阅读说明：本技术 一种盐酸苄丝肼的合成方法 (A kind of synthetic method of benserazide hydrochloride ) 是由 王永 刘利刚 肖祖华 陈冠元 李云峰 于 2019-09-20 设计创作，主要内容包括：本发明涉及一种盐酸苄丝肼的合成方法,具体地,所述方法以丝氨酸甲酯盐酸盐为起始原料,首先进行氨基保护反应,然后依次经过胺酯交换反应、缩合反应、还原反应和脱保护反应后,最终获得了高纯度的盐酸苄丝肼。该方法原料便宜易得、操作简便且每一步产品的纯度和收率都很高,适合工业化。(The present invention relates to a kind of synthetic methods of benserazide hydrochloride; specifically; the method is using serine methyl ester hydrochloride as starting material; amido protecting reaction is carried out first; after amine ester exchange reaction, condensation reaction, reduction reaction and deprotection reaction, it is finally obtained the benserazide hydrochloride of high-purity.This method raw material is cheap and easily-available, purity easy to operate and each step product and yield are all very high, is suitble to industrialization.)

1. the synthetic method of benserazide hydrochloride, which is characterized in that the method includes the steps:

In formula, R is Boc or Cbz；

(1) in atent solvent, compound 7 is subjected to amido protecting with amino protecting agent and is reacted, to form compound 6；

(2) compound 6 and hydrazine hydrate are subjected to amine ester exchange reaction, to form compound 5；

(3) in atent solvent, compound 5 and compound 4 are subjected to condensation reaction, to form compound 3；

(4) in atent solvent, in the presence of reducing agent and catalyst, compound 3 is subjected to reduction reaction, to form chemical combination Object 2；

(5) in atent solvent, compound 2 is subjected to amino deprotection reaction, to form compound 1.

2. synthetic method as described in claim 1, which is characterized in that in step (1), the amino protecting agent is (Boc)₂O or CbzCl。

3. synthetic method as described in claim 1, which is characterized in that in step (2), the hydrazine hydrate be 80% hydration Hydrazine.

4. synthetic method as described in claim 1, which is characterized in that after the completion of reaction include following rear place in step (3) It manages step: after reaction, filtering reaction mixture, obtain the crude product containing compound 3；Then crude product is tied again in methyl alcohol Crystalline substance collects solid, to obtain compound 3.

5. synthetic method as described in claim 1, which is characterized in that in step (3), the purity of obtained compound 3 >= 95%.

6. synthetic method as described in claim 1, which is characterized in that in step (4), the reducing agent is hydrogen.

7. synthetic method as described in claim 1, which is characterized in that in step (4), the catalyst is palladium charcoal or thunder Buddhist nun Nickel.

8. synthetic method as described in claim 1, which is characterized in that after the completion of reaction include following rear place in step (4) It manages step: after reaction, filtering reaction mixture, filter cake is eluted with methanol；Filtrate lower than 40 degree at a temperature of carry out it is dense Contracting, to obtain compound 2.

9. synthetic method as described in claim 1, which is characterized in that in step (4), the purity of obtained compound 2 >= 95%.

10. synthetic method as described in claim 1, which is characterized in that in step (5), after including following after the completion of reaction Processing step: after reaction, reaction mixture lower than 40 degree at a temperature of be concentrated, to obtain concentrate；In 0-5 Under degree, concentrate is beaten in ethanol, to obtain compound 1.

Technical field

The invention belongs to organic synthesis fields, and in particular to a kind of synthetic method of benserazide hydrochloride.

Background technique

Benserazide hydrochloride is shown below, and is a kind of periphery decarboxylase inhibitors, at present on medical market often with it is left-handed DOPA combines the treatment that compound formulation Benserazide is made for Parkinson's disease.

Benserazide hydrochloride is white or off-white color crystalline powder, soluble easily in water, does not dissolve in ethyl alcohol or acetone.Its property pole Its is unstable, extremely sensitive to the variation of solvent pH, light, temperature and humidity.

Summary of the invention

It is an object of the invention to provide a kind of synthetic methods of the benserazide hydrochloride of viable economically and suitable large-scale production.

