CN113200841B - A new process for the synthesis of racemic naproxen based on Heck coupling - Google Patents

Abstract

The invention discloses a new process for synthesizing racemic naproxen based on Heck coupling. The process comprises: (1) 2-X-substituted-6-methoxynaphthalene and crotonamide under the action of a palladium catalyst and a base Heck coupling reaction occurs in aprotic organic solvent to generate 3-(6-methoxynaphthyl-2-)-crotonamide; (2) 3-(6-methoxynaphthyl-2-)- In the alkaline solution of hypochlorite, crotonamide undergoes Hoffman degradation reaction to generate 2-(6-methoxynaphthyl-2-)-propionaldehyde, and 2-(6-methoxynaphthalene- 2-)-Propionaldehyde is directly added with chlorite without separation, and oxidized at room temperature to obtain racemic naproxen. The process of the invention does not need to prepare a highly active Grignard reagent, does not need severe anhydrous conditions, has a high conversion rate, and is easy to purify the product.

Description

A new process for the synthesis of racemic naproxen based on Heck coupling

technical field

The invention relates to a process for synthesizing racemic naproxen, in particular to a new process for synthesizing racemic naproxen based on Heck coupling.

Background technique

The synthesis technique of existing naproxen is mainly based on two basic raw materials, one is 2-acyl-6-methoxynaphthalene (route I or II), and the other is 2-bromo-6-methoxynaphthalene , there are mainly four synthetic routes, as follows:

(I)

(II)

(III)

(IV)

Route I or II are based on 2-acyl-6-methoxynaphthalene as raw material, and have a relatively important defect that 2-acyl-6-methoxynaphthalene is relatively difficult to prepare. In the synthesis of 2-acyl-6-methoxynaphthalene, the first active site of naphthoyl methyl ether is the ortho position of the methoxy group. The existing technology needs to protect this position, and then deprotect it after acylation. The route Longer, resulting in high cost of 2-acyl-6-methoxynaphthalene. Another important defect is that because the process for preparing naproxen with 2-acyl-6-methoxynaphthalene as raw material involves Dazen rearrangement or acyl ortho-halogenation, it is prepared into a ketal and then rearranged, hydrolyzed, and the route is lengthy and intermediate. The product is not easily purified by crystallization.

Route III or IV is based on 2-bromo-6-methoxynaphthalene as starting material, and naproxen is prepared by Grignard reaction or coupling reaction. Although the yield of route III is relatively high, it involves the preparation of anhydrous and oxygen-free Grignard reagents, and the intrusion of water vapor in the industry is likely to cause unstable production quality, and when expanding production, highly active metal magnesium is used, which is safe for safety. Bad production. This type of coupling of route IV has the advantages of short route and cheap raw materials. However, the important defect of this type of coupling is that the conversion rate is low, and while the yield is affected, the unconverted raw material 2-bromo-6-methoxynaphthalene will interfere with the purification of the product.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a new process for synthesizing racemic naproxen based on Heck coupling, which does not require the preparation of highly active Grignard reagents, does not require severe anhydrous conditions, has a high conversion rate, and is easy to purify the product.

In order to achieve the above object, the invention provides a kind of new technology based on Heck coupling synthesis racemic naproxen, the synthetic route of this technology is:

(1) 2-X substituted-6-methoxynaphthalene is subjected to Heck coupling reaction with crotonamide in an aprotic organic solvent under the action of a palladium catalyst and a base to generate 3-(6-methoxynaphthyl- 2-)-crotonamide;

(2) 3-(6-methoxynaphthyl-2-)-crotonamide is subjected to Hoffmann degradation reaction in an alkaline solution of hypochlorite to generate 2-(6-methoxynaphthyl -2-)-Propionaldehyde, 2-(6-methoxynaphthalene-2-)-propionaldehyde is directly added to chlorite without separation, and oxidized at room temperature to obtain racemic naproxen.

