Extraction process of phragmaline derivatives from ENTANDROPHRAGMA CAUDATUM seeds and preparation of pharmacologically active limonoids

Abstract

The present invention is directed to a process for obtaining phragmarin derivatives of formula 1a, e.g. from Entandrophragma caudatum seed extract, formula (1a), in multiple steps to produce therapeutically effective limonoids and limonoid-type compounds therefrom, e.g. compounds of formula (V), together with intermediate products, e.g. of formula (III).

Description

[Technical Field]

[0001] The present invention relates generally to improved preparations of therapeutically active limonoids and novel limonoid-type compounds. [Background technology]

[0002] European Patent No. 2807170 discloses plant-derived limonoids useful for the treatment of sexual dysfunction and possessing sexual enhancement properties. This specification proposes the use of phragmalin esters extracted from the seeds of Chukrasia tabularis as a raw material, and the desired limonoids are obtained through a lengthy process that includes alkaline hydrolysis, conversion to Weinreb amides, and rearrangement of the phragmalin lactone ring. Consequently, the low yields of the manufacturing process described in European Patent No. 2807170 and the difficulty in obtaining raw materials from Chukrasia tabularis make it extremely difficult and expensive to produce limonoids in reasonable quantities for the development and commercialization of limonoid-based therapeutic products. Therefore, a more efficient method for producing the desired limonoids is needed. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] European Patent No. 2807170 Summary of the Invention

[0004] The present disclosure relates to at least one compound of formula Ia and formula Ib: [ka] wherein R1 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, which is unsubstituted or substituted with a halogen, e.g., OH or F. The present invention relates to a method for obtaining a compound comprising the steps of: (i) a composition comprising: at least one compound of formula IIa and formula IIb, [ka] (In the formula, R1 is as defined above, R2 and R3 are independently selected from a linear, branched or cyclic, substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a nicotinyl group; and / or 1. An extract composition from Entandrophragma caudatum comprising at least a 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) providing an extraction composition, wherein R1 is methyl; (ii) subjecting the extracted composition and / or optionally the composition from step (i) to one or more distillations and the introduction of a solvent comprising an aliphatic alkanol; (iii) carrying out an alkanollysis reaction in the presence of an aliphatic alcohol by adding an aliphatic metal alkoxide to initiate the reaction, followed by adding an acid, preferably an organic acid such as acetic acid, to terminate the alkanollysis reaction, to obtain at least one of compounds of formula Ia and formula Ib.

[0005] This specification also discloses methods for preparing compounds of formula Ib from compounds of formula Ia, including: (i) reacting a compound of formula Ia with a base strong enough to open the lactone ring but not strong enough to hydrolyze the R group to form a carboxyl group, preferably barium hydroxide octahydrate in methanol, to obtain a compound of formula III; [ka] (ii) reacting the compound of formula III with a selective oxidizing agent, preferably Dess-Martin periodinane, to give a compound of formula IV; [ka] (iii) reacting the compound of formula IV with a coupling agent, preferably a carbodiimide 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 the compound of formula Ib.

[0006] The present invention is also directed to a process for preparing 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' of formula V, [ka] In the formula, R2' is a linear, branched or cyclic optionally substituted alkyl group having 1 to 6 carbon atoms.

[0007] This specification also covers compounds of formula III. (This specification also covers compounds of claim 13, wherein R1 is methyl.)

[0008] The present specification also covers a compound according to claim 15 or 16, which is obtained or obtainable by the process of step (i) of claim 9.

[0009] This specification also covers compounds of formula IV: The present specification also covers the compound of claim 18, wherein R1 is methyl.

[0010] The present specification also covers a compound according to claim 18 or 19, which is obtained or obtainable by the process of step (ii) of claim 9.

[0011] This specification also covers the monohydrate salt of the compound of formula V, wherein R1 is preferably methyl.

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

[0013] The present specification is also directed to an extract composition of Entandrophragma caudatum prepared from seeds of Entandrophragma caudatum, the extract composition of Entandrophragma caudatum comprising at least one of the compounds of Formula IIa and Formula IIb, the extract composition of Entandrophragma caudatum being produced by: (i) mixing crushed seeds of Entandrophragma caudatum with methanol, filtering, recovering, and concentrating 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 composition of Entandrophragma caudatum.

