Process for the preparation of benserazide hydrochloride and its use in a composition

Abstract

The application belongs to the field of medicine synthesis, and particularly discloses a preparation method of benserazide hydrochloride. The benserazide hydrochloride is prepared by the following steps: 2,3,4-trihydroxybenzaldehyde is used as a starting material to react with hydrazine hydrate to obtain 2,3,4-trihydroxybenzylhydrazine, and then the 2,3,4-trihydroxybenzylhydrazine is subjected to esterolysis reaction with serine methyl ester hydrochloride to obtain the target product benserazide hydrochloride. Compared with the method reported in the prior art, the method has the advantages of short reaction steps, simple reaction conditions, less process impurities, good quality control, simple raw materials, low large-scale production cost, and the like, and therefore the benserazide hydrochloride prepared by the method is good in application in a pharmaceutical composition.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of medicine synthesis, and particularly relates to a preparation method of benserazide hydrochloride. BACKGROUND

[0002] Benserazide hydrochloride is a peripheral decarboxylase inhibitor, and a structural formula is as follows:

[0003] ,

[0004] Benserazide hydrochloride is combined with levodopa to form a compound preparation of dopa hydrazide. Levodopa is an effective drug for treating Parkinson's disease, and its pharmacological action is achieved by converting it into dopamine in the brain through decarboxylase. Dopamine in the brain can improve Parkinson's disease. However, most of the levodopa is converted into dopamine by aromatic amino acid decarboxylase (AADC) in the periphery, and only a small amount can enter the brain. Benserazide hydrochloride, as an AADC inhibitor, can be used in combination with levodopa to inhibit the conversion of levodopa into dopamine in the periphery, thereby increasing the amount of levodopa entering the brain and effectively improving the symptoms of Parkinson's disease.

[0005] Benserazide hydrochloride is sensitive to the pH, temperature and humidity of the solvent due to the presence of phenolic hydroxyl groups, hydrazide and other functional groups in its structure, and has relatively poor stability.

[0006] There are many preparation methods of benserazide hydrochloride reported in literatures and patents at home and abroad, and the more typical methods are as follows.

[0007] The synthetic route reported in the prior art 1 US patent (US3178476) is as follows:

[0008] .

[0009] The route adopts 2,3,4-trihydroxybenzaldehyde as a starting material to perform a condensation reaction with serine hydrazide hydrochloride to obtain compound 4, and then performs a reduction reaction on compound 4 to obtain target compound 1. The process of reducing compound 4 to compound 1 is difficult to scale up, and the solubility of compound 4 and compound 1 in methanol is poor, and the reaction is very slow.

[0010] The synthetic route reported in the prior art 2 world patent (WO2022250620) is as follows:

[0011] .

[0012] The route is the same as the synthetic route of the prior art 1, but the reaction solvent used is different. Compound 5 obtained is a solvate of DMF, and after the solvate of compound 5 is removed, target compound 1 is obtained. The process of removing the solvate DMF solvent is complicated.

[0013] The synthetic route reported by prior art 3 Chinese patent (CN202110103770) is as follows:

[0014] ;

[0015] The reaction steps of this route are longer. Compound 10 is obtained by condensation reaction after protecting the amino group on serine, compound 11 is obtained by hydrogenation reduction, and then salt formation reaction is carried out to obtain the target compound 1. This route uses a fixed bed hydrogenation device, which has no obvious advantages.

[0016] Therefore, there is a need in the art to develop a simple operation, mild reaction, and suitable for industrial production of benserazide hydrochloride synthesis method SUMMARY

[0017] Therefore, the purpose of the present application is to provide a simple operation, mild reaction, and suitable for industrial production of benserazide hydrochloride synthesis method.

[0018] To achieve the technical purpose of the present application, the present application provides a synthesis method of benserazide hydrochloride, which comprises the following steps:

[0019] The synthetic route is as follows:

[0020] .

