RECRYSTALLIZATION OF 5-METHOXY-N,N-DIMETHYLTRYPTAMINE (5-MeO-DMT) IN METHYL TERT-BUTYL ETHER (MTBE) AND LESS THAN 5 WT.% OF ALIPHATIC ANTI-SOLVENT

Abstract

To provide a simple method of purifying 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) so as to obtain the substance in a pharmaceutical grade.SOLUTION: Provided is a method which comprises the steps of dissolving crude 5-MeO-DMT in a solvent at a temperature above room temperature, cooling the obtained solution to a temperature below room temperature to precipitate solid 5-MeO-DMT, separating the solid 5-MeO-DMT from the remaining solution and removing solvent from the crystalline 5-MeO-DMT. In the method, the solvent comprises one or more ethers and less than 5 wt.% of an anti-solvent.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an organic compound, specifically 5-methoxy-N,N-dimethyltryptamine (5- The present invention relates to a method for purifying 5MeO-DMT in a form that meets certain purity requirements. -Further relating to MeO-DMT. [Background technology]

[0002] 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is shown below. It has the formula:

[0003] [ka]

[0004] 5-MeO-DMT is a 5-HT1A receptor agonist and a 5-HT2A receptor agonist. is a naturally occurring serotonergic hallucinogenic tryptamine that acts as a psychedelic be.

[0005] 5-MeO-DMT is synthesized in the pineal gland and retina in humans and is excreted in urine, blood, and cerebrospinal fluid. It has been found in human body fluids.

[0006] 5-MeO-DMT is produced by Dictyosomes incanescens. It was first isolated from the bark of Bufo albarius ( It has been identified as the major active ingredient in the venom of the Bufo alvarius toad.

[0007] The chemical synthesis of 5-MeO-DMT was first reported by Hoshino and Shimoda in 1936. This has been described by ira (Bulletin of Chemical Society of Japan, 11(3), 221-224). No medical or other uses are intended in this publication.

[0008] According to Hoshino and Shimodaira, 5-methoxy-indolyl-3 After reaction of -ethyl-beta-bromide with dimethylamine, the product was isolated and It is purified by distillation. It has also been reported that the material crystallizes from ether-petroleum ether. The terms of the deal were not disclosed.

[0009] The product obtained was described as a fine colorless prism with a melting point of 66-67°C. The amount of impurities contained in the product was not characterized.

[0010] However, the reported melting points and later data on the melting points of 5-MeO-DMT (69–70 °C), it is considered that impurities are still present.

[0011] In addition, the boiling point of 5-MeO-DMT is high even under reduced pressure (208-210 °C at 4 mm). ), distillation is not an advantageous purification method.

[0012] Somei et al. (Chem. Pharm. Bull. 49(1)87-96(2001)) reported that serotonin, N-methylserotonin Tonin, bufotenin, 5-methoxy-N-methyltryptamine, bufobutanoic acid, N-(isopropyl and lespeda reported the synthesis of amine.

[0013] In the context of the synthesis of bufotenin, a mixture of compounds containing 5-MeO-DMT was The product is then purified by chromatography on 5-MeO-D MT was recrystallized from Et2O-hexane. The recrystallization conditions and the amount of impurities in the product were determined. No details regarding the amount were disclosed. The liquid mixture used for recrystallization (Et2O-hexane) The mixture used by Hoshino and Shimodaira (Asan) It is similar to ethyl ether (petroleum ether).

[0014] Based on its biological activity, there has been recent interest in the potential medical uses of 5-MeO-DMT. is growing and, for example, is being investigated for potential medical uses in human clinical trials.

[0015] for use in such human clinical trials and for potential use in approved medical products. High-purity 5-MeO-DMT is required for administration to humans. According to the present invention, the total amount of impurities in the drug substance must be less than 0.5%. and each individual impurity is particularly preferably less than 0.1%.

[0016] Furthermore, limits on the amount of residual solvents should be observed.

[0017] In this context, a simple method for purifying 5-MeO-DMT, especially for pharmaceutical grade, is being investigated. To provide a simple method for purifying 5-MeO-DMT to obtain the substance There is a demand for 5-MeO-DMT in a form that meets specific purity requirements. There is also demand.

