Process for the preparation of 1-fluorocyclopropane carboxylic acid and its use

Abstract

This invention discloses a method for preparing 1-fluorocyclopropionic acid and its application. The preparation method includes the steps of hydrolyzing the 1-fluorocyclopropionic acid ester shown in formula (I) to obtain 1-fluorocyclopropionic acid; wherein R is selected from methyl or ethyl. The preparation method uses readily available raw materials, has a high yield, and low cost, enabling industrial-scale production. This invention also discloses the application of the method for preparing 1-fluorocyclopropionic acid in the preparation of pharmaceuticals.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing 1-fluorocyclopropionic acid and its application. Background Technology

[0002] 1-Fluoro-cyclopropanecarboxylic acid (CAS: 137081-41-5) is an important pharmaceutical intermediate used in the synthesis of VZ185. VZ185 is a highly efficient, rapid, and selective von Hippel-Lindau (VHL)-based dual degradation probe for BRD9 and BRD7, widely used in the development of new inhibitors for tumors, inflammation, metabolic diseases, and neurological disorders; it also has significant value in the development of active compounds such as bactericides. Therefore, 1-Fluoro-cyclopropanecarboxylic acid has a promising market prospect. Its structural formula is as follows.

[0003]

[0004] Most of the reported methods for synthesizing 1-fluorocyclopropionic acid currently suffer from problems such as difficulty in obtaining starting materials or low reaction yields. For example:

[0005] Patent CN110818552A discloses a method for preparing 1-fluorocyclopropionic acid using 1-aminocyclopropionic acid as a raw material. The starting material 1-aminocyclopropionic acid is not easy to obtain, and a large amount of expensive triethylamine trihydrofluoride is required. In addition, a large amount of fluoride-containing wastewater is generated, and the reaction yield is low.

[0006]

[0007] Patent CN107814798A reports a method for preparing 1-fluorocyclopropylcarboxylic acid by oxidation of (1-fluorocyclopropyl)methanol with Jones reagent, but the raw material (1-fluorocyclopropyl)methanol is not easy to obtain.

[0008] US Patent 5126338 discloses a method for preparing 1-fluorocyclopropionic acid from 1-(1-fluoro-cyclopropyl)-ethyl ketone:

[0009]

[0010] The raw material 1-(1-fluoro-cyclopropyl)-ethyl ketone is not readily available. It is known to be prepared by the following three-step reaction, but the reaction path is long and the yield is low.

[0011]

[0012] Existing methods are limited by raw material availability, which hinders their industrial application. Summary of the Invention

[0013] This invention aims to solve at least one of the technical problems existing in the prior art. To this end, this invention proposes a method for preparing 1-fluorocyclopropionic acid, which uses readily available raw materials, has a high reaction yield, and is conducive to industrial production.

[0014] The present invention also proposes the application of the above preparation method.

[0015] The first aspect of this invention relates to a method for preparing 1-fluorocyclopropionic acid, comprising the steps of:

[0016] Hydrolyzing the 1-fluorocyclopropionate ester shown in formula (I) yields 1-fluorocyclopropionate.

[0017]

[0018] R is selected from methyl or ethyl.

[0019] The preparation method of 1-fluorocyclopropionic acid in this embodiment uses 1-fluorocyclopropionic acid ester as the raw material, which can be obtained by one-step condensation reaction. The known method usually uses halobutyrate ester to condense into a ring, and the reaction yield is generally above 80%. Compared with the existing preparation methods of 1-fluorocyclopropionic acid, the raw material of this method is easier to obtain, which is conducive to realizing industrial production.

[0020] 1-Fluorocyclopropanecarboxylic acid is prepared by hydrolysis of 1-fluorocyclopropanecarboxylate. The reaction conditions are mild, the process is simple and easy to implement, and the yield is high (in the specific example, methyl 1-fluorocyclopropanecarboxylate is used for hydrolysis, and the hydrolysis reaction conditions are 30-40℃ / 4h, with a yield of over 86%), which is beneficial for further reducing the preparation cost.

[0021] According to some embodiments of the present invention, the hydrolysis is carried out in the presence of an alkali.

[0022] According to some embodiments of the present invention, the alkali is selected from at least one of sodium hydroxide, potassium hydroxide, or lithium hydroxide.

