Method for preparing chiral prostaglandin enol intermediates and intermediate compounds useful in the method

Abstract

The present invention relates to a method for preparing a chiral prostaglandin enol intermediate with formula 1, the method comprising the steps of: separating the compound with formula 16-(R, S)-10 into its diastereomers by fractional crystallization, reducing the 15-oxo group of the compound with formula 16-(R)-10, thereby obtaining a compound with formula 15-(R, S), 16-(R)-11, subsequently removing the protecting group of the compound with formula 15-(R, S), 16-(R)-11, and separating the compound with formula 1, and optionally crystallizing the compound with formula 1. Optionally, the undesirable isomer formed during fractional crystallization can be epimerized, and the desired isomer of another amount can be recovered from the resulting mixture. The present invention also provides novel intermediates that can be used for the method. The present invention further relates to a method for fractional crystallization of the compound with formula 16-(R, S)-10.

Description

Technical Field

[0001] The present invention relates to a process for preparing a chiral prostaglandin enol intermediate having formula 1. The present invention further relates to an intermediate used in this process and its preparation. Technical Background

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

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

[0004]

[0005] 16-(R)-Methyl-17-(3-methylphenyl)-15-(R)-hydroxyenol

[0006] Numbering of compounds according to prostaglandin numbering

[0007] The name of the compound of formula 1 according to Chemical Abstracts: (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.

[0008]

[0009] Number of compounds according to Chemical Abstracts names

[0010] The preparation of compounds of formula 1 is described in WO 2010029925 A1 and WO 2011111714 A1. Compounds of formula 1 are intermediates of prostaglandin derivatives, which are claimed in said documents.

[0011] According to the known methods described in the above documents (the same methods for preparing compounds of formula 1 are described in the cited applications), optically active 2-(R)-(3-methylphenyl)propionic acid (2) is converted to methyl ester (3) with methanol and sulfuric acid, and chiral phosphonate (4) is prepared by reacting methyl ester (3) with dimethyl methylphosphonate (DMMP). In a Horner-Wadsworth-Emmons (HWE) reaction, chiral phosphonate (4) is reacted with benzoyl-Corey aldehyde (5) in dimethoxyethane (DME) in the presence of sodium hydride base. The resulting protected enone (6) is reduced to benzoyl enol (7) with (-)-B-chloro-diisopinocampheylborane ((-)-DIP-Cl) in THF at -40°C. The benzoyl enol is 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 with hexane:ethyl acetate and ethyl acetate as eluents. No crystallization or state of the product was described.

[0012]

[0013]

[0014] The overall yield of the known method using chiral starting materials is 17% (calculated based on benzoyl-corealdehyde (5)).

[0015] Issues to be resolved

[0016] The disadvantages of the known methods are as follows:

[0017] ● Side chain formation is carried out using expensive 3-(R)-optically active phosphonate (4); the starting material for the synthesis of phosphonate (4) is expensive chiral 2-(R)-(3-methylphenyl)propionic acid (2)

[0018] ● Under the alkaline conditions of the HWE reaction (NaH, DME), the chiral side chain can be easily racemized, resulting in a decrease in the optical purity of the 6-enone

[0019] ●The reduction of the 15-oxo group of the 6-enone was carried out in a deep-freeze reaction at -40°C using a large excess of an expensive chiral reagent ((-)-DIP-Cl).

[0020] Therefore, there is a need for a method for more economically producing compounds having Formula 1 using more readily available starting materials under milder reaction conditions. Summary of the invention

[0021] We have developed a method in which

[0022] The benzoyl protecting group of aldehyde (5) was replaced by p-phenylbenzoyl to facilitate the reduction of the 15-oxo group.

[0023] ● We obtained crystalline enones after construction of the side chain, which allowed separation of enone diastereomers by fractional crystallization

[0024] ● Side chain formation is performed with an inexpensive racemic phosphonate (3-(R,S)-4) ● By using a racemic phosphonate in the HWE reaction, we avoid the disadvantages of using chiral phosphonates, which undergo racemization in alkaline media, reducing production yield and optical purity

[0025] The 15-oxo group of the enone can be reduced using readily available reagents, thus eliminating the need for energy-intensive deep-freeze chemical reactions.

[0026] The key elements of our invention are the provision of a novel enone intermediate (16-(R,S)-10) containing a racemic side chain, which is crystalline, and the separation of the enone diastereomers is accomplished by fractional crystallization.

[0027] Therefore, the present invention relates to a process for preparing a compound having formula 1,

[0028]

[0029] The method comprises the following steps:

[0030] The compound having the formula 16-(R,S)-10 is separated into its diastereoisomers 16-(R)-10 and 16-(S)-10 by fractional crystallization,

[0031]

[0032] 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,

[0033]

[0034] removing the protecting group of the compound of formula 15-(R,S),16-(R)-11 to separate the compound of formula 1,

[0035]

[0036] and optionally, crystallizing the compound of Formula 1.

[0037] The solvent used for the fractional crystallization of the compound of formula 16-(R,S)-10 is preferably selected from C 1-3Preferred are methanol, tert-butyl methyl ether and mixtures thereof. Especially preferred is tert-butyl methyl ether.

[0038] The fractional crystallization of the compound of formula 16-(R,S)-10 preferably comprises

[0039] (a) suspending the compound of formula 16-(R,S)-10 in the solvent, refluxing the suspension, then cooling the mixture to 25° C. to 35° C. and stirring while maintaining the temperature, then filtering, washing and drying the precipitated crystals to obtain crystal K r1 ;

[0040] (b) seeding the filtrate combined with the washing liquid with crystals of the compound of formula 16-(R)-10, cooling the suspension to 0° C. to 5° C. and stirring while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystals K r2 ;as well as

[0041] Optionally

[0042] (c) The previously filtered crystals K r1 The mixture was suspended in the filtrate combined with the washing solution, the suspension was refluxed, and then the mixture was cooled to 25° C. to 35° C. and stirred while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystalline K r3 ;as well as

[0043] (d) seeding the filtrate combined with the washing liquid with the crystals of the compound of formula 16-(R)-10, cooling to 0° C. to 5° C. and stirring while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystals K r4 .

[0044] In step (a) and optionally in step (c) as crystalline K r1 and K r3 A compound of formula 16-(S)-10 is obtained and in step (b) and optionally in step (d) as a crystalline K r2 and K r4 A compound having the formula 16-(R)-10 is obtained.

[0045] The crystal K in step (a) and optional step (c) r1 and K r3 It mainly contains isomer 16-(S)-10. Therefore, crystal K r1 and K r3 In this specification, it is also referred to as a compound having the formula 16-(S)-10 or 16-(S)-PPB-enone.

[0046] The crystal K in step (b) and optional step (d) r2 and K r4 It mainly contains isomer 16-(R)-10. Therefore, crystal K r2 and K r4 It is also referred to in this specification as a compound having the formula 16-(R)-10 or PPB-enone.

[0047] In step (a) and optional step (c), after reflux, the mixture is preferably cooled to 30°C to 32°C and stirred at this temperature.

[0048] Stirring at 25-35°C (preferably 30-32°C) in step (a) and optional step (c) and at 0-5°C in step (b) and optional step (d) is preferably continued for about 0.5-3 hours, more preferably for about 30-60 minutes.

[0049] To maximize yield, it is preferred to also carry out optional steps (c) and (d).

[0050] Optionally, preferably selected from C 1-3 alcohol, tert-butyl methyl ether and a mixture thereof; or a crystalline K obtained by recrystallization from a mixture of the solvent and dichloromethane r2 and / or K r4 For the recrystallization, particularly preferred are mixtures of methanol and dichloromethane or mixtures of tert-butyl methyl ether and dichloromethane, wherein the ratio of dichloromethane is preferably up to 30 vol%; for example a 5:1 mixture of methanol:dichloromethane or a 5:1 mixture of tert-butyl methyl ether:dichloromethane.

[0051] 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 diastereoisomerized. Therefore, in order to increase the yield, it is preferred to obtain crystals K r1 or K r3 Epimerization and repeating the above fractional crystallization.

[0052] The epimerization can be carried out under acidic conditions or basic conditions.The epimerization can be carried out, for example, with triethylamine in ethyl acetate in the presence of silica gel, or with p-toluenesulfonic acid in ethyl acetate in the presence of alumina, or in toluene.

[0053] Preferably, the epimerization is carried out in toluene with p-toluenesulfonic acid at about 65°C-75°C by stirring for about 15 hours-20 hours, or in ethyl acetate with triethylamine in the presence of silica gel at about 55°C-65°C by stirring for about 10 hours-14 hours.

[0054] The 15-oxo group of the compound having the formula 16-(R)-10 can be reduced using methods known in the art, preferably with aqueous sodium borohydride in the presence of silica gel.

[0055] The protecting groups of compounds of formula 15-(R,S)-16-(R)-11 can be removed using known methods, for example, 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 removal by mineral acids in alcohols, etc.

[0056] After deprotection, the desired product is isolated. Separation can be performed using known methods such as crystallization or chromatography or a combination thereof. Preferably, chromatography is applied, by which the desired 15-epimer can be separated from the undesirable 15-epimer and other impurities in a single step. Chromatography can be performed, for example, on a silica gel column with dichloromethane: acetone eluent, preferably with dichloromethane: acetone = 7: 1 followed by a 2: 1 mixture.

[0057] The product-containing fractions are preferably combined and evaporated to obtain the product in the form of an oil. Optionally, the evaporation residue is crystallized to obtain a crystalline hydroxyenol having formula 1. The hydroxyenol is preferably crystallized from an ethereal solvent or solvent mixture, for example from a mixture of tert-butyl methyl ether and diisopropyl ether.

[0058] 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:

[0059]

[0060] The above reaction (known in the literature as the Horner-Wadsworth-Emmons (HWE) reaction) can be carried out using a variety of bases; preferably potassium hydroxide base at about 20°C-25°C, or sodium hydride at about 0°C-10°C.

