invention, in S2, the molar ratio of INT1 to the hydroxide ion in the inorganic base is 1:3 to 6, and further can be 1:4 to 5, specifically, it can be 1:4, 1:4.5 or 1:5.

[0070] As an improvement of the embodiment of the present invention, in the reaction system of S2, the volume ratio of the alcohol organic solvent to the inorganic base aqueous solution is 0.8 to 1.2:0.8 to 1.2. For example, it can be 1:0.8 to 1.2, and specifically, it can be 1:0.9, 1:1 or 1:1.1.

[0071] As an improvement of the embodiment of the present invention, in S2, after the hydrolysis reaction is completed, it further includes a post-treatment step, specifically including:

[0072] S21. First, remove the alcohol organic solvent in the reaction system and wash it with an organic solvent; add an inorganic acid to the aqueous phase to adjust the pH value to 2 to 4, and keep the temperature of the reactants within the range of 0 to 20 °C during this period. The organic solvent used for washing can be selected from one of n-heptane, n-hexane or petroleum ether or a mixed solvent.

[0073] S22. Extract with an organic solvent to obtain an organic phase. The organic solvent used for extraction can be selected from at least one of ethyl acetate, n-butanol, and n-pentanol. For example, ethyl acetate can be used, and the number of extractions can be 1 to 3 times;

[0074] S23. The organic phase is washed and dried to obtain the product. The organic phase is washed with a saturated NaCl aqueous solution.

[0075] In S3 of the embodiment of the present invention, acidic potassium permanganate is used as an oxidant to oxidize the double bond of the enoic acid compound into a carboxyl group to obtain an alkyl-substituted diacid compound as shown in formula I. Since the oxidizing property of acidic potassium permanganate is relatively strong, it is necessary to control the reaction conditions to reduce the occurrence of side reactions and improve the yield and purity.

[0076] First, in the reaction system, applying sulfuric acid and potassium permanganate in a suitable ratio can reduce the occurrence of side reactions.

[0077] Secondly, the addition amount of potassium permanganate has an impact on the yield. If the addition amount of potassium permanganate is small, the product yield is low and the oxidation reaction is incomplete. If the addition amount of potassium permanganate is too large, the increase in side reactions will also cause the yield to decrease.

[0078] After a large number of experimental studies, the inventors found that when the molar ratio of the enoic acid compound to sulfuric acid is 1:2 - 4 and the molar ratio of the enoic acid compound to potassium permanganate is 1:2 - 4, the oxidation reaction has high efficiency, is complete, has a high yield, and the product purity can meet the production requirements. The impurities generated can be separated through simple post-treatment and refining steps, without the need to use a chromatography column for purification, and it is suitable for industrial application.

[0079] Specifically, the molar ratio of the enoic acid compound to sulfuric acid can further be 1:2.6 - 3.6. For example, it can be 1:2.4 - 2.8, 1:2.6 - 3.0, 1:2.8 - 3.2 or 1:3.0 - 3.6. Specifically, it can be 1:2.5, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.2, 1:3.4 or 1:3.5; the molar ratio of INT2 to potassium permanganate can be 1:2.6 - 3.6. For example, it can be 1:2.4 - 2.8, 1:2.6 - 3.0 or 1:2.8 - 3.2. For example, specifically, it can be 1:2.5, 1:2.6, 1:2.7, 1:2.9, 1:3.0 or 1:3.1.

[0080] Finally, since potassium permanganate has strong oxidizing properties, if all the potassium permanganate solid is added at once, the reaction will be intense, and it will also cause incomplete reaction and an increase in side reactions. Therefore, it is preferred to add the potassium permanganate solid continuously or in batches or to drip the potassium permanganate solution, so as to control the reaction rate and reduce the occurrence of side reactions.

