A process for the preparation of ethyl 4-(ethoxycarbonyl)methoxybutanoate

Abstract

The present application relates to the field of C07C organic compound synthesis, and more particularly, the present application provides a preparation process of ethyl (ethoxycarbonyl) ethoxyl butyric acid.The present application takes tert-butyl bromoacetate and 1,4-butanediol as starting materials, and through the process of two-step oxidation and dehydration condensation, an important pharmaceutical intermediate ethyl 4-(ethoxycarbonyl) methoxyl butyric acid is obtained with medium to excellent yield.Compared with the prior art, the preparation process provided by the present application has the advantages of strong operability, safety and no by-products, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention relates to the field of C07C organic compound synthesis, and more specifically, this invention provides a process for preparing ethyl 4-(ethoxycarbonyl)ethoxybutyrate. Background Technology

[0002] As is well known, chain-like organic compounds serve as important building blocks in organic synthesis and pharmaceutical intermediates, used to prepare complex cyclic compounds with potential biological activity. Ethyl 4-(ethoxycarbonyl)ethoxybutyrate, as an important pharmaceutical synthesis intermediate, is a straight-chain organic compound containing two ester groups and an ether bond, and has potential applications in drug synthesis. However, there are few reports on existing methods for preparing ethyl 4-(ethoxycarbonyl)ethoxybutyrate.

[0003] The invention patent with publication number WO2012137982A2 discloses a sulfonamide derivative and its uses. This patent reports a method for synthesizing ethyl 4-(ethoxycarbonyl)methoxybutyrate by stepwise reaction of γ-butyrolactone with compounds such as bromoethane and ethyl diazonium. However, the method disclosed uses ethyl diazonium, which is a flammable, explosive, and highly toxic compound, and is only suitable for milligram-level research and development, thus limiting its practical application in the field of organic synthesis.

[0004] Therefore, providing a safer, more environmentally friendly, simpler, and more efficient synthesis process for ethyl 4-(ethoxycarbonyl)methoxybutyrate is of profound significance in the field of pharmaceutical intermediate preparation. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a process for preparing ethyl 4-(ethoxycarbonyl)methoxybutyrate, comprising the following steps:

[0006] (1) Using tert-butyl bromoacetate and 1,4-butanediol as starting materials, intermediate A was prepared in the presence of alkaline compounds and organic solvents;

[0007] (2) Add a catalyst to intermediate A in step (1) and, in the presence of an oxidant, a redox reaction occurs to obtain 4-tert-butoxycarbonylmethoxybutyric acid.

[0008] (3) Using the 4-tert-butylcarbonylmethoxybutyric acid described in step (2) as a raw material, 4-carbonylmethoxybutyric acid is prepared;

[0009] (4) Add ethanol and thionyl chloride to the 4-carbonylmethoxybutyric acid obtained in step (3) and obtain ethyl 4-(ethoxycarbonyl)methoxybutyric acid by dehydration condensation.

[0010] The structural formula of intermediate A is (1):

[0011] The structural formula of 4-tert-butoxycarbonylmethoxybutyric acid is formula (2):

[0012] The structural formula of 4-carbonylmethoxybutyric acid is formula (3):

[0013] The structural formula of ethyl 4-(ethoxycarbonyl)methoxybutyrate is formula (4):

[0014] As a preferred technical solution of the present invention, the molar ratio of tert-butyl bromoacetate, 1,4-butanediol and basic compound in step (1) is (0.5-1.5):(1.5-2.5):(0.5-1.5).

[0015] As a more preferred technical solution of the present invention, the molar ratio of tert-butyl bromoacetate, 1,4-butanediol and basic compound in step (1) is 1:2:1.1.

[0016] As a preferred technical solution of the present invention, the alkaline compound in step (1) is added in at least 3 portions.

[0017] As a preferred technical solution of the present invention, the alkaline compound in step (1) includes at least one of sodium hydride, sodium hydroxide, lithium hydroxide, and cesium carbonate.

[0018] As a more preferred technical solution of the present invention, the alkaline compound in step (1) is sodium hydride.

[0019] As a preferred technical solution of the present invention, the reaction solvent for preparing intermediate A in step (1) includes at least one of tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, methyl tert-butyl ether, and ethylene glycol dimethyl ether.

[0020] As a more preferred technical solution of the present invention, the reaction solvent for preparing intermediate A in step (1) is tetrahydrofuran.

[0021] As a preferred technical solution of the present invention, the order of adding intermediate A in step (1) is 1,4-butanediol, organic solvent, basic compound, and tert-butyl bromoacetate.

