NEW METHOD FOR SYNTHESIZING 2-FLUOROCYCLOPROPANE CARBOXYLIC ACID

Abstract

Disclosed is a new method for synthesizing 2-fluorocyclopropanecarboxylic acid comprising: 1) performing reaction of 1,1-dichloro-1-fluoroethane with thiophenol in the presence of an alkali, to produce a phenyl sulfide intermediate; 2) performing oxidation reaction of the phenyl sulfide intermediate with Oxone; 3) performing elimination reaction of the product of Step 2) in the presence of an alkali, to obtain 1-fluoro-1-benzenesulfonyl ethylene; 4) performing addition reaction of the 1-fluoro-benzenesulfonyl ethylene with ethyl diazoacetate in the presence of a catalyst, to obtain a cyclopropane intermediate; 5) performing elimination reaction of the cyclopropane intermediate in the presence of an alkali before acidification, to obtain 2-fluorocyclopropanecarboxylic acid. Herein, the synthetic route is short, used materials are bulk commodities, and raw materials are inexpensive and readily available. The process can be safely scaled up by replacing commonly used mCPBA reagents with Oxone. Further, reaction yield is improved, production cost is greatly reduced, and operation is simplified.

Claims

1: A new method for synthesizing 2-fluorocyclopropanecarboxylic acid, comprising the following steps: 1) performing a reaction of 1,1-dichloro-1-fluoroethane with thiophenol in the presence of an alkali, to produce a phenyl sulfide intermediate; 2) performing an oxidation reaction of the phenyl sulfide intermediate with Oxone; 3) performing an elimination reaction of a product obtained in Step 2) in the presence of an alkali, to obtain 1-fluoro-1-benzenesulfonyl ethylene; 4) performing an addition reaction of the 1-fluoro-1-benzenesulfonyl ethylene and ethyl diazoacetate in the presence of a catalyst, to obtain a cyclopropane intermediate; 5) performing an elimination reaction of the cyclopropane intermediate in the presence of an alkali before an acidification, to obtain 2-fluorocyclopropanecarboxylic acid.

2: The new method for synthesizing 2-fluorocyclopropanecarboxylic acid of claim 1, wherein, the alkali of Step 1) is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide, and hydride of an alkali metal or alkaline earth metal.

3: The new method for synthesizing 2-fluorocyclopropanecarboxylic acid of claim 2, wherein, in the step 1), the mass ratio of 1,1-dichloro-1-fluoroethane and thiophenol is (1.1-3.5):1.

4: The new method for synthesizing 2-fluorocyclopropanecarboxylic acid of claim 1, wherein, in the step 2), the mass ratio of the phenyl sulfide intermediate and Oxone is 1:(7-9).

5: The new method for synthesizing 2-fluorocyclopropanecarboxylic acid of claim 1, wherein, the alkali of Step 3) is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide and hydride of an alkali metal or alkaline earth metal, and DBU.

6: The new method for synthesizing 2-fluorocyclopropanecarboxylic acid of claim 5, wherein, in Step 3), the mass ratio of the product obtained in step 2) and the alkali is (1.1-2):1.

7: The new method for synthesizing 2-fluorocyclopropanecarboxylic acid of claim 1, wherein, in Step 4), the mass ratio of 1-fluoro-1-benzenesulfonylethylene and ethyl diazoacetate is (1.1-1.7):1.

8: The new method for synthesizing 2-fluorocyclopropanecarboxylic acid of claim 1, wherein, the catalyst of Step 4) is a rhodium-based catalyst.

9: The new method for synthesizing 2-fluorocyclopropanecarboxylic acid of claim 1, wherein, the alkali of Step 5) is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide, and hydride of an alkali metal or alkaline earth metal.

10: The new method for synthesizing 2-fluorocyclopropanecarboxylic acid of claim 9, wherein, in the step 5), an acid for the acidification is at least one selected from hydrochloric acid, sulfuric acid, nitric acid and perchloric acid.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0038] FIG. 1 is a schematic diagram of a synthesis method according to the present disclosure.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0039] A new method for synthesizing 2-fluorocyclopropane carboxylic acid comprises the following steps:

[0040] 1) performing a reaction of 1,1-dichloro-1-fluoroethane with thiophenol in the presence of an alkali, to produce a phenyl sulfide intermediate;

[0041] 2) performing an oxidation reaction of the phenyl sulfide intermediate with Oxone;

[0042] 3) performing an elimination reaction of the product obtained in Step 2) in the presence of an alkali, to obtain 1-fluoro-1-benzenesulfonyl ethylene;

[0043] 4) performing an addition reaction of 1-fluoro-1-benzenesulfonyl ethylene with ethyl diazoacetate in the presence of a catalyst, to obtain a cyclopropane intermediate;

[0044] 5) performing an elimination reaction of the cyclopropane intermediate in the presence of an alkali before an acidification, to obtain 2-fluorocyclopropanecarboxylic acid.

