Extraction process of fragruminant derivatives from ENTANDROPHRAGMA CAUDATUM seeds and preparation of limonoids with pharmacological activity.

Abstract

This invention provides a method for producing specific limonoid compounds useful for treating sexual dysfunction. [Solution] A process is provided for obtaining a fragmarin derivative (Formula Ia) from an Entandrophragma caudatum seed extract, and for producing therapeutically effective limonoids and limonoid-type compounds therefrom, for example, along with an intermediate product (Formula III), in multiple steps.

Description

[Technical Field]

[0001] The present invention generally relates to improvements in the preparation of therapeutically effective limonoids and novel limonoid-type compounds. [Background technology]

[0002] European Patent No. 2807170 discloses a plant-derived limonoid useful for treating sexual dysfunction and possessing aphrodisiac effects. This specification proposes obtaining the desired limonoid through a lengthy process involving the use of fragmarin ester extracted from the seeds of Chukrasia tabularis, followed by alkaline hydrolysis, conversion to winerebuamide, and rearrangement of the fragmarin lactone ring. However, the manufacturing process described in European Patent No. 2807170 results in low yields, and obtaining the raw material from Chukrasia tabularis is difficult. Therefore, producing a reasonable amount of limonoid for developing and marketing limonoid-based therapeutic products is extremely difficult and expensive. Consequently, a more effective method for producing the desired limonoid is needed. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] European Patent No. 2807170 [Overview of the project]

[0004] This specification relates to at least one of the following compounds of formulas Ia and Ib: [ka] (In the formula, R1 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, which is either unsubstituted or substituted with a halogen such as OH or F.) The method for obtaining [the specified value] includes the following steps. (i) Compositions comprising the following: At least one compound of formula IIa and formula IIb, [ka] (In the formula, R1 is as defined above, The steps include providing R2 and R3 independently selected from linear, branched, or cyclic substituted or unsubstituted alkyl groups having 1 to 6 carbon atoms, or nicotinyl groups, and / or An extract composition from Entandrophragma caudatum comprising at least one compound of formula IIa, wherein, a) R2 and R3 are independently selected from a linear or branched alkyl group having 1 to 6 carbon atoms, or a nicotinyl group. b) A step of providing an extract composition in which R1 is methyl, (ii) The extracted composition from step (i) and / or optionally the composition is subjected to one or more distillations and subjected to the introduction of a solvent containing an aliphatic alkanol, (iii) A step of carrying out an alkanol decomposition reaction to obtain at least one of the compounds of formula Ia and formula Ib by adding an aliphatic metal alkoxide in the presence of an aliphatic alcohol to initiate the reaction, and then adding an acid, preferably an organic acid such as acetic acid, to stop the alkanol decomposition reaction.

[0005] This specification also discloses a method for producing a compound of formula Ib from a compound of formula Ia, which includes: (i) A step of reacting the compound of formula Ia with a base that has sufficient strength to open the lactone ring but not enough to hydrolyze the R1 group to form a carboxyl group, preferably a barium hydroxide octahydrate in methanol, to obtain the compound of formula III. [ka] (ii) Reacting the compound of formula III with a selective oxidizing agent, preferably Dess-Martin periodinane, to obtain a compound of formula IV; [Chemical formula] (iii) Reacting the compound of formula IV with a coupling agent, preferably a carbodiimide-based coupling agent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), in the presence of a sterically hindered organic base, preferably N,N-diisopropylethylamine (DIPEA), to obtain a compound of formula Ib.

[0006] This specification also relates to a method for producing a compound of formula V from a compound of formula Ib by reacting the compound of formula Ib with an esterifying agent and a sterically hindered base to selectively introduce a group R2' of formula V, [Chemical formula] wherein R2' is a linear, branched or cyclic optionally substituted alkyl group having 1 to 6 carbon atoms.

[0007] This specification also relates to the compound of formula III. (This specification also relates to the compound according to claim 13, wherein R1 is methyl). <00​​​​​​​​​​​​​​​​This specification also covers monohydrate salts of compounds of formula V, where R1 is preferably methyl.

[0012] This specification also covers compounds of formula V, provided that R1 is not hydrogen, methyl, or ethyl.

[0013] This specification also covers an Entandrophragma caudatum extract composition prepared from the seeds of Entandrophragma caudatum, the Entandrophragma caudatum extract composition comprising at least one compound of formula IIa and formula IIb, the Entandrophragma caudatum extract composition being prepared by: (i) The crushed seeds of Entandrophragma caudatum are mixed with methanol, filtered, recovered, and concentrated to obtain a concentrated methanol extract. (ii) The concentrated methanol extract is mixed with a low-polarity solvent and a high-polarity solvent to obtain a two-phase composition, the high-polarity solvent phase is discarded to remove polar impurities, and the low-polarity solvent phase is concentrated, preferably by distillation, to obtain an extract of Entandrophragma caudatum.

[0014] In this method, "low-polarity" and "high-polarity" solvents refer to the polarity of the solvents relative to each other.

[0015] This specification also relates to a method for producing an Entandrophragma caudatum extract composition prepared from the seeds of Entandrophragma caudatum, wherein the Entandrophragma caudatum extract composition comprises at least one of the compounds of formula IIa and / or precursors to formula Ib, and the method is as follows: i) A step of mixing crushed seeds with methanol, filtering, recovering, and concentrating to obtain a concentrated methanol extract, (ii) obtaining a two-phase composition by mixing the concentrated methanol extract with a low-polarity solvent and a high-polarity solvent, discarding the high-polarity solvent phase to remove polar impurities, and preferably concentrating the low-polarity solvent phase by distillation to obtain an extract composition of Entandrophragma caudatum;

[0016] In this method, the "low-polarity" solvent and the "high-polarity" solvent refer to the polarity of the solvents relative to each other.

[0017] This specification also discloses a method for producing a compound of (9R,15S,16S,17S,18S)-4-(furan-3-carbonyl)-15-hydroxy-18-(2-methoxy-2-oxoethyl)-4,12,17,19-tetramethyl-7-oxo-8,11,13,20-tetraoxaheptacyclo[10.7.1.1 14 , 17 .0 1 , 10 .0 5 , 10 .0 9 , 15 .0 14 , 19 henicosan-16-yl 2-methylpropanoic acid monohydrate.