[0018] The present invention relates to the purification of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). The method comprises the steps of: dissolving crude 5-MeO-DMT in a solvent at above room temperature; The resulting solution is cooled to a temperature below room temperature to precipitate solid 5-MeO-DMT. P and separating the solid 5-MeO-DMT from the remaining solution; removing the solvent from the crystalline 5-MeO-DMT; Including, The solvent is one or more ethers and less than 5% by weight of an aliphatic hydrocarbon as an anti-solvent. Includes.

[0019] The present invention relates to a method comprising the above steps, wherein the solvent comprises a total of 5 weight percent of any anti-solvent. The antisolvent contains less than 5-MeO-DMT at any temperature that occurs during recrystallization. The solubility depends on the ether used, or, if multiple ethers are used, the amount of ether present in the dissolving solvent. The method further provides a method for preparing a liquid having a solubility of less than 20% in a combination of ethers present in the present invention. Provide.

[0020] The present invention is a form containing impurities in a total amount of less than 0.5 area %, each of which is individually The present invention provides 5-MeO-DMT having an impurity content of less than 0.1 area %. The impurity content is As determined by chromatography as detailed below.

[0021] Specific embodiments are defined in the dependent claims. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows a chromatogram of an example of a 5-MeO-DMT sample analyzed by HPLC as described below. [Diagram 2] FIG. 2 is an enlarged view of the chromatogram of the example. [Diagram 3]FIG. 3 is a plot of peak areas determined by HPLC versus the concentration of 5-MeO-DMT in the analytical samples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention relates to a method for producing 5-methoxy-N,N-dimethyltryptamine ( 5-MeO-DMT) can be purified and recrystallized to obtain pharmaceutical grade material. This is based on the discovery that

[0024] 5-MeO-DMT is available from natural sources as well as via synthetic methods. It is a white to off-white, yellow or orange powder.

[0025] By preparation of 5-MeO-DMT by isolation from natural sources or by chemical synthesis, Generally, material (crude 5-MeO-DMT) is obtained, but this material contains a significant amount of impurities. As it contains these substances, it is not suitable for medical use.

[0026] Crude 5-MeO-DMT may typically contain more than 0.5% total impurities. , and may contain individual impurities in amounts greater than 0.1%.

[0027] Preferably, the crude 5-MeO-DMT used in the process of the present invention contains impurities in a total amount of 5 % or less, preferably 2% or less in total of impurities.

[0028] The color of 5-MeO-DMT indicates the presence of one or more impurities, but may vary depending on the particular preparation. This does not indicate whether the product meets the requirements for pharmaceutical use.

[0029] The purity of the 5-MeO-DMT samples is analyzed by HPLC. The compounds can be identified by their relative retention times (RRT). The detection method is UV detection at 227 nm. It is.

[0030] The preferred columns are reversed-phase columns, particularly octadecyl carbon-bonded silica (C18) columns. It's Ram.

[0031] For elution, mobile phase A (0.013 M ammonium acetate aqueous solution) and mobile phase B (acetate aqueous solution) were used. A mixed solvent based on toluene (toluene, toluene dinitrile) is used. A specific gradient method is described in the following examples. This is explained in detail in 1.

[0032] The percentage value indicating purity is the area % and corresponds to the peak area in the HPLC chromatogram shown above. Based on square footage.

[0033] The inventors have found that recrystallization of crude 5-MeO-DMT in the free base form results in a relatively low melting point. Despite this, the product was of high purity, i.e., the total amount of impurities was less than 0.5%. and the amount of each individual impurity is less than 0.1%. We recognized that this is an appropriate method to obtain

[0034] 5-MeO-DMT can be separated from the solution by cooling in the form of an oil. The inventors have found that solvents containing specific ethers can produce solids of 5-MeO-DMT with improved purity. It has been found that this can be particularly useful for obtaining crystalline solid forms.

[0035] The recrystallization solvent is in particular one or more solvents having a boiling point in the range of 40 to 100° C. at a pressure of 1 bar. or multiple ethers.

[0036] Suitable ethers are aliphatic and cycloaliphatic ethers. These ethers are It does not contain any functional groups other than those at the site.