[0014] "Low polarity" and "high polarity" solvents in this method refer to the polarity of the solvents relative to each other.

[0015] The present specification also relates to a method for producing an extract composition of Entandrophragma caudatum prepared from seeds of Entandrophragma caudatum, wherein the extract composition of Entandrophragma caudatum comprises at least one of a compound of formula IIa and / or a precursor to formula Ib, the method comprising: i) mixing the crushed seeds with methanol, filtering, collecting and concentrating to obtain a concentrated methanol extract; 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, to obtain an extract composition of Entandrophragma caudatum.

[0016] "Low polarity" and "high polarity" solvents in this method refer to the polarity of the solvents relative to each other.

[0017] The present specification also discloses the compound 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 ] Also covered is a method for making the compound henicosan-16-yl 2-methylpropanoic acid monohydrate. [ka] The method comprises: (i) obtaining a compound of formula Ia, wherein R1 is methyl, and / or a compound of formula Ib, wherein R1 is methyl, using the method of any one of claims 1 to 8; (ii) separately collecting and converting the compound of formula Ia to a compound of formula Ib by the method of claim 9; (iii) converting the compound of formula Ib recovered from steps (i) and (ii) using the method of claim 11 or 12 to obtain a compound of formula IIb, wherein R2 is isopropyl; Includes: [Brief explanation of the drawings]

[0018] [Figure 1]The carbon atom numbering for compounds of formula Ia and formula Ib, respectively, is shown. [Figure 2] 1 shows an outline of the preparation of a methanol extract of seeds from Entandrophragma caudatum. [Figure 3] 1 shows an outline of the preparation of an extract composition of Entandrophragma caudatum in ethyl acetate. [Figure 4] 1 shows an outline of the methanolysis reaction carried out according to Example 2. [Figure 5] A three step synthesis is shown for converting compounds of formula Ia to compounds of formula Ib. [Figure 6] 1 shows the IR spectrum of the compound of formula V prepared according to Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0019] Processes for Obtaining Compounds of Formula Ia and / or Formula Ib The present specification is directed to methods that allow for increased yields, for example, to allow for scale-up and industrial commercial production of therapeutically effective limonoids and the resulting novel limonoid-type compounds.

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

[0021] The method includes providing a composition comprising at least one compound of Formula IIa and Formula IIb: [ka] In the formula, R1 is as defined above, and R2 and R3 are independently selected from a linear, branched, or cyclic, substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a nicotinyl group.

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

[0023] Alkanollysis is carried out by initiating the reaction by adding an aliphatic metal alkoxide, followed by quenching the reaction by adding an acid, preferably an organic acid such as acetic acid, to thereby provide at least one of compounds of Formula Ia and Formula Ib.

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

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

[0026] The subsequent purification process for the mixture of at least one of the compounds of Formula Ia and Formula Ib obtained from the alkanol decomposition generally involves successive extraction with polar and non-polar fluids to remove polar and non-polar impurities. This purification process includes drying the mixture, e.g., using a water absorbent to remove water, using a polar extractant, and concentrating under reduced pressure. In this embodiment of the purification process, polar impurities can be first removed with one or more polar fluids, followed by removal of non-polar impurities with one or more non-polar / water-immiscible fluids, prior to drying and concentration.

[0027] In an embodiment of this method, the step of removing polar impurities from the compounds of Formula Ia and Formula Ib can include removing the alkanol-containing solvent from the alkanol decomposition and adding one or more polar extraction fluids, optionally including a water-absorbing agent selected from, for example, sodium sulfate, MgSO4, CaSO4, and CaCl2K2CO3, to remove water to obtain a crude mixture of the compounds. The polar extraction fluid can be ethyl acetate, water, or a mixture thereof, or aqueous sodium chloride solution. However, those skilled in the art will recognize similarly useful alternatives.