Chemical Formula

Brief Description of the Drawings

[0018] [Figure 1]The numbering of the carbon atoms in the compounds of formulas Ia and Ib is shown. [Figure 2] This outlines the preparation of methanol extract from seeds of Entandrophragma caudatum. [Figure 3] This document outlines the preparation of the extract composition of Entandrophragma caudatum in ethyl acetate. [Figure 4] The following is an overview of the methanolysis reaction carried out according to Example 2. [Figure 5] This describes a three-step synthesis for converting the compound of formula Ia to the compound of formula Ib. [Figure 6] The IR spectrum of the compound of formula V prepared according to Example 2 is shown. [Modes for carrying out the invention]

[0019] Method for obtaining compounds of formula Ia and / or formula Ib This specification relates, for example, to therapeutically effective limonoids and methods for increasing yields to enable the scale-up and industrial commercial production of novel limonoid-type compounds obtained.

[0020] In one embodiment, the present invention relates to a method for obtaining compounds of the following formulas Ia and Ib: [ka] In the formula, R1 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, which is either unsubstituted or substituted with one or more groups selected from OH and halogens. For example, R1 may be a methyl group or a trifluoromethyl group.

[0021] This method includes providing a composition comprising at least one compound of the following formulas IIa and IIb, [ka] In the formula, R1 is as defined above, and R2 and R3 are independently selected from linear, branched, or cyclic substituted or unsubstituted C1-C6 alkyl groups or nicotinyl groups.

[0022] In the composition, the compounds of formula IIa and / or IIb may be of natural or synthetic origin, and the composition may contain at least one alkanol solvent suitable for the following alkanol degradation step. Alternatively, the present method provides, or complements, an extract composition of Entandrophragma caudatum (see below). The extract composition of Entandrophragma caudatum comprises at least one compound of formula IIa, where R2 and R3 are independently selected from a linear or branched alkyl group having 1 to 6 carbon atoms, or a nicotinyl group, and R1 is methyl. As the next step of the present method, the aforementioned composition and / or the aforementioned extract composition of Entandrophragma caudatum, comprising at least one compound of formula IIa and formula IIb, is optionally subjected to one or more distillations for the purpose of removing water, and any other solvent may interfere with the subsequent alkanol degradation. In this step, an alkanol solvent suitable for the subsequent alkanol degradation is introduced. The alkanol is preferably selected from linear or branched C1-C6 alcohols.

[0023] Alkanol decomposition is carried out by initiating the reaction by adding an aliphatic metal alkoxide, and then stopping the reaction by adding an acid, preferably an organic acid such as acetic acid, thereby obtaining at least one of the compounds of formula Ia and formula Ib.

[0024] In this embodiment, the method is carried out using an extract composition of Entandrophragma caudatum.

[0025] The extract composition of Entandrophragma caudatum preferably comprises at least one of fragmarin-3,30-di-isobutyrate, fragmarin-3-isobutyrate-30-propionate, fragmarin-3-nicotinate-30-isobutyrate, and / or at least one precursor to the compound of formula Ib.

[0026] A subsequent purification process for purifying a mixture of at least one of the compounds of formulas Ia and Ib obtained from alkanol decomposition generally includes sequential extraction with polar and nonpolar fluids to remove polar and nonpolar impurities. This purification process includes steps of drying the mixture, e.g., removing water using an absorbent, using a polar extract, and concentrating under reduced pressure. In embodiments of this purification process, polar impurities may be removed first using one or more polar fluids before drying and concentration, and then nonpolar impurities may be removed using one or more nonpolar / non-aqueous miscible fluids.

[0027] In embodiments of this method, the step of removing polar impurities from the compounds of formulas Ia and Ib may include removing the solvent containing the alkanol from the alkanol decomposition, adding one or more polar extraction fluids, and optionally adding a water absorbent selected from, for example, sodium sulfate, MgSO4, CaSO4, and CaCl2K2CO3 to remove water, thereby obtaining a crude mixture of the compounds. This polar extract may be ethyl acetate, water, or a mixture thereof, or an aqueous sodium chloride solution. However, those skilled in the art can find similar useful alternatives.

[0028] In this embodiment of the method, the nonpolar impurity is removed by dissolving it in a nonpolar / non-aqueous miscible solvent, preferably hexane, or a solvent with a polarity index similar to hexane, such as pentane, cyclohexane, or heptane, and then discarding the solvent phase containing the nonpolar impurity to obtain a crude mixture.

[0029] In embodiments of this method, the method comprises concentrating the crude mixture obtained or obtainable according to the above by removing polar impurities as outlined above and contacting it at least once with a nonpolar / non-aqueous miscible solvent as outlined above, thereby obtaining the compound of formula Ia and / or formula Ib in solid form.

[0030] In embodiments of this method, the method includes separating the compound of formula Ia from the compound of formula Ib by chromatography, and recovering and purifying the compounds of formula Ia and formula Ib individually. Preferably, the final purity of each compound is at least 90%. Preferably, chromatography is performed after a series of steps to remove polar and nonpolar impurities.

[0031] In embodiments of this method, alkanol decomposition is a methanolysis reaction in methanol solvent, and includes the addition of methoxide, preferably sodium methoxide.

[0032] Method for producing the compound of formula Ib In one embodiment, the present invention relates to a method for producing a compound of formula Ib from a compound of formula Ia (including, as a first step, reacting the compound of formula Ia with a base that has sufficient strength to open the lactone ring but not enough to hydrolyze the R1 group to form a carboxyl group, preferably barium hydroxide octahydrate in methanol, to obtain a compound of formula III). For ring opening of the lactone ring, those skilled in the art can find alternatively suitable bases by using a base or acid containing a hydroxyl group, by using an enzyme, or by using, for example, sodium trimethylsilanolate ((TMS)ONa). [ka]

[0033] In the second step, this method includes reacting the compound of formula III with a selective oxidizing agent to obtain the compound of formula IV. [ka]

[0034] The oxidizing agent in the second step is selected from des-martin periodinane, pyridinium chlorochromate, Swern oxidation (oxalyl chloride and DMSO), Corey-Kim oxidation, Jones oxidation (chromium trioxide), TEMPO, and Burgess reagent. Preferably, the oxidizing agent is des-martin periodinane.

[0035] In the third step, this method involves reacting the compound of formula IV with a coupling agent in the presence of a sterically hindered organic base to obtain the compound of formula Ib, in which the lactone ring has been moved.

[0036] The coupling agent in the third step is selected from carbodiimide coupling agents, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), N,N'-disiclehexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), and DCC / HOBt (hydroxybenzotriazole). Preferably, the coupling agent is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0037] The sterically hindered organic base in the coupling reaction in step 3 is selected from N-diisopropylethylamine (DIPEA), dimethylaminopyridine (DMAP), triethylamine (TEA), and 4-pyrrolidinopyridine (PPY), and preferably the base is N,N-diisopropylethylamine (DIPEA).

