Process for preparing chiral prostaglandin enol intermediates and intermediate compounds useful in the process

Abstract

TIFF2023512405000068.tif97170 The present invention relates to a process for preparing a chiral prostaglandin enol intermediate of Formula 1, comprising the steps of separating a compound of Formula 16-(R,S)-10 into its diastereomers by fractional crystallization, reducing the 15-oxo group of the compound of Formula 16-(R)-10 to obtain a compound of Formula 15-(R,S),16-(R)-11, subsequently removing the protecting group of the compound of Formula 15-(R,S),16-(R)-11, isolating the compound of Formula 1, and optionally crystallizing the compound of Formula 1. Optionally, undesired isomers formed during fractional crystallization can be epimerized, and additional amounts of the desired isomer can be recovered from the resulting mixture. The present invention also provides novel intermediates useful in this process. The present invention further relates to a process for the fractional crystallization of the compound of formula 16-(R,S)-10.

Description

[Technical Field]

[0001] The present invention relates to a process for the preparation of chiral prostaglandin enol intermediates of formula 1. The present invention further relates to intermediates used in this process and their preparation. [Background technology]

[0002] Chiral enols of formula 1 are potential key intermediates for effective prostaglandin and prostacyclin derivatives useful in human therapy.

[0003] The compound of formula 1 is named 16-methyl-17-(3-methylphenyl)-15-hydroxyenol according to the prostaglandin numbering system. [ka]

[0004] The name of the compound of formula 1 according to Chemical Abstracts is (3aR,4R,5R,6aS)-hexahydro-5-hydroxy-4-[(1E,3R,4R)-3-hydroxy-4-(3-methylphenyl)-1-penten-1-yl]-2H-cyclopenta[b]furan-2-one. [ka]

[0005] The preparation of compounds of formula 1 is described in WO 02 / 04799 and WO 02 / 04799. Compounds of formula 1 are intermediates for the prostaglandin derivatives claimed in said documents.

[0006] According to the known process described in the above document (the same method is described for the preparation of the compound of Formula 1 in the cited application), optically active 2-(R)-(3-methylphenyl)propionic acid (2) was converted to the methyl ester (3) with methanol and sulfuric acid, and the chiral phosphonate (4) was prepared by reacting the methyl ester (3) with dimethylmethylphosphonate (DMMP). The chiral phosphonate (4) was reacted with benzoyl-Corey aldehyde (5) in the presence of sodium hydride base in a Horner-Wadsworth-Emmons (HWE) reaction in dimethoxyethane (DME). The resulting protected enone (6) was reduced to the benzoyl enol (7) with (-)-B-chloro-diisopinocampheylborane ((-)-DIP-Cl) in THF at -40 °C. The benzoyl enol was not purified. The benzoyl group was removed with methanolic potassium carbonate to give the chiral enol of formula 1, which was purified by chromatography on a silica gel column using hexane:ethyl acetate and ethyl acetate as eluents. No crystallization or state of the product was described. [ka]

[0007] The overall yield of the known process using chiral starting materials is 17%, calculated based on benzoyl-Corey aldehyde (5). [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2010029925 A1 Brochure [Patent Document 2] International Publication No. 2011111714 A1 Brochure Summary of the Invention [Problem to be solved by the invention]

[0009] The disadvantages of the known processes are: The formation of the side chain is carried out using the expensive 3-(R)-optically active phosphonate (4); the starting material for the synthesis of phosphonate (4) is the expensive chiral 2-(R)-(3-methylphenyl)propionic acid (2). Under the basic conditions of the HWE reaction (NaH, DME), the chiral side chain can easily racemize, resulting in a decrease in the optical purity of the 6-enone. Reduction of the 15-oxo group of the 6 enone is carried out using a large excess of an expensive chiral reagent ((-)-DIP-Cl) in a cryogenically frozen reaction at -40°C.

[0010] Therefore, there is a need for a process for more economically producing compounds of Formula 1 using milder reaction conditions and more readily available starting materials. [Means for solving the problem]

[0011] We, The benzoyl protecting group of aldehyde (5) was replaced with a p-phenylbenzoyl group to facilitate reduction of the 15-oxo group. After the side chain was constructed, a crystalline enone was obtained, which allowed the separation of the enone diastereomers by fractional crystallization. The side chain formation is carried out using inexpensive racemic phosphonates (3-(R,S)-4), The use of racemic phosphonates in the HWE reaction avoids the disadvantage of using chiral phosphonates, which undergo racemization in basic media, reducing production yield and optical purity. The 15-oxo group of the enone can be reduced with readily accessible reagents, thus avoiding the need for energy-intensive cryogenic refrigeration-related chemistry. Developed a process.

[0012] A key element of our invention is the provision of a novel enone intermediate (16-(R,S)-10) containing a racemic side chain that is crystalline, and the achieved separation of the enone diastereomers by fractional crystallization.

[0013] Thus, the present invention provides a compound of formula 1 [ka] 1. A process for preparing a compound of formula (I), comprising: separating the compound of formula 16-(R,S)-10 into its diastereomers 16-(R)-10 and 16-(S)-10 by fractional crystallization; [ka] reducing the 15-oxo group of the compound of formula 16-(R)-10, thereby obtaining a compound of formula 15-(R,S),16-(R)-11; [ka] removing the protecting groups of the compound of formula 15-(R,S),16-(R)-11 and isolating the compound of formula 1; [ka] and optionally crystallizing the compound of formula 1. The present invention relates to a process including:

[0014] The solvent used for fractional crystallization of the compound of formula 16-(R,S)-10 is preferably C 1~3 The alcohols are selected from alcohols, tert-butyl methyl ether and mixtures thereof. Methanol, tert-butyl methyl ether and mixtures thereof are preferred. Tert-butyl methyl ether is particularly preferred.

[0015] The fractional crystallization of the compound of formula 16-(R,S)-10 is preferably carried out by (a) The compound of formula 16-(R,S)-10 is suspended in a solvent, the suspension is refluxed, the mixture is cooled to 25-35°C, and the mixture is stirred while maintaining the temperature, and the precipitated crystals are filtered, washed, and dried, thereby obtaining crystalline K r1 and obtaining; (b) The filtrate combined with the washings is seeded with crystals of the compound of formula 16-(R)-10, the suspension is cooled to 0-5°C and stirred while maintaining the temperature, and the precipitated crystals are subsequently filtered, washed and dried, thereby obtaining crystalline K r2 and obtaining; Optionally (c) Crystalline K previously filtered r1 is suspended in the filtrate combined with the washings, the suspension is refluxed, the mixture is cooled to 25-35°C and stirred while maintaining the temperature, and the precipitated crystals are filtered, washed and dried, thereby obtaining crystalline K r3 and obtaining; (d) The filtrate combined with the washings is seeded with crystals of the compound of formula 16-(R)-10, cooled to 0-5°C, stirred while maintaining the temperature, and then the precipitated crystals are filtered, washed, and dried, thereby obtaining crystalline K r4 and the step of obtaining Includes.

[0016] The compound of formula 16-(S)-10 is prepared in step (a) and optionally in step (c) by crystalline K r1 and K. r3 and the compound of formula 16-(R)-10 is obtained in step (b) and in optional step (d) from crystalline K r2 and K. r4 is obtained as:

[0017] Crystalline K in step (a) and optionally in step (c) r1 and K. r3 contains mainly the isomer 16-(S)-10. Therefore, crystalline K r1 and K. r3 is also referred to in this description as a compound of formula 16-(S)-10 or 16-(S)-PPB-enone.

[0018] Crystalline K in step (b) and optionally in step (d) r2 and K. r4 contains mainly the isomer 16-(R)-10. Therefore, crystalline K r2 and K. r4 is also referred to in this description as a compound of formula 16-(R)-10 or PPB-enone.

[0019] In step (a) and optionally in step (c), after refluxing, the mixture is preferably cooled to 30-32° C. and stirred at this temperature.

[0020] Stirring in step (a) and optional step (c) at 25-35°C (preferably 30-32°C), and in step (b) and optional step (d) at 0-5°C is preferably continued for about 0.5-3 hours, more preferably about 30-60 minutes.

[0021] To maximize yield, optional steps (c) and (d) are preferably performed as well.

[0022] The obtained crystal K r2 and / or K r4 is optionally, preferably C 1~3 It is recrystallized from a solvent selected from alcohol, tert-butyl methyl ether, and mixtures thereof; or mixtures of the aforementioned solvents with dichloromethane. For recrystallization, a mixture of methanol and dichloromethane or a mixture of tert-butyl methyl ether and dichloromethane is particularly preferred, where the proportion of dichloromethane is preferably at most 30% by volume; for example, a 5:1 mixture of methanol:dichloromethane or a 5:1 mixture of tert-butyl methyl ether:dichloromethane.

[0023] Another important aspect of the present invention is that we have found that the "wrong" 16-(S)-isomer obtained by fractional crystallization can be easily epimerized. Therefore, to increase the yield, the obtained crystalline K r1 or K r3 is preferably epimerized and the above fractional crystallization is repeated.

[0024] The epimerization can be carried out under either acidic or basic conditions, for example, with triethylamine in ethyl acetate in the presence of silica gel, or with aluminum oxide in ethyl acetate, or with para-toluenesulfonic acid in toluene.

[0025] Preferably, the epimerization is carried out in toluene with para-toluenesulfonic acid at about 65-75° C. by stirring for about 15-20 hours, or in ethyl acetate in the presence of silica gel with triethylamine at about 55-65° C. by stirring for about 10-14 hours.

[0026] The 15-oxo group of compounds of formula 16-(R)-10 can be reduced using methods known in the art, preferably with an aqueous solution of sodium borohydride in the presence of silica gel.

[0027] The protecting groups of compounds of formula 15-(R,S)-16-(R)-11 can be removed using known methods, such as by methanolysis in the presence of potassium carbonate, or by using NaOMe / methanol, NaOH or other bases in a suitable aqueous-organic solvent mixture, or by mineral acids in alcohols, etc.

[0028] After deprotection, the desired product is isolated. Isolation can be carried out using known methods, such as crystallization or chromatography, or a combination thereof. Preferably, chromatography is applied, which allows the desired 15-epimer to be separated from undesired and other impurities in a single step. Chromatography can be carried out, for example, on a silica gel column using a dichloromethane:acetone eluent, preferably a 7:1 mixture of dichloromethane:acetone, followed by a 2:1 mixture.