[0037] Examples of suitable ethers (boiling points in parentheses) include di-n-propyl ether (90°C), Di-iso-propyl ether (69°C), methyl tert-butyl ether (MTBE) (55°C), ethyl tert-butyl ether (ETBE) (73°C), tert-amino Trimethylbutane (TAME; 2-methoxy-2-methylbutane) (86°C), Cimethane (42.3°C), diethoxymethane (88°C), tetrahydrofuran (66°C) , (+ / -)-Tetrahydro-2-methylfuran (80°C), Tetrahydro-2,5-di Examples include methylfuran (90 to 92°C) and tetrahydropyran (88°C).

[0038] Preferably, the ether has a boiling point in the range of 50-80° C. at 1 bar pressure.

[0039] Preferred examples of ethers are methyl tert-butyl ether (MTBE), ethyl tert-butyl ether (ETA), The most preferred ethers are tert-butyl ether (ETBE) and diisopropyl ether. The tert-butyl ether is methyl tert-butyl ether (MTBE).

[0040] The recrystallization solvent is at least 50%, preferably at least 70%, in particular at least 90%. % of one or more ethers having a boiling point between 40 and 100° C. at 1 bar pressure, in particular containing one or more of the ethers specifically identified above. These percentages means weight percent based on the total weight of the solvent.

[0041] Although other solvents may be present in addition to the ether or ethers, the recrystallization solvent is Less than 5% aliphatic hydrocarbons as antisolvents, preferably less than 2%, more preferably less than 1% Preferably, these limits include the absence of any hydrocarbons. This applies to the element.

[0042] The above percentages refer to weight percent based on the total weight of the recrystallization solvent, including the hydrocarbon antisolvent. .

[0043] Furthermore, preferably, other solvents may be present in addition to the ether or ethers. The recrystallization solvent contains less than 5% of any antisolvent, preferably less than 2%, more preferably less than 1%. % of the recrystallization solvent, specifically antisolvent. These percentages are based on the total amount of recrystallization solvent, including antisolvent. It is based on weight and means % by weight.

[0044] If more than one anti-solvent is present, the limitations set forth above on the anti-solvents are applicable. This refers to the total amount of all anti-solvents used.

[0045] Small amounts of certain anti-solvents may be present in commercially available solvents, e.g., commercially available ether. .

[0046] Preferably, no anti-solvent is added in the process of the present invention.

[0047] As used herein, the term antisolvent refers to a solvent that is capable of reacting with the solvent at any temperature that occurs during recrystallization. The solubility of 5-MeO-DMT in the ether or in more than one ether When used, it has less than 20% of its solubility in the combination of ethers present in the dissolution medium. Solubility is expressed in mg / mL.

[0048] Typical antisolvents are aliphatic hydrocarbons such as petroleum ether, heptane, and hexane. and water.

[0049] In a preferred embodiment, the recrystallization solvent comprises at least 50%, preferably at least In a particular embodiment, the MTBE content is at least 70%, particularly preferably at least 90%. The recrystallization solvent contains at least 98% MTBE. The percentages are based on the total weight of the solvent. All percentages are by weight.

[0050] In a further preferred embodiment, 5-MeO-DMT is used in the presence of a hydrocarbon as an antisolvent. Without any addition, it is purified by recrystallization in 98 wt % MTBE.

[0051] The method of the present invention involves dissolving crude 5-MeO-DMT in a recrystallization solvent. MeO-DMT is dissolved in a recrystallization solvent at a dissolution temperature above room temperature up to the boiling point of the solvent. .

[0052] Room temperature means a temperature within the range of 20 to 25°C. Above room temperature means a temperature above 25°C. and below room temperature means below 20°C.

[0053] In one embodiment, 5-MeO-DMT is recrystallized at a melting temperature in the range of 35-40° C. It is dissolved in a solvent.

[0054] The amount of recrystallization solvent used is sufficient to achieve complete dissolution at the dissolution temperature.

[0055] For example, a saturated solution of at least 25% is obtained. In one embodiment, the amount is is sufficient to achieve a saturated solution.

[0056] Preferably, a saturated solution of at least 50% and up to 90% is obtained.

[0057] After dissolution, the solution is cooled to a temperature below room temperature (i.e., below 20°C) and 5-MeO-DM T is crystallized. A suitable temperature range is 0 to 20° C. In one embodiment, the temperature The range is 7 to 12 degrees Celsius.

[0058] The resulting product can be recovered by filtration.

[0059] To improve purity, the recrystallization may be repeated one or more times.