[0081] The specific addition method is as follows: Add the potassium permanganate solid to the reaction system by means of continuous flow control feeding or batch feeding, and the addition speed is controlled so that the reaction temperature of the reaction system does not exceed 60°C. For example, control the reaction temperature within the range of 20°C - 60°C by the addition speed of the potassium permanganate solid. If the addition speed of the potassium permanganate solid is too fast and the reaction temperature rises too fast and is too high, the yield may decrease due to an increase in by-products. When adding the potassium permanganate solid, sulfuric acid with a concentration of 1 - 2 mol / L can be used. In order to make the reaction system easier to stir, sulfuric acid with a concentration of 1 - 1.5 mol / L can also be used.

[0082] The method of dropping the potassium permanganate solution is as follows: Prepare an aqueous solution of potassium permanganate with a mass percentage concentration of 5% to 6%, then drop it into the reaction system, and finish dropping within 1 to 3 hours. Control the reaction temperature of the reaction system not to exceed 60°C, for example, within the range of 20°C to 60°C, and further within the range of 30°C to 50°C. When adding liquid potassium permanganate, in order to reduce the solvent volume of the reaction system, sulfuric acid with a relatively high concentration can be used, such as 12 to 18 mol / L. The reaction conditions of this method are milder and easier to control.

[0083] As an improvement of the embodiment of the present invention, after adding potassium permanganate, continue to keep warm and stir for 0.5 to 1.5 hours to ensure complete reaction and improve the yield.

[0084] After the oxidation reaction in S3 is completed, it also includes the steps of purifying, drying, and concentrating the alkyl-substituted diacid compounds. Specifically: Filter the oxidized reaction product, wash the obtained filtrate with organic solvent A, extract with organic solvent B to obtain an organic phase; the organic phase is washed with saturated sodium chloride solution, dried, and concentrated to obtain the product. Organic solvent A can be one or more of n-heptane, n-hexane, or petroleum ether; organic solvent B can be one or more of ethyl acetate, n-butanol, or n-pentanol. Among them, drying can be carried out in various ways, for example, by adding anhydrous sodium sulfate. Concentration can be carried out by reduced pressure concentration, specifically at a temperature of 40°C to 50°C.

[0085] As a specific implementation manner of the post-treatment after S3: Filter the reaction product, wash the filter cake with water, combine the filtrates, wash the filtrates with n-heptane, discard the organic phase, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated sodium chloride solution, add anhydrous sodium sulfate for drying, filter, wash with ethyl acetate, and concentrate under reduced pressure at 42°C to 45°C to obtain the product.

[0086] In the embodiment of the present invention, the post-treatment method after S3 adopts the methods of extraction and washing, which maximally ensures the yield of the product. The yield can reach more than 85%, and at the same time, the purity reaches 85% to 90%.

[0087] The product can also be further purified, for example, by increasing the pH value of the solution, washing with different types of organic solvents to remove impurities, and reducing the pH value of the solution for extraction to further obtain a product with improved purity.

[0088] Since the reaction of acidic potassium permanganate as an oxidant is intense, has many side reactions, and a relatively low yield. Therefore, in the field of pharmaceutical synthesis, a new type of oxidation catalyst is generally used, or other reaction routes are adopted. Through accidental research, it is found in the examples of the present invention that the double bond in monoenoic acid is directly oxidized with acidic potassium permanganate to obtain diacid, which has the technical advantage of a short reaction route. And through the control of conditions, products with both yield and purity meeting the preparation requirements can be obtained. The starting materials in the examples of the present invention have a moderate price, and potassium permanganate and sulfuric acid are inexpensive and easily available. Most importantly, the products after oxidation in the examples of the present invention do not need to be purified using a chromatography column, which not only greatly reduces the costs of separation and purification, but also is particularly more suitable for the production of pharmaceutical raw materials.

[0089] In the second aspect of the examples of the present invention, there is also provided a product of alkyl-substituted diacid compounds represented by Formula I obtained by using the above synthesis method, which has a low impurity level and is easy to separate, and can be used in pharmaceutical synthesis.

