Dihydrosparteine D powder

Abstract

The present invention relates to a method of preparing a powder comprising dihydrohuperzine D and a powder comprising dihydrohuperzine D.

Description

Technical Field

[0001] This invention relates to a method for preparing a powder containing dihydroagar alkaloid D and a powder containing dihydroagar alkaloid D. Background Technology

[0002] Dihydrooat alkaloid D is a particularly important compound in the cosmetics industry. It belongs to the alanine family, specifically the anthramide family, also known as hydroxyphenylpropionamide benzoic acid. Dihydrooat alkaloid D has the CAS number 697235-49-7 (listed by the European Chemicals Agency), and its chemical structure is as follows:

[0003]

[0004] Dihydroacid D has been used in a variety of cosmetics. For example, WO 2006 / 134013 A1 describes the use of dihydroacid D in relieving itching and / or reducing skin redness.

[0005] US2006 / 089413 A1 describes dihydrooat alkaloid D as a potential treatment for inhibiting substance P-induced histamine release from mast cells. This can help prevent itching, skin redness, wound spread, or allergic skin reactions.

[0006] Dihydroacid D is typically formulated in cosmetic or pharmaceutical compositions that include other substances. Dihydroacid D is a strongly lipophilic compound with poor solubility in aqueous solvents. Therefore, it is usually first dissolved in a suitable solvent, and the resulting mixture is then further processed into a cosmetic or pharmaceutical composition.

[0007] To further process mixtures containing dihydroazoline D into cosmetic or pharmaceutical compositions, dihydroazoline D must be completely dissolved. The dissolution of dihydroazoline D takes time, which is a significant factor in the production of cosmetic or pharmaceutical compositions, especially in industrial-scale production. Time-consuming production steps increase the cost of the product and limit the maximum production volume per batch. Therefore, reducing the time required for certain steps in the production process is particularly advantageous.

[0008] Therefore, reducing the dissolution time of dihydroacid alkaloid D, and preferably achieving complete dissolution, is highly advantageous. Thus, it is necessary to improve the solubility properties of dihydroacid alkaloid D.

[0009] To dissolve dihydroacid alkaloid D, the substance is provided in powder form and dissolved in a solvent. However, a challenge with using dihydroacid alkaloid D powder is that it often contains agglomerated forms. Typically, dihydroacid alkaloid D forms crystals and then aggregates. These agglomerates pose a challenge to complete dissolution because they tend to form larger and more difficult-to-dissolve clumps when added to a solvent. Dissolving these clumps requires significant time and effort, which is typically necessary to reduce in larger-scale production processes. Summary of the Invention

[0010] Therefore, the main objective of this invention is to provide dihydrooat alkaloid D with better solubility properties.

[0011] The main objective of this invention is achieved through a method for producing a powder containing dihydrooat alkaloid D.

[0012] Dihydroacid D exists in the powder in crystalline form, and the particle size d(0.5) of the dihydroacid D crystals is at least 30 μm.

[0013] The method includes the following steps:

[0014] i) Provides methyl 3-(4-hydroxyphenyl)propionate,

[0015] ii) Provide methyl 2-aminobenzoate,

[0016] iii) Under conditions allowing peptide coupling, methyl 3-(4-hydroxyphenyl)propionate provided in step i) is mixed with methyl 2-aminobenzoate provided in step ii).

[0017] iv) Dry the mixture obtained in step iii) to obtain a powder containing crystallized dihydrooat alkaloid D.

[0018] v) Optionally: recrystallize the crystalline dihydrooat alkaloid D obtained after step iv), preferably in ethyl acetate, acetone, methyl tert-butyl ether, methanol, ethanol, propanol, and more preferably in isopropanol or a mixture thereof.

[0019] vi) Optionally: Dry the mixture obtained in step v) to obtain a powder containing crystallized dihydroagar alkaloid D.

[0020] The term methyl 3-(4-hydroxyphenyl)propionate preferably refers to the compound with Cas number 5597-50-2, and its chemical structure is further preferred as follows:

[0021]

[0022]

[0023] The term 2-aminobenzoate methyl ester preferably refers to the compound with Cas number 134-20-3, and its chemical structure is further preferred as follows:

[0024]

[0025] Surprisingly, it was found that, compared to other methods in the prior art, the powder containing dihydroacid alkaloid D produced using the method according to the invention exhibits larger crystals of dihydroacid alkaloid D. Furthermore, the dihydroacid alkaloid D crystals obtained using the method according to the invention did not show aggregation or showed a significant reduction in aggregation.

