A kind of industrial preparation method of high optical purity acetyl tetrahydrofuran

Abstract

The invention discloses an industrial preparation method of acetyl tetrahydrofuran with a high optical purity, and belongs to the field of chemical synthesis. According to the preparation method, tetrahydrofuroic acid is taken as the raw material and then is chlorinated to obtain tetrahydrofuran carbonyl chloride, tetrahydrofuran carbonyl chloride and Meldrum's acid carry out condensation reactions, and reaction product is hydrolyzed to obtain the target compound namely acetyl tetrahydrofuran. The preparation method has the advantages that the raw material cost is low, the preparation method does not need any Grignard reagent, the product property is stable, the purity can reach 98% or more, the optical purity can reach 99% or more, and the yield can reach 70% or more. The method has applied to industrial production. The product quality is stable. The reaction conditions are mild. The operation is safe and reliable. Dichloromethane can be recycled. The technology has the advantages of good repeatability and low preparation cost, and is a reliable industrial production method of acetyl tetrahydrofuran with a high optical purity.

Description

technical field

[0001] The invention relates to the technical field of drug synthesis, in particular to an industrial preparation method of high optical purity acetyl tetrahydrofuran. Background technique

[0002] Acetyl tetrahydrofuran (chemical name: 1-[(2S)-tetrahydro-2-furyl]ethanone, CAS #: 131328-27-3) is a synthetic antibacterial drug Cefovecin and a new carbapenem The key intermediate, the structure is as formula compound (Ia).

[0003]

[0004] At present, there are mainly the following two commonly used preparation methods reported at home and abroad.

[0005] Method 1: U.S. Patent US2003-114693A, using S-2-tetrahydrofurancarbonitrile as the starting material, reacted with methylmagnesium chloride to prepare S-acetyltetrahydrofuran with a yield of 60%.

[0006]

[0007] The method has simple steps, but the reagent S-2-tetrahydrofurancarbonitrile used is expensive and its source is limited, so it is not suitable for large-scale industrialization, and the met...

Examples

Embodiment 1

[0035] A kind of industrial preparation method of high optical purity S-acetyl tetrahydrofuran, comprises the following steps:

[0036] (1) Preparation of S-tetrahydrofuroyl chloride (Ⅲ)

[0037] Add 100 Kg of S-tetrahydrofurancarboxylic acid, 100 Kg of dichloromethane, and 5 Kg of DMF into the dry reaction kettle, slowly suck in 160 Kg of thionyl chloride, keep stirring at 20-30°C for 3 h, and use liquid caustic soda (that is, liquid state Sodium hydroxide) absorption, then warmed up to 50 ℃, concentrated under reduced pressure, when the vacuum no longer increased, pumped in 50 Kg of dichloromethane, and continued to concentrate three times; after concentration, added 270 Kg of dichloromethane, reduced to At room temperature, in barrels for the next reaction, optical purity: 99.3%;

[0038] (2) Preparation of Condensate (II)

[0039] Add 270 Kg of dichloromethane and 132 Kg of isopropylidene malonate to the reaction kettle, stir and cool down to 5-10°C, add 265 Kg of pyridi...

Embodiment 2

[0043] A kind of industrial preparation method of high optical purity S-acetyl tetrahydrofuran, comprises the following steps:

[0044] (1) Preparation of S-tetrahydrofuroyl chloride (Ⅲ)

[0045] Add 100 Kg of S-tetrahydrofurancarboxylic acid, 120 Kg of toluene, and 4 Kg of pyridine into the dry reaction kettle, slowly pump in 200 Kg of phosphorus oxychloride, keep stirring at 20-40°C for 4 h, and use liquid caustic soda (that is, liquid hydrogen Sodium oxide) to absorb, then heat up to 50 °C, concentrate under reduced pressure, when the vacuum no longer increases, pump in 50 Kg of toluene respectively, and continue to concentrate three times; Prepare for the next reaction, optical purity: 99.3%;

[0046] (2) Preparation of Condensate (II)

[0047] Add 270 Kg of toluene and 132 Kg of isopropylidene malonate to the reaction kettle, stir and cool down to 5-10°C, add 255 Kg of triethylamine, after the addition is complete, add the prepared solution dropwise at -5-0°C while cont...

