CN101928263A - A kind of method for preparing eflurazine hydrochloride - Google Patents

Abstract

The invention discloses a method for preparing eflurazine hydrochloride. In the solvent, with tertiary amine as acid-binding agent, alkali metal halide or tetrabutylammonium halide as catalyst, under the above conditions, 1-[bis(4-fluorophenyl)methyl]piperazine and excess ethyl chloride Oxyacetic acid derivatives are heated and condensed to obtain 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid derivatives, and then hydrolyzed and acidified to obtain ethyl hydrochloride Fluorizine. The raw material is easy to obtain, the operation is simple and convenient, the yield is increased, the cost is reduced, and the method is suitable for industrialized production.

Description

A kind of method for preparing eflurazine hydrochloride

technical field

The invention relates to a method for preparing eflurazine hydrochloride, and the compound can treat allergic rhinitis and conjunctivitis. the

Background technique

Allergic rhinitis (Allergic Rhinitis), also known as allergic rhinitis, is caused by the body's allergy to certain substances. Its pathogenesis is that allergens cause the body to release histamine, causing a series of allergic symptoms to appear. The clinical features of this disease include nasal itching, continuous sneezing, and a large amount of watery nasal discharge, sometimes accompanied by extreme itching in the conjunctiva, palate, and even the external auditory canal. Due to the swelling of the nasal mucosa, patients often have nasal congestion and hyposmia. Patients usually have no obvious systemic symptoms, but if complicated by sinusitis, they may have symptoms such as fever, cheek distending pain, fatigue and anorexia. the

The treatment principles of this disease are: ① avoid inhalation of allergens that can be stimulated; ② apply appropriate antihistamine drugs; ③ antigen desensitization therapy. Antihistamines have been used clinically for many years. Their mechanism is mainly to block histamine receptors and play an anti-allergic effect. They are mainly used for the treatment of allergic rhinitis, allergic conjunctivitis and allergic skin diseases. Antihistamines are divided into the first generation and the second generation. The first generation easily penetrates the blood-brain barrier and produces sedative and anticholinergic effects. The second generation has no or weak central effects and does not cause side effects such as drowsiness. Therefore, it has more advantages in the treatment of allergic diseases. Common antihistamines are loratadine, fexofenadine, chlorpheniramine, cetirizine, azelastine, and astemizole. the

Eflurazine hydrochloride is an antihistamine drug developed by UCB SA in Belgium for the treatment of allergic rhinitis and conjunctivitis. It has completed phase III clinical trials and has begun to enter clinical practice. This product is a selective histamine H1 receptor antagonist, has no obvious anticholinergic and anti-serotonin effects, and has a small central inhibitory effect. It can be taken orally or externally. Topically applied to mucous membranes, the human body has good tolerance and safety to nasal spray administration, and no obvious adverse reactions related to drugs have been found. the

The chemical name of eflurazine hydrochloride is 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride. English chemical name: 2-[2-[4-[bis(4-fluorophenyl)methyl]-piperazinyl]ethoxy acetic acid dihydrochloride. The structural formula is as follows:

In EP0058146, two synthesis methods of eflurazine hydrochloride are described. Method 1: Condensation of 1-[bis(4-fluorophenyl)methyl]piperazine (I) and chloroethoxyacetamide (II) in hot xylene in the presence of sodium carbonate to generate 2-[2 -[4-[bis(4-fluorophenyl)methyl]-1-piperazine]ethoxyl]-acetamide (Ⅲ), then reflux hydrolysis and acidification with 4N NaOH in ethanol to obtain eflurazine hydrochloride . Method two: condense 1-[bis(4-fluorophenyl)methyl]piperazine (I) and methyl chloroethoxyacetate (IV) in hot xylene under the presence of sodium carbonate to generate 2-[ 2-[4-[bis(4-fluorophenyl)methyl]-1-piperazine]ethoxy]-acetic acid methyl ester (V), and then use 1NKOH in ethanol to reflux hydrolysis and acidification to obtain Eflurin hydrochloride Zinc. The synthetic route is as follows:

The reaction is completed by combining (II) and (III) or (IV) in xylene with potassium carbonate as an acid-binding agent under heating, and the reaction yield is moderate or low according to the difference of haloethoxyacetic acid derivatives. the

According to the report of patent WO009849, 2-[4-[bis(4-fluorophenyl)methyl]-1 - piperazine] ethanol (Ⅷ), the condensation product is protonated with sodium methoxide or sodium hydride and then reacted with sodium bromoacetate (Ⅸ), and finally acidified to obtain the target product - eflurazine hydrochloride. The synthetic route is as follows:

The advantage of this route is that Na ₂ CO ₃ or K ₂ CO ₃ is neutralized with HCl in the first step of the condensation reaction to reduce costs and simplify the reaction. Using EtONa instead of NaH as a proton acceptor also reduces costs and is safe to operate. , suitable for industrial production. The disadvantage is that distillation and purification under reduced pressure are required, the price of the raw material compounds for the three reactions is not cheap, and the steps are cumbersome. Therefore prior art needs a kind of low-cost, easy-to-operate, high-yield preparation method of eflurazine hydrochloride.