[0028] In an embodiment of the method, the non-polar impurities are removed by dissolving the non-polar impurities in a non-polar / immiscible solvent, preferably hexane or a solvent with a polarity index similar to hexane, such as pentane, cyclohexane, heptane, and discarding the solvent phase containing the non-polar impurities to obtain a crude mixture.

[0029] In an embodiment of the process, the process comprises removing polar impurities as outlined above and concentrating the crude mixture obtained or obtainable as described above by contacting at least once with a non-polar / non-water-miscible solvent as outlined above, thereby obtaining a compound of formula Ia and / or formula Ib in solid form.

[0030] In an embodiment of the method, the method includes separating the compound of Formula Ia from the compound of Formula Ib by chromatography, and separately recovering and purifying the compounds of Formula Ia and Formula Ib. Preferably, the final purity of each compound is at least 90%. Preferably, the chromatography is performed after successive steps of removing polar and non-polar impurities.

[0031] In an embodiment of the method, the alkanollysis is a methanolysis reaction in a methanol solvent, which involves the addition of a methoxide, preferably sodium methoxide.

[0032] Methods for preparing compounds of formula Ib In one aspect, the present invention relates to a method for preparing a compound of formula Ib from a compound of formula Ia, which comprises, as a first step, reacting a compound of formula Ia with a base strong enough to open the lactone ring but not strong enough to hydrolyze the R group to form a carboxyl group, preferably barium hydroxide octahydrate in methanol, to obtain a compound of formula III. For the lactone ring opening, one skilled in the art can alternatively find a suitable base, such as a base containing a hydroxy group, or an acid, using an enzyme, or using, for example, sodium trimethylsilanolate ((TMS)ONa). [ka]

[0033] In the second step, the method involves 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 Dess-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 Dess-Martin periodinane.

[0035] In the third step, the method comprises reacting the compound of formula IV with a coupling agent in the presence of a sterically hindered organic base, thereby obtaining the lactone ring-shifted compound of formula Ib.

[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'-dicyclohexylcarbodiimide (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 the third step is selected from N-diisopropylethylamine (DIPEA), dimethylaminopyridine (DMAP), triethylamine (TEA), and 4-pyrrolidinopyridine (PPY), preferably the base is preferably N,N-diisopropylethylamine (DIPEA).

[0038] Method for Preparing Compounds of Formula V In one aspect, the present invention relates to a method for preparing 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 a linear, branched, or cyclic, optionally substituted alkyl group having 1 to 6 carbon atoms, and R1 is as defined above. One skilled in the art can envision many different esterifying agents, such as acid chlorides, anhydrides, and the like. Useful sterically hindered bases are described in the previous section. The preparation of compounds of Formula Ib is carried out as outlined in the previous section.

[0040] In one embodiment of the process for preparing 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 embodiments, the method for preparing the compound of formula V may further comprise purifying the compound of formula V successively 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 aspect, the invention relates to a compound of formula III. In an embodiment, the compound has a methyl as the substituent R. In an embodiment, the compound of formula III is obtained or obtainable by a method as outlined above.

[0043] In one aspect, the invention relates to a compound of formula IV: In an embodiment, this compound has methyl as the substituent R1 and is obtained or obtainable by the methods as outlined above.

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

[0045] In one aspect, the invention relates to compounds of formula V, provided that R1 is not methyl, ethyl, or hydrogen.

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

[0047] The Entandrophragma caudatum extract composition is a natural product extracted by crushing Entandrophragma caudatum seeds. The seeds are placed in a glass reactor and extracted with methanol. The slurry is mixed at 40°C for at least 15 hours and then filtered under inert N2 gas pressure. Additional methanol is added to wash the filter cake and piping. The filtrate containing the extract is directed to a container and partially returned to the glass reactor for concentration by vacuum distillation to obtain the 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 composition is recovered as a deep yellow solution in ethyl acetate. The Entandrophragma caudatum extract composition includes phragmarin-3,30-di-isobutyric acid ester, phragmarin-3-isobutyric acid ester-30-propionate, phragmarin-3-nicotinate-30-isobutyric acid ester, and a precursor to the compound of Formula Ib.