[0029] The product-containing fractions are preferably combined and evaporated, thereby obtaining the product in the form of an oil. Optionally, the evaporation residue is crystallized, thereby obtaining the crystalline hydroxyenol of formula 1. The hydroxyenol is preferably crystallized from an ether-type solvent or solvent mixture, for example, from a mixture of tert-butyl methyl ether and diisopropyl ether.

[0030] Compounds of formula 16-(R,S)-10 are preferably prepared by reacting an aldehyde of formula 9 with a racemic phosphonate of formula 3-(R,S)-4: [ka]

[0031] The above reaction, known in the literature as Horner-Wadsworth-Emmons (HWE), can be carried out using a variety of bases; preferably using potassium hydroxide base at about 20-25°C, or sodium hydride at about 0-10°C.

[0032] One of the starting materials for the HWE reaction, the aldehyde of formula 9, is preferably prepared by oxidation of the PPB-Corey lactone of formula 8 in a manner known in the art, for example with dimethyl sulfoxide and, for example, dicyclohexylcarbodiimide in the presence of phosphoric acid, or with sodium hypochlorite in the presence of a catalyst containing a nitroxyl radical, preferably with sodium hypochlorite in the presence of a catalyst containing a nitroxyl radical: [ka]

[0033] The compound of formula 8 (PPB-Corey lactone) is a plentiful and easily accessible compound in prostaglandin chemistry, as it is the starting material for many prostaglandin derivatives.

[0034] Another starting material for the HWE reaction is racemic phosphonate (3-(R,S)-4). The optically active phosphonate of formula 4 and the racemic phosphonate of formula (3-(R,S)-4) are known compounds (WO 2011111714 A1, WO 2010029925 A1). Chiral phosphonates can be prepared from expensive chiral carboxylic acids by costly processes (a study published in J. Chem. Soc., Perkin Trans. 2, 1998, pp. 1767-1775 highlights the difficulty of obtaining the starting chiral carboxylic acid itself), whereas racemic compounds can be prepared from inexpensive racemic carboxylic acids by inexpensive processes.

[0035] Two process variants for the preparation of the racemic compound are provided that are suitable for industrial scale production.

[0036] Thus, the racemic phosphonates of formula (3-(R,S)-4) can be advantageously prepared according to variant A) or B) by the following reaction scheme: [ka] (where transformation A) is alkylating the methylphenylacetic acid of formula 12, preferably with methyl iodide in the presence of a strong base, such as butyllithium or lithium diisopropylamide; converting the resulting methylphenylpropionic acid of formula 13 to the methyl ester of formula 14 using methanol in the presence of an acid, such as hydrochloric acid or sulfuric acid; Subsequently, the methyl ester of formula 14 is reacted with dimethylmethylphosphonate (DMMP) in the presence of a strong base, such as butyllithium or lithium diisopropylamide, thereby obtaining the racemic phosphonate of formula 3-(R,S)-4. Includes; Deformation B) is converting methylphenylacetic acid of formula 12 to methylphenylacetic acid methyl ester of formula 15 using methanol in the presence of an acid, such as hydrochloric acid or sulfuric acid; alkylating the methylphenylacetic acid methyl ester of formula 15, preferably with methyl iodide in the presence of a strong base, such as butyllithium or lithium diisopropylamide, thereby obtaining the methyl ester of formula 14; Subsequently, reacting the methyl ester of formula 14 with dimethylmethylphosphonate (DMMP) in the presence of a strong base, such as butyllithium or lithium diisopropylamide, thereby obtaining the racemic phosphonate of formula 3-(R,S)-4. (including It is prepared by

[0037] A further object of the present invention is to provide the following novel intermediate compounds: Formula 16-(R,S)-10: [ka] The compound Formula 16-(R)-10: [ka] The compound Formula 16-(S)-10: [ka] The compound and Formulas 15-(R,S), 16-(R)-11: [ka] is a compound of

[0038] These compounds are useful as intermediates for the preparation of prostaglandin and prostacyclin derivatives.

[0039] A further object of the present invention is to provide a method for the preparation of a 1~3 1. A process for fractional crystallization of the compound of formula 16-(R,S)-10 using a solvent selected from alcohols, tert-butyl methyl ether and mixtures thereof, preferably selected from methanol, tert-butyl methyl ether and mixtures thereof, comprising: Preferably, (a) The compound of formula 16-(R,S)-10 is suspended in a solvent, the suspension is refluxed, and then the mixture is cooled to 25-35°C and stirred while maintaining the temperature, followed by filtering, washing, and drying the precipitated crystals, thereby obtaining crystalline K r1 and obtaining; (b) The filtrate combined with the washings is seeded with crystals of the compound of formula 16-(R)-10, the suspension is cooled to 0-5°C and stirred while maintaining the temperature, and the precipitated crystals are subsequently filtered, washed and dried, thereby obtaining crystalline K r2 and obtaining; Optionally (c) Crystalline K previously filtered r1 is suspended in the filtrate combined with the washings, the suspension is refluxed, the mixture is then cooled to 25-35°C and stirred while maintaining the temperature, and the precipitated crystals are subsequently filtered, washed and dried, thereby obtaining crystalline K r3 and obtaining; (d) The filtrate combined with the washings is seeded with crystals of the compound of formula 16-(R)-10, cooled to 0-5°C, stirred while maintaining the temperature, and then the precipitated crystals are filtered, washed, and dried, thereby obtaining crystalline K r4 and the step of obtaining Including, where: The compound of formula 16-(S)-10 is prepared in step (a) and optionally in step (c) by crystalline K r1 and K. r3 and the compound of formula 16-(R)-10 is obtained in step (b) and in optional step (d) from crystalline K r2 and K. r4 is obtained as It is a process.

[0040] Both isomers are preferably C 1~3 It can be further purified by recrystallization from a solvent selected from alcohols, tert-butyl methyl ether and mixtures thereof; or from mixtures of said solvents with dichloromethane; preferably from a mixture of methanol and dichloromethane, or from a mixture of tert-butyl methyl ether and dichloromethane.

[0041] A further object of the present invention is a process for the preparation of compounds of formula 16-(S)-10, comprising (a) Reacting a compound of formula 16-(R,S)-10 with C 1~3 The mixture is then cooled to 25-35°C and stirred while maintaining the temperature. The precipitated crystals are then filtered, washed and dried, thereby obtaining crystalline K r1 and obtaining; Optionally (b) seeding the filtrate combined with the washings with crystals of the compound of Formula 16-(R)-10, cooling the suspension to 0-5°C, stirring while maintaining the temperature, and subsequently filtering the precipitated crystals; (c) Crystalline K previously filtered r1 is suspended in the filtrate, the suspension is refluxed, the mixture is cooled to 25-35°C, and stirred while maintaining the temperature, and the precipitated crystals are filtered, washed and dried, thereby obtaining crystalline K r3 and obtaining; Optionally, the resulting crystalline K r1 or K r3 Dichloromethane and C 1~3 recrystallization from a mixture of a solvent selected from an alcohol, tert-butyl methyl ether and mixtures thereof; preferably from a mixture of methanol and dichloromethane, or from a mixture of tert-butyl methyl ether and dichloromethane, thereby obtaining the compound of formula 16-(S)-10. It is a process including:

[0042] Another object of the present invention is to provide a compound of formula I having major peaks in its powder X-ray diffraction pattern obtained using a copper anode at 6.2; 11.4; 14.5; 15.6; 17.4; 18.1; 18.6; 20.4; 23.2 and 24.9 ±0.2 degrees 2-theta. [ka] is a crystalline form of the compound [Brief explanation of the drawings]

[0043] [Figure 1] 1 shows the DSC curve of 16-(R,S)-PPB-enone prepared according to Example 1. [Figure 2] 1 shows the powder X-ray diffraction pattern of 16-(R,S)-PPB-enone prepared according to Example 1. [Figure 3] 1 shows the DSC curve of 16-(R)-PPB-enone prepared according to Example 3.a. [Figure 4] 1 shows the powder X-ray diffraction pattern of 16-(R)-PPB-enone prepared according to Example 3.a. [Figure 5]1 shows the DSC curve of 16-(R)-PPB-enone prepared according to Example 3.b. [Figure 6] 1 shows the powder X-ray diffraction pattern of 16-(R)-PPB-enone prepared according to Example 3.b. [Figure 7] 1 shows the DSC curve of 16-(S)-PPB-enone prepared according to Example 4. [Figure 8] 1 shows the powder X-ray diffraction pattern of 16-(S)-PPB-enone prepared according to Example 4. [Figure 9] 1 shows the DSC curve of the crystalline hydroxyenol prepared according to Example 7. [Figure 10] 1 shows the powder X-ray diffraction pattern of the crystalline hydroxyenol prepared according to Example 7. DETAILED DESCRIPTION OF THE INVENTION

[0044] Terms and abbreviations used in this description As used herein, in reference to an asymmetric carbon atom: The R symbol means that the bonding order of the substituents is clockwise according to the Cahn-Ingold-Prelog rule. The S symbol means that the bonding order of the substituents is counterclockwise according to the Cahn-Ingold-Prelog rule. The symbols R and S mean that the bonding order of the substituents according to the Cahn-Ingold-Prelog rule is clockwise and counterclockwise in equal proportions.

[0045] Enantiomers are those stereoisomeric molecules in which all asymmetric carbon atoms have opposite configurations (ie, they are mirror images of each other).

[0046] Diastereomers are those stereoisomeric molecules that are not mirror images of one another.

[0047] Epimers are those diastereomers that differ only in the configuration of only one chiral center.

[0048] In this description, when ratios are given in relation to liquids, they are meant to be volume / volume ratios.

[0049] Preferably, the starting material for the complete process is Corey lactone (8) containing a PPB protecting group, which is oxidized in the first reaction step to aldehyde (9), which is reacted with 3-(R,S)-4 racemic phosphonate in a Horner-Wadsworth-Emmons (HWE) reaction.

[0050] The starting material for this process can be directly the aldehyde of formula 9. However, the aldehyde is less stable and the PPB-Corey lactone 8 is more readily available and easier to store, making the use of the latter more convenient.

[0051] The resulting enone diastereomers (16-(R,S)-10) are separated by fractional crystallization.