[0060] The purification according to the present invention preferably does not include a column chromatography step. Furthermore, the purification according to the present invention preferably includes a step of distilling the 5-MeO-DMT. Not at all.

[0061] Residual solvent may be at least partially removed from the recovered product under reduced pressure. The weight of the solvent in the Preferably it is NMT 500 ppm, in particular NMT 100 ppm.

[0062] The method of the present invention can reduce the amount of impurities. In particular, the amount of impurities in the 5-MeO-DMT sample can be reduced. The total amount of each of the individual substances in the 5-MeO-DMT sample could be reduced to less than 0.5%. The amount of impurities can be reduced to less than 0.1%. These percentages were determined by HPLC as above. At the same time, the amount of residual solvent can be reduced.

[0063] Thus, according to one aspect of the present invention, the total amount of impurities is less than 0.5 area %. form, wherein the amount of each individual impurity is less than 0.1 area %. The amount of impurities is octadecyl carbon chain bonded silica. (C18) column and 0.013M ammonium acetate and acetonite as eluents. The HPLC assay was performed using a triethylamine-based mixture and UV detection at 227 nm. Determined by the PLC.

[0064] 5-MeO-DMT preferably has a residual solvent content of 5000 ppm or less, preferably is 2500 ppm or less, more preferably 500 ppm or less, and particularly preferably 100 ppm or less. It is provided in the form

[0065] The following examples are intended to further illustrate the invention. EXAMPLES

[0066] [Example 1] Analysis method The purity of 5-MeO-DMT is determined by HPLC. Method parameters

[0067] [Table 1]

[0068] Gradient:

[0069] [Table 2]

[0070] The typical retention time for 5-MeO-DMT is 5.5 minutes.

[0071] Sample preparation (duplicate) An accurately weighed sample (12-18 mg) was placed in a 100-mL measuring flask and dissolved in methanol. Adjust the volume to the correct volume. Mix well.

[0072] Validation of analytical procedures The linearity and precision of the HPLC method used were tested. FTIR, KF and ICP-MS are common techniques and are utilized according to routine procedures. Based on the results, the method is considered fit for purpose.

[0073] Linearity of the HPLC method. A stock solution of 5-MeO-DMT was prepared in methanol; nominal concentration 0.15 mg / ml. obtained.

[0074] [Table 3]

[0075] All duplicate injections were within ±2%.

[0076] The % Y-intercept at the nominal concentration was determined to be 0.8%. As can be seen in Figure 3, is considered to be linear.

[0077] Precision of the HPLC method Six sample solutions were prepared at nominal concentrations (12-18 mg in 100 ml of methanol). The purity results were as follows:

[0078] [Table 4]

[0079] The acceptance criteria for purity values ​​across the six samples was 1% RSD, with actual readings of 0. 07%. Therefore, the analytical method is considered to have sufficient precision.

[0080] [Example 2] Solvent Screening Solubility screening of 5-MeO-DMT was performed in several solvents at both room temperature and reflux. It was carried out.

[0081] In this screening, 200 mg of 5-MeO-DMT was diluted with solvent until completely dissolved. However, the low concentration of the solvent was not sufficient to achieve complete dissolution of the sample in 4 ml of solvent. Compounds with solubility (solubility less than 0.05 mg / ml) were excluded.

[0082] The results of the solubility screening are shown in the table below.

[0083] [Table 5]

[0084] The results of the solubility screening showed that 5-MeO-DMT was very soluble in several solvents at room temperature. It was shown to be well soluble in water and heptane. Low solubility was observed in water and heptane.

[0085] 5-MeO-DMT was not observed to dissolve in MTBE at room temperature, but However, when the hot MTBE solution was cooled to room temperature, crystallization occurred. Since this was not observed, MTBE was not considered to be a suitable solvent for recrystallization.

[0086] [Example 3] First attempts at recrystallization Following the results of the solubility study, mixing of isopropanol (IPA) with heptane or water Several experiments were carried out with the aim of recrystallizing 5-MeO-DMT from 5 -MeO-DMT was dissolved in IPA, and then precipitated by adding water or heptane as an anti-solvent. The aim of the study was to crystallize 5-MeO-DMT. It is found that 5-MeO-DMT is highly soluble in IPA at room temperature. However, 5-MeO-DMT is less soluble in IPA than the other solvents evaluated. IPA was used to maximize recovery of the recrystallized 5-MeO-DMT.

