A process for the preparation of (1r,3s)-cyclopentane-1,3-dicarboxylic acid

Abstract

The application relates to a preparation method of (1R, 3S)-cyclopentane-1, 3-dicarboxylic acid. Ozone is used as an oxidant, the reaction condition is mild, a continuous flow mode is adopted, an intermediate state is obtained after a tubular reactor is mixed with gas and liquid, a second section adopts a continuous oxidation mode, a target product reaction liquid is obtained in a full continuous mode, a new process of continuous oxidation synthesis is realized, decomposition of unstable ozone intermediate state is avoided, and the safety risk of temporarily storing the ozone intermediate state solution is avoided. The method implements the requirement of green chemistry. In conclusion, the technical scheme provided by the application has good economic effect, a large amount of waste is avoided, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate synthesis, specifically to a method for preparing (1R,3S)-cyclopentane-1,3-dicarboxylic acid. Background Technology

[0002] (1R,3S)-cyclopentane-1,3-dicarboxylic acid is an important fragment in drug design, and its derivatives have high biological activity and are widely used in the chemical, chemical, and pharmaceutical fields. (1R,3S)-cyclopentane-1,3-dicarboxylic acid itself is also a very important pharmaceutical intermediate, widely used in the synthesis of isoquinoline-corticosteroid conjugates (WO2022232602A1) targeting ocular inflammatory diseases such as ocular surface autoimmune diseases or the ocular manifestations of HIV; autoimmune and inflammatory disease targets such as BTK (WO2016109223A1); and antitumor targets such as KRAS (WO2022111521A1), CDK9 (CN113149996 A), and the JAK family (WO2019239387 A1). In recent years, linking (1R,3S)-cyclopentane-1,3-dicarboxylic acid with specific structures to seek screening drugs with good activity has become one of the hot topics in drug discovery research. Therefore, (1R,3S)-cyclopentane-1,3-dicarboxylic acid is a very promising drug intermediate.

[0003]

[0004] CN116813547A discloses a method for preparing 1,3-cyclopentanedicarboxylic acid from norbornene, using sodium periodate or potassium permanganate as the oxidant and ruthenium as the catalyst. The oxidation byproducts generated in this method are manganese salt solid wastes, and the post-treatment is complex, requiring a series of operations such as filtration, washing, quenching, extraction, concentration, and pulping. The process has a high PMI (Process Quality Index), generates a large amount of waste, and is costly.

[0005]

[0006] The paper "TREK Channel Family Activator with a Well-Defined Structure-Activation Relationship for Pain and Neurogenic Infiammation" (J.Med.Chem.2020,63,3665-3677) describes a method for preparing (1R,3S)-cyclopentane-1,3-dicarboxylic acid via RuCl3 and NaIO4, but the yield of this method was not reported, and the reaction scale was only in the milligram range.

[0007] The paper "Highly Efficient Biocatalytic Desymmetrization of Meso Carbocyclic 1,3-Dicarboxamides: A Versatile Route for Enantiopure 1,3-Disubstituted Cyclohexanes and Cyclopentanes" (Organic Chemistry Frontiers (2019), 6(6), 808-812) reports a method using ozone for the reaction: a stirred solution of norbornene in methanol is cooled to -78°C for the reaction; the reaction scale in this paper is also at the milligram level. Ozone is a green and environmentally friendly oxidant, suitable for industrial production. However, due to the difficulty of using ozone for the reaction and the reaction temperature of -78°C, scale-up production is difficult, and therefore there are no reports of large-scale industrial production. Therefore, it is of great significance to develop a green and environmentally friendly method for the preparation of (1R,3S)-cyclopentane-1,3-dicarboxamides that can achieve industrial-scale production. Summary of the Invention

[0008] Objective of this invention: The objective of this invention is to overcome the problems of cumbersome post-processing and the generation of large amounts of waste, making it unsuitable for industrial production, in the existing processes for preparing (1R,3S)-cyclopentane-1,3-dicarboxylic acid (Compound I). This invention provides an improved method for preparing (1R,3S)-cyclopentane-1,3-dicarboxylic acid (Compound I). This new process uses ozone as the oxidant, with oxygen as the byproduct, achieving a green, waste-free oxidation process for norbornene. Furthermore, the ozone oxidation liquid is directly subjected to a second stage of continuous oxidation, realizing a continuous oxidation synthesis process. The reactor is a tubular reactor, realizing a gas-liquid feed oxidation process, which also facilitates the development of derivative products, making it suitable for industrial production.

[0009] The present invention provides a method for preparing a compound of formula I, comprising the following steps: dissolving a compound of formula II in an organic solvent, using a continuous flow tubular reactor, obtaining an intermediate state under the action of oxidant 1, and then using continuous oxidation under the action of oxidant 2 to generate compound of formula I.

[0010]

[0011] Preferably, the organic solvent is selected from one or more of acetonitrile / water, acetone / water, methanol, acetonitrile, or DCM.

