CN104817446B - A kind of preparation method of Fructus Rhodomyrti alkanal - Google Patents

Abstract

The invention discloses a preparation method of myrtle alkanal, which comprises the following steps connected in sequence: A, β-pinene undergoes hydroboration-oxidation reaction to generate myrtanol; B, myrtanol and active Dimethyl sulfoxide undergoes selective oxidation to produce myrtle alkanal. The synthesis method of myrtle alkanal described in the present invention uses β-pinene as a raw material through hydroboration oxidation, high-efficiency synthesis of myrtle alkanol, the yield is greater than 90%, and then through the process of active dimethyl sulfoxide Selective oxidation to prepare myrtle alkanal at room temperature with a yield greater than 80%, and the overall yield of converting the initial raw material β-pinene to myrtle alkanal is greater than 72%. Compared with the existing method, the present invention has cheap and easy-to-obtain reaction raw materials, mild reaction conditions, high product purity and high yield, cheap and easy-to-obtain reaction raw materials, and greatly reduces the preparation cost of myrtle alkanal.

Description

A kind of preparation method of myrtle alkanal

technical field

The invention relates to a preparation method of myrtle alkanal, which belongs to the field of organic synthesis.

Background technique

Myrtle alkanal widely exists in plants such as myrtle, lotus magnolia, and Polygonum spicosa, and has potential antibacterial activity, antiviral activity, and blood pressure lowering effect in mammals. In addition, in the field of organic synthesis, myrtle alkanal is an important precursor compound, and a large number of derivative compounds with potential antibacterial, antiviral or antitumor activities can be synthesized through various reaction pathways.

Currently, various methods for the synthesis of myrtle alkanals have been reported. One of the methods is to synthesize the epoxide of β-pinene through a rearrangement reaction to synthesize myrtle alkanal. This synthesis method is to first synthesize the epoxide of β-pinene with β-pinene, and then catalyze it with Lewis acid. Under the rearrangement reaction, myrtle alkanal is generated. The disadvantage of this method is that the overall yield of myrtle alkanal converted from β-pinene is not high, and the preparation of the catalyst is complicated and difficult to obtain. Another method is to synthesize myrtle alkanal through selective reduction of myrtenal. This reaction process requires selective catalysts such as cuprous and nickel borides to catalyze it. The disadvantage is that myrtenene Aldehydes need to be pre-prepared by other reactions, and catalysts are not readily available. In addition, myrtle alkanal can also be prepared by selective oxidation of myrtle alkanol. It has been reported that ammonium peroxide combined with sodium bromite is used as a selective oxidant to oxidize myrtle alkanol to myrtle alkanal, but the disadvantage is that the oxidant is too expensive and not easy to obtain. Therefore, it is of great importance to develop low-cost, simple and efficient methods for the preparation of myrtle alkanals.

Contents of the invention

In order to solve the defects in the prior art such as complex preparation process of myrtle alkanal, high preparation cost and difficult acquisition of raw materials, the invention provides a preparation method of myrtle alkanal.

In order to solve the problems of the technologies described above, the technical scheme adopted in the present invention is as follows:

A preparation method of myrtle alkanal, comprising the following steps connected in sequence:

A, β-pinene generates myrtanol through hydroboration-oxidation reaction;

B. Selective oxidation reaction of myrtanol and active dimethyl sulfoxide to generate myrtle alkanal.

The molecular structural formula of described myrtle alkanal is:

The reaction equation of above-mentioned preparation method is:

The above preparation method has the advantages of simple reaction process, mild conditions, cheap and easy-to-obtain reaction raw materials, high overall reaction yield, high product purity, etc., and the reaction raw materials are cheap and easy to obtain.

The above-mentioned active dimethyl sulfoxide is an oxidant, and it is preferably a highly active oxidant formed by dimethyl sulfoxide and DCC under the action of acid. In this application, dimethyl sulfoxide will be in a large excess (more than 6 times molar amount), and it will act as a solvent at the same time.

In order to further ensure the mildness of the reaction conditions and improve the product yield, the borohydride reagent in the hydroboration-oxidation reaction in step A is: a mixture of sodium borohydride and boron trifluoride ether, wherein sodium borohydride, trifluoride The molar ratio of boron fluoride ether to β-pinene is (3-4):(4-5):8.

The above-mentioned reaction can be carried out at normal temperature by selecting the hydroboration reagent and its dosage. In order to further ensure the quality and yield of the obtained product, the hydroboration reaction temperature is -10-30° C., and the reaction time is 4-24 hours.

