CN103058903B - Synthesis method for allicin derivative - Google Patents

Abstract

The invention discloses a method for synthesizing allicin derivatives. The allicin derivatives have the following general structural formula: The synthetic method comprises the steps of: As a raw material, proline is used as a catalyst, reacting with hydrogen peroxide in a solvent; wherein: R ¹ and R ² are the same or different, and both are C ₁ -C ₄ alkane groups or C ₂ -C ₄ alkene groups. The synthesis method of the invention has the advantages of mild reaction conditions, simple and convenient operation, high reaction yield, cleanness and environmental protection, etc., is suitable for industrial production requirements, and provides feasibility for the wide popularization and application of the allicin derivatives.

Description

A kind of synthetic method of allicin derivatives

technical field

The invention relates to a synthesis method of allicin derivatives, belonging to the technical field of organic synthesis.

Background technique

Garlic (Alliiridum) is a traditional Chinese edible and medicinal plant. Allicin is an active ingredient extracted and isolated from garlic bulbs. Its structural formula is CH ₂ =CH-CH ₂ -SSS-CH ₂ -CH=CH ₂ , and its chemical name is For diallyl trisulfide. Scientific research results show that allicin has various medical and health care functions, and it has different degrees of inhibition and killing effects on various bacteria, viruses, fungi and other pathogenic microorganisms and tumors. In addition, it also has blood pressure lowering, It has pharmacological activities such as lowering blood fat, lowering blood sugar, improving immunity and anti-oxidation. At present, allicin is mainly used clinically as an antibacterial drug, and has the reputation of a natural broad-spectrum antibiotic, which is suitable for bacterial infections and deep fungal infections. However, allicin has shortcomings such as strong irritation and poor stability, which greatly limits its popularization and application.

At present, domestic and foreign scholars mainly use physical methods such as embedding method and microwave ultrasonic method to reduce the irritation of allicin, but these methods cannot fundamentally solve the problem, and may reduce the pharmacological activity of allicin. Among them, the D-cyclodextrin encapsulation method is recognized as a better method, but there are also problems such as low encapsulation efficiency, unsatisfactory effect, and high cost. Studies have shown that: allicin derivatives with the following general structural formula

It not only has stable properties and no peculiar smell, but also has good disinfection and sterilization effects, which can fundamentally solve the shortcomings of allicin such as strong irritation and poor stability (J.Am.Chem.Soc., 1947, 69, 1710-1713.). But there is a series of problems (J.Am.Chem.Soc., 1949,71 , 3565～3566 and J.Am.Chem.Soc., 1997, 119, 9309～9310 and J.Org.Chem., 1978, 43(13), 2728～2730), are not suitable for industrial production, so that affect the Widespread application of derivatives.

Contents of the invention

Aiming at the above-mentioned problems and defects in the prior art, the present invention provides a method for synthesizing the above-mentioned allicin derivatives with mild preparation conditions, high yield, simple operation, clean and environment-friendly.

For realizing above-mentioned purpose of the invention, the technical scheme that the present invention adopts is as follows:

A kind of synthetic method of allicin derivatives, described allicin derivatives has following general structural formula:

Its synthetic method comprises the following steps: with As a raw material, proline is used as a catalyst, reacting with hydrogen peroxide in a solvent; wherein: R ¹ and R ² are the same or different, and both are C ₁ -C ₄ alkane groups or C ₂ -C ₄ alkene groups.

The synthetic method of described allicin derivatives may also include the following steps: As a raw material, proline is used as a catalyst, under the action of an oxidant, it reacts with hydrogen peroxide in a solvent; wherein: R ¹ and R ² are the same or different, both are C ₁ -C ₄ alkane groups or C ₂ -C ₄ alkenyl group.

Said R ¹ and R ² are preferably the same, and both are preferably methyl, ethyl, propyl, butyl, isopropyl or allyl.

said The molar ratio to hydrogen peroxide is recommended to be 1:1 to 1:5; preferably 1:1 to 1:3.

The reaction temperature is recommended to be 0-60°C; preferably 0-40°C.

The solvent is recommended to be water, ethyl acetate, tetrahydrofuran, methyl tetrahydrofuran, tert-butyl methyl ether, acetonitrile, methylene chloride or 1,2-dichloroethane; preferably water, tert-butyl methyl ether, acetonitrile or 1 , 2-dichloroethane.

The oxidizing agent is recommended to be concentrated sulfuric acid, concentrated nitric acid, chlorine, sodium hypochlorite, peroxy tert-butanol or m-chloroperbenzoic acid; preferably concentrated nitric acid, chlorine, peroxy-tert-butanol or m-chloroperbenzoic acid.

The molar ratio of the oxidizing agent to hydrogen peroxide is recommended to be 0.1:1-0.8:1; preferably 0.2:1-0.5:1.

