CN104447396B - Benzoin oxime derivative and preparation method thereof - Google Patents

Abstract

The present invention relates to a kind of benzoin oxime derivative and preparation method thereof, and the structural formula of benzoin oxime derivative is: Preparation method Under the catalysis _{of sodium} hydride, react malonate with propargyl bromide in anhydrous acetonitrile to obtain a white solid product _; Under the catalysis of /CuI, triethylamine was used as the base to react in anhydrous acetonitrile to obtain a light brown solid product; under the condition of 95‑105 ° C, the light brown solid product was reacted with benzooxime in toluene to obtain benzooxime derivative things. The invention provides a brand-new synthesis method of multi-substituted benzoin oxime to generate a series of new benzoin oxime derivatives. Compared with common benzoin oxime derivatives, the benzoin oxime derivatives prepared by the present invention have multiple rings, and their structures are more complex and diverse, and will also show broader application prospects in chemical production and clinical medicine.

Description

A kind of benzoin oxime derivative and preparation method thereof

technical field

The invention relates to the field of organic compounds, in particular to a benzoin oxime derivative and a preparation method thereof.

Background technique

Benzoin, benzoin oxime and their derivatives are widely used in industrial production and scientific research. For example, benzoin, benzoin oxime and their derivatives are important intermediates in organic synthesis and fine chemicals, and are widely used in chemical industry, medicine, spices, chelating agents, coatings and other fields. In view of the special importance of benzoin, benzoin oxime and their derivatives, how to expand the synthetic route of benzoin oxime and its derivatives has aroused countless organic synthesizers and chemists to actively think, and came up with some very effective methods.

The common synthetic methods of benzoin and benzoin oxime are:

1. Using sodium cyanide and potassium cyanide as catalysts:

With sodium cyanide and potassium cyanide as catalysts, benzaldehyde molecules condense to generate benzoin, and then use benzoin to react with hydroxylamine hydrochloride under the action of alkali anhydrous potassium carbonate to prepare benzoin oxime, but sodium cyanide and potassium cyanide are highly toxic. Poisons pose a huge threat to human and environmental safety, and are inconvenient to use.

2. Taking vitamin B1 as a catalyst:

Mix 1.8g vitamin B1, 6L water, 15mL ethanol and 15mL benzaldehyde, slowly add 150g/L NaOH dropwise, adjust the pH to 9-10, shake well, and reflux at 60-75°C for 75min. The reaction mixture was cooled to room temperature, and light yellow crystals were precipitated. The temperature was lowered in an ice bath to complete the crystallization, and the best yield of synthetic benzoin was obtained. Then react benzoin with hydroxylamine hydrochloride under the action of alkali anhydrous potassium carbonate to obtain benzoin oxime. This method has a high yield, and avoids the use of highly toxic drugs potassium cyanide and sodium cyanide, and is environmentally friendly.

Contents of the invention

Aiming at the deficiencies in the prior art, the invention provides a benzoin oxime derivative and a preparation method thereof.

The technical scheme adopted in the present invention is:

A kind of benzoin oxime derivative, its structural formula is:

Wherein E ₁ ＝E ₂ ＝CO ₂ R, R is straight-chain alkyl, branched-chain alkyl, unsaturated hydrocarbon group or aromatic hydrocarbon group; R ₁ and R ₂ are hydrogen, straight-chain alkyl, branched-chain alkyl, halogen or Alkoxy and its corresponding derivatives.