[0038] Method for producing the compound of formula V In one embodiment, the present invention relates to a method for producing a compound of formula V from a compound of formula Ib by reacting the compound of formula Ib with an esterifying agent and a sterically hindered base to selectively introduce the group R2' into formula V. [ka]

[0039] In formula V, R2' is an optionally substituted linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and R1 is as previously defined. Those skilled in the art can conceive of many different esterifying agents, such as acid chlorides, anhydrides, and the like. Useful sterically hindered bases are discussed in the previous section. The preparation of the compounds of formula Ib is carried out according to the outline in the previous section.

[0040] In one embodiment of the method for producing the compound of formula V, R2' is isopropyl, R1 is methyl, the esterifying agent is isobutyryl chloride, and DMAP-HCl is used as the sterically hindered base.

[0041] In this embodiment, a method for producing a compound of formula V may further include successively purifying the compound of formula V with a polar solvent and a polar solvent, and finally washing the compound with a bipolar solvent, preferably acetone and water, thereby obtaining a solid monohydrate of the compound of formula V.

[0042] compound In one embodiment, the present invention relates to a compound of formula III. In this embodiment, the compound has a methyl substituent R1. In this embodiment, the compound of formula III is obtained or can be obtained by the method outlined above.

[0043] In one embodiment, the present invention relates to a compound of formula IV. In this embodiment, the compound has a methyl substituent R1 and is obtained or can be obtained by the method outlined above.

[0044] In one embodiment, the present invention relates to a monohydrate salt of a compound of formula V, for example, a compound having a substituent, preferably R1, as methyl.

[0045] In one embodiment, the present invention relates to a compound of formula V, provided that R1 is not methyl, ethyl, or hydrogen.

[0046] Extraction composition of Entandrophragma caudatum and method for producing the same Another aspect of the present invention relates to an Entandrophragma caudatum extract composition prepared from the seeds of Entandrophragma caudatum, wherein the Entandrophragma caudatum extract composition comprises at least one precursor to compounds of formula IIa and formula IIb and / or to compounds of formula Ib.

[0047] The Entandrophragma caudatum extract is a natural product obtained by crushing and extracting the seeds of Entandrophragma caudatum. The seeds are placed in a glass reactor and methanol is added for extraction. The slurry is mixed at 40°C for at least 15 hours and filtered under inert N2 gas pressure. Further methanol is added to wash the filter cake and piping. The filtered solution containing the extract is led to a container and partially returned to the glass reactor for concentration by vacuum distillation to obtain a methanol extract. The methanol extract is concentrated to dryness, dissolved in ethyl acetate, and washed with water. The ethyl acetate is concentrated, and the Entandrophragma caudatum extract is recovered as a dark yellow solution in ethyl acetate. The Entandrophragma caudatum extract contains fragmarin-3,30-di-isobutyrate, fragmarin-3-isobutyrate-30-propionate, fragmarin-3-nicotinate-30-isobutyrate, and precursors to the compound of formula Ib.

[0048] For example, the extract composition of Entandrophragma caudatum, i) The crushed seeds of Entandrophragma caudatum are mixed with methanol, filtered, recovered, and concentrated to obtain a concentrated methanol extract. ii) It can be produced by mixing a concentrated methanol extract with a low-polarity solvent and a high-polarity solvent to obtain a two-phase composition, discarding the high-polarity solvent phase to remove polar impurities, and concentrating the low-polarity solvent phase, preferably by distillation, to obtain an extract of Entandrophragma caudatum.

[0049] In the embodiment of the extraction composition, the low-polarity solvent during the process forms an azeotropic mixture with the high-polarity solvent. Preferably, the low-polarity solvent is ethyl acetate and the high-polarity solvent is water, but any combination of low-polarity / high-polarity solvents is possible for those skilled in the art. More preferably, the low-polarity solvent and the high-polarity solvent are ethyl acetate and water, respectively, with a volume ratio of 2:1.

[0050] Embodiments of the extraction composition include at least one of the following: the compound fragmarin-3,30-di-isobutyrate, fragmarin-3-isobutyrate-30-propionate, fragmarin-3-nicotinate-30-isobutyrate, and a precursor for the compound of formula Ib.

[0051] Another aspect of the present invention relates to a method for producing an Entandrophragma caudatum extract composition as described above, prepared from the seeds of Entandrophragma caudatum, wherein the Entandrophragma caudatum extract composition comprises at least one compound according to formula IIa and formula IIb, and the method is as follows: i) A step of mixing crushed seeds of Entandrophragma caudatum with methanol, filtering, recovering, and concentrating to obtain a concentrated methanol extract, ii) A step of obtaining an extract of Entandrophragma caudatum by mixing a low-polarity solvent and a high-polarity solvent with a concentrated methanol extract to obtain a two-phase composition, discarding the high-polarity solvent phase to remove polar impurities, and concentrating the low-polarity solvent phase, preferably by distillation. Includes.

[0052] In the embodiment of this method, the low-polarity solvent in step ii) forms an azeotropic mixture with water, preferably the low-polarity solvent contains ethyl acetate and the high-polarity solvent contains water. Preferably, the low-polarity solvent and the high-polarity solvent in step ii) are ethyl acetate and water, respectively, and more preferably in a volume ratio of 2:1.

[0053] Method for producing the monohydrate of compound VI In yet another aspect of the present invention, the compound of formula VI (9R,15S,16S,17S,18S)-4-(furan-3-carbonyl)-15-hydroxy-18-(2-methoxy-2-oxoethyl)-4,12,17,19-tetramethyl-7-oxo-8,11,13,20-tetraoxaheptacyclo[10.7.1.1 14 , 17 .0 1 , 10 .0 5 , 10 .0 9 , 15 .0 14 , 19 This relates to a method for producing henicosan-16-yl 2-methylpropanoic acid monohydrate. [ka]

[0054] This method includes a step of using the method outlined above to obtain at least one of the compound of formula Ia where R1 is methyl, and / or the compound of formula Ib where R1I is methyl. In the next optional step, the compound of formula Ia is recovered separately and converted to the compound of formula Ib using the method outlined above. Next, the collected compound of formula Ib where R2 is isopropyl is converted to formula VI using the method outlined above (see formula VI). Finally, the purification and washing methods outlined above are applied to obtain the monohydrate of formula VI.

[0055] In this embodiment of the method, the starting material is an extract composition of Entandrophragma caudatum prepared as described above.

[0056] experiment Example 1: Preparation of an extract composition from the seeds of Entandrophragma caudatum Procedure overview: The Entandrophragma caudatum extract is a natural product obtained by crushing and extracting the seeds of Entandrophragma caudatum. The seeds are placed in a glass reactor and methanol is added for extraction. The slurry is mixed at 40°C for at least 15 hours, and then filtered under inert N2 gas pressure. Further methanol is added to wash the filter cake and piping. The filtered solution containing the extract is led to a container and partially returned to the glass reactor for concentration by vacuum distillation to obtain a methanol extract. The methanol extract is concentrated to dryness, dissolved in ethyl acetate, and washed with water. The ethyl acetate is concentrated, and the Entandrophragma caudatum extract is recovered as a dark yellow solution in ethyl acetate. The Entandrophragma caudatum extract contains fragmarin-3,30-di-isobutyrate, fragmarin-3-isobutyrate-30-propionate, fragmarin-3-nicotinate-30-isobutyrate, and precursors to the compound of formula Ib.