Compared with the prior art, the synthesis method of the present invention has the advantages of mild reaction conditions, simple and convenient operation, high reaction yield, cleanness and environmental protection, etc., is suitable for industrial production requirements, and provides a good foundation for the wide application of the allicin derivatives. feasibility.

Detailed ways

The present invention will be described in further detail and completely below in conjunction with the embodiments.

Embodiment 1: Methyl methyl thiosulfinate preparation of

Dimethyl disulfide (20g) and L-proline (2g) were dissolved in acetonitrile (10ml), and hydrogen peroxide (30%, 40g) was added dropwise thereto at 0°C; stirred, and the temperature was naturally raised to 25°C, After the reaction is complete, remove acetonitrile under reduced pressure at 20°C; add dichloromethane to extract and separate layers, collect the organic layer, wash with saturated brine, and dry with anhydrous sodium sulfate; concentrate under reduced pressure at 20°C to remove the solvent , the obtained light yellow oily product is 18.7 g of methyl methyl thiosulfinate, the molar yield is 80%, and the HPLC purity is >90%.

Embodiment 2: methyl methyl thiosulfonate preparation of

Dimethyl disulfide (40g) and L-proline (4g) were dissolved in methyl tetrahydrofuran (10ml), and hydrogen peroxide (30%, 150g) was added dropwise thereto at 10°C; stirred and naturally warmed to 30 ℃, after the reaction is complete, remove methyl tetrahydrofuran under reduced pressure at 20°C; add dichloromethane to extract and separate layers, collect the organic layer, wash with saturated brine, and dry with anhydrous sodium sulfate; reduce pressure at 20°C Concentrate and remove the solvent to obtain a light yellow oily product, 46 g of methyl methyl thiosulfonate, with a molar yield of 85% and an HPLC purity of >90%.

Embodiment 3: Ethyl ethyl thiosulfinate preparation of

Diethyl disulfide (100g) and L-proline (5g) were dissolved in 1,2-dichloroethane (40ml), and hydrogen peroxide (30%, 160g) was added dropwise thereto at 10°C; stirred , raised the temperature to 40°C, after the reaction was complete, added dichloromethane to extract and separate the layers, collected the organic layer, washed with saturated brine, and dried with anhydrous sodium sulfate; concentrated under reduced pressure at 20°C, and removed the solvent to obtain The light yellow oily product was 90 g of ethyl thiosulfinate, the molar yield was 80%, and the HPLC purity was >90%.

Embodiment 4: ethyl ethyl thiosulfonate preparation of

Diethyl disulfide (10g) and L-proline (1g) were dissolved in methyl tert-butyl ether (10ml), and hydrogen peroxide (30%, 22g) was added dropwise thereto at 10°C; Add tert-butanol peroxide (6g), and slowly raise the temperature to 60°C. After the reaction is complete, concentrate under reduced pressure at 20°C to remove the solvent; add dichloromethane to extract and separate layers, collect the organic layer, and wash with saturated brine. Dry with anhydrous sodium sulfate; concentrate under reduced pressure at 20°C to remove the solvent, and obtain a light yellow oily product, 10 g of ethyl ethyl thiosulfonate, with a molar yield of 78% and an HPLC purity of >90%.

Embodiment 5: Isopropyl isopropyl thiosulfinate preparation of

Isopropyl disulfide (50g) and L-proline (1g) were dissolved in ethyl acetate (15ml), and hydrogen peroxide (30%, 76g) was added dropwise thereto at 10°C; stirred and heated to 40°C , after the reaction was complete, dichloromethane was added to extract and separate the layers, the organic layer was collected, washed with saturated brine, and dried with anhydrous sodium sulfate; concentrated under reduced pressure at 20°C to remove the solvent, and the obtained light yellow oily product, namely It is 45 g of isopropyl isopropyl thiosulfinate, the molar yield is 82%, and the HPLC purity is >90%.

Embodiment 6: Isopropyl isopropyl thiosulfonate preparation of

Isopropyl disulfide (50g) and L-proline (1g) were dissolved in acetonitrile (15ml), and hydrogen peroxide (30%, 160g) was added dropwise thereto at 10°C; concentrated nitric acid (9g ), slowly warming up to 50°C, after the reaction is complete, concentrate under reduced pressure at 20°C to remove the solvent; add dichloromethane to extract and separate the layers, collect the organic layer, wash with saturated brine, and dry with anhydrous sodium sulfate; Concentrate under reduced pressure at 20°C to remove the solvent, and the obtained light yellow oily product is 47 g of isopropyl isopropylthiosulfonate, with a molar yield of 78% and an HPLC purity of >90%.

