Synthetic method of aromatic cyano compound

Abstract

The invention relates to a synthesis method of an aromatic cyano compound, which comprises the following steps: carrying out reflux reaction on an aldehyde compound as shown in a formula I serving as a raw material in hydroxylamine hydrochloride and methylbenzene to prepare an oxime compound as shown in a formula II, and reacting the oxime compound as shown in the formula II under the catalytic conditions of a silane reagent and halogen to obtain the aromatic cyano compound as shown in the formula II. And concentrating to obtain the compound shown in the formula III and having aromatic cyano groups. The method has the advantages of cheap and easily available raw materials, reusable condensing agent and catalyst, less three wastes, low cost, environmental protection, high yield and purity of the obtained compound, and suitableness for industrial production.

Description

Technical Field

[0001] The invention relates to the field of organic chemistry, in particular to a method for synthesizing an aromatic cyano compound. Background Art

[0002] 4-tert-Butyl-3-hydroxy-2,6-dimethylbenzonitrile is an important medical and chemical intermediate. The synthesis of the nitrile group is one of its difficulties. It is usually prepared by a substitution reaction between halogenated benzene and cyanide salts. However, cyanide salts are highly toxic chemicals and pose great safety risks during use. At the same time, the wastewater produced also causes great pollution to the water environment.

[0003] At present, there are several methods for the synthesis of cyanide: Method 1: Halogenated hydrocarbons undergo substitution reaction with cyanide salts under metal catalysis. This method mainly uses cyanide salts. The cyanide salts contained in wastewater pose a greater safety risk to its use and also have a greater impact on the water environment.

[0004] This method is not widely used at present.

[0005] Method 2: Dehydration of amide to prepare cyano group. Amide generates cyano group when dehydrated by phosphorus oxychloride, phosphorus pentoxide, phosphorus pentachloride, thionyl chloride, etc. However, it is still in the laboratory stage due to safety reasons and excessive waste.

[0006] Method 3, first prepare aldoxime, and then prepare cyano from aldoxime. This method is currently used more frequently, and many processes have been derived, mainly including:

[0007] 1: Aldoxime reacts with acetic anhydride as solvent and water under base catalysis to prepare cyano compounds.

[0008] 2: Aldoxime in dichloromethane, using Tf 2 O and imidazole catalyzed the preparation of cyanide.

[0009] 3: Aldoxime is used in a solvent to prepare cyanide in the presence of a metal catalyst such as palladium acetate, copper acetate, triphenylphosphine, ferric chloride, tin chloride, etc.

[0010] Route 3 is the current mainstream method for synthesizing aromatic cyanides, with a high yield, but it also has problems such as difficulty in post-treatment separation, instability, difficulty in removing metal ions brought by metal catalysts, and difficulty in treating wastewater.

[0011] Considering that 4-tert-butyl-3-hydroxy-2,6-dimethylbenzonitrile is an important medical and chemical intermediate in pharmaceutical chemical industry, it is necessary to develop a more advantageous preparation process for this intermediate. Summary of the invention

[0012] In order to solve the above defects in the prior art, the technical solution provided by the present invention is as follows:

[0013] The present invention first provides an aromatic cyano or oxime compound, the structural formula of which is:

[0014]

[0015] Another aspect of the present invention provides a method for preparing an aromatic cyano compound of formula III, which comprises preparing a compound of formula III from an oxime compound of formula II in the presence of a condensing agent and a catalyst,

[0016]

[0017] The above-mentioned catalyst is a halogen, preferably any one of iodine, chlorine, bromine and the like.

[0018] The condensation agent is a silanization agent, preferably any one of trimethylsilyl iodide, trimethylsilyl chloride, trimethylsilyl bromide and trimethylsilylimidazole.

[0019] The reaction temperature may be 50-110°C, and most preferably 57-106°C.

[0020] At the same time, a method for preparing an aromatic oxime compound of formula II is provided, which comprises preparing an oxime compound of formula II by condensing an aldehyde compound of formula I with a hydroxylamine compound,

[0021]

[0022] Suitable reaction conditions include using toluene or xylene under reflux, and the pH value of the reaction solution can range from 8 to 11, and most preferably from 8 to 9.