In order to further ensure the mildness of the reaction conditions and improve the product yield, the oxidation reagent in the hydroboration-oxidation reaction in step A is any one of the following two types: the first is sodium perborate tetrahydrate, the second The first is a mixture of sodium hydroxide and hydrogen peroxide; when the oxidizing agent is sodium perborate tetrahydrate, the molar ratio of sodium perborate tetrahydrate to β-pinene is (1～2):1; when the oxidizing agent is hydrogen When the mixture of sodium oxide and hydrogen peroxide is used, the molar ratio of sodium hydroxide, hydrogen peroxide and β-pinene is (0.5～1):(1～2):1.

The above-mentioned selection of oxidizing reagent and dosage can make the reaction be carried out at an environment slightly higher than normal temperature. In order to further ensure the quality and yield of the obtained product, the oxidation reaction temperature is 35-45°C, and the reaction time is 1-3h .

In order to further ensure the yield of the product obtained and the quality of the product obtained, in the preparation method of the above-mentioned myrtle alkanal, step A comprises the following steps:

A1. In the first solvent, mix β-pinene, sodium borohydride and boron trifluoride ether in a molar ratio of 8:(3~4):(4~5), at -10~30°C, React for 4 to 24 hours to obtain dimyrtyl boron, and the first solvent is tetrahydrofuran, diethyl ether, diglyme or cyclohexane;

A2. Any one of the following steps A21 or A22:

A21. Add sodium hydroxide and hydrogen peroxide to the material obtained in step A1, and react at 35-45°C for 1-3 hours to obtain myrtanol, wherein sodium hydroxide, hydrogen peroxide and β-pinene The molar ratio of alkene is (0.5～1):(1～2):1;

A22. Add sodium perborate tetrahydrate to the material obtained in step A1, and react at 35-45°C for 1-3 hours to obtain myrtanol, wherein the molar ratio of sodium perborate tetrahydrate to β-pinene For (1～2):1.

The amount of the above-mentioned first solvent is preferably: 3-5 times the volume of β-pinene.

Preferably, ethanol, water or methanol is added to quench the hydroboration reaction after the reaction in step A1 is completed, and the amount of ethanol, water or methanol is preferably 1/4-1/2 of the mass of β-pinene.

After the above-mentioned step A2 has been reacted, it is preferably purified as follows: add a sufficient amount of saturated aqueous sodium thiosulfate solution to the resulting reaction material to remove excess hydrogen peroxide, then separate liquids, wash with water, and wash with saturated brine, and finally anhydrous sodium sulfate Dry and serve.

In order to further ensure the yield of the obtained product and the quality of the obtained product, while ensuring the mildness of the reaction, in the above-mentioned preparation method of myrtle alkanal, step B is to mix N,N'-bicyclic Mix hexylcarbimide, acid and myrtanol according to the molar ratio of (2~5):(0.125~0.5):1, and react at 20~35°C for 1~24h to obtain myrtane Aldehydes, wherein the second solvent is a mixed solution of dimethyl sulfoxide and benzene, a mixed solution of dimethyl sulfoxide and dichloromethane, or dimethyl sulfoxide.

The hydroboration oxidation reaction of the present application has a high yield ratio. Therefore, after basic extraction and washing, the purity of myrtanol can reach about 96%. Therefore, its molar amount in step B can be accurately confirmed.

In order to further improve the purity of the product obtained, preferably, after the oxidation reaction of the above-mentioned step B is completed, it is preferred to add methanol dissolved in oxalic acid to react for 1.5-3 hours in the reaction system, so that oxalic acid can be mixed with excess DCC (N, N'- Dicyclohexylcarboimide) forms an acid anhydride, and then reacts with methanol to generate methyl oxalate, which converts DCC into DCU, which is insoluble in water and organic solvents and can be removed by filtration.

Preferably, after the above step B reaction is completed, purify according to the following method: filter to remove the white precipitate in the obtained reaction system, pour the filtrate into a sufficient amount of ice water, add ethyl acetate for extraction, separate the liquid, keep the organic phase, and then wash with water , washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and then separated by silica gel column chromatography to obtain myrtle alkanal.

The amount of the second solvent is preferably 6-30 times the molar amount of the myrtol.

In order to further improve the yield and quality of myrtle alkanal, the acid is phosphoric acid, dichloroacetic acid or trifluoroacetic acid.