[0087] In the first small-scale experiments, 5-MeO-DMT(2 00 mg) was dissolved in the minimum amount of IPA required (0.3 mL, 1.5 volumes). After cooling to room temperature, no crystallization was observed. Heptane was added dropwise with the aim of precipitating the aldehyde. Unfortunately, the addition of heptane 5-MeO-DMT was found as an oil rather than a precipitate. When the experiment was repeated using water as the antisolvent, oiling also occurred.

[0088] In the second attempt at crystallization from a mixture of IPA and water or heptane, the oiling stopped. To attempt to reduce the pH, the solvent addition was reversed. 9.5 volumes (1.9 mL) of heptane was added to the 5- After adding MeO-DMT (200 mg), the resulting slurry was warmed to 80° C. IPA (2.1 vol, 0.4 mL) was added dropwise until complete dissolution was observed. Upon cooling to room temperature, the material did not crystallize. Attempts to use 5.3 vol., 1 mL) or cooling to room temperature did not result in crystallization.

[0089] To investigate whether crystallization is possible by reducing the volume of the solvent mixture used, % IPA in heptane (9.4 vol, 1.9 mL) until all material is completely dissolved. 5-MeO-DMT (200 mg) was added dropwise at 80°C until the mixture dissolved. After cooling, oil formation was observed. 34% IPA in water (10.7 vol.) was added to 5-MeO- Oiling also occurred when DMT (200 mg) was added at 80°C.

[0090] The above-mentioned method using a heptane solution containing 17% IPA and an aqueous solution containing 34% IPA was used. The experiment was repeated at 60° C. Unfortunately, in both cases oiling was observed upon cooling.

[0091] In addition, a small-scale final experiment was carried out using a solvent in which 5-MeO-DMT has a higher solubility. Ethanol (0.5 volumes, 0.1 mL) was dissolved in 5-MeO-DMT (200 mM g) at 60°C, and then water was added dropwise. However, when water was added to the batch, 5 -MeO-DMT oil formation was observed.

[0092] Table 2 below shows a summary of the small scale recrystallization experiments.

[0093] [Table 6]

[0094] [Example 4] Crystallization after heating and oiling To avoid the oiling of 5-MeO-DMT during crystallization, a larger scale experiment was performed. With increasing scale, greater control over the addition of anti-solvent, more careful addition It was predicted that the cloud point could be potentially determined and oil formation could be avoided. (2.0 g) was heated to 60°C and the minimum amount of IPA (0.8 After cooling to room temperature, no crystallization was observed, so The flask was reheated back to 60°C. Water was added dropwise until the solution became cloudy. Unfortunately, The cloud point could not be determined because 5-MeO-DMT oiled out of solution without becoming cloudy. Ta.

[0095] Despite being converted from solution to oil, crystallization of 5-MeO-DMT was still possible. To determine if any of the above was the case, the solvent was removed by evaporation to give an orange oil. After cooling the oil in the refrigerator overnight, an orange crystalline solid was obtained. Although the crystallization of MT was slow, even after heating and oiling, the crystallization of 5-MeO-DMT was The results showed that crystallization was still possible.

[0096] [Example 5] Large scale crystallization attempts using MTBE / heptane. When using solvent mixtures of either heptane or water with IPA or ethanol However, problems arose and the solvent system using MTBE was reconsidered.

[0097] So far, no crystallization has been observed from MTBE after cooling to room temperature. In the second attempt of crystallization from TBE, the solution was further cooled to 0-5 °C.

[0098] Add MTBE (1 mL, 0.5 vol) to the crystalline solid at 45-50 °C until completely dissolved. This amount of MTBE added was less than the 2.4 volumes mentioned above, and it is likely that the solvent test From the small scale attempts that have been carried out.

[0099] After dissolution, the batch is cooled to 0-5°C over 40 minutes to form a very thick mixture which results in crystallization. A clear viscous solution was obtained.

[0100] The batch was warmed back up to 45-50°C and then cooled to room temperature over 1 hour. Stir at room temperature for 30 minutes. After stirring, the batch became a very thick viscous solution and an additional 0.4 mL (0.2 vol) of M After the TBE was added, the batch was stirred for an additional 15 minutes. After stirring, a thin slurry was obtained. .