[0026] Interestingly, the dihydroacid alkaloid D powder obtained by the method according to the present invention is a white fine powder, while the dihydroacid alkaloid D powder obtained by other methods in the prior art is more precisely a slightly yellow lumpy powder.

[0027] Surprisingly, it was found that the powder obtained by the method according to the invention exhibits better solubility properties compared to powder obtained by another method using existing technology. It was also found that the powder obtained by the method according to the invention achieves complete dissolution in, for example, butanediol in a significantly shorter time.

[0028] The particle geometry (e.g., diameter), particle size distribution profile, and average particle size can be measured by any suitable method, such as photon correlation spectroscopy and laser diffraction. Preferably, in the context of this invention, the average particle size is determined using a particle size analyzer (e.g., Mastersizer 2000, Malvern Panalytical GmbH, Kassel, Germany).

[0029] According to step iii) of the method of the present invention, dihydrooat alkaloid D is preferably completely or substantially completely dissolved in the obtained mixture.

[0030] Preferably, the term "substantially completely dissolved" means that, based on the weight of dihydroacid D provided in step i), at least 80 wt.% of dihydroacid D is dissolved, preferably at least 85 wt.%, more preferably at least 87.5 wt.%, more preferably at least 90 wt.%, particularly preferably at least 92.5 wt.%, especially preferably at least 95 wt.%, and even more preferably at least 97.5 wt.%.

[0031] As used herein, the term "coupling reaction" is known in the field of peptide synthesis. Typically, the carboxyl group of one compound reacts with the amino group of another compound to form a peptide bond. Condensation reactions that form peptide bonds can replace coupling reactions. In the case of a coupling reaction between methyl 3-(4-hydroxyphenyl)propionate and methyl 2-aminobenzoate, the carboxylmethyl group of methyl 3-(4-hydroxyphenyl)propionate reacts with the amino group of methyl 2-aminobenzoate to form a peptide bond, thereby forming dihydrooat alkaloid D.

[0032] Preferably, in step iii) of the method according to the invention, the conditions for allowing the peptide coupling reaction include a temperature of 0°C to 120°C, preferably 15°C to 100°C, more preferably 50°C to 90°C, and particularly preferably 60°C to 85°C.

[0033] Preferably, in step iii) of the method according to the invention, the conditions for allowing the peptide coupling reaction include a time of 5 minutes to 24 hours, preferably 10 minutes to 21 hours, more preferably 0.5 hours to 18 hours, particularly preferably 0.75 hours to 15 hours, and especially preferably 1 hour to 10 hours.

[0034] Preferably, in step iii) of the method according to the invention, the conditions that allow the peptide coupling reaction include a solvent, preferably water.

[0035] Preferably, in step iii) of the method according to the invention, the conditions for allowing the peptide coupling reaction include a solvent-free reaction.

[0036] Preferably, in step iii) of the method according to the invention, methyl 3-(4-hydroxyphenyl)propionate provided in step i) and methyl 2-aminobenzoate provided in step ii) are mixed with one, two, or all of a solvent selected from dimethylformamide (preferably N,N-dimethylformamide), water, and 2-butoxyethanol. Therefore, the method according to the invention preferably further includes the following steps:

[0037] - Provide one, two, or all of the solvents selected from dimethylformamide (preferably N,N-dimethylformamide), water, and 2-butoxyethanol.

[0038] Surprisingly, the presence of dimethylformamide (preferably N,N-dimethylformamide), water, and / or 2-butoxyethanol promoted the coupling reaction, thereby increasing the yield of the formed dihydrooat alkaloid D.

[0039] Preferably, the mixing of methyl 3-(4-hydroxyphenyl)propionate and methyl 2-aminobenzoate with one or two solvents as described above can be carried out in any order of the compounds to be mixed (for example, methyl 3-(4-hydroxyphenyl)propionate and methyl 2-aminobenzoate can be mixed first, and then one or two solvents can be mixed, or methyl 3-(4-hydroxyphenyl)propionate or methyl 2-aminobenzoate can be mixed first with one or two solvents, and then another compound can be mixed, wherein the other compound may also be mixed with one or two solvents before mixing).

