Preparation method of 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one

Abstract

The invention discloses a method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one, comprising the steps of: adding 2-hydroxy-3-oxoglutaric acid to a first solvent, adding a condensing agent, and obtaining 3,5-dioxotetrahydrofuran-2-carboxylic acid; adding 3,5-dioxotetrahydrofuran-2-carboxylic acid and 2-bromo-2,2-ethyl difluoroacetate to a second solvent, and then adding a base to react to obtain 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid; adding 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid to a third solvent, reducing with a reducing agent, and obtaining 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one. The present invention has simple process, easy operation, environmental protection and pollution-free, and is easy to industrial-scale production, and the reaction conditions are mild, the conversion rate is high, and the product quality is good.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one. Background Art

[0002] 3,3-Difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one is an intermediate in the synthesis of gemcitabine, which is a new type of synthetic difluoronucleoside antimetabolite anti-tumor drug. It has been approved for marketing in many countries and is clinically used to treat non-small cell lung cancer and pancreatic cancer. Gemcitabine has low toxicity and a novel mechanism of action. It is a very promising combination chemotherapy drug that can significantly prolong the survival of cancer patients and improve their quality of life.

[0003] The existing disclosed preparation methods of 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one mostly use R-glyceraldehyde acetone as a starting material, first react with ethyl difluorobromoacetate to obtain R-type 2,2-difluoro-3-hydroxy-3-(2,2-dimethyloxy-4-yl) propionate, and then hydrolyze to obtain 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one, wherein R-glyceraldehyde acetone is mostly synthesized from D-mannitol, the route is long and the yield is extremely low, a large amount of raw materials are wasted, resulting in excessively high costs, and the product lacks market competitiveness. Summary of the invention

[0004] The object of the present invention is to provide a method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one to solve the problems raised in the above background technology.

[0005] To achieve the above object, the technical solution adopted by the present invention is: a method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one, comprising the following steps:

[0006] S1) adding 2-hydroxy-3-oxoglutaric acid to a first solvent and adding a condensing agent to obtain 3,5-dioxotetrahydrofuran-2-carboxylic acid;

[0007] S2) adding 3,5-dioxotetrahydrofuran-2-carboxylic acid and ethyl 2-bromo-2,2-difluoroacetate to a second solvent, and then adding a base to react to obtain 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid;

[0008] S3) adding 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid to a third solvent and reducing it with a reducing agent to obtain 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one.

[0009] As a further optimization, the condensing agent in S1 is one or more of CDI, DCC, MNBA, and 2,2'-pyridine disulfide, and the molar ratio of the condensing agent to 2-hydroxy-3-oxoglutaric acid is (1-1.5):1, preferably 1.1:1.

[0010] As a further optimization, the first solvent in S1 is one or more of dichloromethane, tetrahydrofuran, DMF, DMSO, and ethyl acetate, preferably dichloromethane, and the weight ratio of dichloromethane to 2-hydroxy-3-oxoglutaric acid is (1-10):1, and 10:1 can be selected.

[0011] As a further optimization, the molar ratio of ethyl 2-bromo-2,2-difluoroacetate to 3,5-dioxotetrahydrofuran-2-carboxylic acid in S2 is (0.8-1.2):1, and 1:1 can be selected.

[0012] As a further optimization, the base in S2 is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and cesium carbonate, and the molar ratio of the base to 3,5-dioxotetrahydrofuran-2-carboxylic acid is (1-1.5):1, and 1:1 can be selected.

[0013] As a further optimization, the second solvent in S2 is one or more of dichloromethane, tetrahydrofuran, toluene, DMF, and ethyl acetate, preferably toluene or DMF, and the weight ratio of the second solvent to 3,5-dioxotetrahydrofuran-2-carboxylic acid is (1-10):1, and 10:1 can be selected.

[0014] As a further optimization, the third solvent in S3 is methanol or ethanol, and the weight ratio of the third solvent to 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid is (1-10):1, and 10:1 can be selected.