[0048] For example, the extract composition of Entandrophragma caudatum is i) Mixing crushed seeds of Entandrophragma caudatum with methanol, filtering, collecting and concentrating to obtain a concentrated methanol extract; ii) 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 composition of Entandrophragma caudatum.

[0049] In an embodiment of the extraction composition, the low polarity solvent in the process forms an azeotrope with the high polarity solvent. Preferably, the low polarity solvent is ethyl acetate and the high polarity solvent is water, but a combination of low polarity solvent and high polarity solvent 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, in a volume ratio of 2:1.

[0050] Embodiments of the extraction composition include the compounds phragmarin-3,30-di-isobutyrate and at least one of phragmarin-3-isobutyrate-30-propionate, phragmarin-3-nicotinate-30-isobutyrate, and a precursor to the compound of formula Ib.

[0051] Another aspect of the present invention relates to a method for producing an extract composition of Entandrophragma caudatum as described above prepared from seeds of Entandrophragma caudatum, wherein the extract composition of Entandrophragma caudatum comprises at least one of the compounds according to Formula IIa and Formula IIb, the method comprising: i) mixing crushed seeds of Entandrophragma caudatum with methanol, filtering, recovering and concentrating to obtain a concentrated methanol extract; 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, to obtain an extract composition of Entandrophragma caudatum; Includes:

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

[0053] Process for preparing the monohydrate of the compound of formula VI In yet another aspect of the present invention, there is provided a 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 ]The present invention relates to a method for producing henicos-16-yl 2-methylpropanoic acid monohydrate. [ka]

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

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

[0056] Experimental Section Example 1: Preparation of an extract composition from Entandrophragma caudatum seeds Summary of steps: The Entandrophragma caudatum extract composition is a natural product extracted by crushing Entandrophragma caudatum seeds. The seeds are placed in a glass reactor and extracted with methanol. The slurry is mixed at 40°C for at least 15 hours and then filtered under inert N2 gas pressure. Additional methanol is added to wash the filter cake and piping. The filtrate containing the extract is directed to a container and partially returned to the glass reactor for concentration by vacuum distillation to obtain the 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 composition is recovered as a deep yellow solution in ethyl acetate. The Entandrophragma caudatum extract composition includes phragmarin-3,30-di-isobutyrate, phragmarin-3-isobutyrate-30-propionate, phragmarin-3-nicotinate-30-isobutyrate, and a precursor to the compound of Formula Ib.

[0057] Detailed instructions Step 1: Preparation of methanol extract (see Figure 2 for procedure overview) Methanol (approximately 800 L) was charged into a nitrogen-filled glass reactor and stirring was initiated. Approximately 100 kg of crushed Entandrophragma caudatum seeds were added. The glass reactor was then evacuated and backfilled with nitrogen. The reactor temperature was set to 40 °C, and the contents were stirred for at least 15–20 hours. Next, a pressurized nitrogen atmosphere was applied, and the mixture was filtered through a polyamide filter cloth (25 μm), and the filtrate was collected in a container. Methanol was then charged into a feed vessel (approximately 100 L), and the methanol was directly charged from the feed vessel to the filter (twice, 50 L each time) without passing through the glass reactor, and the filtrate was collected in a container. The procedure was then repeated, and the mixture was filtered again through a polyamide filter cloth. The filter cake was then dried under vacuum for at least 1 hour. The filtrate was then charged into the glass reactor (total volume approximately 800 L), and the contents were stirred. The methanol solvent was then 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 200 L remained in the glass vessel. Care must be taken not to distill too much methanol, as the residue would become too sticky and difficult to remove from the glass vessel. The jacket temperature was then adjusted to approximately 20-25°C, and the concentrated methanol extract was recovered.