[0061] One of the starting materials for the HWE reaction, the aldehyde having formula 9 is preferably prepared by oxidation of the PPB-core lactone having formula 8:

[0062]

[0063] The oxidation is carried out in a manner known in the art, for example with dimethyl sulfoxide in the presence of phosphoric acid and, for example, dicyclohexylcarbodiimide, or with sodium hypochlorite in the presence of a catalyst containing nitroxyl groups, preferably with sodium hypochlorite in the presence of a catalyst containing nitroxyl groups.

[0064] The compound having formula 8 (PPB-core lactone) is a readily available compound which can be used in large quantities in prostaglandin chemistry because it is a starting material for a large number of prostaglandin derivatives.

[0065] Other starting materials for the HWE reaction are racemic phosphonates (3-(R,S)-4). Optically active phosphonates of formula 4 and racemic phosphonates of formula (3-(R,S)-4) are known compounds (WO 2011111714 A1, WO2010029925 A1). Chiral phosphonates can be prepared from expensive chiral carboxylic acids by expensive methods (studies published in J. Chem. Soc., Perkin Trans. [Chemistry Puerkin Reaction Journal] 2, 1998, pp. 1767-1775 emphasize the difficulty of obtaining the starting chiral carboxylic acid itself), while racemic compounds can be prepared from inexpensive racemic carboxylic acids by inexpensive methods.

[0066] Two process variants for the preparation of racemic compounds are provided which are suitable for industrial-scale production.

[0067] Thus, according to variant A) or B), the racemic phosphonate of formula (3-(R,S)-4) is advantageously prepared by the following reaction scheme:

[0068]

[0069] Among them, variant A) includes:

[0070] The methylphenylacetic acid of formula 12 is alkylated preferably with methyl iodide in the presence of a strong base such as butyl lithium or lithium diisopropylamide;

[0071] The resulting methylbenzene propionic acid of formula 13 is converted into a methyl ester of formula 14 using methanol in the presence of an acid such as hydrochloric acid or sulfuric acid;

[0072] The methyl ester of formula 14 is then reacted with dimethyl methylphosphonate (DMMP) in the presence of a strong base such as butyl lithium or lithium diisopropylamide to obtain a racemic phosphonate of formula 3-(R,S)-4;

[0073] And variant B) comprises:

[0074] Converting methylphenylacetic acid having formula 12 to methylphenylacetate having formula 15 using methanol in the presence of an acid such as hydrochloric acid or sulfuric acid;

[0075] Alkylation of the methylphenylacetate of formula 15 is preferably carried out with methyl iodide in the presence of a strong base such as butyl lithium or lithium diisopropylamide to obtain the methyl ester of formula 14;

[0076] The methyl ester of formula 14 is then reacted with dimethyl methylphosphonate (DMMP) in the presence of a strong base such as butyl lithium or lithium diisopropylamide to obtain the racemic phosphonate of formula 3-(R,S)-4.

[0077] Another object of the present invention is the following novel intermediate compounds:

[0078] Compounds having the formula 16-(R,S)-10:

[0079]

[0080] Compounds having the formula 16-(R)-10:

[0081]

[0082] Compounds having the formula 16-(S)-10:

[0083]

[0084] And a compound having the formula 15-(R,S),16-(R)-11:

[0085]

[0086] These compounds are useful as intermediates for the preparation of prostaglandin and prostacyclin derivatives.

[0087] Another object of the present invention is a process for the fractional crystallization of a compound of formula 16-(R,S)-10 using a 1-3 Alcohol, tert-butyl methyl ether and mixtures thereof, preferably a solvent selected from methanol, tert-butyl methyl ether and mixtures thereof;

[0088] The method preferably comprises

[0089] (a) suspending the compound of formula 16-(R,S)-10 in the solvent, refluxing the suspension, and then cooling the mixture to 25° C. to 35° C. and stirring while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystal K r1 ;

[0090] (b) seeding the filtrate combined with the washing liquid with crystals of the compound of formula 16-(R)-10, cooling the suspension to 0° C. to 5° C. and stirring while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystals K r2 ;as well as

[0091] Optionally

[0092] (c) The previously filtered crystals Kr1 The precipitated crystals are suspended in the filtrate combined with the washing solution, the suspension is refluxed, and the mixture is then cooled to 25° C. to 35° C. and stirred while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystalline K r3 ;as well as

[0093] (d) seeding the filtrate combined with the washing liquid with the crystals of the compound of formula 16-(R)-10, cooling to 0° C. to 5° C. and stirring while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystals K r4 ,

[0094] wherein in step (a) and optionally in step (c) as crystalline K r1 and K r3 A compound of formula 16-(S)-10 is obtained and in step (b) and optionally in step (d) as a crystalline K r2 and K r4 A compound having the formula 16-(R)-10 is obtained.

[0095] The two isomers can be further purified by recrystallization, preferably from a 1-3 The invention relates to a method for preparing the precipitate of the present invention. The precipitate is preferably recrystallized from a solvent selected from the group consisting of alcohol, tert-butyl methyl ether and mixtures thereof; or from a mixture of said solvent and dichloromethane; preferably from a mixture of methanol and dichloromethane, or from a mixture of tert-butyl methyl ether and dichloromethane.

[0096] Another object of the present invention is a method for preparing a compound of formula 16-(S)-10, the method comprising

[0097] (a) suspending a compound having the formula 16-(R,S)-10 in a mixture selected from C 1-3 The suspension is refluxed in a solvent selected from an alcohol, tert-butyl methyl ether and a mixture thereof, preferably methanol, tert-butyl methyl ether and a mixture thereof, and then the mixture is cooled to 25° C. to 35° C. and stirred while maintaining the temperature, and then the precipitated crystals are filtered, washed and dried to obtain crystalline K r1 ;

[0098] and optionally

[0099] (b) seeding the filtrate combined with the washing liquid with crystals of the compound of formula 16-(R)-10, cooling the suspension to 0° C. to 5° C. and stirring while maintaining the temperature, followed by filtering the precipitated crystals; and

[0100] (c) The previously filtered crystals K r1The mixture was suspended in the filtrate, the suspension was refluxed, and then the mixture was cooled to 25° C. to 35° C. and stirred while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystalline K r3 ;

[0101] and optionally,

[0102] From dichloromethane and selected from C 1-3 alcohol, tert-butyl methyl ether and a mixture thereof; preferably from a mixture of methanol and dichloromethane, or from a mixture of tert-butyl methyl ether and dichloromethane to obtain crystals K r1 or K r3 , thereby obtaining the compound having formula 16-(S)-10.

[0103] Another object of the present invention is a crystalline form of a compound of formula 1,

[0104]

[0105] The crystalline form has main peaks 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-θ in its powder X-ray diffraction pattern obtained using a copper anode. BRIEF DESCRIPTION OF THE DRAWINGS

[0106] Figure 1 The DSC curve of 16-(R,S)-PPB-enone prepared according to Example 1 is shown.

[0107] Figure 2 The powder X-ray diffraction pattern of 16-(R,S)-PPB-enone prepared according to Example 1 is shown.

[0108] Figure 3 Shown is the DSC curve of 16-(R)-PPB-enone prepared according to Example 3.a.

[0109] Figure 4 Shown is the powder X-ray diffraction pattern of 16-(R)-PPB-enone prepared according to Example 3.a.

[0110] Figure 5 Shown is the DSC curve of 16-(R)-PPB-enone prepared according to Example 3.b.

[0111] Figure 6 Shown is the powder X-ray diffraction pattern of 16-(R)-PPB-enone prepared according to Example 3.b.

[0112] Figure 7The DSC curve of 16-(S)-PPB-enone prepared according to Example 4 is shown.

[0113] Figure 8 The powder X-ray diffraction pattern of 16-(S)-PPB-enone prepared according to Example 4 is shown.

[0114] Fig. 9 The DSC curve of the crystalline hydroxy enol prepared according to Example 7 is shown.

[0115] Fig.10 The powder X-ray diffraction pattern of the crystalline hydroxy enol prepared according to Example 7 is shown.

[0116] Terms and abbreviations used in this manual

[0117] As used herein, with respect to an asymmetric carbon atom,

[0118] The R designation means that the order of attachment of substituents according to the Cahn-Ingold-Prelog rule is clockwise,

[0119] The S designation means that the order of attachment of substituents according to the Kahn-Ingel-Prelog rule is counterclockwise,

[0120] The R,S notation means that the order of attachment of substituents according to the Kahn-Ingel-Prelog rule is in the same proportion clockwise and counterclockwise.

[0121] Enantiomers are those stereoisomers in which all asymmetric carbon atoms are in opposite configurations (ie, they are mirror images of each other).

[0122] Diastereoisomers are those stereoisomers of molecules that are not mirror images of each other.

[0123] Diastereoisomers are those diastereomers that differ only in the configuration of a single chiral center.

[0124] In this specification, when ratios are given with respect to liquids, they mean volume / volume ratios. DETAILED DESCRIPTION

[0125] Preferably, the starting material for the overall process is a core lactone (8) containing a PPB protecting group, which is oxidized to an aldehyde (9) in a first reaction step and the 9 aldehyde is reacted with a 3-(R,S)-4-racemic phosphonate in a Horner-Wadsworth-Emmons (HWE) reaction.

[0126] The starting material of the method can be directly the aldehyde of formula 9. However, due to the poor stability of aldehydes, PPB-corinamide 8 is more readily available and easier to store, so the latter is more convenient to use.

[0127] The obtained enone diastereomer (16-(R,S)-10) was separated by fractional crystallization.

[0128] The undesired "wrong" isomer (16-(S)-10) can be epimerized in acidic or basic media. After reaching a 1:1 16-(R)-10:16-(S)-10 isomer ratio, additional amounts of the desired isomeric PPB-enone can be obtained by fractional crystallization.

[0129] The crystals of PPB-enone were combined and the 15-oxo group was reduced to a hydroxyl group. After removing the protecting group of the p-phenylbenzoyl protected enol (15-(R,S),16-(R)-11), the desired compound of formula 1 was isolated.

