CN113200841B - Novel process for synthesizing racemic naproxen based on Heck coupling - Google Patents

Novel process for synthesizing racemic naproxen based on Heck coupling Download PDF

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CN113200841B
CN113200841B CN202110433122.XA CN202110433122A CN113200841B CN 113200841 B CN113200841 B CN 113200841B CN 202110433122 A CN202110433122 A CN 202110433122A CN 113200841 B CN113200841 B CN 113200841B
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crotonamide
heck coupling
racemic naproxen
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methoxynaphthyl
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张倩云
周宏伟
任炼军
石磊
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Jiaxing University
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Abstract

The invention discloses a novel process for synthesizing racemic naproxen based on Heck coupling, which comprises the following steps: (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-methoxy naphthyl-2-) -crotonamide in an alkaline solution of hypochlorite to generate 2- (6-methoxy naphthyl-2-) -propionaldehyde, directly adding chlorite without separation into the 2- (6-methoxy naphthyl-2-) -propionaldehyde, and oxidizing at room temperature to obtain the racemic naproxen. The process of the invention does not need to prepare highly active Grignard reagent, does not need strict anhydrous condition, has higher conversion rate and is easy to purify the product.

Description

Novel process for synthesizing racemic naproxen based on Heck coupling
Technical Field
The invention relates to a process for synthesizing racemic naproxen, in particular to a novel process for synthesizing racemic naproxen based on Heck coupling.
Background
The existing synthesis process of naproxen is mainly based on two basic raw materials, one is 2-acyl-6-methoxynaphthalene (route I or II), the other is 2-bromo-6-methoxynaphthalene, and four synthesis routes are mainly provided, specifically as follows:
(I)
Figure BDA0003031138420000011
(II)
Figure BDA0003031138420000012
(III)
Figure BDA0003031138420000013
(IV)
Figure BDA0003031138420000014
route I or II is based on 2-acyl-6-methoxynaphthalene as starting material, and has the important disadvantage that 2-acyl-6-methoxynaphthalene is relatively difficult to prepare. In the synthesis of 2-acyl-6-methoxy naphthalene, the first active site of naphthyl methyl ether is the ortho position of methoxy, the position needs to be protected in the prior art, and deprotection is carried out after acylation, so that the route is long, and the cost of the 2-acyl-6-methoxy naphthalene is high. Another important drawback is that the process for preparing naproxen from 2-acyl-6-methoxynaphthalene involves Dazen rearrangement or acyl ortho-halogenation, followed by ketal formation, rearrangement and hydrolysis, and has long route and difficult crystallization and purification of intermediate products.
Route III or IV based on 2-bromo-6-methoxynaphthalene as a starting material, naproxen is prepared by a grignard reaction or a coupling reaction. Route III, although having a high yield, involves the preparation of anhydrous and oxygen-free grignard reagents, and the invasion of industrial moisture is likely to cause unstable production quality, and the use of highly active magnesium metal in scale-up production is not favorable for safe production. The coupling of the type of route IV has the advantages of short route and cheap raw materials. However, an important drawback of this type of coupling is the low conversion, which affects the yield, while the unconverted starting material, 2-bromo-6-methoxynaphthalene, interferes with the purification of the product.
Disclosure of Invention
The invention aims to provide a novel process for synthesizing racemic naproxen based on Heck coupling, which does not need to prepare a highly active Grignard reagent or strict anhydrous condition, has higher conversion rate and is easy to purify the product.
In order to achieve the purpose, the invention provides a novel process for synthesizing racemic naproxen based on Heck coupling, and the synthetic route of the process is as follows:
Figure BDA0003031138420000021
(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-methoxy naphthyl-2-) -crotonamide in an alkaline solution of hypochlorite to generate 2- (6-methoxy naphthyl-2-) -propionaldehyde, directly adding chlorite without separation into the 2- (6-methoxy naphthyl-2-) -propionaldehyde, and oxidizing at room temperature to obtain the 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
Figure BDA0003031138420000022
The aprotic organic solvent is selected from N, N-dimethyl methylAny one or more than two of amide, 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 PdLnYmL is selected from aryl phosphine ligands, n is an integer between 0 and 4; y is selected from halogen anions or carboxylate radical, and m is an integer between 0 and 4; 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.
Preferably, the Heck coupling reaction is: 2-bromo-6-methoxynaphthalene and PdYmDissolving 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.
Preferably, the 2-bromo-6-methoxynaphthalene and PdYmThe molar ratio of the ligand L to the crotonamide to the base is 1: 0.005: 0.01: 1.5: 2.
preferably, the base is triethylamine; the ligand L is tri (2-methylphenyl) -phosphine; the PdymIs PdCl2。
Preferably, after the Heck coupling reaction is completed, insoluble matter is filtered off, the filtrate is concentrated, the concentrate is extracted with hot water, the aqueous phase is discarded, and the residue is recrystallized with aqueous ethanol, methanol or isopropanol to obtain 3- (6-methoxynaphthyl-2-) crotonamide.