[0057] Detailed instructions Step 1: Preparation of methanol extract (See Figure 2 for an overview of the procedure) Approximately 800 L of methanol was added to a nitrogen-filled glass reactor, and stirring was started. Approximately 100 kg of crushed Entandrophragma caudatum seeds were added. The glass reactor was then evacuated and refilled with nitrogen. The reactor temperature was set to 40°C, and the contents were stirred for at least 15-20 hours. Next, the mixture was filtered through a polyamide filter cloth (25 μm) under a pressurized nitrogen atmosphere, and the filtrate was collected in a container. Then, methanol was added to a feed container (approximately 100 L), and methanol was added directly to the filter from the feed container without passing through the glass reactor (twice, 50 L each time), and the filtrate was collected in the container. Next, the procedure was repeated, and the mixture was filtered again through the polyamide filter cloth. The filter cake was then dried under vacuum for at least 1 hour. Next, the filtrate was added to a glass reactor (totaling approximately 800 L), and the contents were stirred. Subsequently, the methanol solvent was removed by distillation under vacuum at a jacket temperature of 40-70°C (internal temperature during distillation was approximately 21-29°C). Distillation was continued until approximately 200L remained in the glass container. Care must be taken not to distill the methanol too much, as the residue becomes too viscous and difficult to remove from the glass container. After that, the jacket temperature was adjusted to approximately 20-25°C, and the concentrated methanol extract was recovered.

[0058] Step 2: Preparation of an extract of Entandrophragma caudatum in ethyl acetate (see Figure 3 for an overview of the procedure). The concentrated methanol extract prepared in step 1 (approximately 400 L, i.e., two batches from step 1) was placed in a nitrogen-filled glass reactor, the reactor temperature was adjusted to 75°C, and the stirrer was started. Methanol was removed by distillation under vacuum to obtain a dry mixture, and then the temperature was adjusted to 20°C. Next, ethyl acetate (HCl) (approximately 400 L) was added to the reactor. Then, water (approximately 170 L) was added. The reactor temperature was set to 40°C, and the contents of the reactor were stirred for approximately 30 minutes while maintaining the temperature at 40°C. The agitator was then stopped, and the two phases were separated for 30-60 minutes until phase separation was achieved. Next, the aqueous layer was discarded. Subsequently, the reactor temperature was adjusted to 55-75°C, and the mixture remaining after water removal was concentrated under vacuum. Distillation was stopped when the volume decreased to approximately 50 L (i.e., when approximately 350 L of distillate had been recovered). The extract of Entandrophragma caudatum in ethyl acetate was then recovered. If stored for later use, the extract was stored at 5°C ± 3°C.

[0059] Example 2: Synthesis of compound V Procedure overview (see also Figure 4): The starting material for the synthesis of the compound of formula V includes a mixture of the substance extracted from the seeds of Entandrophragma caudatum and the solvent remaining from the extraction procedure. This Entandrophragma caudatum extract was prepared according to Example 1. This starting material contains approximately 10% of two different compounds, primarily of formula IIa, and possibly one or more precursor molecules for compounds of formula Ib, which are the target substances for further synthesis. The two most important molecules of formula IIa identified in the extract of Entandrophragma caudatum are as follows: a. Fragmarin 3,30-diisobutyrate b. Fragmarin 3-isobutyrate-30-propionate The precursor molecule of formula Ib has not been fully identified. The two compounds of formula IIa and the likely precursor of formula Ib contained in the seed extract are converted to compounds of formula Ia and Ib, respectively, via a methanolysis procedure, and then purified to obtain pure compounds of formula Ia and Ib. Subsequently, the compound of formula Ia is converted to the compound of formula Ib in three synthetic steps. The compound of formula Ib is finally converted to the compound of formula V in a single step.

[0060] Detailed instructions: Conversion of the compound of formula IIa and the precursor of formula Ib to the compounds of formulas Ia and Ib. Metanolysis: Figure 4 shows an overview of the methanolysis reaction.

[0061] The ethyl acetate extract (138 kg from the previous step) was dissolved in methanol (690 L, 5 vol) and distilled until no more distillate was observed. Methanol (690 L, 5 vol) was added to the mass and the mixture was further distilled at 45°C until no more distillate was observed, yielding 105 kg of solvent-free extract as a brown syrup residue.

[0062] The extraction residue (105 kg, 1.0 equivalent) was dissolved in methanol (1050 L, 10.0 V) and cooled to 15 ± 5 °C. Sodium methoxide (15.75 kg, 0.15% w / w) was added in four equal portions at a temperature below 30 °C, with a 10-minute time interval between each addition (exothermic reaction of 5-10 °C was observed during the addition of sodium methoxide). The reaction mixture was stirred at 45 ± 5 °C for 40 hours.

[0063] Post-processing: The pH of the reaction mixture was adjusted to 6.0–7.0 using acetic acid (approximately 15.75 kg, approximately 0.15% w / w) at 15±5°C, and purified water (315 L, 3.0 V) was added at less than 30°C. The reaction mixture was concentrated under reduced pressure below 45°C to remove methanol. The residue was diluted with ethyl acetate (1050 L, 10.0 V), and purified water (420 L, 4.0 V) was added, followed by sodium chloride (21 kg, 0.2% w / w), and the mixture was stirred for 15 minutes. The two-phase medium was separated and re-extracted with ethyl acetate (735 L, 7.0 V). The combined organic layers were washed with 10% aqueous sodium chloride solution (735 L, 7.0 V), separated, and dried on anhydrous sodium sulfate (approximately 21 kg, 0.2% w / w). The organic layers were concentrated under reduced pressure below 45°C to obtain a crude mixture of compounds of formulas Ia and Ib.

[0064] Hexane slurry, followed by column purification: Hexane (1050 L, 10.0 V) was added to the residue, and the mixture was heated to 40 ± 5 °C and stirred for 2 hours. The mixture was cooled to 25 ± 5 °C and stirred for 8 hours. The precipitated solid was collected by filtration and washed with hexane (210 L, 2.0 V) to obtain approximately 13.36 kg of a crude mixture of compounds of formulas Ia and Ib as a pale yellow solid (all nonpolar impurities were washed away using hexane purification). Compounds of formulas Ia and Ib were separated from the crude mixture by column chromatography. After column chromatography, approximately 4.17 kg of compound Ia and approximately 2.94 kg of compound Ib were obtained.