[0130]

[0131]

[0132] The individual steps of the overall process starting from PPB-core lactone are described in detail below.

[0133] Step 1: Oxidation

[0134] The primary hydroxyl group of the PPB protected core lactone (8) can be oxidized by any known oxidation method that selectively converts the primary hydroxyl group to an aldehyde. The oxidation method may involve, for example

[0135] Chromium-containing oxidants such as Collins reagent (chromium trioxide-pyridine complex, CrO 3 .Py 2 ), pyridinium dichromate, or pyridinium chlorochromate

[0136] Hypervalent iodine reagents such as Dess-Martin oxidation

[0137] Activated dimethyl sulfoxide (DMSO), such as Swern oxidation, Pfitzner-Moffatt oxidation

[0138] Sodium hypochlorite (aqueous solution or crystalline pentahydrate) in the presence of a nitroxyl-containing catalyst such as TEMPO (2,2,6,6-tetramethyl-piperidin-1-oxyl) or AZADO (2-azaadamantane-N-oxyl).

[0139] Oxidation of PPB-core lactone was carried out using the Pfitzner-Moffat oxidation system containing activated dimethyl sulfoxide-DCC (dicyclohexylcarbodiimide) and Anelli oxidation using sodium hypochlorite-TEMPO oxidant.

[0140] Pfitzner-Moffat oxidation (J.Am.Chem.Soc.,1963,85,3027-3028):

[0141]

[0142] Annerelli oxidation (J.Org.Chem., 1987, 52, 2559-2562):

[0143]

[0144] Both oxidations are suitable for the preparation of PPB-Corey aldehyde (9). No isolation of the aldehyde is required prior to the Horner-Wadsworth-Emmons (HWE) reaction.

[0145] However, the Annerley oxidation is considered to be more preferred because the Pfitzner-Moffat oxidation produces very unpleasant byproducts dimethyl sulfide (which has a nasty odor) and DCU (dicyclohexylurea). When purifying PPB-enone, the removal of DCU requires expensive and time-consuming column chromatography because fully crystalline DCU will contaminate the crystalline PPB-enone.

[0146] After oxidation, the sensitive aldehyde does not need to be isolated from the reaction mixture; preferably, the resulting reaction mixture is used in the next reaction step.

[0147] Step 2: HWE reaction

[0148] The HWE reaction (R. Bruckner, Organic Mechanism, ed. by M. Harmata, Springer-Verlag Berlin Heidelberg 2010) was used to react the p-phenylbenzoyl protecting group-containing coreydride (9) with a racemic phosphonate (3-(R,S)-4). Several bases are available in the literature for the formation of the phosphonate anion; among them, sodium hydride and potassium hydroxide were selected for our experiments.

[0149]

[0150] The use of two bases to form the phosphonate anion is suitable because the HWE reaction between the phosphonate anion and PPB-Corey aldehyde (9) is complete in both cases. However, from a scale-up point of view, the use of potassium hydroxide solution is preferred.

[0151] Potassium hydroxide solutions are much easier to handle than sodium hydride dispersions (which are sensitive to air humidity), so no anhydrous medium is required, and the anion formation and HWE reaction require less cooling energy than is the case with NaH base.

[0152] The yield of 16-(R,S)-PPB-enone (16-(R,S)-10) was highest when the oxidation was performed by the Anneli 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 contained PPB-enone (16-(R)-10) ("good") and its diastereomer 16-(S)-PPB-enone (16-(S)-10) ("wrong") isomer in a ratio of 1:1.

[0153]

[0154] Step 3: Fractional crystallization

[0155] It is well known in the chemical literature that diastereomers differ in their physical properties (e.g. https: / / en.wikipedia.org / wiki / Diastereomer , downloaded on May 20, 2019). Therefore, in the early stages of development, we attempted to separate the PPB-enone diastereomers by column chromatography. Although we did not find an efficient, industrially applicable chromatographic separation with good yields, we obtained pure diastereomers by this technique. Both isomers (16-(R)-10 and 16-(S)-10) obtained after chromatographic separation were crystalline.

[0156] Thereafter, several solvents for the fractional crystallization of diastereomers were tried, and C 1-3 Alcohols and tert-butyl methyl ether are suitable for this purpose.

[0157] The solubility (g / 100 ml) of the PPB-enone isomer in some of the solvents in which crystallization was attempted is shown below:

[0158]

[0159] Based on solubility data, at C 1-3Fractional crystallization in alcohols and tert-butyl methyl ether (TBME) can be carried out with relatively good yields (however, it should be noted that diisopropyl ether (DIPE), which is also an ether, is not suitable in terms of solubility). Particularly preferred are methanol and tert-butyl methyl ether and mixtures of these solvents.

[0160] After repeating the crystallization procedure several times, it was found that in the case of methanol, the first generation product crystallized in some batches with a 16-(S)-PPB-enone content several percentage points higher. The experiment shows that the use of TBME makes the technology more robust, and in contrast to methanol, no anomalies were observed. Another advantage is that the "good" 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 get a much cleaner product. Already in the first generation, the 16-(S) impurity is only about 2.5%, which is reduced to about 0.5% after recrystallization. This is very advantageous because the total amount of impurities in the final product can be no more than 1.5%. Therefore, fewer crystallization steps produce purer products.

[0161] Furthermore, removal of the 16-(S) impurity from the final product is much more difficult, requiring multiple recrystallizations of the hydroxyenol (1), so it would be particularly advantageous to obtain a purer product initially.

[0162] Comparison of fractional crystallization in TBME and methanol:

[0163]

[0164] Based on the above, tert-butyl methyl ether is a particularly preferred solvent for fractional crystallization, especially on an industrial scale.

[0165] In both alcohol and TBME, the less soluble 16-(S)-PPB-enone (16-(S)-10) precipitated first during the fractional crystallization at about 30°C.

[0166] The fractional crystallization is preferably carried out by: reacting 16-(R,S)-PPB-enone in tert-butyl methyl ether or in C 1-3 The mixture is refluxed in the alcohol or in a mixture thereof for preferably about 15 minutes to 60 minutes, and the reaction mixture is then cooled to about 25°C to 35°C, preferably about 30°C to 32°C, and stirred while maintaining this temperature for another 0.5 hour to 3 hours, preferably about 30 minutes.

[0167] Filter the precipitated crystals of 16-(S)-PPB-enone (K r1 ), the filtrate is seeded with PPB-eneketone crystals, cooled to about 0°C-5°C, and the desired isomer (16-(R)-isomer) is crystallized over 0.5 hour-3 hours, preferably over about 1 hour (Kr2 ).

[0168] PPB-enone seeds were obtained by column chromatography of the diastereoisomer mixture on silica gel using chloroform: tert-butyl methyl ether as eluent.

[0169] Preferably, by filtering K r1 Additional 16-(R)-isomer PPB-enone can be recovered from the crystallization mixture by adding the crystals to the mother liquor, heating the suspension to reflux, and repeating the crystallization process. r3 ) is crystallized at about 25°C-35°C, and then the mother liquor is seeded with PPB-eneketone crystals, cooled to 0°C-5°C, and the second generation of PPB-eneketone crystals (K r4 ).

[0170] Based on experimental data, the use of methanol or a crystallization solvent mixture containing methanol requires more recrystallizations to produce a product with the desired epimeric purity.

[0171] Yields of fractional crystallization from TBME based on data from the following specific examples:

[0172] PPB-eneketone (K r2 and K r4 The yield of the above-mentioned product (together) is as follows: 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%.

[0173] Merged K r2 and K r4 The crystals can be recrystallized from a TBME: dichloromethane mixture. The yield of the recrystallization is 98%.

[0174] The yield of 16-(S)-PPB-eneketone (K r3 Amount of 16-(R,S)-PPB-enone (16-(R,S)-10): 48.5%.

[0175] Epimerization

[0176] Another advantage of our approach is that the "wrong" isomer 16-(S)-PPB-enone (16-(S)-10) can be epimerized in both basic and acidic media.

[0177] With respect to epimerization, it is noted that since the molecule is also sensitive to bases and acids (degradation / elimination would be expected), it was surprisingly found that the compound could be epimerized in acceptable yields. This was true for both acidic and basic conditions. The epimerization equilibrium was at approximately a 1:1 isomer ratio. Additional PPB-enone could be obtained by fractional crystallization from a reaction mixture containing a 1:1 ratio of PPB-enone diastereomers. Depending on the conditions used, the yield increase calculated based on 16-(R,S)-PPB-enone (which could be achieved by a single epimerization in this manner) was approximately 12%-17% (24%-34% based on 16-(S)-PPB-enone).

[0178] Repeated epimerization of 16-(S)-PPB-enone can significantly increase the yield of PPB-enone (theoretically up to almost 100%), but the by-products formed during the epimerization significantly reduce the maximum yield of PPB-enone. In our experience, repeated epimerization does not lead to a significant increase in yield.

[0179]

[0180] Considering the PPB-enone crystals obtained via epimerization, the yield of PPB-enone was 47% (calculated based on 16-(R,S)-PPB-enone).

[0181] The combined PPB-enone crystals can be recrystallized from a dichloromethane:TBME mixture in 98% yield to further increase its purity if desired.

[0182] Step 4: Restore

[0183] 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), the diastereomeric impurity 15-(S)-PPB-enol (15-(S), 16-(R)-11) is formed.

[0184]

[0185] The reduction can be performed according to conventional methods in the art.

[0186] Reduction with aqueous sodium borohydride in the presence of silica gel (US 6482959 B1) showed that a larger amount of the expected isomer was produced. After reduction, the isomer ratio in the crude product was PPB-enol:15-(S)-PPB-enol=6:4.

[0187] After reduction, the quenched and worked-up reaction mixture was used in the next reaction step without separation of the diastereomers.

[0188] Step 5: Deprotection, separation and crystallization

[0189] The final transformation is the removal of the p-phenylbenzoyl protecting group, which can be carried out, for example, by known methods commonly used in prostaglandin chemistry, by methanolysis in the presence of potassium carbonate. Other reagents may also be used, for example NaOMe / methanol, NaOH or other bases in a suitable aqueous-organic solvent mixture, or mineral acids in alcohols.