[0015] As a further optimization, the reducing agent in S3 is sodium borohydride-iodine, and the molar ratio of sodium borohydride to 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid is (2-3):1, and 2:1 can be selected; the molar ratio of iodine to 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid is (0.9-1.2):1, and 1:1 can be selected.

[0016] The preparation process of the present invention is as follows:

[0017]

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0019] 1. The process of the present invention is simple, easy to operate, environmentally friendly and pollution-free, safe to operate, and easy to industrial-scale production;

[0020] 2. The reaction conditions of the present invention are mild, the conversion rate is high and the product quality is good. DETAILED DESCRIPTION

[0021] The following are specific embodiments of the present invention, which further describe the technical solutions of the present invention, but the present invention is not limited to these embodiments.

[0022] Example 1

[0023] A method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one comprises the following steps:

[0024] S1) Add 162g of 2-hydroxy-3-oxoglutaric acid and 1.6kg of dichloromethane to a 2L three-necked flask, cool to 0°C, slowly add 178g of CDI under temperature control, raise the temperature to 25°C and react for 2h, detect the end of the reaction, add the reaction solution to water, separate the layers, wash the organic phase with water twice, dry, and evaporate to dryness to obtain 136.8g of 3,5-dioxotetrahydrofuran-2-carboxylic acid;

[0025] S2) 136.8g 3,5-dioxotetrahydrofuran-2-carboxylic acid, 192.7g ethyl 2-bromo-2,2-difluoroacetate, 1.3kg toluene and 100.6g sodium carbonate were added to a 2L three-necked flask, and the temperature was raised to 80°C, and the reaction was kept warm for 10h. After the reaction was completed, the temperature was raised to 110°C and refluxed vigorously for 10h. The disappearance of the intermediate was detected, and the reaction was completed. The reaction solution was cooled to 25°C, the reaction solution was filtered, 1L water was added to the filtrate, and the layers were separated. The aqueous phase was extracted once with 500mL toluene, the organic phases were combined, washed twice with 2L water, washed once with saturated brine, and concentrated to dryness to obtain 140.2g 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid, which was determined to be 98.8% by HPLC;

[0026] S3) Add 140.2 g of 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid and 1.4 kg of methanol to a 2L three-necked flask, control the temperature at 25°C, slowly add 58.9 g of sodium borohydride in batches, wait for all bubbles to disappear after the addition, then add 197.6 g of iodine in batches, react for 6 hours after the addition, detect the end of the reaction, adjust the pH to neutral with 10% hydrochloric acid, dry the methanol at low temperature, extract the aqueous phase with EA, wash the organic layer with water twice, wash once with saturated brine, dry, and evaporate to dryness to obtain 113.9 g of 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one, which was determined to be 98.7% by HPLC.

[0027] Example 2

[0028] A method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one comprises the following steps:

[0029] S1) Add 162g 2-hydroxy-3-oxoglutaric acid and 1.6kg dichloromethane to a 2L three-necked flask, cool to 0°C, slowly add 226.9g DCC under temperature control, raise the temperature to 25°C and react for 2h, detect the end of the reaction, add the reaction solution to water, separate the layers, wash the organic phase with water twice, detect that there is no DCU residue by LC, dry, and evaporate to dryness to obtain 134.3g 3,5-dioxotetrahydrofuran-2-carboxylic acid;

[0030] S2) 134.3g of 3,5-dioxotetrahydrofuran-2-carboxylic acid, 189.1g of ethyl 2-bromo-2,2-difluoroacetate, 1.3kg of toluene and 128.6g of potassium carbonate were added to a 2L three-necked flask, and the temperature was raised to 80°C. The reaction was kept warm for 10h. After the reaction was completed, the temperature was raised to 110°C and refluxed vigorously for 10h. The disappearance of the intermediate was detected, and the reaction was completed. The reaction solution was cooled to 25°C, the reaction solution was filtered, 1L of water was added to the filtrate, the layers were separated, and the aqueous phase was extracted once with 500mL of toluene. The organic phases were combined, washed twice with 2L of water, washed once with saturated brine, and concentrated to dryness to obtain 137.5g of 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid, which was determined to be 99% by HPLC.

