CN102887838A - Preparation method of guanfacine hydrochloride - Google Patents

Abstract

The invention discloses a preparation method of guanfacine hydrochloride, comprising the steps of carrying out esterification reaction to obtain 2,6-dichlorobenzene methyl acetate by taking 2,6-dichlorobenzene acetic acid and methanol as raw materials and taking concentrated sulfuric acid as a catalyst, carrying out reaction on industrial-grade sodium ethoxide-ethanol solution and guanidine hydrochloride to obtain free guanidine ethanol solution, dissolving the obtained 2,6-dichlorobenzene methyl acetate in absolute ethyl alcohol to obtain 2,6-dichlorobenzene methyl acetate solution, carrying out reaction on the 2,6-dichlorobenzene methyl acetate solution and the free guanidine ethanol solution to obtain guanfacine, and finally dissolving the obtained guanfacine in absolute ethyl alcohol and adding hydrogen chloride ethanol solution for reaction to obtain the product guanfacine hydrochloride. According to the preparation method, the preparation of free guanidine is improved by selecting the industrial-grade sodium ethoxide-ethanol solution which is low in cost and wide in source and the use of the relatively expensive sodium iso-propoxide and isopropanol is avoided, so that the cost is greatly reduced, the operation is more simple and convenient, the process is stable and the yield and purity are improved.

Description

The preparation method of guanfacine hydrochloride

technical field

The invention relates to the pharmaceutical preparation technology in the field of pharmacy, in particular to a preparation method of guanfacine hydrochloride.

Background technique

Guanfacine hydrochloride is an antihypertensive drug used to treat moderate to severe hypertension. The chemical name is N-amidino-2-(2,6-dichlorophenyl)acetamide monohydrochloride, its molecular formula is: C ₉ H ₉ Cl ₂ N ₃ O·HCl, its molecular weight is 282.55, and its structural formula is:

Guanfacine hydrochloride is a white to off-white crystalline powder, insoluble in water and ethanol, and has a relatively high solubility in methanol (>30mg/mg).

，规格为1mg或2mg。 Guanfacine hydrochloride is a selective α ₂ -adrenergic receptor potentiator, which was first used in the treatment of moderate to severe hypertension.

, the specification is 1mg or 2mg.

Since guanfacine hydrochloride has a strong central action, and the drug has a high plasma protein binding rate, the release rate of the common dosage form is too fast, resulting in a high peak blood concentration, which induces side effects, such as drowsiness, dizziness, difficulty falling asleep, Nausea, vomiting, forgetfulness, etc.

Contents of the invention

The technical problem to be solved in the present invention is to provide a guanfacine hydrochloride method with simpler operation, lower production cost, simple process steps, higher yield and higher purity in view of the deficiencies in the existing preparation methods of guanfacine hydrochloride. Xin's preparation method.

In order to solve the above problems, the technical solution adopted in the present invention is:

The present invention provides a kind of preparation method of guanfacine hydrochloride, described preparation method comprises the following steps:

a, the preparation of 2,6-dichlorophenylacetic acid methyl ester:

Using 2,6-dichlorophenylacetic acid and methanol as raw materials, using concentrated sulfuric acid (concentrated sulfuric acid with a mass percentage concentration of 98%) as a catalyst, first add raw material methanol into the reaction vessel, and then add raw material 2,6- Dichlorophenylacetic acid, add catalyst concentrated sulfuric acid dropwise, heat and reflux, 2,6-dichlorophenylacetic acid and methanol undergo esterification reaction at 80-90 °C, and the end point of the esterification reaction is determined by TLC until the raw material point disappears After the esterification reaction is finished, excess methanol is removed, the resulting reaction solution is poured into ice water and mixed to obtain a solution, then ethyl acetate is used to extract the obtained solution, after the extraction, the organic phase is combined, and saturated sodium bicarbonate is used to extract the organic phase. Washing, drying with anhydrous sodium sulfate, filtering, and finally distilling off ethyl acetate to obtain a colorless transparent liquid is methyl 2,6-dichlorophenylacetate;

The volume of methanol added is 4 to 6 times the mass of 2,6-dichlorophenylacetic acid; the added amount of concentrated sulfuric acid is 1 to 3 times the molar weight of 2,6-dichlorophenylacetic acid;