[0190] The desired product is then separated from the resulting mixture. Separation can be performed using methods known in the art such as crystallization or chromatography or a combination thereof. Preferably, chromatography is used, by which the desired 15-epimer can be separated from undesirable epimers and other impurities in one step.

[0191] Chromatography is preferably carried out, for example, on a silica gel column with dichloromethane:acetone as eluent. The fractions containing the desired epimer are combined and evaporated.

[0192] The evaporation residue corresponds to the hydroxyenol product having formula 1.

[0193] If desired, the hydroxyenol 1 can also be obtained in crystalline form by crystallizing the residue from an ethereal solvent or a mixture of ethereal solvents, preferably from a mixture of tert-butyl methyl ether and diisopropyl ether.

[0194] Yield: 48% of hydroxy enol (1) in the form of an oil [calculated based on PPB-enone (16-(R)-10)]

[0195] Yield: 35% crystalline hydroxy enol (1) [calculated based on PPB-enone (16-(R)-10)]

[0196] Preparation of racemic phosphonate (3-(R,S)-4) used as starting material

[0197] The racemic phosphonate (3-(R,S)-4) required for the HWE reaction can be prepared from known compounds by known chemical procedures. For our experiments, the racemic phosphonate (3-(R,S)-4) was prepared in two ways starting from 3-methylphenylacetic acid.

[0198] According to method A, in the first step, methylphenylacetic acid (12) is alkylated, the resulting methylphenylpropionic acid (13) is converted into a methyl ester (14), and the methyl ester is reacted with dimethyl methylphosphonate (DMMP) in the presence of a strong base to obtain a racemic phosphonate (3-(R,S)-4).

[0199] According to method B, the first two steps are reversed, ie, the starting methylphenylacetic acid (12) is first esterified with methanol, and the resulting methylphenylacetate (15) is alkylated to obtain methylphenylpropionate (14).

[0200]

[0201] Method A)

[0202] Alkylation of methylphenylacetic acid (12) was carried out with methyl iodide using either butyl lithium or lithium diisopropylamide (LDA) as base. For both bases, the conversion was above 99.5%, but lithium diisopropylamide was preferred for industrial feasibility as it does not require deep freezing and is safer to scale up.

[0203] The esterification of methylbenzene propionic acid (13) was carried out with methanol in the presence of concentrated hydrochloric acid or concentrated sulfuric acid. For both acids, the conversion was higher than 95%, so it is considered that the use of less corrosive sulfuric acid is more preferred.

[0204] Phosphonates (3-(R,S)-4) are prepared by reacting methyl methylbenzene propionate (14) with dimethyl methylphosphonate (DMMP) in the presence of a strong base. The base used in this case is also butyl lithium or lithium diisopropylamide. The use of butyl lithium produces fewer by-products, but the reaction requires deep freezing, while the reaction temperature of lithium diisopropylamide base is 0°C-10°C (J. Org. Chem. [Journal of Organic Chemistry] 2009, 74, 7574-7576).

[0205] Method B)

[0206] In method B), methylphenylacetic acid (12) is esterified in the first reaction step. The esterification is carried out in methanol in the presence of concentrated sulfuric acid. The resulting methylphenylacetic acid methyl ester (15) is alkylated with iodomethane in the presence of LDA.

[0207] The methyl toluenepropionate (14) thus obtained is converted into the phosphonate (3-(R,S)-4) as described in process A).

[0208] The above methods (both A and B) provide industrially applicable methods for preparing 3-(R,S)-4.

[0209] The yield of the compound of formula 3-(R,S)-4 calculated based on methylphenylacetic acid (Route A, Examples 8.1.2, 8.1.3 and 8.1.5) was 90.2%, (Route B, Example 8.2): 92.9%.

[0210] In summary, a novel process for preparing optically active hydroxy enols of formula 1 is disclosed. 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 WO 2010029925 A1 and WO2011111714 A1.

[0211] We have found that novel intermediate 16-(R,S)-PPB-enone can be prepared from readily available starting materials, is crystalline, and can be separated into diastereoisomers by fractional crystallization.

[0212] We have also found that the undesired isomer 16-(S)-PPB-enone can be epimerized in both alkaline and acidic media. In the equilibrium reaction mixture, the ratio of diastereomers is PPB-enone:16-(S)-PPB-enone=1:1.

[0213] After epimerization, fractional crystallization can provide additional amounts of the desired isomeric PPB-enone.

[0214] PPB-enone and its 16-dimers 16-(S)-PPB-enone and 16-(R,S)-PPB-enone are novel compounds.

[0215] We have found that PPB-enone (16-(R)-10) can be advantageously reduced with aqueous sodium borohydride in the presence of silica gel. The ratio of diastereoisomers formed during the reduction is PPB-enol:15-(S)-PPB-enol=6:4.

[0216] PPB-enol and its 15-dimers 15-(S)-PPB-enol and 15-(R,S)-PPB-enol are novel compounds.

[0217] Preferably, the compound of formula 16-(R,S)-10 can be prepared from an optically active core lactone (8) containing a p-phenylbenzoyl (PPB) protecting group, which can be used in large quantities in prostaglandin chemistry, and a racemic phosphonate of formula 3-(R,S)-4, which in turn can be prepared simply from inexpensive starting materials, by oxidizing the primary hydroxyl group of the PPB-core lactone (8) and reacting the PPB-core aldehyde (9) thus obtained with the racemic phosphonate (3-(R,S)-4) in a Horner-Wadsworth-Emmons (HWE) reaction. The product 16-(R,S)-PPB-enone contains diastereomers in a ratio of 1:1, which differ in the configuration of the 16-methyl group.

[0218] With regard to the yields of the process of the invention and known processes, we note the following:

[0219] Preparation of phosphonates of formula 4 and racemic phosphonates of formula 3-(R,S)-4 (starting materials for forming side chains):

[0220] - Known method, chiral synthesis (Examples 1 and 2 of EP 2343292):

[0221] Yield of chiral phosphonate of Formula 4 based on 2-(R)-(3-methylphenyl)propanoic acid of Formula 2: 75.9%

[0222] - The racemic synthesis described in this application:

[0223] 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%

[0224] Route B) (Example 8.2): Yield of racemic phosphonate of formula 3-(R,S)-4 based on methylphenylacetic acid of formula 12: 92.9%

[0225] By the methods described in this application, racemic phosphonates can be prepared from racemic starting materials in higher yields than known chiral phosphonates prepared from the corresponding chiral starting materials (90.2% and 92.9% yields, respectively, instead of 75.9%; in the latter case, the yield is calculated from the earlier starting material).

[0226] The hydroxy enol of formula 1 is prepared from the phosphonate of formula 4 and the racemic phosphonate of formula 3-(R,S)-4, respectively:

[0227] - Known method (Examples 3 to 5 of EP 2343292):

[0228] Starting from a chiral phosphonate of formula 4: 15.3%

[0229] - Process according to the invention [Examples 1.b. (considering the yield based on 3-(R,S)-4), (2+5.4), 6. and 7 (no crystallization)]:

[0230] Starting from a racemic phosphonate of formula (3-(R,S)-4): 14.8%

[0231] Relative to the good isomer, ie based on the compound having formula 4: 29.6%

[0232] Starting from racemic starting materials, we have almost reached the yields obtained starting from chiral starting materials according to known methods, i.e. starting from a given amount of racemic starting materials, we can produce almost the same amount of chiral target compound as produced by known methods starting from the same amount of chiral starting materials. If we calculate for the "good" isomer, the yield is almost doubled from 15.3 to 29.6.

[0233] Preparation of hydroxy enols of formula 1 from chiral or racemic (3-methylphenyl) propionic acid (the above two stages together)

[0234] - Known method (Examples 1 to 5 of EP 2343292):

[0235] Based on 2-(R)-(3-methylphenyl)propionic acid (compound having formula 2): 11.6%

[0236] - Process according to the invention [Examples 8.1.3., 8.1.5., 1.b (considering the yield based on 3-(R,S)-4), (2+5.4), 6. and 7 (no crystallization)]:

[0237] Based on 2-(R,S)-(3-methylphenyl)propionic acid (compound having formula 13): 13.3%

[0238] Relative to the good isomer, ie based on the compound having formula 2: 26.6%

[0239] Starting from the racemic starting material we have exceeded the yields described for the chiral starting material. If calculated based on the "good" isomer the yield is more than doubled from 11.6% to 26.6%.

[0240] Preparation of hydroxy enols of Formula 1 from "primary" prostaglandin starting materials:

[0241] - Known method (Examples 3 to 5 of EP 2343292):

[0242] Based on benzoyl-corial aldehyde (5): 17.0%

[0243] - Process according to the invention [Examples 1.b, (2+5.4), 6. and 7 (no crystallization)]:

[0244] Based on PPB-core lactone (8): 19.2%

[0245] An increase in yield of 2.2 percentage points was achieved, which corresponds to a relative increase of 13% (this value would be even higher if we could provide data for the aldehyde, but the sensitive aldehyde is not isolated from the reaction mixture, so we consider one more reaction step).

[0246] We note that, due to the incorporation of racemic side chains into the starting material, half of the material, in principle, does not form the desired end product. Therefore, if we carry out all steps in the same way with the same efficiency, the yield would theoretically be half that of the known method, i.e. 8.5% (compared to this, we achieved 19.2%).

[0247] However, we have achieved and even exceeded the yields of known processes by greatly increasing the overall yield of the process by incorporating racemic side chains and separating the desired isomers at a later intermediate stage of the process (by fractional crystallization). The increase in yield is presumably due to several factors, including:

[0248] - We avoid losses due to racemization of chiral side chains,

[0249] - separation of the racemic protected enone intermediate into its diastereomers by fractional crystallization is highly efficient (in addition, crystals containing a higher proportion of the undesired isomer can be diastereomerized and further fractionally crystallized to produce additional desired isomers)

[0250] - Reduction of the 15-oxo group is performed more efficiently (and under milder reaction conditions). Regarding the complete process starting from PPB-core lactone (8), we note the following:

[0251] The process is more economical than known processes because only one starting material is optically active, namely PPB-core lactone (8), which is available in large quantities. No expensive resolution of the racemic phosphonate (3-(R,S)-4) or its expensive stereoselective synthesis is required.