The present invention provides the synthetic method of benserazide hydrochloride, the method includes the steps:

In formula, R is Boc or Cbz；

(1) in atent solvent, compound 7 is subjected to amido protecting with amino protecting agent and is reacted, to form compound 6；

(2) compound 6 and hydrazine hydrate are subjected to amine ester exchange reaction, to form compound 5；

(3) in atent solvent, compound 5 and compound 4 are subjected to condensation reaction, to form compound 3；

(4) in atent solvent, in the presence of reducing agent and catalyst, compound 3 is subjected to reduction reaction, to be formed Compound 2；

(5) in atent solvent, compound 2 is subjected to amino deprotection reaction, to form compound 1.

In another preferred example, in step (1), the amino protecting agent is (Boc)₂O or CbzCl.

In another preferred example, in step (1), the amino protecting agent is (Boc)₂O。

In another preferred example, in step (1), the amido protecting reaction carries out under alkaline condition.

In another preferred example, the alkaline condition is the condition that pH is 8-10.

In another preferred example, in step (1), the atent solvent is tetrahydrofuran, dioxane, methylene chloride, two Chloroethanes or combinations thereof.

In another preferred example, in step (1), the ratio between the additional amount of the atent solvent and the mole of compound 7 are 0.5:1~1:1 (L:mol).

In another preferred example, in step (1), the amido protecting reaction carries out under 0-15 degree (or 0-5 degree).

In another preferred example, in step (1), the amido protecting reaction carries out 1-5 hours (or 1-2 hours).

In another preferred example, after the completion of reaction include following post-processing step in step (1): after reaction, using Ethyl acetate extracts reaction mixture, collects organic phase and is concentrated, to obtain compound 6.

In another preferred example, contained after step (1) is the following steps are included: compound 7 is mixed with atent solvent The reactant of compound 7；After being 8-10 to pH with reactant of the alkaline aqueous solution adjusting containing compound 7, it is added dropwise contains thereto There is the solution of amino protecting agent to carry out amido protecting reaction；After reaction, reaction mixture is extracted with ethyl acetate, collection has Machine phase is simultaneously concentrated, to obtain compound 6.

In another preferred example, the alkaline aqueous solution is sodium bicarbonate aqueous solution, potassium bicarbonate aqueous solution or combinations thereof.

In another preferred example, in step (1), purity >=95% of obtained compound 6；More preferably >=96%.

In another preferred example, in step (1), yield >=90%.

In another preferred example, in step (2), the hydrazine hydrate be 80% hydrazine hydrate.

In another preferred example, in step (2), the molar ratio of the hydrazine hydrate and compound 6 is 2:1~1.5:1.

In another preferred example, in step (2), the amine ester exchange reaction carries out under 0-30 degree (or room temperature).

In another preferred example, in step (2), the amine ester exchange reaction carries out 10-30 hours (or 10-20 hours).

In another preferred example, after the completion of reaction include following post-processing step in step (2): after reaction, to Water and ethyl alcohol are added in reaction mixture, is then concentrated under reduced pressure, obtains concentrate；Ethyl alcohol and acetic acid second are added into concentrate Ester is recrystallized at room temperature, collects the crystal of precipitation, to obtain compound 5.

In another preferred example, step (2) hydrazine hydrate is added dropwise into compound 6, so the following steps are included: under 0-5 degree Carry out amine ester exchange reaction at room temperature afterwards；After reaction, water and ethyl alcohol are added into reaction mixture, then depressurizes dense Contracting, obtains concentrate；Ethyl alcohol and ethyl acetate are added into concentrate, is recrystallized at room temperature, collects the crystal of precipitation, To obtain compound 5.

In another preferred example, the ratio between mole of the additional amount of the water and ethyl alcohol and compound 6 for 1:1~1:3 (L: mol)；Preferably 1:2 (L:mol).

In another preferred example, the amount ratio of the water and ethyl alcohol is 1:5~1:3 (ml:ml)；Preferably 1:4 (ml: ml)。

In another preferred example, the ratio between the additional amount of the ethyl alcohol and ethyl acetate and the mole of compound 6 are 1.5:1 ~1:1 (L:mol)；Preferably 1.1:1 (L:mol).

In another preferred example, the amount ratio of the ethyl alcohol and ethyl acetate is 1:5~1:15 (ml:ml)；Preferably 1:10 (ml:ml).