B, the preparation of free guanidine ethanol solution:

First, absolute ethanol is added to technical grade sodium ethoxide to fully dissolve to obtain technical grade sodium ethoxide ethanol solution, then guanidine hydrochloride is added at room temperature, the quality of guanidine hydrochloride added is 1 to 2 times the quality of technical grade sodium ethoxide, and Afterwards, fully stir, react for 16-24 h, and filter after the reaction to obtain free guanidine ethanol solution;

c, the preparation of guanfacine:

Dissolving the 2,6-dichlorophenylacetic acid methyl ester prepared in step a in absolute ethanol whose volume is 2 to 4 times the mass of 2,6-dichlorophenylacetic acid methyl ester to obtain 2,6-dichlorophenylacetic acid Methyl ester solution; then dropwise add 2 to 3 times the free guanidine ethanol solution prepared in step b of the volume of 2,6-dichlorophenylacetic acid methyl ester solution to stir, and react at room temperature, as measured by TLC, when 2 , when the point of methyl 6-dichlorophenylacetate disappears, the reaction reaches the end point. After the reaction, the ethanol is spin-dried, and the obtained reactant is washed with dichloromethane, suction filtered, vacuum-dried after suction filtration, and obtained after drying The white solid is guanfacine;

d, the preparation of guanfacine hydrochloride:

Add guanfacine prepared in step c to 1 to 2 times the volume of absolute ethanol for stirring and suspension, then dropwise add 1 to 2 times the volume of hydrogen chloride ethanol solution for stirring, and react at 20 to 40°C for 6 to After 12 hours of reaction, a reaction product was obtained, and the obtained reaction product was filtered, and then vacuum-dried to obtain a white solid after drying, which was the product of guanfacine hydrochloride.

According to the above-mentioned preparation method of guanfacine hydrochloride, the reaction solution obtained in step a is poured into ice water and mixed to obtain a solution. During this process, the volume ratio between the ice water and the reaction solution obtained is 3 to 5: 1.

According to the above-mentioned preparation method of guanfacine hydrochloride, as described in step a, ethyl acetate is then used to extract the obtained solution, and the volume ratio between ethyl acetate and the obtained solution is 3 to 5 during the extraction process. :1.

According to the above-mentioned preparation method of guanfacine hydrochloride, as described in step b, at first dehydrated alcohol is added into technical grade sodium ethoxide and fully dissolved, and the volume of dehydrated alcohol added in this process is 4～6 of the quality of technical grade sodium ethoxide. times.

According to the above-mentioned preparation method of guanfacine hydrochloride, vacuum drying is carried out after the suction filtration described in step c, and the conditions for vacuum drying are that the vacuum degree is 0.06-0.09 mPa, the temperature is 50-70 ° C, and the drying time is 12-16 mPa. h.

According to the above-mentioned preparation method of guanfacine hydrochloride, vacuum drying is carried out after filtering as described in step d, and the conditions of vacuum drying are that the vacuum degree is 0.06-0.09 mPa, the temperature is 50-70°C, and the drying time is 12-16 h .

Positive beneficial effect of the present invention:

1. The technical scheme of the present invention selects 2,6-dichlorophenylacetic acid as the starting raw material, methyl esterifies in methanol under the catalysis of concentrated sulfuric acid to obtain 2,6-dichlorophenylacetic acid methyl ester, and then guanidine in free guanidine ethanol solution Decomposition obtains guanfacine, and guanfacine is salified in ethanol hydrogen chloride solution to obtain guanfacine hydrochloride.

2, the technical scheme of the present invention has selected the industrial grade sodium ethylate ethanol solution with low cost and wide sources to improve the preparation process of free guanidine, avoiding the use of more expensive sodium isopropoxide and isopropanol, and ethanol is easier to recycle as a solvent, and It can be recycled directly, which greatly reduces the preparation cost and makes the operation easier. The technological operation steps adopted by the technical solution of the present invention are simple and the technological process is stable.

