Preparation method of 2, 5-dihydrofuran-3-carboxylic acid tert-butyl ester

Abstract

The 2, 5-dihydrofuran-3-carboxylic acid tert-butyl ester is an important medical intermediate and is widely used for preparing various furan compounds. The invention discloses a preparation method of 2, 5-dihydrofuran-3-carboxylic acid tert-butyl ester, and belongs to the technical field of organic synthesis. The method has the advantages of cheap and easily available raw materials, low cost, simple steps, mild and continuous reaction conditions, relatively low requirements on equipment, and product purity of more than 98.0%, is suitable for large-scale production, and can be widely applied to the field of pharmacy.

Description

Technical Field

[0001] This invention relates to a method for preparing tert-butyl 2,5-dihydrofuran-3-carboxylic acid, belonging to the field of organic synthesis technology. Background Technology

[0002] 2,5-Dihydrofuran-3-carboxylic acid tert-butyl ester is an important pharmaceutical intermediate from which various furan derivatives can be synthesized for new drug development. For example, this compound can be asymmetrically hydrogenated to obtain a chiral 3-carboxyfuran ring, and can be electrophilically added to chiral 3-carboxy-4-amino amino acid furans using chiral amines. It can also be ring-closed to form bridged ring compounds, etc. Summary of the Invention

[0003] This invention provides a method for preparing a niraparib intermediate.

[0004] Commercially available methods for synthesizing tert-butyl 2,5-dihydrofuran-3-carboxylic acid have shortcomings. This invention makes several improvements, such as adding tetrabutylammonium bromide in the second step, which significantly reduces the amount of sodium borohydride used and noticeably increases the reaction rate. The third step replaces the commonly used Mitsunobu reaction, thereby reducing solvent usage, shortening reaction vessel usage time, and simplifying post-processing.

[0005] The specific steps are as follows:

[0006] First step of the ring-closing reaction:

[0007] Ethyl glycolate and tert-butyl acrylate form a furan ring under the action of a strong base sodium hydrogen, yielding intermediate 1.

[0008] The second step is the reduction of the carbonyl group:

[0009] Intermediate 1 is reduced to a hydroxyl group by sodium borohydride. The addition of tetrabutylammonium bromide significantly reduces the amount of sodium borohydride used and substantially increases the reaction rate, yielding intermediate 2.

[0010] The third step is the elimination of the hydroxyl group:

[0011] Intermediate 2 is dissolved in dichloromethane and DMSO, and triethylamine, DMAP, and MsCl are added to eliminate the hydroxyl groups and form double bonds, thereby obtaining the final product.

[0012] Beneficial effects of the invention

[0013] The process route is easy to operate.

[0014] The reactants are cheap and readily available, and the resulting products have high purity. Attached Figure Description

[0015] Figure 1This is a schematic diagram of the color development of a TLC plate after the first step of the ring-closing reaction in this invention;

[0016] Figure 2 This is a schematic diagram of the color development of the TLC plate after the reduction of the carbonyl group in the second step of this invention;

[0017] Figure 3 This is a schematic diagram of the color development of the TLC plate after the elimination of hydroxyl groups in the third step of this invention. Detailed Implementation

[0018] The present invention will be further illustrated below with specific examples. These embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0019] Example 1

[0020] first step

[0021] Add 500L of tetrahydrofuran to a dry 2000L reactor, and purge with nitrogen to replace the nitrogen. Start stirring, cool in an ice-salt bath at 5-10℃, add 24kg of sodium hydroxide in batches, then add 62.4kg of ethyl glycolate dropwise (completed over 5.5 hours), hold for 15 minutes, raise the temperature to 25℃ and hold for 1 hour, raise the temperature to 35-40℃ and hold for 1 hour, cool in an ice bath at 10-15℃, add 500L of LDMSO in batches, and add 92.16kg of tert-butyl acrylate dropwise at 10-15℃ (exothermic and delayed foaming, completed over 9.5 hours), hold for 15 minutes, then slowly raise the temperature to 25-30℃ and hold for 2 hours (the temperature rise should be controlled...). Slowly (continuously releasing gas), prepare dilute hydrochloric acid with 36L concentrated hydrochloric acid and 300L water for later use; under stirring and temperature control at 10-20℃ (ice-salt bath), pump the reaction solution into the prepared dilute hydrochloric acid in batches, add 400L ethyl acetate, stir for 10min, let stand for 1h, separate the upper oil layer, filter the middle emulsion layer, extract the aqueous layer with 100L×2 ethyl acetate, combine the organic phases, wash the oil layer with 200L×2 saturated brine, concentrate at 40℃ under negative pressure to obtain 132kg crude product, proceed directly to the next reaction without purification.