所述非质子性有机溶剂选自N,N-二甲基甲酰胺、二甲亚砜、N,N-二甲基乙酰胺、乙腈、二氧六环、甲苯、苯、二甲苯和四氢呋喃中任意一种或两种以上；所述巴豆酰胺的结构中，双键的构型为Z型或E型，或巴豆酰胺为二种构型的混合物；所述钯催化剂为PdL_nY_m，L选自芳基膦配体，n为0到4之间的整数；Y选自卤素负离子或羧酸根，m为0到4之间的整数；所述Heck偶联反应中的碱选自三乙胺、二乙胺、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、磷酸钾、磷酸钠、乙酸钾和乙酸钠中任意一种或两种以上；所述霍夫曼降级反应中的碱选自氢氧化钾和/或氢氧化钠。Wherein, in the structure of the 2-X substituted-6-methoxynaphthalene, X is selected from halogen or halogen-like, and the halogen-like is selected from

The aprotic organic solvent is selected from N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, acetonitrile, dioxane, toluene, benzene, xylene and tetrahydrofuran Any one or more than two; in the structure of the crotonamide, the configuration of the double bond is a Z type or an E type, or the _crotonamide is a mixture of two configurations; the palladium catalyst is _PdLnYm , L is selected from aryl phosphine ligands, n is an integer between 0 and 4; Y is selected from halogen anion or carboxylate, m is an integer between 0 and 4; the base in the Heck coupling reaction is selected from triethyl Any one or more of amine, diethylamine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, potassium acetate and sodium acetate; the alkali in the Hoffmann degradation reaction Selected from potassium hydroxide and/or sodium hydroxide.

Preferably, the Heck coupling reaction is as follows: dissolving 2-bromo-6-methoxynaphthalene, _PdYm , ligand L, crotonamide and alkali in an aprotic organic solvent, and sealing after nitrogen purging It was heated to 130°C and reacted with stirring to obtain 3-(6-methoxynaphthyl-2-)-crotonamide.

Preferably, the molar ratio of 2-bromo-6-methoxynaphthalene, PdY _m , ligand L, crotonamide and base is 1:0.005:0.01:1.5:2.

Preferably, the base is triethylamine; the ligand L is tris(2-methylphenyl)-phosphine; and the PdY _m is PdCl ₂ .

Preferably, after the Heck coupling reaction is completed, the insolubles are filtered off, the filtrate is concentrated, the concentrate is extracted with hot water, the aqueous phase is discarded, and the residue is recrystallized with water-containing ethanol, methanol or isopropanol to obtain 3- (6-Methoxynaphthyl-2-)crotonamide.

Preferably, after the Heck coupling reaction is completed, diatomaceous earth is used to filter out insoluble matter.

Preferably, the Hoffmann degradation reaction is as follows: in a polar solvent containing hypochlorite and hydroxide, dropwise adding a non-ferrous compound containing 3-(6-methoxynaphthyl-2-)crotonamide. Protic organic solvent, keep the reaction temperature not more than 10 ℃, after the reaction is over, remove the hypochlorite in the reaction solution, then adjust the pH value to neutral, and heat under reflux to obtain 2-(6-methoxynaphthalene wherein, the polar solvent is selected from water or methanol aqueous solution.

Preferably, the molar ratio of the hypochlorite, hydroxide and 3-(6-methoxynaphthyl-2-)crotonamide is 1.2:2.4:1; the hypochlorite is sodium hypochlorite or hypochlorite Potassium chlorate, the hydroxide is sodium hydroxide or potassium hydroxide.

Preferably, the hypochlorite and chlorite are removed by using an aqueous solution of sulfite.

Preferably, after the reaction of the 2-(6-methoxynaphthalene-2-)-propionaldehyde and chlorite is completed, the pH of the solution is adjusted to be less than 3, cooled, filtered, and the filter cake is washed with water, and the filtrate adopts dichloride. After extraction with methane or dichloroethane, the mixture is concentrated, the concentrate is combined with the filter cake, and recrystallized with aqueous ethanol, methanol or isopropanol to obtain racemic naproxen.