3. Adopt the technical scheme of the present invention to prepare guanfacine hydrochloride, and its yield and purity have been improved. Technical scheme of the present invention compares with existing guanfacine hydrochloride preparation method, and the yield of the present invention has improved 50% (document Bream JB et al. Arzneim-Forsch, 1975, 25:1477 report molar total yield is 27.2%, this The total molar yield of the invention is 77.5%); the liquid phase purity of the product guanfacine hydrochloride obtained in the present invention is 100%, and each technical index meets the USP34 standard.

4. The product guanfacine hydrochloride can be prepared by utilizing the technical solution of the present invention, which is proved by accompanying drawings 1, 2 and 3, fully illustrated by accompanying drawings 1-3, and the product obtained by utilizing the technical solution of the present invention is guanfacine hydrochloride .

Description of drawings:

Fig. 1 The infrared absorption spectrogram of product Guanfacine hydrochloride obtained from the present invention;

Fig. 2 The hydrogen spectrogram of product Guanfacine hydrochloride obtained from the present invention;

Fig. 3 is the mass spectrogram of product guanfacine hydrochloride obtained in the present invention.

Detailed ways:

The present invention is further set forth below in conjunction with embodiment, but content of the present invention is not limited.

Embodiment 1: the preparation method of guanfacine hydrochloride of the present invention, the detailed steps of described preparation method are as follows:

a, the preparation of 2,6-dichlorophenylacetic acid methyl ester:

Using 2,6-dichlorophenylacetic acid and methanol as raw materials, using concentrated sulfuric acid (98% concentration of concentrated sulfuric acid by mass) as a catalyst, the volume of methanol added is 5 times the mass of 2,6-dichlorophenylacetic acid , the quality of concentrated sulfuric acid added is 1 times of the quality of 2,6-dichlorophenylacetic acid;

First, the raw material methanol is added to the reaction vessel, then the raw material 2,6-dichlorophenylacetic acid is added, the catalyst concentrated sulfuric acid is added dropwise, and heating and reflux is carried out. 2,6-dichlorophenylacetic acid and methanol undergo esterification reaction at 85°C. Measured by TLC until the raw material point disappears, it is the end point of the esterification reaction; after the esterification reaction is completed, excess methanol is removed, and the resulting reaction solution is poured into ice water and mixed to obtain a solution (the volume added between the ice water and the gained reaction solution ratio of 4:1), and then use ethyl acetate to extract the obtained solution (the volume ratio between ethyl acetate and the obtained solution is 4:1), combine the organic phase after extraction, and use saturated bicarbonate Wash the obtained organic phase with sodium, dry and filter with anhydrous sodium sulfate, and finally evaporate ethyl acetate to obtain a colorless transparent liquid that is methyl 2,6-dichlorophenylacetate;

B, the preparation of free guanidine ethanol solution:

First add absolute ethanol to industrial grade sodium ethoxide to fully dissolve (the volume of absolute ethanol added is 5 times the mass of industrial grade sodium ethoxide) to obtain industrial grade sodium ethoxide ethanol solution, then add guanidine hydrochloride and hydrochloric acid at room temperature The quality of guanidine added is 2 times of the quality of industrial-grade sodium ethylate, fully stirred after adding, reacted for 20h, and filtered after the reaction to obtain free guanidine ethanol solution;

c, the preparation of guanfacine:

Dissolve the 2,6-dichlorophenylacetic acid methyl ester prepared in step a in absolute ethanol whose volume is 3 times the mass of 2,6-dichlorophenylacetic acid methyl ester to obtain 2,6-dichlorophenylacetic acid methyl ester solution; then dropwise add 3 times the free guanidine ethanol solution prepared in step b of the volume of 2,6-dichlorophenylacetic acid methyl ester solution to stir, and react at room temperature, as determined by TLC, when 2,6-dichlorophenylacetic acid When the point of methyl chlorophenylacetate disappears, the reaction reaches the end point. After the reaction, the ethanol is spin-dried, and the gained reactant is washed with dichloromethane, suction filtered, and vacuum-dried after the suction filtration (vacuum degree is 0.08mPa, temperature at 60°C, and the drying time was 14 h), the white solid obtained after drying was guanfacine;

d, the preparation of guanfacine hydrochloride:

Add guanfacine prepared in step c to 2 times the volume of absolute ethanol for stirring and suspension, then dropwise add 2 times the volume of hydrogen chloride ethanol solution for stirring, react at 30°C for 9 hours, and obtain the reaction product after the reaction, The resulting reaction product was filtered, and then vacuum-dried (vacuum degree of 0.08 mPa, temperature of 60°C, drying time of 14 h), and a white solid was obtained after drying, which was the product of guanfacine hydrochloride.