[0040] Dimethylformamide is an organic compound with the chemical formula (CH3)2NC(O)H. Preferably, the term dimethylformamide refers to N,N-dimethylformamide, whose CAS number is 68-12-2, and preferably has the following chemical structure:

[0041]

[0042] 2-Butoxyethanol is an organic compound belonging to the ethylene glycol ether family, with the chemical formula BuOC2H4OH (Bu=CH3CH2CH2CH2). It is also commonly referred to as ethylene glycol monobutyl ether. Preferably, 2-butoxyethanol has the CAS number 111-76-2 and preferably has the following chemical structure:

[0043]

[0044] Preferably, in step iii) of the method according to the invention, dimethylformamide and 2-butoxyethanol are mixed, wherein the weight ratio of dimethylformamide to 2-butoxyethanol mixed in step iii) is 1:5 to 15:1, preferably 1:2 to 10:1, more preferably 1:1 to 5:1, and particularly preferably 1.5:1 to 2:1.

[0045] Preferably, in step iv) of the method according to the invention, drying is performed by drum drying.

[0046] Preferably, drying is carried out in step iv) of the method according to the invention to achieve a moisture content of up to 5 wt.% based on the total weight of the dried mixture, preferably up to 4 wt.%, preferably up to 3 wt.%, preferably up to 2 wt.%, preferably up to 1 wt.%, preferably up to 0.75 wt.%, particularly preferably up to 0.5 wt.%, further preferably up to 0.25 wt.%, and even more preferably up to 0.1 wt.%.

[0047] Preferably, in step vi) of the method according to the invention, drying is performed by drum drying.

[0048] Preferably, drying is carried out in step vi) of the method according to the invention to achieve a moisture content of up to 5 wt.% based on the total weight of the dried mixture, preferably up to 4 wt.%, preferably up to 3 wt.%, preferably up to 2 wt.%, preferably up to 1 wt.%, preferably up to 0.75 wt.%, particularly preferably up to 0.5 wt.%, further preferably up to 0.25 wt.%, and even more preferably up to 0.1 wt.%.

[0049] Preferably, in step v) of the method according to the invention, the solid component is dissolved in a recrystallization medium at a weight ratio (solid component: recrystallization medium) of 1:5, preferably in ethyl acetate, acetone, methyl tert-butyl ether, methanol, ethanol, propanol, isopropanol or a mixture thereof, preferably in a boiling state. Preferably, the resulting solution is then cooled and treated with ultrasound or seed crystals to promote recrystallization.

[0050] Preferably, the weight ratio of methyl 3-(4-hydroxyphenyl)propionate to methyl 2-aminobenzoate mixed in step iii) is 1:5 to 25:1, more preferably 1:3 to 20:1, further preferably 1:1 to 15:1, especially preferably 3:1 to 10:1, more preferably 4:1 to 7.5:1, and even more preferably 5.5:1 to 6:1.

[0051] The present invention further relates to a powder comprising

[0052] a) Dihydrooat alkaloid D, and

[0053] b1) Methyl 3-(4-hydroxyphenyl)propionate, and / or

[0054] b2) Methyl aminobenzoate,

[0055] Dihydroaerol D exists in crystalline form.

[0056] The particle size d(0.5) of the dihydroagar alkaloid D crystals is at least 30 μm.

[0057] The content described herein regarding the method according to the invention applies accordingly to the powder according to the invention.

[0058] As described above, the powder obtained by the method according to the invention has several advantages. The method according to the invention involves reacting methyl 3-(4-hydroxyphenyl)propionate with methyl 2-aminobenzoate. Typically, these precipitates are not 100% consumed, and a portion of the precipitates remains. Therefore, the presence of one or both of these compounds indicates that the method according to the invention can be used to produce powder. Thus, the powder generally possesses the advantages described herein.

[0059] Preferably, the powder according to the invention comprises methyl 3-(4-hydroxyphenyl)propionate and methyl 2-aminobenzoate.

[0060] As described above, it was surprisingly found that the dihydroacid alkaloid D crystals in the powder obtained by the method according to the invention were larger than those obtained by other methods in the prior art. It was found that the particle size d(0.5) of the dihydroacid alkaloid D crystals in the powder obtained by the method according to the invention was at least 30 μm, while the particle size d(0.5) of the dihydroacid alkaloid D crystals obtained by other methods in the prior art was smaller.

[0061] Preferably, the particle size d(0.5) of the dihydroagar alkaloid D crystals in the powder according to the present invention is at least 35 μm, more preferably at least 40 μm, and particularly preferably at least 45 μm.