When the acid is trifluoroacetic acid, it is preferable to add pyridine in an amount 3-5 times the molar amount of trifluoroacetic acid.

The technologies not mentioned in the present invention refer to the prior art.

The synthesis method of myrtle alkanal described in the present invention uses β-pinene as a raw material through hydroboration oxidation, high-efficiency synthesis of myrtle alkanol, the yield is greater than 90%, and then through the process of active dimethyl sulfoxide Selective oxidation to prepare myrtle alkanal at room temperature with a yield greater than 80%, and the overall yield of conversion from the initial raw material β-pinene to myrtle alkanal is greater than 72%. Compared with the existing method, the present invention has cheap and easy-to-obtain reaction raw materials, mild reaction conditions, high product purity (greater than 90%), high yield, low-cost and easy-to-obtain reaction raw materials, and greatly reduces the production rate of myrtle alkanal. preparation cost.

Description of drawings

Fig. 1 is the H NMR spectrogram (A) of embodiment 1 gained myrtanol;

Fig. 2 is the FT-IR spectrogram (B) of embodiment 1 gained myrtanol;

Fig. 3 is the 1H NMR spectrogram (A) of embodiment 4 gained myrtle alkanal;

Fig. 4 is the FT-IR spectrogram (B) of the myrtle alkanal obtained in Example 4.

detailed description

In order to better understand the present invention, the content of the present invention is further illustrated below in conjunction with the examples, but the content of the present invention is not limited to the following examples.

Example 1

Synthesis of myrtanol:

Add 55.3g β-pinene (0.4mol, purity 98.5%), 5.92g sodium borohydride (0.15mol, purity 96%), 28.67g trifluoride Boron ethyl ether solution (0.2mol, purity 46.8-47.8%) and 200mL of tetrahydrofuran were reacted at 0-5°C for 6h to obtain dimyrtyl boron, and the next step reaction was continued without separation; After adding 30mL of ethanol to quench the hydroboration reaction, add 68mL of 3mol/L sodium hydroxide aqueous solution and 60mL of 30% hydrogen peroxide solution successively, and react at 40-45°C for 3h. After the reaction was finished, add sufficient saturated aqueous sodium thiosulfate solution to remove excess hydrogen peroxide, separate liquid, wash with water, wash with saturated saline, dry over anhydrous sodium sulfate, and evaporate the solvent to obtain 57.5 g of myrtle alkanol with a purity of 96.8%, yield 90.3%. Structural characterization: IRv: 3313cm ^-1 (OH), 1041cm ^-1 (CO); ¹ H NMR (300MHz, CDCl ₃ ) δ: ¹ H NMR (300MHz, CDCl ₃ ) δ: 3.55 (dd, J＝7.6, 5.2 Hz,2H),2.44-2.31(m,1H),2.31-2.14(m,1H),2.05-1.97(m,2H),1.98-1.78(m,4H),1.54-1.35(m,1H), 1.19 (s, 3H), 0.97 (s, 3H), 0.93 (d, J = 9.6 Hz, 1H). ESI-MS m/z = 154 [M] ⁺ . Structural characterization proved that the product was myrtanol.

Example 2

Synthesis of myrtanol:

Add 55.3g β-pinene (0.4mol, purity 98.5%), 7.88g sodium borohydride (0.2mol, purity 96%), 28.67g trifluoride Boron ethyl ether solution (0.2mol, purity 46.8-47.8%) and 200mL of tetrahydrofuran were reacted at 5-10°C for 8h to obtain dimyrtyl boron, and the next step reaction was continued without separation; After adding 30mL of ethanol to quench the hydroboration reaction, add 92mL of 3mol/L sodium hydroxide aqueous solution and 90mL of 30% hydrogen peroxide solution successively, and react at 40-45°C for 3h. After the reaction was finished, add sufficient saturated aqueous sodium thiosulfate solution to remove excess hydrogen peroxide, separate liquid, wash with water, wash with saturated saline, dry over anhydrous sodium sulfate, and evaporate the solvent to obtain 57.9 g of myrtle alkanol with a purity of 96.1%, yield 90.2%. Structural characterization: IRv: 3313cm ^-1 (OH), 1041cm ^-1 (CO); ¹ H NMR (300MHz, CDCl ₃ ) δ: ¹ H NMR (300MHz, CDCl ₃ ) δ: 3.55 (dd, J＝7.6, 5.2 Hz,2H),2.44-2.31(m,1H),2.31-2.14(m,1H),2.05-1.97(m,2H),1.98-1.78(m,4H),1.54-1.35(m,1H), 1.19 (s, 3H), 0.97 (s, 3H), 0.93 (d, J = 9.6 Hz, 1H). ESI-MS m/z = 154 [M] ⁺ . Structural characterization proved that the product was myrtanol.