[0052] The undesired, "wrong" isomer (16-(S)-10) can be epimerized in acidic or basic media. After reaching an approximately 1:1 isomer ratio of 16-(R)-10:16-(S)-10, additional amounts of the desired isomer, PPB-enone, can be obtained by fractional crystallization.

[0053] The crystals of PPB-enone are combined and the 15-oxo group is reduced to a hydroxyl group. After deprotection of the p-phenylbenzoyl-protected enol (15-(R,S),16-(R)-11), the desired compound of formula 1 is isolated. [ka]

[0054] Starting from PPB-Corey lactone, the individual steps of the overall process are detailed below.

[0055] Step 1: Oxidation The primary hydroxyl group of the PPB-protected Corey lactone (8) can be oxidized by any known oxidation method that selectively converts a primary hydroxyl group to an aldehyde. Oxidation methods include, for example: Chromium-containing oxidizing agents such as Collins' reagent (chromium trioxide-pyridine complex, CrO3·Py2), pyridinium dichromate, or pyridinium chlorochromate Hypervalent iodine reagents such as Dess-Martin oxidation Activated dimethyl sulfoxide (DMSO), such as Swern oxidation and Pfitzner-Moffatt oxidation Sodium hypochlorite (aqueous solution or crystalline pentahydrate) in the presence of a catalyst containing a nitroxyl radical [such as TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) or AZADO (2-azaadamantane-N-oxyl)] may include:

[0056] The oxidation of PPB-Corey lactone is carried out by the Pfitzner-Moffatt oxidation system containing activated dimethyl sulfoxide-DCC (dicyclohexylcarbodiimide) and Anelli oxidation using sodium hypochlorite-TEMPO oxidant.

[0057] Pfitzner-Moffatt oxidation (J.Am.Chem.Soc.,1963,85,3027-3028): [ka] Anelli oxidation (J.Org.Chem.,1987,52,2559-2562): [ka]

[0058] Both oxidations are suitable for the preparation of PPB-Corey aldehyde (9). It is not necessary to isolate the aldehyde before the Horner-Wadsworth-Emmons (HWE) reaction.

[0059] However, the Anelli oxidation is considered preferable because the Pfitzner-Moffatt oxidation procedure produces highly unpleasant by-products, dimethyl sulfide and DCU (dicyclohexylurea), which have an unpleasant odor. Removal of DCU requires costly and time-consuming column chromatography when purifying PPB-enone, because DCU, which crystallizes well, contaminates the crystalline PPB-enone.

[0060] After oxidation, it is not necessary to isolate the sensitive aldehyde from the reaction mixture; preferably, the resulting reaction mixture is carried on to the next reaction step.

[0061] Step 2: HWE reaction Corey aldehyde (9), containing a p-phenylbenzoyl protecting group, is reacted with racemic phosphonate (3-(R,S)-4) using the HWE reaction (R. Bruckner, Organic Mechanism, M. Harmata, ed., Springer-Verlag Berlin Heidelberg 2010). There are several bases available in the literature for the formation of the phosphonate anion; among these, sodium hydride and potassium hydroxide were chosen for our experiments. [ka]

[0062] In both cases, the formation of the phosphonate anion was adequate with both bases, as the HWE reaction between the phosphonate anion and PPB-Corey aldehyde (9) was complete. However, from a scale-up perspective, the use of potassium hydroxide solution is preferred.

[0063] Potassium hydroxide solutions are much easier to handle than sodium hydride dispersions, which are sensitive to air humidity, so an anhydrous medium is not required, and the anion formation and HWE reaction require less cooling energy than when using NaH base.

[0064] The yield of 16-(R,S)-PPB-enone (16-(R,S)-10) was highest when oxidation was carried out by the Anelli method and potassium hydroxide solution was used to form the phosphonate anion. In this case, the yield of 16-(R,S)-PPB-enone, crystallized from isopropanol, was 85%. The product contains PPB-enone (16-(R)-10) (the "correct") and its epimer, 16-(S)-PPB-enone (16-(S)-10) (the "incorrect") isomer in a 1:1 ratio. [ka]

[0065] Step 3: Fractional crystallization It is well known in the chemical literature that diastereomers have different physical properties (e.g., https: / / en.wikipedia.org / wiki / Diastereomer, downloaded May 20, 2019). Therefore, early in the development process, we attempted to separate the PPB-enone diastereomers by column chromatography. Although we did not find an effective, industrially applicable chromatographic separation in good yield, we did obtain pure epimers by this technique. Both isomers (16-(R)-10 and 16-(S)-10) obtained after chromatographic separation were crystalline.

[0066] Subsequently, several solvents for fractional crystallization of diastereomers were tried, and C 1~3 Alcohols and tert-butyl methyl ether have been found to be suitable for this purpose.

[0067] The solubilities (g / 100 ml) of the PPB-enone isomers in some of the solvents in which crystallization has been attempted are shown below.

[0068] [Table 1]

[0069] Based on solubility data, C 1~3 Fractional crystallization in alcohol and tert-butyl methyl ether (TBME) can be carried out in relatively good yields (however, it should be noted that diisopropyl ether (DIPE), which is also an ether, is not suitable from the standpoint of solubility). Methanol and tert-butyl methyl ether, as well as mixtures of these solvents, are particularly preferred.

[0070] After repeating the crystallization procedure several times, it was found that in the case of methanol, the first-generation product crystallized with a 16-(S)-PPB-enone content higher than 2 or 3 percent in some batches. Experiments showed that the use of TBME made this technique more robust; no exceptions were observed with methanol. An additional advantage is that the "right" isomer is slightly more soluble in TBME than in methanol, while the 16-(S)-derivative is equally insoluble in both solvents at room temperature. This may be the reason why we obtained a much cleaner product. Already in the first generation, the 16-(S) impurity was only about 2.5%, which decreased to about 0.5% after recrystallization. This is highly advantageous, since the total amount of impurities in the final product cannot exceed 1.5%. Thus, fewer crystallization steps result in a purer product.

[0071] Additionally, removal of the 16-(S) impurity from the final product is much more difficult and requires multiple recrystallizations of the hydroxyenol (1), so it is particularly advantageous to obtain a purer product initially.

[0072] Comparison of fractional crystallization in TBME and methanol:

[0073] [Table 2]

[0074] Based on the above, tert-butyl methyl ether is a particularly preferred solvent for fractional crystallization, especially on an industrial scale.

[0075] The 16-(S)-PPB-enone (16-(S)-10), which is less soluble in both alcohol and TBME, precipitates first during fractional crystallization at about 30°C.

[0076] Fractional crystallization is preferably carried out by crystallizing 16-(R,S)-PPB-enone in tert-butyl methyl ether or C for about 15 to 60 minutes. 1~3 This is carried out by refluxing in an alcohol or a mixture thereof, and then the reaction mixture is cooled to about 25-35°C, preferably about 30-32°C, and stirred for an additional 0.5-3 hours, preferably about 30 minutes, while maintaining the temperature.

[0077] Precipitated crystals of 16-(S)-PPB-enone (K r1 ) is filtered, the filtrate is seeded with PPB-enone crystals, cooled to about 0-5°C, and the desired isomer (16-(R)-isomer) is allowed to crystallize over a period of 0.5-3 hours, preferably about 1 hour (K r2 ).

[0078] PPB-enone seeds were obtained by column chromatography of the diastereomeric mixture on a silica gel column using chloroform: tert-butyl methyl ether as the eluent.

[0079] Preferably, filtered K r1 Additional 16-(R)-isomer, PPB-enone, can be recovered from the crystallization mixture by adding the crystals to the mother liquor, reheating the suspension to reflux, and repeating the crystallization process.r3 ) is crystallized at about 25-35°C, and then the mother liquor is seeded with PPB-enone crystals and cooled to 0-5°C to obtain second generation PPB-enone crystals (K r4 ).

[0080] Based on experimental data, the use of methanol or methanol-containing crystallization solvent mixtures requires more recrystallization to yield product of the desired epimeric purity.

[0081] Fractional crystallization yields from TBME based on data from the following specific example: PPB-enone(K r2 and K. r4 Yield of 16-(R,S)-PPB-enone (16-(R,S)-10) combined: calculated based on the starting 16-(R,S)-PPB-enone (16-(R,S)-10): 31%, based on the PPB-enone (16-(R)-10) contained therein: 62%.

[0082] Combined K r2 and K. r4 The crystals can be recrystallized from a TBME:dichloromethane mixture. The recrystallization yield is 98%.

[0083] 16-(S)-PPB-enone(K r3 Yield (amount of 16-(R,S)-PPB-enone): 48.5% calculated based on the starting 16-(R,S)-PPB-enone (16-(R,S)-10).

[0084] Epimerization A further advantage of our process is that the "wrong" isomer, 16-(S)-PPB-enone (16-(S)-10), can be epimerized in both basic and acidic media.

[0085] Regarding epimerization, it is noteworthy that, because the molecule is sensitive to bases and even acids (decomposition / elimination can be expected), it was surprisingly found that the compound can be epimerized in acceptable yields. This is true for both acidic and basic conditions. The epimerization equilibrium is at an approximately 1:1 isomer ratio. From the reaction mixture containing the PPB-enone diastereomers in a 1:1 ratio, additional PPB-enone can be obtained by fractional crystallization. The yield increase that can be achieved in this way by epimerization is approximately 12-17% calculated based on 16-(R,S)-PPB-enone (24-34% based on 16-(S)PPB-enone), depending on the conditions used.

[0086] Repeated epimerization of 16-(S)-PPB-enone can significantly increase the yield of PPB-enone (theoretically, up to 100%), but by-products formed during the epimerization significantly reduce the maximum yield of PPB-enone. In our experience, repeated epimerization does not result in a noticeable increase in yield. [ka]

[0087] Considering the PPB-enone crystals obtained by epimerization, the yield of PPB-enone is 47% (calculated based on 16-(R,S)-PPB-enone).

[0088] The combined PPB-enone crystals can be recrystallized from a dichloromethane:TBME mixture in 98% yield to further enhance their purity, if necessary.

[0089] Step 4: Reduction The next step is the reduction of the 15-oxo group of PPB-enone (16-(R)-10). During the reduction, in addition to the expected product, PPB-enol (15-(R),16-(R)-11), an epimeric impurity, 15-(S)-PPB-enol (15-(S),16-(R)-11), is also formed. [ka]

[0090] The reduction can be carried out according to methods conventional in the art.