[0252] The overall yield is higher than that of known methods.

[0253] The hydroxy enol (1) prepared according to our process is preferably crystalline, whereas in the known process the product is not crystalline; its appearance or physical state is not described or characterized. However, the crystalline intermediate is easier to handle and is generally more stable than other forms (e.g. oils).

[0254] The diastereomeric mixture containing a p-phenylbenzoyl protecting group (16-(R,S)-PPB-enone) is crystalline, and the crystalline epimers of the diastereomeric enone can be separated by fractional crystallization. Note that the differences between the 16-(R,S)-PPB-enone epimers are very small, with only the small methyl group in different spatial positions, so it is surprising that the epimers can be separated by fractional crystallization.

[0255] • It has been found that the reduction of the 15-oxo group proceeds under mild conditions, thus eliminating the need to use the methods described in WO2010029925 A1 and WO 2011111714 A1 using chiral reagents and -40°C.

[0256] The following non-limiting examples serve to illustrate the invention.

[0257] The following parameters were used for X-ray, DSC and NMR recordings:

[0258] X-ray diffraction pattern:

[0259] Instrument: Panalytical X'pert Pro

[0260] Starting position [°2θ]: 2.0084

[0261] End position [°2θ]: 39.9864

[0262] Measurement temperature [℃]: 25.00

[0263] Anode material: Cu

[0264] K-α1 1.54060

[0265] K-α2 1.54443

[0266] DSC:

[0267] Instrument: METTLER TOLEDO DSC1 STARe system, Stare basic version V9.30

[0268] Method: Starting temperature: 30℃

[0269] Final temperature: 150℃

[0270] Heating rate: 5℃ / min

[0271] Amount: 2mg-6mg, porous aluminum crucible (40μl)

[0272] NMR:

[0273] Instrument: Bruker Avance III 500MHz

[0274] Solvent: DMSO

[0275] Example 1: Preparation of 16-(R,S)-PPB-eneketone

[0276] Oxidation and HWE reactions

[0277] 4-phenylbenzoic acid [(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]ester

[0278]

[0279] Example 1.a

[0280] Oxidation : Pfitzner-Moffat oxidation

[0281] 5.94 kg of p-phenylbenzoyl-corinamide (PPB-corinamide) (8) was suspended in 41 kg of distilled toluene, 9.0 kg of N,N-dicyclohexylcarbodiimide was added, and 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. While maintaining this temperature, the reaction mixture was stirred, and then 2×0.65 L of 0.75 M phosphoric acid in DMSO was added every 30 minutes. After adding the second 0.65 L of phosphoric acid in DMSO, stirring was continued for another 30 min.

[0282] HWE reaction

[0283] A solution of 3-(R,S)-4-phosphonate was added to the reaction mixture containing PPB-cory aldehyde (9) formed after oxidation at -30°C. After the HWE reaction was completed (about 40 min), 67 L of 1M sodium bisulfate solution was added to the reaction mixture and stirred at room temperature for about 1.5 hours. The crystallization reaction mixture was placed in a centrifuge and the centrifuged crystals were washed with 43 kg of dichloromethane. The filtrate and washings were combined, washed with 1M sodium bicarbonate solution to neutrality, 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 prepared with toluene using a mixture of dichloromethane and ethyl acetate. The fractions containing the product were combined, concentrated at atmospheric pressure, and the concentrate was crystallized with isopropanol. The crystal suspension was stirred at 0°C-5°C to complete the crystallization. The crystals were then filtered, washed and dried.

[0284] Yield: 5.56 kg (67%), melting point: 127°C-146°C.

[0285] Preparation of phosphonate solution (Base: Sodium hydride):

[0286] 0.943 kg of sodium hydride was weighed into 15.6 kg of distilled toluene in an anhydrous atmosphere and then at 0° C., 6.15 kg of 3-(R,S)-4-phosphonate in 11 L of distilled toluene was added at 0° C.-10° C. After the addition, cooling was stopped and the reaction mixture was stirred until complete dissolution.

[0287] Example 1.b

[0288] Oxidation : Annerelli Oxidation

[0289] 2.6g potassium bromide, 55.1g sodium bicarbonate, 77.0g PPB-Corey lactone (8), 0.683g TEMPO and 540mL dichloromethane were added to a mixture of 640mL dichloromethane and 33.5mL isopropanol. Under vigorous stirring, the reaction mixture was cooled to -5°C to 0°C, and 119mL sodium hypochlorite solution (1.93M aqueous solution) was added, and then stirred while maintaining the temperature. When the oxidation was complete, 390mL water and 77mL 20% sodium thiosulfate solution were added to the reaction mixture at 10°C-20°C. After addition, the reaction mixture was stirred at 30°C-35°C for about 30 minutes, and then each phase was separated, and the aqueous phase was extracted with 130mL dichloromethane. The combined organic phase contained 9PPB-Corey aldehyde, which was used for the next reaction step (HWE reaction) without further purification.

[0290] HWE reaction

[0291] Under an inert atmosphere, the solution of PPB-Cory aldehyde (9) formed in the oxidation step is added to the phosphonate solution cooled to 0°C-5°C, and the reaction mixture is then stirred while maintaining the temperature. After the reaction is complete, the reaction mixture is poured onto 180 ml of 2M sodium bisulfate solution at 5°C-10°C.

[0292] And after stirring, the phases were separated, the organic phase was concentrated under reduced pressure and the solvent of the concentrate was changed to isopropanol. During concentration, crystallization began. Additional isopropanol was added to the crystallization reaction mixture, which was then stirred at 0°C-5°C for 3 hours. The crystals were filtered, washed with chilled isopropanol and dried.

[0293] Yield: 91.86 g (85%).

[0294] Preparation of phosphonate solution (Alkali: potassium hydroxide aqueous solution):

[0295] At room temperature under inert atmosphere, 76.77 g of the phosphonate (3-(R,S)-4) were weighed into 146 mL of dichloromethane 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.

[0296] The DSC curve of 16-(R,S)-PPB-eneketone is shown in Figure 1 middle.

[0297] The powder X-ray diffraction pattern of 16-(R,S)-PPB-enone is shown in Figure 2 The characteristic peaks are listed in Table 1 below.

[0298] Table 1

[0299]

[0300]

[0301] 16-(R,S)-PPB-eneketone 13 C NMR and 1 The assignments of the H NMR spectra are shown in Table 2 below.

[0302]

[0303] The structures and numbering of PPB-enone (A) and 16-(S)-PPB-enone (B) used for NMR data

[0304] Table 2

[0305]

[0306]

[0307]

[0308] $ :and 13 The C NMR signals partially overlap. $$ : Partially overlapping 13 C NMR signals. *, **, + , ++ , +++ , & , && , &&& , # , ## , Partially overlapping 1 H NMR signal. + : With DMSO-d 6 Solvent 1 H NMR signals partially overlap. ***、 ++ , & , &&& , ## , ### :Unknown impurities in the sample 1 The H NMR signals partially overlap.

[0309] Example 2 (reference example): Preparation of PPB-eneketone (16-(R)-10)

[0310] Column chromatography

[0311] 4-phenylbenzoic acid [(3aR,4R,5R,6aS)-4-[(E,4R)-4-(m-tolyl)-3-oxo-pent-1-ene [2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl]ester

[0312]

[0313]

[0314] 1.595 g of 16-(R,S)-PPB-enone (16-(R,S)-10) was dissolved in 5 ml of chloroform: tert-butyl methyl ether = 30: 1. Chromatography was performed on a column made of 50 g of silica gel using chloroform: tert-butyl methyl ether = 30: 1 and 10: 1 as eluents.

[0315] The epimer having the formula 16-(R)-10 eluted first and the epimer having the formula 16-(S)-10 eluted thereafter, both as oils.

[0316] Yield: PPB-enone: 0.367 g, 23% (oil that crystallized upon standing)

[0317] 16-(S)-PPB-enone: 0.073 g, 4.6% (oil that crystallized upon standing)

[0318] The obtained crystals can be used as seeds in fractional crystallization.

[0319] Example 3: Preparation of PPB-eneketone (16-(R)-10)

[0320] Fractional crystallization

[0321] 4-phenylbenzoic acid [(3aR,4R,5R,6aS)-4-[(E,4R)-4-(m-tolyl)-3-oxo-pent-1-ene [2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl]ester

[0322]

[0323] Example 3.a.: Fractional crystallization with tert-butyl methyl ether

[0324] 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 reflux for about 30 minutes, the mixture was cooled to 30°C-32°C and stirred for another 30 minutes while maintaining the temperature. The crystals (K r1 ) filtered, washed and dried. First, the undesirable isomer 16-(S)-PPB-enone precipitated; in the filtered crystals, the ratio of 16-(S)-PPB-enone:PPB-enone was about 78:22.

[0325] The filtrate combined with the washing solution was seeded with PPB-enone crystals (16-(R)-10), and the suspension was cooled to 0°C to 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.

[0326] In the filtrate combined with the washing liquid, the previously filtered K r1 Crystals (16-(S)-PPB-enone, 16-(S)-10) were suspended, and the suspension was heated to reflux. After reflux for about 30 minutes, the mixture was cooled to 30°C-32°C and stirred for an additional hour while maintaining the temperature. r3 , 16-(S)-PPB-enone, 16-(S)-10) was filtered, washed and dried.

[0327] Yield of 16-(S)-PPB-enone: 2.706 kg (48.5%), purity greater than 85% (HPLC)

[0328] 16-(S)-PPB-enone can be further purified according to Example 4.