[0058] Step 2: Preparation of an extract composition of Entandrophragma caudatum in ethyl acetate (see Figure 3 for an overview of the procedure) The concentrated methanol extract prepared in step 1 above (approximately 400 L, i.e., two batches of step 1) was charged into a nitrogen-filled glass reactor, the temperature of the reactor was adjusted to 75°C, and the agitator was started. The methanol was removed by distillation under vacuum to give a dry mixture, after which the temperature was adjusted to 20°C. Ethyl acetate (EtOAc) (about 400 L) was then charged to the reactor, followed by water (about 170 L). The reactor temperature was set to 40°C, and the contents of the reactor were stirred for about 30 minutes while maintaining the temperature at 40°C. The agitator was then stopped and the two phases were allowed to separate for 30-60 minutes until phase separation was achieved. The aqueous layer was then discarded. The temperature of the reactor was then adjusted to 55-75°C, and the mixture remaining after water removal was concentrated under vacuum. Distillation was stopped when the volume was reduced to approximately 50 L (i.e., approximately 350 L of distillate had been collected). The Entandrophragma caudatum extract in ethyl acetate was then collected. The extract was stored at 5°C ± 3°C for future use.

[0059] Example 2: Synthesis of Compound of Formula V Summary of steps (see also Figure 4): The starting material for the synthesis of the compound of Formula V comprises a mixture of material extracted from Entandrophragma caudatum seeds and solvent remaining from the extraction procedure. This Entandrophragma caudatum extract composition was prepared according to Example 1. This starting material contains two different compounds, primarily molecules of formula IIa, and possibly about 10% of one or more precursor molecules to compounds of formula Ib, as substances of interest for further synthesis. The two most important molecules of formula IIa identified in the extract composition of Entandrophragma caudatum are: a. Phragmarin 3,30-diisobutyric acid ester b. Phragmarin 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. Compound Ia is then converted to compound Ib in three synthetic steps. Compound Ib is finally converted to compound V in one step.

[0060] Detailed steps: Conversion of Compounds of Formula IIa and Precursors of Formula Ib to Compounds of Formula Ia and Ib Methanolysis: An outline of the methanolysis reaction is shown in Figure 4.

[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 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 equiv.) 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 with a 10-minute time interval between each addition at a temperature below 30 °C (a 5-10 °C exotherm was observed during the sodium methoxide addition). The reaction mixture was stirred at 45 ± 5 °C for 40 h.

[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 <30°C. The reaction mixture was concentrated under reduced pressure at <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) followed by sodium chloride (21 kg, 0.2% w / w) was added and stirred for 15 minutes. The biphasic medium was separated and re-extracted with ethyl acetate (735 L, 7.0 V). The combined organic layer was washed with 10% aqueous sodium chloride (735 L, 7.0 V), separated, and dried over anhydrous sodium sulfate (approximately 21 kg, 0.2% w / w). The organic layer was concentrated under reduced pressure at <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, 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 formula Ia and Ib as a pale yellow solid (all non-polar impurities were washed away using hexane purification). Compounds of formula Ia and Ib were separated from the crude mixture by column chromatography. After column chromatography, approximately 4.17 kg of compound of formula Ia and approximately 2.94 kg of compound of formula Ib were obtained.

[0065] Purification of 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, slowly brought to 25±5°C, and stirred for 6 hours. The solid was collected by filtration 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 give approximately 2.13 kg of compound of Formula Ia.

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

[0067] Purification of 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 h, slowly brought to 25±5° C., and stirred for 6 h. The solid was collected by filtration and washed with IPA (2.9 L, 1.0 V).

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

[0069] The wet solids (1.07 kg) were stirred with ethyl acetate (4.6 L, 3.0 V) at 50±5° C. for 1 hour, then slowly brought to 25±5° C. and stirred for 6 hours. The solids were collected by filtration and washed with ethyl acetate (1.5 L, 1.0 V).

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

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

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

[0073] Workup: After complete consumption of the starting material by TLC, the reaction mixture was acidified to pH 5-6 with 10% aqueous acetic acid (about 8.24 L, 4.0 V) and concentrated at a temperature below 40 °C to remove methanol. The residue was extracted twice with (10.3 L * 2, 5 V * 2). The combined organic layer was washed with brine (8.2 L, 4.0 V), dried over anhydrous sodium sulfate, filtered, and the organic layer was kept as it was for the next step.

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

[0075] Step 2: Oxidation (Compound of Formula IV) To the stirred organic layer (compound of Formula III) was added a suspension of Dess-Martin periodinane (1.72 kg, 1.1 equiv.) in DCM (16.5 L, 8 V) at 0-5 °C. The resulting reaction (white suspension) was stirred at 10-15 °C for 3 h. The reaction progress was monitored by TLC (5% MeOH / DCM + 1 drop of AcOH, visualization: KMnO4 stain).