[0023] According to some embodiments of the present invention, the molar ratio of the base to 1-fluorocyclopropionate is >1:1.

[0024] According to some embodiments of the present invention, the molar ratio of the base to 1-fluorocyclopropionate is 1.1-1.3:1, for example, it can be 1.1:1, 1.2:1, 1.3:1, etc.

[0025] It should be noted that the present invention does not impose any particular limitation on the amount of water added during the hydrolysis process; the appropriate amount of water can be selected by referring to existing similar reactions.

[0026] According to some embodiments of the present invention, the hydrolysis temperature is 0-60°C.

[0027] According to some embodiments of the present invention, the hydrolysis temperature is 30-40°C.

[0028] According to some embodiments of the present invention, the hydrolysis time is 3-5 hours.

[0029] According to some embodiments of the present invention, the process further includes adjusting the pH to 1-5 after the hydrolysis. The product is a carboxylic acid, which dissolves in water as a carboxylate after the reaction. By controlling the final pH, it is made to exist in the form of a free acid, which facilitates product purification.

[0030] Furthermore, the pH is adjusted to 2-3 after the hydrolysis.

[0031] According to some embodiments of the present invention, the pH adjustment is performed using an inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. Further, the inorganic acid can be dilute hydrochloric acid (mass fraction less than 20%).

[0032] According to some embodiments of the present invention, the method further includes a first extraction and a first purification of the reactants. It will be understood that when the preparation method includes a pH adjustment step, the first extraction and the first purification are performed after pH adjustment.

[0033] According to some embodiments of the present invention, the extractant for the first extraction is selected from at least one of dichloromethane, methyl tert-butyl ether, and ethyl acetate.

[0034] According to some embodiments of the present invention, the first extraction is performed multiple times, for example, 2-3 times.

[0035] According to some embodiments of the present invention, in the first extraction, the mass ratio of the extractant to 1-fluorocyclopropionate used in each extraction is 3-4:1. This ratio better ensures extraction efficiency.

[0036] According to some embodiments of the present invention, the first purification method is pulping, recrystallization, or distillation.

[0037] According to some embodiments of the present invention, the first purification method is pulping, and the solvent used is selected from n-heptane, n-hexane, cyclohexane, and petroleum ether.

[0038] According to some embodiments of the present invention, prior to the first purification, the extract phase is further concentrated.

[0039] According to some embodiments of the present invention, the concentration temperature is 50-70°C. The concentration pressure can be selected as atmospheric pressure or negative pressure.

[0040] According to some embodiments of the present invention, the yield of the 1-fluorocyclopropionic acid is >86%.

[0041] According to some embodiments of the present invention, the 1-fluorocyclopropionate is obtained by reacting the cyclopropionate of formula (II) with a fluorinated reagent in the presence of an organolithium and a solvent;

[0042]

[0043] R is selected from methyl or ethyl.

[0044] The above-mentioned method for preparing 1-fluorocyclopropane esters mainly uses methyl cyclopropane (CAS: 2868-37-3) and ethyl cyclopropane (CAS: 4606-07-9) as raw materials, which are both commercially available and have advantages in terms of overall production cost.

[0045] According to some embodiments of the present invention, the organolithium is an aminolithium compound. Aminolithium compounds have suitable activity and are less likely to generate byproducts.

[0046] According to some embodiments of the present invention, the organolithium is selected from hexamethyldisilamide lithium, or prepared by reacting alkyl lithium with an organic amine. When amide lithium compounds are not readily available or easy to store, alkyl lithium and organic amine can be used as raw materials to form amide lithium compounds in situ. After modification with organic amine, the activity of alkyl lithium is reduced, which can reduce the generation of by-products.

[0047] According to some embodiments of the present invention, the alkyl lithium is selected from at least one of n-butyllithium, n-hexyllithium, and n-octyllithium.

[0048] According to some embodiments of the present invention, the organic amine is selected from at least one of diethylamine, diisopropylamine, and hexamethyldisilamine.

[0049] According to some embodiments of the present invention, the molar ratio of the organic amine to alkyl lithium is >1:1.

[0050] According to some embodiments of the present invention, the molar ratio of the organic amine to alkyl lithium is >1:1 and ≤1.1:1.

[0051] According to some embodiments of the present invention, the molar ratio of the organic amine to the cyclopropionate is >1:1.