[0091] Reduction with aqueous sodium borohydride in the presence of silica gel (U.S. Pat. No. 6,482,959 B1) showed that the expected isomer was produced in large amounts. After reduction, the isomer ratio in the crude product was PPB-enol:15-(S)-PPB-enol = 6:4.

[0092] After reduction, the quenched and worked-up reaction mixture was carried to the next reaction step without separation of the diastereomers.

[0093] Step 5: Deprotection, isolation and crystallization The final transformation is the removal of the p-phenylbenzoyl protecting group, which can be carried out by known methods commonly used in prostaglandin chemistry, for example, by methanolysis in the presence of potassium carbonate. Other reagents, such as NaOMe / methanol, NaOH or other bases in suitable aqueous-organic solvent mixtures, or mineral acids in alcohols, can also be used.

[0094] The desired product is then isolated from the resulting mixture. Isolation can be carried out using methods known in the art, such as crystallization or chromatography, or a combination thereof. Preferably, chromatography is applied, which allows for the separation of the desired 15-epimer from undesired epimers and from other impurities in one step.

[0095] Chromatography is preferably carried out on a silica gel column using, for example, dichloromethane:acetone as eluent. Fractions containing the desired epimer are combined and evaporated.

[0096] The evaporation residue corresponds to the hydroxyenol product of formula 1.

[0097] The hydroxyenol 1 can also be obtained in crystalline form, if desired, by crystallization of the residue from an ethereal solvent or ethereal solvent mixture, preferably from a mixture of tert-butyl methyl ether and diisopropyl ether. Yield: 48% hydroxyenol (1) in the form of an oil [calculated based on PPB-enone (16-(R)-10)] Yield: 35% crystalline hydroxyenol (1) [calculated based on PPB-enone (16-(R)-10)]

[0098] Preparation of racemic phosphonate (3-(R,S)-4) used as starting material The racemic phosphonate (3-(R,S)-4) required for the HWE reaction can be prepared from known compounds by known chemical steps. For our experiments, the racemic phosphonate (3-(R,S)-4) was prepared in two ways, starting from 3-methylphenylacetic acid.

[0099] According to Method A, methylphenylacetic acid (12) was alkylated in the first step, and the resulting methylphenylpropionic acid (13) was converted to the methyl ester (14), which was reacted with dimethylmethylphosphonate (DMMP) in the presence of a strong base to give the racemic phosphonate (3-(R,S)-4).

[0100] According to Method B, the first two steps are reversed, i.e., the starting methylphenylacetic acid (12) is first esterified with methanol, and the resulting methylphenylacetic acid methyl ester (15) is alkylated to give methylphenylpropionic acid methyl ester (14). [ka]

[0101] Method A) Alkylation of methylphenylacetic acid (12) was carried out with methyl iodide using butyllithium or lithium diisopropylamide (LDA) as the base. Conversions were greater than 99.5% for both bases, but for industrial feasibility, lithium diisopropylamide is preferred because it does not require cryogenic freezing and is safer to scale up.

[0102] Esterification of methylphenylpropionic acid (13) was carried out with methanol in the presence of concentrated hydrochloric acid or concentrated sulfuric acid. Conversions were greater than 95% for both acids, so the use of less corrosive sulfuric acid may be preferable.

[0103] The phosphonate (3-(R,S)-4) was prepared by reacting methylphenylpropionic acid methyl ester (14) with dimethylmethylphosphonate (DMMP) in the presence of a strong base. The base used in this case was also butyllithium or lithium diisopropylamide. The use of butyllithium produced fewer by-products, but the reaction required cryogenic freezing, whereas the reaction temperature for the lithium diisopropylamide base was 0-10°C (J. Org. Chem. 2009, 74, 7574-7576).

[0104] Method B) In Method B), methylphenylacetic acid (12) was esterified in the first reaction step. The esterification was carried out in methanol in the presence of concentrated sulfuric acid. The resulting methylphenylacetic acid methyl ester (15) was alkylated with methyl iodide in the presence of LDA.

[0105] The thus obtained methylphenylpropionic acid methyl ester (14) was converted to the phosphonate (3-(R,S)-4) as described in Method A).

[0106] The above methods (both A and B) provide an industrially applicable process for the preparation of 3-(R,S)-4.

[0107] The yield of the compound of formula 3-(R,S)-4 (Route A, Examples 8.1.2, 8.1.3 and 8.1.5) calculated based on methylphenylacetic acid was 90.2% and (Route B, Example 8.2): 92.9%.

[0108] In summary, a novel process is disclosed for the preparation of optically active hydroxy enols of formula 1. The hydroxy enols of formula 1 can be valuable intermediates in the synthesis of prostaglandin and prostacyclin end products and derivatives, such as those described in WO2010029925 A1 and WO2011111714 A1.

[0109] We have found that a novel intermediate, 16-(R,S)-PPB-enone, can be prepared from readily available starting materials, which is crystalline and can be separated into diastereomers by fractional crystallization.

[0110] We also found that the undesired isomer, 16-(S)-PPB-enone, can be epimerized in both basic and acidic media, resulting in a 1:1 diastereomeric ratio of PPB-enone to 16-(S)-PPB-enone in the equilibrium reaction mixture.

[0111] After epimerization, fractional crystallization can provide additional amounts of the desired isomer, PPB-enone.

[0112] PPB-enone and its 16-epimers, 16-(S)-PPB-enone and 16-(R,S)-PPB-enone, are novel compounds.

[0113] We found that PPB-enone (16-(R)-10) can be advantageously reduced with aqueous sodium borohydride in the presence of silica gel, forming diastereomers in a ratio of 6:4:PPB-enol:15-(S)-PPB-enol during the reduction.

[0114] PPB-enol and its 15-epimers, 15-(S)-PPB-enol and 15-(R,S)-PPB-enol, are novel compounds.

[0115] Preferably, the compound of formula 16-(R,S)-10 can be prepared from optically active Corey lactone (8) containing a p-phenylbenzoyl (PPB) protecting group, which is available in large quantities in prostaglandin chemistry, and from the racemic phosphonate of formula 3-(R,S)-4, which in turn can be easily prepared from inexpensive starting materials, by oxidation of the primary hydroxyl group of PPB-Corey lactone (8) and reaction of the thus obtained PPB-Corey aldehyde (9) with the racemic phosphonate (3-(R,S)-4) in a Horner-Wadworth-Emmons (HWE) reaction. The product, 16-(R,S)-PPB-enone, contains diastereomers in a 1:1 ratio, differing in the configuration of the 16-methyl group.

[0116] With respect to the yield of the present process and known processes, we consider the following: Preparation of phosphonates of formula 4 and racemic phosphonates of formula 3-(R,S)-4 (starting materials used to form the side chains): - known process, chiral synthesis (Examples 1 and 2 of EP 2343292): Yield of chiral phosphonate of formula 4 based on 2-(R)-(3-methylphenyl)propionic acid of formula 2: 75.9% - the racemic synthesis described herein: Route A) (Examples 8.1.2, 8.1.3, and 8.1.5): Yield of racemic phosphonate of formula 3-(R,S)-4 based on racemic (3-methylphenyl)propionic acid of formula 13: 90.2% Route B) (Example 8.2): Yield of racemic phosphonate of formula 3-(R,S)-4 based on methylphenylacetic acid of formula 12: 92.9% Pay attention to.

[0117] By the process described in this application, racemic phosphonates can be prepared from racemic starting materials in higher yields than known chiral phosphonates from the corresponding chiral starting materials (instead of 75.9%, the yields are 90.2% and 92.9%, respectively; in the latter case, the yield is calculated from the earlier starting material).

[0118] Preparation of hydroxy enols of formula 1 from phosphonates of formula 4 and racemic phosphonates of formula 3-(R,S)-4, respectively: - known process (EP 2343292 examples 3-5): Starting from the chiral phosphonate of formula 4: 15.3% - Process according to the invention [Example 1.b. (taking into account the yield based on 3-(R,S)-4), (2+5.4), 6. and 7, without crystallization]: Starting from the racemic phosphonate of formula (3-(R,S)-4): 14.8% For the appropriate isomer, i.e. based on the compound of formula 4: 29.6%

[0119] Starting from racemic starting material, we have achieved nearly the same yield as that obtained starting from chiral starting material according to known processes, i.e., from a given amount of racemic starting material, one can produce nearly the same amount of chiral target compound as from the same amount of chiral starting material by known processes. When we calculate with respect to the "proper" isomer, the yield nearly doubles from 15.3 to 29.6.

[0120] Preparation of Hydroxy Enols of Formula 1 from Chiral or Racemic (3-Methylphenyl)propionic Acid (the Two Steps Above Together) - known process (EP 2343292 examples 1 to 5): Based on 2-(R)-(3-methylphenyl)propionic acid (compound of formula 2): 11.6% - Process according to the invention [Examples 8.1.3., 8.1.5., 1.b (taking into account the yield based on 3-(R,S)-4)), (2+5.4), 6. and 7, without crystallization]: Based on 2-(R,S)-(3-methylphenyl)propionic acid (compound of formula 13): 13.3% For the appropriate isomer, i.e. based on the compound of formula 2: 26.6%

[0121] Starting from racemic starting material, we exceeded the yields reported for chiral starting material: the yield more than doubled from 11.6% to 26.6% when calculated based on the "appropriate" isomer.

[0122] Preparation of hydroxy enols of formula 1 from "primary" prostaglandin starting materials: - known process (EP 2343292 examples 3-5): Based on benzoyl-Corey aldehyde (5): 17.0% - Process according to the invention [Examples 1.b, (2+5.4), 6. and 7, without crystallization]: based on PPB-Corey lactone (8): 19.2%

[0123] A 2.2 percentage point increase in yield was achieved, which corresponds to a relative increase of 13% (this value would be even higher if we could provide data on the aldehyde, but the sensitive aldehyde was not isolated from the reaction mixture because we would have considered another reaction step).

[0124] We note that in principle half of the material fails to form the desired end product due to incorporation of the racemic side chain into the starting material, so if we performed all the steps in the same way with the same efficiency, theoretically the yield would be half that of the known process, i.e. 8.5% (compared to the 19.2% we achieved).