[0045] FIG. 1 is a schematic diagram of the synthesizing method according to the present disclosure. The schematic diagram is merely an example of the synthesizing method. It shall be appreciated that the method of the present disclosure is not limited to the related materials as shown in FIG. 1.

[0046] Preferably, the alkali of Step 1) is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide, and hydride of an alkali metal or alkaline earth metal. More preferably, the alkali of Step 1) is at least one selected from sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Still more preferably, the alkali of Step 1) is at least one selected from sodium alkoxide, potassium alkoxide, sodium hydroxide and potassium hydroxide. Still more preferably, the alkali of Step 1) is at least one selected from sodium hydroxide and potassium hydroxide.

[0047] Preferably, in Step 1), the mass ratio of 1,1-dichloro-1-fluoroethane and thiophenol is (1.1-3.5):1. More preferably, in Step 1), the mass ratio of 1,1-bischloro-1-fluoroethane and thiophenol is (1.2-3.4):1. Still more preferably, in Step 1), the mass ratio of 1,1-dichloro-1-fluoroethane and thiophenol is (1.3-3.3):1.

[0048] Preferably, in Step 2), the mass ratio of the phenyl sulfide intermediate and Oxone is 1: (7-9). More preferably, in Step 2), the mass ratio of the phenyl sulfide intermediate and Oxone is 1: (7.2-8.8). More preferably, in Step 2), the mass ratio of the phenyl sulfide intermediate and Oxone is 1:(7.4-8.6). Still more preferably, in Step 2), the mass ratio of the phenyl sulfide intermediate and Oxone is 1: (7.6-8.4).

[0049] Preferably, the alkali of Step 3) is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide, and hydride of an alkali metal or alkaline earth metal and DBU. More preferably, the alkali of Step 3) is at least one selected from sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and DBU. More preferably, the alkali of Step 3) is at least one selected from sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, and DBU. Still more preferably, the alkali of Step 3) is at least one selected from potassium t-butoxide, potassium hydroxide, and DBU.

[0050] Preferably, in step 3), the mass ratio of the product obtained in step 2) and the alkali is (1.1-2):1. More preferably, in step 3), the mass ratio of the product obtained in Step 2) and the alkali is (1.2-1.9):1. Still more preferably, in step 3), the mass ratio of the product obtained in Step 2) and the alkali is (1.3-1.8):1.

[0051] Preferably, the solvent for the reaction of Step 3) is a polar solvent. More preferably, the solvent for the reaction of Step 3) is at least one selected from water, methanol, ethanol, propanol, isopropanol, acetone, tetrahydrofuran, dimethyl sulfoxide. Still more preferably, the solvent for the reaction of Step 3) is at least one selected from water, methanol, and tetrahydrofuran.

[0052] Preferably, in Step 4), the mass ratio of 1-fluoro-1-benzenesulfonylethylene and ethyl diazoacetate is (1.1-1.7):1. More preferably, in Step 4), the mass ratio of 1-fluoro-1-benzenesulfonyl ethylene and ethyl diazoacetate is (1.2-1.6):1. Still more preferably, in Step 4), the mass ratio of 1-fluoro-1-benzenesulfonylethylene and ethyl diazoacetate is (1.3-1.5):1.

[0053] Preferably, the catalyst of Step 4) is a rhodium-based catalyst. More preferably, the catalyst of Step 4) is an organic rhodium catalyst. Still more preferably, the catalyst of Step 4) is a rhodium acetate dimer. Most preferably, the catalyst of Step 4) is a rhodium triphenylacetate dimer.

[0054] Preferably, in Step 4), the mass ratio of the catalyst to 1-fluoro-1-phenylsulfonylethylene is 0.5-1.5%. More preferably, in Step 4), the mass ratio of the catalyst to 1-fluoro-1-phenylsulfonylethylene is 0.8-1.2%. Most preferably, in step 4), the mass ratio of the catalyst to 1-fluoro-1-benzenesulfonylethylene is 1.0%.

[0055] Preferably, the alkali of Step 5) is at least one selected from alkoxide, carbonate, bicarbonate, hydroxide, and hydride of an alkali metal or alkaline earth metal. More preferably, the alkali of Step 5) is at least one selected from sodium alkoxide, potassium alkoxide, magnesium alkoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride. Still more preferably, the alkali of Step 5) is at least one selected from magnesium ethoxide, sodium ethoxide, potassium t-butoxide, sodium hydroxide, and potassium hydroxide. Still more preferably, the alkali of Step 5) is at least one selected from magnesium ethoxide, sodium hydroxide and potassium hydroxide.

[0056] Preferably, in step 5), the acid for the acidification is at least one selected from hydrochloric acid, sulfuric acid, nitric acid and perchloric acid. More preferably, in step 5), the acid for the acidification is at least one selected from hydrochloric acid and sulfuric acid. Most preferably, in step 5), the acid for the acidification is hydrochloric acid.

[0057] Hereinafter the contents of the present disclosure will be explained in further details with reference to specific examples.