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

[0077] Step 3: Ring formation (compound of formula Ib) To the stirred organic layer of the compound of Formula IV was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) (0.702 kg, 1.0 equiv.) followed by diisopropylethylamine (DIPEA) (0.957 L, 1.5 equiv.) over 30 minutes at 10±5°C. The resulting reaction was stirred at 10±5°C for 2 hours. Reaction progress was monitored by TLC (10% MeOH / DCM for consumption of starting material, 80% ethyl acetate / hexanes for product elution, visualization: KMnO4 stain).

[0078] Workup: After TLC showed complete consumption of the compound of formula IV, 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 more 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) below 40° C., concentrated to a 3.0 volume level with respect to the compound of Formula Ib, and stirred at 50±5° C. for 1 hour. The reaction 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 give 1.1 kg of a wet solid of the compound of Formula Ib. The wet solid was dried in a vacuum tray dryer at 40±5° C. to give 0.85 kg of the compound of Formula Ib.

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

[0081] [Table 1]

[0082] Synthesis of Compounds of Formula V from Compounds of Formula Ib To a solution of compound of Formula Ib (322 g, 1.0 equiv.) in dry dimethylformamide (DMF) (1.6 L, 5.0 V) was added 4-N,N-dimethylaminopyridine hydrochloride (DMAP.HCl) (91 g), followed by isobutyryl chloride (92 g, 1.5 equiv.) at 25±5° C. The reaction was heated to 60±5° C. and stirred for 6 hours. After 6 hours, DMAP.HCl (45.6 g) was added to the reaction, followed by isobutyryl chloride (61.2 g, 1.0 equiv.) at 60±5° C., after which the reaction was continued for an additional 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 was brought to a temperature of 25±5°C and stirred at this temperature for 4 hours. The solid 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 stirred at 40±5° C. for 2 hours. The solid was collected by filtration 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 give 456 g of crude product of Formula V (crude purity by HPLC: 79.97%).

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

[0085] Ethyl acetate slurry-2: The crude product (249 g) was stirred with ethyl acetate (373 ml, 1.5 V) at 50±5°C for 1 hour. The reaction 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 (0.45 L, 1.0 V). (Wet solid weight: 236.6 g, LOD corrected: 230 g (LOD: 2.6% w / w) (HPLC purity: 98.68%, impurities: RRT 0.68: 1.38%)

[0086] Ethyl acetate slurry-3: The crude product (230 g) was stirred with ethyl acetate (460 ml, 2.0 V) at 50±5°C for 1 hour. The reaction mass 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 (115 ml, 1.0 V). (Wet solid weight: 191.6 g, purity by HPLC: 99.8% with impurities: RRT 0.68: 0.12%)

[0087] The wet solid was dried under reduced pressure at 40±5° C. for not less than 10 hours to give 185.4 g of crude compound of formula V.

[0088] Purify with acetone / purified water to obtain the desired monohydrate: Crude compound of Formula V (181.4 g) was stirred with acetone (1.3 L, 7.0 V) at 45±5°C for 30 minutes to give a clear solution. Purified water (2.8 L, 15.0 V) was added to the reaction mixture over 1 hour and stirred at 45±5°C for an additional 1 hour. 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 give 188 g of a wet product of Formula V monohydrate. The wet solid was dried under reduced pressure at 40±5°C for 16 hours or more and then sieved to give 179 g of compound of Formula V monohydrate.