[0329] The filtrate combined with the washing liquid was seeded with PPB-enone (16-(R)-10), cooled to 0°C to 5°C, and stirred for 1 hour while maintaining the temperature. r4 )(PPB-enone, 16-(R)-10) was filtered, washed with cold (0°C-5°C) tert-butyl methyl ether and dried.

[0330] PPB-eneketone (K r2 and K r4 Yield: 1.71 kg (31%) of colorless crystals.

[0331] The combined PPB-enone (16-(R)-10) crystals were dissolved in a tert-butyl methyl ether: dichloromethane = 5:1 mixture (10.3 L) at 40° C.-42° C., and about 25 L of tert-butyl methyl ether was added thereto, seeded with PPB-enone (16-(R)-10), and after stirring for about 30 minutes, the suspension was cooled to 0° C.-5° C. After stirring for about 1 hour, the crystals were filtered, washed with cold tert-butyl methyl ether and dried.

[0332] Yield: 1.67 kg (98%), colorless crystals.

[0333] Yield of PPB-enone obtained by fractional crystallization of the diastereomeric mixture 16-(R,S)-PPB-enone (in TBME solvent): 1.67 kg (30%).

[0334] Isomer ratio in the PPB-enone product thus obtained determined by HPLC:

[0335] PPB-enone:16-(S)-PPB-enone=99.6:0.4

[0336] The DSC curve of PPB-eneketone is shown in Figure 3 middle.

[0337] The powder X-ray diffraction pattern of PPB-eneketone is shown in Figure 4 The characteristic peaks are listed in Table 3 below.

[0338] Table 3

[0339]

[0340]

[0341] PPB-eneketone 13 C NMR and 1 The assignments of the H NMR spectra are given in Table 4 below.

[0342]

[0343] Structure and numbering of PPB-enone as used for NMR data

[0344] Table 4

[0345]

[0346]

[0347] $ : Partially overlapping 13 C NMR signals. *, **, ***, ## : Partially overlapping 1 H NMR signal. # :With sample impurities 1 The H NMR signals partially overlap. & : With DMSO solvent 1 The H NMR signals overlap.

[0348] Example 3.b: Fractional crystallization with methanol

[0349] 5.58 g of 16-(R,S)-PPB-enone (16-(R,S)-10) was suspended in 167 mL of methanol and then heated to reflux. After reflux for about 30 minutes, the mixture was cooled to 30°C-32°C and stirred for another 30 minutes while maintaining the temperature. The crystals (K r1) filtered, washed and dried. First, the undesired isomer 16-(S)-PPB-enone precipitates.

[0350] The filtrate combined with the washings was seeded with PPB-enone crystals (16-(R)-10), and the suspension was cooled to 0°C-5°C and stirred for 1 hour. r2 , PPB-enone, 16-(R)-10) was filtered, washed with cold (0°C-5°C) methanol and dried.

[0351] In the filtrate combined with the washing liquid, the previously filtered K r1 Crystals (16-(S)-PPB-enone, 16-(S)-10) were suspended, and the suspension was heated to reflux. After reflux for about 30 minutes, the mixture was cooled to 30°C-32°C and stirred for an additional hour while maintaining the temperature. r3 , 16-(S)-PPB-enone, 16-(S)-10) was filtered, washed and dried. This gave 2.9 g of K r3 Crystals (yield 52%), purity greater than 78% (HPLC).

[0352] The filtrate combined with the washing liquid was seeded with PPB-enone (16-(R)-10), cooled to 0°C to 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.

[0353] Yield (K r2 and K r4 Crystals): 1.69 kg (30%) colorless crystals.

[0354] The combined PPB-enone (16-(R)-10) crystals were dissolved in a methanol: dichloromethane = 5:1 mixture at 40° C.-42° C., and about 25 mL of methanol was added thereto, seeded with PPB-enone (16-(R)-10), and after stirring for about 30 minutes, the suspension was cooled to 0° C.-5° C. After stirring for about 1 hour, the crystals were filtered, washed with cold methanol and dried.

[0355] The precipitated crystals were dissolved in methanol:dichloromethane=5:1, and the above crystallization was repeated.

[0356] Yield (for two recrystallization steps): 1.62 g (96%), colorless crystals.

[0357] Yield of PPB-enone obtained by fractional crystallization of the diastereomeric mixture 16-(R,S)-PPB-enone (in methanol solvent): 1.62 g (29%).

[0358] Isomer ratio in the PPB-enone product thus obtained determined by HPLC:

[0359] PPB-enone: 16-(S)-PPB-enone = 97.89: 2.11

[0360] Notice : When this method is repeated several times, at about every fourth repetition, the precipitated K r2 +K r4 The amount of crystals increased from 1.69 g to 1.70 g-1.75 g and contained more than 10% of the undesired epimer 16-(S)-PPB-enone.

[0361] The DSC curve of PPB-eneketone is shown in Figure 5 middle.

[0362] The powder X-ray diffraction pattern of PPB-ene ketone is shown in Figure 6 The characteristic peaks are listed in Table 5 below.

[0363] Table 5

[0364]

[0365]

[0366] PPB-eneketone 13 C NMR and 1 The assignments of the H NMR spectra are given in Table 6 below.

[0367]

[0368] Structure and numbering of PPB-enone as used for NMR data

[0369] Table 6

[0370]

[0371]

[0372]

[0373] $ : Partially overlapping 13 C NMR signals. *, **, ***, ## : Partially overlapping 1 H NMR signal. # :With sample impurities 1 The H NMR signals partially overlap. & : With DMSO solvent 1 The H NMR signals overlap.

[0374] Example 4: Crystallization of 16-(S)-PPB-eneketone (16-(S)-10)

[0375] 4-phenylbenzoic acid [(3aR,4R,5R,6aS)-4-[(E,4S)-4-(m-tolyl)-3-oxo-pent-1-ene [2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl]ester

[0376] 10 g of K prepared in Example 3.a was added 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 under stirring at room temperature. The precipitated crystals were filtered, washed, dried, and then the crystallization was repeated twice. The final crystallized product (16-(S)-PPB-enone) contained less than 2% of PPB-enone.

[0377] Yield: 6.4 g (64%), melting point: 168.6°C-169.5°C

[0378] The DSC curve of 16-(S)-PPB-eneketone is shown in Figure 7 middle.

[0379] The powder X-ray diffraction pattern of 16-(S)-PPB-eneketone is shown in Figure 8 The characteristic peaks are listed in Table 7 below.

[0380] Table 7

[0381]

[0382]

[0383] 16-(S)-PPB-eneketone 13 C NMR and 1 The assignments of the H NMR spectra are given in Table 8 below.

[0384]

[0385] Structure and numbering of 16-(S)-PPB-enone as used for NMR data

[0386] Table 8

[0387]

[0388]

[0389] $ :With PPB-IP-eneketone 13 The C NMR signals partially overlap. $$ : Partially overlapping 13 C NMR signal. *, +++, & : Partially overlapping 1 H NMR signal. **、***、 + , ++ , # , ### , & :With PPB-IP-ene ketone impurity 1 The H NMR signals partially overlap. ## :With unknown impurities 1 The H NMR signals partially overlap.

[0390] Example 5: Epimerization of 16-(S)-PPB-enone (16-(S)-10) followed by preparation of PPB-enone from the mixture by fractional crystallization according to Example 3.a

[0391] Example 5.1

[0392] 5.000 g is used as K in Example 3.a. r3 The obtained 16-(S)-PPB-enone (16-(S)-10) was dissolved in 100 mL of ethyl acetate, to which 5.0 g of silica gel and 2.50 mL of triethylamine were then added, and stirred at 55° C.-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, filtered, and 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 give PPB-enone (16-(R)-10).

[0393] Yield of PPB-enone: 1.442 g (29%, based on 16-(S)-PPB-enone (K r3 ) calculated; 14.5%, calculated based on the starting 16-(R,S)-PPB-enone).

[0394] Example 5.2

[0395] 5.000 g is used as K in Example 3.a. r3 The obtained 16-(S)-PPB-enone (16-(S)-10) was dissolved in 150 mL of ethyl acetate, to which 75.0 g of alumina was added, which was then stirred at 20°C-25°C for about 1.5 hours. At the end of the reaction, the isomer ratio was about 1:1, and 10%-15% of by-products were formed. The reaction mixture was then cooled, filtered, and 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 give PPB-enone (16-(R)-10).

[0396] Yield: 0.865 g (17%, calculated based on 16-(S)-PPB-enone; 8.5%, calculated based on 16-(R,S)-PPB-enone).

[0397] Example 5.3

[0398] 5.000 g is used as K in Example 3.a. r3 The obtained 16-(S)-PPB-eneketone (16-(S)-10) was dissolved in 100 mL of toluene, and 0.500 g of pTsOH. 2 O in 2.5 mL of tetrahydrofuran, which was then stirred at 65°C-75°C for about 15 hours-20 hours. At the end of the reaction, the isomer ratio was about 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 give PPB-enone (16-(R)-10).

[0399] Yield: 1.698 g (34% calculated on 16-(S)-PPB-enone; 17% calculated on 16-(R,S)-PPB-enone).

[0400] Example 5.4

[0401] 57.771 g is used as K in Example 3.a. r3 The obtained 16-(S)-PPB-enone (16-(S)-10) was dissolved in 1155 mL of ethyl acetate, to which 28.8 g of silica gel and 57.7 ml of triethylamine were added, and then stirred at 55° C.-65° C. for about 12 hours. At the end of the reaction, the isomer ratio was about 1:1, and 10%-15% of by-products were formed. The reaction mixture was then cooled, filtered, and 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 give PPB-enone (16-(R)-10).

[0402] Yield: 20.10 g (34.8%, calculated based on 16-(S)-PPB-enone; 17.4%, calculated based on 16-(R,S)-PPB-enone).

[0403] The obtained PPB-enone (16-(R)-10) crystals can be recrystallized from a mixture of tert-butyl methyl ether: dichloromethane = 5:1 as described in Example 3.a.