[0031] S3) Add 137.5 g of 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid and 1.4 kg of methanol to a 2L three-necked flask, control the temperature at 25°C, slowly add 57.8 g of sodium borohydride in batches, wait for all bubbles to disappear after the addition, then add 192.3 g of iodine in batches, react for 6 hours after the addition, detect the end of the reaction, adjust the pH to neutral with 10% hydrochloric acid, dry the methanol at low temperature, extract the aqueous phase with EA, wash the organic layer with water twice, wash once with saturated brine, dry, and evaporate to dryness to obtain 111.7 g of 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one, which was determined to be 99.3% by HPLC.

[0032] Example 3

[0033] A method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one comprises the following steps:

[0034] S1) Add 162g of 2-hydroxy-3-oxoglutaric acid and 1.6kg of dichloromethane to a 2L three-necked flask, cool to 0°C, slowly add 242.3g of 2,2'-pyridine disulfide under temperature control, raise the temperature to 25°C and react for 2h, detect the end of the reaction, add the reaction solution to water, separate the layers, wash the organic phase with water twice, dry, and evaporate to dryness to obtain 137.2g of 3,5-dioxotetrahydrofuran-2-carboxylic acid;

[0035] S2) 137.2g 3,5-dioxotetrahydrofuran-2-carboxylic acid, 193.2g ethyl 2-bromo-2,2-difluoroacetate, 1.3kg toluene and 131.2g potassium carbonate were added to a 2L three-necked flask, and the temperature was raised to 80°C, and the reaction was kept warm for 10h. After the reaction was completed, the temperature was raised to 110°C and refluxed vigorously for 10h. The intermediate disappeared when the reaction was detected, and the reaction was completed. The reaction solution was cooled to 25°C, the reaction solution was filtered, 1L water was added to the filtrate, and the layers were separated. The aqueous phase was extracted once with 500mL toluene, the organic phases were combined, washed twice with 2L water, washed once with saturated brine, and concentrated to dryness to obtain 136.1g 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid, which was determined to be 99% by HPLC;

[0036] S3) Add 136.1 g of 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid and 1.4 kg of methanol to a 2L three-necked flask, control the temperature at 25°C, slowly add 57.2 g of sodium borohydride in batches, wait for all bubbles to disappear after the addition, then add 190.3 g of iodine in batches, react for 6 hours after the addition, detect the end of the reaction, adjust the pH to neutral with 10% hydrochloric acid, dry the methanol at low temperature, extract the aqueous phase with EA, wash the organic layer with water twice, wash once with saturated brine, dry, and evaporate to dryness to obtain 118.3 g of 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one, which was determined to be 98.9% by HPLC.

[0037] Example 4

[0038] A method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one comprises the following steps:

[0039] S1) Add 162 g of 2-hydroxy-3-oxoglutaric acid and 1.6 kg of dichloromethane to a 2 L three-necked flask, cool to 0°C, slowly add 178.2 g of CDI under temperature control, raise the temperature to 25°C and react for 2 h, detect the end of the reaction, add the reaction solution to water, separate the layers, wash the organic phase with water twice, dry, and evaporate to dryness to obtain 132.2 g of 3,5-dioxotetrahydrofuran-2-carboxylic acid;