[0101] Heptane (0.7 mL, 0.35 vol) was added dropwise and the batch was stirred for an additional 15 min. A thicker slurry was obtained. The batch was cooled to 0-5°C and then heptane (0.7 ml) was added. L, 0.35 vol) was added dropwise. Once filtered, the isolated solid was dissolved in cold heptane (2 After washing with 1×2 mL of ethyl acetate and drying overnight under vacuum, a pale orange solid was obtained. The purity of the solid obtained (1.44 g, 72% recovery) was analyzed by HPLC.

[0102] The experimental conditions are summarized in Table 3. The results of the analysis are shown in Table 4.

[0103] [Example 6] Crystallization using MTBE / heptane A second experiment was performed utilizing MTBE / heptane. g) was dissolved in MTBE (1.4 mL, 0.7 vol) at 45-50 °C and then stirred for 70 min. Cool to room temperature. Upon crystallization, stop stirring and warm the batch back up to 45-50°C and add additional M TBE (1 mL, 0.5 vol) was added. The resulting slurry was allowed to cool back to room temperature and stirred. The mixture was diluted with heptane (1 mL, 0.5 vol). Upon addition of heptane, a large amount of material was It was observed that the walls of the container were coated with MTB, so an additional amount of MTB was added to remove this material. E (1 mL, 0.5 vol) was added. After stirring for 90 min at room temperature, the batch was filtered and Then, MTBE:heptane (2:1, 1 mL, 0.5 vol) and heptane (1 mL, After drying, the pale orange solid was 1.13 g (57% yield). The purity of the isolated material was analyzed by HPLC.

[0104] The experimental conditions are summarized in Table 3. The results of the analysis are shown in Table 4.

[0105] [Example 7] Crystallization using MTBE / heptane 5-MeO-DMT (2.0 g) was dissolved in MTBE (2 mL, 1.0 vol) at 45-50 °C. After dissolution, the mixture was cooled to room temperature over 1 hour. After stirring at room temperature for 1.5 hours, the resulting slurry was The solution was diluted with MTBE (2 × 1 mL, 1.0 vol) over 20 min. Then, heptane (1 mL, 0.5 vol) was added over 5 min and the batch was then stirred at room temperature for 2 h. After cooling to 8-12°C over 10 minutes, the batch was stirred at 8-12°C for 15 minutes and then further It was diluted with heptane (1 mL, 0.5 vol.). After stirring for an additional 10 min at 8-12 °C, The batch was cooled to 0-5°C over 10 minutes and then stirred for an additional 15 minutes. Add ethanol (2 mL, 1.0 vol) over 5 min and then stir the batch at 0-5 °C for 1 h. The batch was filtered and washed with MTBE:heptane (1:1, 2 mL, 1.0 vol). After drying, 1.37 g (69% yield) of a pale orange solid was obtained. The purity of the isolates was analyzed by HPLC.

[0106] The experimental conditions are summarized in Table 3. The results of the analysis are shown in Table 4.

[0107] [Example 8] Crystallization from MTBE In an attempt to further increase the purity of the recrystallized material, MTBE was used exclusively as the solvent. The experiment was carried out by dissolving 5-MeO-DMT (2.0 g) in MTBE (4 mL, 2.0 vol). After dissolving at 35-40℃, the mixture was cooled to room temperature over 30 minutes. After stirring at room temperature for 50 minutes, No crystallization was observed. Therefore, the batch temperature was reduced to 7-12°C over 30 minutes. After stirring for 10 minutes at 7-12°C, crystallization occurred. After stirring for 1 hour at 7-12°C, After that, the batch was filtered and washed with MTBE (1 mL, 0.5 vol) at 7-12 °C. After this, the batch was pulled dry under vacuum for 3.5 hours to give 1.02 g ( The purity of the isolated solid was analyzed by HPLC.

[0108] The experimental conditions are summarized in Table 3. The results of the analysis are shown in Table 4.

[0109] Table 3 below summarizes the conditions for a larger scale attempt at recrystallizing 5-MeO-DMT. show.

[0110] [Table 7]

[0111] Table 4 below shows the impurity profile of the material isolated from the recrystallization experiment.