The novel process of synthesizing racemic naproxen based on Heck coupling of the present invention has the following advantages:

The process of the present invention uses 2-halogenated-6-methoxynaphthalene as a raw material instead of 2-acyl-6-methoxynaphthalene, which has advantages in raw material cost, and is different from the use of 2-halogenated-6-methoxynaphthalene. Compared with the method based on naphthalene, the method of the present invention does not need to prepare a highly active Grignard reagent, does not need severe anhydrous conditions, has a higher conversion rate, and is easy to purify the product. In addition, the process of the present invention uses a small amount of metal catalyst, and has low cost and low environmental pressure. The selection of the solvent and catalyst for the coupling reaction in the process of the present invention ensures that the reaction yield of the process of the present invention is high, and the temperature control and solvent selection of the Hoffman degradation reaction play a key role in the conversion of reactants.

Description of drawings

Fig. 1 is the hydrogen nuclear magnetic spectrum of 3-(6-methoxynaphthyl-2-)crotonamide of the present invention.

Fig. 2 is the carbon nuclear magnetic spectrum of 3-(6-methoxynaphthyl-2-)crotonamide of the present invention.

Fig. 3 is the hydrogen nuclear magnetic spectrum of racemic naproxen of the present invention.

Fig. 4 is the carbon nuclear magnetic spectrum of racemic naproxen of the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

Example 1

A new technology based on Heck coupling synthesis racemic naproxen, the concrete steps of this technology are as follows:

(1) Synthesis of intermediate 3-(6-methoxynaphthyl-2-)crotonamide

24 g (0.1 mol) 2-bromo-6-methoxynaphthalene, 88 mg (0.5 mmol) palladium chloride, 304 mg (1 mmol) tris(2-methylphenyl)-phosphine, 13 g (0.15 mol) crotonamide and 20 g (0.2 mol) triethylamine were dissolved in 100 mL of dimethylformamide, purged with nitrogen for three times, and heated to 130° C. in an airtight manner, and stirred continuously for 20 h.

After the reaction was completed, it was cooled, the insolubles were filtered off with celite, the solvent was removed from the filtrate in vacuo, the residue was extracted twice with hot water, the aqueous phase was discarded, and the residue was recrystallized with ethanol to obtain 20.5 g of 3-(6). -Methoxynaphthyl-2-)crotonamide (see Figures 1 and 2 for hydrogen NMR and carbon spectra), the yield was 85%.

(2) Synthesis of racemic naproxen

In 100 mL of an aqueous solution containing 0.12 mol of sodium hypochlorite and 0.24 mol of sodium hydroxide, drop 150 mL of a dioxane solution containing 24 g (0.1 mol) of 3-(6-methoxynaphthyl-2-) crotonamide, on ice. The reaction temperature of the bath is kept not more than 10°C. After the reaction of the raw materials is monitored by thin layer chromatography, the sodium sulfite aqueous solution is added dropwise until the starch potassium iodide test paper no longer turns blue.

Use phosphoric acid (other acids have poor effect) to adjust the pH value to neutrality, heat under reflux for 3 hours, cool to room temperature, add aqueous sodium chlorite solution, and stir overnight until thin layer chromatography shows that the reaction of arylpropionaldehyde is complete.

Use phosphoric acid (other acids have poor effect) to adjust the pH of the solution to less than 3, cool in an ice-water bath, filter, and wash the filter cake with water. The filtrate was extracted with dichloromethane, and the solvent was removed in vacuo. The residue was combined with the filter cake and recrystallized from ethanol to obtain 19.2 g of racemic naproxen with a yield of 83%.

While the content of the present invention has been described in detail by way of the above preferred embodiments, it should be appreciated that the above description should not be construed as limiting the present invention. Various modifications and alternatives to the present invention will be apparent to those skilled in the art upon reading the foregoing. Accordingly, the scope of protection of the present invention should be defined by the appended claims.

Claims (10)

1. A novel process for synthesizing racemic naproxen based on Heck coupling is characterized in that the synthesis route of the process is as follows:

(1) performing Heck coupling reaction on 2-X substituted-6-methoxynaphthalene and crotonamide in an aprotic organic solvent under the action of a palladium catalyst and alkali to generate 3- (6-methoxynaphthyl-2-) -crotonamide;

(2) carrying out Hofmann degradation reaction on 3- (6-methoxynaphthyl-2-) -crotonamide in an alkaline solution of hypochlorite to generate 2- (6-methoxynaphthyl-2-) -propionaldehyde, directly adding chlorite without separation into the 2- (6-methoxynaphthyl-2-) -propionaldehyde, and oxidizing at room temperature to obtain racemic naproxen;

wherein in the structure of the 2-X substituted-6-methoxynaphthalene, X is selected from halogen or halogen-like, and the halogen-like is selected from halogen