Embodiment 3

[0051] A kind of industrial preparation method of high optical purity R-acetyl tetrahydrofuran, comprises the following steps:

[0052] (1) Preparation of R-tetrahydrofuroyl chloride (Ⅲ)

[0053] Add 100 Kg of R-tetrahydrofurancarboxylic acid, 100 Kg of tetrahydrofuran, and 5 Kg of DMF into the dry reaction kettle, slowly suck in 160 Kg of thionyl chloride, keep stirring at 20-30°C for 3 h, and use liquid caustic soda (that is, liquid hydrogen Sodium Oxide) absorption, and then warmed up to 50 ° C, concentrated under reduced pressure, when the vacuum no longer increased, pumped in 50 Kg of dichloromethane, and continued to concentrate three times. After concentrating, add 270 Kg of tetrahydrofuran, drop to room temperature, and put it in barrels for the next reaction, optical purity: 99.4%;

[0054] (2) Preparation of Condensate (II)

[0055] Add 270 Kg of tetrahydrofuran and 132 Kg of isopropylidene malonate to the reaction kettle, stir and cool down to 5-10°C, add 273 Kg o...

technical field

[0001] The invention relates to the technical field of drug synthesis, in particular to an industrial preparation method of high optical purity acetyl tetrahydrofuran. Background technique

[0002] Acetyl tetrahydrofuran (chemical name: 1-[(2S)-tetrahydro-2-furyl]ethanone, CAS #: 131328-27-3) is a synthetic antibacterial drug Cefovecin and a new carbapenem The key intermediate, the structure is as formula compound (Ia).

[0003]

[0004] At present, there are mainly the following two commonly used preparation methods reported at home and abroad.

[0005] Method 1: U.S. Patent US2003-114693A, using S-2-tetrahydrofurancarbonitrile as the starting material, reacted with methylmagnesium chloride to prepare S-acetyltetrahydrofuran with a yield of 60%.

[0006]

[0007] The method has simple steps, but the reagent S-2-tetrahydrofurancarbonitrile used is expensive and its source is limited, so it is not suitable for large-scale industrialization, and the met...

Examples

Embodiment 1

[0035] A kind of industrial preparation method of high optical purity S-acetyl tetrahydrofuran, comprises the following steps:

[0036] (1) Preparation of S-tetrahydrofuroyl chloride (Ⅲ)

[0037] Add 100 Kg of S-tetrahydrofurancarboxylic acid, 100 Kg of dichloromethane, and 5 Kg of DMF into the dry reaction kettle, slowly suck in 160 Kg of thionyl chloride, keep stirring at 20-30°C for 3 h, and use liquid caustic soda (that is, liquid state Sodium hydroxide) absorption, then warmed up to 50 ℃, concentrated under reduced pressure, when the vacuum no longer increased, pumped in 50 Kg of dichloromethane, and continued to concentrate three times; after concentration, added 270 Kg of dichloromethane, reduced to At room temperature, in barrels for the next reaction, optical purity: 99.3%;

[0038] (2) Preparation of Condensate (II)

[0039] Add 270 Kg of dichloromethane and 132 Kg of isopropylidene malonate to the reaction kettle, stir and cool down to 5-10°C, add 265 Kg of pyridi...

Embodiment 2

[0043] A kind of industrial preparation method of high optical purity S-acetyl tetrahydrofuran, comprises the following steps:

[0044] (1) Preparation of S-tetrahydrofuroyl chloride (Ⅲ)

[0045] Add 100 Kg of S-tetrahydrofurancarboxylic acid, 120 Kg of toluene, and 4 Kg of pyridine into the dry reaction kettle, slowly pump in 200 Kg of phosphorus oxychloride, keep stirring at 20-40°C for 4 h, and use liquid caustic soda (that is, liquid hydrogen Sodium oxide) to absorb, then heat up to 50 °C, concentrate under reduced pressure, when the vacuum no longer increases, pump in 50 Kg of toluene respectively, and continue to concentrate three times; Prepare for the next reaction, optical purity: 99.3%;

[0046] (2) Preparation of Condensate (II)

[0047] Add 270 Kg of toluene and 132 Kg of isopropylidene malonate to the reaction kettle, stir and cool down to 5-10°C, add 255 Kg of triethylamine, after the addition is complete, add the prepared solution dropwise at -5-0°C while cont...

Embodiment 3

[0051] A kind of industrial preparation method of high optical purity R-acetyl tetrahydrofuran, comprises the following steps:

[0052] (1) Preparation of R-tetrahydrofuroyl chloride (Ⅲ)

[0053] Add 100 Kg of R-tetrahydrofurancarboxylic acid, 100 Kg of tetrahydrofuran, and 5 Kg of DMF into the dry reaction kettle, slowly suck in 160 Kg of thionyl chloride, keep stirring at 20-30°C for 3 h, and use liquid caustic soda (that is, liquid hydrogen Sodium Oxide) absorption, and then warmed up to 50 ° C, concentrated under reduced pressure, when the vacuum no longer increased, pumped in 50 Kg of dichloromethane, and continued to concentrate three times. After concentrating, add 270 Kg of tetrahydrofuran, drop to room temperature, and put it in barrels for the next reaction, optical purity: 99.4%;

[0054] (2) Preparation of Condensate (II)

[0055] Add 270 Kg of tetrahydrofuran and 132 Kg of isopropylidene malonate to the reaction kettle, stir and cool down to 5-10°C, add 273 Kg o...

Images