Embodiment 2: basically the same as Embodiment 1, the difference is:

In step a: the volume of methanol added is 4 times the mass of 2,6-dichlorophenylacetic acid, and the mass of concentrated sulfuric acid added is 0.5 times the mass of 2,6-dichlorophenylacetic acid;

2,6-dichlorophenylacetic acid and methanol are subjected to esterification reaction at 80°C; the resulting reaction solution is poured into ice water and mixed to obtain a solution (the volume ratio between ice water and the obtained reaction solution is 3:1) , and then use ethyl acetate to extract the obtained solution (the volume ratio between ethyl acetate and the obtained solution is 3:1);

In step b: at first dehydrated alcohol is added in technical grade sodium ethylate and fully dissolved (the volume that dehydrated alcohol adds is 6 times of technical grade sodium ethylate quality), obtains technical grade sodium ethylate ethanolic solution; The quality that guanidine hydrochloride adds is 1.5 times the mass of industrial grade sodium ethoxide, fully stirred after adding, and reacted for 24 hours;

In step c: dissolve the 2,6-dichlorophenylacetic acid methyl ester prepared in step a in dehydrated alcohol whose volume is 4 times the mass of 2,6-dichlorophenylacetic acid methyl ester; then dropwise add 2.5 times to 2 , Stir the free guanidine ethanol solution prepared in step b of the volume of 6-dichlorophenylacetic acid methyl ester solution; carry out vacuum drying after suction filtration (vacuum degree is 0.09mPa, temperature is 50°C, and drying time is 12 h);

In step d: add the guanfacine prepared in step c to 1.5 times the volume of absolute ethanol for stirring and suspension, then dropwise add 1.5 times the volume of hydrogen chloride ethanol solution for stirring, and react at 20°C for 12h, after the reaction The reaction product was obtained, and the obtained reaction product was filtered, and then vacuum-dried (vacuum degree of 0.09mPa, temperature of 50°C, and drying time of 12 h).

Embodiment 3: basically the same as Embodiment 1, the difference is:

In step a: the volume of methanol added is 6 times the mass of 2,6-dichlorophenylacetic acid, and the mass of concentrated sulfuric acid added is 1.5 times the mass of 2,6-dichlorophenylacetic acid;

2,6-dichlorophenylacetic acid and methanol are subjected to esterification reaction at 90°C; the resulting reaction solution is poured into ice water and mixed to obtain a solution (the volume ratio between ice water and the resulting reaction solution is 5:1) , and then use ethyl acetate to extract the obtained solution (the volume ratio between ethyl acetate and the obtained solution is 5:1);

In step b: at first dehydrated alcohol is joined in technical grade sodium ethylate and fully dissolved (the volume that dehydrated alcohol adds is 4 times of technical grade sodium ethylate quality), obtains technical grade sodium ethylate ethanolic solution; The quality that guanidine hydrochloride adds is 1 times the mass of industrial grade sodium ethoxide, fully stirred after adding, and reacted for 18 hours;

In step c: dissolve the 2,6-dichlorophenylacetic acid methyl ester prepared in step a in dehydrated alcohol whose volume is 2 times the mass of 2,6-dichlorophenylacetic acid methyl ester; then dropwise add 2 times to 2 , Stir the free guanidine ethanol solution prepared in step b of the volume of 6-dichlorophenylacetic acid methyl ester solution; carry out vacuum drying after suction filtration (vacuum degree is 0.06mPa, temperature is 70°C, and drying time is 12 h);

In step d: Add guanfacine prepared in step c to 1 volume of absolute ethanol for stirring and suspension, then dropwise add 1 volume of hydrogen chloride ethanol solution for stirring, and react at 40°C for 6 hours, after the reaction The reaction product was obtained, and the obtained reaction product was filtered, and then vacuum-dried (vacuum degree of 0.06mPa, temperature of 70°C, and drying time of 12 h).