In another preferred example, in step (2), purity >=95% of obtained compound 5；More preferably >=98%.

In another preferred example, in step (2), yield >=90%.

In another preferred example, in step (3), the atent solvent is methanol, ethyl alcohol, isopropanol, tetrahydrofuran, dioxy Six rings or combinations thereof.

In another preferred example, in step (3), the ratio between the additional amount of the atent solvent and the mole of compound 5 are 3:1~2:1 (L:mol).

In another preferred example, in step (3), the condensation reaction carries out at room temperature.

In another preferred example, in step (3), the condensation reaction carries out 10-30 hours (or 15-20 hours).

In another preferred example, after the completion of reaction include following post-processing step: after reaction, filtering reaction mixing Object obtains the crude product containing compound 3；Then crude product is recrystallized in methyl alcohol, solid is collected, to obtain compound 3.

In another preferred example, step (3) is the following steps are included: in atent solvent, at room temperature, compound 5 and changes It closes object 4 and carries out condensation reaction；After reaction, reaction mixture is filtered, the crude product containing compound 3 is obtained；Then by crude product It recrystallizes in methyl alcohol, solid is collected, to obtain compound 3.

In another preferred example, the ratio between mole of the additional amount of the methanol and compound 5 for 1:1~1:3 (L: mol)；Preferably 1:2 (L:mol).

In another preferred example, in step (3), purity >=95% of obtained compound 3.

In another preferred example, in step (3), purity >=98% of obtained compound 3.

In another preferred example, in step (3), yield >=95%.

In another preferred example, in step (4), the atent solvent is methanol, ethyl alcohol, isopropanol or combinations thereof.

In another preferred example, in step (4), the ratio between the additional amount of the atent solvent and the mole of compound 3 are 10:1~8:1 (L:mol).

In another preferred example, in step (4), the reducing agent is hydrogen.

In another preferred example, the pressure of the hydrogen is 2-5 bars.

In another preferred example, in step (4), the catalyst is palladium charcoal or Raney's nickel.

In another preferred example, in step (4), the catalyst is palladium charcoal.

In another preferred example, in step (4), the reduction reaction carries out at room temperature.

In another preferred example, in step (4), the reduction reaction carries out 1-10 hours (or 5 hours).

In another preferred example, after the completion of reaction include following post-processing step in step (4): after reaction, mistake Reaction mixture is filtered, filter cake is eluted with methanol；Filtrate lower than 40 degree at a temperature of be concentrated, to obtain compound 2.

In another preferred example, step (4) is the following steps are included: at room temperature, in the presence of reducing agent and catalyst, incite somebody to action Compound 3 carries out reduction reaction；After reaction, reaction mixture is filtered, filter cake is eluted with methanol；Filtrate is being lower than 40 degree At a temperature of be concentrated, to obtain compound 2.

In another preferred example, in step (4), purity >=95% of obtained compound 2.

In another preferred example, in step (4), purity >=98% of obtained compound 2.

In another preferred example, in step (4), yield >=95%.

In another preferred example, in step (5), the atent solvent is ethyl alcohol, methanol, isopropanol, tetrahydrofuran, dioxy Six rings or combinations thereof.

In another preferred example, in step (5), the ratio between the additional amount of the atent solvent and the mole of compound 2 are 70:1~80:1 (L:mol).

In another preferred example, in step (5), the amino deprotection reaction carries out in acid condition.

In another preferred example, the acid condition is in ethanol solution hydrochloride or hydrochloric acid methanol.

In another preferred example, in step (5), the amino deprotection reaction carries out at room temperature.

In another preferred example, in step (5), the amino deprotection reaction carries out 5-20 hours (or 5-10 hours).

It in another preferred example, after the completion of reaction include following post-processing step: after reaction, instead in step (5) Answer mixture lower than 40 degree at a temperature of be concentrated, to obtain concentrate；Under 0-5 degree, in ethanol by concentrate Mashing, to obtain compound 1.

In another preferred example, step (5) is the following steps are included: under 0-5 degree, toward containing compound 2 and atent solvent Mixture in ethanol solution hydrochloride is added dropwise；Then amino deprotection reaction is carried out at room temperature；After reaction, reaction mixing Object lower than 40 degree at a temperature of be concentrated, to obtain concentrate；Under 0-5 degree, concentrate is beaten in ethanol, from And obtain compound 1.