[0065] Purification of the compound of formula Ia: Crude compound of formula Ia (4.17 kg) was stirred with isopropyl alcohol (IPA) (8.3 L, 2.0 V) at 50 ± 5 °C for 1 hour, then slowly reduced to 25 ± 5 °C and stirred for 6 hours. The solid was filtered and recovered, and washed with IPA (2.1 L, 0.5 V). The wet solid (2.32 kg) was dried in a vacuum tray dryer at 40 ± 5 °C to obtain approximately 2.13 kg of compound of formula Ia.

[0066] Analysis data: Purity (HPLC): 98.4%

[0067] Purification of the compound of formula Ib: Crude compound of formula Ib (2.94 kg) was stirred with IPA (8.8 L, 3.0 V) at 50 ± 5 °C for 1 hour, then slowly reduced to 25 ± 5 °C and stirred for 6 hours. The solid was collected by filtration and washed with IPA (2.9 L, 1.0 V).

[0068] The wet solid (1.53 kg (after LOD correction)) was stirred with ethyl acetate (4.6 L, 3.0 V) at 50 ± 5 °C for 1 hour, then slowly reduced to 25 ± 5 °C and stirred for 6 hours. The solid was collected by filtration and washed with ethyl acetate (1.5 L, 1.0 V).

[0069] The wet solid (1.07 kg) was stirred with ethyl acetate (4.6 L, 3.0 V) at 50 ± 5 °C for 1 hour, then slowly reduced to 25 ± 5 °C and stirred for 6 hours. The solid was filtered and recovered, and washed with ethyl acetate (1.5 L, 1.0 V).

[0070] The wet solid (0.85 kg) was stirred with ethyl acetate (1.7 L, 2.0 V) at 50 ± 5 °C for 1 hour, then slowly reduced to 25 ± 5 °C and stirred for 6 hours. The solid was collected by filtration and washed with ethyl acetate (0.4 L, 0.5 V). The wet solid (0.58 kg) was dried in a vacuum tray dryer at 40 ± 5 °C to obtain approximately 0.335 kg of the compound of formula Ib.

[0071] Analysis data: Purity (HPLC): 99.5%

[0072] A three-step synthesis to convert the compound of formula Ia to the compound of formula Ib (see Figure 5). Step 1: Ring opening of the lactone ring (compound of formula III) A suspension of barium hydroxide octahydrate (1.16 kg, 1.0 equivalent) in methanol (10.3 L, 5.0 V) was cooled to 0-5°C, and compound Ia (2.06 kg, 1.0 equivalent) was added in 4 equivalents over 15 minutes at 0-5°C. The resulting reaction mixture was stirred at 0-10°C for 2 hours (the reactants became homogeneous as the reaction progressed). The progress of the reaction was monitored by TLC (60% ethyl acetate / hexane for consumption of starting materials, 10% methanol / dichloromethane (MeOH / DCM) for product elution, visualization: KMnO4 staining).

[0073] Workup: After completely consuming the starting materials by TLC, the reaction mixture was acidified to pH 5-6 with a 10% aqueous acetic acid solution (approximately 8.24 L, 4.0V), concentrated at a temperature below 40°C to remove methanol. The residue was extracted twice with (10.3 L*2, 5V*2). The combined organic layers were washed with saline solution (8.2 L, 4.0V), dried on anhydrous sodium sulfate, filtered, and the organic layer was set aside for the next step.

[0074] Analysis data: Purity (HPLC): 99.5%

[0075] Step 2: Oxidation (compound of formula IV) A suspension of des-martin periodinane (1.72 kg, 1.1 equivalents) in DCM (16.5 L, 8V) was added to the stirred organic layer (compound of formula III) at 0-5°C. The resulting reaction product (white suspension) was stirred at 10-15°C for 3 hours. The progress of the reaction was monitored by TLC (5% MeOH / DCM + 1 drop of AcOH, visualization: KMnO4 staining).

[0076] Workup: After completely consuming the compound (of formula III) by TLC, the reaction mixture was quenched with a 20% sodium thiosulfate aqueous solution in purified water (20.6 L, 10V) and stirred for 30 minutes (the reaction mixture became clear, and a clear separation of the organic and aqueous layers was observed). These layers were separated, and the aqueous layer was extracted using DCM (10.3 L, 5.0V). The combined organic layers were washed with brine (10.3 L, 5.0V), dried over anhydrous sodium sulfate, and filtered. For the compound of formula Ia below 40°C, the organic layer was concentrated to a 10-fold volume level and set aside for the next step.

[0077] Step 3: Ring formation (compound of formula Ib) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) (0.702 kg, 1.0 equivalent) was added to the stirred organic layer of the compound of formula IV, followed by the addition of diisopropylethylamine (DIPEA) (0.957 L, 1.5 equivalents) over 30 minutes at 10±5°C. The resulting reaction mixture was stirred at 10±5°C for 2 hours. The progress of the reaction was monitored by TLC (10% MeOH / DCM for consumption of starting materials, 80% ethyl acetate / hexane for product elution confirmation, visualization: KMnO4 staining).

[0078] Workup: After the compound of formula IV was completely consumed by TLC, the reaction mixture was quenched with water (20.6 L, 10.0 L), the layers were separated, and the aqueous layer was extracted with DCM (10.3 L, 5.0 V). The combined organic layers were washed with brine (10.3 L, 5.0 V), dried over anhydrous sodium sulfate, and filtered. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure at 40°C until no distillate was observed.

[0079] Purification of the compound of formula Ib: The crude compound of formula Ib was chased with ethyl acetate (12.3 L, 6.0 V) at a temperature below 40°C, concentrated to a volume level of 3.0 with respect to the compound of formula Ib, and stirred at 50 ± 5°C for 1 hour. The reaction mixture was gradually cooled to 25 ± 5°C over 1 hour and stirred at 25 ± 5°C for 6 hours. The solid was collected by filtration and washed with ethyl acetate (2.1 L, 1.0 V) to obtain 1.1 kg of wet solid of the compound of formula Ib. The wet solid was dried in a vacuum tray dryer at 40 ± 5°C to obtain 0.85 kg of the compound of formula Ib.

[0080] Analysis data: Purity (HPLC): 95.4%

[0081] [Table 1]

[0082] Synthesis of compound V from compound Ib To a solution of compound Ib (322 g, 1.0 equivalent) in dried dimethylformamide (DMF) (1.6 L, 5.0 V), 4-N,N-dimethylaminopyridine hydrochloride (DMAP.HCl) (91 g), followed by isobutyryl chloride (92 g, 1.5 equivalents), was added at 25 ± 5 °C. The reaction mixture was heated to 60 ± 5 °C and stirred for 6 hours. After 6 hours, DMAP.HCl (45.6 g) was added to the reaction mixture, followed by isobutyryl chloride (61.2 g, 1.0 equivalent) at 60 ± 5 °C, and the reaction was continued for a further 4 hours. The reaction was monitored by HPLC.