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

[0090] [Table 2]

[0091] Specific rotation: -49.8° The IR spectrum of the resulting compound is shown in FIG. 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] While the present invention has been described in conjunction with the detailed description thereof, it will be understood that the above description is intended to be illustrative, but not limiting, of the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. [1] A method for obtaining at least one compound of formula Ia and formula Ib, comprising: [ka] wherein R1 is a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and is unsubstituted or substituted with, for example, OH or a halogen (e.g., F), and the method comprises: (i) a composition comprising: at least one compound of formula IIa and formula IIb, [ka] (In the formula, R1 is as defined above, R2 and R3 are independently selected from a linear, branched or cyclic, substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a nicotinyl group; and / or 1. An extract composition from Entandrophragma caudatum comprising at least a 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) providing an extract composition, wherein R1 is methyl; (ii) subjecting the extracted composition and / or optionally the composition from step (i) to one or more distillations and the introduction of a solvent comprising an aliphatic alkanol; (iii) carrying out an alkanollysis reaction in the presence of an aliphatic alcohol by adding an aliphatic metal alkoxide to initiate the reaction, followed by adding an acid, preferably an organic acid such as acetic acid, to quench the alkanollysis reaction, to obtain at least one of the compounds of Formula Ia and Formula Ib. [2] The method according to [1], which is carried out using the 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 phragmarin-3,30-di-isobutyric acid ester, phragmarin-3-isobutyric acid ester-30-propionate, phragmarin-3-nicotinate-30-isobutyric acid ester, and / or precursors of the compound of formula Ib. [4] The method according to any one of [1] to [3], (a) removing the fatty alcohol; (b) adding one or more polar extractants, and optionally (c) adding a water-absorbing agent selected from, for example, sodium sulfate, MgSO4, CaSO4, CaCl2, K2CO3 to remove moisture, thereby obtaining a crude mixture of the compounds; The method further comprises removing polar impurities from said compounds of Formula Ia and Formula Ib by [5] The method according to any one of [1] to [4], further comprising the step of removing the non-polar impurities by dissolving the non-polar impurities in a water-immiscible solvent, preferably hexane or a solvent having a polarity index similar to that of hexane, such as pentane, cyclohexane, or heptane, and discarding the solvent phase containing the non-polar impurities to obtain a crude mixture. [6] The method according to [4] or [5], comprising concentrating the crude mixture obtained or obtainable by [5], and contacting the crude mixture with the water-immiscible solvent according to [5] at least once, 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 separately recovering and purifying the compounds of formula Ia and formula Ib, preferably wherein the final purity of each of the compounds is at least 90%. [8] The method according to any one of [1] to [7], wherein the alkanol decomposition is a metalysis reaction in a methanol solvent, and includes adding methoxide, preferably sodium methoxide. [9] A method for producing a compound of formula Ib from a compound of formula Ia, comprising: (i) reacting a compound of formula Ia with a base strong enough to open the lactone ring but not strong enough to hydrolyze the R group to form a carboxyl group, preferably barium hydroxide octahydrate in methanol, to obtain a compound of formula III: [ka] (ii) reacting a compound of formula III with a selective oxidizing agent, preferably Dess-Martin periodinane, to give a compound of formula IV; [ka] (iii) reacting the compound of formula IV with a coupling agent, preferably a carbodiimide 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 the compound of formula Ib; A method comprising:

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

[11] 1. A process 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: [ka] wherein R2' is a linear, branched or cyclic optionally substituted 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 the compound of formula Ib is obtained according to the method according to any one of [9] or

[10] .

[14] The method according to any one of

[11] to

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

[15] A compound of formula III.

[16] The compound according to

[15] , wherein R1 is methyl.

[17] The compound according to

[15] or

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

[18] Compound of formula IV.

[19] The compound according to

[18] , wherein R1 is methyl.

[20] The compound according to

[18] or

[19] , which is obtained or obtainable by the method of step (ii) of [9]. [twenty one] A monohydrate salt of the 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] 1. An extract composition of Entandrophragma caudatum prepared from seeds of Entandrophragma caudatum, comprising at least one compound according to formula IIa and a precursor to formula Ib, (i) mixing crushed seeds of Entandrophragma caudatum with methanol, filtering, collecting and concentrating 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]

[23] 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 comprises ethyl acetate and the polar solvent comprises water. [twenty five]

[24] 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] The extraction composition according to any one of

[23] to

[25] , comprising at least one of the compounds phragmarin-3,30-di-isobutyric acid ester, phragmarin-3-isobutyric acid ester-30-propionate, and phragmarin-3-nicotinate-30-isobutyric acid ester.

