A process for the preparation of 1,1-cyclobutyl dicarboxylic acid

Abstract

The application belongs to the field of organic synthesis and particularly relates to a preparation method of 1,1-cyclobutyl dicarboxylic acid. The preparation method comprises the following steps: S1. ethyl cyanoacetate is reacted with 1,3-dibromopropane under the action of an alkali catalyst to obtain ethyl 1-cyanocyclobutylcarboxylate; and S2. the ethyl 1-cyanocyclobutylcarboxylate is subjected to a hydrolysis reaction under the action of an acid catalyst or an alkali catalyst to obtain 1,1-cyclobutyl dicarboxylic acid. In the application, ethyl cyanoacetate and 1,3-dibromopropane are used as raw materials, a cycloalkylation reaction occurs under the action of an alkali catalyst, and then the cyano group and the ester group are simultaneously hydrolyzed to obtain the target product. The preparation method of the application is simple in operation, high in yield and low in cost, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 1,1-cyclobutyldicarboxylic acid. Background Technology

[0002] Carboplatin was discovered by Clear et al. in 1980, first marketed in the UK in 1986, and approved by the US FDA in 1989, with its application gradually expanding. my country approved the production of carboplatin powder and injections in 1990. Carboplatin is a second-generation platinum-based antitumor drug with anticancer activity similar to cisplatin, but its nephrotoxicity, ototoxicity, neurotoxicity, and especially gastrointestinal reactions are significantly lower than cisplatin, and its antitumor spectrum is not as broad. Its mechanism of action mainly involves inducing inter- and intra-strand cross-linking of DNA, interfering with DNA molecules, and inhibiting cellular DNA synthesis. It primarily acts on the N-7 and O-6 atoms of guanine in DNA, producing cytotoxic effects. 1,1-Cyclobutyldicarboxylic acid, as an important raw material for carboplatin, has attracted much attention regarding its preparation method.

[0003] Currently, the main method for synthesizing 1,1-cyclobutyldicarboxylic acid is the route disclosed in Chinese invention patent CN112745219A:

[0004] .

[0005] The proposed route first involves the cycloalkylation of diethyl malonate with 1,3-dibromopropane, followed by ester hydrolysis to obtain the target product. However, experiments revealed that the yield and purity of the cycloalkylation reaction under this route did not meet expectations, resulting in a low overall yield. Furthermore, the cycloalkylation reaction under this route requires high levels of moisture and is complex to operate, thus hindering large-scale industrial production. Summary of the Invention

[0006] To address the shortcomings of the existing technology, this invention provides a method for preparing 1,1-cyclobutyldicarboxylic acid. This method is simple to operate, yields a high amount of acid, and is low in cost.

[0007] The specific technical solution is as follows:

[0008] A method for preparing 1,1-cyclobutyldicarboxylic acid includes the following steps:

[0009] S1. Ethyl cyanoacetate was reacted with 1,3-dibromopropane in the presence of an alkaline catalyst to give ethyl 1-cyanocyclobutylcarboxylate;

[0010] S2. 1-Cyanocyclobutylcarboxylic acid ethyl ester is hydrolyzed in the presence of an acid catalyst or a base catalyst to obtain 1,1-cyclobutyldicarboxylic acid.

[0011] In the above preparation method: ethyl cyanoacetate and 1,3-dibromopropane first undergo a cycloalkylation reaction under alkaline catalysis to generate ethyl 1-cyanocyclobutylcarboxylate. The cyano group and ester group of ethyl 1-cyanocyclobutylcarboxylate then undergo hydrolysis simultaneously under acid or alkaline catalysis to generate the target product, 1,1-cyclobutyldicarboxylic acid. The preparation route is as follows:

[0012] .

[0013] Furthermore, in step S1: the base catalyst is an organic base and / or an inorganic base.

[0014] The organic base is at least one of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), sodium methoxide, sodium ethoxide, and potassium tert-butoxide.

[0015] The inorganic base is at least one of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate.

[0016] Furthermore, in step S1: the reaction temperature is 50~60℃; the preferred reaction time is 2~3h.

[0017] Furthermore, in step S1, the molar ratio of 1,3-dibromopropane to ethyl cyanoacetate is preferably 1:(1.0~1.2).

[0018] Furthermore, in step S1, the preferred mass ratio of ethyl cyanoacetate to the base catalyst is 1:(2.0~5.0).

[0019] Further, in step S1: the reaction solvent is at least one selected from N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, ethyl acetate, ethanol, and acetonitrile, preferably N,N-dimethylformamide. The preferred ratio of ethyl cyanoacetate to solvent is 1 g : (5.0~15.0) mL.

[0020] Specifically, in step S1: 1,3-dibromopropane, solvent and base catalyst are mixed and stirred, and then ethyl cyanoacetate is added to carry out the reaction.