[0022] As a preferred technical solution of the present invention, the addition temperature of the alkaline compound and tert-butyl bromoacetate in step (1) is -10 to 0°C.

[0023] As a more preferred technical solution of the present invention, the addition temperature of the alkaline compound and tert-butyl bromoacetate in step (1) is -5°C.

[0024] As a preferred technical solution of the present invention, the reaction temperature for preparing intermediate A in step (1) is 20-30℃.

[0025] As a more preferred technical solution of the present invention, the reaction temperature for preparing intermediate A in step (1) is 25°C.

[0026] As a preferred technical solution of the present invention, the molar ratio of intermediate A, catalyst and oxidant in step (2) is (0.5-1.5):(0.05-0.01):(1.5-2).

[0027] As a more preferred technical solution of the present invention, the molar ratio of intermediate A, catalyst and oxidant in step (2) is 1:0.07:1.72.

[0028] As a preferred technical solution of the present invention, the raw materials for preparing 4-tert-butoxycarbonylmethoxybutyric acid in step (2) also include a buffer solution.

[0029] As a preferred embodiment of the present invention, the buffer solution is a phosphate buffer solution.

[0030] As a preferred technical solution of the present invention, the catalyst in step (2) is TEMPO.

[0031] As a preferred technical solution of the present invention, the oxidant in step (2) includes at least one of sodium chlorite, sodium hypochlorite, and sodium chlorate.

[0032] As a more preferred technical solution of the present invention, the oxidant in step (2) is sodium chlorite and sodium hypochlorite, and the molar ratio of sodium chlorite and sodium hypochlorite is (1.5-2):(0.01-0.05).

[0033] As a preferred embodiment of the present invention, the molar ratio of sodium chlorite to sodium hypochlorite is 1.7:0.02.

[0034] As a preferred technical solution of the present invention, the reaction solvent for the redox reaction in step (2) includes at least one of acetonitrile, tetrahydrofuran, tert-butanol, dimethyl sulfoxide, and water.

[0035] As a more preferred technical solution of the present invention, the reaction solvent of the redox reaction in step (2) is acetonitrile and water, and the volume ratio of acetonitrile to water is (30-40):(20-30).

[0036] As a preferred embodiment of the present invention, the volume ratio of acetonitrile to water is 35:21.

[0037] As a preferred technical solution of the present invention, the addition temperature of the catalyst and oxidant in step (2) is -5 to 15°C.

[0038] As a more preferred technical solution of the present invention, the addition temperature of the catalyst and oxidant in step (2) is 10°C.

[0039] As a preferred technical solution of the present invention, the raw materials for preparing 4-carbonylmethoxybutyric acid in step (3) also include hydrochloric acid.

[0040] As a preferred technical solution of the present invention, the molar ratio of 4-carbonylmethoxybutyric acid and thionyl chloride in step (4) is (0.5-1.5):(1.5-2.5).

[0041] As a more preferred technical solution of the present invention, the molar ratio of 4-carbonylmethoxybutyric acid and thionyl chloride in step (4) is 1:2.

[0042] As a preferred technical solution of the present invention, the addition temperature of thionyl chloride in step (4) is -5 to 5°C.

[0043] As a more preferred technical solution of the present invention, the addition temperature of thionyl chloride in step (4) is 1°C.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] 1. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate provided by the present invention, when using tert-butyl bromoacetate and 1,4-butanediol as raw materials for preparing intermediate A, the excellent stability of tert-butyl bromoacetate in this system can protect the ester groups in tert-butyl bromoacetate from participating in subsequent reactions, effectively avoiding the generation of by-products, improving the utilization rate of raw materials, saving costs, and enhancing the success rate of synthesizing the target product;

[0046] 2. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate provided by the present invention involves adding TEMPO, phosphate buffer, sodium chlorite and sodium hypochlorite to intermediate A. By strictly controlling the order and temperature of addition, after the reaction is completed, the crude product of 4-tert-butoxycarbonylmethoxybutyric acid is obtained by pH adjustment, extraction and concentration. It can be directly used in the next step of the reaction without further purification. The post-processing is simple and easy to operate, and there are no excessive by-products in the reaction system, which lays a good foundation for the synthesis of 4-carbonylmethoxybutyric acid.