[0090] Taking the synthesis of the compound represented by Formula IA as an example below, the synthesis method of alkyl-substituted diacid compounds is described:

[0091]

[0092] Specifically, it includes the following steps:

[0093] S1. Using ethyl 2-methylbutyrate and allyl bromide as raw materials, reacting in the presence of a non-nucleophilic strong base to generate INT1-A; the reaction equation is as follows:

[0094]

[0095] S2. Hydrolyzing INT1-A under alkaline conditions to obtain INT2-A; the reaction equation is as follows:

[0096]

[0097] S3. Oxidizing INT2-A under the action of sulfuric acid and potassium permanganate to oxidize the double bond to a carboxyl group to obtain the IA compound; the reaction equation is as follows:

[0098]

[0099] As a specific embodiment of S1: Under anhydrous and anaerobic conditions, a non-nucleophilic strong base stored in an organic solvent is added, and the temperature is lowered to -60°C to -10°C. SM1-A dissolved in a dry organic solvent is added dropwise, and the temperature is maintained at -60°C to -10°C during the dropwise addition. After the addition, this temperature is maintained for 20 to 30 minutes; SM2-A dissolved in a dry organic solvent is added dropwise, and the temperature is maintained at -60°C to -10°C during the dropwise addition. After the addition, this temperature is maintained for 25 to 35 minutes; dilute hydrochloric acid is added dropwise to adjust the pH to 5 to 6 to terminate the reaction, and the temperature is maintained at -50°C to 5°C during the dropwise addition.

[0100] In S2, the mass-volume ratio of INT1-A to the alcoholic organic solvent is 1:5 to 9, where the unit of mass is g and the unit of volume is mL. The volume ratio of the aqueous solution of inorganic base to the alcoholic organic solvent is 1:0.8 to 1.2, and specifically, 1:0.9, 1:1, or 1:1.1 can be used. The mass-volume ratio of INT1-A to water is 1:3 to 7, and specifically, 1:4, 1:5, or 1:6 can be used, where the unit of mass is g and the unit of volume is mL.

[0101] As a specific embodiment of S2: INT1-A is mixed with ethanol and an aqueous solution of NaOH. 6 to 12 mL of ethanol is added per gram of INT1-A, and the molar ratio of INT1-A to NaOH is 1:4; The reaction is refluxed for 6 to 12 hours. After the reaction is completed, ethanol is removed by rotary evaporation under reduced pressure and diluted with water. It is washed twice with n-heptane, and the organic phase is discarded. Hydrochloric acid is added dropwise to the aqueous phase to adjust the pH value to 2 to 4. The reactants are separated, the aqueous phase is extracted with ethyl acetate, the combined organic phases are washed with a saturated NaCl aqueous solution, dried, filtered, the filter cake is rinsed with ethyl acetate, and concentrated under reduced pressure to obtain the product. Among them, the dosage of n-heptane is: 3 to 6 mL of n-heptane is added per gram of INT2-A, preferably 4 to 5 mL. The dosage of EA is: 5 to 8 mL of EA is added per gram of INT2-A, preferably 6 to 7 mL. The dosage of the saturated sodium chloride solution is: 3 to 6 mL of the saturated sodium chloride solution is added per gram of INT2-A, preferably 4 to 5 mL.

[0102] As a specific embodiment of S3: INT2-A is mixed with a 1 to 2 mol / L sulfuric acid solution, and potassium permanganate solid is added continuously or in batches while controlling the addition rate. The temperature of the reaction system is controlled at 20°C to 60°C. After the addition is completed, stirring is continued for 30 to 60 minutes. After the reaction is completed, it is filtered, and the filter cake is washed with an appropriate amount of water, and the filtrates are combined. The filtrate is washed with n-heptane, and the organic phase is discarded. The aqueous phase is extracted with EA, the combined organic phases are washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the bottle wall is rinsed with EA and then the filter cake is rinsed, and concentrated under reduced pressure at 42°C to 45°C to obtain the IA compound.