[0021] Step 1: Amine reduction reaction of 2,3,4-trihydroxybenzaldehyde with hydrazine hydrate in a polar solvent to obtain 2,3,4-trihydroxybenzyl hydrazine, the reaction formula is as follows:

[0022] ;

[0023] In step 1, the polar solvent is methanol, ethanol, tetrahydrofuran, DMF, acetonitrile, DMAC or a combination thereof;

[0024] In step 1, the reducing agent is one or a combination of pd / C, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride;

[0025] In step 1, the ratio of the amount of polar solvent added to the mass of the compound is 10:1 to 15:1 (ml: g);

[0026] In step 1, the hydrazine hydrate is 80% hydrazine hydrate;

[0027] In step 1, the molar ratio of hydrazine hydrate to 2,3,4-hydroxybenzaldehyde is 1.2 to 1.5:1;

[0028] In step 1, the amine reduction reaction is carried out at 0-15℃;

[0029] In step 1, the amine reduction reaction is performed for 2-5 h.

[0030] In step 1, the purity of the obtained 2,3,4-trihydroxybenzylhydrazine is ≥98%.

[0031] In step 1, the yield is ≥90%.

[0032] In step 2, the hydrazinolysis reaction of 2,3,4-trihydroxybenzylhydrazine and serine methyl ester hydrochloride in a polar solvent obtains the target compound benserazide hydrochloride, and the reaction formula is as follows:

[0033]

[0034] In step 2, the polar solvent is methanol, ethanol, tetrahydrofuran, DMF, acetonitrile, DMAC or a combination thereof.

[0035] In step 2, the ratio of the amount of the polar solvent added to the mass of 2,3,4-trihydroxybenzylhydrazine is 10:1-15:1 (ml: g).

[0036] In step 2, the molar ratio of 2,3,4-trihydroxybenzylhydrazine to serine methyl ester hydrochloride is 1:1-1.2.

[0037] In step 2, the reaction is performed at 30-50°C.

[0038] In step 2, the reaction is performed for 8-12 h.

[0039] In step 2, the purity of the obtained benserazide hydrochloride is ≥99%.

[0040] In step 2, the yield is ≥80%.

[0041] In step 2, after the reaction is completed, cooling to 20-25°C, adding 10-15 times the volume of isopropanol, stirring at 20-25°C for 12-18 h, filtering, and drying obtain benserazide hydrochloride.

[0042] The present application has the advantages of short steps, convenient operation and being beneficial to mass production.

[0043] The present application has the advantages of mild preparation conditions, less process impurities, and a purity of ≥99% of the prepared benserazide hydrochloride.

[0044] ​The present application provides a preparation route and method of benserazide hydrochloride, which has the advantages of short preparation route, easy availability of raw materials, simple operation, high yield, less impurities, high product purity, etc. The prepared benserazide hydrochloride has a purity of >99% and a total yield of >70%. Embodiments

[0045] For further understanding of the present application, the preparation method of benserazide hydrochloride provided by the present application is described in detail below in combination with examples. It should be understood that these examples are only for further detailed description of the features of the present application, and are not a limitation on the scope of the present application or the scope of claims of the present application.

[0046] Example 1

[0047] 1) Preparation of 2,3,4-trihydroxybenzylhydrazine

[0048] 2,3,4-trihydroxybenzaldehyde (50 g, 0.324 mol) and hydrazine hydrate (26 g, 0.41 mol) were added to 600 ml of methanol, stirred at room temperature for 30 min, cooled to 10°C, and then sodium borohydride (6.2 g, 0.16 mol) was slowly added. After the addition was completed, the reaction was carried out at 10°C for 3 h. After the reaction was completed, the remaining material was concentrated under reduced pressure, and then 300 ml of ethanol was added. After stirring for 12 h, the product was filtered and dried to obtain 51 g of product with a yield of 92% and an HPLC purity of 98.3%.