[0052] According to some embodiments of the present invention, the molar ratio of the organic amine to the cyclopropionate is 1.1-1.2:1.

[0053] According to some embodiments of the present invention, the molar ratio of the organolithium to the cyclopropionate is >1:1.

[0054] According to some embodiments of the present invention, the molar ratio of the organolithium to cyclopropionate is 1.05-1.15:1, for example, it can be 1.05:1, 1.1:1, 1.15:1, etc. Controlling the organolithium to be in appropriate excess can reduce costs.

[0055] According to some embodiments of the present invention, the fluorinated reagent is selected from at least one of N-fluorobisbenzenesulfonamide and 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis(tetrafluoroborate) salt (Selectfluor, CAS: 140681-55-6).

[0056] According to some embodiments of the present invention, the molar ratio of the fluorinated reagent to the cyclopropionic acid ester is ≥1:1.

[0057] According to some embodiments of the present invention, the molar ratio of the fluorinated reagent to the cyclopropionic acid ester is 1-1.1:1. By controlling the fluorinated reagent to be in appropriate excess, the cost can be reduced.

[0058] According to some embodiments of the present invention, the solvent is selected from at least one of tetrahydrofuran, dichloromethane, acetonitrile, toluene, and methyl tert-butyl ether.

[0059] It should be noted that the present invention does not limit the amount of solvent used, and the amount of solvent can be selected based on experience.

[0060] According to some embodiments of the present invention, the temperature of the reaction is -50 to 30°C.

[0061] According to some embodiments of the present invention, the reaction temperature after the feeding is completed is 20-30°C, and the reaction time is more than 12 hours.

[0062] According to some embodiments of the present invention, the preparation method of the 1-fluorocyclopropionate is specifically as follows: first, organolithium is dissolved in a solvent, and then cyclopropionate and fluorinated reagent are added sequentially for reaction.

[0063] According to some embodiments of the present invention, the fluorinated reagent is pre-prepared as a solution for addition, which facilitates control of the addition rate and thus regulates the reaction rate. The solvent used can be selected from those types suitable for the reaction process, and there is no limitation on the solution concentration range; a suitable amount of solvent that can dissolve the reagent can be selected.

[0064] According to some embodiments of the present invention, the feeding environment for the cyclopropionic acid ester and the fluorinated reagent is an inert atmosphere. The inert atmosphere may be a nitrogen atmosphere.

[0065] According to some embodiments of the present invention, the feeding temperature of the cyclopropionic acid ester and the fluorinated reagent is -50 to 0°C. Because the reaction is highly exothermic, the fluorinated reagent can be added slowly in batches at the end to control the feeding temperature consistently within the aforementioned low-temperature range, thus avoiding uncontrollable reactions due to excessively high temperatures.

[0066] According to some embodiments of the present invention, after the reaction is completed, the reaction is further quenched with water.

[0067] According to some embodiments of the present invention, the method for preparing the 1-fluorocyclopropionate ester further includes performing a second extraction and a second purification on the reactants.

[0068] According to some embodiments of the present invention, the extractant for the second extraction is selected from at least one of dichloromethane, methyl tert-butyl ether, and ethyl acetate.

[0069] According to some embodiments of the present invention, the second extraction is performed multiple times, for example, 2-3 times.

[0070] According to some embodiments of the present invention, in the second extraction, the mass ratio of the extractant to cyclopropionate used in each extraction is 2-3:1.

[0071] According to some embodiments of the present invention, the second purification method is vacuum distillation.

[0072] According to some embodiments of the present invention, the temperature of the vacuum distillation is 80-90°C and the vacuum degree is 0.05-0.08 MPa.

[0073] According to some embodiments of the present invention, the extraction phase is further washed with water before the second purification.

[0074] According to some embodiments of the present invention, the water washing is followed by concentration.

[0075] According to some embodiments of the present invention, the concentration temperature is controlled at 60-80°C. The concentration pressure can be selected as atmospheric pressure or negative pressure.

[0076] The second aspect of this invention relates to the application of the method for preparing 1-fluorocyclopropionic acid in the preparation of pharmaceuticals.

[0077] It is understood that the drug is prepared using 1-fluorocyclopropionic acid as an intermediate, and the drug may specifically be VZ185.