[0103] As a specific embodiment of S3: Mix INT2-A with a sulfuric acid solution of 16 - 18 mol / L, prepare an aqueous solution of potassium permanganate with a mass percentage concentration of 5% - 6%, and add it dropwise to the reaction system while controlling the reaction temperature of the reaction system within the range of 20°C - 60°C. After the reaction is completed, filter, wash the filter cake with an appropriate amount of water, and combine the filtrates. Wash the filtrate with n-heptane, and discard the organic phase. Extract the aqueous phase with EA, combine the organic phases, wash with a saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, wash the bottle wall with EA and then wash the filter cake, and concentrate under reduced pressure at 42°C - 45°C to obtain the crude IA product. Add an alkaline aqueous solution to the crude IA product obtained by concentration under reduced pressure to adjust the pH to alkaline, wash with EA, then add an acidic aqueous solution dropwise to adjust the pH to acidic, extract the aqueous phase with EA, combine the organic phases, and then dry and concentrate to obtain the refined IA product. The refined IA product prepared by the method of this example has a low impurity level and is easy to separate, and can be used as a raw material for drug synthesis.

[0104] Example 1

[0105] This example illustrates the synthesis method of alkyl-substituted diacid compounds using the compound shown as IA as an example:

[0106] S1: Use ethyl 2-methylbutyrate and allyl bromide as raw materials to produce INT1-A;

[0107] Under anhydrous and anaerobic conditions, add 1265 mL (1.1 eq) of a THF + n-hexane (v:v = 12:25) solution of 2 mol / L lithium diisopropylamide (LDA) to the reaction vessel, cool down to -20°C, add 300 g (1.0 eq) of ethyl 2-methylbutyrate dissolved in THF, and keep the internal temperature not higher than -10°C during the addition. After the addition, maintain this temperature for 30 min; add 306.1 g (1.1 eq) of allyl bromide dissolved in THF, and keep the internal temperature not higher than -10°C during the addition. After the addition, maintain this temperature for 30 min; add a 2M hydrochloric acid solution dropwise, and keep the internal temperature not higher than 5°C during the addition, and adjust the pH to 5.

[0108] Discard the aqueous phase of the reaction solution, and wash the organic phase with 600 mL of 1 mol / L hydrochloric acid, 600 mL of saturated NaHCO3 aqueous solution, and 600 mL of saturated NaCl aqueous solution respectively, and concentrate under reduced pressure to obtain the product.

[0109] S2: Hydrolyze INT1-A under alkaline conditions to obtain INT2-A;

[0110] To the product of S1, add sodium hydroxide solution (dissolve 350.3 g (4.0 eq) of sodium hydroxide in 1200 mL of water), 2400 mL of 95% ethanol solution, heat under reflux for 8 hours. After the reaction is completed, distill under reduced pressure, add 1200 mL of water for dilution and then transfer it to a separatory funnel, and wash it 3 times with n - heptane.

[0111] Discard the organic phase. Dropwise add 6M hydrochloric acid to the aqueous phase to adjust the pH value to 3. Extract the aqueous phase 2 times with EA, combine the organic phases, wash with saturated NaCl aqueous solution, dry with anhydrous NaSO4, filter, and concentrate under reduced pressure to obtain 283.6 g of INT2 - A (reddish - brown oil), with a yield of 86.7% and a purity of 96.20%.

[0112] S3: INT2 - A undergoes an oxidation reaction under the action of acidic potassium permanganate to obtain the IA compound;

[0113] Weigh 283.6 g (1.0 eq) of the product of S2, add it to the reaction vessel, add 3762 mL (2.8 eq) of 1.5M sulfuric acid solution, stir, continuously add 945.7 g (3.0 eq) of KMnO4, control the addition rate, keep the temperature of the reaction system at 50 °C, record the total duration of adding potassium permanganate after the addition is completed, and continue to stir for 60 min.

[0114] Work - up: After the reaction is completed, filter, wash the filter cake 2 times with water, combine to obtain 270 mL of filtrate. Wash the filtrate 2 times × 1026 mL with n - heptane, and discard the organic phase. Extract the aqueous phase 2 times × 1540 mL with EA, combine the organic phases, wash 1 time with saturated sodium chloride solution, 1 time × 1026 mL, dry the organic phase with anhydrous sodium sulfate, filter, wash the bottle wall with EA and then wash the filter cake, a total of 2 times, concentrate under reduced pressure at 42 °C to obtain 272.2 g of white waxy solid. The yield of the IA compound is 85.2% and the purity is 88.54%.