In another preferred example, after the mashing in ethanol is ethyl alcohol is added in concentrate and is beaten, it is cooled to 0-5 It spends and stirs 1-5 hours, solid is collected by filtration, to obtain compound 1.

In another preferred example, the mashing carries out under 30-50 degree (such as 40 degree).

In another preferred example, the ratio between the additional amount of ethyl alcohol and the mole of compound 2 are 1.5:1~2:1 (L:mol).

In another preferred example, the solid collected after filtering passes through under 40-50 degree to be dried under reduced pressure, to be changed Close object 1.

In another preferred example, in step (5), purity >=95% of obtained compound 1；More preferably >=99%.

In another preferred example, in step (5), yield >=93%.

Present invention has the main advantage that

The present invention provides a kind of synthetic method of new benserazide hydrochloride, this method is with serine methyl ester hydrochloride Beginning raw material, after first passing around amido protecting, then with hydrazine hydrate carry out amine ester exchange reaction, be condensed with tri hydroxybenzaldehyde it is anti- It answers, react to have obtained the benserazide by amido protecting by hydrogen reducing, finally by removing amino protecting group, finally obtain Benserazide hydrochloride.

Whole route can avoid using DMF, to avoid the DMF solvent compound for forming benserazide hydrochloride, eliminate subsequent remove Remove the tedious steps of DMF.The finally obtained benserazide hydrochloride of synthetic method of the invention is non-solvent compound.And it is of the invention In synthetic method, raw materials and reagents are cheap and easily-available, integrated operation is easy, product postprocessing is simple；Every single step reaction is produced It (has been more than 90%, some has been even more than 95%, wherein especially from compound 5 to compound 1 that the yield of object is very high Synthesis step, 80%) total recovery has been more than；The product purity that every single step reaction obtains is very high (to be more than 95%, has had It has been even more than 98%, wherein especially from compound 5 to the synthesis step of compound 1, the purity of each step product is above 98%；99.5%) purity of especially final step product hydrochloric acid benserazide has reached.The conjunction of benserazide hydrochloride of the invention It is very suitable to industrialize at method.

It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, In This no longer tires out one by one states.

Specific embodiment

The present invention provides a kind of synthetic methods of benserazide hydrochloride (i.e. compound 1) that new route is as follows:

In formula, R is Boc or Cbz.

Specifically, the synthetic method of the benserazide hydrochloride may include following steps (1) to step (5):

Step (1) is in atent solvent (such as tetrahydrofuran), by compound 7 and amino protecting agent (such as (Boc)₂O or CbzCl amido protecting reaction) is carried out, to form compound 6.

In another preferred example, in step (1), the amido protecting reaction carries out under alkaline condition.For example, being in pH Under conditions of 8-10.

In another preferred example, in step (1), the amido protecting reaction carries out under 0-15 degree (or 0-5 degree).

In another preferred example, in step (1), the amido protecting reaction carries out 1-5 hours (or 1-2 hours).

In another preferred example, contained after step (1) is the following steps are included: compound 7 is mixed with atent solvent The reactant of compound 7；After being 8-10 to pH with reactant of the alkaline aqueous solution adjusting containing compound 7, it is added dropwise contains thereto There is the solution of amino protecting agent to carry out amido protecting reaction；After reaction, reaction mixture is extracted with ethyl acetate, collection has Machine phase is simultaneously concentrated, to obtain compound 6.

In another preferred example, the alkaline aqueous solution is sodium bicarbonate aqueous solution.

In another preferred example, in step (1), purity >=95% of obtained compound 6；More preferably >=96%.

In another preferred example, in step (1), yield >=90%.

Compound 6 and hydrazine hydrate (such as 80% hydrazine hydrate) are carried out amine ester exchange reaction by step (2), thus formed Close object 5.

In another preferred example, in step (2), the amine ester exchange reaction carries out under 0-30 degree (or room temperature).

In another preferred example, in step (2), the amine ester exchange reaction carries out 10-30 hours (or 10-20 hours).

