Improved synthesis of raclosibin derivatives

Abstract

The present invention relates to the improved synthesis of serosibin and alkyl derivatives of serosibin, such as ethyl serosibin (4-phosphoryloxy-N, N-diethyltryptamine, also referred to as phosphoryloxy-DET, PO-DET or CEY-39), and also to intermediates useful in the synthesis of these compounds.

Description

Background Art

[0001] The present invention relates to an improved synthesis of psilocybin (IUPAC name: 4-phosphoryloxy-N,N-dimethyltryptamine, 3-[2-(dimethylamino)ethyl]-1H-indol-4-yl-dihydrogen phosphate) and alkyl derivatives of psilocybin (e.g., ethyl psilocybin (IUPAC name: mono-[3-(2-diethylamino-ethyl)-1H-indol-4-yl] phosphate)), and also to intermediates used in the synthesis of these compounds.

[0002] Psilocybin and its derivatives (such as its dephosphorylated active metabolite, psilocin) have recently received renewed attention for their potential usefulness in treating various psychological disorders (Dinis-Olivera RJ Drug Metab. Rev. 2017, 49(1), 84-91). For example, the compounds have been shown to be useful in treating depression.

[0003] Psilocybin was first isolated from the mushroom P. Mexicana in the laboratory of Albert Hoffmann in 1958 (Hofmann, A., Frey, A., Ott, H., Petrzilika, F., Troxler, F.; Experimentia 14, 1958, 397-399). Shirota et al. recently published a simple large-scale synthesis of psilocybin and psilocybin without the need for a chromatographic purification step (Shirota O., Hakamata, W. and Goda Y.; J. Nat. Prod. 2003, 66(6), 885-887).

[0004] The synthesis of alkyl derivatives of psilocybin, such as ethyl psilocybin (4-phosphoryloxy-N,N-diethyltryptamine), also known as phosphoryloxy-DET, PO-DET or CEY-39, has been disclosed in US Pat. No. 3,075,992.

[0005] Macor, Post and Ryan disclosed a simple synthesis of 5-amino-3-(2-dimethylaminoethyl)indole (https: / / doi.org / 10.1080 / 00397919308020402).

[0006] However, when these compounds are prepared on a large scale using the synthetic methods described in the prior art, low overall yields are obtained. Moreover, the required chromatographic purification steps severely hinder the scale-up, and these steps are more difficult to implement at the scale. Therefore, there is a need for alternative synthetic methods, especially when synthesized on a multi-gram or kilogram scale, especially when complying with good manufacturing practice requirements, which can achieve higher overall yields.

[0007] Document WO 2022 / 016289 discloses a method for preparing psilocybin starting from psilocybin and (tert-BuO)2POCl. In certain embodiments, the method disclosed in WO 2022 / 016289 requires the use of CCl4, which is not very favorable for scaling up the reaction and its industrial application.

[0008] Troxler F. et al. (Helvetica Chimica Acta, Vol. 42, No. 6, p. 207302193) disclose the phosphorylation of hydroxyindole derivatives using dibenzylphosphoryl chloride.

[0009] It is therefore an object of the present invention to provide a novel process for the preparation of alkyl derivatives of psilocybin, such as ethyl psilocybin, with improved overall yields, particularly when synthesized on a multi-gram or kilogram scale, while avoiding chromatographic purification.

[0010] The inventors have found that, surprisingly, said object can be achieved by the synthesis method outlined in the present patent application and claimed in the appended claims.

[0011] Therefore, the present invention provides a method for preparing a compound of formula (I),

[0012]

[0013] Where each R is independently C 1-6 Alkyl (preferably methyl or ethyl), wherein the method comprises the step of reacting the compound of formula (Id) with (EtO)2POCl(DECP). Preferably, the reaction product of the compound of formula (Id) with DECP is further reacted with trimethylsilyl bromide (TMSBr) to obtain the compound of formula (I).

[0014]

[0015] In a preferred process according to the invention, R is methyl.

[0016] In one embodiment of the present invention, the w / w ratio of the compound of formula (Id) to (DECP) is between 0.8 and 1.2, preferably between 1.0 and 1.2, more preferably between 1.10 and 1.15, even more preferably about 1.12, even more preferably 1.12.

[0017] In another embodiment of the present invention, DECP is added dropwise over a period of 10 to 20 minutes.

[0018] In a further embodiment of the present invention, the reaction of the compound of formula (Id) with DECP is carried out in acetonitrile.

[0019] In a further embodiment of the present invention, the reaction of the compound of formula (Id) with DECP is carried out at a temperature between 50°C and 70°C, preferably at a temperature between 55°C and 65°C, more preferably at a temperature between 57°C and 63°C, even more preferably at a temperature of about 60°C, and even more preferably at a temperature of 60°C.

[0020] In a further embodiment of the present invention, the reaction of the compound of formula (Id) with DECP is carried out in the presence of a base, preferably wherein the base is N-ethyldiisopropylamine.

[0021] In a further embodiment of the invention, the reaction of the compound of formula (Id) with DECP is carried out for a period of at least 150 minutes, until at least 99% of the compound of formula (Id) has reacted.

[0022] In a further embodiment of the present invention, the compound of formula (Id) is reacted with DECP, the solvent is changed to toluene, and an aqueous NaOH solution is added thereto, followed by phase separation. Preferably, NaOH is added at a concentration of 0.5M to 1.0M, preferably at a concentration of about 0.75M, more preferably at a concentration of 0.75M.

[0023] In a further embodiment of the method of the present invention, after the reaction of the compound of formula (Id) with DECP is completed, the solvent is changed to cyclopentylmethylether (CPME), and CPME containing HCl is added to the reaction mixture to obtain a crude product precipitate. In a preferred embodiment of the present invention, the CPME containing HCl is about a 3M solution, and / or wherein the solution is added dropwise over a period of 25 to 35 minutes, and / or wherein the solution is added at a temperature of 15°C to 20°C, preferably at a temperature of 17°C to 23°C, more preferably at a temperature of about 20°C, and even more preferably at a temperature of 20°C.

[0024] In another aspect of the invention, the reaction of a compound of formula (Id) with DECP affords a crude product of formula (Ie).

[0025]

[0026] In a preferred embodiment of the present invention, the crude product precipitated from the CPME upon addition of HCl comprises a compound of formula (Ie). In formula (Ie), each R is as defined for formula (I).

[0027] It should be understood that in the embodiment of the present invention where the compound of formula (Id) is reacted with DECP, the skilled person will recognize that DECP can be replaced by a compound of formula (R'O)2POCl, wherein each R' is independently selected from C 1-6 alkyl, -CH2-aryl or -CH2-heteroaryl, preferably wherein each R' is independently selected from C 1-6 alkyl and -CH2-aryl, more preferably wherein each R' is independently C 1-6 Thus, within the scope of the present invention, in the first step of the process of the present invention, the compound of formula (Id) may be reacted with a compound of formula (R'O)2POCl, wherein each R' is independently selected from C 1-6 Alkyl, -CH2-aryl or -CH2-heteroaryl, preferably selected from C 1-6 In particular, suitable C 1-6 Alkyl is ethyl and tert-butyl. In particular, a suitable -CH2-aryl is benzyl.

[0028] In a further embodiment of the present invention, the reaction product of the compound of formula (Id) and DECP is further reacted with trimethylsilyl bromide (TMSBr) to obtain a compound of formula (I), wherein preferably, the w / w ratio of TMSBr to the compound of formula (Id) is between 1.5 and 2.5, preferably between 1.8 and 2.4, more preferably between 2.0 and 2.3, even more preferably about 2.1, even more preferably 2.07.

[0029] In a further embodiment of the present invention, the reaction product of a compound of formula (Id) with diethylchlorophosphate (DECP) is reacted with TMSBr in acetonitrile, whereby TMSBr is preferably added at a temperature between 30°C and 50°C, preferably at a temperature between 35°C and 45°C, more preferably at a temperature between 37°C and 43°C, even more preferably at a temperature of about 40°C, even more preferably at a temperature of 40°C.

[0030] In a further embodiment of the present invention, the reaction product of the compound of formula (Id) and DECP is reacted with TMSBr at a temperature between 50°C and 70°C, preferably at a temperature between 55°C and 65°C, more preferably at a temperature between 57°C and 63°C, even more preferably at a temperature of about 60°C, and even more preferably at a temperature of 60°C.

[0031] In a further preferred embodiment of the present invention, the reaction with TMSBr is carried out for at least 150 minutes until at least 99% of the reaction product of the compound of formula (Id) with DECP is consumed.

[0032] In a further preferred embodiment of the invention, after the reaction with TMSBr, the solvent is changed to methanol, wherein the methanol is preferably removed by distillation and the remaining solid residue is dissolved in methanol and the solution thus obtained is treated with activated carbon and filtered.

[0033] In a further embodiment of the invention, the obtained reaction product with TMSBr is subjected to a solvent shift into water, wherein the pH of the solution is preferably set to a value in the range between pH=3.8 and pH=4.2 by adding 1 M NaOH.

[0034] In a further embodiment of the present invention, the w / w ratio of 1 M NaOH solution to the original amount of compound of formula (Id) added is about 4.0, more preferably 4.0.

[0035] In a further embodiment of the invention, the final product of formula (I) is precipitated from aqueous solution at a pH between 3.8 and 4.2 and / or at a temperature below 20°C, preferably at a temperature of about 15°C, more preferably at a temperature of 15°C.

[0036] In a further embodiment of the present invention, the final product of formula (I) is treated with water / acetone under reflux.

[0037] In a further embodiment of the present invention, the process further comprises the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id), wherein preferably, in the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id), LAH is used as a reducing agent, wherein in a preferred embodiment, the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id) is carried out in toluene, dioxane or CPME, preferably in toluene, more preferably, said step is carried out under reflux. In formula (Ic), each R is as defined for formula (I).

[0038]

[0039] In a further preferred embodiment of the present invention, in the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id), NaBH4 is used as a reducing agent.

[0040] In a further preferred embodiment of the present invention, the method further comprises reacting a compound of formula (Ia) with oxalyl chloride (COCl) 2 and subsequently reacting the resulting product with a dialkylamine (R 2 NH) (e.g., with diethylamine). In R 2 NH, each R is as defined for formula (I).

[0041]

[0042] In a further preferred embodiment of the present invention, the reaction of the compound of formula (Ia) with (COCl)2 is carried out in CPME at a temperature between 0°C and 10°C.

[0043] In a further preferred embodiment of the present invention, the reaction of a compound of formula (Ia) with (COCl)2 gives a compound of formula (Ib), wherein the compound of formula (Ib) is reacted with R2NH to give a compound of formula (Ic). In R2NH, each R is as defined for formula (I).

[0044]

[0045] The present invention will be more fully understood by referring to the following embodiments. However, these embodiments should not be construed as limiting the scope of the present invention.

[0046] The experimental procedures described in the Examples section below are further illustrated by the accompanying figures, which show the following apparatus setup.

[0047] FIG1 depicts the apparatus setup for step 1 of the embodiment, which depicts the acyl chloride formation step in the preparation process of acetoxyindole glyoxylic acid diethylamide and the corresponding mass flow and mass balance diagram, and the amide formation step in the preparation process of acetoxyindole glyoxylic acid diethylamide and the corresponding mass flow and mass balance diagram.