[0047] 3. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate provided by the present invention uses 6 mol / L hydrochloric acid to hydrolyze 4-tert-butoxycarbonylmethoxybutyric acid. On the one hand, this avoids the use of flammable, explosive, and highly corrosive concentrated sulfuric acid and nitric acid, significantly improving the operability and safety of the preparation process; on the other hand, it reduces the production of by-products during the reaction and increases the yield of the target product, 4-carbonylmethoxybutyric acid.

[0048] 4. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate provided by the present invention involves adding thionyl chloride and ethanol to 4-carbonylmethoxybutyric acid and then performing an esterification reaction at 80°C to obtain ethyl 4-(ethoxycarbonyl)methoxybutyrate, an important pharmaceutical intermediate in the pharmaceutical field, with a yield of 84.2%.

[0049] 5. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate provided by the present invention uses tert-butyl bromoacetate and 1,4-butanediol as starting materials for the preparation of ethyl 4-(ethoxycarbonyl)methoxybutyrate. Through multi-step oxidation, hydrolysis and esterification, ethyl 4-(ethoxycarbonyl)methoxybutyrate is obtained. The entire preparation process is highly operable and safe, and at the same time, it does not pollute the environment, does not harm the operators, and no by-products are generated during the reaction. Each raw material has excellent atom utilization rate and is suitable for industrial production. Attached Figure Description

[0050] Figure 1 The 1H NMR spectrum of intermediate A prepared in Example 1. Detailed Implementation

[0051] Example

[0052] Example 1

[0053] Example 1 provides a process for preparing ethyl 4-(ethoxycarbonyl)methoxybutyrate, comprising the following steps:

[0054] (1) Preparation of intermediate A: Under argon protection, 28g of 1,4-butanediol and 250mL of tetrahydrofuran were added sequentially to a 1L three-necked flask. After stirring for 5min, the temperature was lowered to -5℃, and 6.8g of sodium hydride was added in 6 portions over 40min. The temperature was then raised to 25℃ and reacted for 2h. Then, a tetrahydrofuran solution of tert-butyl bromoacetate (30g / 52mL) was slowly added dropwise at -5℃, and the reaction was carried out at 25℃ for 15h. After the reaction was completed, the reaction solution was poured into 300mL of ice water and extracted three times with 300mL of ethyl acetate. The combined organic phase was extracted once with 200mL of saturated sodium chloride aqueous solution. After drying with anhydrous sodium sulfate and concentration, intermediate A was obtained. The GC purity of intermediate A was 97.5%, and the yield was 28.6%.

[0055] (2) Preparation of 4-tert-butoxycarbonylmethoxybutyric acid: At 30°C, 7g of intermediate A and 35mL of acetonitrile were added to a 250mL three-necked flask, stirred for 5min, and then 70mL of phosphate buffer was added. After cooling to 10°C, 0.37g of TEMPO was added. Immediately afterward, 4.2mL of sodium hypochlorite and 6.64g / 21mL of sodium chlorite aqueous solution were slowly added dropwise using two constant pressure dropping funnels. After the addition was completed, the reaction was carried out at 25°C for 12h. The reaction was monitored by TLC. After the reaction was completed, 50g of ice was added to the reaction system, the pH was adjusted to 1.5 with 2mol / L hydrochloric acid, and then extracted three times with 100mL of ethyl acetate. The concentrated 4-tert-butoxycarbonylmethoxybutyric acid was directly used in the next step of the reaction.

[0056] (3) Preparation of 4-carbonylmethoxybutyric acid: 39 mL of 6 mol / L hydrochloric acid was added to 7.8 g of 4-tert-butoxycarbonylmethoxybutyric acid, and the mixture was reacted at 25 °C for 20 h. The reaction was monitored by TLC. After the 4-tert-butoxycarbonylmethoxybutyric acid was completely reacted, the water in the reaction system was concentrated to remove it. 30 mL of ethanol was added, and the organic phase was concentrated. The above operation was repeated 3 times. The obtained 4-carbonylmethoxybutyric acid was directly used in the next step of the reaction.

[0057] (4) Preparation of ethyl 4-(ethoxycarbonyl)methoxybutyrate: At 32℃, 6g of 4-carbonylmethoxybutyric acid and 60mL of ethanol were added sequentially to a 250mL single-necked flask. After stirring for 10min, the temperature was lowered to 1℃, and 8.1g of thionyl chloride was slowly added dropwise. After the addition was completed, the temperature was raised to 80℃ and the reaction was refluxed for 14h. The reaction was detected by TLC. After the 4-carbonylmethoxybutyric acid had reacted completely, the reaction system cooled to room temperature was slowly poured into 100mL of ice water and extracted three times with 50mL of ethyl acetate. The combined organic phase was extracted once with 100mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (gradient elution) using petroleum ether, petroleum ether and ethyl acetate as eluents to obtain 6.3g of the target product ethyl 4-(ethoxycarbonyl)methoxybutyrate.