[0062] Preferably, the particle size d(0.5) of the dihydroagar alkaloid D crystals is 35 μm to 100 μm, more preferably 40 μm to 80 μm, particularly preferably 42.5 μm to 60 μm, and especially preferably 45 μm to 50 μm.

[0063] More preferably, in the powder according to the invention, the particle size d(0.9) of the dihydroagaric alkaloid D crystals is at least 140 μm, preferably at least 150 μm, and particularly preferably at least 160 μm.

[0064] Preferably, the particle size d(0.9) of the dihydroagar alkaloid D crystals is 140 μm to 200 μm, more preferably 150 μm to 190 μm, and particularly preferably 160 μm to 170 μm.

[0065] It was found that larger particle sizes contribute to improved solubility properties as described herein. However, it was found that the particle size d(0.5) was obtained only by the method according to the invention. The same applies to the particle size d(0.9).

[0066] For the powder according to the invention, it is preferred that the powder further contains

[0067] c) One or more solvents selected from dimethylformamide (preferably N,N-dimethylformamide) and 2-butoxyethanol.

[0068] Preferably, the powder according to the invention further comprises

[0069] c) Dimethylformamide.

[0070] Preferably, the powder according to the invention further comprises

[0071] c) 2-Butoxyethanol.

[0072] Preferably, the powder according to the invention further comprises

[0073] c) Dimethylformamide and 2-butoxyethanol.

[0074] Preferably, the powder according to the invention further comprises

[0075] c) N,N-dimethylformamide and 2-butoxyethanol.

[0076] Preferably, the powder according to the present invention comprises dihydroagar alkaloid D, methyl 3-(4-hydroxyphenyl)propionate, methyl 2-aminobenzoate, dimethylformamide, preferably N,N-dimethylformamide, and 2-butoxyethanol.

[0077] Preferably, the amount of dihydroacid D in the powder according to the invention is at least 50 wt.-%, preferably at least 60 wt.-%, preferably at least 70 wt.-%, preferably at least 75 wt.-%, preferably at least 80 wt.-%, preferably at least 85 wt.-%, preferably at least 90 wt.-%, preferably at least 92.5 wt.-%, preferably at least 95 wt.-%, preferably at least 97.5 wt.-%, preferably at least 99 wt.-%.

[0078] Preferably, the amount of methyl 3-(4-hydroxyphenyl)propionate in the powder according to the invention is 0.01 wt.% to 30 wt.% based on the total weight of the powder, preferably 0.1 wt.% to 25 wt.% more preferably 0.5 wt.% to 20 wt.% more preferably 1 wt.% to 15 wt.% more preferably 2.5 wt.% to 10 wt.% more preferably 3 wt.% to 8 wt.% more preferably.

[0079] Preferably, the amount of methyl 2-aminobenzoate in the powder according to the invention is 0.01 wt.% to 30 wt.% based on the total weight of the powder, more preferably 0.1 wt.% to 25 wt.%; more preferably 0.5 wt.% to 20 wt.%; more preferably 1 wt.% to 15 wt.%; more preferably 2.5 wt.% to 10 wt.%; more preferably 3 wt.% to 8 wt.%

[0080] Preferably, the amount of dimethylformamide in the powder according to the invention, preferably N,N-dimethylformamide, is 0.01 wt.-% to 30 wt.-% based on the total weight of the powder, more preferably 0.1 wt.-% to 25 wt.-%, more preferably 0.5 wt.-% to 20 wt.-%, more preferably 1 wt.-% to 15 wt.-%, more preferably 2.5 wt.-% to 10 wt.-%, more preferably 3 wt.-% to 8 wt.-%.

[0081] Preferably, in the powder according to the invention, the amount of N,N-dimethylformamide in the powder is 0.01 wt.-% to 30 wt.-%, preferably 0.1 wt.-% to 25 wt.-%, preferably 0.5 wt.-% to 20 wt.-%, preferably 1 wt.-% to 15 wt.-%, preferably 2.5 wt.-% to 10 wt.-%, preferably 3 wt.-% to 8 wt.-%.

[0082] Preferably, the moisture content of the powder according to the invention, based on the total weight of the powder, is at most 5 wt.-%, preferably at most 4 wt.-%, preferably at most 3 wt.-%, preferably at most 2 wt.-%, preferably at most 1 wt.-%, preferably at most 0.75 wt.-%, particularly preferably at most 0.5 wt.-%, further preferably at most 0.25 wt.-%, and even more preferably at most 0.1 wt.-%.