A preparation method of benzoin oxime derivatives, comprising the following steps:

(1) Using sodium hydride as a catalyst, adding malonate and propargyl bromide to anhydrous acetonitrile in an ice-water bath, stirring and reacting, and obtaining a white solid product after purification and separation, namely compound 1;

The molar ratio of sodium hydride, malonate, and propargyl bromide is 4-5:1:2.2-3.2;

The concentration of the malonate in anhydrous acetonitrile is 0.5-0.8mol/L;

The malonate is selected from alkyl malonate, unsaturated alkyl malonate, aromatic alkyl malonate;

The purification and separation is to wash the product with water, extract it with ethyl acetate, spin dry under reduced pressure, and separate it by column chromatography with ethyl acetate:petroleum ether at a volume ratio of 1:100;

The reaction time is more than 5h;

(2) Compound 1 was mixed with phenylethynyl bromide or substituted phenylethynyl bromide in an anhydrous and oxygen-free catalytic system of Pd(PPh ₃ ) ₂ Cl ₂ /CuI, with triethylamine as base and anhydrous acetonitrile As a solvent, the reaction was stirred at room temperature, and after purification and separation, a light brown solid product was obtained, namely the precursor compound 2;

The amount of compound 1, phenylethynyl bromide or substituted phenylethynyl bromide, Pd(PPh ₃ ) ₂ Cl ₂ , and triethylamine is 1:2.2-3.2:0.0085-0.014:4-5;

The substituents of the substituted phenylethynyl bromide are linear alkyl, branched alkyl, halogen or alkoxy and corresponding derivatives thereof;

The concentration of the compound 1 in anhydrous acetonitrile is 0.32-0.6mol/L;

In the anhydrous and oxygen-free catalytic system of Pd(PPh ₃ ) ₂ Cl ₂ /CuI, the molar ratio of Pd(PPh ₃ ) ₂ Cl ₂ to CuI is 3:1;

The purification and separation is to wash the product with water, extract it with ethyl acetate, spin dry under reduced pressure, and separate it by column chromatography with ethyl acetate:petroleum ether at a volume ratio of 1:100;

The reaction time is more than 10h;

(3) Under the condition of 95-105°C, the precursor compound 2 prepared in step (2) was reacted with benzoin oxime in toluene for more than 10 hours, and the product was purified and separated to obtain yellow solid compound 3, which is the target product benzoin oxime derivatives;

The substance ratio of the precursor compound 2 to benzoin oxime is 1:1.1-1.5;

The concentration of precursor compound 2 in toluene is 0.2-0.5mol/L;

The purification and separation are as follows: washing the product with water, extracting with ethyl acetate, spin-drying under reduced pressure, and separating by column chromatography with ethyl acetate:petroleum ether at a volume ratio of 1:30.

Compared with the prior art, the present invention provides a brand-new synthesis method of multi-substituted benzoin oxime to generate a series of new benzoin oxime derivatives. Compared with common benzoin oxime derivatives, the benzoin oxime derivatives prepared by the present invention have multiple rings, and their structures are more complex and diverse, and will also show broader application prospects in chemical production and clinical medicine.

detailed description

Example 1

A benzoin oxime derivative, the structural formula is:

A kind of preparation method of benzoin oxime derivative, described preparation method comprises the following steps:

a. Precursor synthesis;

b. Synthesis of the target product;

c. Purification.

Wherein, a, precursor synthesis, comprises the following steps:

(1) With 830mmol sodium hydride as a catalyst, 200mmol diethyl malonate and 440mmol propargyl bromide were added to 250mL anhydrous acetonitrile in an ice-water bath, stirred and reacted for 8 hours, the product was washed with water, extracted with ethyl acetate, and Press and spin dry, column chromatography (volume ratio ethyl acetate:petroleum ether=1:100) to obtain a white solid product, namely compound 1;

(2) Mix 80mmol of compound 1 and 200mmol of phenylethynyl bromide in an anhydrous and oxygen-free catalytic system of 1.3gPd(PPh ₃ ) ₂ Cl ₂ /CuI, the mass ratio of Pd(PPh ₃ ) ₂ Cl ₂ to CuI 3:1, with 320mmol triethylamine as base, with 200ml anhydrous acetonitrile as solvent, stirring and reacting at room temperature for 12 hours, the product was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, column chromatography (volume ratio acetic acid Ethyl ester: petroleum ether = 1:100) to obtain a light brown solid product, namely precursor compound 2.