[0012] More preferably, the organic solvent is acetonitrile / water.

[0013] Preferably, the reaction solution prepared by the compound of Formula I and the organic solvent has a mass fraction of 5% to 9%.

[0014] Preferably, the oxidant 1 is ozone.

[0015] Preferably, the oxidant 2 is selected from sodium hypochlorite / Tempo, sodium chlorite, potassium permanganate, or ozone / Tempo.

[0016] More preferably, the oxidant 2 is sodium hypochlorite / Tempo, and the molar ratio of the compound of formula I to sodium hypochlorite is in the range of 1:2 to 3; the amount of Tempo used is 5‰ of the mass of the compound of formula I.

[0017] Preferably, the catalyst is sodium bromide.

[0018] Preferably, the pH adjuster is sodium bicarbonate.

[0019] Preferably, the reaction temperature of the reaction section between the compound of formula I and oxidant 1 is -15 to -5°C, and the reaction temperature of the reaction section between the intermediate product obtained under the action of oxidant 1 and oxidant 2 is 0 to 5°C.

[0020] Beneficial effects

[0021] This invention provides a method for preparing (1R,3S)-cyclopentane-1,3-dicarboxylic acid, using norbornene as a raw material, to generate (1R,3S)-cyclopentane-1,3-dicarboxylic acid (compound I) under the action of ozone. Compared with existing synthesis processes, the new process adopts a continuous flow reaction mode, solving the problems of difficult operation and cumbersome post-processing in the original synthesis route. Furthermore, this synthesis process avoids the use of hazardous oxidants: using ozone as the oxidant and oxygen as the byproduct, it achieves a green, byproduct-free, and solid waste-free norbornene oxidation process. The reaction conditions are mild, eliminating the need for a -78°C low-temperature reaction condition. The ozone oxidation liquid is directly subjected to a second stage of continuous oxidation, realizing a continuous oxidation synthesis process, avoiding the decomposition of unstable ozone intermediates and the safety risks of temporarily storing ozone intermediate solutions. The reactor is a tubular reactor, realizing a gas-liquid feed oxidation process. This method implements the requirements of green chemistry, can improve production capacity, and maintains a yield of approximately 70%. In summary, the technical solution provided by this invention has good economic benefits, reduces production costs, and is suitable for industrial production. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings in the following description are some embodiments of the present invention.

[0023] Figure 1This is a diagram of the continuous reaction apparatus used in this invention. Detailed Implementation

[0024] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are implemented under the premise of the technical solution of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0025] Example 1

[0026]

[0027] Reaction: Norbornene (20g) was dissolved in a mixed solution of 10% water and 90% acetonitrile, stirred until dissolved, to prepare a 5% (w / w) norbornene feed solution. The ozone generator gas flow rate was set to 800mL / min, the ozone reactor internal temperature to -10~-15℃, and the feed pump flow rate to 10mL / min. Feeding was initiated. GC showed complete reaction of the feed, and the reaction solutions were combined and collected. The internal temperature of the collected reaction solution was controlled at 0-5℃, and sodium bicarbonate (12g), TEMPO (0.1g), and sodium bromide (16g) were added in batches. A 10% sodium hypochlorite aqueous solution (474.4g, 3eq.) was slowly added dropwise while maintaining the temperature. After the addition was complete, the mixture was kept at this temperature and stirred for 2-3 hours. Stirring was stopped when GC showed complete reaction of the ozone intermediate.

[0028] Post-treatment: Sodium bisulfite (5.5 g) was slowly added to the reaction solution in batches. After the addition was complete, the mixture was stirred for 1-2 hours. Then, 36% hydrochloric acid aqueous solution was added to adjust the pH of the reaction solution to about 1. Sodium chloride (7.12 g) was then added to the reaction solution. The mixture was extracted separately with 4V isopropanol. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain 7.83 g of product, with a yield of 70.3%.

[0029] Example 2

[0030]

[0031] Reaction: 1 kg of norbornene was dissolved in a mixed solution of 10% water and 90% acetonitrile, stirred until dissolved, to prepare a 5% (w / w) norbornene feedstock solution. The ozone generator gas flow rate was set to 25-35 L / min, the ozone reactor internal temperature to -10 to -15℃, and the feed pump flow rate to 120-200 mL / min. Feeding began. GC showed complete reaction of the feedstock, and the reaction solutions were combined and collected. The internal temperature of the collected reaction solution was controlled at 0-5℃. Sodium bicarbonate (600 g), TEMPO (5 g), and sodium bromide (800 g) were added in batches, and a 10% sodium hypochlorite aqueous solution (23.72 kg, 3 eq.) was slowly added dropwise while maintaining the temperature. After the addition was complete, the mixture was kept at this temperature and stirred for 2-3 hours. Stirring was stopped when GC showed that the ozone intermediate reaction was complete.