[0058] In step (4), during the column chromatography purification process, gradient elution is performed sequentially using petroleum ether, a petroleum ether and ethyl acetate eluent with a volume ratio of 10:1, and a petroleum ether and ethyl acetate eluent with a volume ratio of 4:1.

[0059] Comparative Example 1

[0060] The specific implementation method of Comparative Example 1 is the same as that of Example 1, except that the molar ratio of tert-butyl bromoacetate, 1,4-butanediol and sodium hydride in step (1) is 1:2:2.

[0061] Comparative Example 2

[0062] The specific implementation method of Comparative Example 2 is the same as that of Example 1, except that the oxidant in step (2) is sodium chlorite.

[0063] Comparative Example 3

[0064] The specific implementation method of Comparative Example 3 is the same as that of Example 1, except that the molar ratio of 4-carbonylmethoxybutyric acid and thionyl chloride in step (4) is 1:1.5.

[0065] Performance testing

[0066] The yields of intermediate A and ethyl 4-(ethoxycarbonyl)methoxybutyrate obtained in Example 1 and Comparative Examples 1-3 were tested, and the data are shown in Table 1.

[0067] Yield = (Actual mass weighed / Theoretical mass) × 100%

[0068] Table 1

[0069]

[0070]

Claims

1. A preparation process for ethyl 4-(ethoxycarbonyl)methoxybutyrate, characterized in that, Includes the following steps: (1) Using tert-butyl bromoacetate and 1,4-butanediol as starting materials, intermediate A was prepared in the presence of alkaline compounds and organic solvents; (2) Add a catalyst to intermediate A in step (1) and, in the presence of an oxidant, a redox reaction occurs to obtain 4-tert-butoxycarbonylmethoxybutyric acid; (3) Using the 4-tert-butylcarbonylmethoxybutyric acid described in step (2) as a raw material, 4-carbonylmethoxybutyric acid is prepared; (4) Add ethanol and thionyl chloride to the 4-carbonylmethoxybutyric acid described in step (3) and obtain ethyl 4-(ethoxycarbonyl)methoxybutyrate by dehydration condensation; Among them, the structural formula of intermediate A is formula (1): ; The structural formula of 4-tert-butoxycarbonylmethoxybutyric acid is formula (2): ; The structural formula of 4-carbonylmethoxybutyric acid is formula (3): ; The structural formula of ethyl 4-(ethoxycarbonyl)methoxybutyrate is formula (4): ; The raw materials for preparing 4-tert-butoxycarbonylmethoxybutyric acid in step (2) also include a buffer solution, which is a phosphate buffer solution; The catalyst in step (2) is TEMPO; The oxidant in step (2) is sodium chlorite and sodium hypochlorite, and the molar ratio of sodium chlorite to sodium hypochlorite is (1.5-2):(0.01-0.05). The catalyst and oxidant in step (2) are added at a temperature of -5 to 15°C.

2. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate according to claim 1, characterized in that, The molar ratio of tert-butyl bromoacetate, 1,4-butanediol, and the basic compound in step (1) is (0.5-1.5):(1.5-2.5):(0.5-1.5).

3. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate according to claim 1, characterized in that, The alkaline compound in step (1) is added in at least three separate additions.

4. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate according to claim 1, characterized in that, In step (1), the order of adding intermediate A is as follows: 1,4-butanediol, organic solvent, basic compound, and tert-butyl bromoacetate.

5. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate according to claim 1 or 4, characterized in that, The addition temperature of the alkaline compound and tert-butyl bromoacetate in step (1) is -10~0℃.

6. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate according to claim 1, characterized in that, The molar ratio of intermediate A, catalyst and oxidant in step (2) is (0.5-1.5):(0.05-0.01):(1.5-2).

7. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate according to claim 1, characterized in that, The raw materials for preparing 4-carbonylmethoxybutyric acid in step (3) also include hydrochloric acid.

8. The preparation process of ethyl 4-(ethoxycarbonyl)methoxybutyrate according to claim 1, characterized in that, The molar ratio of 4-carbonylmethoxybutyric acid and thionyl chloride in step (4) is (0.5-1.5):(1.5-2.5).

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