[0048] FIG2 depicts the apparatus setup for step 2 of the example, which illustrates the preparation process of 4-HO-DET and the corresponding mass flow and mass balance diagrams.

[0049] FIG3 depicts the apparatus setup for step 3 of the example, which illustrates the process for preparing crude ethylpsilocybin and the corresponding mass flow and mass balance diagrams.

[0050] FIG. 4 depicts the apparatus setup for step 4 of the example, which illustrates the preparation of the final ethylpsilocybin product and the corresponding mass flow and mass balance diagrams.

[0051] Figure 5 shows the analytical data of acetoxyindole glyoxylic acid diethylamide (the product of step 1 in the example), namely, HPLC data (Part 1), including UV-VIS spectra (Parts 2 and 3), 1 H and 13 LC-MS data of C NMR spectra (parts 4 and 5, respectively), and DSC measurements (part 6).

[0052] FIG6 shows analytical data of 4-hydroxy-N,N-diethylethocin (4-OH-DET, the product of step 2 in the example), namely HPLC data (Part 1), including UV-VIS spectra (Parts 2 and 3), 1 H and 13 LC-MS data of C NMR spectra (fractions 4 and 5, respectively), and DSC measurements.

[0053] 7 shows analytical data of crude ethylpsilocybin (product of step 3 in Example), namely HPLC data (part 1), LC-MS data including UV-VIS spectrum (parts 2 and 3), and DSC measurement (part 4).

[0054] FIG8 shows analytical data of ethylpsilocybin (API / drug / final product), the product of step 4 in the example, namely, HPLC data (Part 1), including UV-VIS spectra (Parts 2 and 3), 1 H and 13 LC-MS data of C NMR spectra (fractions 4 and 5, respectively), and DSC measurements.

[0055] Fig. 9 An exemplary reaction scheme leading to psilocybin (a compound of formula (I) wherein both R are methyl) is shown.

[0056] Figure 10 shows the HPLC data of acetoxyindole glyoxylic acid diethylamide (Part 1) and 1 H-NMR spectrum (Part 2).

[0057] Figure 11 shows the HPLC data of 4-hydroxydimethyltryptamine (Part 1) and 1 H-NMR spectrum (Part 2).

[0058] Figure 12 shows the HPLC data of psilocybin (Part 1) and the 1 H-NMR spectrum (Part 2). DETAILED DESCRIPTION

[0059] The invention is illustrated in the following embodiments.It should be understood that unless indicated to the contrary, all possible combinations of disclosed steps and / or features are contemplated.

[0060] In one embodiment, the present invention relates to a process for preparing a compound of formula (I),

[0061]

[0062] Where each R is independently C 1-6 Preferably, each R is independently methyl or ethyl. More preferably, each occurrence of R is ethyl.

[0063] The process of the present invention comprises the step of reacting a compound of formula (Id) with (EtO)2POCl (which may also be referred to as diethyl chlorophosphate or DECP).

[0064]

[0065] Preferably, in the method of the present invention, the w / w ratio of the compound of formula (Id) to (DECP) is between 0.8 and 1.2. More preferably, the w / w ratio of the compound of formula (Id) to (DECP) is between 1.0 and 1.2. Even more preferably, the w / w ratio of the compound of formula (Id) to (DECP) is between 1.10 and 1.15. Even more preferably, the w / w ratio of the compound of formula (Id) to (DECP) is about 1.12. Most preferably, the w / w ratio of the compound of formula (Id) to (DECP) is 1.12.

[0066] As understood herein, whenever referring to a number representing a ratio or concentration, the term "about" is intended to be understood as preferably ±2%, more preferably ±1%. In addition, as understood herein, whenever referring to a temperature, the term "about" is intended to be understood as preferably ±1°C, more preferably ±0.5°C.

[0067] The technician who carries out the step of reacting the compound of formula (Id) with DECP will be able to arrange the appropriate mixing of the two components. According to the inventors, it can be considered that it is preferred to react in a manner to avoid DECP exceeding (Id) too much at any given time. This can be achieved by adding (or dosing) DECP to (Id). Therefore, it is preferred that DECP is added to (Id). It is further preferred that DECP is added dropwise to (Id) within a time of at least 10 minutes, more preferably within a time between 10 minutes and 30 minutes, and even more preferably within a time between 10 minutes and 20 minutes.

[0068] According to the present inventors, the reaction of DECP with the compound of formula (Id) is preferably carried out in a polar aprotic solvent (e.g., in acetonitrile or DMF). For this reaction, a particularly preferred solvent is acetonitrile. Therefore, in a further embodiment of the present invention, the reaction of the compound of formula (Id) with DECP is carried out in acetonitrile.

[0069] Use the solvent (characterized in that it has relatively high boiling point under normal conditions) including acetonitrile or DMF, can flexibly select reaction temperature according to the requirement of reactant.According to the present inventors, the reaction of compound of formula (Id) and DECP is preferably carried out at a temperature between 50 ℃ and 70 ℃, more preferably at a temperature between 55 ℃ and 65 ℃, even more preferably at a temperature between 57 ℃ and 63 ℃, even more preferably at a temperature of about 60 ℃, even more preferably at a temperature of 60 ℃.

[0070] The reaction of the compound of formula (Id) and DECP is carried out in the presence of a base. The inventors have determined that a preferred base is N-ethyl diisopropylamine. However, this is not meant to be restrictive, and the technician will consider using other bases to determine their performance in the method of the present invention.

[0071] Preferably, according to the present invention, the reaction of the compound of formula (Id) with DECP is carried out until a certain desired component of the compound of formula (Id) has reacted. This should be understood as being equivalent to a certain component of the compound of formula (Id) that has been consumed, regardless of the reaction experienced by the compound. Preferably, the reaction is carried out until at least 90%, at least 95% or 99% of the compound of formula (Id) has reacted. More preferably, the reaction is carried out until at least 90% of the compound of formula (Id) has reacted. Preferably, the progress of the reaction is monitored by analyzing a sample from the reaction mixture using LC-MS or GC-MS. Therefore, the inventors have determined that, preferably, the reaction between DECP and the compound of formula (Id) is carried out for a period of at least 150 minutes, until at least 99% of the compound of formula (Id) has reacted.

[0072] Then, in the next step of the reaction of the compound of formula (Id) and DECP, the solvent is changed to toluene, and the NaOH aqueous solution is added thereto. As is apparent to the technician, it is expected that phase separation occurs at this time. The technician responsible for preparing a suitable NaOH solution for this purpose preferably does not exceed the NaOH concentration of 2.0M. Preferably, in the aqueous phase being added, the concentration of NaOH is 0.5M to 1.0M, preferably the concentration is about 0.75M, and more preferably the concentration is 0.75M. This treatment step of the reaction mixture can also be referred to as basic aqueous workup by the technician. The aqueous phase is separated from the toluene phase. The aqueous phase so obtained during the treatment process is preferably extracted twice with toluene, and the toluene component (which includes the reaction product of the compound of formula (Id) and DECP according to the present inventors) is merged. Then the toluene phase so merged is washed with a diluted NaOH aqueous solution (e.g., with a 0.1M NaOH solution, but other concentrations are also considered to be suitable) and subsequently washed twice with deionized water. As known to the skilled person, the aqueous work-up will be completed by stirring the toluene phase thus obtained with activated carbon, drying with sodium sulfate and filtering the fraction thus obtained on Celite.The toluene fraction thus treated is ready for the next step.

[0073] After the reaction of the compound of formula (Id) with DECP is completed, and after toluene / aqueous NaOH treatment as described above is performed, the solvent is changed to cyclopentyl methyl ether (CPME). Subsequently, CPME containing HCl is added to the reaction mixture to obtain a crude product precipitate. Preferably, the solvent exchange is carried out by evaporating the previous solvent while gradually adding the target solvent (CPME herein). The concentration of the preferred CPME containing HCl is no more than 5M, more preferably 2-4M. In a preferred embodiment, the CPME containing HCl is about 3M solution. In order to avoid undesirable side reactions, as is apparent to the technician, the CPME solution containing HCl is added dropwise over a certain period of time. Preferably, the CPME solution containing HCl is added dropwise over a period of at least 10 minutes, preferably over a period of at least 20 minutes. More preferably, the CPME solution containing HCl is added dropwise over a period of 20 to 40 minutes, even more preferably over a period of 25 to 35 minutes. As is apparent to the technician, the temperature is preferably controlled during the addition of the CPME containing HCl to the reaction mixture. Therefore, in a preferred embodiment of the present invention, the solution is added at a temperature between 15°C and 25°C, preferably at a temperature between 17°C and 23°C, more preferably at a temperature of about 20°C, even more preferably at a temperature of 20°C.

[0074] According to the present inventors, after adding CPME containing HCl, a precipitate of a crude product of the reaction of a compound of formula (Id) with DECP is formed. Then, as will be apparent to the skilled person, the suspension thus obtained is preferably filtered under reduced pressure, and the filter cake thus obtained is washed with CPME. The filter cake (which may also be referred to as a crude product of the reaction of a compound of formula (Id) with DECP) is then dried under reduced pressure.

[0075] Without being bound by theory, it is noted that the reaction of the compound of formula (Id) with DECP affords a crude product of formula (Ie).

[0076]

[0077] In formula (Ie), each R is as defined for formula (I). Therefore, according to the present inventors, as described above, the crude product precipitated from CPME after addition of HCl comprises a compound of formula (Ie). Therefore, in a preferred embodiment of the present invention, the reaction of a compound of formula (Id) with DECP yields a crude product of formula (Ie). In a further preferred embodiment of the present invention, the crude product precipitated from CPME after addition of HCl comprises a compound of formula (Ie).

[0078] According to the present inventors, the compound of formula (If) can be present in the reaction mixture. In formula (If), each R is as defined for formula (I). Without being limited by theory, the present inventors assume that due to the presence of ethyl chloride (which is formed when the compound of formula (Id) reacts with DECP according to the present inventors), this product is formed as a by-product of the reaction of DECP with the compound of formula (Id). Other possible reasons for the occurrence of this side reaction include the presence of ethyl chloride impurities in the preparation of DECP already used. According to the present inventors, the compound of formula (If) can also be formed in the alkylation reaction of the amine group (which is shown in the above formula in protonated form) with DECP in (Id) or (Ie). Therefore, according to the present inventors, the compound of formula (If) can be present in the crude product of the compound of formula (Id) and DECP. The present inventors have demonstrated that the compound of formula (If) can be exhausted in the reaction mixture, or substantially removed from the reaction mixture by aqueous treatment.

[0079]

[0080] The present inventors have detected a compound of formula (Ig) from the reaction of a compound of formula (Id) with DECP.

[0081]

[0082] In formula (Ig), each R is as defined for formula (I). The inventors assume that the compound of formula (Ig) is formed during the alkaline aqueous treatment of the product. According to the inventors, the compound of formula (Ig) (if present in the reaction mixture) can be extracted during the alkaline aqueous treatment and can therefore be separated from the product. However, the inventors have noticed that the formation of the compound of formula (Ig) may have a significant impact on the productive rate of the method.