[0404] Yield: 19.70 g (98%).

[0405] Example 6, Reduction of PPB-eneketone

[0406] Reduction of 15-oxo group

[0407] 4-Phenylbenzoic acid [(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]ester

[0408]

[0409] Reduction with sodium borohydride in the presence of silica gel:

[0410] 1.51kg PPB-enone (16-(R)-10) is dissolved in 13.7L dichloromethane, 2.04kg silica gel is added, and the suspension is cooled to 0°C ± 5°C under an inert atmosphere. Under vigorous stirring, a solution of 0.183kg sodium borohydride in 340mL water is added. The reaction mixture is stirred while maintaining the temperature. After stirring for 1 hour, 270mL methanol is added. After the reduction is complete (about 5 hours-8 hours), a solution of 515mL concentrated hydrochloric acid in 2.05L water is carefully added at 0°C ± 5°C, and then 1.36L methanol is added after cooling is stopped. After stirring for about 20 minutes, the reaction mixture is filtered, the filtered solid is washed with dichloromethane: methanol = 5: 1, the combined filtrate is fully stirred, and each phase is separated. The organic layer is washed with water, and then washed with a saturated sodium chloride solution, dried over sodium sulfate, and then the desiccant is filtered out, washed and evaporated.

[0411] Yield: 1.52 kg (100%), viscous oil. Isomer ratio: PPB-enol: 15-(S)-PPB-enol = 6:4.

[0412] Example 7, Removal of PPB Protecting Group

[0413] (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

[0414]

[0415]

[0416] At 40°C-45°C, 1.36 kg of PPB-enol (15-(R,S), 16-(R)-11) of Example 6 was dissolved in 4.9 L of distilled methanol, and 0.38 kg of potassium carbonate was added. While maintaining the temperature, the reaction mixture was stirred for 1 hour, then cooled to 0°C-5°C, and 4.28 L of 1 M hydrochloric acid solution was added. While maintaining the temperature, stirring was continued for 1 hour, and then the precipitated crystals were filtered out and washed with a methanol-water mixture. 3.62 L of 1 M hydrochloric acid was added to the combined filtrate, and it was stirred at room temperature for 30 minutes-45 minutes. After the stirring was completed, the reaction mixture was concentrated under reduced pressure. The concentrated solution was extracted with 2×10 L of dichloromethane, the combined organic phase was washed with 1 M sodium bicarbonate, the washing solution was extracted with 5 L of dichloromethane, the combined organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate, the desiccant was filtered out, washed with dichloromethane, and the washing solution was added to the organic phase. The combined organic phases were concentrated under reduced pressure (to about 3.5 kg).

[0417] The evaporated concentrate was purified by chromatography on a silica gel column prepared with a dichloromethane:acetone=7:1 solvent mixture using dichloromethane:acetone=7:1 and thereafter dichloromethane:acetone=2:1 solvent mixture as eluent. The product-containing fractions were combined and concentrated under reduced pressure.

[0418] Yield: 415.93 g (48%) thick oil.

[0419] Preference is given to crystallizing the evaporation residue.

[0420] To this end, the evaporation residue was dissolved in tert-butyl methyl ether using a bath at 40° C. to 50° C. and then cooled to 0° C. to 5° C. with stirring. After the start of crystallization, the crystal suspension was stirred for an additional 25 to 35 minutes and crystallization was completed by adding diisopropyl ether. While maintaining this temperature, the mixture containing the precipitated crystals was stirred for an additional hour.

[0421] The crystals were filtered, washed and dried at room temperature to constant weight.

[0422] Yield: 303.6 g (73% for the crystallization step), colorless crystals.

[0423] Although the compound itself is known, for example from patent applications Nos. WO 2010029925 A1 and WO2011111714 A1, crystalline forms of the compound are not described or characterized therein.

[0424] The crystal form is characterized by a melting point of 72.5°C-73.4°C and an optical rotation [α] D =25° (measured in 1% ethanol solution at 20°C).

[0425] The DSC curve of the crystalline hydroxy enol is shown in Fig. 9 middle.

[0426] The powder X-ray diffraction pattern of hydroxy enol is shown in Fig.10 The characteristic peaks are listed in Table 9 below.

[0427] Table 9

[0428]

[0429] Hydroxy enolate 13 C NMR spectroscopy and 1 The assignments of the H NMR spectra are shown in Table 10 below.

[0430]

[0431] Structure and numbering of hydroxy enols

[0432] Table 10

[0433]

[0434]

[0435] $ : Partially overlapping 13 C NMR signals. *, **, ***, + , ++ : Partially overlapping 1 H NMR signal

[0436] Example 8, Preparation of racemic phosphonates

[0437] (2-Oxo-3-m-tolyl-butyl)-phosphonic acid dimethyl ester

[0438] Example 8.1, Route A

[0439] Starting Materials :Methylphenylacetic acid

[0440] Reaction steps :Alkylation (methylation)

[0441] Esterification (formation of methyl ester)

[0442] Phosphonate formation

[0443]

[0444] 8.1.1. Preparation of methylbenzene (13)

[0445] a.) Base: Butyl lithium

[0446] 4.31kg methylphenylacetic acid (12) is dissolved in 38.0kg anhydrous tetrahydrofuran. Under an inert atmosphere, the reaction mixture is cooled to -60°C to -75°C, and 26.2kg 15% butyl lithium solution is added. After the addition, the reaction mixture is stirred for another 15 minutes, and then 805mL diisopropylamine (DIPA) is added while maintaining the temperature. After stirring for 15 minutes, the reaction mixture is heated to -30°C, and 3.60L iodomethane is added. Cooling is stopped, and after stirring for 10min, the reaction mixture is loaded on 98L 1M sodium bisulfate. After sedimentation, each phase is separated, and the aqueous phase is extracted with tert-butyl methyl ether. The combined organic phase is washed with saturated sodium chloride solution (3x 32kg), and in the first washing step, 81.8g sodium pyrosulfite is also added to the mixture. The organic layer is dried over sodium sulfate, the desiccant is filtered out, washed, and the filtrate is evaporated under reduced pressure.

[0447] Yield: 4.62 kg (98%), orange liquid.

[0448] 8.1.2. Preparation of methylbenzene (13)

[0449] b.) Base: lithium diisopropylamide (LDA)

[0450] Preparation of LDA solution :

[0451] 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 butyl lithium solution was added. The reaction mixture was stirred at -10°C for 2 hours.

[0452] Alkylation :

[0453] 80g of methylphenylacetic acid (12) was dissolved in 800mL of anhydrous tetrahydrofuran. Under an inert atmosphere, the solution was cooled to -20°C, and then, while maintaining the temperature, the prepared LDA solution was added thereto. The reaction mixture was stirred at -10°C for 30 minutes, and then 40mL of iodomethane was added at -20°C to -10°C. After addition, the reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was then quenched with 1200mL of 2M sodium bisulfate solution, and after vigorous mixing, each phase was separated. The aqueous phase was extracted with tert-butyl methyl ether. The combined organic phase was washed twice with saturated sodium chloride solution, and in the first washing step, 1.52g of sodium pyrosulfite was also added to the mixture. The organic layer was dried over sodium sulfate, the desiccant was filtered out, washed, and the filtrate was evaporated under reduced pressure.

[0454] Yield: 87.5 g (100%), orange liquid.

[0455] 8.1.3. Preparation of methyl methylbenzene (14)

[0456] a.) Esterification using hydrochloric acid

[0457] 4.60 kg of methylbenzene propionic acid (13) was dissolved in 35 kg of distilled methanol, 350 ml of concentrated hydrochloric acid was added, and it was stirred at room temperature. After reaching the desired conversion rate (about 12 hours), 1.17 L of triethylamine was added to the reaction mixture, which was then concentrated to about 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 a saturated sodium chloride solution, dried over sodium sulfate, the desiccant was filtered out, washed with toluene, and the filtrate was evaporated under reduced pressure.

[0458] Yield: 4.74 kg (95%), yellow liquid.

[0459] 8.1.4. Preparation of methyl methylbenzene (14)

[0460] b.) Esterification using sulfuric acid

[0461] 4.60 kg of methylbenzene propionic acid (13) was dissolved in 36 kg of distilled methanol, 225 ml of concentrated sulfuric acid was added, and it was stirred at 20° C.-25° C. After 1 hour, 890 g of sodium carbonate was added to the reaction mixture under vigorous stirring, and it was then concentrated to about 4.6 kg under reduced pressure. 32 kg of tert-butyl methyl ether was added to the concentrate, it was washed three times with 10% sodium carbonate solution, and the combined aqueous phases were extracted once with tert-butyl methyl ether, the combined organic phases were dried over sodium sulfate, the desiccant was filtered off, washed, and the combined filtrate was evaporated.

[0462] Yield: 3.25 kg (65%), yellow liquid.

[0463] 8.1.5. Preparation of racemic phosphonate (3-(R,S)-4)

[0464] a.) Base: Butyl lithium

[0465] Under an inert atmosphere, 23.8 kg of 15% butyl lithium solution was added to 49 kg of distilled toluene, and the reaction mixture was then cooled to -75°C to -85°C, and while maintaining the temperature, a solution of 8.25 kg of dimethyl methylphosphonate (DMMP) in 24 kg of distilled toluene was added. While maintaining the temperature, the reaction mixture was stirred for 30 minutes, and then at -75°C to -85°C, a solution of 4.74 kg of methylbenzene propionate (14) in 20 kg of distilled toluene was added. After stirring for 30 minutes, the reaction mixture was loaded onto a mixture of 70 L of 1 M sodium bisulfate solution and 13 L of saturated sodium chloride solution. The mixture was stirred at room temperature for 30 minutes, the phases were separated after settling, and the aqueous phase was extracted with 2×20 L of toluene, the combined organic phase was washed with a saturated sodium chloride solution, and dried over sodium sulfate. The desiccant was filtered out, washed, and the combined filtrate was evaporated under reduced pressure.

[0466] Yield: 6.83 kg (95%), light yellow oil.