Wherein b, target product synthesis, comprises the following steps:

Under the condition of 100° C., 0.44 g of precursor compound 2 and 0.34 g of benzoin oxime were reacted in 3 mL of toluene for 12 hours to obtain compound 3, the crude product of benzoin oxime derivative.

Wherein, c, purification comprises the following steps:

The crude product of the benzoin oxime derivative prepared in step b was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, and separated by column chromatography (volume ratio ethyl acetate:petroleum ether=1:30) to obtain a yellow solid product, namely benzoin Oxime derivative, the column chromatography yield is 65.2%.

The structure of the yellow solid product was determined by; ¹ H NMR; ¹³ C NMR.

Yellow solid product:

¹ H NMR (300MHz, CDCl ₃ ) δ7.96(s,1H), 7.93(s,1H), 7.81(s,1H), 7.78(s,1H), 7.54–7.25(m,16H), 6.63( s,1H), ,4.29–4.22(m,4H), 3.73(s,2H), 3.66(s,2H),1.32-1.27(t,6H).

¹³ C NMR(75MHz,CDCl ₃ )δ196.89,171.49,166.91,144.95，144.48,143.29,139.96,134.86,134.64,134.44,132.04,131.23,130.46,129.88,129.15,129.09,129.03,128.87,128.33,128.20,128.00 , 127.71, 127.31, 123.53, 119.13, 114.09, 95.54, 87.32, 77.31, 77.06, 76.81, 61.83, 59.45, 40.97, 39.03, 14.07.

Example 2

A benzoin oxime derivative, the structural formula is:

A kind of preparation method of benzoin oxime derivative, described preparation method comprises the following steps:

a. Precursor synthesis;

b. Synthesis of the target product;

c. Purification.

Wherein, a, precursor synthesis, comprises the following steps:

(1) With 800mmol sodium hydride as a catalyst, 200mmol diisopropyl malonate and 500mmol propargyl bromide were added to 200ml anhydrous acetonitrile in an ice-water bath, stirred and reacted for 10 hours, the product was washed with water, extracted with ethyl acetate, Spinning to dryness under reduced pressure, column chromatography (volume ratio of ethyl acetate:petroleum ether=1:100) gave a white solid product, namely compound 3;

(2) Mix 80mmol of compound 1 and 200mmol of p-methylphenylethynyl bromide in 2.17g of Pd(PPh ₃ ) ₂ Cl ₂ /CuI anhydrous and oxygen-free catalytic system, Pd(PPh ₃ ) ₂ Cl ₂ /CuI in Pd The molar ratio of (PPh ₃ ) ₂ Cl ₂ to CuI is 3:1, 350mmol triethylamine is used as the base, 250ml anhydrous acetonitrile is used as the solvent, the reaction is stirred at room temperature for 10 hours, the product is washed with water, washed with ethyl acetate Extraction, spin-drying under reduced pressure, and column chromatography (volume ratio of ethyl acetate:petroleum ether=1:100) yielded a light brown solid product, namely precursor compound 3.

Wherein b, target product synthesis, comprises the following steps:

Under the condition of 100° C., 0.47 g of precursor compound 3 and 0.32 g of benzoin oxime were reacted in 5 mL of toluene for 11 hours to obtain compound 4, the crude product of benzoin oxime derivative.

Wherein, c, purification comprises the following steps:

The crude product of the benzoin oxime derivative prepared in step b was washed with water, extracted with ethyl acetate, spin-dried under reduced pressure, and separated by column chromatography (volume ratio ethyl acetate:petroleum ether=1:30) to obtain a yellow solid product, namely benzoin Oxime derivative, the column chromatography yield is 73.6%.

The structure of the yellow solid product was determined by; ¹ H NMR; ¹³ C NMR.