[0078] Given that the aforementioned embodiments have advantages such as readily available raw materials and high yield in the preparation of the intermediate 1-fluorocyclopropionic acid, using it in the production of related drugs can reduce costs and facilitate the industrial production of related drugs.

[0079] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0080] Figure 1 It is the methyl 1-fluorocyclopropionate prepared in Example 1. 1 HNMR spectrum.

[0081] Figure 2 It is the 1-fluorocyclopropionic acid prepared in Example 1. 1 HNMR spectrum. Detailed Implementation

[0082] The embodiments of the present invention are described in detail below. These embodiments are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Unless otherwise specified, all reagents used are commercially available conventional reagents.

[0083] Example 1

[0084]

[0085] (1) Synthesis of methyl 1-fluorocyclopropionate

[0086] Add hexamethyldisilamide lithium (92.0 g, 0.550 mol) and tetrahydrofuran (200 ml) to a reaction flask, stir, cool to -10°C, purge with nitrogen, add methyl cyclopropionate (50.0 g, 0.499 mol), and maintain the temperature for 20 min. Slowly add N-fluorobis(benzenesulfonamide) (164.0 g, 0.520 mol) in tetrahydrofuran (tetrahydrofuran volume: 450 ml) in 5 batches, controlling the temperature during addition to not exceed 0°C. After addition, reflux at 1- The temperature was slowly increased to room temperature over 2 hours and kept at that temperature overnight (>12 hours). After the reaction was completed, the reaction solution was poured into water to quench the reaction. The solution was extracted twice with 100g of methyl tert-butyl ether (100g*2). The combined organic layers were washed once with water. The solution was concentrated at atmospheric pressure and 60-80℃ until no more liquid flowed out. The solution was then distilled under reduced pressure at 80-90℃ (vacuum degree 0.06Mpa) to obtain methyl 1-fluorocyclopropanecarboxylate (31.2g, 0.264mol), with a yield of 52.9% and a purity of 96%, as a pale yellow liquid. 1 HNMR spectrum as follows Figure 1 As shown.

[0087] (2) Synthesis of 1-fluorocyclopropionic acid

[0088] Methyl 1-fluorocyclopropanecarboxylate (31.2 g, 0.264 mol), water (100 ml), and 32% sodium hydroxide solution (commercially available reagent, 39.4 g, 0.315 mol sodium hydroxide) were added to a reaction flask. The reaction was carried out at 30-40 °C for 4 h. After the reaction, the pH of the reaction solution was adjusted to 2-3 with 15% dilute hydrochloric acid. The solution was extracted three times with 100 g of dichloromethane (100 g * 3). The solution was concentrated at atmospheric pressure and 50-70 °C until no more liquid flowed out, yielding crude 1-fluorocyclopropanecarboxylic acid. The crude product was then slurried with n-heptane to obtain 1-fluorocyclopropanecarboxylic acid (24.2 g, 0.232 mol), with a yield of 88.1% and a purity of 98%, as a white solid. 1 HNMR spectrum as follows Figure 2 As shown.

[0089] Example 2

[0090] (1) Synthesis of methyl 1-fluorocyclopropionate

[0091] Add diisopropylamine (35.4 g, 0.350 mol), tetrahydrofuran (150 ml), and a 2.5 M hexane solution of n-butyllithium (90.0 g, 0.330 mol, a commonly used commercial reagent, sold in solution form) to a reaction flask. Stir, cool to -12°C, and purge with nitrogen. Add methyl cyclopropionate (30.0 g, 0.300 mol) and incubate for 1 hour. Slowly add a tetrahydrofuran solution of N-fluorobis(benzenesulfonamide) (97.8 g, 0.310 mol) in 5 batches, controlling the temperature... During the feeding process, the temperature should not exceed 0℃. After the addition is complete, the temperature should be slowly raised to room temperature within 1-2 hours and kept at that temperature overnight (>12 hours). After the reaction is complete, the reaction solution should be poured into water to quench the reaction. Extract twice with 60g of methyl tert-butyl ether (60g*2). Combine the organic layers and wash once with water. Concentrate at atmospheric pressure and 60-80℃ until no more liquid flows out. Distill under reduced pressure at 80-90℃ (vacuum degree 0.06Mpa) to obtain methyl 1-fluorocyclopropanecarboxylate (17.0g, 0.144mol), with a yield of 48.0% and a purity of 95%, as a pale yellow liquid. 1 HNMR spectrum and Figure 1 similar.

