WO2015197909A1

WO2015197909A1 - Process for the preparation of a crystalline polymorph of 2-amino-3-hydroxy-n'-(2,3,4-trihydroxybenzyl)propanehydrazide (benserazide) hydrochloride

Info

Publication number: WO2015197909A1
Application number: PCT/FI2015/000030
Authority: WO
Inventors: Tuija Jokela; Anssi SALMINEN; Martti Hytönen
Original assignee: Fermion Oy
Priority date: 2014-06-27
Filing date: 2015-06-25
Publication date: 2015-12-30

Abstract

The present invention is related to the process for the preparation of benserazide well as novel hydrated form and a dimethyl formamide solvate thereof.

Description

PROCESS FOR THE PREPARATION OF A CRYSTALLINE POLYMORPH OF

2-AMINO-3-HYDROXY-N'-(2,3,4-TRIHYDROXYBENZYL)PROPANEHYDRAZIDE (BENSERAZIDE) HYDROCHLORIDE

Field of the invention

The invention provides an improved process for the preparation of benserazide hydrochloride. Also provided are a novel polymorphic form of an intermediate and a novel hydrate of benserazide.

Background of the invention

Benserazide is an INN name for 2-amino-3-hydroxy-N'-(2,3,4- trihydroxybenzyl)propanehydrazide (DL-serine,2-[(2,3,4-trihydroxyphenyl)rnethyl]- hydrazide), which has the following structure (I):

(I)

Benserazide is used as a hydrochloride salt e.g. for the treatment of Parkinson's disease in combination with L-dopa.

Preparation of benserazide hydrochloride starting from 2-amino-3- hydroxypropanehydrazide (DL-serine hydrazide) hydrochloride has been described in US3178476. PL209729 describes a process where benserazide is made from DL-serine by reacting the corresponding DL-serine hydrazide hydrochloride and 2,3,4

trihydroxybenzaldehyde in a mixture of water and ethanol. Solvent is needed in large amount, 1250 ml per 0.53 moles of 2,3,4-trihydroxybenzaldehyde. In GB 1250279 is described the preparation of L- benserazide hydrochloride by hydrogenating compound of formula (Π): HCI

(Π)

Another method described comprises the conversion of the group or groups convertible into the hydroxyl groups (Ri, R₂ and R₃) and/or into the a-amino-β- hydroxyethyl group (R₄) in a compound of formula (ΠΓ)

(m)

In the processes described the reaction of 2,3,4-trihydroxy benzaldehyde with DL-serine hydrazide (L-serine hydrazide) hydrochloride was performed in water- methanol or water- ethanol mixture as a solvent. The hydrogenation was carried out in methanol. Methanol is needed in large excess to dissolve benserazide, and the solvent needs to be evaporated to smaller volume before the product can be precipitated. The product is a dihydrate and its filtration is difficult. In addition benserazide and the intermediate are unstable in water-alcohol mixtures. Benserazide has several polymorphic forms and it forms solvates easily. In commercial tablets has been found polymorphic form designated here as form I and it has an x-ray diffraction pattern as depicted in figure 1.

Thus, it is desirable to provide an improved method for producing benserazide in high yield and purity with the method also being economically feasible and suitable for use in a large scale. Summary of the invention

The present invention provides a process for the preparation of benserazide hydrochloride of formula (I)

(I) comprising a) reacting 2,3,4-trihydroxy benzaldehyde with 2-amino-3- hydroxypropanehydrazide hydrochloride in a solvent selected from dimethyl formamide (DMF), dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP) or a mixture of dimethyl formamide and isopropanol to obtain (E)-2-amino-3-hydroxy-N'- (2,3,4-trihydroxybenzylidene)propanehydrazide hydrochloride, b) hydrogenating (E)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene)- propanehydrazide hydrochloride to obtain benserazide hydrochloride, c) isolating the obtained benserazide hydrochloride as a solvate, d) drying the obtained solvate, e) suspending the dried solvate of benserazide hydrochloride in an alcoholic solvent, f) isolating benserazide hydrochloride, and g) optionally drying the benserazide hydrochloride obtained. The invention is also directed to novel polymorphic form of benserazide hydrochloride (form IX), which is a dimethyl formamide solvate.