[0115] Take 10 g of the white waxy solid, add 1 mol / L sodium hydroxide to adjust the pH to 10, add and wash 2 times × 90 mL with EA, then dropwise add 1 mol / L hydrochloric acid to adjust the pH to 1. Extract the aqueous phase 2 times × 90 mL with EA, combine the organic phases, dry and concentrate to obtain the IA refined product with a purity of 95.23%. The 1 1H - NMR spectrum is as Figure 1 shown.

[0116] Example 2

[0117] The preparation method of Example 1 is adopted, with the difference that:

[0118] In S3, 29.7 g (1.0 eq) of the product of S2 was taken and added to a reaction vessel. 390.2 mL (2.8 eq) of 1.5 M sulfuric acid solution was added, and the mixture was stirred. 1.6 L of an aqueous solution of potassium permanganate with a mass percentage concentration of 6% was prepared and added dropwise to the reaction system over the same total duration as in Example 1. The temperature of the reaction system was controlled at 50 °C, and after the addition, stirring was continued for 60 min.

[0119] After the reaction was completed, filtration was carried out, and the filter cake was washed twice with an appropriate amount of water. The filtrates were combined. The filtrate was washed twice with n-heptane, and the organic phase was discarded. The aqueous phase was extracted twice with EA, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filter cake was rinsed twice with EA after rinsing the bottle wall with EA. Concentration was carried out under reduced pressure at 42 °C. The yield of the IA compound was calculated to be 84.5%, and the purity was 86.4%.

[0120] Example 3

[0121] The method of Example 1 was used for preparation, except that the addition amount of the solvent in S2 was as shown in Table 1: After the reaction was completed, the product yield was weighed and calculated, and the product purity was detected. The results are shown in Table 1.

[0122] Table 1

[0123] Number Addition method Yield (%) Purity (%) 1 Without adding ethanol 37.6 84.75 2 Adding 1000 mL of 95% ethanol by volume 80.5 93.35 3 Adding 4000 mL of 95% ethanol solution 84.2 95.82 4 When preparing sodium hydroxide solution, add 1680 mL of water for dissolution 91.7 95.71 5 When preparing sodium hydroxide solution, add 3000 mL of water for dissolution 88.4 95.26 6 Adding 2400 mL of isopropanol 90.9 93.54

[0124] According to the above examples, it can be found that during the hydrolysis reaction, if no alcohol organic solvent is added, the product yield is significantly reduced; if the addition amount of the alcohol organic solvent is too large or too small, the product yield will both decrease.

[0125] Example 4

[0126] 1. The method of Example 1 was used for preparation, except that the concentration of sulfuric acid in S3 was changed, as shown in Table 2 specifically. After the reaction was completed, the product yield was weighed and calculated, and the product purity was detected. The results are shown in Table 2.

[0127] Table 2

[0128] Number Sulfuric acid concentration Sulfuric acid dosage Potassium permanganate dosage Yield (%) Purity (%) 1 0.5M 2.8 eq 3.0 eq 50.1 81.72 2 1.0M 2.8 eq 3.0 eq 81.6 88.32 3 2M 2.8 eq 3.0 eq 85.5 88.48

[0129] According to the above examples, it can be found that when the sulfuric acid concentration is low, the product yield is low and the purity is also relatively low. After increasing the sulfuric acid concentration, the yield is significantly improved.

[0130] 2. The method of Example 1 was used for preparation, except that the amount of sulfuric acid in S3 was changed, as shown in Table 3 specifically. After the reaction was completed, the product yield was weighed and calculated, and the product purity was detected. The results are shown in Table 3.

[0131] Table 3

[0132]

[0133] As can be found from the above embodiments, when the amount of sulfuric acid used is too small, the yield of the product is low and the purity is also relatively low. When the amount of sulfuric acid used is too large, the yield shows a downward trend.