[0467] 8.1.6. Preparation of racemic phosphonate (3-(R,S)-4)

[0468] b.) Base: LDA

[0469] Preparation of LDA solution :

[0470] Under inert atmosphere, a solution of 13.9 mL of diisopropylamine in 45 mL of anhydrous tetrahydrofuran was cooled to 0°C, and 54 mL of butyllithium solution (1.6 M in hexane) was added dropwise. After the addition, it was stirred for 20 minutes.

[0471] Phosphonate formation:

[0472] To a solution of 6.36 g of methyl phenylpropionate (14) in 64 ml of anhydrous tetrahydrofuran, 37.7 ml of dimethyl methylphosphonate are added under an inert atmosphere. The prepared LDA solution is added dropwise at 0° C. After stirring for 5-10 minutes, the reaction mixture is acidified with 5N hydrochloric acid (pH=2-3) under vigorous stirring, and the phases are separated, the aqueous phase is extracted with ethyl acetate, the organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulfate, the desiccant is filtered off, washed, and the combined filtrates are evaporated. Yield: 8.91 g (92.4%).

[0473] Example 8.2, Route B

[0474] Starting Materials :Methylphenylacetic acid

[0475] Reaction steps :Esterification (formation of methyl ether)

[0476] Alkylation (methylation)

[0477] Phosphonate formation

[0478]

[0479] Preparation of methyl phenylacetate (15)

[0480] 31.74 g of methylphenylacetic acid (12) was dissolved in 315 ml of methanol. While stirring at room temperature, 1.8 ml of concentrated sulfuric acid was added thereto. After the reaction was completed (2 hours to 3 hours), the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 210 ml of dichloromethane, washed with 1 M sodium bicarbonate solution, and then washed with saturated brine, dried over sodium sulfate, the desiccant was filtered out, washed, and the combined filtrate was evaporated.

[0481] Yield: 34.11 g (98.3%) of oil.

[0482] Preparation of methyl methylbenzene propionate (14)

[0483] 19.2mL diisopropylamine is dissolved in 345mL anhydrous tetrahydrofuran. Under inert atmosphere, it is cooled to -60 ℃, and 85.9mL 1.6M solution of butyl lithium in hexane is added dropwise while stirring. After post-stirring for 10 minutes, a solution of 15.01g methyl phenylacetic acid methyl ester (15) in 16ml anhydrous tetrahydrofuran is added dropwise to the reaction mixture. After post-stirring for 10 minutes, 15mL iodomethane is added. After stirring for 15 minutes, the reaction mixture is poured on 340mL 2N hydrochloric acid. Separate each phase, extract the aqueous phase with diisopropyl ether, wash the organic phase with 1M sodium bicarbonate solution, then wash with saturated brine, dry over sodium sulfate, filter out the desiccant, wash, and evaporate the combined filtrate.

[0484] Yield: 16.21 g (99.5%).

Claims

1. A method for preparing a compound of formula 1, The Method The following steps are involved: The compound having the formula 16-(R,S)-10 is separated into its diastereoisomers 16-(R)-10 and 16-(S)-10 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, removing the protecting group of the compound of formula 15-(R,S),16-(R)-11 to separate the compound of formula 1, and optionally, crystallizing the compound of Formula 1.

2. The method according to claim 1, in, The solvent used for the fractional crystallization of the compound of formula 16-(R,S)-10 is selected from C 1-3 alcohol, tert-butyl methyl ether and mixtures thereof.

3. The method according to claim 2, in, The solvent is selected from methanol, tert-butyl methyl ether and a mixture thereof.

4. The method according to claim 2, in, The fractional crystallization of the compound having the 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° C. to 35° C. and stirring while maintaining the temperature, then filtering, washing and drying the precipitated crystals to obtain crystal K r1 ; (b) seeding the filtrate combined with the washing liquid with the crystals of the compound of formula 16-(R)-10, cooling the suspension to 0° C. to 5° C. and stirring while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystals K r2 ;as well as Optionally (c) The previously filtered crystals K r1 The mixture was suspended in the filtrate combined with the washing solution, the suspension was refluxed, and then the mixture was cooled to 25° C. to 35° C. and stirred while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystalline K r3 ;as well as (d) seeding the filtrate combined with the washing liquid with the crystals of the compound of formula 16-(R)-10, cooling to 0° C. to 5° C. and stirring while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystals K r4 , wherein in step (a) and optionally in step (c) as crystalline K r1 and K r3 A compound of formula 16-(S)-10 is obtained and in step (b) and optionally in step (d) as a crystalline K r2 and K r4 A compound having the formula 16-(R)-10 is obtained.

5. The method according to claim 4, comprising the further step of: 1-3 alcohol, tert-butyl methyl ether and a mixture thereof; or recrystallize these crystals from a mixture of the solvent and dichloromethane. r2 and / or K r4 .

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

7. The method according to any one of claims 4 to 6, comprising the further step of: subjecting the obtained crystal K r1 or K r3 Epimerization under acidic or basic conditions, followed by repeated fractional crystallization according to any one of claims 4 to 6.

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

9. The method according to any one of claims 1 to 6, in, The 15-oxo group of the compound of formula 16-(R)-10 is reduced with aqueous sodium borohydride in the presence of silica gel.

10. The method according to any one of claims 1 to 6, in, The compound of formula 1 is isolated by chromatography.

11. The method according to claim 10, in, The chromatography was performed on a silica gel column using dichloromethane:acetone as eluent.

12. The method according to any one of claims 1 to 6, in, The obtained compound of formula 1 is crystallized from an ethereal solvent or a solvent mixture.

13. The method according to claim 12, in, The solvent is a mixture of tert-butyl methyl ether and diisopropyl ether.

14. The method according to any one of claims 1 to 6, in, The compound of formula 16-(R,S)-10 is prepared by reacting an aldehyde of formula 9 with a racemic phosphonate of formula 3-(R,S)-4:

15. The method according to claim 14, in, The reaction is carried out with potassium hydroxide base at 20°C to 25°C or with sodium hydride at 0°C to 10°C.

16. The method according to claim 14, in, According to variant A) or B), the racemic phosphonate of formula (3-(R,S)-4) is prepared by the following reaction scheme: Among them, variant A) includes: Alkylation of a methylphenylacetic acid having formula 12; The resulting methylbenzene propionic acid of formula 13 is converted into a methyl ester of formula 14 using methanol in the presence of an acid; The methyl ester of formula 14 is then reacted with dimethyl methylphosphonate (DMMP) in the presence of a strong base to obtain a racemic phosphonate of formula 3-(R,S)-4; And variant B) comprises: Converting methylphenylacetic acid having formula 12 to methylphenylacetate having formula 15 using methanol in the presence of an acid; Alkylating the methyl phenylacetic acid methyl ester of formula 15 to obtain the methyl ester of formula 14; The methyl ester of formula 14 is then reacted with dimethyl methylphosphonate (DMMP) in the presence of a strong base to obtain the racemic phosphonate of formula 3-(R,S)-4.

17. A compound having the formula 16-(R,S)-10:

18. A compound having the formula 16-(R)-10:

19. A compound having the formula 16-(S)-10:

20. A compound having the formula 15-(R,S),16-(R)-11:

21. A method for fractional crystallization of a compound of formula 16-(R,S)-10, This method uses a selection from C 1-3 Solvents of alcohol, tert-butyl methyl ether and mixtures thereof; The method includes (a) suspending the compound of formula 16-(R,S)-10 in the solvent, refluxing the suspension, then cooling the mixture to 25° C. to 35° C. and stirring while maintaining the temperature, then filtering, washing and drying the precipitated crystals to obtain crystal K r1 ; (b) seeding the filtrate combined with the washing liquid with crystals of the compound of formula 16-(R)-10, cooling the suspension to 0° C. to 5° C. and stirring while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystals K r2 ;as well as Optionally (c) The previously filtered crystals K r1 The mixture was suspended in the filtrate combined with the washing solution, the suspension was refluxed, and then the mixture was cooled to 25° C. to 35° C. and stirred while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystalline K r3 ;as well as (d) seeding the filtrate combined with the washing liquid with the crystals of the compound of formula 16-(R)-10, cooling to 0° C. to 5° C. and stirring while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystals K r4 , wherein in step (a) and optionally in step (c) as crystalline K r1 and K r3 A compound of formula 16-(S)-10 is obtained and in step (b) and optionally in step (d) as a crystalline K r2 and K r4 A compound having the formula 16-(R)-10 is obtained, and optionally, Selected from C 1-3 alcohol, tert-butyl methyl ether and a mixture thereof; or the crystals obtained by recrystallization from a mixture of the solvent and dichloromethane.

22. The method according to claim 21, in, The solvent used for the fractional crystallization and recrystallization is selected from methanol, tert-butyl methyl ether and mixtures thereof.

23. A method for preparing a compound of formula 16-(S)-10, The method includes (a) suspending a compound having the formula 16-(R,S)-10 in a mixture selected from C 1-3 The suspension is refluxed in a solvent of alcohol, tert-butyl methyl ether and a mixture thereof, and then the mixture is cooled to 25° C. to 35° C. and stirred while maintaining the temperature, and then the precipitated crystals are filtered, washed and dried to obtain crystalline K r1 ; and optionally (b) seeding the filtrate combined with the washing liquid with crystals of the compound of formula 16-(R)-10, cooling the suspension to 0° C. to 5° C. and stirring while maintaining the temperature, followed by filtering the precipitated crystals; and (c) The previously filtered crystals K r1 The mixture was suspended in the filtrate, the suspension was refluxed, and then the mixture was cooled to 25° C. to 35° C. and stirred while maintaining the temperature, followed by filtering, washing and drying the precipitated crystals to obtain crystalline K r3 ; and optionally, from dichloromethane and selected from C 1-3 The crystal K obtained by recrystallization from a mixture of a solvent of alcohol, tert-butyl methyl ether and a mixture thereof r1 or K r3 , thereby obtaining the compound having formula 16-(S)-10.

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