[0040] S2) 132.2g 3,5-dioxotetrahydrofuran-2-carboxylic acid, 186.1g ethyl 2-bromo-2,2-difluoroacetate, 1.3kg toluene and 298.2g cesium carbonate were added to a 2L three-necked flask, and the temperature was raised to 80°C, and the reaction was kept warm for 10h. After the reaction was completed, the temperature was raised to 110°C and refluxed vigorously for 10h. The intermediate disappeared when the reaction was detected, and the reaction was completed. The reaction solution was cooled to 25°C, the reaction solution was filtered, 1L water was added to the filtrate, and the layers were separated. The aqueous phase was extracted once with 500mL toluene, the organic phases were combined, washed twice with 2L water, washed once with saturated brine, and concentrated to dryness to obtain 132.4g 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid, which was determined to be 98.6% by HPLC;

[0041] S3) Add 136.1 g of 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid and 1.4 kg of methanol to a 2L three-necked flask, control the temperature at 25°C, slowly add 55.6 g of sodium borohydride in batches, wait for all bubbles to disappear after the addition, then add 185.1 g of iodine in batches, react for 6 hours after the addition, detect the end of the reaction, adjust the pH to neutral with 10% hydrochloric acid, dry the methanol at low temperature, extract the aqueous phase with EA, wash the organic layer with water twice, wash once with saturated brine, dry, and evaporate to dryness to obtain 112.8 g of 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one, which was determined to be 99.1% by HPLC.

[0042] It can be seen from Examples 1 to 4 that the method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one of the present invention has mild reaction conditions and high conversion rate.

[0043] The specific embodiments described herein are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the appended claims.

Claims

1. A method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one, characterized in that: The steps include: S1) adding 2-hydroxy-3-oxoglutaric acid to a first solvent, and adding a condensing agent to obtain 3,5-dioxotetrahydrofuran-2-carboxylic acid, wherein the condensing agent is one or more of CDI, DCC, MNBA, and 2,2'-pyridine disulfide, and the molar ratio of the condensing agent to 2-hydroxy-3-oxoglutaric acid is (1-1.5):1; S2) adding 3,5-dioxotetrahydrofuran-2-carboxylic acid and ethyl 2-bromo-2,2-difluoroacetate to a second solvent, and then adding a base to obtain 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid, wherein the base is one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, and cesium carbonate, and the molar ratio of the base to 3,5-dioxotetrahydrofuran-2-carboxylic acid is (1-1.5):1; S3) adding 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid to a third solvent and reducing it with a reducing agent to obtain 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one, wherein the reducing agent is sodium borohydride-iodine, and the molar ratio of sodium borohydride to 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid is (2-3):1, and the molar ratio of iodine to 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid is (0.9-1.2):

1.

2. The method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one according to claim 1, characterized in that: The molar ratio of the condensing agent to 2-hydroxy-3-oxoglutaric acid in S1 is 1.1:

1.

3. The method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one according to claim 1, characterized in that: The first solvent in S1 is one or more of dichloromethane, tetrahydrofuran, DMF, DMSO, and ethyl acetate, and the weight ratio of the first solvent to 2-hydroxy-3-oxoglutaric acid is (1-10):

1.

4. The method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one according to claim 1, characterized in that: The molar ratio of ethyl 2-bromo-2,2-difluoroacetate to 3,5-dioxotetrahydrofuran-2-carboxylic acid in S2 is (0.8-1.2):

1.

5. The method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one according to claim 1, characterized in that: The molar ratio of ethyl 2-bromo-2,2-difluoroacetate to 3,5-dioxotetrahydrofuran-2-carboxylic acid in S2 is 1:

1.

6. The method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one according to claim 1, characterized in that: The second solvent in S2 is one or more of dichloromethane, tetrahydrofuran, toluene, DMF, and ethyl acetate, and the weight ratio of the second solvent to 3,5-dioxotetrahydrofuran-2-carboxylic acid is (1-10):

1.

7. The method for preparing 3,3-difluoro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one according to claim 1, characterized in that: The third solvent in S3 is methanol or ethanol, and the weight ratio of the third solvent to 4,4-difluoro-3,5-dioxotetrahydrofuran-2-carboxylic acid is (1-10):1.

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