[0083] The inventors further assume that the formation of the compound of formula (Ig) can preferably be suppressed (or reduced) by controlling the temperature, duration and pH of the reaction. More preferably, the formation of the compound of formula (Ig) can be suppressed (or reduced) by controlling the temperature. Therefore, it is preferred that the addition of NaOH is carried out at a temperature of 0° C. to 5° C. Preferably, the internal temperature of the reactor is considered here.

[0084] Preferably, within the scope of the present invention, the reaction product of the compound of formula (Id) and DECP as described above is further reacted with TMSBr to obtain the compound of formula (I). This reaction may also be referred to herein as a deprotection reaction.

[0085] Thus, the present invention relates to a process for preparing a compound of formula (I),

[0086]

[0087] Where each R is independently C 1-6 Alkyl, preferably each R is independently methyl or ethyl,

[0088] The method comprises the step of reacting a compound of formula (Id) with (EtO)2POCl(DECP),

[0089]

[0090] Wherein, the reaction product of the compound of formula (Id) and DECP is further reacted with TMSBr to obtain the compound of formula (I).

[0091] Preferably, the w / w ratio of the reaction product of TMSBr and DECP and the compound of formula (Id) is between 1.5 and 2.5. More preferably, the w / w ratio of TMSBr and the compound of formula (Id) is between 1.75 and 2.25. Even more preferably, the w / w ratio of TMSBr and the compound of formula (Id) is between 1.9 and 2.1. Even more preferably, the w / w ratio of TMSBr and the compound of formula (Id) is about 2.0. Even more preferably, the w / w ratio of TMSBr and the compound of formula (Id) is 2.0.

[0092] Preferably, the compound of formula (Id) reacts with TMSBr in a polar aprotic solvent. Therefore, acetonitrile is a suitable solvent for the reaction. Therefore, preferably, the reaction product of DECP and (Id) reacts with TMSBr in acetonitrile. As the technician will appreciate, this step will include dissolving the crude product obtained in the previous step (which according to the present invention can be a compound of formula (Ie)) in acetonitrile. Therefore, as known to those skilled in the art, preferably, within the scope of the present invention, the crude product of the reaction of the compound of formula (Id) is loaded into a suitable reactor together with a solvent (preferably acetonitrile).

[0093] Preferably, TMSBr is added to the reaction product of compound (Id) and DECP, preferably, TMSBr is added to the reaction product of compound (Id) and DECP (dissolved as described above) within 5 to 10 minutes at a temperature between 30°C and 50°C. More preferably, TMSBr is added to the reaction product of compound (Id) and DECP (dissolved as described above) at a temperature of 35°C to 45°C. Even more preferably, TMSBr is added to the reaction product of compound (Id) and DECP (dissolved as described above) at a temperature of 37°C to 43°C. Even more preferably, TMSBr is added to the reaction product of compound (Id) and DECP (dissolved as described above) at a temperature of about 40°C. Even more preferably, TMSBr is added to the reaction product of compound (Id) and DECP (dissolved as described above) at a temperature of 40°C.

[0094] Preferably, the reaction product of the compound of formula (Id) and DECP is reacted with TMSBr at a temperature between 50°C and 70°C. More preferably, the reaction product of the compound of formula (Id) and DECP is reacted with TMSBr at a temperature between 55°C and 65°C. Even more preferably, the reaction product of the compound of formula (Id) and DECP is reacted with TMSBr at a temperature between 57°C and 63°C. Even more preferably, the reaction product of the compound of formula (Id) and DECP is reacted with TMSBr at a temperature of about 60°C. Even more preferably, the reaction product of the compound of formula (Id) and DECP is reacted with TMSBr at a temperature of 60°C.

[0095] The progress of the reaction of the reaction product of the compound of formula (Id) with DECP and TMSBr will be monitored. Preferably, according to the present invention, the reaction of the reaction product of the compound of formula (Id) with DECP with TMSBr is carried out until a certain desired component of the product has reacted. This should be understood as being equivalent to a certain component of the product being consumed, regardless of the reaction experienced by the compound. Preferably, the reaction is carried out until at least 90%, at least 95% or 99% of the product has reacted. More preferably, the reaction is carried out until at least 90% of the product has reacted. Preferably, the reaction progress is monitored by analyzing a sample from the reaction mixture using LC-MS or GC-MS. Therefore, the inventors have determined that, preferably, the reaction between the reaction product of DECP with the compound of formula (Id) (which may be a compound of formula (Ie) according to the present invention) and TMSBr is carried out for a period of at least 150 minutes until at least 99% of the product (which may be a compound of formula (Ie)) has reacted.

[0096] The present invention also includes embodiments in which TMSBr is replaced by TMSI (as known to the skilled person, TMSI can be generated in situ using TMSCl and an iodide salt such as KI). It is further apparent to the skilled person that in TMSBr (or TMSI / TMSCl, if applicable), the methyl group may be replaced by other alkyl groups (e.g. selected from C 1-6 However, as described herein, most preferably, TMSBr is used in the present invention.

[0097] Preferably, after the reaction is complete, the solvent is changed to methanol and the reaction mixture is stirred in methanol. Preferably, the stirring is carried out at a temperature between 55°C and 65°C. More preferably, the stirring is carried out at a temperature between 57°C and 63°C. Even more preferably, the stirring is carried out at a temperature of about 60°C. Even more preferably, the stirring is carried out at a temperature of 60°C. Preferably, the stirring is carried out for a period of at least 20 minutes, more preferably for a period of 25 to 35 minutes, even more preferably for a period of about 30 minutes, even more preferably for a period of 30 minutes.

[0098] Preferably, methanol is distilled from the reaction mixture at this time point. It should be understood that preferably at least 50%, more preferably at least 70% of the methanol is distilled off. As the technician understands, some byproducts and byproducts of the reaction can also be removed from the reaction mixture together with methanol. The residue containing residual methanol thus obtained is further supplemented with methanol and stirred. Preferably, the stirring is carried out at a temperature between 55°C and 65°C. More preferably, the stirring is carried out at a temperature between 57°C and 63°C. Even more preferably, the stirring is carried out at a temperature of about 60°C. Even more preferably, the stirring is carried out at a temperature of 60°C. Preferably, the stirring is carried out for a time of at least 20 minutes, more preferably a time of 25 to 35 minutes, even more preferably a time of about 30 minutes, even more preferably a time of 40 minutes.

[0099] In one embodiment, the methanol can be completely removed and the solid residue thus obtained after the removal of the methanol is dissolved again in methanol and the solution thus obtained is preferably first incubated with activated carbon and subsequently filtered through diatomaceous earth.

[0100] Then, preferably the solvent is changed to water. Therefore, most of the methanol can be distilled off and water can be added. The pH of the solution thus obtained is set to a value in the range between pH=3.8 and pH=4.2. Preferably, as known to the skilled person, the setting of pH is completed by adding an aqueous solution of NaOH. Preferably, according to the present inventors, 1M NaOH solution is used. Therefore, the present inventors have used a w / w ratio of about 4 for the compound of formula (Id) of 1M NaOH solution and the original amount.

[0101] Preferably, once the pH has been set to a value in the range between pH=3.8 and pH=4.2, the reaction mixture is concentrated under reduced pressure to reduce its volume.

[0102] Thus, and preferably, the final product of formula (I) is precipitated from the aqueous solution thus obtained, after setting the pH to a value between 3.8 and 4.2, and preferably, as described above, after partially concentrating the solution. Preferably, after setting the pH to a value in the range between pH=3.8 and pH=4.2, about four volumes, preferably four volumes (wherein said volumes are understood relative to the volume of the aqueous solution of the product of formula (I) obtained) of isopropanol are added to the aqueous solution and distillation / concentration is carried out at a jacket temperature of 70+ / -5°C until about 3 volumes (as understood herein) of solution remain in the reactor. In order to increase the yield of the process, the temperature of the process is controlled. Preferably, the aqueous solution is maintained at a temperature of less than 20°C. More preferably, the aqueous solution is maintained at a temperature of about 15°C. Even more preferably, the aqueous solution is maintained at a temperature of 15°C. It should preferably be understood that cooling to a jacket temperature of 15°C as described herein is carried out within 360 minutes.

[0103] Preferably, the precipitated product thus obtained is filtered under reduced pressure and preferably washed with deionized water, deionized water / methanol mixture (preferably in a ratio of 1:1 v / v) and methanol. The product thus obtained is then dried under reduced pressure. Thus a crude preparation of a compound of formula (I) is obtained.

[0104] According to the inventors, a compound of formula (Ih) may be present in the reaction mixture, wherein each R is as defined for formula (I). Without being limited by theory, the inventors postulate that this product may be formed due to the presence of ethyl bromide in the reaction mixture (which, according to the inventors, is formed when the reaction product of a compound of formula (Id) with DECP (which may be a compound of formula (Ie)) is reacted with TMSBr). The inventors have surprisingly found that during the crystallization of a compound of formula (I), a compound of formula (Ih) may be separated from the product of the deprotection reaction (i.e., from the compound of formula (I)).

[0105]

[0106] The inventors have further detected a compound of formula (Ii) formed in the reaction of a compound of formula (Id) with the product of the reaction between DECP and TMSBr, wherein each R is as defined for formula (I). The inventors have surprisingly found that during the crystallization of the compound of formula (I), the compound of formula (Ii) can be separated from the product of the deprotection reaction (i.e., from the compound of formula (I)).

[0107]

[0108] Therefore, the present invention further relates to an embodiment, wherein the crude product of formula (I) thus obtained (which according to the present invention may contain other impurities, including compounds of formula (Ih) and / or compounds of formula (II)) is recrystallized or reslurried, preferably reslurried from water / acetone. Therefore, the crude product of formula (I) of the present invention as described herein is slurried in water / acetone and refluxed at a temperature of 60°C. Then, the recrystallized / reslurried mixture is cooled to a temperature of about 20°C, the precipitate formed is filtered off, washed with water / acetone (1:1) and acetone, and dried under vacuum.

[0109] In one embodiment of the present invention, the process of the present invention comprises the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id), wherein each R is as defined for formula (I).

[0110]

[0111] Several reducing agents suitable for reducing keto and amide groups can be used in embodiments of the present method. Thus, in one embodiment, LAH (also known as LiAlH4) is used in the reduction reaction. Preferably, in a specific embodiment, the reduction is carried out in toluene, dioxane or CPME. More preferably, the reduction is carried out in toluene, preferably under reflux.

[0112] In the reaction of ketoamide (Ic) with LAH, in a first step, the compound of formula (Ic) is charged into a reactor together with toluene and any residual water is removed by carrying out an azeotropic distillation of toluene / water. After the distillation is complete and the reaction mixture is cooled to a temperature between 55°C and 65°C, preferably to a temperature of about 60°C, more preferably to a temperature of 60°C, a THF solution containing LAH (preferably a 2.0M-3.0M solution, in particular a 2.4M solution) is added. As known to the skilled person, during the addition of LAH, both heat and gaseous hydrogen will be released from the reaction mixture. Therefore, it is clear to the skilled person that care should be taken in the process, for example by controlling the dosage of LAH, and / or by a light flow comprising a gas (e.g. nitrogen) so as to avoid an increase in the concentration of hydrogen.