、

Or

；

The aprotic organic solvent is selected from one or more of N, N-dimethylformamide, dimethyl sulfoxide, N-dimethylacetamide, acetonitrile, dioxane, toluene, benzene, xylene and tetrahydrofuran;

in the structure of the crotonamide, the configuration of a double bond is Z type or E type, or the crotonamide is a mixture of two configurations;

the palladium catalyst is PdL_nY_mL is selected from arylphosphine ligands, n is an integer between 0 and 4, and n is not 0; y is selected from halogen anions or carboxylate radicals, m is an integer between 0 and 4, and m is not 0;

the alkali in the Heck coupling reaction is selected from any one or more than two of triethylamine, diethylamine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, potassium acetate and sodium acetate;

the alkali in the Hofmann degradation reaction is selected from potassium hydroxide and/or sodium hydroxide.

2. The novel Heck coupling-based process for synthesizing racemic naproxen according to claim 1, wherein the Heck coupling reaction is: 2-bromo-6-methoxynaphthalene and PdY_mDissolving the ligand L, crotonamide and alkali in an aprotic organic solvent, purging with nitrogen, sealing, heating to 130 ℃, and reacting under stirring to obtain the 3- (6-methoxynaphthyl-2-) -crotonamide.

3. The novel Heck coupling-based process for synthesizing racemic naproxen according to claim 2, wherein the 2-bromo-6-methoxynaphthalene, PdY_mThe molar ratio of the ligand L to the crotonamide to the base is 1: 0.005：0.01：1.5：2。

4. The novel Heck coupling based racemic naproxen synthesis process according to claim 2, wherein the base is triethylamine; the ligand L is tri (2-methylphenyl) -phosphine; the Pdy_mIs PdCl₂。

5. The novel process for synthesizing racemic naproxen based on Heck coupling according to claim 2, characterized in that after the Heck coupling reaction is finished, insoluble substances are filtered, the filtrate is concentrated, the concentrate is extracted by hot water, the water phase is discarded, and the residue is recrystallized by hydrous ethanol, methanol or isopropanol to obtain 3- (6-methoxy-naphthyl-2-) crotonamide.

6. The novel Heck coupling-based racemic naproxen synthesis process according to claim 5, wherein after the Heck coupling reaction is finished, insoluble substances are filtered out by using diatomite.

7. The novel Heck coupling based racemic naproxen synthesis process according to claim 1, wherein the hofmann degradation reaction is: dripping an aprotic organic solvent containing 3- (6-methoxynaphthyl-2-) crotonamide into a polar solvent containing hypochlorite and hydroxide, keeping the reaction temperature not higher than 10 ℃, removing the hypochlorite in a reaction liquid after the reaction is finished, then adjusting the pH value to be neutral, and heating and refluxing to obtain 2- (6-methoxynaphthyl-2-) -propionaldehyde;

wherein the polar solvent is selected from water or aqueous methanol.

8. The novel Heck coupling based process for the synthesis of racemic naproxen according to claim 7, characterized in that the molar ratio of hypochlorite, hydroxide and 3- (6-methoxynaphthyl-2-) crotonamide is 1.2: 2.4: 1; the hypochlorite is sodium hypochlorite or potassium hypochlorite, and the hydroxide is sodium hydroxide or potassium hydroxide.

9. The novel Heck coupling based process for the synthesis of racemic naproxen according to claim 7, wherein said hypochlorite and chlorite are removed by using an aqueous sulfite solution.

10. The novel Heck-based coupling synthesis process of racemic naproxen according to claim 1, wherein after the 2- (6-methoxynaphthalene-2-) -propionaldehyde reacts with chlorite, the solution is adjusted to have a pH value of less than 3, the solution is cooled, filtered, the filter cake is washed with water, the filtrate is extracted by dichloromethane or dichloroethane and then concentrated, the concentrate is combined with the filter cake, and the filtrate is recrystallized by using aqueous ethanol, methanol or isopropanol to obtain racemic naproxen.

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