Still another aspect of the present invention is a novel hydrated form of benserazide, designated herein as form VI.

It has been found that, in contrast to processes described in earlier publications where methanol-water mixture is used as a solvent, using dimethyl formamide or other solvents of the invention as a solvent, benserazide hydrochloride may be made in one- pot and obtained in good yield and purity. The product is easy to filtrate and

considerably less solvent is needed. Both benserazide hydrochloride and the

intermediate are stable in the solvents of the invention.

Figures:

Figure 1 shows an XRD diagram of polymorphic form I obtained in example 3. Figure 2 shows an XRD diagram of hydrated form VI obtained in example 6.

Figure 3 shows an XRD diagram of DMF solvate form IX obtained in example 2.

Detailed description of the invention

In accordance with the present invention 2,3,4-trihydroxy benzaldehyde is reacted with 2-amino-3-hydroxypropanehydrazide hydrochloride in a solvent where 2,3,4-trihydroxy benzaldehyde and the product are soluble, to obtain (E)-2-amino-3- hydroxy-N'-(2,3,4-trihydroxybenzylidene) propanehydrazide hydrochloride, which is further hydrogenated to obtain benserazide hydrochloride.

Suitable reaction solvents are e.g. dimethylacetamide (DMA), N-methyl-2- pyrrolidone (NMP), dimethyl formamide (DMF) and its mixture with n- or isopropanol. Preferred solvent is dimethyl formamide due to its best ability to dissolve benserazide. Solvents of the invention are needed in the reaction only 2 - 4 volumes and no concentration is needed before the addition of antisolvent in case the intermediate is isolated. In earlier processes alcohol-water mixtures used as a solvent are needed at least 12 volumes compared to the product.

The reaction of 2,3,4-trihydroxy benzaldehyde with 2-amino-3- hydroxypropanehydrazide hydrochloride is suitably carried out in the temperature from ambient to 70 °C, optionally from 35 °C to 50 °C. The reaction time depends on the temperature used, e.g. in 50 °C the reaction will be completed in about two hours. The reaction mixture may be filtered to remove unsolved impurities and unreacted 2-amino- 3-hydroxypropanehydrazide hydrochloride, and used thereafter in the hydrogenation step. The DMF solution of (E)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene)- propanehydrazide hydrochloride is stable at least two days.

Alternatively the obtained (E)-2-amino-3-hydroxy-N'-(2,3,4- trihydroxybenzylidene)-propanehydrazide hydrochloride may be isolated from the reaction mixture by precipitation e.g. by adding a suitable alcohol, e.g. butanol and optionally seeding.

If the (E)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene)- propanehydrazide hydrochloride is isolated after step a), it will be redissolved for hydrogenation in a solvent selected from dimethylacetamide (DMA), N-methyl-2- pyrrolidone (NMP), dimethyl formamide (DMF) and its mixture with isopropanol. Hydrogenation of (E)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene)- propanehydrazide hydrochloride is carried out at 1-3 bar pressure in ambient temperature. In the process a suitable catalyst e.g. Pd/C catalyst is used. In about 7 hours the conversion above 99 % to benserazide may be obtained.

Benserazide hydrochloride may be isolated from the reaction mixture e.g. by precipitating it out of the solution as a solvate by using a suitable antisolvent.

Antisolvent may be selected from ethanol, methanol, isopropanol, ethylacetate, cyclopentyl methyl ether, n-propanol or their mixtures with water. A preferred antisolvent is a mixture of water and propanol. The solvate is dried in vacuum to constant weight so that the water content is below 2.5 % (KF). DMF solvate of 2- amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)-propanehydrazide hydrochloride is a new polymorphic form IX.