[0113] Preferably, the reaction of the compound of formula (Ic) with the reducing agent is carried out until a certain desired component of the compound has reacted. This should be understood to be equivalent to a certain component of the compound having been consumed, regardless of the reaction the compound has undergone. Preferably, the reaction is carried out until at least 90%, at least 95% or 99% of the compound has reacted. More preferably, the reaction is carried out until at least 99% of the compound has reacted. Preferably, the progress of the reaction is monitored by analyzing a sample from the reaction mixture using LC-MS or GC-MS.

[0114] Once a certain desired component of the compound of formula (Ic) has been consumed, as described above, an additional volume of toluene is preferably charged to the reactor and the reaction mixture is further concentrated. A saturated solution of sodium-potassium tartrate is then added. The composition thus obtained is preferably stirred at a temperature of about 40° C., and the organic phase is separated from the aqueous phase. The aqueous phase is washed with toluene (preferably multiple times, for example 4 times) so that it can be extracted. The toluene phases thus obtained are combined, washed with a half-saturated sodium-potassium tartrate solution, incubated with activated carbon, dried over sodium sulfate and / or filtered through diatomaceous earth.

[0115] Thereafter, the product is preferably crystallized from isopropyl acetate / n-heptane. Therefore, the organic phase is concentrated and isopropyl acetate / n-heptane is added. Crystallization is induced by incubation, whereby the temperature is first lowered to 0° C. and then to −30° C. The crystallized compound of formula (Id) is isolated by filtration under reduced pressure and the filtrate obtained is then dried under vacuum.

[0116] According to the present inventors, the compound of formula (Ij) can be formed in the reduction process of the compound of formula (Ic), wherein each R is as defined for formula (I). However, the present inventors have surprisingly found that the compound of formula (Ij) can be separated from the compound of formula (Id) in the crystallization process from isopropyl acetate / n-heptane. The present invention further assumes that this compound, as an intermediate of reduction, requires a higher temperature for further reduction / conversion. Therefore and preferably, the temperature obtainable by boiling toluene, dioxane or CPME is required. The temperature corresponds to the boiling point of toluene, dioxane or CPME, respectively.

[0117]

[0118] In another embodiment of the present invention, the compound of formula (Ic) is reduced by using NaBH4.

[0119] In another embodiment of the present invention, the present invention relates to a process of the present invention, wherein the process further comprises the step of reacting a compound of formula (Ia) with (COCl)2 and subsequently reacting the resulting product with R2NH. Each R in R2NH is as defined for formula (I).

[0120]

[0121] Preferably, the reaction is carried out in CPME as a solvent, wherein oxalyl chloride and the compound of formula (Ia) should be dissolved. In the reaction, it is preferred to use an excess of oxalyl chloride exceeding the compound of formula (Ia), such as at least 1.1 molar ratio, at least 1.5 molar ratio or at least 2.0 molar ratio of oxalyl chloride to the compound of formula (Ia). It is particularly preferred to use a molar ratio of about 1.5, more preferably 1.5 oxalyl chloride to the compound of formula (Ia). Preferably, an excess of oxalyl chloride is provided over the entire duration of the reaction. Therefore, for example, a solution of the compound of formula (Ia) is preferably added dropwise to an oxalyl chloride solution.

[0122] The reaction temperature is preferably controlled, and preferably the reaction between oxalyl chloride and the compound of formula (Ia) is carried out at a temperature not greater than 20°C, preferably at a temperature between 0°C and 20°C, more preferably at a temperature between 0°C and 10°C.

[0123] The progress of the reaction is preferably controlled by monitoring the compound of formula (Ia). Therefore, the reaction between oxalyl chloride and the compound of formula (Ia) is preferably carried out until a certain desired component of the compound has reacted. This should be understood as being equivalent to a certain component of the compound having been consumed, regardless of the reaction experienced by the compound. Preferably, the reaction is carried out until at least 90%, at least 95% or 99% of the compound has reacted. More preferably, the reaction is carried out until at least 99% of the compound has reacted. Preferably, the progress of the reaction is monitored by using LC-MS or GC-MS to analyze a sample from the reaction mixture.

[0124] Preferably, as described above, once a desired component of the compound of formula (Ia) has reacted, the reaction mixture is diluted with a solvent, preferably CPME, and the solvent is distilled off from the reaction mixture while removing the oxalyl chloride.

[0125] Preferably, n-heptane is added to the reaction mixture, preferably at a temperature not exceeding 20° C., preferably at a temperature between 0° C. and 20° C., more preferably at a temperature between 0° C. and 10° C., even more preferably at a temperature of about 0° C., even more preferably at a temperature of 0° C. Thus, the reaction product of the compound of formula (Ia) with oxalyl chloride precipitates and is isolated by filtration and then washed with n-heptane. The filtrate thus obtained is dried by exposure to a stream of nitrogen.

[0126] According to the present inventors, the reaction of a compound of formula (Ia) with oxalyl chloride gives a compound of formula (Ib).

[0127]

[0128] As understood herein, the reaction product of a compound of formula (Ia) with oxalyl chloride (which, according to the present inventors, may be a compound of formula (Ib)) will react with an amine of formula R2NH (wherein each R is as defined for formula (I)) to give a compound of formula (Ic).

[0129] Preferably, the reaction is carried out in 2-MeTHF. Therefore, the reaction product of the compound of formula (Ia) and oxalyl chloride can be directly dissolved in 2-MeTHF after filtering and drying under nitrogen, while still being placed in a filter funnel. The two substrates dissolved in the solvent are stirred together to monitor the progress of the reaction. Preferably, the reaction product of the compound of formula (Ia) and oxalyl chloride is added to the amine at a temperature between -10 ° C and 5 ° C. In a certain component (e.g., at least 90%, at least 95%, or at least 99%) of the reaction product of the compound of formula (Ia) and oxalyl chloride, the reaction is stopped by adding 1N HCl aqueous solution to the reaction mixture. Subsequently, phase separation is carried out, and the separated organic phase is washed with HCl aqueous solution, for example, with 0.5MHCl solution. Then the aqueous phase thus produced is washed with 2-MeTHF, and the combined organic phase is washed with water, incubated with activated carbon and filtered through diatomaceous earth.

[0130] The solution thus obtained is concentrated and crystallization of the product starts, thereby reducing the temperature to -20° C. The precipitated product of formula (Ic) is filtered, washed with 2-MeTHF, 2-MeTHF / n-heptane (preferably 1:1 v / v) and n-heptane and dried under vacuum.

[0131] It should be understood that in the embodiment of the present invention where the compound of formula (Id) is reacted with DECP, the skilled person will recognize that DECP can be replaced by a compound of formula (R'O)2POCl, wherein each R' is independently selected from C 1-6 alkyl, -CH2-aryl or -CH2-heteroaryl, preferably wherein each R' is independently selected from C 1-6 alkyl and -CH2-aryl, more preferably wherein each R' is independently C 1-6 Thus, within the scope of the present invention, in the process of the present invention, the compound of formula (Id) may be reacted with a compound of formula (R'O)2POCl, wherein each R' is independently selected from C 1-6 alkyl, -CH2-aryl or -CH2-heteroaryl, preferably independently selected from C 1-6 alkyl and -CH2-aryl, more preferably wherein each R' is independently C 1-6 In particular, suitable C 1-6 Alkyl is ethyl and tert-butyl. In particular, a suitable -CH2-aryl is benzyl.

[0132] As used herein, the term "alkyl" refers to a monovalent saturated acyclic (i.e., non-cyclic) hydrocarbon group, which may be straight-chain or branched. Thus, an "alkyl" group does not contain any carbon-carbon double bonds or any carbon-carbon triple bonds. 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl) or butyl (e.g., n-butyl, isobutyl, sec-butyl or tert-butyl). Unless otherwise defined, the term "alkyl" preferably refers to C 1-4 Alkyl, more preferably refers to methyl or ethyl, and even more preferably refers to methyl. The skilled person knows the abbreviations typically used for different alkyl groups, such as Me for methyl, Et for ethyl, Bu for butyl, or tBu for tert-butyl.

[0133] As used herein, the term "aryl" refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings and bridged ring systems and / or fused ring systems containing at least one aromatic ring (e.g., a ring system consisting of two or three fused rings, wherein at least one of these fused rings is aromatic; or a bridged ring system consisting of two or three rings, wherein at least one of these bridged rings is aromatic). "Aryl" may, for example, refer to phenyl, naphthyl, dihydronaphthyl (dialiny) (i.e., 1,2-dihydronaphthyl), tetrahydronaphthyl (tetralinyl) (i.e., 1,2,3,4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl or azulenyl. Unless otherwise defined, "aryl" preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.

[0134] As used herein, the term "heteroaryl" refers to aromatic ring groups, including monocyclic aromatic rings and bridged and / or fused ring systems containing at least one aromatic ring (e.g., ring systems consisting of two or three fused rings, wherein at least one of the fused rings is aromatic; or bridged ring systems consisting of two or three rings, wherein at least one of the bridged rings is aromatic), wherein the aromatic ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may be optionally oxidized, and further wherein one or more carbon ring atoms may be optionally oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the aromatic ring group may contain one or two O atoms and / or one or two S atoms (which may be optionally oxidized) and / or one, two, three or four N atoms (which may be optionally oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and at least one carbon ring atom (which may be optionally oxidized) is present in the corresponding heteroatom-containing ring."Heteroaryl" may refer to, for example, thienyl (i.e., phenylthio), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furanyl (i.e., a furan group), benzofuranyl, isobenzofuranyl, chromanyl, chromenyl (e.g., 2H-1-benzopyranyl or 4H-1-benzopyranyl), isochromenyl (e.g., 1H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathiinyl, pyrrolyl (e.g., 1H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., a pyridine group; e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl), pyrazinyl, pyrimidine , pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, naphthyridinyl, phenanthrolinyl (e.g., [1,10]phenanthrolinyl, [1,7]phenanthrolinyl, or [4,7]phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (i.e., furazanyl), or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazolyl, 2H-tetrazolyl, triazolyl (e.g., 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl or 4H-1,2,4-triazolyl), benzotriazolyl, 1H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3 ,5-triazine), furano[2,3-c]pyridinyl, dihydrofuropyridinyl (e.g., 2,3-dihydrofuro[2,3-c]pyridinyl or 1,3-dihydrofuro[3,4-c]pyridinyl), imidazopyridinyl (e.g., imidazo[1,2-a]pyridinyl or imidazo[3,2-a]pyridinyl), quinazolinyl, thienopyridinyl, tetrahydrothienopyridinyl (e.g., 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl), dibenzofuranyl, 1,3-benzodioxolyl, benzodioxanyl (e.g., 1,3-benzodioxanyl or 1,4-benzodioxanyl), or coumarinyl.Unless otherwise defined, the term "heteroaryl" preferably refers to a 5- to 14-membered (more preferably a 5- to 10-membered) monocyclic or fused ring system comprising one or more (e.g., one, two, three or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, "heteroaryl" refers to a 5- or 6-membered monocyclic ring comprising one or more (e.g., one, two or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.