[0134] 3. The preparation is carried out by the method of Example 1, except that the amount of potassium permanganate in S3 is changed, as specifically shown in Table 4. After the reaction is completed, the product yield is weighed and calculated, and the product purity is detected. The results are shown in Table 4.

[0135] Table 4

[0136]

[0137]

[0138] As can be found from the above embodiments, when the amount of potassium permanganate used is small, the yield of the product is low and the purity is also relatively low. As the amount of potassium permanganate used increases, both the yield and the purity increase to a certain extent. However, when the amount of potassium permanganate used further increases, there is no further increase in the yield and purity.

[0139] Example 5

[0140] The preparation is carried out by the method of Example 1, except that the addition method of potassium permanganate in S3 and the controlled temperature of the internal temperature are changed. After the reaction is completed, the product yield is weighed and calculated, and the product purity is detected. The results are shown in Table 5.

[0141] Table 5

[0142] Number Potassium permanganate addition method Yield (%) Purity (%) 1 All potassium permanganate is directly added to the reaction system without controlling the internal temperature 28.6 70.53 2 Add potassium permanganate in batches and control the internal temperature at 15°C 40.3 75.35 3 Add potassium permanganate in batches and control the internal temperature at 70°C 58.4 70.24

[0143] As can be found from this embodiment, when all of the potassium permanganate is directly added to the reaction system, the reaction is violent, the heating rate is fast, the temperature is high, and the side reactions increase significantly. Therefore, the yield is significantly reduced.

[0144] If the control of the reaction internal temperature is improper, it will also have a significant impact on the yield and purity.

[0145] Example 6

[0146] The preparation is carried out by the method of Example 1, except that the solvent for the post-treatment in S3 is changed. After the reaction is completed, the product yield is weighed and calculated, and the product purity is detected. The results are shown in Table 6.

[0147] Table 6

[0148] Number Organic solvent for filtrate washing Solvent for extraction Yield (%) Purity (%) 1 n-Hexane EA 85.4 79.32 2 Petroleum ether EA 84.8 77.15 3 n-Heptane n-Butanol 86.6 75.54

[0149] It can be found according to this embodiment that changing the type of organic solvent used in the post-treatment in S3 has a certain impact on both the yield and purity of the product.

[0150] Example 7

[0151] The preparation was carried out by the method of Example 1, except that the volume of the solvent in the post-treatment in S3 was changed. After the reaction was completed, the product yield was weighed and calculated, and the product purity was detected. The results are shown in Table 7.

[0152] Table 7

[0153]

[0154]

[0155] It can be found according to this embodiment that by selecting the volume of the solvent used in the post-treatment within the scope of the embodiments of the present invention, the purity and yield of the product can be ensured.

[0156] Comparative Example 1

[0157] The preparation was carried out according to the method of Example 1, except that:

[0158] 297.25 g (1.0 eq) of the product of S2 and 3902 mL of water were weighed and stirred, and 991.2 g (3.0 eq) of KMnO4 was continuously added at the same total duration as in Example 1. The temperature of the reaction system was controlled at 50 °C, and after the addition was completed, stirring was continued for 60 min. After the reaction was completed, 1.5 M sulfuric acid was added to adjust the pH of the reaction system to 1. Then the same post-treatment steps as in Example 1 were carried out. The product yield was weighed and calculated to be 38.7%, and the purity was 80.5%.

[0159] It can be seen from this comparative example that if acid is not added during the oxidation process, the oxidation rate is slower, the reaction is incomplete, the product yield is lower, and the purity is also poor.