EXAMPLE

Example 1 for Step 1

[0058] At room temperature, 10 g of thiophenol was added into 50 mL of methanol, and then 18 g of 40% NaOH solution was gradually added. 32 g of precooled 1, 1-dichloro-1-fluoroethane (Freon 141b) was added into the mixture, followed by stirring intensely overnight at 40-50 C. The reaction solution was cooled to room temperature, and 20 mL of concentrated hydrochloric acid was gradually added. The reaction solution was concentrated, so as to remove most of methanol. Then, it was extracted with ethyl acetate, washed with a saturated sodium carbonate solution, dried, and concentrated, so as to obtain 11 g of a crude product of a phenyl sulfide intermediate (Product 1 as shown in FIG. 1). The yield of the crude product was 59%.

Example 2 for Step 1

[0059] In an ice bath, 15 g of thiophenol, 20 g of 1,1-dichloro-1-fluoroethane, and 1.5 g of triethyl benzyl ammonium chloride were added into 100 mL of a toluene solution. After stirring, 80 mL of 50% sodium hydroxide solution was gradually added, followed by stirring intensely overnight at room temperature. The reaction solution was extracted twice with toluene. The separated organic phase was washed with saturated sodium bicarbonate, dried, and concentrated, so as to obtain 20 g of a crude product of a phenylene sulfide intermediate (Product 1 as shown in FIG. 1). The yield of the crude product was 71%.

Example 1 for Step 2

[0060] 117 g of Oxone was added into 175 mL water at room temperature. The reaction solution was cooled to 0 C., and then 14 g of the crude phenyl sulfide intermediate in methanol (175 mL) was gradually added. The temperature of the reaction solution was slowly increased to room temperature, followed by stirring overnight. It was concentrated so as to remove methanol. The reaction solution was extracted twice with 200 mL of dichloromethane. The organic phase was washed with saturated brine, dried and concentrated to give 18 g of a yellow oily product (Product 2 as shown in FIG. 1).

Example 2 for Step 2

[0061] 115 g of Oxone was added into 85 mL water at room temperature. The reaction solution was cooled to 0 C. and then 15 g of the crude phenyl sulfide intermediate in methanol (85 mL) was gradually added. The temperature of the reaction solution was slowly increased to room temperature, followed by stirring overnight. The reaction solution was filtered with diatomite. The filtrate was concentrated to remove methanol, and then the reaction solution was extracted twice with 200 mL of dichloromethane. The organic phase was washed with brine, dried and concentrated to give 16 g of a yellow oily product (Product 2 as shown in FIG. 1).

Example 1 for Step 3

[0062] 11 g of potassium t-butoxide was dissolved in 100 mL of THF and cooled to 0 C. 15 g of the yellow oily product obtained in Step 2) was dissolved in 50 mL of THF and gradually added dropwise into the potassium t-butoxide solution. The temperature of the reaction solution was slowly increased to room temperature, followed by heating reflux overnight. After cooling, 200 mL of a saturated ammonium chloride solution was added and then concentrated to remove a part of THF. The reaction solution was extracted twice with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate, dried, concentrated, followed by crystallization with n-hexane, so as to give 12 g of a light brown solid (Product 3 as shown in FIG. 1).

Example 2 for Step 3

[0063] 16 g of potassium hydroxide was dissolved in 12 mL of water and stirred for 0.5 h. Then, 12 g of methanol was gradually added. After stirring, 26 g of the yellow oily product obtained in Step 2) was added into the reaction solution. Then, the reaction solution was heated to 90 C. and hold for 3 hours, and then was cooled to room temperature. The reaction solution was extracted three times with methyl t-butyl ether. The organic phase was washed with saturated brine, dried, and concentrated, followed by crystallization with n-hexane, so as to give 18 g of a light brown solid (Product 3 as shown in FIG. 1).

Example for Step 4

[0064] 17 g of the product obtained in Step 3) and 0.17 g of a rhodium triphenylacetate dimer catalyst were dissolved in 50 mL of methylene chloride, and then 12 g of ethyl diazoacetate in dichloromethane (40 mL) was gradually added dropwise. After stirring for 2 hours, the reaction solution was washed with diluted hydrochloric acid and washed with saturated sodium bicarbonate solution. The organic phase was concentrated to give 35 g of an oily product (Product 4 as shown in FIG. 1).

Example for Step 5

[0065] The oily product obtained in Step 4) was dissolved in 50 mL of ethanol and then 6.5 g of magnesium powder and 1 g of mercuric chloride were added. The mixture was stirred overnight and then poured into 50 mL of diluted hydrochloric acid (IN). It was extracted three times with n-hexane, and then the organic phase was dried, filtered and concentrated. The concentrated crude product was added into a solution of 30 mL water and 4 g sodium hydroxide, and stirred for one hour. The reaction solution was acidified with concentrated hydrochloric acid to realize pH=1. It was extracted three times with methyl t-butyl ether. The combined organic phases were concentrated, and then 10 mL of isopropyl ether was added, cooled and crystallized, so as to give 6.1 g of a white solid of 2-fluorocyclopropanecarboxylic acid (Product 5 as shown in FIG. 1).