[0023] The condensation reaction is carried out in the presence of a solvent, and the solvent is an alcohol solvent.

[0024] The reaction temperature may be 95-113°C, most preferably 105-113°C.

[0025] In the present invention, a method for preparing an aromatic cyano compound of formula III is provided, wherein an aldehyde compound of formula I is reacted with a hydroxylamine compound to obtain an oxime compound of formula II, and the oxime compound of formula II is reacted with a condensing agent and a catalyst to obtain a compound of formula III having an aromatic cyano group.

[0026]

[0027] The specific steps include:

[0028] After dissolving the compound of formula I in hydroxylamine hydrochloride, ethanol and water, sodium hydroxide solution is added to the reaction solution to adjust the pH value to alkaline, filter, concentrate the filtrate to dryness, add toluene, heat to reflux and dehydrate for 4 to 6 hours, quench the reaction with water, extract, combine the organic phases, evaporate and concentrate to obtain compound II;

[0029] After adding the condensation agent trimethylhalosilane and the catalyst halogen, the temperature was raised to reflux for reaction for 6 to 8 hours, evaporated and concentrated to obtain a crude product, and the crude product was slurried with heptane to obtain compound III.

[0030] Compared with the prior art, the invention has the following beneficial effects: the invention uses the aldehyde compound of formula I as a raw material, performs a reflux reaction in hydroxylamine hydrochloride and toluene to prepare the oxime compound of formula II, and then concentrates the oxime compound of formula II under halogen catalysis to prepare the compound of formula III having an aromatic cyano group. The process has the advantages of cheap and easy-to-obtain raw materials, reusable silane reagents and halogens, less three wastes, low cost, green and environmental protection, high yield and purity of the obtained compound, and is suitable for industrial production. DETAILED DESCRIPTION

[0031] The following is a detailed description of the preferred embodiments of the present invention so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0032] Example 1

[0033] Preparation of 4-tert-butyl-3-hydroxy-2,6-dimethylbenzaldehyde oxime (compound of formula II): 7.7 g (0.11 mol) of NH 2 OH.HCI was added to 20 ml of ethanol and 20 ml of water to dissolve, and the pH value was adjusted to 8-9 with 30% sodium hydroxide solution, and then concentrated to dryness. 20 ml of ethanol was added to filter out sodium chloride, and the filtrate was further concentrated to dryness. 20.6 g (0.1 mol) of compound I and 100 ml of toluene were added, and the temperature was raised to 113 ° C. and refluxed for dehydration for 4-6 h. The reaction was completed, and the reaction was quenched with water and extracted with EA (3 times 60 ml). The organic phases were combined, evaporated and concentrated to obtain compound II, 21.4 g, and the yield was 97%.

[0034] Preparation of 4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl cyanide (compound of formula III): Add 22.6g (0.1mol) of compound II to 60g (0.3mol) of trimethylsilyl iodide, then add 1.3g (0.005mol) of iodine, heat to 106°C and reflux for 6-8h. After the reaction is completed, evaporate to dryness and concentrate to obtain a crude product. The crude product is slurried with heptane to obtain the target compound III, 19.3g, with a yield of 95% and a purity of 97%. 1H NMR (400MHz, Chloroform-d) δ7.05 (s, 1H), 4.86 (s, 1H), 2.44 (d, J=7.6Hz, 6H), 1.40 (s, 9H).

[0035] Example 2

[0036] Preparation of 4-tert-butyl-3-hydroxy-2,6-dimethylbenzaldehyde oxime (compound of formula II): 2 OH.HCI 7.7g (0.11mol) was added to 20ml ethanol and 20ml water to dissolve, and the pH value was adjusted to 8-9 with 30% sodium hydroxide solution, and then concentrated to dryness. 20ml ethanol was added to filter out sodium chloride, and the filtrate was further concentrated to dryness. Compound I, 20.6g (0.1mol), and xylene 100ml were added, and the temperature was raised to 140°C and refluxed for dehydration for 4-6h. The reaction was completed, and the reaction was quenched with water and extracted with EA (3 times 60ml). The organic phases were combined, evaporated and concentrated to obtain compound II, 21.6g, with a yield of 98%.