Anhydrous benserazide hydrochloride is obtained from the dried solvate by suspending it in a solvent selected from C1-C4 alcohols, their mixtures and their mixtures with water. E.g. a 1:1 mixture of aqueous ethanol and 1 -propanol may be used. The precipitate is isolated from the solvent and washed with e.g. ethanol until no traces of the reaction solvent are detected. The precipitate is dried under vacuum into a constant weight to obtain anhydrous benserazide hydrochloride. Polymorphic form of the benserazide obtained is a known polymorphic form I, which has an X-ray diffraction pattern as depicted in figure 1.

Drying of the solvate is essential for obtaining the desired polymorphic form I of anhydrous product. In case wet product is used in the final suspension step, the product will be a hydrate. This novel hydrated form of benserazide hydrochloride is designated here as form VI . This polymorphic form has a powder x-ray diffraction pattern which is substantially as shown in Figure 2. Main peaks are at 18.6 (41.1%), 22.7 (39.5%), 23.0 (39.5 %), 25.5 (37.6 %), 27.2 (100.0 %), 27.9 (55.0%), 33.1 (39.0%), and 34.6 (31.6%) ±0.2 deg. 2-theta. Other characteristic peaks are at 13.8 (26.9%), 19.6 (20.3%), 21.23 (24.4%), 24.1 (18.4 %), 34.3 (23.7%) and 37.8 (20.4%) +0.2 deg. 2-theta. Relative intensities in parenthesis.

The polymorphic form VI of benserazide may be formulated into

pharmaceutical dosage forms like tablets or capsules, and used for the treatment of e.g. Parkinson's disease in combination with L-dopa.

One aspect of the present invention is a novel compound, which is dimethyl formamide solvate of the (E)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)- propanehydrazide hydrochloride, which contains about 10 % dimethyl formamide. This solvate is an intermediate in the process of the present invention if dimethyl formamide is used as a solvent. This novel polymorphic form IX has a powder x-ray diffraction pattern which is substantially as shown in Figure 3. Main peaks are at 7.0 (100%), 9.7 (56.1%), 16.0 (61.7%), 18.8 (58.8%), 19.4 (50.9%), 27.1 (50.4%), and 28.0 (67.2%), +0.2 deg 2-theta. Additional characteristic peaks are at 18.6 (43.0%), 22.3 (40.5%), and 25.0 (41.0%) +0.2 deg 2-theta. Relative intensities in parenthesis.

Analytical methods

The x-ray diffractograms were recorded with a Panalytical X'Pert PRO MPD x- ray powder diffractometer equipped with a PW3050/60 theta/theta goniometer using the following parameters. X-ray radiation: Cu/45kV/40mA, filter: Ni, divergence slit: automatic (irradiated sample length 10 mm), incident beam mask: 15 mm, incident beam anti-scatter slit: l[deg.], incident beam Soller slit: 0.04 rad, sample spinner: 60 rpm (Panalytical PW3064), secondary beam Soller slit: 0.04 rad, detector: Panalytical X'Celerator (scanning mode window 1.019[deg.]), scan record mode: continuous, sampling step: 0.017 [deg.], meas.time per step: 10.24 s, scan range: 3[deg.] to 40[deg.]. The invention is further illustrated by the following non-limiting examples.

Examples

EXAMPLE 1.

Synthesis of (E)-2-aiiuno-3-hydroxy-NX2,3,4-triliydroxybenzylidene)- propanehydrazide hydrochloride

DMF (Ν,Ν-Dimethyl formamide 50 ml) was charged into a reaction vessel followed by 2,3,4-trihydroxybenzaldehyde (12.5 g). The mixture was stirred at ambient temperature until a clear solution was achieved. The other starting material 2-amino-3- hydroxypropanehydrazide hydrochloride ( 13.9 gl) was added into a solution. The reaction mixture was heated to 35 - 50 °C and stirring was continued until no starting material was left according to HPLC monitoring. At 50°C the reaction was complete in about 2 hours. After filtering, the reaction vessel was rinsed with DMF (N,N-dimethyl formamide, 11 ml) which was combined with the original filtrate. The obtained solution was used directly in next hydrogenation step without separate isolation of the reaction product.

EXAMPLE 2.