[27] 1. A method for producing an extract composition of Entandrophragma caudatum prepared from seeds of Entandrophragma caudatum, the extract composition comprising at least one compound according to formula IIa and / or precursor of formula Ib, the method comprising: (i) mixing crushed seeds of Entandrophragma caudatum with methanol, filtering, recovering and concentrating to obtain a concentrated methanol extract; (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; A method comprising:

[28]

[27] The method according to

[27] , wherein the low polarity solvent in step (ii) forms an azeotrope with water, and preferably the low polarity solvent comprises ethyl acetate and the high polarity solvent comprises 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] 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 ] a method for producing henicosan-16-yl 2-methylpropanoic acid monohydrate, comprising: [ka] The method comprises: (i) using the method according to any one of [1] to [8] to obtain at least one of a compound of formula Ia in which R1 is methyl and a compound of formula Ib in which R1 is methyl; (ii) separately recovering the compound of formula Ia and converting it to a compound of formula Ib by the method described in [9]; (iii) 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, wherein R2 is isopropyl; A method comprising:

[31] The method of

[30] , further comprising obtaining the monohydrate of the compound of formula VI by carrying out the method of

[14] .

[32] The method according to

[30] or

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

[27] to

[29] and then carrying out the method according to any one of [1] to [8].

[34] The method according to

[33] , further comprising obtaining a compound of formula V by carrying out the method according to

[11] to

[14] .

Claims

1. The following formula III: 【Chemistry 1】 wherein R1 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and is substituted or unsubstituted. Compound.

2. The compound of claim 1, wherein R1 is methyl.

3. A method for preparing a compound of formula III according to claim 1 or 2, comprising: Formula Ia below: 【Chemistry 2】 wherein R1 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and is substituted or unsubstituted. with a base to obtain a compound of formula III.

4. The method of claim 3, wherein the base is barium hydroxide octahydrate in methanol.

5. Formula IV below: 【Transformation 3】 wherein R1 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and is substituted or unsubstituted. Compound.

6. The compound of claim 5, wherein R1 is methyl.

7. A method for preparing a compound of formula IV according to claim 5 or 6, comprising: The following formula III: 【Chemistry 4】 reacting a compound of formula (IV) with an oxidizing agent to obtain a compound of formula (IV).

8. The method of claim 7, wherein the oxidizing agent is Dess-Martin periodinane.

9. Formula V below: 【Transformation 5】 wherein R1 is methyl and R2' is an optionally substituted linear, branched or cyclic alkyl group having 1 to 6 carbon atoms. Monohydrate of the compound.

10. Formula VI below: 【Transformation 6】 10. The monohydrate of claim 9, wherein R2' is isopropyl.

11. Formula V below: 【Transformation 7】 wherein R1 is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted, provided that R1 is not hydrogen, methyl, or ethyl; and R2' is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, optionally substituted. Compound.

12. the below described: 【Transformation 8】 1. A method for producing a compound of formula Ib from a compound of formula Ia of the formula (i) reacting a compound of formula Ia with a base to obtain: 【Chemistry 9】 obtaining a compound of formula III: (ii) reacting the compound of formula III with an oxidizing agent to produce: 【Chemistry 10】 obtaining a compound of formula IV: (iii) reacting the compound of formula IV with a coupling agent in the presence of an organic base to obtain a compound of formula Ib; wherein R1 is a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted.

13. providing a compound of formula Ib, and reacting the compound of formula Ib with an esterifying agent and a base to obtain a compound of formula V: 【Chemistry 11】 wherein R2′ is a linear, branched, or cyclic alkyl group having 1 to 6 carbon atoms, and may be substituted.

13. The method of claim 12, wherein the R2' group is selectively introduced to produce a compound of formula:

14. 14. The method of claim 13, wherein R2' is isopropyl and R1 is methyl, and the compound of formula Ib is reacted with isobutyryl chloride and DMAP-HCl.

15. 15. The method of claim 13 or 14, further comprising purifying the compound of formula V successively with a low polarity solvent and successively with a bipolar solvent, thereby obtaining a solid monohydrate of the compound of formula V.

Images