[0160] The above are only specific embodiments of the present invention, enabling those skilled in the art to understand or implement the present invention. Various modifications to these embodiments will be obvious to those skilled in the art. The general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to these embodiments described herein, but will conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for synthesizing an alkyl-substituted diacid compound, characterized in that, Comprising at least the following steps: S1. Using the carboxylic acid ester shown as SM1 and the haloalkene shown as SM2 as raw materials, reacting in the presence of a non-nucleophilic strong base to obtain an enoate compound shown as INT1; S2. Hydrolyzing the enoate compound shown as INT1 under basic conditions to obtain an enoic acid compound shown as INT2; S3. Oxidizing the enoic acid compound shown as INT2 under the action of sulfuric acid and potassium permanganate to obtain an alkyl-substituted diacid compound shown as Formula I; Wherein, R1, R2, and R3 are each independently selected from C1-C6 alkyl; n is an integer from 1 to 12, and X represents a halogen.

2. The synthesis method according to claim 1, wherein R1 and R2 are each independently selected from C1-C3 alkyl; Optionally, R1 and R2 are each independently selected from methyl, ethyl, or propyl; Optionally, n is an integer from 1 to 6; Optionally, X is selected from F, Cl, Br, I.

3. The synthesis method according to claim 1, wherein R1 is methyl, both R2 and R3 are ethyl, n = 1, and X is Br.

4. The synthesis method according to claim 1, characterized in that, In S1, the non-nucleophilic strong base is selected from lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, trityllithium, tritylsodium, tritylpotassium; Optionally, the reaction in S1 is carried out in an organic solvent selected from one of tetrahydrofuran, methyl tert-butyl ether, diethyl ether, diisopropyl ether.

5. The synthesis method according to any one of claims 1 to 4, characterized in that In S1, The molar ratio of SM1 to SM2 is 1:0.8 - 1.2; Optionally, the molar ratio of SM1 to the non-nucleophilic strong base is 1:0.8 - 1.2; Optionally, the reaction temperature is -60°C to -10°C; Optionally, the reaction time is 20 - 40 minutes.

6. The synthesis method according to any one of claims 1 to 4, characterized in that, The hydrolysis reaction in S2 is carried out in the simultaneous presence of an alcohol organic solvent and an aqueous solution of an inorganic base; Optionally, the inorganic base is selected from one of sodium hydroxide and potassium hydroxide; Optionally, the hydrolysis reaction temperature is the reflux temperature; Optionally, the hydrolysis reaction time is 6 - 18 hours.

7. The synthesis method according to claim 6, characterized in that, In S2, the molar ratio of the enoate compound shown as INT1 to the hydroxide ions in the inorganic base is 1:3 - 6; Optionally, the volume ratio of the alcohol organic solvent to the aqueous solution of the inorganic base is 0.8 - 1.2:0.8 - 1.

2.

8. The synthesis method according to any one of claims 1 to 4, characterized in that, In S3, the molar ratio of the enoic acid compound shown as INT2 to sulfuric acid is 1:2 - 4, preferably 2.4 - 3.6; Optionally, the molar ratio of the enoic acid compound shown as INT2 to potassium permanganate is 1:2 - 4, preferably 2.4 - 3.

6.

9. The synthesis method according to any one of claims 1 to 4, characterized in that, In S3, the addition method of potassium permanganate is to continuously or batchwise add solid potassium permanganate or dropwise add a potassium permanganate solution; Optionally, in the method of continuously or batchwise adding solid potassium permanganate, the concentration of sulfuric acid is 1 - 2 mol / L; in the method of dropwise adding a potassium permanganate solution, the concentration of sulfuric acid is 12 - 18 mol / L; Optionally, in S3, when adding potassium permanganate, the reaction temperature in the reaction system is controlled at 20°C to 60°C, preferably 30°C to 50°C; Optionally, in S3, after the oxidation reaction is completed, a post-treatment step is further included, including: filtering the reaction product, washing the obtained filtrate with organic solvent A, extracting with organic solvent B to obtain an organic phase; washing the organic phase with saturated sodium chloride solution and drying to obtain a crude product; the organic solvent A is preferably one or more of n-heptane, n-hexane or petroleum ether; the organic solvent B is preferably one or more of ethyl acetate, n-butanol, n-pentanol.

10. An alkyl-substituted diacid compound product obtained by the synthesis method according to any one of claims 1 to 9.

Images