[0083] Post-processing: After the reaction was complete, the reaction mixture was cooled to 25±5°C, filtered through a Celite bed, and washed with DMF (320 ml, 1.0 V). The filtrate was passed through a 0.2 micron cartridge and washed with DMF (320 ml, 1.0 V). Purified water (8.0 L, 25.0 V) was added to a separate reaction vessel and cooled to 15 ± 5°C. The filtrate was slowly added to the reaction contents over 1 hour at 15 ± 5°C (reverse quench). The reaction mixture was brought to a temperature of 25 ± 5°C and stirred at that temperature for 4 hours. The solid matter was collected by filtration and washed with purified water (0.65 L, 2.0 V). Purified water (1.6 L, 5V) was added to the wet solid and the mixture was stirred at 40±5°C for 2 hours. The solid was filtered and recovered, and washed with purified water (0.65 L, 2V). The wet solid was dried under reduced pressure at 40±5°C for 12 hours to obtain 456 g of the crude product of formula V (crude purity by HPLC: 79.97%).

[0084] Purification of ethyl acetate: Ethyl acetate slurry-1: Crude product (456g) was stirred with ethyl acetate (1.36L, 3.0V) at 50±5°C for 1 hour. The reaction mixture was gradually cooled to 25±5°C over 1 hour and stirred at 25±5°C for 4 hours. The solids were collected by filtration and washed with ethyl acetate (0.45L, 1.0V). (Wet solids weight: 295g, after loss on drying (LOD): 249g (LOD: 15.6% w / w) (HPLC purity: 97.7% and impurities: RRT 0.68: 1.38%)

[0085] Ethyl acetate slurry-2: Crude product (249g) was stirred with ethyl acetate (373ml, 1.5V) at 50±5°C for 1 hour. The reaction mixture was gradually cooled to 25±5°C over 1 hour and stirred at 25±5°C for 4 hours. The solid was collected by filtration and washed with ethyl acetate (0.45L, 1.0V). (Wet solid weight: 236.6g, after LOD correction: 230g (LOD: 2.6% w / w) (HPLC purity: 98.68%, impurities: RRT 0.68: 1.38%)

[0086] Ethyl acetate slurry-3: Crude product (230g) was stirred with ethyl acetate (460ml, 2.0V) at 50±5°C for 1 hour. The reaction mixture was gradually cooled to 25±5°C over 1 hour, and stirred at 25±5°C for 4 hours. The solid was collected by filtration and washed with ethyl acetate (115ml, 1.0V). (Wet solid weight: 191.6g, purity by HPLC: 99.8%, impurities: RRT0.68:0.12%)

[0087] The wet solid was dried under reduced pressure at 40±5℃ for more than 10 hours to obtain 185.4 g of the crude compound of formula V.

[0088] Purify with acetone / purified water to obtain the desired monohydrate: Crude compound V (181.4 g) was stirred with acetone (1.3 L, 7.0 V) at 45 ± 5 °C for 30 minutes to obtain a clear solution. Purified water (2.8 L, 15.0 V) was added to the reaction mixture over 1 hour, and the mixture was stirred for another 1 hour at 45 ± 5 °C. The reaction mixture was gradually cooled to 25 ± 5 °C and stirred for 6 hours. The solid was collected by filtration and washed with acetone / purified water (278 ml, 1.0 V) to obtain 188 g of the wet product of compound V monohydrate. The wet solid was dried under reduced pressure at 40 ± 5 °C for more than 16 hours, and then sieved to obtain 179 g of compound V monohydrate.

[0089] Analysis data: Purity (HPLC): 99.9%

[0090] [Table 2]

[0091] Specific rotation: -49.8° The IR spectrum of the generated compound is shown in Figure 6. NMR data: 1H-NMR (DMSO, 400 MHz): δ8.64(s,1H), 7.78(s,1H), 6.75(dd,1H), 5.09(s,1H), 4.69(s,1H), 3.92(s,1H), 3.41(s,3H), 2.68(m,3H), 2.35(m,2H), 2.24(m,3H) , 1.95(m,2H), 1.67(m,1H), 1.55(d,4H), 1.42(s,3H), 1.26(d,6H), 1.18(m,1H), 1.04(s,1H), 0.76(s,3H)LCMS:453.3[M+H], HPLC purity:98.50%

[0092] The present invention is described in conjunction with its detailed description, but it should be understood that the above description is intended to illustrate, not limit, the scope of the invention as defined by the appended claims. Other aspects, advantages and modifications are included within the scope of the following claims. [1] A method for obtaining at least one compound of formula Ia and formula Ib, [ka] In the formula, R1 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and is either unsubstituted or substituted with, for example, OH or a halogen (such as F), and the method described above is (i) Compositions comprising the following: At least one compound of formula IIa and formula IIb, [ka] (In the formula, R1 is as defined above, The steps include providing R2 and R3 independently selected from linear, branched, or cyclic substituted or unsubstituted alkyl groups having 1 to 6 carbon atoms, or nicotinyl groups, and / or An extract composition from Entandrophragma caudatum comprising at least one compound of formula IIa, wherein, c) R2 and R3 are independently selected from a linear or branched alkyl group having 1 to 6 carbon atoms, or a nicotinyl group. d) R1 is methyl, a process to provide an extractable composition, (ii) The extracted composition from step (i) and / or optionally the composition is subjected to one or more distillations and subjected to the introduction of a solvent containing an aliphatic alkanol, (iii) A method comprising the step of carrying out an alkanol decomposition reaction to obtain at least one of the compounds of formula Ia and formula Ib by adding an aliphatic metal alkoxide in the presence of an aliphatic alcohol to initiate the reaction, and then adding an acid, preferably an organic acid such as acetic acid, to terminate the alkanol decomposition reaction. [2] The method according to [1], using the aforementioned extract composition of Entandrophragma caudatum. [3] The method according to [1] or [2], wherein the extract composition of Entandrophragma caudatum comprises at least one of the following: fragmarin-3,30-di-isobutyrate, fragmarin-3,30-isobutyrate-30-propionate, fragmarin-3,30-nicotinate-30-isobutyrate, and / or a precursor of the compound of formula Ib. [4] A method according to any one of the items [1] to [3], (a) Remove the aliphatic alcohol, (b) Add one or more polar extracts, and optionally, (c) For example, water absorbent selected from sodium sulfate, MgSO4, CaSO4, CaCl2 K2CO3 is added to remove water and obtain a crude mixture of the compound. A method further comprising the step of removing polar impurities from the compounds of formulas Ia and Ib by doing so. [5] The method according to any one of [1] to [4], further comprising the step of removing the nonpolar impurities by dissolving the nonpolar impurities in a non-aqueous miscible solvent, preferably hexane, or a solvent having a polarity index similar to hexane, such as pentane, cyclohexane, or heptane, and discarding the solvent phase containing the nonpolar impurities to obtain a crude mixture. [6] The method according to [4] or [5], comprising the steps of: concentrating the crude mixture obtained or obtainable by [5], and contacting the crude mixture at least once with the non-aqueous miscible solvent described in [5], thereby obtaining the compound of formula Ia and / or formula Ib in solid form. [7] The method according to any one of [1] to [6], further comprising the steps of separating the compound of formula Ia from the compound of formula Ib, and further recovering and purifying the compounds of formula Ia and formula Ib individually, preferably wherein the final purity of each compound is at least 90%. [8] The method according to any one of [1] to [7], wherein the alkanol decomposition is a metallization reaction in a methanol solvent, and further comprising the addition of methoxide, preferably sodium methoxide. [9] A method for producing a compound of formula Ib from a compound of formula Ia, (i) A step of reacting a compound of formula Ia with a base that has sufficient strength to open the lactone ring but not enough to hydrolyze the R1 group to form a carboxyl group, preferably a barium hydroxide octahydrate in methanol, to obtain a compound of formula III below, [ka] (ii) A step of reacting the compound of formula III with a selective oxidizing agent, preferably des-martinperiodinane, to obtain the compound of formula IV, [ka] (iii) A step of obtaining a compound of formula Ib by reacting a compound of formula IV with a coupling agent, preferably a carbodiimide coupling agent, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) in the presence of a sterically hindered organic base, preferably N,N-diisopropylethylamine (DIPEA), Methods that include...