[0135] Thus, the process of the invention for preparing a compound of formula (I) may comprise the step of reacting a compound of formula (Id) with (R'O)2POCl,

[0136]

[0137] wherein each R is as defined for formula (I),

[0138] Wherein each R' is independently selected from C 1-6 alkyl, -CH2-aryl or -CH2-heteroaryl, preferably wherein each R' is independently selected from C 1-6 alkyl and -CH2-aryl, more preferably wherein each R' is independently C 1-6 In particular, suitable C 1-6 Alkyl is methyl, ethyl and tert-butyl. In particular, a suitable -CH2-aryl is benzyl. Therefore, in the method of the present invention, particularly preferred compounds (R'O)2POCl are (MeO)2POCl, (EtO)2POCl, (tBuO)2POCl and (benzyl-O)2POCl, more preferably (EtO)2POCl, (tBuO)2POCl and (benzyl-O)2POCl, even more preferably (EtO)2POCl and (tBuO)2POCl, still more preferably (EtO)2POCl (also referred to as DECP).

[0139] Preferably, within the scope of the present invention, the reaction product of the compound of formula (Id) as described above with (R'O)2POCl (preferably DECP) is further reacted with TMSBr to obtain the compound of formula (I). This reaction may also be referred to herein as a deprotection reaction.

[0140] Thus, the present invention relates to a process for preparing a compound of formula (I),

[0141]

[0142] Where each R is independently C 1-6 Alkyl, preferably methyl or ethyl,

[0143] The method comprises the step of reacting a compound of formula (Id) with (R'O)2POCl,

[0144]

[0145] Wherein each R' is independently selected from C 1-6 alkyl, -CH2-aryl and -CH2-heteroaryl, wherein the reaction product of the compound of formula (Id) and said (R'O)2POCl is further reacted with TMSBr to obtain the compound of formula (I).

[0146] Although in the present specification, the method is described in detail for the embodiment in which R' is ethyl, the skilled person will recognize that the method of the present invention can be extended to the entire provided range of R', that is, R' is C 1-6 Alkyl, -CH2-aryl or -CH2-heteroaryl. The embodiment of the present invention wherein both R' are ethyl is particularly preferred and exemplified herein.

[0147] It is further clear to the skilled person that the compound of formula (Id) and (R'O)2POCl (wherein each R' is independently selected from C 1-6 The reaction product of a compound of formula (Id) with (R'O)2POH can also be obtained under different conditions, for example by reacting a compound of formula (Id) with (R'O)2POH under conditions resulting in the presence of (R'O)2POCl, for example in the presence of a base and tetrachloromethane, or wherein (R'O)2POCl is generated in situ in the presence of NCS (N-chlorosuccinimide) and THF, as described in WO 2022 / 016289. Therefore, when referring to a compound of formula (Id) with (R'O)2POCl (wherein each R' is independently selected from C 1-6 Alkyl, -CH2-aryl and -CH2-heteroaryl (preferably independently selected from C 1-6 Alkyl and -CH2-aryl, more preferably independently C 1-6 alkyl)) is obtained, the product is not limited to the product obtained by reacting a compound of formula (Id) with (R'O)2POCl (wherein each R' is independently selected from C 1-6alkyl, -CH2-aryl and -CH2-heteroaryl), but also includes the products obtained in any other way, for example by reacting a compound of formula (Id) with (R'O)2POH under conditions resulting in the presence of (R'O)2POCl, as described in WO 2022 / 016289.

[0148] If a product is obtainable in the reaction of a compound of formula (Id) with DECP, the inventors have postulated (without being bound by theory) that the product is a compound of the formula: Each R is as defined for formula (I), preferably each R is independently methyl or ethyl.

[0149]

[0150] If a product can be obtained in the reaction of a compound of formula (Id) with (R'O)2POCl as defined above, the inventors further assume that the product is a compound of formula (Ie-1) or a salt thereof (e.g., HCl salt). Each R is as defined for formula (I), preferably each R is independently methyl or ethyl, and each R' is as defined for (R'O)2POCl.

[0151]

[0152] Therefore, in view of the above, in one embodiment, the present invention relates to a method for obtaining a compound of formula (I),

[0153]

[0154] Where each R is independently C 1-6 Alkyl, preferably methyl or ethyl,

[0155] The method comprises the step of reacting the product obtainable in the reaction of a compound of formula (Id) with (R'O)2POCl with TMSBr to obtain a compound of formula (I),

[0156]

[0157] Wherein each R' is independently selected from C 1-6 alkyl, -CH2-aryl and -CH2-heteroaryl.

[0158] Preferably, each R' is independently selected from C 1-6 Alkyl and -CH2-aryl, more preferably, each R' is independently C 1-6 Even more preferably, both R's are ethyl (in other words, each R' is ethyl).

[0159] Further embodiments and / or implementations of the invention are disclosed in the following numbered items.

[0160] 1. A method for preparing a compound of formula (I),

[0161]

[0162] wherein each R is independently methyl or ethyl,

[0163] The method comprises the step of reacting a compound of formula (Id) with (EtO)2POCl(DECP)

[0164]

[0165] 2. The method according to item 1, wherein each R is a methyl group.

[0166] 3. The method according to item 1 or 2, wherein the w / w ratio of the compound of formula (Id) to (DECP) is between 0.8 and 1.2, preferably between 1.0 and 1.2, more preferably between 1.10 and 1.15, even more preferably about 1.12, even more preferably 1.12.

[0167] 4. The method according to any one of items 1 to 3, wherein DECP is added dropwise over a period of 10 to 20 minutes.

[0168] 5. The method according to any one of items 1 to 4, wherein the reaction of the compound of formula (Id) with DECP is carried out in acetonitrile.

[0169] 6. A method according to any one of items 1 to 5, wherein the reaction of the compound of formula (Id) with DECP is carried out at a temperature between 50°C and 70°C, preferably at a temperature between 55°C and 65°C, more preferably at a temperature between 57°C and 63°C, even more preferably at a temperature of about 60°C, even more preferably at a temperature of 60°C.

[0170] 7. The method according to any one of items 1 to 6, wherein the reaction of the compound of formula (Id) with DECP is carried out in the presence of a base, preferably wherein the base is N-ethyldiisopropylamine.

[0171] 8. The process according to any one of items 1 to 7, wherein the reaction of the compound of formula (Id) with DECP is carried out for at least 150 minutes, until at least 99% of the compound of formula (Id) has reacted.

[0172] 9. The method according to any one of items 1 to 8, wherein after the reaction of the compound of formula (Id) with DECP, the solvent is changed to toluene, and an aqueous NaOH solution is added thereto, followed by phase separation.

[0173] 10. The method according to item 8, wherein NaOH is added at a concentration of 0.5M to 1.0M, preferably at a concentration of about 0.75M, more preferably at a concentration of 0.75M.

[0174] 11. The method according to any one of items 1 to 10, wherein after the reaction of the compound of formula (Id) with DECP is completed, the solvent is changed to CPME and CPME containing HCl is added to the reaction mixture to obtain a crude product precipitate.

[0175] 12. The method according to claim 11, wherein the CPME containing HCl is about 3M solution, and / or wherein the solution is added dropwise over a period of 25 to 35 minutes, and / or wherein the solution is added at a temperature of 15°C to 20°C, preferably at a temperature of 17°C to 23°C, more preferably at a temperature of about 20°C, and even more preferably at a temperature of 20°C.

[0176] 13. The method according to any one of items 1 to 12, wherein the compound of formula (Id) is reacted with DECP to obtain a crude product of formula (Ie)

[0177]

[0178] 14. A process according to any one of items 1 to 13, wherein the crude product precipitated from the CPME after addition of HCl comprises a compound of formula (Ie).

[0179] 15. The method according to any one of items 1 to 14, wherein the reaction product of the compound of formula (Id) and DECP is further reacted with TMSBr to obtain the compound of formula (I).

[0180] 16. The method according to item 15, wherein the w / w ratio of TMSBr to the compound of formula (Id) is between 1.5 and 2.5, preferably between 1.8 and 2.4, preferably between 2.0 and 2.3, even more preferably about 2.1, even more preferably 2.07.

[0181] 17. The method according to item 15 or 16, wherein the reaction product of the compound of formula (Id) and DECP is reacted with TMSBr in acetonitrile.

[0182] 18. A process according to any one of items 15 to 17, wherein TMSBr is added at a temperature between 30°C and 50°C, preferably at a temperature between 35°C and 45°C, more preferably at a temperature between 37°C and 43°C, even more preferably at a temperature of about 40°C, even more preferably at a temperature of 40°C.

[0183] 19. A process according to any one of items 15 to 18, wherein the reaction product of the compound of formula (Id) and DECP is reacted with TMSBr at a temperature between 50°C and 70°C, preferably between 55°C and 65°C, more preferably between 57°C and 63°C, even more preferably at about 60°C, even more preferably at 60°C.

[0184] 20. The process according to any one of items 15 to 19, wherein the reaction with TMSBr is carried out for at least 150 minutes until at least 99% of the reaction product of the compound of formula (Id) and DECP is consumed.

[0185] 21. The process according to any one of items 15 to 20, wherein after the reaction with TMSBr, the solvent is changed to methanol.

[0186] 22. The process according to any one of items 15 to 21, wherein the product obtained from the reaction with TMSBr is solvent-transformed into water, wherein the pH of the solution is preferably set to a value in the range between pH=3.8 and pH=4.2 by adding 1 M NaOH.

[0187] 23. The method according to item 22, wherein the w / w ratio of 1 M NaOH solution to the original amount of compound of formula (Id) added is about 4.0, more preferably 4.0.

[0188] 24. The process according to item 22 or 23, wherein the final product of formula (I) is precipitated from an aqueous solution at a pH between 3.8 and 4.2 and / or at a temperature below 20°C, preferably at a temperature of about 15°C, more preferably at a temperature of 15°C.

[0189] 25. The process according to any one of items 1 to 24, wherein the final product of formula (I) is reslurried after treatment with water / acetone under reflux.

[0190] 26. The method according to any one of items 1 to 25, further comprising the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id)

[0191]

[0192] 27. The method according to item 26, wherein, in the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id), LAH is used as a reducing agent.

[0193] 28. The process according to item 27, wherein the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id) is carried out in toluene, dioxane or CPME, preferably in toluene,

[0194] Preferably, the step is carried out under reflux.

[0195] 29. The method according to item 26, wherein in the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id), NaBH4 is used as a reducing agent.

[0196] 30. The method according to any one of items 26 to 29, wherein the method further comprises the step of reacting the compound of formula (Ia) with (COCl)2, and then reacting the resulting product with R2NH

[0197]

[0198] 31. The process according to item 30, wherein the reaction of the compound of formula (Ia) with (COCl)2 is carried out in CPME at a temperature between 0°C and 10°C.

[0199] 32. The method according to item 30 or 31, wherein the reaction of the compound of formula (Ia) with (COCl)2 gives a compound of formula (Ib),

[0200]

[0201] Therein, the compound of formula (Ib) is reacted with R2NH to obtain the compound of formula (Ic).

[0202] Other embodiments and implementations of the invention are disclosed in the following numbered clauses.

[0203] 1. A method for preparing a compound of formula (I):

[0204]

[0205] wherein each R is independently methyl or ethyl,

[0206] The method comprises the step of reacting a compound of formula (Id) with (EtO)2POCl(DECP)

[0207]

[0208] 2. The method according to clause 1, wherein each R is a methyl group.