[0125] However, by incorporating a racemic side chain and separating the desired isomer at a later intermediate in the process (by fractional crystallization), we have achieved and even exceeded the production of known processes, and we have greatly improved the overall yield of the process. This improvement in production is likely due to: - We avoid the loss of chiral side chains due to racemization, - separation of the racemic protected enone intermediate into its epimers by fractional crystallization is efficient (in addition, crystals containing a higher proportion of the undesired isomer are epimerized and further fractional crystallization yields more of the desired isomer); - Reduction of the 15-oxo group is carried out more efficiently (and under milder reaction conditions) This is due to several factors, such as:

[0126] Regarding the complete process starting from PPB-Corey lactone (8), we note the following: It is more economical than known processes because only one of the starting materials, the optically active PPB-Corey lactone (8), is available in large quantities. Costly resolution of the racemic phosphonate (3-(R,S)-4) or its expensive stereoselective synthesis is not required. The overall yield is higher than that of known processes. The hydroxyenol (1) prepared according to our process preferably crystallizes, whereas in known processes, the product does not crystallize; its appearance or state of matter is not described or characterized. However, crystalline intermediates are easier to handle and generally more stable than other forms (e.g., oils). The diastereomeric mixture containing the p-phenylbenzoyl protecting group (16-(R,S)-PPB-enone) is crystalline, and separation of the crystalline epimers of the diastereomeric enone is possible by fractional crystallization. It is noteworthy that the differences between the 16-(R,S)-PPB-enone epimers are very small, consisting only of small methyl groups in different spatial positions, and therefore it is surprising that the epimers can be separated by fractional crystallization. It has been found that the reduction of the 15-oxo group occurs under mild conditions, so that it is not necessary to use the chiral reagents and the -40°C application methods described in WO2010029925 A1 and WO2011111714 A1.

[0127] The following non-limiting examples serve to illustrate the present invention.

[0128] X-ray, DSC and NMR recordings were taken using the following parameters: X-ray diffractogram: Equipment:Panalytical X'pert Pro Start position [°2Theta]:2.0084 End position [°2Theta]: 39.9864 Measurement temperature [℃]:25.00 Anode material: Cu K-Alpha1[Å]:1.54060 K-Alpha2[Å]:1.54443 DSC: Equipment: METTLER TOLEDO DSC1 STARe System, Stare basic V9.30 Method: Starting temperature: 30℃ End temperature: 150℃ Heating rate: 5℃ / min Amount: 2-6 mg, perforated aluminum crucible (40 μl) NMR: Equipment:Bruker Avance III 500MHz Solvent: DMSO [Example]

[0129] Example 1: Preparation of 16-(R,S)-PPB-enone Oxidation and HWE Reactions [(3aR,4R,5R,6aS)-4-[(E)-4-(m-tolyl)-3-oxo-pent-1-enyl]-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl]4-phenylbenzoate [ka]

[0130] Example 1.a Oxidation: Pfitzner-Moffatt oxidation 5.94 kg of p-phenylbenzoyl Corey lactone (PPB-Corey lactone) (8) was suspended in 41 kg of distilled toluene, and 9.0 kg of N,N-dicyclohexylcarbodiimide was added. Then, under an inert atmosphere, 3.4 L of a 0.75 M solution of phosphoric acid in dimethyl sulfoxide (DMSO) was added. After stirring for 30 minutes, the reaction mixture was heated to 50°C. The reaction mixture was stirred while maintaining the temperature, and then 2 × 0.65 L of 0.75 M phosphoric acid in DMSO was added every 30 minutes. After the addition of the second 0.65 L portion of phosphoric acid in DMSO, it was stirred again for 30 minutes.

[0131] HWE reaction A solution of 3-(R,S)-4-phosphonate was added to the reaction mixture formed after oxidation, containing PPB-Corey aldehyde (9), at -30 °C. After the HWE reaction was complete (approximately 40 min), 67 L of 1 M sodium hydrogen sulfate solution was added to the reaction mixture, which was stirred at room temperature for approximately 1.5 h. The crystalline reaction mixture was placed in a centrifuge, and the centrifuged crystals were washed with 43 kg of dichloromethane. The filtrate and washings were combined, neutralized with 1 M sodium bicarbonate solution, then washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated. The evaporated concentrate was diluted with dichloromethane and then purified by chromatography on a silica gel column pre-treated with toluene using a mixture of dichloromethane and ethyl acetate. The product-containing fractions were combined and concentrated at atmospheric pressure, and the concentrate was crystallized from isopropanol. The crystalline suspension was stirred at 0-5 °C to complete the crystallization. The crystals were then filtered, washed, and dried. Yield: 5.56 kg (67%), mp: 127-146°C.

[0132] Preparation of phosphonate solution (base: sodium hydride): To 15.6 kg of distilled toluene, 0.943 kg of sodium hydride was weighed under an anhydrous atmosphere, and then at 0° C. a solution of 6.15 kg of 3-(R,S)-4 phosphonate in 11 L of distilled toluene was added at 0-10° C. After the addition, the cooling was removed and the reaction mixture was stirred until complete dissolution.

[0133] Example 1.b Oxidation: Anelli oxidation To a mixture of 640 mL of dichloromethane and 33.5 mL of isopropanol, 2.6 g of potassium bromide, 55.1 g of sodium bicarbonate, 77.0 g of PPB-Corey lactone (8), 0.683 g of TEMPO, and 540 mL of dichloromethane were added. With vigorous stirring, the reaction mixture was cooled to -5 to 0 °C, and 119 mL of sodium hypochlorite solution (1.93 M aqueous solution) was added, followed by stirring while maintaining the temperature. When the oxidation was complete, 390 mL of water and 77 mL of 20% sodium thiosulfate solution were added to the reaction mixture at 10 to 20 °C. After the addition, the reaction mixture was stirred for approximately 30 minutes at 30 to 35 °C, and then the phases were separated and the aqueous phase was extracted with 130 mL of dichloromethane. The combined organic phase contained PPB-Corey aldehyde of formula 9, which was used in the next reaction step (HWE reaction) without further purification.

[0134] HWE reaction To the solution of phosphonate cooled to 0-5°C, the solution of PPB-Corey aldehyde (9) formed in the oxidation step was added under an inert atmosphere, and the reaction mixture was then stirred while maintaining the temperature. After completion of the reaction, the reaction mixture was poured into 180 mL of 2 M sodium hydrogen sulfate solution at 5-10°C. After stirring, the phases were separated, and the organic phase was concentrated under reduced pressure, and the concentrate solvent was changed to isopropanol. During concentration, crystallization occurred. Additional isopropanol was added to the crystalline reaction mixture, which was then stirred for 3 hours at 0-5°C. The crystals were filtered, washed with cold isopropanol, and dried. Yield: 91.86g (85%).

[0135] Preparation of phosphonate solution (base: aqueous potassium hydroxide): 76.77 g of phosphonate (3-(R,S)-4) was weighed into 146 mL of dichloromethane at room temperature under an inert atmosphere, and a solution of 14.68 g of potassium hydroxide in 24.6 mL of water was added. After complete dissolution, the reaction mixture was cooled to 0° C.

[0136] The DSC curve of 16-(R,S)-PPB-enone is shown in FIG.

[0137] The powder X-ray diffraction pattern of 16-(R,S)-PPB-enone is shown in Figure 2, and the characteristic peaks are listed in Table 1 below.

[0138] [Table 3]

[0139] 16-(R,S)-PPB-enone 13 C and 1 The H NMR spectral assignments are shown in Table 2 below. [ka]

[0140] [Table 4]

[0141] [Table 5]

[0142] Example 2 (Reference Example): Preparation of PPB-enone (16-(R)-10) Column chromatography [(3aR,4R,5R,6aS)-4-[(E,4R)-4-(m-tolyl)-3-oxo-pent-1-enyl]-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl]4-phenylbenzoate [ka] 1.595 g of 16-(R,S)-PPB-enone (16-(R,S)-10) was dissolved in 5 ml of chloroform:tert-butyl methyl ether (chloroform:tert-butyl methyl ether) (30:1). Chromatography was performed on a 50 g column of silica gel using chloroform:tert-butyl methyl ether (chloroform:tert-butyl methyl ether) (30:1 and 10:1) as eluents.

[0143] The epimer of formula 16-(R)-10 was eluted first, followed by the epimer of formula 16-(S)-10, both of which were eluted as oils. Yield: PPB-enone: 0.367 g, 23% (oil that crystallizes on standing) 16-(S)-PPB-enone: 0.073 g, 4.6% (oil that crystallizes on standing)

[0144] The resulting crystals can be used as seeds in fractional crystallization.

[0145] Example 3: Preparation of PPB-enone (16-(R)-10) fractional crystallization [(3aR,4R,5R,6aS)-4-[(E,4R)-4-(m-tolyl)-3-oxo-pent-1-enyl]-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl]4-phenylbenzoate [ka]

[0146] Example 3a.: Fractional crystallization in tert-butyl methyl ether 5.58 kg of 16-(R,S)-PPB-enone (16-(R,S)-10) was suspended in 167 L of tert-butyl methyl ether and then heated to reflux. After refluxing for approximately 30 minutes, the mixture was cooled to 30-32°C and stirred for an additional 30 minutes while maintaining the temperature. Crystals (K r1 ) was filtered, washed, and dried. The undesired isomer, 16-(S)-PPB-enone, precipitated first; in the filtered crystals, the ratio of 16-(S)-PPB-enone to PPB-enone was approximately 78:22.

[0147] The filtrate combined with the washings was seeded with PPB-enone crystals (16-(R)-10), and the suspension was cooled to 0-5°C and stirred for 1 hour while maintaining the temperature. r2, PPB-enone, 16-(R)-10) was filtered, washed with cold tert-butyl methyl ether and dried.

[0148] The filtrate combined with the wash solution was added to the previously filtered K r1 The crystals (16-(S)-PPB-enone, 16-(S)-10) were suspended and the suspension was heated to reflux. After refluxing for approximately 30 minutes, the mixture was cooled to 30-32°C and stirred for an additional hour while maintaining the temperature. The crystals (K r3 , 16-(S)-PPB-enone, 16-(S)-10) was filtered, washed and dried. Yield of 16-(S)-PPB-enone: 2.706 kg (48.5%), purity >85% (HPLC).

[0149] 16-(S)-PPB-enone can be further purified according to Example 4.