In another preferred example, step (2) hydrazine hydrate is added dropwise into compound 6, so the following steps are included: under 0-5 degree Carry out amine ester exchange reaction at room temperature afterwards；After reaction, water and ethyl alcohol (such as water and ethyl alcohol are added into reaction mixture Ratio be 1:4, ml:ml), be then concentrated under reduced pressure, obtain concentrate；Be added into concentrate ethyl alcohol and ethyl acetate (such as The ratio of ethyl alcohol and ethyl acetate is 1:10, ml:ml), it is recrystallized at room temperature, collects the crystal of precipitation, to obtain Compound 5.

In another preferred example, in step (2), purity >=95% of obtained compound 5；More preferably >=98%.

In another preferred example, in step (2), yield >=90%.

Step (3) carries out condensation reaction in atent solvent (such as isopropanol), by compound 5 and compound 4, thus shape At compound 3.

In another preferred example, in step (3), the condensation reaction carries out at room temperature.

In another preferred example, in step (3), the condensation reaction carries out 10-30 hours (or 15-20 hours).

In another preferred example, step (3) is the following steps are included: in atent solvent, at room temperature, compound 5 and changes It closes object 4 and carries out condensation reaction；After reaction, reaction mixture is filtered, the crude product containing compound 3 is obtained；Then by crude product It recrystallizes in methyl alcohol, solid is collected, to obtain compound 3.

In another preferred example, in step (3), purity >=95% of obtained compound 3；More preferably >=98%.

In another preferred example, in step (3), yield >=95%.

Step (4) exists in atent solvent (such as methanol) in reducing agent (such as hydrogen) and catalyst (such as palladium charcoal) Under, compound 3 is subjected to reduction reaction, to form compound 2.

In another preferred example, the pressure of the hydrogen is 2-5 bars.

In another preferred example, in step (4), the reduction reaction carries out at room temperature.

In another preferred example, in step (4), the reduction reaction carries out 1-10 hours (or 5 hours).

In another preferred example, step (4) is the following steps are included: at room temperature, in the presence of reducing agent and catalyst, incite somebody to action Compound 3 carries out reduction reaction；After reaction, reaction mixture is filtered, filter cake is eluted with methanol；Filtrate is being lower than 40 degree At a temperature of be concentrated, to obtain compound 2.

In another preferred example, in step (4), purity >=95% of obtained compound 2；More preferably >=98%.

In another preferred example, in step (4), yield >=95%.

Step (5) carries out amino deprotection reaction in atent solvent (such as ethyl alcohol), by compound 2, thus formed Close object 1.

In another preferred example, in step (5), the amino deprotection reaction carries out in acid condition.For example, in salt In sour ethanol solution.

In another preferred example, in step (5), the amino deprotection reaction carries out at room temperature.

In another preferred example, in step (5), the amino deprotection reaction carries out 5-20 hours (or 5-10 hours).

In another preferred example, step (5) is the following steps are included: under 0-5 degree, toward containing compound 2 and atent solvent Mixture in ethanol solution hydrochloride is added dropwise；Then amino deprotection reaction is carried out at room temperature；After reaction, reaction mixing Object lower than 40 degree at a temperature of be concentrated, to obtain concentrate；Under 0-5 degree, concentrate is beaten in ethanol, from And obtain compound 1.

In another preferred example, after the mashing in ethanol is ethyl alcohol is added in concentrate and is beaten, it is cooled to 0-5 It spends and stirs 1-5 hours, solid is collected by filtration, to obtain compound 1.

In another preferred example, the ratio between the additional amount of ethyl alcohol and the mole of compound 2 are 1.5:1~2:1 (L:mol).

In another preferred example, the solid collected after filtering passes through under 40-50 degree to be dried under reduced pressure, to be changed Close object 1.

In another preferred example, in step (5), purity >=95% of obtained compound 1；More preferably >=99%.

In another preferred example, in step (5), yield >=93%.

Benserazide hydrochloride property is unstable, extremely sensitive to the variation of solvent pH, light, temperature and humidity.Therefore, Synthetic hydrochloric acid benserazide is extremely difficult.And product benserazide hydrochloride (i.e. compound 1) yield that synthetic method of the invention obtains It is very high with purity；And this method raw material is cheap and easily-available, easy to operate, can obtain in industrial applications more preferably economical Benefit.

Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are weight percent and weight Number.Experimental material used in following embodiment and reagent can obtain unless otherwise instructed from commercially available channel.