[0083] Preferably, the moisture content described herein is determined by Karl Fischer titration, loss on drying, or a halogen moisture analyzer.

[0084] More preferably, the powder according to the invention can be obtained by or is obtained by the method according to the invention. The method according to the invention yields dihydroamarine D with the properties described herein, particularly the size and characteristics of dihydroamarine D crystals and improved solubility. Therefore, the powder obtained by or is obtained by the method according to the invention also possesses the properties described herein. Attached Figure Description

[0085] Figure 1 The visual evaluation results of Example 3 are shown.

[0086] Figure 2 The microscopic evaluation results of Example 4 are shown. Detailed Implementation

[0087] Other aspects and advantages of the invention will be described in the following preferred embodiments.

[0088] Example

[0089] Example 1: Preparation of dihydrooat alkaloid D

[0090] Methyl 3-(4-hydroxyphenyl)propionate and methyl 2-aminobenzoate are provided in a weight ratio of 5.8 (methyl 3-(4-hydroxyphenyl)propionate and methyl 2-aminobenzoate).

[0091] In addition, N,N-dimethylformamide and 2-butoxyethanol are provided in a weight ratio of 1.75 (N,N-dimethylformamide and 2-butoxyethanol).

[0092] All compounds were mixed and subjected to peptide coupling reaction at 75°C for 10 minutes. The resulting mixture was then dried to a water content of less than 0.1 wt.%.

[0093] The obtained powder was analyzed by gas chromatography-mass spectrometry (GC-MS), and the high yield of dihydrooat alkaloid D was confirmed.

[0094] Example 2: Preparation of dihydrooat alkaloid D (comparative example)

[0095] o-aminobenzoic acid and mifepristone acid were refluxed in toluene for 3 hours.

[0096] The resulting product was mixed with 4-hydroxybenzaldehyde in a 1:1 ratio and refluxed with 1 equivalent of piperidine in toluene (10:1) for 2 hours. The reaction water was removed, and the mixture was cooled, precipitated, and filtered. The resulting product was crystallized from acetone / ethanol.

[0097] The crystallized product was filtered and washed with water until all chlorides were removed. The resulting product was dried and recrystallized from acetone / ethanol.

[0098] The corresponding process is described in the article “The role of carboxylic group position on the antiradical activity of synthetic analogues of oat antioxidants” published by Mierina, Inese et al. in the Journal of Chemical and Pharmaceutical Research, 7(6), 2015, 416-427.

[0099] The obtained product was hydrated in methanol with Pd / C for 8 hours at room temperature under a pressure of less than 20 bar.

[0100] The corresponding process is described in "Preparation of 2(3-phenylpropanoylamino)benzoic acid derivatives" published by Liang, Weizhou et al. and CN115626879A.

[0101] The obtained powder was analyzed by GC-MS, and the high yield of dihydrooat alkaloid D was confirmed.

[0102] Example 3: Visual Assessment

[0103] The powders of Examples 1 and 2 were prepared and then stored for 4 weeks for visual evaluation.

[0104] The powder from Example 1 was found to be a white, fine powder. The powder from Example 2 was slightly yellow and clump-like. The results are as follows... Figure 1 As shown.

[0105] Example 4: Microscopic evaluation

[0106] The powders of Examples 1 and 2 were prepared and evaluated using a 10x microscope.

[0107] The powder of Example 1 was found to exhibit larger crystals than the powder of Example 2. Furthermore, the powder of Example 1 did not show agglomeration, while agglomerates appeared in the powder of Example 2. The results are as follows... Figure 2 As shown.

[0108] Example 5: Colorimetric Method

[0109] The powders of Examples 1 and 2 were prepared and completely dissolved in a mixture of butanediol and pentanediol (weight ratio 1:1), and measured with a colorimeter.

[0110] The following results were obtained:

[0111] Powder of Example 1 Powder of Example 2 <![CDATA[L * ]]> 100.1 99.7 <![CDATA[a * ]]> -0.3 -0.3 b* 1.1 1.5

[0112] The solution containing the powder of Example 2 was found to be slightly more yellow than the solution containing the powder of Example 1.

[0113] Example 6: Particle size distribution:

[0114] The powders from Examples 1 and 2 were prepared and analyzed using a Mastersizer 2000 particle size analyzer (Malvern Panalytical GmbH, Kassel, Germany).