Yellow solid product:

¹ H NMR (300MHz, CDCl ₃ ) δ7.95(s,1H),7.92(s,1H),7.80(s,1H),7.78(s,1H),7.53–7.19(m,10H),7.14– 7.06(m,4H), 6.60(s,1H), ,5.12–5.04(m,2H), 3.68(s,2H), 3.61(s,2H), 2.36(s,3H), 2.32(s,3H ), 1.30-1.25(t, 12H).

¹³ C NMR(75MHz,CDCl ₃ )δ197.10,171.12,166.54,144.90，144.51,142.96,138.05,137.15,136.89,134.88,134.37,133.04,131.88,131.05,129.91,129.11,129.01,128.97,128.83,128.41,128.30 .

Claims (8)

1. a benzoin oxime derivative, its structural formula is: 2. the preparation method of benzoin oxime derivative as claimed in claim 1, comprises the following steps: (1) Using sodium hydride as a catalyst, malonate and propargyl bromide are added to anhydrous acetonitrile in an ice-water bath, stirred and reacted for more than 5 hours, and a white solid product is obtained after purification and separation, that is, compound 1; the malonate The ester is diethyl malonate or diisopropyl malonate; (2) Compound 1 was mixed with phenylethynyl bromide or substituted phenylethynyl bromide in an anhydrous and oxygen-free catalytic system of Pd(PPh ₃ ) ₂ Cl ₂ /CuI, with triethylamine as base and anhydrous acetonitrile as a solvent, stirred and reacted at room temperature for more than 10 hours, and obtained a light brown solid product after purification and separation, that is, precursor compound 2; the substituted phenylethynyl bromide is p-methylphenylethynyl bromide; (3) Under the condition of 95-105°C, the precursor compound 2 prepared in step (2) was reacted with benzoin oxime in toluene for more than 10 hours, and the product was purified and separated to obtain yellow solid compound 3, which is the target product benzoin oxime derivatives. 3. preparation method as claimed in claim 2 is characterized in that: in described step (1), the substance ratio of sodium hydride, diethyl malonate or diisopropyl malonate, propargyl bromide 4-5:1:2.2-3.2, the concentration of diethyl malonate or diisopropyl malonate in anhydrous acetonitrile is 0.5-0.8mol/L. 4. The preparation method according to claim 2, characterized in that: in the step (1), purification and separation are washing the product with water, extracting it with ethyl acetate, spin-drying under reduced pressure, and using 1:100 volume ratio Ethyl acetate: separation by petroleum ether column chromatography. 5. The preparation method according to claim 2, characterized in that: in the step (2), compound 1, phenylethynyl bromide or p-methylphenylethynyl bromide, Pd(PPh ₃ ) ₂ Cl ₂ , triethyl The amount of the amine substance is 1:2.2-3.2:0.0085-0.014:4-5, and the concentration of the compound 1 in anhydrous acetonitrile is 0.32-0.6mol/L. 6. The preparation method according to claim 2, characterized in that: in the anhydrous and oxygen-free catalytic system of Pd(PPh ₃ ) ₂ Cl ₂ /CuI in the step (2), Pd(PPh ₃ ) ₂ Cl ₂ The molar ratio of CuI and CuI is 3:1; the purification and separation are washing the product with water, extracting it with ethyl acetate, spin-drying under reduced pressure, and using ethyl acetate:petroleum ether column chromatography with a volume ratio of 1:100 separate. 7. The preparation method according to claim 2, characterized in that: in the step (3), the amount ratio of precursor compound 2 to benzoin oxime is 1:1.1-1.5, and the amount of precursor compound 2 in toluene The concentration is 0.2-0.5mol/L. 8. The preparation method according to claim 2, characterized in that: the purification and separation in the step (3) is to wash the product with water, extract with ethyl acetate, and spin dry under reduced pressure, with a volume ratio of 1:30 Ethyl acetate: Petroleum ether column chromatography.