Example 3

Synthesis of myrtanol:

Add 55.3g β-pinene (0.4mol, purity 98.5%), 5.92g sodium borohydride (0.15mol, purity 96%), 28.67g trifluoride Boron ethyl ether solution (0.2mol, purity 46.8-47.8%) and 200mL of tetrahydrofuran were reacted at 0-5°C for 6h to obtain dimyrtyl boron, and the next step reaction was continued without separation; After adding 30 mL of ethanol to quench the hydroboration reaction, add 63.4 g of sodium perborate tetrahydrate (0.4 mol, purity 97%), and react at 30-35° C. for 3 h. After the reaction, add enough saturated aqueous sodium thiosulfate solution to remove excess hydrogen peroxide, separate liquid, wash with water, wash with saturated saline, dry over anhydrous sodium sulfate, and evaporate the solvent to obtain 58.1 g of myrtle alkanol with a purity of 96.7 %, yield 91.1%. Structural characterization: IRv: 3313cm ^-1 (OH), 1041cm ^-1 (CO); ¹ H NMR (300MHz, CDCl ₃ ) δ: ¹ H NMR (300MHz, CDCl ₃ ) δ: 3.55 (dd, J＝7.6, 5.2 Hz,2H),2.44-2.31(m,1H),2.31-2.14(m,1H),2.05-1.97(m,2H),1.98-1.78(m,4H),1.54-1.35(m,1H), 1.19 (s, 3H), 0.97 (s, 3H), 0.93 (d, J = 9.6 Hz, 1H). ESI-MS m/z = 154 [M] ⁺ . Structural characterization proved that the product was myrtanol.

Example 4

Synthesis of myrtle alkanals:

Add 0.798g myrtanol (obtained in Example 1, 5mmol, purity 96.8%), 3.258g N,N'-dicyclohexylcarbodiethylene Amine (15mmol, purity 95%), 0.144g phosphoric acid (1.25mmol, purity 85%) and dimethyl sulfoxide 20mL, react at 25°C for 15h, add 1.261g oxalic acid (pre-dissolved in 10mL methanol), stop after 2h reaction. After removing the white precipitate in the system by filtration, pour the filtrate into a sufficient amount of ice water, add ethyl acetate to extract, separate the liquid, keep the organic phase, wash with water, wash with saturated saline, dry over anhydrous sodium sulfate, and evaporate the solvent to obtain The crude product of myrtle alkanal was separated by silica gel column chromatography to obtain 0.678 g of myrtle alkanal with a purity of 90.3% and a yield of 80.1%. Structural characterization: IR v: 2806cm ^-1 , 2700cm ^-1 (HC=O), 1719cm ^-1 (C=O); ¹ H NMR (500MHz, CDCl ₃ ) δ: 9.77(s,1H), 2.75(dd, J=10.3,3.4Hz,1H),2.55(d,J=7.2Hz,1H),1.97-1.84(m,6H),1.34(d,J=4.6Hz,1H),1.22(s,3H), 0.72(s,3H).ESI-MS m/z=152[M] ⁺ . Structural characterization proves that the product is myrtle alkanal.

Example 5

Synthesis of myrtle alkanals:

Add 0.798g myrtanol (obtained in Example 3, 5mmol, purity 96.8%), 3.258g N,N'-dicyclohexylcarbodiethylene Amine (15mmol, purity 95%), 0.144g trifluoroacetic acid (1.25mmol, purity 99%), 0.396g pyridine (5mmol, purity 99.5%) and dimethyl sulfoxide 20mL, react at 25°C for 24h, add 1.261 g oxalic acid (pre-dissolved in 10mL methanol), stop the reaction after 2h. After removing the white precipitate in the system by filtration, pour the filtrate into a sufficient amount of ice water, add ethyl acetate to extract, separate the liquid, keep the organic phase, wash with water, wash with saturated saline, dry over anhydrous sodium sulfate, and evaporate the solvent to obtain The crude product of myrtle alkanal was separated by silica gel column chromatography to obtain 0.66 g of myrtle alkanal with a purity of 91.2% and a yield of 79.23%. Structural characterization: IR v: 2806cm ^-1 , 2700cm ^-1 (HC=O), 1719cm ^-1 (C=O); ¹ H NMR (500MHz, CDCl ₃ ) δ: 9.77(s,1H), 2.75(dd, J=10.3,3.4Hz,1H),2.55(d,J=7.2Hz,1H),1.97-1.84(m,6H),1.34(d,J=4.6Hz,1H),1.22(s,3H), 0.72(s,3H).ESI-MS m/z=152[M] ⁺ . Structural characterization proves that the product is myrtle alkanal.