[0115] The powder of Example 1 has a particle size d(0.5) of 46.579 and a particle size d(0.9) of 163.476.

[0116] The particle size of the powder from Example 2 was also measured; however, no definitive measurement results could be obtained due to the formation of agglomerates, as Mastersizer 2000 analysis identified the agglomerates as (very large) particles. Nevertheless, it was observed that, apart from the very large particles, the particle size of the powder from Example 2 was generally smaller than that of the powder from Example 1.

[0117] Example 7: Solubility Assessment

[0118] Prepare the powders of Examples 1 and 2.

[0119] Butylene glycol is heated to 70°C. Pentylene glycol is added while stirring to obtain mixture M1.

[0120] Due to the addition of pentylene glycol, mixture M1 was cooled to 60°C, and powders from Example 1 or Example 2 were added respectively. After adding the powders, the resulting mixtures were stirred directly, and the solubility was assessed visually.

[0121] It was found that the powder of Example 1 was distributed throughout the mixture M1 upon addition. In contrast, the powder of Example 2 mainly settled to the bottom of the flask upon addition.

[0122] When the mixture is stirred, both powders are distributed throughout the mixture.

[0123] However, after stirring for 5 minutes, the mixture containing Example 1 was more translucent than the mixture containing Example 2, which showed a rather white, milky appearance. The effect was even more pronounced after stirring for 10 minutes. Therefore, even under the same dissolving conditions, the powder of Example 1 dissolved faster than the powder of Example 2.

Claims

1. A method for preparing a powder comprising dihydrohypeastrine D, wherein dihydrohypeastrine D is present in the powder in crystalline form, wherein the dihydrohypeastrine D crystals have a particle size d(0.5) of at least 30 pm, the method comprising the steps of i) providing 3-(4-hydroxyphenyl)propionic acid methyl ester, ii) providing 2-amino benzoic acid methyl ester, iii) mixing the 3-(4-hydroxyphenyl)propionic acid methyl ester provided in step i) with the 2-amino benzoic acid methyl ester provided in step ii) under conditions allowing a peptide coupling reaction, iv) drying the mixture obtained in step iii) to obtain a powder comprising crystallized dihydrohypeastrine D, v) optionally: recrystallizing the crystallized dihydrohypeastrine D obtained after step iv), and vi) optionally: drying the mixture obtained in step v) to obtain a powder comprising crystallized dihydrohypeastrine D.

2. The method according to claim 1, wherein in step v) the recrystallization is carried out in ethyl acetate, acetone, methyl tert-butyl ether, methanol, ethanol, propanol or mixtures thereof.

3. The method according to claim 1, wherein in step v) the recrystallizing is carried out in ethyl acetate, acetone, methyl tert-butyl ether, metha nol, ethanol, isopropanol or mixtures thereof.

4. The method according to claim 1, wherein in step iii) the 3-(4-hydroxyphenyl)propionic acid methyl ester provided in steps i) and the 2-amino benzoic acid methyl ester provided in step ii) are mixed with one, two or all solvents selected from the group consisting of dimethylformamide, water and 2-butoxyethanol.

5. The method according to claim 4, wherein the dimethylformamide is N,N-dimethylformamide.

6. The method according to claim 1, wherein the 3-(4-hydroxyphenyl)propionic acid methyl ester and the 2-amino benzoic acid methyl ester mixed in step iii) are in a weight ratio of 1:5 to 25:

1.

7. The method according to claim 6, wherein the 3-(4-hydroxyphenyl)propionic acid methyl ester mixed with the 2-amino benzoic acid methyl ester in step iii) are in a weight ratio of 1:3 to 20:

1.

8. The method according to claim 6, wherein the 3-(4-hydroxypheny l)propionic acid methyl ester mixed with the 2-amino benzoic acid methyl es ter in step iii) are in a weight ratio of 1:1 to 15:

1.

9. The method according to claim 6, wherein the 3-(4-hydroxyphen yl)propionic acid methyl ester mixed with the 2-amino benzoic acid methyl e ster in step iii) are in a weight ratio of 3:1 to 10:

1.

10. The method according to claim 6, wherein the 3-(4-hydroxyphen- yl)propionic acid methyl ester mixed with the 2-amino benzoic ac id methyl ester in step iii) are in a weight ratio of 4:1 to 7.5:

1.