[0022] TLC board reference appendix Figure 1 EA:PE = 1:5, phosphomolybdic acid color development.

[0023] Example 2

[0024] Step 2

[0025] Add 132 kg of intermediate 2 and 500 L of dichloromethane to a clean 1000 L reactor, and start the stirrer.

[0026] Stir, add 250L of water and 1.2kg of tetrabutylammonium bromide, and add 3.24kg of sodium borohydride in batches at 10-20℃. After the addition is complete, keep the mixture at this temperature for 30 minutes. After the reaction is complete, let it stand and separate into layers. Extract the aqueous layer with 100L of dichloromethane three times. Combine the oil layers. Adjust the pH of the oil layer to 4-5 with 1N dilute hydrochloric acid (pH=3 for large-scale production). Then adjust the pH to 7-8 with 100L of saturated sodium bicarbonate aqueous solution. Stir for 15 minutes and let stand for 40 minutes to separate the lower oil layer. Wash the oil layer with 100L of water (pH=7), dry with anhydrous sodium sulfate, and concentrate at 40℃ to obtain 145kg of crude product. Add 290L of petroleum ether and heat to dissolve completely. Cool down to -5℃ and keep warm overnight. Filter to obtain 26kg (wet weight). The product was not completely precipitated, so the mother liquor was retained.

[0027] TLC board reference appendix Figure 2 EA:PE = 1:2, phosphomolybdic acid color development.

[0028] Example 3

[0029] Step 3

[0030] Add 26 kg of intermediate and 130 L of dichloromethane to a 500 L dry reactor, and start stirring.

[0031] After the system is clarified, cool it down by 5-10℃ and add 1.3 kg DMAP and 56.5 kg triethylamine. Slowly add 31.7 kg methanesulfonyl chloride, heat it up to 15-20℃ and keep it at that temperature for 40 h. After the reaction is complete, pour it into 150 L of water, stir for 15 min, let it stand and separate the oil layer. Extract the aqueous layer with DCM 25 L × 3 times, combine the organic phases, wash the oil layer with 37.5 L of water, adjust the pH to 5-6 with 1N dilute hydrochloric acid, separate the lower oil layer, wash with 75 L of water (pH = 7), wash with 75 L of saturated sodium bicarbonate aqueous solution, wash with 75 L of water, dry and concentrate to dryness, dissolve in 400 L of 20% EA / PE solution, filter through silica gel, and repeatedly rinse the silica gel with 20% EA / PE solution (1 kg of crude product consumes 2.7 kg of silica gel and 25 L of solvent). Concentrate the filtrate to dryness and distill to obtain 18.1 kg of product, GC > 98%, HNMR qualified.

[0032] TLC board reference appendix Figure 3 EA:PE = 1:2, phosphomolybdic acid color development.

[0033] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing tert-butyl 2,5-dihydrofuran-3-carboxylic acid, characterized in that, Includes the following steps: First step of the ring-closing reaction: Ethyl glycolate and tert-butyl acrylate form a furan ring under the action of a strong base sodium hydrogen, yielding intermediate 1. The second step is the reduction of the carbonyl group: Intermediate 1 is reduced to a hydroxyl group by sodium borohydride. The addition of tetrabutylammonium bromide significantly reduces the amount of sodium borohydride used and substantially increases the reaction rate, yielding intermediate 2. The third step is the elimination of the hydroxyl group: Intermediate 2 is dissolved in dichloromethane and DMSO, and triethylamine, DMAP, and MsCl are added to eliminate the hydroxyl groups and form double bonds, thereby obtaining the final product.

2. The method for preparing tert-butyl 2,5-dihydrofuran-3-carboxylic acid according to claim 1, characterized in that... The solvent used in the first step, and the method of adding the materials.

3. The method for preparing tert-butyl 2,5-dihydrofuran-3-carboxylic acid according to claim 1, characterized in that... The second step, the reduction of the carbonyl group, involves the addition of tetrabutylammonium bromide, which significantly increases the reaction rate.

4. The method for preparing tert-butyl 2,5-dihydrofuran-3-carboxylic acid according to claim 1, characterized in that... The third step, the elimination of hydroxyl groups, uses MsCl, which simplifies post-processing and facilitates industrial production.

Images