[0032] Post-treatment: Sodium bisulfite (1100g) was slowly added to the reaction solution in batches. After the addition was complete, the mixture was stirred for 1-2 hours. Then, 36% hydrochloric acid aqueous solution was added to adjust the pH of the reaction solution to approximately 1-2. Sodium chloride (120.3g) was then added to the reaction solution. The mixture was extracted separately with 4V isopropanol. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain 1814.11g of product, with a yield of 56.59%.

[0033] Comparative Experiment Example 1

[0034]

[0035]

[0036] Based on the results of the comparative experiment, the purity of the product was extremely low when only ozone was used for the reaction. Therefore, it was believed that other oxidants needed to be added for the reaction, and various oxidants were tried in subsequent experiments.

[0037] Comparative Experiment Example 2

[0038]

[0039] Following the method in Example 1, screening tests were conducted on the reaction reagents and reaction conditions, and the results are shown in Tables 1-3.

[0040] Table 1 Solvent Screening for the Ozone Oxidation Stage

[0041] Serial Number Mass fraction of the solution prepared from compound II solvent Reaction temperature (°C) Central control purity (%) 1 5％ methanol -5 19.30 2 5％ Acetonitrile -5 53.90 3 5％ dichloromethane -5 45.55 4 5％ acetone -5 Pipe blockage 5 5％ Acetonitrile / water -5 89.74 6 5％ Acetone / Water -5 89.20

[0042] Through this screening, the acetonitrile / water mixture was finally determined as the reaction solvent. Since the second-stage oxidation uses sodium chlorite / sodium hypochlorite as oxidants, acetone was excluded as it might be oxidized to carboxylic acid along with the acetone.

[0043] Table 2 shows the optimization and screening of mass fraction conditions for preparing solutions of compounds of formula II.

[0044] Serial Number Mass fraction (%) of the solution prepared from compound II Central control purity (%) 1 5 89.74 2 7 79.51 3 9 53.68

[0045] As the concentration increases, the overall purity of the reaction decreases, therefore 5% wt is preferred.

[0046] Table 3. Optimization and screening of material usage in the sodium hypochlorite system reaction.

[0047] (10% sodium hypochlorite (main oxidant), sodium bicarbonate (to adjust system pH), sodium bromide (catalytic effect), TEMPO (intermediate bridge for oxidation))

[0048]

[0049]

[0050] In summary, the preferred reaction conditions are: 3 eq of sodium hypochlorite, 2.5% (by mass of sodium hypochlorite) of sodium bicarbonate, 0.38 eq of sodium bromide, and 0.5‰ of TEMPO.

[0051] Table 4. Screening of materials used in the post-treatment of the sodium hypochlorite system.

[0052]

[0053] Based on the experimental results, and considering that sodium hypochlorite directly adds acid to produce chlorine gas, sodium bisulfite was used for quenching first.

[0054] As can be seen from the examples, the preferred reaction conditions of this application for (1R,3S)-cyclopentane-1,3-dicarboxylic acid (compound of formula I) have a high reaction conversion rate and a significant reduction in production cost, making them suitable for industrial production.

[0055] While the specific embodiments of the present invention have been described above, they are not intended to limit the scope of protection of the present invention. For those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a compound of formula I, characterized in that... It includes the following steps: Compound II is dissolved in an organic solvent and, using a continuous flow tubular reactor, is given an intermediate state under the action of oxidant 1. Then, through continuous oxidation under the action of oxidant 2, compound I is generated.

2. The preparation method according to claim 1, characterized in that: The organic solvent is selected from one or more of acetonitrile / water, acetone / water, methanol, acetonitrile, or DCM.

3. The preparation method according to claim 1, characterized in that: The organic solvent is acetonitrile / water.

4. The preparation method according to claim 1, characterized in that: The reaction solution prepared by the compound of Formula I with the organic solvent has a mass fraction of 5% to 9%.

5. The preparation method according to claim 1, characterized in that: The oxidant 1 is ozone.

6. The preparation method according to claim 1, characterized in that: The oxidant 2 is selected from one of sodium hypochlorite / Tempo, sodium chlorite, potassium permanganate, or ozone / Tempo.

7. The preparation method according to claim 1, characterized in that: The oxidant 2 is sodium hypochlorite / Tempo, and the molar ratio of the compound of formula I to sodium hypochlorite is in the range of 1:2 to 3; the amount of Tempo used is 5‰ of the mass of the compound of formula I.

8. The preparation method according to claim 1, characterized in that: The catalyst is sodium bromide.

9. The preparation method according to claim 1, characterized in that: The pH adjuster is sodium bicarbonate.

10. The preparation method according to claim 1, characterized in that: The reaction temperature of the compound of formula I with oxidant 1 is -15 to -5℃, and the reaction temperature of the intermediate product obtained under the action of oxidant 1 with oxidant 2 is 0 to 5℃.

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