Claims (5)

1. a kind of preparation method of Fructus Rhodomyrti alkanal, it is characterised in that：Including following steps connected in order：

A, the reaction of nopinene Jing hydroboration-oxidations generate myrtanol；

Fructus Rhodomyrti alkanal generated and selective oxidation reaction in B, myrtanol and activated dimethylsulfoxide there is；

In step A hydroboration-oxidation reaction in hydroborating agents be：The mixture of sodium borohydride and boron trifluoride diethyl etherate,

Wherein, the mol ratio of sodium borohydride, boron trifluoride diethyl etherate and nopinene is（3~4): (4~5): 8；

Step B is that, in the second solvent, by N, N'- Dicyclohexylcarbodiimides, acid and myrtanol are according to mol ratio（2~ 5）:（0.125~0.5）:1 mixing, at 20 ~ 35 DEG C, after 1 ~ 24 h of reaction, obtains Fructus Rhodomyrti alkanal, wherein, the second solvent is two The mixed liquor or dimethyl sulfoxide of the mixed liquor, dimethyl sulfoxide and dichloromethane of first sulfoxide and benzene；

Oxidising agent in step A in hydroboration-oxidation reaction is any one of following two：The first is four hydrations

Dexol, is for second the mixture of sodium hydroxide and hydrogen peroxide；When oxidising agent is four hydrated sodium perborate, Four hydrated sodium perborates are (1 ~ 2) with the mol ratio of nopinene:1；When the mixing that oxidising agent is sodium hydroxide and hydrogen peroxide During thing, the mol ratio of sodium hydroxide, hydrogen peroxide and nopinene is（0.5~1）:（1~2）: 1；

Oxidizing reaction temperature is 35 ~ 45 DEG C, and the response time is 1 ~ 3 h；

Step A comprises the steps：

A1, in the first solvent, by nopinene, sodium borohydride and boron trifluoride diethyl etherate press 8:（3~4）:（4 ~ mol ratio 5) is mixed Close, at -10 ~ 30 DEG C, react 4 ~ 24 h, obtain two Fructus Rhodomyrti boron alkyls, first solvent is tetrahydrofuran, ether, two sweet Diethylene glycol dimethyl ether or hexamethylene；

A2, for following steps A21 or step A22 in any step：

A21, sodium hydroxide and hydrogen peroxide will be added in the material obtained by step A1, and at 35 ~ 45 DEG C, react 1 ~ 3 h, obtain Fructus Persicae Golden ma's alkanol, wherein, the mol ratio of sodium hydroxide, hydrogen peroxide and nopinene is（0.5~1）:（1~2）: 1；

A22, four hydrated sodium perborates will be added in the material obtained by step A1, at 30 ~ 35 DEG C, react 1 ~ 3 h, obtain Fructus Rhodomyrti Alkanol, wherein, four hydrated sodium perborates with the mol ratio of nopinene are（1~2）:1.

2. the preparation method of Fructus Rhodomyrti alkanal as claimed in claim 1, it is characterised in that：Hydroboration temperature is -10 ~ 30 DEG C, the response time is 4 ~ 24 h.

3. the preparation method of Fructus Rhodomyrti alkanal as claimed in claim 1 or 2, it is characterised in that：The reaction of above-mentioned steps A1 terminates Ethanol, water or methanol quenching hydroboration is added afterwards, wherein, the consumption of ethanol, water or methanol is the 1/4- of nopinene quality 1/2。

4. the preparation method of Fructus Rhodomyrti alkanal as claimed in claim 1 or 2, it is characterised in that：The acid is phosphoric acid, two chloroethenes Acid or trifluoroacetic acid.

5. the preparation method of Fructus Rhodomyrti alkanal as claimed in claim 1 or 2, it is characterised in that：When acid is trifluoroacetic acid, three Fluoroethanoic acid and pyridine compounding use, wherein, 3-5 times for trifluoroacetic acid mole of pyridine mole dosage.