[10] The method according to [9], wherein the compound of formula Ia is obtained or can be obtained by the method described in any one of [1] to [6].

[11] A method for producing a compound of formula V from a compound of formula Ib by reacting a compound of formula Ib with an esterifying agent and a sterically hindered base, thereby selectively introducing the group R2' of formula V as follows: [ka] A method wherein R2' is an optionally substituted linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms.

[12] The method according to

[11] , wherein R2' is isopropyl, R1 is methyl, DMAP-HCl is used as the sterically hindered base, and isobutyryl chloride is the esterifying agent.

[13] The method according to

[11] or

[12] , wherein a compound of formula Ib is obtained according to the method described in either [9] or

[10] .

[14] The method according to any one of

[11] to

[13] , further comprising the steps of: continuously purifying the compound of formula V with a low-polarity solvent, preferably ethyl acetate; and continuously purifying it with a bipolar solvent, preferably acetone and water, or a mixture thereof, thereby obtaining a solid monohydrate of the compound of formula V.

[15] Compounds of formula III.

[16] The compound described in

[15] , wherein R1 is methyl.

[17] The compound described in

[15] or

[16] , which can be obtained or obtained by the method of step (i) of [9].

[18] Compound of formula IV.

[19] The compound described in

[18] , wherein R1 is methyl.

[20] The compound described in

[18] or

[19] , which can be obtained or obtained by the method of step (ii) of [9]. [twenty one] A monohydrate salt of a compound according to formula V, wherein R1 is preferably methyl. [twenty two] A compound according to formula V, provided that R1 is not hydrogen, methyl, or ethyl. [twenty three] An extract composition of Entandrophragma caudatum, prepared from the seeds of Entandrophragma caudatum, comprising at least one compound according to formula IIa and a precursor for formula Ib, (i) The crushed seeds of Entandrophragma caudatum are mixed with methanol, filtered, recovered, and concentrated to obtain a concentrated methanol extract. (ii) An extract composition produced by mixing the concentrated methanol extract with a low-polarity solvent and a high-polarity solvent to obtain a two-phase composition, discarding the polar solvent phase to remove polar impurities, and concentrating the low-polarity solvent phase preferably by distillation to obtain the extract composition of Entandrophragma caudatum. [twenty four] The extraction composition according to

[23] , wherein the low-polarity solvent in step (ii) forms an azeotrope with water, and preferably the low-polarity solvent contains ethyl acetate and the polar solvent contains water. [twenty five] The extraction composition according to

[24] , wherein the low-polarity solvent and the high-polarity solvent in step ii) are ethyl acetate and water, respectively, in a volume ratio of 2:1.

[26] An extraction composition according to any one of

[23] to

[25] , comprising at least one of the aforementioned compounds: Fragmarin-3,30-di-isobutyrate, Fragmarin-3-isobutyrate-30-propionate, and Fragmarin-3-nicotinate-30-isobutyrate.

[27] A method for producing an extract composition of Entandrophragma caudatum, prepared from the seeds of Entandrophragma caudatum and comprising at least one compound according to formula IIa and / or a precursor of formula Ib, (i) A step of mixing crushed seeds of Entandrophragma caudatum with methanol, filtering, recovering, and concentrating to obtain a concentrated methanol extract, (ii) The steps of: (ii) Mixing the concentrated methanol extract with a low-polarity solvent and a high-polarity solvent to obtain a two-phase composition; discarding the high-polarity solvent phase to remove polar impurities; and concentrating the low-polarity solvent phase, preferably by distillation, thereby obtaining the extract composition of Entandrophragma caudatum; Methods that include...

[28] The method according to

[27] , wherein the low-polarity solvent in step (ii) forms an azeotrope with water, preferably the low-polarity solvent contains ethyl acetate and the high-polarity solvent contains water.

[29] The method according to

[27] or

[28] , wherein the low-polarity solvent and the high-polarity solvent in step (ii) are ethyl acetate and water, respectively, in a volume ratio of 2:1.

[30] Compound of formula VI, 9R,15S,16S,17S,18S-4-(furan-3-carbonyl)-15-hydroxy-18-(2-methoxy-2-oxoethyl)-4,12,17,19-tetramethyl-7-oxo-8,11,13,20-tetraoxaheptacyclo[10.7.1.1 14 , 17 .0 1 , 10 .0 5 , 10 .0 9 ,15 .0 14 , 19 A method for producing henicosan-16-yl 2-methylpropanoic acid monohydrate, [ka] The method described above is (i) A step of using the method described in any one of [1] to [8] in order to obtain at least one of the compound of formula Ia in which R1 is methyl and the compound of formula Ib in which R1 is methyl, (ii) A step of separately recovering the compound of formula Ia and converting it to the compound of formula Ib by the method described in [9], (iii) A step of converting the compound of formula Ib recovered from steps (i) and (ii) using the method described in

[11] or

[12] to obtain a compound of formula IIb in which R2 is isopropyl, Methods that include...