11. The method according to claim 6, wherein the 3-(4-hydroxyphen - yl)propionic acid methyl ester mixed with the 2-amino benzoic a cid methyl ester in step iii) are in a weight ratio of 5.5:1 to 6:

1.

12. The process according to claim 1, wherein in step iv) and / or step vi) the powder is dried to a moisture content of at most 5 wt.-%, based on the total weight of the powder.

13. The process according to claim 12, wherein in step iv) and / or step vi) the powder is dried to a moisture content of at most 4 wt.-%, based on the total weight of the powder.

14. The process according to claim 12, wherein in step iv) and / or step vi) the powder is dried to a moisture content of at most 3 wt.-%, based on the total weight of the powder.

15. The process according to claim 12, wherein in step iv) and / or step vi) the powder is dried to a moisture content of at most 2 wt.-%, based on the total weight of the powder.

16. The process according to claim 12, wherein in step iv) and / or step vi) the powder is dried to a moisture content of at most 1 wt.-%, based on the total weight of the powder.

17. The process according to claim 12, wherein in step iv) and / or step vi) the powder is dried to a moisture content of at most 0.75 wt.-%, based on the total weight of the powder.

18. The process according to claim 12, wherein in step iv) and / or step vi) the powder is dried to a moisture content of at most 0.5 wt.-%, based on the total weight of the powder.

19. The process according to claim 12, wherein in step iv) and / or step vi) the powder is dried to a moisture content of at most 0.25 wt.-%, based on the total weight of the powder.

20. The process according to claim 12, wherein in step iv) and / or step vi) the powder is dried to a moisture content of at most 0.1 wt.-%, based on the total weight of the powder.

21. A powder comprising a) dihydrohypeakine D, and b1) methyl 3-(4-hydroxyphenyl)propanoate, and / or b2) methyl 2-aminobenzoate, wherein dihydrohypeakine D is present in crystalline form, wherein the dihydrohypeakine D crystals have a particle size d(0.5) of at least 30 pm.

22. The powder according to claim 21, wherein the dihydrohypeakine D crystals have a particle size d(0.5) of at least 35 pm.

23. The powder according to claim 22, wherein the dihydrohypeakine D crystals have a particle size d(0.5) of at least 40 pm.

24. The powder according to claim 22, wherein the dihydrohypeakine D crystals have a particle size d(0.5) of at least 45 pm.

25. The powder according to claim 22, wherein the dihydrohypeakine D crystals have a particle size d(0.5) from 35 pm to 100 pm.

26. The powder according to claim 22, wherein the dihydrohypeakine D crystals a particle size d(0.5) from 40 pm to 80 pm.

27. The powder according to claim 22, wherein the particle size d(0.5) of the dihydrohypeakine D crystals is from 42.5 pm to 60 pm.

28. The powder according to claim 22, wherein the particle size d(0.5) of the dihydrohypeakine D crystals is from 45 pm to 50 pm.

29. The powder according to claim 21, wherein the particle size d(0.9) of the dihydrohypeakine D crystals is at least 140 pm.

30. The powder according to claim 29, wherein the particle size d(0.9) of the dihydrohypeakine D crystals is at least 150 pm.

31. The powder according to claim 29, wherein the particle size d(0.9) of the dihydrohypeakine D crystals is at least 160 pm.

32. The powder according to claim 29, wherein the particle size d(0.9) of the dihydrohypeakine D crystals is from 140 pm to 200 pm.

33. The powder according to claim 29, wherein the particle size d(0.9) of the dihydrohypeakine D crystals is from 150 pm to 190 pm.

34. The powder according to claim 29, wherein the particle size d(0.9) of the dihydrohypeakine D crystals is from 160 pm to 170 pm.

35. The powder according to claim 21, further comprising c) one or more solvents selected from the group consisting of dimethylformamide and 2-butoxyethanol.

36. The powder according to claim 35, wherein the dimethylformamide is N,N- dimethylformamide.

37. The powder according to claim 21, wherein the amount of dihydrohypeakine D in the powder is at least 50 wt.-%, based on the total weight of the powder.

38. The powder according to claim 37, wherein the amount of dihydrohypeakine D in the powder is at least 60 wt.-%, based on the total weight of the powder.

39. The powder according to claim 37, wherein the amount of dihydrohypeakine D in the powder is at least 70 wt.-%, based on the total weight of the powder.

40. The powder according to claim 37, wherein the amount of dihydrohypeakine D in the powder is at least 75 wt.-%, based on the total weight of the powder.