[0092] (2) Synthesis of 1-fluorocyclopropionic acid

[0093] Methyl 1-fluorocyclopropanecarboxylate (17.0 g, 0.144 mol), water (60 ml), and 32% sodium hydroxide solution (commercially available reagent, 21.2 g, 0.170 mol sodium hydroxide) were added to a reaction flask. The reaction was carried out at 30-40 °C for 4 h. After the reaction was complete, the pH of the reaction solution was adjusted to 2-3 with 15% dilute hydrochloric acid. The solution was extracted three times with 60 g of dichloromethane (60 g * 3). The solution was concentrated at atmospheric pressure and 50-70 °C until no more liquid flowed out, yielding crude 1-fluorocyclopropanecarboxylic acid. The crude product was then slurried with n-heptane to obtain 1-fluorocyclopropanecarboxylic acid (12.9 g, 0.124 mol), with a yield of 86.1% and a purity of 98%, as a white solid. 1 HNMR spectrum and Figure 2 similar.

[0094] The present invention has been described in detail above with reference to the embodiments. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A method for preparing 1-fluorocyclopropionic acid, characterized in that, Including the following steps: Hydrolyzing the 1-fluorocyclopropionate ester shown in formula (I) yields 1-fluorocyclopropionic acid; ； The 1-fluorocyclopropionate is obtained by reacting the cyclopropionate of formula (II) with a fluorinated reagent in the presence of organolithium and a solvent; ； Wherein, R is selected from methyl or ethyl; The fluorinated reagent is selected from at least one of N-fluorobisbenzenesulfonamide and 1-chloromethyl-4-fluoro-1,4-diazotized bicyclo[2.2.2]octanebis(tetrafluoroborate) salt; The organolithium is selected from hexamethyldisilamide lithium, or prepared by reacting alkyl lithium with an organic amine; wherein the organic amine is selected from at least one of diethylamine, diisopropylamine, and hexamethyldisilamide; and the alkyl lithium is selected from at least one of n-butyllithium, n-hexyllithium, and n-octyllithium. The hydrolysis is carried out in the presence of an alkali.

2. The method for preparing 1-fluorocyclopropionic acid according to claim 1, characterized in that, The molar ratio of the base to 1-fluorocyclopropionate is >1:1; and optionally, the hydrolysis temperature is 0-60°C.

3. The method for preparing 1-fluorocyclopropionic acid according to claim 1, characterized in that, After hydrolysis, adjust the pH to 1-5.

4. The method for preparing 1-fluorocyclopropionic acid according to claim 1, characterized in that, It also includes a first extraction and a first purification of the hydrolyzed reactants; and optionally, the extractant for the first extraction is selected from at least one of dichloromethane, methyl tert-butyl ether, and ethyl acetate; and optionally, the first purification is carried out by pulping, recrystallization, or distillation.

5. The method for preparing 1-fluorocyclopropionic acid according to claim 1, characterized in that, The molar ratio of the organolithium to cyclopropionate is >1:1; Optionally, the molar ratio of the fluorinated reagent to the cyclopropionate is ≥1:1; Optionally, the solvent is selected from at least one of tetrahydrofuran, dichloromethane, acetonitrile, toluene, and methyl tert-butyl ether.

6. The method for preparing 1-fluorocyclopropionic acid according to claim 1, characterized in that, The molar ratio of the organic amine to alkyl lithium is >1:1; and optionally, the molar ratio of the organic amine to cyclopropionate is >1:

1.

7. The method for preparing 1-fluorocyclopropionic acid according to claim 1, characterized in that, The reaction temperature is -50 to 30°C; and optionally, the reaction temperature after the addition of materials is 20 to 30°C, and the reaction time is more than 12 hours.

8. The method for preparing 1-fluorocyclopropionic acid according to claim 1, characterized in that, It also includes a second extraction and a second purification of the 1-fluorocyclopropane ester obtained from the reaction; and optionally, the extractant for the second extraction is selected from at least one of dichloromethane, methyl tert-butyl ether, and ethyl acetate; and optionally, the second purification is carried out by vacuum distillation.

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