[0209] 3. The process according to clause 1 or 2, wherein the w / w ratio of the compound of formula (Id) to (DECP) is between 0.8 and 1.2, preferably between 1.0 and 1.2, more preferably between 1.10 and 1.15, even more preferably about 1.12, even more preferably 1.12,

[0210] Preferably, DECP is added dropwise over a period of 10 to 20 minutes.

[0211] 4. The process according to any one of clauses 1 to 3, wherein the reaction of the compound of formula (Id) with DECP is carried out in acetonitrile,

[0212] Preferably, the reaction of the compound of formula (Id) with DECP is carried out at a temperature between 50°C and 70°C, more preferably at a temperature between 55°C and 65°C, even more preferably at a temperature between 57°C and 63°C, even more preferably at a temperature of about 60°C, even more preferably at a temperature of 60°C,

[0213] and / or

[0214] Wherein, the reaction of the compound of formula (Id) with DECP is carried out in the presence of a base, preferably wherein the base is N-ethyldiisopropylamine,

[0215] and / or

[0216] Wherein, the reaction of the compound of formula (Id) with DECP is carried out for a period of at least 150 minutes until at least 99% of the compound of formula (Id) has reacted.

[0217] 5. The method according to any one of items 1 to 4, wherein after the reaction of the compound of formula (Id) with DECP, the solvent is changed to toluene, and an aqueous NaOH solution is added thereto, followed by phase separation,

[0218] Preferably wherein NaOH is added at a concentration of 0.5M to 1.0M, more preferably at a concentration of about 0.75M, even more preferably at a concentration of 0.75M,

[0219] and / or

[0220] After the reaction of the compound of formula (Id) with DECP is completed, the solvent is changed to CPME, and CPME containing HCl is added to the reaction mixture to obtain a crude product precipitate.

[0221] Preferably, the CPME containing HCl is about 3M solution, and / or wherein the solution is added dropwise over a period of 25 to 35 minutes, and / or wherein the solution is added at a temperature of 15°C to 20°C, preferably at a temperature of 17°C to 23°C, more preferably at a temperature of about 20°C, even more preferably at a temperature of 20°C.

[0222] 6. The process according to any one of clauses 1 to 5, wherein the compound of formula (Id) is reacted with DECP to obtain a crude product of formula (Ie),

[0223]

[0224] Preferably wherein the crude product precipitated from the CPME upon addition of HCl comprises a compound of formula (Ie).

[0225] 7. The process according to any one of clauses 1 to 6, wherein the reaction product of the compound of formula (Id) and DECP is further reacted with TMSBr to obtain the compound of formula (I),

[0226] Preferably wherein the w / w ratio of TMSBr to the compound of formula (Id) is between 1.5 and 2.5, more preferably between 1.8 and 2.4, even more preferably between 2.0 and 2.3, even more preferably about 2.0, even more preferably 2.07,

[0227] Preferably, the reaction product of the compound of formula (Id) and DECP is reacted with TMSBr in acetonitrile.

[0228] 8. The process according to clause 7, wherein TMSBr is added at a temperature between 30°C and 50°C, preferably at a temperature between 35°C and 45°C, more preferably at a temperature between 37°C and 43°C, even more preferably at a temperature of about 40°C, even more preferably at a temperature of 40°C,

[0229] and / or

[0230] wherein the reaction product of the compound of formula (Id) and DECP is reacted with TMSBr at a temperature between 50°C and 70°C, preferably at a temperature between 55°C and 65°C, more preferably at a temperature between 57°C and 63°C, even more preferably at a temperature of about 60°C, and even more preferably at a temperature of 60°C,

[0231] and / or

[0232] The reaction with TMSBr is carried out for at least 150 minutes until at least 99% of the reaction product of the compound of formula (Id) and DECP is consumed.

[0233] 9. The process according to clause 7 or 8, wherein after the reaction with TMSBr, the solvent is changed to methanol, and / or

[0234] wherein the product obtained by the reaction with TMSBr is subjected to solvent conversion into water, wherein the pH of the solution is preferably set to a value in the range of pH=3.8 to pH=4.2 by adding 1M NaOH, preferably wherein the w / w ratio of 1M NaOH solution to the original amount of compound of formula (Id) added is about 4.0, more preferably 4.0, preferably wherein the final product of formula (I) precipitates from the aqueous solution at a pH between 3.8 and 4.2 and / or at a temperature below 20°C, preferably at a temperature of about 15°C, more preferably at a temperature of 15°C.

[0235] 10. The process according to any one of clauses 1 to 9, wherein the final product of formula (I) is reslurried after treatment with water / acetone under reflux.

[0236] 11. The method according to any one of clauses 1 to 10, further comprising the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id)

[0237]

[0238] 12. The process according to item 11, wherein in the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id), LAH is used as a reducing agent,

[0239] Preferably wherein the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id) is carried out in toluene, dioxane or CPME, preferably in toluene,

[0240] Preferably, the step is carried out under reflux.

[0241] 13. The process according to item 11, wherein in the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id), NaBH4 is used as a reducing agent.

[0242] 14. A method according to any one of clauses 11 to 13, wherein the method further comprises the step of reacting a compound of formula (Ia) with (COCl)2, and then reacting the resulting product with R2NH

[0243]

[0244] 15. The process according to item 14, wherein the reaction of the compound of formula (Ia) with (COCl)2 is carried out in CPME at a temperature between 0°C and 10°C,

[0245] and / or

[0246] Wherein, the reaction of the compound of formula (Ia) with (COCl)2 gives the compound of formula (Ib),

[0247]

[0248] Therein, the compound of formula (Ib) is reacted with R2NH to obtain the compound of formula (Ic).

[0249] The present invention will be illustrated by the following examples, which however should not be construed as limiting.

[0250] Example

[0251] Example 1: Preparation of ethylpsilocybin according to the present invention

[0252] Herein, a scaled-up process for preparing ethylpsilocybin according to the present invention is described below.

[0253] Step 1: In Figure 1 Part 1 In the apparatus shown in , a process for preparing acetoxyindole oxacetylchloride from 4-acetoxyindole.

[0254] Step 1a : As shown in Figure 1, a solution of oxalyl chloride in cyclopentyl methyl ether (CPME) was prepared in a 5-liter glass reaction vessel.

[0255] Prepare a solution of (1 volume) 4-acetoxyindole in 5 volumes of CPME (preferably in a 2 L glass bottle).

[0256] The 4-acetoxyindole solution was slowly added to the oxalyl chloride solution under stirring. Stirring was maintained until sufficient 4-acetoxyindole was converted into acetoxyindoleoxaacetyl chloride. The reaction mixture was then concentrated under reduced pressure and repeatedly diluted with CPME, followed by distillation (at least twice).

[0257] The resulting suspension was then diluted with n-heptane and further stirred in a reaction vessel at 0°C as Figure 1 Part 1 (Position 2). The product suspension was filtered using a 1-liter glass filter and washed twice with 2.5 volumes of n-heptane. The filter cake was then dried under a weak stream of nitrogen.

[0258] Mass flow and mass balance diagrams are shown in Figure 1 Part 3 Shown in.

[0259] Step 1b :Then in Figure 1 Part 2In the apparatus shown in FIG. 1 , the acetoxyindoleoxaacetyl chloride from step 1a was dissolved in 16.9 volumes of 2-methyltetrahydrofuran (2-MeTHF) in one 5-L glass reaction vessel and mixed with 2.1 equivalents of a solution of diethylamine in 2-MeTHF (1 volume of diethylamine and 2 volumes of 2-MeTHF) in a second 5-L glass reaction vessel.

[0260] The mixture is then further stirred until sufficient acetoxyindoleoxaacetyl chloride has reacted. 4.5 volumes of a solution of 1 N HCl are then added to the reaction mixture. A phase separation step is then performed, whereby the upper organic phase is then separated. The organic phase is then washed again with 4.5 volumes of 0.5 M HCl. The combined aqueous wash solutions are then extracted twice with 4.5 volumes of 2-MeTHF and subsequently with 2.3 volumes of deionized water. Activated carbon (12.5 g) is then added to the organic phase with stirring, followed by 100 g of diatomaceous earth (such as Celpure TM ) The mixture was filtered. The organic phase thus obtained was concentrated under vacuum and cooled at a temperature of -20°C to obtain a product suspension (it may be necessary to incubate the precipitate to obtain a suspension). The suspension was then filtered. The filter cake thus obtained was then washed twice with 1.4 volumes of 2-methyltetrahydrofuran (MeTHF). The organic phase containing acetoxyindole glyoxylic acid diethylamide was then further concentrated under vacuum. 163 g of acetoxyindole glyoxylic acid diethylamide was obtained.

[0261] Mass flow and mass balance diagrams are shown in Figure 1 Part 4 and shown in Section 5.

[0262] The analytical data of the obtained product are shown in FIG5 .

[0263] HPLC measurements were performed according to the following protocol:

[0264]

[0265] HPLC data such as Figure 5 Part 1 shown.

[0266] LC-MS was performed at a flow rate of 0.5 ml (5 min) using a restrictive capillary with a pre-column using mobile phase A (ACN: water 1:1). Detection was performed at a wavelength of 220 nm. LC-MS measurements (Figure 5, parts 2 and 3) showed the presence of two peaks: 303.2 m / z: [M+H] + and 605.4m / z:[2M+H] + Further details about the LC-MS measurements are as follows:

[0267] a. Thermofisher Vanquish ISQ series (single quadrupole)

[0268] b. Heated electrospray ionization (HESI): positive mode (3000 V; 50 μA); ion transfer tube temperature 300° C.; evaporator temperature 282° C.

[0269] Measured at 400 MHz in DMSO-d6 using a Bruker Avance 400 spectrometer 1 H NMR spectrum. Figure 5 Part 4 As shown, the observed peaks are summarized as follows:

[0270] serial number Shift 1(ppm) H's type J(Hz) Atom 1 Multiplet 1 (ppm) 1 1.04 3 t 6.97 22,20 M03 [0.99..1.09] 2 1.16 3 t 9.10 22,20 M04 [1.11..1.22] 3 2.35 3 s - 17 M10 [2.26..2.43] 4 3.18 2 q 6.93 21,19 M02 [3.12..3.23] 5 3.41 2 q 7.10 21,19 M01 [3.37..3.49] 6 6.92 1 dd 9.60,0.76 6 M09 [6.82..7.02] 7 7.29 1 t 7.86 7 M08 [7.23..7.40] 8 7.45 1 dd 8.11,0.76 8 M07 [7.41..7.52] 9 8.05 1 s - 2 M06 [7.98..8.13] 10 12.48 1 br.s. - 1 M05 [12.33..12.62]

[0271] Measured using a Bruker Avance 400 spectrometer at 125 MHz in DMSO-d6 13 C NMR spectrum. Figure 5 Part 5 As shown, the observed peaks are summarized as follows:

[0272] serial number Displacement (ppm) atom 1 186.3 10(C=O) 2 169.7 13(C=O) 3 167.7 15(C=O) 4 144.5 5(CO) 5 139.8 9(CN) 6 139.3 2(CN) 7 124.7 7(CH) 8 118.7 4(C) 9 115.9 6(CH) 10 113.2 3(C) 11 111.2 8(CH) 12 42.0 19 / 21(CH2) 13 38.5 19 / 21(CH2) 14 21.7 17(CH2) 15 14.5 20 / 22(CH2) 16 13.2 20 / 22(CH2)

[0273] DSC measurements were performed using a Mettler Toledo thermal analysis DSC3+ and aluminum crucibles (40 μL). DSC screening was typically performed as follows: 20°C-300°C, 10°C / min, data point 1.00 sec. DSC measurements were performed as follows: Figure 5 Part 6 shown.