[0049] 2) Preparation of benserazide hydrochloride

[0050] 2,3,4-trihydroxybenzylhydrazine (30 g, 0.176 mol) and serine methyl ester hydrochloride (33 g, 0.21 mol) were dissolved in 300 ml of methanol and heated to 40°C for 10 h. After the reaction was completed, the reaction was cooled to 20-25°C, and then isopropyl alcohol (300 ml) was slowly added. After stirring for 10 h at 20-25°C, the product was filtered and washed with 50 ml of isopropyl alcohol once. After drying, benserazide hydrochloride (42 g) was obtained with a yield of 81% and an HPLC purity of 99.1%. Example

[0051] 1) Preparation of 2,3,4-trihydroxybenzylhydrazine

[0052] Take 2,3,4-trihydroxybenzaldehyde (100 g, 0.628 mol), hydrazine hydrate (60 g, 0.94 mol) into 1500 ml of methanol, stir at room temperature for 30 min, cool to 15 °C, add sodium borohydride (12 g, 0.314 mol), after adding, react at 15 °C for 3 h, the reaction is completed, concentrate under reduced pressure, add 600 ml of ethanol to the residue, stir for 12 h, filter and dry to obtain 100.5 g of product, the yield is 91%, and the HPLC purity is 98.5%.

[0053] 2) Preparation of benserazide hydrochloride

[0054] Dissolve 2,3,4-trihydroxybenzylhydrazine (100 g, 0.587 mol) and serine methyl ester hydrochloride (91 g, 0.587 mol) in 1000 ml of methanol, heat to 45 °C and react for 10 h, after the reaction is completed, cool to 20-25 °C, slowly add 1500 ml of isopropyl alcohol, stir at 20-25 °C for 12 h, filter, wash the filter cake with 100 ml of isopropyl alcohol once, and dry to obtain 142 g of benserazide hydrochloride, the yield is 82%, and the HPLC purity is 99.3%.

[0055] Example 3

[0056] Preparation of dopa benserazide tablets, prescription

[0057] Substance Amount Levodopa 100g Benserazide hydrochloride 28.5g Mannitol 51.6g Microcrystalline cellulose 19.3g Crospovidone 10g Pre-gelatinized starch 10g Red iron oxide 1.5g Dicalcium phosphate, anhydrous 50g Ethyl cellulose 1.5g Silicon dioxide 0.5g Magnesium stearate 2.75g ;

[0058] Preparation method:

[0059] Preparation of levodopa granules: take the prescription amount of levodopa, mannitol, microcrystalline cellulose and cross-linked povidone, and perform wet granulation with starch paste as the binder, dry, and sieve to 18 mesh to obtain levodopa granules;

[0060] Preparation of benserazide hydrochloride granules: take the prescription amount of benserazide hydrochloride and anhydrous calcium hydrogen phosphate, and perform wet granulation with ethyl cellulose solution as the binder, dry, and sieve to 18 mesh to obtain benserazide hydrochloride granules;

[0061] Total mixing: mix the levodopa granules, benserazide hydrochloride benserazide granules, and the prescription proportion of amine, plus silicon dioxide and magnesium stearate.

[0062] Tableting: select a 12 mm diameter round punch to prepare dopa benserazide tablets.

Claims

1. A method for preparing benserazide hydrochloride, comprising the following steps: ； (1) 2,3,4-trihydroxybenzaldehyde is subjected to amination reduction with hydrazine hydrate in a polar solvent to obtain 2,3,4-trihydroxybenzylhydrazine; (2) 2,3,4-trihydroxybenzylhydrazine is subjected to hydrazinolysis of ester with serine methyl ester hydrochloride in a polar solvent to obtain the target compound benserazide hydrochloride; In step (1), the polar solvent is methanol, ethanol, tetrahydrofuran, DMF, acetonitrile, DMAC or a combination thereof, the reducing agent is one or a combination of pd / C, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, the molar ratio of hydrazine hydrate to 2,3,4-hydroxybenzaldehyde is 1.2-1.5:1, and the reaction temperature is 0-15°C; In step (2), the polar solvent is methanol, ethanol, tetrahydrofuran, DMF, acetonitrile, DMAC or a combination thereof, the molar ratio of 2,3,4-trihydroxybenzylhydrazine to serine methyl ester hydrochloride is 1:1-1.2, and the reaction temperature is 30-50°C; after the reaction is completed, it is cooled to 20-25°C, 10-15 times the volume of isopropanol is added, stirring is continued for 12-18 h for crystallization, filtration is performed, and drying is performed to obtain benserazide hydrochloride.

2. The production method according to claim 1, wherein In step (1), the hydrazine hydrate is 80% hydrazine hydrate.

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