Synthesis of 2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)- propanehydrazide hydrochloride, Ο.ΙΝ,Ν-dimethylformamide solvate

5% Pd/C paste (6.71 g, ~50-57m-% water wet) was charged into a

hydrogenation reactor, which was first flushed three times with inert gas (nitrogen). (E)- 2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene)-propanehydrazide hydrochloride DMF filtrate from the previous phase was then charged into the reactor (23g of (E)-2- amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene)-propanehydrazide hydrochloride in 61 ml DMF). Hydrogenation reaction took place at 1-3 bar and ambious temperature. After about 7h reaction (HPLC conv. > 99%), the catalyst was removed by filtration and the reactor tank was washed with minimum amount of DMF (23 ml) which was used for washing the catalyst cake . The product 2-amino-3-hydroxy-N'-(2,3,4- trihydroxybenzyl)-propanehydrazide hydrochloride, Ο.ΙΝ,Ν-dimethylformamide solvate was precipitated out of the DMF solution by adding water (23 ml) and 1-propanol (240 ml) at ambient temperature. The mixture was stirred over night and filtered to isolate the precipitate. The precipitate was washed with ethanol (46 ml) and dried under vacuum at 40 to 50°C to constant weight. Isolated yield of dried material was 16.8g (70.6%) HPLC-purity 94.4a%, DMF 4.8a% (corresponds to a crystal form IX, which is a DMF-solvate).

EXAMPLE 3.

Synthesis of 2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)- propanehydrazide hydrochloride anhydrate

Dried 2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)propanehydrazide hydrochloride, Ο.ΙΝ,Ν-dimethylformamide solvate (precipitate, 1.9 g,) was charged into a flask. A mixture of 1: 1 volumes of 90% aqueous ethanol (10 ml) and 1-propanol (10 ml) were added. The mixture was stirred at ambient temperature over night and filtered to get a wet precipite, which was washed with aq. 1-propanol (1: 10) a' 10 ml until no DMF was left according to HPLC analysis. Wet precipitate was dried under vacuum at 40-50 °C into a constant weight 1.49g to obtain 2-amino-3-hydroxy-N'-(2,3,4- trihydroxybenzyl)-propanehydrazide hydrochloride anhydrate, which is a known polymorphic form I.

EXAMPLE 4

Synthesis of (E)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene) propanehydrazide hydrochloride with separate isolation (precipitation with aqueous n-BuOH)

DMF (Ν,Ν-Dimethyl formamide 80 ml) was charged into a reaction vessel followed by 2,3,4-trihydroxybenzaldehyde (20 g). The mixture was stirred at ambient temperature until a clear solution was achieved. The other starting material 2-amino-3- hydroxypropanehydrazide hydrochloride (21.20 g) was added into a solution. The reaction mixture was heated to 30 °C and stirring was continued until no starting material was left according to HPLC monitoring. After filtering the reaction mixture, water (5 ml) was added at ambient temperature. 1-Butanol (200 ml) was gradually added together with a seed crystal. Cooling to 5 °C during a 3h period. The precipitate formed was filtered and washed with ethanol and dried at 60 °C at ca. 150 mbar pressure to yield (E)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene)- propanehydrazide hydrochloride as anhydrate 31.82g (84 % yield). EXAMPLE 5

Synthesis of 2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)

propanehydrazide hydrochloride, Ο.ΙΝ,Ν-dimethylformamide starting from isolated (E)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene)- propanehydrazide hydrochloride 5% Pd/C paste (6.71 g) (~50-57m-% water wet) was charged into a hydrogenation reactor. (E)-2-arnino-3-hydroxy-N'-(2,3,4- trihydroxybenzylidene)propanehydrazide hydrochloride (12.5 g) was then charged into the reactor dissolved in 37.5 ml DMF. Reaction took place at 1-3 bar at ambious temperature in vigorous stirring. After about 7h reaction (HPLC conv. > 99%), the catalyst was removed by filtering and the reactor tank was washed with minimum amount of DMF (N,N-Dimethyl formamide (23 ml) which was used for washing the catalyst cake . The product 2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl) propanehydrazide hydrochloride, Ο.ΙΝ,Ν-dimethylformamide solvate was precipitated out of the DMF solution by adding water (12 ml) and 1-propanol (63 ml) at ambient temperature. The mixture was stirred over night and filtered to isolate the precipitate. The precipitate was washed with ethanol (46 ml) and dried under vacuum at 40 to 50°C to constant weight. Isolated yield of dried material was 8.8g. HPLC-purity 94.4a%, DMF 4.8a% (corresponds to a crystal form ΓΧ, which is a DMF-solvate).