[0274] Step 2: Figure 2 Part 1 In the apparatus shown, the process of preparing 4-hydroxy-indole-3-ethyl diethylamide (4-HO-DET) from acetoxyindole glyoxylic acid diethylamide.

[0275] Then, in a nitrogen atmosphere, in a 5-liter glass reaction vessel, the ketoamide (100 g) from step 1b was mixed with 15 volumes of toluene. Then, under stirring (50 to 250 rpm) (950 to 850 mbar, jacket temperature (Ta) of 130 ± 5 ° C), azeotropic distillation of toluene / water was carried out to obtain about 3 volumes of distillate (1). The solution was then cooled to 60 ° C, which resulted in precipitation of the product and formation of a suspension. Then, under stirring (50 rpm to 250 rpm), 370 mL of tetrahydrofuran (THF) containing lithium aluminum hydride (LAH) (2.4 M) was slowly added at a temperature of 60 ° C to 70 ° C. Then, under reflux, the reaction mixture was heated to a temperature of 120 ° C for at least 3 hours under stirring (50 to 250 rpm). Then, without reflux, the reaction mixture was further stirred. As a process control step, the amount of the ketoamide that had reacted was determined. Toluene was added again and the reaction mixture was concentrated. The reaction mixture was cooled to ≤55 ° C. A saturated solution of sodium potassium tartrate is added and the reaction mixture is stirred (50 to 250 rpm) for at least 30 minutes at a temperature of 40 ± 3 ° C. A phase separation step is then performed in which the aqueous phase is extracted four times with toluene. The combined organic phases are washed with a semi-saturated sodium potassium tartrate solution. The aqueous phase is then back-extracted with toluene and the toluene extract obtained is added to the combined organic phases extracted with the sodium potassium tartrate solution. Activated carbon is then added to the organic phase under stirring. The mixture is then dried over sodium sulfate and filtered through diatomaceous earth (such as Celpure) using a 3 liter glass filter. TM ) was filtered to clarify. The filtrate was then further dried over sodium sulfate and passed through diatomaceous earth (such as Celpure TM ) is filtered. The organic phase is then further concentrated. Isopropyl acetate and n-heptane are then added. The mixture is then cooled. Crystallization in the reaction mixture is then initiated, and the jacket temperature (Ta) is slowly reduced to 0°C within 30±5 minutes and then to -30°C again within 600±30 minutes. The product suspension is then filtered and the resulting filter cake is washed with isopropyl acetate / n-heptane (1:1 v / v). The filter cake is then dried under vacuum. The product 4-hydroxy-N,N-diethyltryptamine (4-HO-DET) is isolated.

[0276] Mass flow and mass balance diagrams are shown in Figure 2 Part 2 and shown in Section 3.

[0277] The analytical data of the obtained product are shown in FIG6 .

[0278] HPLC measurements were performed as described above. Figure 6 Part 1 Shown in.

[0279] LC-MS was performed as described above. These measurements (Figure 6, parts 2 and 3) have shown at 233.3 m / z: [M+H] + There is a peak.

[0280] Measured at 400 MHz in DMSO-d6 using a Bruker Avance 400 spectrometer 1 H NMR spectrum. Figure 6 Part 4 As shown, the observed peaks are summarized as follows:

[0281] serial number Shift 1(ppm) H's type J(Hz) Atom 1 Multiplet 1 (ppm) 1 0.95 6 t 7.10 14,17 M11 [0.88..1.04] 2 2.53 4 m - 13,16 M10 [2.50..2.58] 3 2.65 2 m - 11 M09 [2.26..2.72] 4 2.84 2 m - 10 M08 [2.78..2.90] 5 6.25 1 dd 7.35,1.01 6 M06 [6.20..6.29] 6 6.74 1 m - 8 M05 [6.69..6.76] 7 6.80 1 m - 7 M04 [6.77..6.84] 8 6.92 1 d 2.28 2 M03 [6.87..6.99] 9 10.59 1 br.s. - 1 M02 [10.48..10.75] 10 11.39 1 s - 15 M01 [11.35..11.49]

[0282] Measured using a Bruker Avance 400 spectrometer at 125 MHz in DMSO-d6 13 C NMR spectrum. Figure 6 Part 5 As shown, the observed peaks are summarized as follows:

[0283] serial number Displacement (ppm) atom 1 152.2 5(CO) 2 139.2 9(CN) 3 122.4 7(CH) 4 121.7 2(CH) 5 117.7 4(C) 6 113.4 3(C) 7 104.4 6(CH) 8 103.1 8(CH) 9 55.8 11(CH2) 10 47.3 13 / 16(CH2) 11 25.1 10(CH2) 12 11.6 14 / 17(CH2)

[0284] DSC measurements were performed as described above. Figure 6 Part 6 Shown in.

[0285] Step 3: In Figure 3 Part 1 In the apparatus shown, a process for preparing crude ethylpsilocybin from 4-HO-diethyltryptamine (4-HO-DET) via DET-diethylphosphate x HCl as an intermediate.

[0286] Step 3a : Phosphorylation step

[0287] As shown in Figure 4, 4-HO-DET (50 g) obtained in step 2 is charged with 197 g of acetonitrile into a 1-liter glass reaction vessel, and the mixture is then heated to a batch temperature (TI) of 60°C. 55.6 g of N-ethyldiisopropylamine is then added. After the addition of diethyl chlorophosphate, the mixture is further stirred at a TI of 60°C. As a process control step, the amount of remaining 4-HO-DET is determined. The solvent is then changed to toluene. The reaction mixture is then cooled from room temperature to a TI of 0°C. 0.75 M caustic soda is then added. A phase separation step is then performed, whereby the aqueous phase is extracted twice with toluene. The combined organic phase is first washed with 0.1 N NaOH and then washed twice with deionized water. Activated carbon is then added to the organic phase under stirring and then dried with sodium sulfate, and toluene is used in the washing step to pass through diatomaceous earth (such as Celpure TM The mixture was clarified by filtration through a diatomaceous earth (e.g. Celpure). The solvent was then changed to cyclopentyl methyl ether (CPME). CPME containing 3M HCl was then added and the suspension was again filtered through diatomaceous earth (e.g. CelpureTM P1000) to separate the intermediate HCl salt. The filter cake is then washed twice with CPME. The amount of the resulting TET-diethyl phosphate xHCl is then determined as a process control step. The filter cake is then further dried under reduced pressure.

[0288] Step 3b : Deprotection

[0289] DET-diethyl phosphate x HCl was charged to a reaction vessel in the presence of acetonitrile. The reaction mixture was then heated to a batch temperature (TI) of 40°C. Bromotrimethylsilane was then added and the reaction mixture was heated to a TI of 60°C under stirring. As a process control step, the amount of DET-diethyl phosphate x HCl remaining was determined. The solvent was then changed to methanol. The reaction mixture was then stirred at a temperature of 50°C. The solvent was then distilled off. The residue was mixed with methanol again and the mixture was further stirred at a temperature of 50°C. A solvent change to water was then performed. The pH of the mixture was then adjusted to a pH between 3.8 and 4.2 with 1N NaOH. Isopropanol was charged and the reaction mixture was then concentrated under reduced pressure. A temperature increase step was then performed to a jacket temperature (Ta) set point of 15°C. The resulting suspension was then filtered. The filter cake was then washed sequentially first with deionized water, then with a deionized water / methanol mixture and finally with methanol alone. The resulting product was then dried under reduced pressure. The resulting product was collected and the yield of the crude ethylpsilocybin product was then determined.

[0290] Mass flow and mass balance diagrams are shown in Figure 3 Part 2 to Part 4.

[0291] The analytical data of the obtained product are shown in FIG7 .

[0292] HPLC measurements were performed as described above. Figure 7 Part 1 Shown in.

[0293] LC-MS was performed as described above. These measurements (Figure 7, parts 2 and 3) have shown at 313.3 m / z: [M+H] + 、527.4m / z:[2M-HPO4] + and 625.4m / z:[2M+H] + There is a peak.

[0294] DSC measurements were performed as described above. Figure 7 Part 4 Shown in.

[0295] Step 4 : Process for preparing ethylcyclohexene from the crude ethylpsilocybin product from step 3b in the apparatus as outlined in FIG. 4 .

[0296] The crude ethylpsilocybin product (80 g of step 3b) was charged into an oxygen-free (inert gas) 1 liter glass reaction vessel as shown in FIG5 . 40 g of deionized water and 62.5 g of acetone were added sequentially, and the mixture was then stirred (50 to 250 rpm) at a jacket temperature set point (Ta) of 65±3° C. for at least 16 hours. The suspension was then cooled to Ta=30° C. The product suspension was then filtered using a 1 liter glass nutsch. The wet cake was first washed twice with 80 g of a water / acetone mixture and then washed separately with 62.5 g of acetone, the washing liquid being kept with the cake for at least 5 minutes. The washed cake was then separated by filtration and then first dried by blowing nitrogen thereon and then further dried in a vacuum chamber under reduced pressure at a temperature of 40° C. The yield of ethylpsilocybin was then determined to be 72.0 g.

[0297] The analytical data of the obtained product are shown in FIG8 .

[0298] HPLC measurements were performed as described above. Figure 8 Part 1 Shown in.

[0299] LC-MS was performed as described above. These measurements (Figure 8, parts 2 and 3) have shown at 313.3 m / z: [M+H] + 、527.4m / z:[2M-HPO4] + and 625.4m / z:[2M+H] + There is a peak.

[0300] Measured using a Bruker Avance 400 spectrometer at 400 MHz in DMSO-d6 + trifluoroacetic acid 1 H NMR spectrum. Figure 8 Part 4 As shown, the observed peaks are summarized as follows:

[0301] serial number Shift 1(ppm) H's type J(Hz) Atom 1 Multiplet 1 (ppm) 1 0.97 6 t 7.22 19,14 M07 [0.85..1.09] 2 2.93 6 m - 18,13,11 M06 [2.80..3.01] 3 3.06 2 m - 10 M05 [3.01..3.14] 4 6.73 1 d 7.96 6 M04 [6.68..6.77] 5 6.86 1 t 7.98 7 M03 [6.82..6.90] 6 6.93 1 s - 2 M02 [6.91..6.97] 7 7.01 1 d 8.11 8 M01 [6.97..7.06]

[0302] Measured using a Bruker Avance 400 spectrometer at 125 MHz in DMSO-d6 + trifluoroacetic acid 13 C NMR spectrum. Figure 8 Part 5 As shown, the observed peaks are summarized as follows:

[0303] DSC measurements were performed as described above. Figure 8 Part 6 Shown in.

[0304] Example 2: Preparation of Psilocybin According to the Invention

[0305] exist Fig. 9The complete reaction scheme for obtaining psilocybin according to the process of the present invention is shown in FIG.