Contents of the invention

The invention relates to a preparation method of eflurazine hydrochloride, the purpose of which is to reduce the cost, improve the condensation reaction yield and simplify the separation and purification operation. the

In order to realize the above-mentioned purpose of the invention, the technical scheme provided by the present invention is as follows:

In solvent, with tertiary amine as acid-binding agent, alkali metal halide or tetrabutylammonium halide as catalyst, under the above conditions, 1-[bis(4-fluorophenyl)methyl]piperazine (2) and Excessive chloroethoxyacetic acid derivatives (3) are heated and condensed to obtain 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid derivatives (4 ), hydrolyzed to obtain eflurazine (5), and then acidified with hydrochloric acid to obtain eflurazine hydrochloride (1). the

The solvent is one of polar and non-polar solvents such as dimethylformamide, toluene, and xylene, or a mixture of more than one, and the best is xylene. the

The tertiary amine alkyl group is a C1-4 alkyl group, preferably a C2-3 alkyl group. the

The catalyst alkali metal halide alkali metal is sodium or potassium, the halogen is bromine or iodine; the halogen in the catalyst tetraalkylammonium halide is bromine or iodine, and the alkyl group is a C1-4 alkyl group, preferably a C3-4 alkyl group . the

The reaction temperature is 90-180°C, preferably 110-160°C. 

The chloroethoxyacetic acid derivative is chloroethoxyacetic acid ester, and the alcohol forming an ester with chloroethoxyacetic acid is a C1-4 alcohol, preferably a C1-2 alcohol. the

The molar ratio of 1-[bis(4-fluorophenyl)methyl]piperazine to the chloroethoxyacetic acid derivative is 1:1.0-2.0 mol, preferably 1:1.2-1.8 mol. the

The reaction time is 6-30 hours, preferably 10-25 hours. the

The invention provides the method for preparing eflurazine hydrochloride, comprising the following steps:

(1) In a solvent, with tertiary amine as acid binding agent, alkali metal halide or tetrabutylammonium halide as catalyst, 1-[bis(4-fluorophenyl)methyl]piperazine and chloroethoxyacetic acid Derivatives, after heating to reflux for 6 hours, add excess chloroethoxyacetic acid derivatives, continue to reflux for 8 hours, and condense to obtain 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazine Base] ethoxy] acetic acid derivatives. the

(2) The reaction solution was suction filtered, the filter cake was washed with a solvent, and the filtrate was rotary evaporated. the

(3) After adding the solvent, the raffinate is directly added to the aqueous sodium hydroxide solution for hydrolysis without purification. the

(4) Separate the water layer, adjust the pH value of the water phase with aqueous sodium hydroxide until the solution becomes turbid, extract with dichloromethane, and spin evaporate. the

(5) The residue was acidified with hydrochloric acid to obtain eflurazine hydrochloride. the

The advantage of the method for preparing eflurazine hydrochloride provided by the invention is:

(1) The product obtained by the preparation method of the present invention has high purity and high yield. the

(2) The raw materials in the present invention are simple and easy to obtain, the cost is low, the solvent is less toxic and easy to recycle. the

(3) The preparation process of the present invention is simple, which greatly simplifies the separation and purification operation in the later stage. the

Detailed ways

Embodiment one

Preparation of ethyl 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetate

1-[bis(4-fluorophenyl)methyl]piperazine 5.74g (0.02mol), ethyl chloroethoxyacetate 3.34g (0.02mol), triethylamine 4.04g (0.04mol), xylene 30ml , Heated to reflux, added 0.67 g (0.004 mol) of ethyl chloroethoxyacetate after 10 h of reaction and continued to reflux for 8 h. Stop the reaction, filter with suction, wash the filter cake with 20 ml of hot toluene, rotate the filtrate, and directly hydrolyze the residue without purification to obtain eflurizine hydrochloride. Yield 68.5%. the