41. The powder according to claim 37, wherein the amount of dihydrohypeakine D in the powder is at least 80 wt.-%, based on the total weight of the powder.

42. The powder according to claim 37, wherein the amount of dihydrohypeakine D in the powder is at least 85 wt.-%, based on the total weight of the powder.

43. The powder according to claim 37, wherein the amount of dihydrohypeakine D in the powder is at least 90 wt.-%, based on the total weight of the powder.

44. The powder according to claim 37, wherein the amount of dihydrohypeakine D in the powder is at least 92.5 wt.-%, based on the total weight of the powder.

45. The powder according to claim 37, wherein the amount of dihydroheterophyllidine D in the powder is at least 95 wt.-%, based on the total weight of the powder.

46. The powder according to claim 37, wherein the amount of dihydroheterophyllidine D in the powder is at least 97.5 wt.-%, based on the total weight of the powder.

47. The powder according to claim 37, wherein the amount of dihydroheterophyllidine D in the powder is at least 99 wt.-%, based on the total weight of the powder.

48. The powder according to claim 21, wherein the amount of methyl 3-(4- hydroxyphenyl)propanoate in the powder is from 0.01 wt.-% to 30 wt.-%, based on the total weight of the powder, and / or wherein the amount of methyl 2-aminobenzoate in the powder is from 0.01 wt.-% to 30 wt.-%, based on the total weight of the powder.

49. The powder according to claim 48, wherein the amount of methyl 3-(4- hydroxyphenyl)propanoate in the powder is from 0.1 wt.-% to 25 wt.-%, based on the total weight of the powder.

50. The powder according to claim 48, wherein the amount of methyl 3-(4- hydroxyphenyl)propanoate in the powder is from 0.5 wt.-% to 20 wt.-%, based on the total weight of the powder.

51. The powder according to claim 48, wherein the amount of methyl 3-(4- hydroxyphenyl)propanoate in the powder is from 1 wt.-% to 15 wt.-%, based on the total weight of the powder.

52. The powder according to claim 48, wherein the amount of methyl 3-(4- hydroxyphenyl)propanoate in the powder is from 2.5 wt.-% to 10 wt.-%, based on the total weight of the powder.

53. The powder according to claim 48, wherein the amount of methyl 3-(4- hydroxyphenyl)propanoate in the powder is from 3 wt.-% to 8 wt.-%, based on the total weight of the powder.

54. The powder according to claim 48, wherein the amount of methyl 2- aminobenzoate in the powder is from 0.1 wt.-% to 25 wt.-%, based on the total weight of the powder.

55. The powder according to claim 48, wherein the amount of methyl 2- aminobenzoate in the powder is from 0.5 wt.-% to 20 wt.-%, based on the total weight of the powder.

56. The powder according to claim 48, wherein the amount of methyl 2- aminobenzoate in the powder is from 1 wt.-% to 15 wt.-%, based on the total weight of the powder.

57. The powder according to claim 48, wherein the amount of methyl 2- aminobenzoate in the powder is from 2.5 wt.-% to 10 wt.-%, based on the total weight of the powder.

58. The powder according to claim 48, wherein the amount of methyl 2- aminobenzoate in the powder is from 3 wt.-% to 8 wt.-%, based on the total weight of the powder.

59. The powder according to claim 21, wherein the amount of dimethylformamide in the powder is from 0.01 to 30 wt.-%, based on the total weight of the powder.

60. The powder according to claim 59, wherein the dimethylformamide is N,N- dimethylformamide.

61. The powder according to claim 59, wherein the amount of dimethylformamide in the powder is from 0.1 to 25 wt.-%, based on the total weight of the powder.

62. The powder according to claim 59, wherein the amount of dimethylformamide in the powder is from 0.5 to 20 wt.-%, based on the total weight of the powder.

63. The powder according to claim 59, wherein the amount of dimethylformamide in the powder is from 1 to 15 wt.-%, based on the total weight of the powder.

64. The powder according to claim 59, wherein the amount of dimethylformamide in the powder is from 2.5 to 10 wt.-%, based on the total weight of the powder.

65. The powder according to claim 59, wherein the amount of dimethylformamide in the powder is from 3 to 8 wt.-%, based on the total weight of the powder.

66. The powder according to any one of claims 21 to 65, obtainable or obtained by the method according to any one of claims 1 to 20.

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