[0306] Step 1b - Acetoxyindole glyoxylic acid dimethylamide

[0307] Method Description:

[0308] - Acetoxyindoleoxaacetyl chloride (20 g) (obtained in step 1 of Example 1 above) was dissolved in 2-MeTHF (261.8 g, 13.1 vol.).

[0309] - THF (63.8 g, 2.0 eq) containing 2 m dimethylamine was charged into the reactor and cooled to Ti: -10°C to -5°C

[0310] - Add the acid chloride solution to the amine solution, keeping the internal temperature at Ti: -10°C to 5°C

[0311] - Place the container for the acid chloride solution rinsed with 2-MeTHF (27.2 g, 1.6 vol.) into the reactor

[0312] - Collect IPC samples (Stir the reaction mass at Ti: 0°C until IPC results are available)

[0313] - The reaction mass was concentrated under reduced pressure at Ta:40°C to about 5 vol.

[0314] - Add 2-MeTHF (193 g, 10.8 vol.) to the reaction mass

[0315] - The reaction mass was concentrated again to about 5 vol.

[0316] - 2-MeTHF (177 g, 10 vol.) was added to the reaction mass, thereby removing (at least to some extent) THF and replacing it with 2-MeTHF (according to the inventors, the presence of THF had an adverse effect on the processing).

[0317] - 0.5 m HCl (4 vol.) was slowly added to the reaction mixture, maintaining the internal temperature at Ti: 0°C to 15°C

[0318] - If the reaction mass is a suspension: filter the reaction mass and wash the filter cake with 1:1 v / v (2.5 vol.) of 2-MeTHF / water; dry the filter cake under reduced pressure at Ta: 40°C to obtain the first batch of product (about 30% yield).

[0319] - The combined mother liquor and washing liquid are charged to the reactor and the phases are separated

[0320] - The aqueous phase was extracted with ethyl acetate (5 vol.) (ethyl acetate in this case was shown to improve phase separation when compared to 2-Me-THF (which was used in Example 1 involving ethylpsilocybin))

[0321] - The combined organic phases were washed twice with NaHCO3 (5 vol.)

[0322] - The organic phase was charged into a reactor and concentrated under reduced pressure at Ta: 60°C to about 2.5 vol.

[0323] - Cooling gradient: Ta: 0°C in 60 min, then stirring at Ta: 0°C for 60 min

[0324] - The suspension was filtered off and the filter cake was washed with ethyl acetate (1 volume)

[0325] - Dry the filter cake under reduced pressure at Ta: 40°C

[0326] - The second batch is about 22%

[0327] The analytical data of the product thus obtained are shown in FIG10 .

[0328] Step 2: Psilocin (4-hydroxydimethyltryptamine)

[0329] Method Description:

[0330] The same method as the synthesis of 4-hydroxy-N,N-diethyltryptamine (4-HO-DET) in Example 1 was used, except that:

[0331] -CPME as reaction solvent

[0332] - No carbon treatment in the process

[0333] - Yield: 70%

[0334] The analytical data of the obtained product are shown in FIG11 .

[0335] Step 3: Psilocybin

[0336] Method Description:

[0337] - Using the same method as for the synthesis of ethylpsilocybin (see Example 1 above)

[0338] - Yield: 25%

[0339] The analytical data of the product thus obtained are shown in FIG12 .

Claims

1. A method for preparing a compound of formula (I), in, Each R is independently C 1-6 Alkyl, preferably methyl or ethyl, The method comprises the step of reacting a compound of formula (Id) with (R'O)2POCl, Wherein each R' is independently selected from C 1-6 alkyl, -CH2-aryl and -CH2-heteroaryl, The reaction product of the compound of formula (Id) and (R'O)2POCl is further reacted with TMSBr to obtain the compound of formula (I).

2. The method according to claim 1, wherein: (R'O)2POCl is (MeO)2POCl, (EtO)2POCl, (tBuO)2POCl or (benzyl-O)2POCl, more preferably (EtO)2POCl or (tBuO)2POCl, even more preferably (EtO)2POCl.

3. A method for preparing a compound of formula (I) according to claim 1 or 2, in, Each R is independently C 1-6 Alkyl, preferably methyl or ethyl, The method comprises the step of reacting a compound of formula (Id) with (EtO)2POCl(DECP), Wherein, the reaction product of the compound of formula (Id) and DECP is further reacted with TMSBr to obtain the compound of formula (I).

4. The method according to any one of claims 1 to 3, wherein: Each R is independently methyl or ethyl.

5. The method according to any one of claims 1 to 3, wherein: Each R is methyl.

6. The method according to any one of claims 1 to 3, wherein: Each R is ethyl.

7. A method according to claim 3 or any one of claims 4 to 6 as appended to claim 3, wherein: The w / w ratio of the compound of formula (Id) to (DECP) is between 0.8 and 1.2, preferably between 1.0 and 1.2, more preferably between 1.10 and 1.15, even more preferably about 1.12, even more preferably 1.12, Preferably, DECP was added dropwise over a period of 10 to 20 minutes.

8. A method according to claim 3 or 7, or any one of claims 4 to 6 as dependent on claim 3, wherein The reaction of the compound of formula (Id) with DECP is carried out in acetonitrile.

9. The method according to claim 8, wherein: The reaction of the compound of formula (Id) with DECP is carried out at a temperature between 50°C and 70°C, preferably at a temperature between 55°C and 65°C, more preferably at a temperature between 57°C and 63°C, even more preferably at a temperature of about 60°C, and even more preferably at a temperature of 60°C.

10. The method according to claim 8 or 9, wherein: The reaction of the compound of formula (Id) with DECP is carried out in the presence of a base, preferably wherein the base is N-ethyldiisopropylamine.

11. The method according to any one of claims 8 to 10, wherein: The reaction of the compound of formula (Id) with DECP is carried out for a period of at least 150 minutes until at least 99% of the compound of formula (Id) has reacted.

12. A method according to any one of claims 3 or 7 to 11 or any one of claims 4 to 6 when dependent on claim 3, wherein: After the compound of formula (Id) reacts with DECP, the solvent is changed to toluene, and an aqueous NaOH solution is added thereto, followed by phase separation. Preferably, NaOH is added at a concentration of 0.5M to 1.0M, more preferably at a concentration of about 0.75M, even more preferably at a concentration of 0.75M.

13. A method according to any one of claims 3 or 7 to 12 or any one of claims 4 to 6 when dependent on claim 3, wherein: After the reaction of the compound of formula (Id) with DECP is completed, the solvent is changed to CPME and CPME containing HCl is added to the reaction mixture to obtain a crude product precipitate. Preferably, the CPME containing HCl is about 3M solution, and / or wherein the solution is added dropwise over a period of 25 to 35 minutes, and / or wherein the solution is added at a temperature of 15°C to 20°C, preferably at a temperature of 17°C to 23°C, more preferably at a temperature of about 20°C, even more preferably at a temperature of 20°C.

14. A method according to any one of claims 3 or 7 to 13, or any one of claims 4 to 6 when dependent on claim 3, wherein: The compound of formula (Id) is reacted with DECP to obtain a crude product of formula (Ie), Preferably, The crude product precipitated from CPME upon addition of HCl comprises the compound of formula (Ie).

15. The method according to any one of claims 1 to 14, wherein: The w / w ratio of TMSBr to the compound of formula (Id) is between 1.5 and 2.5, more preferably between 1.8 and 2.4, even more preferably between 2.0 and 2.3, even more preferably about 2.0, even more preferably 2.

07.

16. The method according to any one of claims 1 to 15, wherein: The reaction product of a compound of formula (Id) with (R'O)2POCl, preferably with DECP, is reacted with TMSBr in acetonitrile.

17. The method according to any one of claims 1 to 16, wherein: TMSBr is added at a temperature between 30°C and 50°C, preferably at a temperature between 35°C and 45°C, more preferably at a temperature between 37°C and 43°C, even more preferably at a temperature of about 40°C, even more preferably at a temperature of 40°C.

18. The method according to any one of claims 1 to 17, wherein: The reaction product of a compound of formula (Id) with (R'O)2POCl, preferably with DECP, is reacted with TMSBr at a temperature between 50°C and 70°C, preferably at a temperature between 55°C and 65°C, more preferably at a temperature between 57°C and 63°C, even more preferably at a temperature of about 60°C, even more preferably at a temperature of 60°C.

19. The method according to any one of claims 1 to 18, wherein: The reaction with TMSBr is carried out for at least 150 minutes until at least 99% of the reaction product of the compound of formula (Id) with (R'O)2POCl, preferably with DECP, is consumed.

20. The method according to any one of claims 1 to 19, wherein: After reaction with TMSBr, the solvent was changed to methanol.

21. The method according to any one of claims 1 to 20, wherein: The obtained reaction product with TMSBr is subjected to solvent shift into water, wherein the pH of the solution is preferably set to a value in the range of pH=3.8 to pH=4.2 by adding 1 M NaOH, preferably wherein the w / w ratio of 1 M NaOH solution to the original amount of compound of formula (Id) added is about 4.0, more preferably 4.0, preferably wherein the final product of formula (I) precipitates from the aqueous solution at a pH between 3.8 and 4.2 and / or at a temperature below 20°C, preferably at a temperature of about 15°C, more preferably at a temperature of 15°C.

22. The method according to any one of claims 1 to 21, wherein: The final product of formula (I) was reslurried after treatment with water / acetone at reflux.

23. The method according to any one of claims 1 to 22, further comprising the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id) 24. The method according to claim 23, wherein: In the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id), LAH is used as a reducing agent, Preferably, The step of reducing the compound of formula (Ic) to obtain the compound of formula (Id) is carried out in toluene, dioxane or CPME, preferably in toluene, Preferably, the step is carried out under reflux.

25. The method according to claim 23, wherein: In the step of reducing the compound of formula (Ic) to obtain the compound of formula (Id), NaBH4 is used as a reducing agent.

26. The method according to any one of claims 23 to 25, wherein: The method further comprises the steps of reacting a compound of formula (Ia) with (COCl)2, and then reacting the resulting product with R2NH 27. The method according to claim 26, wherein: The reaction of the compound of formula (Ia) with (COCl)2 is carried out in CPME at a temperature between 0°C and 10°C, and / or Wherein, the reaction of the compound of formula (Ia) with (COCl)2 gives the compound of formula (Ib), Therein, the compound of formula (Ib) is reacted with R2NH to obtain the compound of formula (Ic).

28. A method for obtaining a compound of formula (I): in, Each R is independently C 1-6 Alkyl, preferably methyl or ethyl, The method comprises the step of reacting the product obtainable in the reaction of the compound of formula (Id) with (R'O)2POCl with TMSBr to obtain the compound of formula (I), Wherein each R' is independently selected from C 1-6 alkyl, -CH2-aryl and -CH2-heteroaryl.

29. The method of claim 28, wherein each R' is independently C 1-6 alkyl or -CH2-aryl, preferably wherein each R' is independently C 1-6 Alkyl, more preferably wherein, Both R' are ethyl.

30. The method according to claim 28 or 29, wherein: The product obtainable in the reaction of a compound of formula (Id) with (R'O)2POCl is a compound of the formula: or a salt thereof, preferably the HCl salt, wherein R and R' are as defined in claim 28 or 29.

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