[0037] Preparation of 4-tert-butyl-3-hydroxy-2,6-dimethylbenzonitrile (compound of formula III): Add 22.6 g (0.1 mol) of compound II to 43.4 g (0.4 mol) of trimethylsilyl chloride, and then add 1.0 g (0.006 mol) of bromine, raise the temperature to 57°C and reflux for reaction for 6 to 8 hours. After the reaction is completed, evaporate and concentrate to obtain a crude product. The crude product is slurried with heptane to obtain the target compound III, 18.9 g, with a yield of 93% and a purity of 98%.

[0038] Example 3

[0039] Preparation of 4-tert-butyl-3-hydroxy-2,6-dimethylbenzaldehyde oxime (compound of formula II): 2OH.HCI 7.7g (0.11mol) was added to 20ml ethanol and 20ml water to dissolve, and the pH value was adjusted to 9-10 with 30% sodium hydroxide solution, and then concentrated to dryness. 20ml ethanol was added to filter out sodium chloride, and the filtrate was further concentrated to dryness. Then 20.6g (0.1mol) of compound I and 100ml of toluene were added, and the temperature was raised to 113°C and refluxed for dehydration for 4-6h. After the reaction was completed, the reaction was quenched with water and extracted with EA (3 times 60ml), and the organic phases were combined, evaporated and concentrated to obtain 21.2g of compound II with a yield of 96%.

[0040] Preparation of 4-tert-butyl-3-hydroxy-2,6-dimethylbenzonitrile (compound of formula III): 22.6 g (0.1 mol) of compound II was added to 61.2 g (0.4 mol) of trimethylsilyl bromide, and then 1.6 g (0.01 mol) of catalyst bromine was added, the temperature was raised to 80°C and refluxed for 6 to 8 hours. After the reaction was completed, the crude product was evaporated and concentrated to obtain a crude product. The crude product was slurried with heptane to obtain the target compound III, 19.1 g, with a yield of 94% and a purity of 98%.

[0041] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention specification, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. An aromatic cyano or oxime compound, characterized in that: The structural formula is:

2. A method for preparing an aromatic cyano compound of formula III, characterized in that: The oxime compound of formula II is used to prepare the compound of formula III in the presence of a condensing agent and a catalyst, 3. The preparation method according to claim 2, characterized in that: The condensation agent is a silane reagent.

4. The preparation method according to claim 2, characterized in that: The catalyst is a halogen.

5. The preparation method according to claim 2, characterized in that: The reaction temperature is 50-110°C.

6. The preparation method according to claim 3, characterized in that: The condensation agent is any one of trimethyl iodosilane, trimethyl chlorosilane and trimethyl bromosilane.

7. A method for preparing an aromatic oxime compound of formula II, characterized in that: The oxime compound of formula II is prepared by condensing the aldehyde compound of formula I with the hydroxylamine compound.

8. The preparation method according to claim 7, characterized in that: The reaction temperature is 110-140°C.

9. The preparation method according to claim 7, characterized in that: The condensation reaction is carried out in the presence of a solvent, and the solvent is an alcohol solvent.

10. A method for preparing an aromatic cyano compound of formula III, characterized in that: The oxime compound of formula II is prepared by reacting the aldehyde compound of formula I with the hydroxylamine compound, and the oxime compound of formula II is prepared in the presence of a condensing agent and a catalyst to obtain a compound of formula III having an aromatic cyano group. The specific steps include: After dissolving the compound of formula I in hydroxylamine hydrochloride, ethanol and water, sodium hydroxide solution is added to the reaction solution to adjust the pH value to alkaline, filter, concentrate the filtrate to dryness, add toluene, heat to reflux and dehydrate for 4 to 6 hours, quench the reaction with water, extract, combine the organic phases, evaporate and concentrate to obtain compound II; After adding the condensation agent trimethylhalosilane and the catalyst halogen, the temperature was raised to reflux for reaction for 6 to 8 hours, evaporated and concentrated to obtain a crude product, and the crude product was slurried with heptane to obtain compound III.

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