[0021] Further, in step S1: after the reaction is completed, distillation and washing with brine are performed. Specifically, after the reaction is completed, the reaction system is first cooled to 30~40℃, filtered, the filter cake is washed with N,N-dimethylformamide, the filtrate is distilled under reduced pressure, the product obtained from distillation is added to a saturated sodium chloride solution, stirred and washed, and after separating the aqueous phase, ethyl 1-cyanocyclobutylcarboxylate is obtained.

[0022] Further, in step S2: the acid catalyst is at least one of hydrochloric acid, hydrobromic acid, and sulfuric acid, preferably hydrochloric acid. Specifically, concentrated hydrochloric acid with a concentration of 20 wt% or more is used, preferably concentrated hydrochloric acid with a concentration of 36 wt% to 38 wt%; the preferred ratio of ethyl cyanoacetate to concentrated hydrochloric acid is 1 g : (1.0 to 3.0) mL.

[0023] Further, in step S2: the alkaline catalyst is at least one selected from sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate, preferably sodium hydroxide. Specifically, a sodium hydroxide solution with a concentration of 20 wt% or higher is used. The preferred ratio of ethyl cyanoacetate to sodium hydroxide solution is 1 g : (3.0~10.0) mL.

[0024] Furthermore, in step S2: the reaction temperature is 80~90℃; the preferred reaction time is 6~18h.

[0025] Further, in step S2: after the reaction is complete, the product is extracted, concentrated, recrystallized, and dried. Specifically, the reaction solution is extracted with an extraction solvent, the organic phase is dried and filtered, the filtrate is concentrated under reduced pressure, a recrystallization solvent is added, the temperature is raised to 80-82℃ and refluxed with stirring for 0.5-1 h, the temperature is lowered to below -5℃ and kept at that temperature with stirring for 0.5-2 h; then filtered, and the filter cake is dried to obtain 1,1-cyclobutyldicarboxylic acid.

[0026] Specifically, in step S2: ethyl 1-cyanocyclobutylcarboxylate undergoes a hydrolysis reaction under the action of an alkaline catalyst. After the reaction is completed, the pH of the reaction solution is adjusted to 0.5~2, and then extracted, concentrated, recrystallized and dried.

[0027] The extraction solvent used in the extraction is at least one of ethyl acetate, methyl isobutyl ketone, dichloromethane, dichloroethane, and methyl tert-butyl ether, preferably methyl isobutyl ketone.

[0028] The recrystallization solvent used in the recrystallization is at least one of acetonitrile, ethyl acetate, methyl tert-butyl ether, dichloromethane, dichloroethane, and methyl isobutyl ketone, preferably acetonitrile.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] This invention uses ethyl cyanoacetate and 1,3-dibromopropane as raw materials, and involves a cycloalkylation reaction under alkaline catalysis, followed by acid or alkaline hydrolysis to obtain the target product. The preparation method of this invention is simple to operate, has a high yield, and is low in cost, making it suitable for industrial production. Attached Figure Description

[0031] Figure 1 The HPLC chromatogram of 1,1-cyclobutyldicarboxylic acid prepared in Example 1 is shown below.

[0032] Figure 2 The HPLC chromatogram of 1,1-cyclobutyldicarboxylic acid prepared in Example 2 is shown. Detailed Implementation

[0033] The embodiments of the present invention will be described in further detail below with reference to the accompanying drawings and examples. The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention. Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0034] Example 1

[0035] The preparation steps of 1,1-cyclobutyldicarboxylic acid are as follows:

[0036] S1. Add 100 g of 1,3-dibromopropane, 500 mL of N,N-dimethylformamide, and 200 g of potassium carbonate to a reaction flask, start stirring, and slowly add 60 g of ethyl cyanoacetate. After the addition is complete, heat to 60 °C and react for 2.5 h. Monitor the reaction for completeness using GC, cool to 40 °C, filter, and wash the filter cake with 100 mL of N,N-dimethylformamide. Distill the filtrate under reduced pressure, add the distilled product to 400 mL of saturated sodium chloride solution, stir and wash, and separate the aqueous phase to obtain ethyl 1-cyanocyclobutylcarboxylate, which can be used directly in the next step.

[0037] S2. Ethyl 1-cyanocyclobutylcarboxylate obtained in step S1 and 100 mL of 37 wt% concentrated hydrochloric acid were added to the reaction flask. Stirring was started, and the mixture was heated to 90 °C and reacted for 12 h. The reaction was monitored by HPLC until complete. The mixture was cooled to room temperature, and the reaction solution was extracted three times with 200 mL of methyl isobutyl ketone. The organic phases were combined, dried over anhydrous sodium sulfate for 0.5 h, filtered, and the filtrate was concentrated under reduced pressure. 100 mL of acetonitrile was added, and the mixture was heated to 82 °C and refluxed with stirring for 0.5 h. The temperature was then slowly lowered to -10 °C and maintained at this temperature with stirring for 1 h. The mixture was filtered, and the filter cake was dried at 50 °C with forced air to obtain 32.8 g of 1,1-cyclobutyldicarboxylic acid. The overall yield of the two steps was 46%, and the purity was 99.6%.