Claims (6)

1. the preparation method of a Guanfacine Hydrochloride is characterized in that, described preparation method may further comprise the steps:

A, 2, the preparation of 6-fenac methyl esters:

With 2,6-fenac and methyl alcohol are raw material, take the vitriol oil as catalyzer, at first material benzenemethanol are added in the reaction vessel, then add raw material 2, the 6-fenac drips the catalyzer vitriol oil, carries out reflux, 2,6-fenac and methyl alcohol carry out esterification under 80～90 ℃, measures to the disappearance of raw material point through TLC, and then be the esterification terminal point; Esterification is removed excessive methyl alcohol after finishing, the gained reaction solution poured into be mixed to get solution in the frozen water, then adopt ethyl acetate that the solution that obtains is extracted, merge organic phase after the extraction, adopt saturated sodium bicarbonate to the gained organic phase wash, anhydrous sodium sulphate carries out drying, filtration, steam except ethyl acetate at last, obtain colourless transparent liquid and be 2,6-fenac methyl esters;

The volume that described methyl alcohol adds is 4～6 times of 2,6-fenac quality; The add-on of the described vitriol oil is 1～3 times of 2,6-fenac molar weight;

The preparation of b, free guanidine ethanolic soln:

At first dehydrated alcohol is joined fully dissolving in the technical grade sodium ethylate, obtain the technical grade alcohol sodium alcohol solution, then add at ambient temperature Guanidinium hydrochloride, the quality that Guanidinium hydrochloride adds is 1～2 times of technical grade sodium ethylate quality, fully stir after the adding, reaction 16～24 h, reaction is filtered after finishing, and obtains free guanidine ethanolic soln;

The preparation of c, guanfacine:

With step a prepare 2,6-fenac methyl esters is dissolved in the dehydrated alcohol that volume is 2～4 times of 2,6-fenac methyl esters quality, obtains 2,6-fenac methyl ester solution; Then drip 2～3 times to 2, the free guanidine ethanolic soln of the step b preparation of 6-fenac methyl ester solution volume stirs, react at ambient temperature, measure through TLC, when 2, when the point of 6-fenac methyl esters disappears, then be reacted to terminal point, be spin-dried for ethanol after reaction finishes, the gained reactant is adopted methylene dichloride washs, suction filtration, carry out vacuum-drying behind the suction filtration, obtain white solid after the drying and be guanfacine;

The preparation of d, Guanfacine Hydrochloride:

The guanfacine of step c preparation is added in the dehydrated alcohol of 1～2 times of volume and carry out stirring suspension, then the ethanol solution of hydrogen chloride that drips 1～2 times of volume stirs, under 20～40 ℃ of conditions, react 6～12h, obtain reaction product after the reaction, its gained reaction product is filtered, carry out vacuum-drying after the filtration, obtaining white solid after the drying is the Guanfacine Hydrochloride product.

2. the preparation method of Guanfacine Hydrochloride according to claim 1 is characterized in that: described in the step a gained reaction solution poured into and be mixed to get solution in the frozen water, the volume ratio that frozen water and gained reaction solution add between the two in this process is 3～5:1.

3. the preparation method of Guanfacine Hydrochloride according to claim 1, it is characterized in that: then adopt ethyl acetate that the solution that obtains is extracted described in the step a, the volume ratio that ethyl acetate and the solution that obtains add between the two in the extraction process is 3～5:1.

4. the preparation method of Guanfacine Hydrochloride according to claim 1, it is characterized in that: at first dehydrated alcohol is joined fully dissolving in the technical grade sodium ethylate described in the step b, the volume that dehydrated alcohol adds in this process is 4～6 times of technical grade sodium ethylate quality.

5. the preparation method of Guanfacine Hydrochloride according to claim 1, it is characterized in that: carry out vacuum-drying described in the step c behind the suction filtration, its vacuum drying condition is that vacuum tightness is 0.06～0.09 mPa, and temperature is 50～70 ℃, and be 12～16 h time of drying.

6. the preparation method of Guanfacine Hydrochloride according to claim 1, it is characterized in that: carry out vacuum-drying after filtering described in the steps d, its vacuum drying condition is that vacuum tightness is 0.06～0.09 mPa, and temperature is 50～70 ℃, and be 12～16 h time of drying.

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