Preferably, after the Heck coupling reaction is finished, insoluble materials are filtered by using diatomite.
Preferably, the hoffman degradation reaction is as follows: dripping an aprotic organic solvent containing 3- (6-methoxynaphthyl-2-) crotonamide into a polar solvent containing hypochlorite and hydroxide, keeping the reaction temperature not more 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.
Preferably, 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.
Preferably, the hypochlorite, chlorite is removed using an aqueous sulfite solution.
Preferably, 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, a filter cake is washed with water, filtrate is extracted by dichloromethane or dichloroethane and then concentrated, the concentrate and the filter cake are combined, and the mixture is recrystallized by using ethanol, methanol or isopropanol containing water to obtain the racemic naproxen.
The novel process for synthesizing racemic naproxen based on Heck coupling has the following advantages:
the process of the invention adopts 2-halo-6-methoxynaphthalene as the raw material instead of 2-acyl-6-methoxynaphthalene, which has advantages in raw material cost, and compared with the method adopting 2-halo-6-methoxynaphthalene, the method of the invention does not need to prepare highly active Grignard reagent, does not need strict anhydrous condition, has higher conversion rate and is easy to purify the product. In addition, the process of the invention uses less metal catalyst, and has low cost and low environmental pressure. The selection of the solvent and the catalyst for the coupling reaction in the process ensures that the process has high reaction yield, and the temperature control and the solvent selection of the Hofmann degradation reaction have a key effect on the conversion of reactants.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 3- (6-methoxynaphthyl-2-) crotonamide of the present invention.
FIG. 2 shows the nuclear magnetic carbon spectrum of 3- (6-methoxy naphthyl-2-) crotonamide of the present invention.
FIG. 3 is a nuclear magnetic hydrogen spectrum of racemic naproxen of the present invention.
FIG. 4 is a nuclear magnetic carbon spectrum of racemic naproxen of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A novel process for synthesizing racemic naproxen based on Heck coupling comprises the following specific steps:
(1) synthesis of intermediate 3- (6-methoxy naphthyl-2-) crotonamide
Figure BDA0003031138420000041
24 g (0.1mol) of 2-bromo-6-methoxynaphthalene, 88 mg (0.5mmol) of palladium chloride, 304 mg (1mmol) of tris (2-methylphenyl) -phosphine, 13 g (0.15mol) of crotonamide and 20 g (0.2mol) of triethylamine are dissolved in 100mL of dimethylformamide and, after purging with nitrogen three times, are heated to 130 ℃ in a closed manner and stirred for 20 h.
After the reaction was completed, cooling was performed, insoluble materials were filtered off with celite, the solvent was removed in vacuo from the filtrate, the residue was extracted twice with hot water, the aqueous phase was discarded, and the residue was recrystallized from ethanol to obtain 20.5 g of 3- (6-methoxynaphthyl-2-) crotonamide (nuclear magnetic hydrogen spectrum and carbon spectrum are shown in FIGS. 1 and 2), with a yield of 85%.
(2) Synthesis of racemic naproxen
Figure BDA0003031138420000051
150mL of dioxane solution containing 24 g (0.1mol) of 3- (6-methoxynaphthyl-2-) crotonamide is added dropwise into 100mL of aqueous solution containing 0.12mol of sodium hypochlorite and 0.24mol of sodium hydroxide, the reaction temperature is kept at 10 ℃ in an ice bath, and after the raw materials are completely reacted by thin-layer chromatography, aqueous sodium sulfite solution is added dropwise until the potassium iodide starch test paper does not turn blue any more.
Adjusting pH value to neutral by phosphoric acid (other acids have poor effect), heating and refluxing for 3h, cooling to normal temperature, adding sodium chlorite aqueous solution, stirring overnight until the thin-layer chromatography shows that the aryl propionaldehyde is completely reacted.
Adjusting the pH value of the solution to be less than 3 by adopting phosphoric acid (other acids have poor effects), cooling in an ice water bath, filtering, and washing a 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 give 19.2 g of racemic naproxen with a yield of 83%, the nuclear magnetic hydrogen and carbon spectra are shown in fig. 3 and fig. 4.
While the present invention has been described in detail with reference to the preferred embodiments, it should be understood that the above description should not be taken as limiting the invention. Various modifications and alterations to this invention will become apparent to those skilled in the art upon reading the foregoing description. Accordingly, the scope of the invention should be determined from the following 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:
Figure DEST_PATH_IMAGE001
(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
Figure DEST_PATH_IMAGE002
、
Figure DEST_PATH_IMAGE003
Or
Figure DEST_PATH_IMAGE004
；
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 PdLnYmL 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 PdYmDissolving 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, PdYmThe 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 PdymIs 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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