Example 7: Allyl Allyl Thiosulfonate preparation of

Diallyl disulfide (10g) and L-proline (1g) were dissolved in water (10ml), and hydrogen peroxide (30%, 22g) was added dropwise thereto at 10°C, stirred, and heated to 50°C, After the reaction was complete, dichloromethane was added to extract the layers, and the organic layer was collected, washed with saturated brine, and dried with anhydrous sodium sulfate; concentrated under reduced pressure at 20°C, and the solvent was removed to obtain a light yellow oily product, namely It is 10 g of allyl thiosulfonate allyl ester, the molar yield is 82%, and the HPLC purity is >90%.

Example 8: Allyl Allyl Thiosulfinate preparation of

Diallyl disulfide (10g) and L-proline (1g) were dissolved in methyl tetrahydrofuran (10ml), hydrogen peroxide (30%, 10g) was added dropwise thereto at 20°C, stirred, and the temperature was raised to 40 ℃, after the reaction was complete, dichloromethane was added to extract and separate the layers, the organic layer was collected, washed with saturated brine, and dried with anhydrous sodium sulfate; concentrated under reduced pressure at 20 ℃ to remove the solvent to obtain a light yellow oily product, That is, 9 g of allyl thiosulfinic acid allyl ester, the molar yield is 80%, and the HPLC purity is >90%.

Example 9: Allyl methylthiosulfinate preparation of

Dissolve methallyl disulfide (20g) and L-proline (1g) in 1,2-dichloroethane (10ml), drop hydrogen peroxide (30%, 43g) therein at 10°C Stir and heat up to 40°C. After the reaction is complete, add dichloromethane to extract and separate layers, collect the organic layer, wash with saturated brine, and dry with anhydrous sodium sulfate; concentrate under reduced pressure at 20°C to remove the solvent to obtain The pale yellow oily product is 19 g of allyl methylthiosulfinate, the molar yield is 85%, and the HPLC purity is >90%.

Embodiment 10: Ethyl methylthiosulfonate preparation of

Methyl ethyl disulfide (20g) and L-proline (1g) were dissolved in acetonitrile (10ml), and hydrogen peroxide (30%, 86g) was added dropwise thereto at 10°C; sodium hypochlorite (46g) was added under stirring ), slowly warming up to 60°C, after the reaction is complete, concentrate under reduced pressure at 20°C to remove the solvent; add dichloromethane to extract and separate layers, collect the organic layer, wash with saturated brine, and dry with anhydrous sodium sulfate; Concentrate under reduced pressure at 20°C, remove the solvent, and obtain a light yellow oily product, 19 g of ethyl methylthiosulfonate, with a molar yield of 75% and an HPLC purity of >90%.

In summary, the allicin derivatives synthesized by the method of the present invention have the advantages of mild reaction conditions, simple operation, high reaction yield, clean and environmental protection, etc., and are suitable for industrial production requirements.

It is necessary to point out here that: the above-mentioned embodiments are only used to further illustrate the present invention, and cannot be interpreted as limiting the protection scope of the present invention, and those skilled in the art make some non-essential improvements and adjustments according to the above-mentioned contents of the present invention All belong to the protection scope of the present invention.

Claims (6)

1. a synthetic method for garlicin analog derivative, described garlicin analog derivative has following general structure:

it is characterized in that, described synthetic method comprise the steps: with for raw material, proline(Pro) is catalyzer, under oxygenant effect, in solvent with hydroperoxidation; Wherein: R ¹with R ²difference, described R ¹for methyl, R ²for ethyl or allyl group;

Described with the mol ratio of hydrogen peroxide be 1:1～1:5;

Described oxygenant and the mol ratio of hydrogen peroxide are 0.1:1～0.8:1;

Described temperature of reaction is 0～60 ℃;

Described solvent is water, ethyl acetate, tetrahydrofuran (THF), methyltetrahydrofuran, t-butyl methyl ether, acetonitrile, methylene dichloride or 1,2-ethylene dichloride;

Described oxygenant is the vitriol oil, concentrated nitric acid, chlorine, clorox, peroxy tert-butyl alcohol or metachloroperbenzoic acid.

2. the synthetic method of garlicin analog derivative according to claim 1, is characterized in that: described with the mol ratio of hydrogen peroxide be 1:1～1:3.

3. the synthetic method of garlicin analog derivative according to claim 1, is characterized in that: described temperature of reaction is 0～40 ℃.

4. the synthetic method of garlicin analog derivative according to claim 1, is characterized in that: described solvent is water, t-butyl methyl ether, acetonitrile or 1,2-ethylene dichloride.

5. the synthetic method of garlicin analog derivative according to claim 1, is characterized in that: described oxygenant is concentrated nitric acid, chlorine, peroxy tert-butyl alcohol or metachloroperbenzoic acid.

6. the synthetic method of garlicin analog derivative according to claim 1, is characterized in that: described oxygenant and the mol ratio of hydrogen peroxide are 0.2:1～0.5:1.