EXAMPLE 6.

Synthesis of 2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl) propanehydrazide hydrochloride hydrate, novel polymorphic form VI

2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)propanehydrazide hydrochloride, Ο.ΙΝ,Ν-dimethylformamide solvate ( 10.0 g) was charged into a flask directly after filtration of the BENSE-IV-R precipitate and without pre-drying. A mixture of 1 : 1 volumes of 90% aqueous ethanol (25 ml) and 1-propanol (25 ml) was added. The mixture was stirred at ambient temperature over night and filtered to get a wet precipite, which was washed with aq. EtOH a' 10 ml until no DMF was left according to HPLC analysis. Wet precipitate was dried under vacuum at 30-50 °C into a constant weight 2.30g. The product was benserazide hydrochloride polymorphic form VI, which is a hydrate.

Claims

1 A process for the preparation of benserazide hydrochloride comprising; a) reacting 2,3,4-trihydroxy benzaldehyde with 2-amino-3- hydroxypropanehydrazide hydrochloride in a solvent selected from dimethyl formamide (DMF), dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP) or a mixture of dimethyl formamide and isopropanol to obtain (E)-2-amino-3-hydroxy-N'- (2,3 ,4-trihydroxybenzylidene)propanehydrazide hydrochloride, b) hydrogenating (E)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene)- propanehydrazide hydrochloride to obtain benserazide hydrochloride, c) isolating the obtained benserazide hydrochloride as a solvate, d) drying the obtained solvate, e) suspending the dried solvate of benserazide hydrochloride in an alcoholic solvent, f) isolating benserazide hydrochloride, and g) optionally drying the benserazide hydrochloride obtained.

2. A process of claim 1 wherein the isolation of step c) is carried out by using an antisolvent.

3. A process of claim 2 wherein the reaction mixture is added to an antisolvent.

4. A process of claim 1 wherein the solvent in step a) is dimethyl formamide.

5. A process of claim 1 wherein the obtained (E)-2-amino-3-hydroxy-N' (2,3,4-trihydroxybenzylidene)propanehydrazide hydrochloride is isolated after step a) .

6. A process of claim 1 wherein the drying in step d) is performed in vacuum at the temperature from 30 °C to 60 °C.

7. A process of claim 1 wherein the solvent in step e) contains water.

8. A process of claim 7 wherein the solvent in step e) is a mixture of aqueous ethanol and 1-propanol.

9. A process of claim 1 wherein steps a) and b) are performed in one-pot without isolating the (E)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzylidene)- propanehydrazide hydrochloride obtained in step a).

10. A compound which is dimethyl formamide solvate of the (E)-2-amino-3- hydroxy-N'-(2,3,4-trihydroxybenzyl)-propanehydrazide hydrochloride.

11. A solvate of claim 10 having an a powder x-ray diffraction spectrum having main peaks at 7.0, 9.7, 16.0, 18.8, 19.4, 27.1 and 28.1, ±0.2 deg 2-theta.

12. A solvate according to claim 1 1 characterised by X-ray diffraction pattern as depicted in figure 3.

13. Polymorphic form VI which is a hydrated form of (E)-2-amino-3- hydroxy-N'-(2,3,4-trihydroxybenzyl)-propanehydrazide hydrochloride having an x-ray pattern with characteristic peaks at 18.6, 22.7, 23.0, 25.5, 27.2, 27.9, 33.1, and 34.6. +0.2 deg. 2-theta.

14. Polymorphic from according to claim 13 characterised by X-ray diffraction pattern as depicted in figure 2.