Example two

Preparation of Methyl 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetate

1-[bis(4-fluorophenyl)methyl]piperazine 5.74g (0.02mol), methyl chloroethoxyacetate 3.05g (0.02mol), triisopropylamine 5.72g (0.04mol), tetrabutyl Ammonium iodide 0.07g (0.2mmol), xylene 30ml, heated to reflux, reacted for 10h, added 0.61g (0.004mol) of ethyl chloroethoxyacetate and continued to reflux for 8h. Stop the reaction, filter with suction, wash the filter cake with 20 ml of hot toluene, rotate the filtrate, and directly hydrolyze the residue without purification to obtain eflurizine hydrochloride. Yield 80.2%. the

Embodiment three

Preparation of ethyl 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetate

1-[bis(4-fluorophenyl)methyl]piperazine 5.74g (0.02mol), ethyl chloroethoxyacetate 3.34g (0.02mol), potassium iodide 0.033g (0.2mmol), triethylamine 4.04g (0.04mol), xylene 30ml, heated to reflux, after 10h of reaction, added 0.67g (0.004mol) of methyl chloroethoxyacetate and continued to reflux for 8h. Stop the reaction, filter with suction, wash the filter cake with 20 ml of hot toluene, rotate the filtrate, and directly hydrolyze the residue without purification to obtain eflurizine hydrochloride. Yield 75.3%. the

Embodiment four

Preparation of Methyl 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetate

1-[bis(4-fluorophenyl)methyl]piperazine 5.74g (0.02mol), methyl chloroethoxyacetate 3.05g (0.02mol), tetrabutylammonium iodide 0.07g (0.2mmol), 4.04g (0.04mol) of triethylamine and 30ml of xylene were heated to reflux. After 10 hours of reaction, 0.67g (0.004mol) of methyl chloroethoxyacetate was added to continue to reflux for 8 hours. Stop the reaction, filter with suction, wash the filter cake with 20 ml of hot toluene, rotate the filtrate, and directly hydrolyze the residue without purification to obtain eflurizine hydrochloride. Yield 85.8%. the

Embodiment five

Preparation of ethyl 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetate

1-[bis(4-fluorophenyl)methyl]piperazine 5.74g (0.02mol), ethyl chloroethoxyacetate 3.34g (0.02mol), tetrabutylammonium bromide 0.06g (0.2mmol), 5.72g (0.04mol) of triisopropylamine and 30ml of xylene were heated to reflux. After 10 hours of reaction, 0.67g (0.004mol) of ethyl chloroethoxyacetate was added to continue to reflux for 6 hours. Stop the reaction, filter with suction, wash the filter cake with 20 ml of hot toluene, rotate the filtrate, and directly hydrolyze the residue without purification to obtain eflurizine hydrochloride. Yield 83.1%. the

The above examples are further explanations of the present invention, but the present invention is not limited to these examples, and these examples do not limit the protection scope of the present invention in any way. the

Claims (8)

1. a method for preparing efletirizine dihydrochloride makes by following reaction, and reaction equation is as follows:

In solvent, with tertiary amine as acid binding agent, alkali metal halide or halogenation TBuA are as catalyzer, under these conditions, two (4-fluorophenyl) methyl of 1-[] piperazine (2) and excess chlorine ethoxyacetic acid ester (3) add thermal condensation and get 2-[2-[4-[pair of (4-fluorophenyl) methyl]-the 1-piperazinyl] oxyethyl group] acetic ester (3), hydrolysis gets Efletirizine (5), gets efletirizine dihydrochloride (1) with hcl acidifying again.

2. method according to claim 1 is characterized in that solvent is one or more mixtures in polarity and non-polar solvent such as dimethyl formamide, toluene, the dimethylbenzene, and the best is a dimethylbenzene.

3. method according to claim 1 is characterized in that the tertiary amine alkyl R as acid binding agent ₃R is the alkyl of C1～4 among the N, and the best is the alkyl of C2～3.

4. method according to claim 1 is characterized in that basic metal is sodium or potassium in the alkali metal halide and halogenation tetra-allkylammonium as catalyzer, and halogen is a bromine or iodine, and alkyl is the alkyl of C1～4, and the best is the alkyl of C3～4.

5. method according to claim 1 is characterized in that temperature of reaction is 90～180 ℃, and the best is 110～160 ℃.

6. method according to claim 1 is characterized in that the chloroethoxy acetogenin as raw material is the chloroethoxy acetic ester, and the alcohol that forms ester with chloroethoxy acetate is the alcohol of C1～4, and the best is the alcohol of C1～2.

7. method according to claim 1 is characterized in that two (4-fluorophenyl) methyl of 1-[] piperazine and chloroethoxy acetogenin mol ratio be 1: 1.0～2.0mol, the best is 1: 1.2～1.8mol.

8. method according to claim 1 is characterized in that the reaction times is 6～30h, and the best is 10～25h.