[31] The method according to

[30] further comprises obtaining a monohydrate of the compound according to formula VI by carrying out the method according to

[14] .

[32] The method according to

[30] or

[31] , wherein the starting material in step (i) is an extract composition of Entandrophragma caudatum as described in any one of

[27] to

[29] .

[33] A method for obtaining at least one of the compounds of formula Ia and Ib, comprising carrying out the method described in

[27] to

[29] and thereafter the method described in any one of [1] to [8].

[34] The method according to

[33] further comprises obtaining a compound of formula V by carrying out the methods described in

[11] to

[14] .

Claims

1. below: 【Chemistry 1】 [In the formula, R1 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and is substituted with OH or a halogen, or is unsubstituted.] A method for producing a therapeutically effective limonoid from a compound of formula Ia, a compound of formula Ib, or both thereof, (i) Below: 【Chemistry 2】 [In the formula, R1 is as defined above, and R2 and R3 are independently selected from linear, branched, or cyclic substituted or unsubstituted alkyl groups having 1 to 6 carbon atoms, or from nicotinyl groups.] A step of providing a composition (composition 1) comprising a compound of formula IIa, a compound of formula IIb, or both thereof, and / or A step of providing an extract composition (composition 2) from Entandrophragma caudatum, comprising at least a compound of formula IIa (R2 and R3 are independently selected from a linear or branched alkyl group having 1 to 6 carbon atoms, or a nicotinyl group, and R1 is methyl), (ii) A step of subjecting composition 1 and / or composition 2 to one or more distillations and introducing a solvent containing an aliphatic alkanol, (iii) A step of carrying out an alkanol decomposition reaction to obtain the compound of formula Ia, the compound of formula Ib, or both, by adding an aliphatic metal alkoxide in the presence of an aliphatic alcohol to initiate the reaction, and then adding an acid to stop the alkanol decomposition reaction. Methods that include...

2. The method according to claim 1, wherein the method is carried out using the extraction composition of Entandrophragma caudatum.

3. The method according to claim 1, wherein the extract composition of Entandrophragma caudatum comprises at least one of the following: fragmarin-3,30-diisobutyrate, fragmarin-3-isobutyrate-30-propionate, fragmarin-3-nicotinate-30-isobutyrate, and / or a precursor of the compound of formula Ib.

4. (a) Remove the aliphatic alcohol, (b) Add one or more polar extracts, optionally, (c) Sodium sulfate, MgSO ４ CaSO ４ CaCl ２ K ２ CO ３ A water-absorbing agent selected from the above is added to remove moisture and obtain a crude mixture of the compounds. The method according to claim 1, further comprising the step of removing polar impurities from the compounds of formula Ia and formula Ib by means of the method.

5. The method according to claim 1, further comprising the step of removing the nonpolar impurities by dissolving the nonpolar impurities in a non-aqueous miscible solvent and discarding the solvent phase containing the nonpolar impurities to obtain a crude mixture.

6. The method according to claim 5, comprising the steps of concentrating a crude mixture, contacting the crude mixture with a non-aqueous miscible solvent at least once, thereby obtaining the compound of formula Ia and / or formula Ib in a solid form.

7. The method according to claim 1, further comprising the steps of chromatographically separating the compound of formula Ia from the compound of formula Ib, and further recovering and purifying the compounds of formula Ia and formula Ib individually.

8. The method according to claim 1, wherein the alkanol decomposition is a metallization reaction in a methanol solvent, and further comprises the addition of sodium methoxide.

9. The method according to claim 7, comprising producing a compound of formula Ib from a recovered compound of formula Ia, (iv) The compound of formula Ia is reacted with a base, as follows: 【Transformation 3】 The process of obtaining the compound of formula III, (v) The compound of formula III is reacted with an oxidizing agent to obtain the following: 【Chemistry 4】 The process of obtaining the compound of formula IV, (vi) A step of obtaining a compound of formula Ib by reacting a compound of formula IV with a coupling agent in the presence of an organic base, The above method, including.

10. We provide a compound of formula Ib, and react the compound of formula Ib with an esterifying agent and a base to obtain the following compound V: 【Transformation 5】 [In the formula, R2' is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and may be substituted.] The method according to claim 1, wherein an R2' group is selectively introduced to produce the compound.

11. The method according to claim 10, wherein R2' is isopropyl, R1 is methyl, and the compound of formula Ib is reacted with isobutyryl chloride and DMAP-HCl.

12. The method according to claim 10, further comprising purifying the compound of formula V sequentially with a low-polarity solvent and then sequentially purifying it with a bipolar solvent to obtain a solid monohydrate of the compound of formula V.

13. A method for producing an extract composition of Entandrophragma caudatum, wherein the extract composition of Entandrophragma caudatum is prepared from the seeds of Entandrophragma caudatum and is of the following formula IIa: 【Transformation 6】 [In the formula, R1 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and is substituted with an OH group or a halogen, or is unsubstituted; R2 and R3 are independently selected from linear, branched, or cyclic substituted or unsubstituted alkyl groups having 1 to 6 carbon atoms, or from a nicotinyl group.] The extract composition of Entandrophragma caudatum contains the following compounds: (i) A step of mixing crushed seeds of Entandrophragma caudatum with methanol, filtering, recovering, and concentrating to obtain a concentrated methanol extract, (ii) The steps of (ii) mixing the concentrated methanol extract with a low-polarity solvent and a high-polarity solvent to obtain a two-phase composition, discarding the high-polarity solvent phase to remove polar impurities, and concentrating the low-polarity solvent phase to obtain the extract composition of Entandrophragma caudatum, The above method, which is generated by...

14. The method according to claim 13, wherein the low-polarity solvent in step (ii) forms an azeotrope with water.

15. The method according to claim 13, wherein the low-polarity solvent is ethyl acetate and the high-polarity solvent is water.

16. The following formula VI: 【Transformation 7】 A method for producing a monohydrate of, (i) A step of producing a compound of formula Ia in which R1 is methyl and a compound of formula Ib in which R1 is methyl using the method of claim 1, (ii) A step of separately recovering the compound of formula Ia and converting it to the compound of formula Ib, (iii) A step of converting the compound of formula Ib recovered from steps (i) and (ii) into a compound of formula VI in which R1 is methyl, Methods that include...

17. The method according to claim 16, further comprising the steps of continuously purifying the compound of formula VI with a low-polarity solvent and continuously purifying it with a bipolar solvent to obtain a monohydrate of the compound of formula VI.

18. The method according to claim 16, wherein the starting material of step i is an extract composition of Entandrophragma caudatum.

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