[0150] The filtrate combined with the washings was seeded with PPB-enone (16-(R)-10), cooled to 0-5°C, and stirred for 1 hour while maintaining the temperature. r4 , PPB-enone, 16-(R)-10) was filtered, washed with cold (0-5°C) tert-butyl methyl ether, and dried. PPB-enone(K r2 and K. r4 Yield: 1.71 kg (31%) colorless crystals.

[0151] The combined PPB-enone (16-(R)-10) crystals were dissolved in a 5:1 mixture of tert-butyl methyl ether and dichloromethane (10.3 L) at 40-42 °C, approximately 25 L of tert-butyl methyl ether was added, and PPB-enone (16-(R)-10) was seeded. After stirring for approximately 30 minutes, the suspension was cooled to 0-5 °C. After stirring for approximately 1 hour, the crystals were filtered, washed with cold tert-butyl methyl ether, and dried. Yield: 1.67 kg (98%), colorless crystals.

[0152] Yield of PPB-enone obtained by fractional crystallization (in TBME solvent) of the diastereomeric mixture 16-(R,S)-PPB-enone: 1.67 kg (30%).

[0153] The isomer ratio in the thus obtained PPB-enone product as determined by HPLC: PPB-enone:16-(S)-PPB-enone=99.6:0.4

[0154] The DSC curve of PPB-enone is shown in FIG.

[0155] The powder X-ray diffraction pattern of PPB-enone is shown in Figure 4, and the characteristic peaks are listed in Table 3 below.

[0156] [Table 6]

[0157] [Table 7]

[0158] PPB-enone 13 C and 1 The H NMR spectral assignments are given in Table 4 below. [ka]

[0159] [Table 8]

[0160] [Table 9]

[0161] Example 3.b: Fractional crystallization in methanol 5.58 kg of 16-(R,S)-PPB-enone (16-(R,S)-10) was suspended in 167 L of methanol and then heated to reflux. After refluxing for approximately 30 minutes, the mixture was cooled to 30-32°C and stirred for an additional 30 minutes while maintaining the temperature. Crystals (K r1 ) was filtered, washed, and dried. First, the undesired isomer, 16-(S)-PPB-enone, precipitated.

[0162] The filtrate combined with the washings was seeded with PPB-enone crystals (16-(R)-10), and the suspension was cooled to 0-5 °C and stirred for 1 h. r2 , PPB-enone, 16-(R)-10) was filtered, washed with cold (0-5°C) methanol, and dried.

[0163] The filtrate combined with the wash solution was added to the previously filtered K r1 The crystals (16-(S)-PPB-enone, 16-(S)-10) were suspended and the suspension was heated to reflux. After refluxing for approximately 30 minutes, the mixture was cooled to 30-32°C and stirred for an additional hour while maintaining the temperature. The crystals (K r3 , 16-(S)-PPB-enone, 16-(S)-10) was filtered, washed and dried. r3 Crystals (52% yield) were obtained with a purity of over 78% (HPLC).

[0164] The filtrate combined with the washings was seeded with PPB-enone crystals (16-(R)-10), cooled to 0-5°C, and stirred for 1 hour while maintaining the temperature. r4 ) (PPB-enone, 16-(R)-10) was filtered, washed with cold methanol and dried. Yield (K r2 and K. r4 Crystals): 1.69 kg (30%) colorless crystals.

[0165] The combined PPB-enone (16-(R)-10) crystals were dissolved in a 5:1 mixture of methanol and dichloromethane at 40-42 °C, approximately 25 mL of methanol was added, and PPB-enone (16-(R)-10) was seeded and stirred for approximately 30 minutes. The suspension was then cooled to 0-5 °C. After stirring for approximately 1 hour, the crystals were filtered, washed with cold methanol, and dried.

[0166] The precipitated crystals were dissolved in methanol:dichloromethane=5:1, and the above crystallization was repeated. Yield (for two recrystallization steps): 1.62 g (96%), colorless crystals.

[0167] Yield of PPB-enone obtained by fractional crystallization (from methanol solvent) of the diastereomeric mixture 16-(R,S)-PPB-enone: 1.62 g (29%).

[0168] The isomer ratio in the thus obtained PPB-enone product, as determined by HPLC, was: PPB-enone:16-(S)-PPB-enone=97.89:2.11.

[0169] NOTE: When this process was repeated several times, approximately every 4 repetitions, precipitated K r2 +K r4 The amount of crystals increased from 1.69 g to 1.70-1.75 g and contained more than 10% of the undesired epimer, 16-(S)-PPB-enone.

[0170] The DSC curve of PPB-enone is shown in FIG.

[0171] The powder X-ray diffraction pattern of PPB-enone is shown in Figure 6, and the characteristic peaks are listed in Table 5 below.

[0172] [Table 10]

[0173] PPB-enone 13 C and 1The H NMR spectral assignments are given in Table 6 below. [ka]

[0174] [Table 11]

[0175] [Table 12]

[0176] Example 4: Crystallization of 16-(S)-PPB-enone (16-(S)-10) [(3aR,4R,5R,6aS)-4-[(E,4S)-4-(m-tolyl)-3-oxo-pent-1-enyl]-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl]4-phenylbenzoate 10 g of K prepared in Example 3.a r3 The crystals (containing at least 85% of 16-(S)-PPB-enone) were dissolved in 60 mL of dichloromethane, and then 200 mL of tert-butyl methyl ether was added with stirring at room temperature. The precipitated crystals were filtered, washed, and dried, and the crystallization was repeated two more times. The product of the last crystallization (16-(S)-PPB-enone) contained less than 2% of PPB-enone. Yield: 6.4g (64%), MP: 168.6-169.5℃

[0177] The DSC curve of 16-(S)-PPB-enone is shown in FIG. The powder X-ray diffraction pattern of 16-(S)-PPB-enone is shown in Figure 8, and the characteristic peaks are listed in Table 7 below.

[0178] [Table 13]

[0179] [Table 14]

[0180] 16-(S)-PPB-enone 13 C and 1 The H NMR spectral assignments are given in Table 8 below. [ka]

[0181] [Table 15]

[0182] [Table 16]

[0183] Example 5: Preparation of PPB-enone from the mixture by epimerization of 16-(S)-PPB-enone (16-(S)-10) followed by fractional crystallization according to Example 3.a Example 5.1 In Example 3.a, K r3 5.000 g of 16-(S)-PPB-enone (16-(S)-10) obtained as above was dissolved in 100 mL of ethyl acetate, and then 5.0 g of silica gel and 2.50 mL of triethylamine were added thereto and stirred at 55-65 °C for about 23 hours. At the end of the reaction, the isomer ratio was approximately 1:1, and 10-15% of by-products were formed. The reaction mixture was then cooled and filtered, the crystals were washed with ethyl acetate, and the combined filtrate was evaporated. The evaporation residue was fractionally crystallized as described in Example 3.a to obtain PPB-enone (16-(R)-10). Yield of PPB-enone: 1.442 g (29% calculated based on 16-(S)-PPB-enone (Kr3), 14.5% calculated based on starting 16-(R,S)-PPB-enone).

[0184] Example 5.2 In Example 3.a, K r3 5.000 g of 16-(S)-PPB-enone (16-(S)-10) obtained as above was dissolved in 150 mL of ethyl acetate, 75.0 g of aluminum oxide was added thereto, and then it was stirred at 20-25 °C for about 1.5 hours. At the end of the reaction, the isomer ratio was approximately 1:1, and 10-15% of by-products were formed. The reaction mixture was then cooled and filtered, the crystals were washed with ethyl acetate, and the combined filtrate was evaporated. The evaporation residue was fractionally crystallized as described in Example 3.a to obtain PPB-enone (16-(R)-10). Yield: 0.865 g (17% calculated based on 16-(S)-PPB-enone, 8.5% calculated based on 16-(R,S)-PPB-enone).

[0185] Example 5.3 In Example 3.a, K r3 5.000 g of 16-(S)-PPB-enone (16-(S)-10) obtained as above was dissolved in 100 mL of toluene, and a solution of 0.500 g of pTsOH·HO in 2.5 mL of tetrahydrofuran was added to it. Then, it was stirred at 65-75 °C for about 15-20 hours. At the end of the reaction, the isomer ratio was approximately 1:1, and about 5% of by-products were formed. The reaction mixture was then cooled and neutralized with 0.422 mL of triethylamine. The precipitate was filtered, the crystals were washed with toluene, and the combined filtrate was evaporated. The evaporation residue was fractionally crystallized as described in Example 3.a to obtain PPB-enone (16-(R)-10). Yield: 1.698 g (34% calculated based on 16-(S)-PPB-enone, 17% calculated based on 16-(R,S)-PPB-enone).

[0186] Example 5.4 In Example 3.a, K r357.771 g of 16-(S)-PPB-enone (16-(S)-10) obtained as above was dissolved in 1155 mL of ethyl acetate, and 28.8 g of silica gel and 57.7 mL of triethylamine were added thereto. Then, it was stirred at 55-65 °C for about 12 hours. At the end of the reaction, the isomer ratio was approximately 1:1, and 10-15% of by-products were formed. The reaction mixture was then cooled and filtered, the crystals were washed with ethyl acetate, and the combined filtrate was evaporated. The evaporation residue was fractionally crystallized as described in Example 3.a to obtain PPB-enone (16-(R)-10). Yield: 20.10 g (34.8% calculated based on 16-(S)-PPB-enone, 17.4% calculated based on 16-(R,S)-PPB-enone).

[0187] The resulting PPB-enone (16-(R)-10) crystals can be recrystallized from a 5:1 mixture of tert-butyl methyl ether:dichloromethane as described in Example 3.a. Yield: 19.70g (98%).

[0188] Example 6, Reduction of PPB-enone Reduction of 15-oxo group [(3aR,4R,5R,6aS)-4-[(E,4R)-3-hydroxy-4-(m-tolyl)pent-1-enyl]-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl]4-phenylbenzoate [ka]

[0189] Reduction with sodium borohydride in the presence of silica gel: 1.51 kg of PPB-enone (16-(R)-10) was dissolved in 13.7 L of dichloromethane, 2.04 kg of silica gel was added, and the suspension was cooled to 0±5°C under an inert atmosphere. Under vigorous stirring, a solution of 0.183 kg of sodium borohydride in 340 mL of water was added. The reaction mixture was stirred while maintaining the temperature. After stirring for 1 hour, 270 mL of methanol was added. After the reduction was complete (approximately 5-8 hours), a solution of 515 mL of concentrated hydrochloric acid in 2.05 L of water was carefully added at 0±5°C. Then, after removing the cooling, 1.36 L of methanol was added. After stirring for approximately 20 minutes, the reaction mixture was filtered, and the filtered solid was washed with dichloromethane:methanol (5:1). The combined filtrate was thoroughly stirred and the phases were separated. The organic layer was washed with water, then saturated sodium chloride solution, dried over sodium sulfate, and then filtered to remove the drying agent, washed, and evaporated. Yield: 1.52 kg (100%), sticky oil. Isomer ratio: PPB-enol:15-(S)-PPB-enol = 6:4.