[0038] HPLC analysis confirmed the successful synthesis of 1,1-cyclobutyldicarboxylic acid, as shown in the HPLC chromatogram. Figure 1 As shown in Table 1, the HPLC peak results are as follows.

[0039] Table 1. HPLC peak results of the product from Example 1

[0040]

[0041] Example 2

[0042] The preparation steps of 1,1-cyclobutyldicarboxylic acid are as follows:

[0043] S1. Same as in Example 1.

[0044] S2. Ethyl 1-cyanocyclobutylcarboxylate obtained in step S1 and 300 mL of 25 wt% sodium hydroxide solution were added to the reaction flask. Stirring was started, and the temperature was raised to 90 °C for 8 h. The reaction was monitored by HPLC until complete. The temperature was lowered to room temperature, and the pH of the reaction solution was adjusted to 1 with concentrated hydrochloric acid. The reaction solution was extracted three times with 200 mL of methyl isobutyl ketone. The organic phases were combined, dried over anhydrous sodium sulfate for 0.5 h, filtered, and the filtrate was concentrated under reduced pressure. 100 mL of acetonitrile was added, and the temperature was raised to 82 °C and stirred under reflux for 0.5 h. The temperature was slowly lowered to -10 °C and stirred for 1 h. The mixture was filtered, and the filter cake was dried under blast heat at 50 °C to obtain 32.1 g of 1,1-cyclobutyldicarboxylic acid. The overall yield of the two steps was 45%, and the purity was 99.7%.

[0045] HPLC analysis confirmed the successful synthesis of 1,1-cyclobutyldicarboxylic acid, as shown in the HPLC chromatogram. Figure 2 As shown in Table 2, the HPLC peak results are as follows.

[0046] Table 2. HPLC peak results of the product from Example 2

[0047]

[0048] Example 3

[0049] 1,1-Cyclobutyldicarboxylic acid was prepared according to Example 1, except that the reaction temperature in step S1 was 50°C. Other technical features were the same as in Example 1.

[0050] Example 4

[0051] 1,1-Cyclobutyldicarboxylic acid was prepared according to Example 2, except that the reaction temperature in step S2 was 80°C. Other technical features were the same as in Example 1.

[0052] Comparative Example 1

[0053] The preparation steps of 1,1-cyclobutyldicarboxylic acid are as follows:

[0054] S1. Prepared according to the method disclosed in section

[0057] of the specification published in CN112745219A. The amount of diethyl malonate used is 80 g, and the amounts of other reagents are used in the same proportions according to this method.

[0055] S2. The ester hydrolysis method is the same as step S2 in Example 2.

[0056] The overall yield of the two steps was 40.5%, and the purity was 99.4%.

[0057] The above examples and comparative examples demonstrate that the present invention provides a novel method for preparing 1,1-cyclobutyldicarboxylic acid. Compared with the synthetic routes in the prior art, the preparation method of the present invention has a higher overall yield, lower process requirements, and is more suitable for industrial production.

[0058] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing 1,1-cyclobutyldicarboxylic acid, characterized in that, Includes the following steps: S1. Ethyl cyanoacetate was reacted with 1,3-dibromopropane in the presence of an alkaline catalyst to give ethyl 1-cyanocyclobutylcarboxylate; S2. 1-Cyanocyclobutylcarboxylic acid ethyl ester is hydrolyzed in the presence of an acid catalyst or a base catalyst to obtain 1,1-cyclobutyldicarboxylic acid.

2. The preparation method according to claim 1, characterized in that, In step S1: the base catalyst is an organic base and / or an inorganic base; The organic base is at least one of DBU, sodium methoxide, sodium ethoxide, and potassium tert-butoxide; The inorganic base is at least one of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate.

3. The preparation method according to claim 1, characterized in that, In step S1: the reaction temperature is 50~60℃.

4. The preparation method according to claim 1, characterized in that, In step S1: the reaction solvent is at least one of N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, ethyl acetate, ethanol, and acetonitrile.

5. The preparation method according to claim 1, characterized in that, In step S1: After the reaction is complete, distillation and washing with brine are performed.

6. The preparation method according to claim 1, characterized in that, In step S2: The acid catalyst is at least one of hydrochloric acid, hydrobromic acid, and sulfuric acid; The alkaline catalyst is at least one of sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate.

7. The preparation method according to claim 1, characterized in that, In step S2: the reaction temperature is 80~90℃.

8. The preparation method according to claim 1, characterized in that, In step S2: After the reaction is complete, the product is extracted, concentrated, recrystallized and dried.

9. The preparation method according to claim 8, characterized in that, In step S2: the extraction solvent used in the extraction is at least one of ethyl acetate, methyl isobutyl ketone, dichloromethane, dichloroethane, and methyl tert-butyl ether.

10. The preparation method according to claim 8, characterized in that, In step S2: the recrystallization solvent used in recrystallization is at least one of acetonitrile, ethyl acetate, methyl tert-butyl ether, dichloromethane, dichloroethane, and methyl isobutyl ketone.

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