[0112] [Table 8]

[0113] Table 3 shows a summary of the conditions used in each larger scale recrystallization experiment. In all cases the overall purity of the material is increased, with the impurities at RRT 1.24 being The analysis showed that the impurities were removed to less than 0.10%. Impurities in the elution solution were also reduced in all three experiments, but only in the experiment according to Example 8, the NMT was reduced to 0.10. % target. Based on these results, all impurities were The most suitable conditions for obtaining materials with less than 0.10% of phosphate are shown in the experiment according to Example 8. It is clear that the conditions are as follows. The solvent analysis of the sample according to Example 8 was carried out under NMT5000pp The study showed that the MTBE level was 17 ppm, relative to the expected limit of m. Examples of the invention of this application include the following: [1] Purify 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) 1. A method comprising: dissolving crude 5-MeO-DMT in a solvent at a temperature above room temperature; The resulting solution is cooled to a temperature below room temperature to precipitate solid 5-MeO-DMT. Top and separating the solid 5-MeO-DMT from the remaining solution; removing the solvent from the crystalline 5-MeO-DMT; Including, The solvent comprises one or more ethers and less than 5% by weight of an aliphatic carbon as an anti-solvent. The method comprises the steps of: [2] The one or more ethers have a boiling point in the range of 40 to 100°C under a pressure of 1 bar. The method according to [1] above, having a point. [3] The one or more ethers are methyl tert-butyl ether (MTBE). , ethyl tert-butyl ether (ETBE), and diisopropyl ether. The method according to the above [1] or [2], wherein [4] The recrystallization solvent is at least 50% by weight, preferably at least 70% by weight, particularly Any of the above [1] to [3], which contains at least 90% by weight of one or more ethers. The method according to any one of claims 1 to 5. [5] The method according to any one of [1] to [4] above, wherein the recrystallization solvent contains less than 2% by weight of aliphatic hydrocarbons. 2. The method according to any one of claims 1 to 11. [6] The method according to [5] above, wherein the recrystallization solvent contains less than 1% by weight of aliphatic hydrocarbons. method. [7] The above [1] to [6], wherein the recrystallization solvent contains at least 98% by weight of MTBE. 2. The method according to claim 1 . [8] The solvent comprises less than 5% by weight of any anti-solvent in total, and the anti-solvent is used in the recrystallization. The solubility of 5-MeO-DMT at any temperature occurring during solubility in the ether or, if multiple ethers are used, the ethers present in the dissolving solvent Any one of the above [1] to [7] means a liquid having a solubility of less than 20% in the combination of ter. The method according to claim 5. [9] The method according to [8] above, wherein the recrystallization solvent contains less than 2% by weight of an antisolvent.

[10] The method according to [9] above, wherein the recrystallization solvent contains less than 1% by weight of an antisolvent.

[11] Any of the above [1] to

[10] , wherein the solution is cooled to a temperature in the range of 0 to 20° C. 3. The method according to claim 1 .

[12] The method according to

[11] above, wherein the temperature is in the range of 7 to 12°C.

[13] Any of the above [1] to

[12] , further comprising a step of reducing the amount of residual recrystallization solvent. The method according to any one of claims 1 to 5.

[14] The total amount of impurities was determined by HPLC with UV detection at 227 nm. HP reduced to less than 0.5 area % and / or using UV detection at 227 nm The amount of each individual impurity, as determined by LC, is reduced to less than 0.1 area %. The method according to any one of [1] to

[13] .

[15] The HPLC method comprises using an octadecyl carbon chain bonded silica (C18) column and an eluent. A mixture of 0.013M ammonium acetate and acetonitrile was used. The method according to

[14] above, wherein the method is carried out using

[16] Any of

[13] to

[15] , in which the amount of residual solvent in the product is 5000 ppm or less. The method according to any one of claims 1 to 5.

[17] 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) , the total amount of impurities is less than 0.5 area %, and the amount of each individual impurity is less than 0.1 area % The amount of impurities is less than 100% by weight, and the amount of impurities is less than 100% by weight using an octadecyl carbon chain bonded silica (C18) column and an eluent. A mixture of 0.013M ammonium acetate and acetonitrile was used as the As determined by HPLC with UV detection at 227 nm, 5-Methoxy-N,N-dimethyltryptamine.

[18] The 5-M according to

[17] above, further comprising a residual solvent content of 5000 ppm or less. eO-DMT.

Claims

[Claim 1] The invention described in the present specification.

Images