[0190] Example 7, Removal of the PPB Protecting Group (3aR,4R,5R,6aS)-5-Hydroxy-4-[(E,3R,4R)-3-hydroxy-4-(m-tolyl)pent-1-enyl]-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-2-one [ka] 1.36 kg of PPB-enol (15-(R,S),16-(R)-11) from Example 6 was dissolved in 4.9 L of distilled methanol at 40-45°C, and 0.38 kg of potassium carbonate was added. While maintaining the temperature, the reaction mixture was stirred for 1 hour, then it was cooled to 0-5°C, and 4.28 L of 1 M hydrochloric acid solution was added. While maintaining the temperature, stirring was continued for 1 hour, then the precipitated crystals were filtered off and washed with a methanol-water mixture. 3.62 L of 1 M hydrochloric acid was added to the combined filtrate, which was stirred at room temperature for 30-45 minutes. Upon completion of stirring, the reaction mixture was concentrated under reduced pressure. The concentrated solution was extracted with 2 x 10 L of dichloromethane, the combined organic phases were washed with 1 M sodium bicarbonate, the washings were extracted with 5 L of dichloromethane, the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, the drying agent was filtered off, washed with dichloromethane, and the washings were added to the organic phase, and the combined organic phases were concentrated under reduced pressure (to approximately 3.5 kg).

[0191] The evaporated concentrate was purified by chromatography on a silica gel column prepared with dichloromethane:acetone = 7:1, then dichloromethane:acetone = 2:1 as eluent. The product-containing fractions were combined and concentrated under reduced pressure. Yield: 415.93g (48%) thick oil.

[0192] The evaporation residue is preferably crystallized.

[0193] To do this, the evaporation residue was dissolved in tert-butyl methyl ether using a bath at 40-50°C and then cooled to 0-5°C with stirring. After crystallization began, the crystal suspension was stirred for an additional 25-35 minutes and then completed by adding diisopropyl ether. The mixture containing the precipitated crystals was stirred for an additional hour while maintaining the temperature.

[0194] The crystals were filtered, washed and dried at room temperature to constant weight. Yield: 303.6 g (73% with respect to the crystallization step), colorless crystals.

[0195] The compound itself is known, for example from patent applications WO 2010029925 A1 and WO 2011111714 A1, but the crystalline form of this compound is not described or characterized therein.

[0196] The crystalline form has a melting point of 72.5-73.4°C and [α] D It is characterized by an optical rotation of 25° (measured in 1% ethanol solution at 20°C).

[0197] The DSC curve of the crystalline hydroxyenol is shown in FIG.

[0198] The powder X-ray diffraction pattern of the hydroxyenol is shown in Figure 10 and the characteristic peaks are listed in Table 9 below.

[0199] [Table 17]

[0200] Hydroxyenol 13 C and 1 The H NMR spectral assignments are shown in Table 10 below. [ka]

[0201] [Table 18]

[0202] Example 8, Preparation of Racemic Phosphonates (2-oxo-3-m-tolyl-butyl)phosphonic acid dimethyl ester Example 8.1, Route A Starting material: methylphenylacetic acid Reaction step: Alkylation (methylation) Esterification (formation of methyl esters) Phosphonate formation [ka] 8.1.1. Preparation of methylphenylpropionic acid (13) a) Base: Butyllithium 4.31 kg of methylphenylacetic acid (12) was dissolved in 38.0 kg of anhydrous tetrahydrofuran. Under an inert atmosphere, the reaction mixture was cooled to -60 to -75 °C, and 26.2 kg of 15% butyllithium solution was added. After the addition, the reaction mixture was stirred for an additional 15 minutes, and then 805 mL of diisopropylamine (DIPA) was added while maintaining the temperature. After stirring for 15 minutes, the reaction mixture was heated to -30 °C, and 3.60 L of methyl iodide was added. After removing the cooling and stirring for 10 minutes, the reaction mixture was poured into 98 L of 1 M sodium hydrogen sulfate. After settling, the phases were separated, and the aqueous phase was extracted with tert-butyl methyl ether. The combined organic phases were washed with saturated sodium chloride solution (3 × 32 kg). In the first washing step, 81.8 g of sodium metabisulfite was also added to the mixture. The organic layer was dried over sodium sulfate, the drying agent was filtered off, and the filtrate was evaporated under reduced pressure. Yield: 4.62 kg (98%), orange liquid.

[0203] 8.1.2. Preparation of methylphenylpropionic acid (13) b) Base: Lithium diisopropylamide (LDA) Preparation of LDA solution: 187 mL of diisopropylamine was dissolved in 300 mL of anhydrous tetrahydrofuran. Under an inert atmosphere, the solution was cooled to -20°C, and then 511 mL of 2.5 M butyllithium solution was added dropwise. The reaction mixture was stirred at -10°C for 2 hours.

[0204] Alkylation 80 g of methylphenylacetic acid (12) was dissolved in 800 mL of anhydrous tetrahydrofuran. Under an inert atmosphere, the solution was cooled to -20 °C, and then the prepared LDA solution was added to it while maintaining the temperature. The reaction mixture was stirred for 30 minutes at -10 °C, and then 40 mL of methyl iodide was added at -20 to -10 °C. After the addition, the reaction mixture was stirred for 30 minutes at 0 °C. The reaction mixture was then quenched with 1200 mL of 2 M sodium hydrogen sulfate solution, and after vigorous stirring, the phases were separated. The aqueous phase was extracted with tert-butyl methyl ether. The combined organic phases were washed twice with a saturated sodium chloride volume; in the first washing step, 1.52 g of sodium metabisulfite was also added to the mixture. The organic layer was dried over sodium sulfate, the drying agent was filtered off, and the filtrate was evaporated under reduced pressure. Yield: 87.5g (100%), orange liquid.

[0205] 8.1.3. Preparation of methylphenylpropionic acid methyl ester (14) a) Esterification using hydrochloric acid 4.60 kg of methylphenylpropionic acid (13) was dissolved in 35 kg of distilled methanol, 350 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature. After the desired conversion was reached (approximately 12 hours), 1.17 L of triethylamine was added to the reaction mixture, which was then concentrated to approximately 15 L at atmospheric pressure. 40 kg of toluene was added, and after vigorous stirring, the aqueous phase was separated. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, the drying agent was removed by filtration, washed with toluene, and the filtrate was evaporated under reduced pressure. Yield: 4.74 kg (95%), yellow liquid.

[0206] 8.1.4. Preparation of methylphenylpropionic acid methyl ester (14) b) Esterification using sulfuric acid 4.60 kg of methylphenylpropionic acid (13) was dissolved in 36 kg of distilled methanol, 225 ml of concentrated sulfuric acid was added, and the mixture was stirred at 20-25°C. After 1 hour, 890 g of sodium carbonate was added to the reaction mixture with vigorous stirring, and then it was concentrated to approximately 4.6 kg under reduced pressure. 32 kg of tert-butyl methyl ether was added to the concentrate, which was washed three times with 10% sodium carbonate solution. The combined aqueous phase was extracted once with butyl methyl ether. The combined organic phase was dried over sodium sulfate, the drying agent was filtered off, the washings were removed, and the combined filtrate was evaporated. Yield: 3.25 kg (65%), yellow liquid.

[0207] 8.1.5. Preparation of Racemic Phosphonate (3-(R,S)-4) a.) Base: Butyllithium 23.8 kg of 15% butyllithium solution was added to 49 kg of distilled toluene under an inert atmosphere. The reaction mixture was then cooled to -75 to -85 °C, and a solution of 8.25 kg of dimethylmethylphosphonate (DMMP) in 24 kg of distilled toluene was added while maintaining the temperature. The reaction mixture was stirred for 30 minutes while maintaining the temperature, and then a solution of 4.74 kg of methylphenylpropionic acid methyl ester (14) in 20 kg of distilled toluene was added at -75 to -85 °C. After stirring for 30 minutes, the reaction mixture was poured into a mixture of 70 L of 1 M sodium hydrogen sulfate solution and 13 L of saturated sodium chloride solution. The mixture was stirred at room temperature for 30 minutes, and after settling, the phases were separated. The aqueous phase was extracted with 2 × 20 L of toluene. The combined organic phase was washed with saturated sodium chloride solution and then dried over sodium sulfate. The drying agent was filtered off, and the combined filtrate was evaporated under reduced pressure. Yield: 6.83 kg (95%), pale yellow oil.

[0208] 8.1.6. Preparation of Racemic Phosphonate (3-(R,S)-4) b.) Base: LDA Preparation of LDA solution A solution of 13.9 mL of diisopropylamine in 45 mL of anhydrous tetrahydrofuran was cooled to 0° C. under an inert atmosphere, and 54 mL of butyllithium solution (1.6 M in hexane) was added dropwise. After addition, it was stirred for 20 minutes.

[0209] Phosphonate formation: To a solution of 6.36 g of methylphenylpropionic acid methyl ester (14) in 64 ml of anhydrous tetrahydrofuran was added 37.7 ml of dimethylmethylphosphonate under an inert atmosphere. The prepared LDA solution was added dropwise at 0°C. After 5-10 minutes of stirring, the reaction mixture was acidified with 5N hydrochloric acid (pH = 2-3) under vigorous stirring, the phases were separated, the aqueous phase was extracted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution, it was dried over sodium sulfate, the drying agent was filtered off, and the combined filtrates were evaporated. Yield: 8.91 g (92.4%).

[0210] Example 8.2, Route B Starting material: Methylphenylacetic acid Reaction step: Esterification (formation of methyl ester) Alkylation (methylation) Phosphonate formation [ka] Preparation of methylphenylacetic acid methyl ester (15) 31.74 g of methylphenylacetic acid (12) was dissolved in 315 ml of methanol. 1.8 mL of concentrated sulfuric acid was added to it while stirring at room temperature. After completion of the reaction (2-3 h), the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 210 mL of dichloromethane, washed with 1 M sodium bicarbonate solution and then saturated brine, dried over sodium sulfate, filtered to remove the drying agent, and the combined filtrate was evaporated. Yield: 34.11g (98.3%) oil.

[0211] Preparation of methylphenylpropionic acid methyl ester (14) 19.2 mL of diisopropylamine was dissolved in 345 mL of anhydrous tetrahydrofuran. Under an inert atmosphere, it was cooled to -60°C, and 85.9 mL of a 1.6 M solution of butyllithium in hexane was added dropwise with stirring. After 10 minutes of stirring, a solution of 15.01 g of methylphenylacetic acid methyl ester (15) in 16 mL of anhydrous tetrahydrofuran was added dropwise to the reaction mixture. After 10 minutes of stirring, 15 mL of methyl iodide was added. After 15 minutes of stirring, the reaction mixture was poured into 340 mL of 2 N hydrochloric acid. The phases were separated, the aqueous phase was extracted with diisopropyl ether, and the organic phase was washed with 1 M sodium bicarbonate solution and then saturated brine, dried over sodium sulfate, the drying agent was filtered off, and the combined filtrates were evaporated. Yield: 16.21g (99.5%).

Claims

1. Formula 1 【Chemistry 1】 A method for preparing a compound of the formula separating the compound of formula 16-(R,S)-10 into its diastereomers 16(R)-10 and 16-(S)-10 by fractional crystallization; 【Chemistry 2】 reducing the 15-oxo group of the compound of formula 16-(R)-10, thereby obtaining a compound of formula 15-(R,S),16-(R)-11; 【Transformation 3】 removing the protecting group of the compound of formula 15-(R,S),16-(R)-11 and isolating the compound of formula 1; 【Chemistry 4】 and optionally crystallizing the compound of formula 1. A method comprising:

2. The solvent used for fractional crystallization of the compound of formula 16-(R,S)-10 is C 1～3 2. The method of claim 1, wherein the hydroxybenzoate is selected from the group consisting of alcohols, tert-butyl methyl ether, and mixtures thereof.

3. 3. The method of claim 2, wherein the solvent is selected from methanol, tert-butyl methyl ether, and mixtures thereof.

4. The fractional crystallization of the compound of formula 16-(R,S)-10 comprises: (a) suspending the compound of formula 16-(R,S)-10 in the solvent, refluxing the suspension, then cooling the mixture to 25-35°C and stirring while maintaining the temperature, then filtering, washing and drying the precipitated crystals, thereby obtaining crystalline K r1 obtaining a (b) seeding the filtrate combined with the wash with crystals of the compound of formula 16-(R)-10, cooling the suspension to 0-5°C and stirring while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals, thereby obtaining crystalline K r2 obtaining a Optionally (c) Crystal K obtained in step (a) r1 is suspended in the filtrate combined with the washings, the suspension is refluxed, the mixture is then cooled to 25-35°C and stirred while maintaining the temperature, the precipitated crystals are then filtered, washed and dried, thereby obtaining crystalline K r3 obtaining a (d) The filtrate combined with the washings is seeded with crystals of the compound of Formula 16-(R)-10, cooled to 0-5°C, stirred while maintaining the temperature, and then the precipitated crystals are filtered, washed, and dried, thereby obtaining crystalline K r4 and the step of obtaining Including, wherein the compound of formula 16-(S)-10 is prepared in step (a) and optionally in step (c) from crystalline K r1 and K. r3 and the compound of formula 16-(R)-10 is obtained in step (b) and in optional step (d) as crystalline K r2 and K. r4 4. The method according to claim 2 or 3, wherein the compound is obtained as follows:

5. C 1～3 The crystal K is obtained from a solvent selected from alcohol, tert-butyl methyl ether, and mixtures thereof; or a mixture of the solvent with dichloromethane. r2 and / or K r4 5. The method of claim 4, comprising the further step of recrystallizing

6. The method of claim 5, wherein the solvent is a mixture of methanol and dichloromethane or a mixture of tert-butyl methyl ether and dichloromethane.

7. The obtained crystal K r1 or K r3 under acidic or basic conditions, followed by repeated fractional crystallization as claimed in any one of claims 4 to 6.

8. 8. The process of claim 7, wherein the epimerization is carried out in toluene with para-toluenesulfonic acid at 65-75°C by stirring for a period of 15-20 hours or in ethyl acetate in the presence of silica gel with triethylamine at 55-65°C by stirring for a period of 10-14 hours.

9. The method according to any one of claims 1 to 8, wherein the 15-oxo group of the compound of formula 16-(R)-10 is reduced with an aqueous solution of sodium borohydride in the presence of silica gel.

10. The method of any one of claims 1 to 7, wherein the compound of formula 1 is isolated by chromatography.

11. 11. The method of claim 10, wherein the chromatography is carried out on a silica gel column using dichloromethane:acetone as the eluent.

12. The method according to any one of claims 1 to 11, wherein the compound of formula 1 is crystallized from an ethereal solvent or solvent mixture.

13. 13. The method of claim 12, wherein the solvent is a mixture of tert-butyl methyl ether and diisopropyl ether.

14. Compounds of formula 16-(R,S)-10 can be prepared by reacting an aldehyde of formula 9 with a racemic phosphonate of formula 3-(R,S)-4: 【Transformation 5】 The method of any one of claims 1 to 13, wherein the compound is prepared by reacting

15. 15. The process of claim 14, wherein the reaction is carried out with potassium hydroxide base at 20-25°C or with sodium hydride at 0-10°C.

16. The racemic phosphonates of formula (3-(R,S)-4) can be prepared according to variant A) or B) by the following reaction scheme: 【Transformation 6】 (wherein, Variation A) is alkylating the methylphenylacetic acid of formula 12; converting the resulting methylphenylpropionic acid of formula 13 to the methyl ester of formula 14 using methanol in the presence of an acid; Subsequently, reacting the methyl ester of formula 14 with dimethylmethylphosphonate (DMMP) in the presence of a strong base, thereby obtaining the racemic phosphonate of formula 3-(R,S)-4. Including; Variation B) is converting methylphenylacetic acid of formula 12 to methylphenylacetic acid methyl ester of formula 15 using methanol in the presence of an acid; alkylating said methylphenylacetic acid methyl ester of formula 15, thereby obtaining a methyl ester of formula 14; Subsequently, reacting the methyl ester of formula 14 with dimethylmethylphosphonate (DMMP) in the presence of a strong base, thereby obtaining the racemic phosphonate of formula 3-(R,S)-4. (including 16. The method of claim 14 or 15, wherein the compound is prepared by

17. C 1～3 alcohol, tert-butyl methyl ether, and mixtures thereof. The reaction of the compound of formula 16-(R,S)-10 using a solvent 【Transformation 7】 A method for fractional crystallization of a compound of the formula (a) suspending the compound of formula 16-(R,S)-10 in the solvent, refluxing the suspension, then cooling the mixture to 25-35°C and stirring while maintaining the temperature, then filtering, washing and drying the precipitated crystals, thereby obtaining crystalline K r1 obtaining a (b) The filtrate combined with the wash solution is treated with a compound of formula 16-(R)-10 【Transformation 8】 The suspension is cooled to 0-5°C and stirred while maintaining the temperature, and the precipitated crystals are subsequently filtered, washed and dried, thereby obtaining crystalline K r2 obtaining a Optionally (c) Crystal K obtained in step (a) r1 is suspended in the filtrate combined with the washings, the suspension is refluxed, the mixture is then cooled to 25-35°C and stirred while maintaining the temperature, the precipitated crystals are then filtered, washed and dried, thereby obtaining crystalline K r3 obtaining a (d) The filtrate combined with the washings is seeded with crystals of the compound of Formula 16-(R)-10, cooled to 0-5°C, stirred while maintaining the temperature, and then the precipitated crystals are filtered, washed, and dried, thereby obtaining crystalline K r4 and the step of obtaining Including, where: Formula 16-(S)-10 【Chemistry 9】 The compound of formula (I) is prepared in step (a) and optionally in step (c) by crystalline K r1 and K. r3 and the compound of formula 16-(R)-10 is obtained in step (b) and in optional step (d) as crystalline K r2 and K. r4 is obtained as Optionally, the crystalline K obtained in steps (a), (b), (c) and / or (d) r1 , K. r2 , K. r3 and / or K r4 , C 1～3 recrystallization from a solvent selected from alcohol, tert-butyl methyl ether and mixtures thereof, or mixtures of said solvents with dichloromethane; A method comprising:

18. 18. The process of claim 17, wherein the solvent used in the fractional crystallization and the recrystallization is selected from methanol, tert-butyl methyl ether, and mixtures thereof.

19. Formula 16-(S)-10 【Chemistry 10】 A method for preparing a compound of the formula (a) Formula 16-(R,S)-10 【Chemistry 11】 The compound of C 1～3 The mixture is then cooled to 25-35°C and stirred while maintaining the temperature, and the precipitated crystals are filtered, washed and dried, thereby obtaining crystalline K r1 obtaining a Optionally (b) The filtrate combined with the wash solution is treated with a compound of formula 16-(R)-10 【Chemistry 12】 seeding the suspension with crystals of the compound of formula (I), cooling the suspension to 0-5°C, stirring while maintaining the temperature, and subsequently filtering the precipitated crystals; (c) Crystal K obtained in step (a) r1 is suspended in the filtrate, the suspension is refluxed, the mixture is then cooled to 25-35°C and stirred while maintaining the temperature, the precipitated crystals are then filtered, washed and dried, thereby obtaining crystalline K r3 obtaining a Optionally, the obtained crystalline K r1 or K r3 with dichloromethane and C 1～3 recrystallizing from a mixture of a solvent selected from alcohol, tert-butyl methyl ether, and mixtures thereof, thereby obtaining a compound of formula 16-(S)-10; A method comprising:

20. 17.4±0.2; 18.1±0.2; 18.6±0.2; 20.4±0.2; 23.2±0.2 and 24.9±0.2 degrees in its powder X-ray diffraction pattern obtained using a copper anode. 【Chemistry 13】 Crystals of the compound.

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