Method for producing intermediate compound for synthesizing posaconazole and intermediate compound produced using the same

Abstract

The present invention relates to a method for preparing a compound which is an intermediate for synthesizing the drug posaconazole, and the intermediate compound prepared thereby. The method for preparing the compound of formula I provided by the present invention includes using methyl 4-(2,4-difluorophenyl)-4-pentenoate or its reduction product 4-(2,4-difluorophenyl)-4-pentenecarboxaldehyde as starting material, reacting it with formaldehyde or polyformaldehyde in the presence of a chiral catalyst, then carrying out specific oxidation, esterification and halogenation cyclization, and further hydrolysis and acid treatment. The preparation method of the present invention has the advantages of mild reaction conditions, simple reaction process, high total yield and high purity of the target product, and is suitable for industrial production. TIFF2025509925000049.tif38153

Description

[Technical field]

[0001] The present invention relates to the field of medicinal chemistry, and more specifically to methods for preparing compounds that are intermediates for the preparation of posaconazole, and to intermediate compounds prepared using these methods. [Background technology]

[0002] Posaconazole is a second-generation antifungal drug used for immunocompromised patients or patients for whom other antifungal drugs such as amphotericin B, fluconazole, and itraconazole are ineffective, and patients who are not resistant to these antibacterial drugs. Posaconazole was first launched in Europe on October 25, 2005, and was subsequently approved for sale by the US FDA on September 15, 2006. The compound of formula IX below is a key intermediate for synthesizing the drug posaconazole (abbreviated as "key intermediate of posaconazole" in this specification), which is further converted to obtain posaconazole, and the reaction scheme is as follows:

[0003] [ka]

[0004] Several patent documents have reported methods for producing the compound of formula IX, for example, U.S. Patent No. 5,661,151 (Patent Document 1) discloses a method for producing the posaconazole main ring (Scheme 1), which uses 2'-chloro-2,4-difluoroacetophenone as a starting material, and finally obtains the compound of formula IX through a Witting reaction and conformational inversion.

[0005] [ka]

[0006] However, the reaction steps of the synthesis scheme are lengthy, and at least four steps use the dangerous strong alkali NaH, and the third step uses the additional peroxide t-butyl hydroperoxide (TBHP), making it too dangerous.

[0007] In the specification of Chinese Patent Application Publication No. 103635465 (Patent Document 2) filed by Sandoz of Switzerland in 2012, 2'-chloro-2,4-difluoroacetophenone is used as a starting material to prepare a Grignard reagent instead of the Witting reaction route (Scheme 2).

[0008] [ka]

[0009] Although the reaction steps of this synthesis scheme are relatively short and the reaction conditions are mild, the final product has a high content of isomers, and requires purification two or more times, resulting in high waste.

[0010] China Patent Publication No. 101824009 (Patent Document 3) discloses a method for obtaining 2-(2,4-difluorophenyl)propenol by a Witting reaction of 1-chloro-2,4-difluoroacetophenone, and then obtaining a product through multi-step reactions such as Sharpless epoxidation, nucleophilic substitution, condensation, and reduction (Scheme 3).

[0011] [ka]

[0012] However, in multiple reaction steps of this synthesis scheme, intermediates are separated and purified by column chromatography, resulting in low yields and high production costs, which are disadvantageous for industrial production.

[0013] U.S. Patent Application Publication No. 2014 / 343285 (Patent Document 4), filed in 2012 by MSN Laboratories Limited of India, discloses the following synthetic route to obtain a target product by using m-difluorobenzene as a starting material, Friedel-Crafts acylation, Witting reaction, amide condensation, methylolation, halogenation cyclization, reduction reaction, aminoalkylation, and esterification (Scheme 4).

[0014] [ka]

[0015] However, this synthesis scheme is prone to the generation of intramolecular ring-closure impurities, which can be removed but affect the yield. Furthermore, this process requires flammable and expensive n-butyllithium and highly hygroscopic and corrosive titanium tetrachloride to produce 2-oxazolidone lithium salt, which is not suitable for large-scale production.

[0016] Thus, there is a need in the art for methods of preparing compounds that are intermediates in the synthesis of posaconazole (sometimes abbreviated herein as "posaconazole intermediates"), and in particular for novel methods of preparing the compound of formula IX, which is a key intermediate for posaconazole. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] U.S. Pat. No. 5,661,151 [Patent Document 2] China Patent Application Publication No. 103635465 [Patent Document 3] China Patent Application Publication No. 101824009 [Patent Document 4] US Patent Application Publication No. 2014 / 343285 Summary of the Invention

[0018] In view of this, one object of the present invention is to overcome the above shortcomings and provide a novel method for preparing a compound which is an intermediate of posaconazole, particularly a novel method for preparing the compound of formula IX which is a key intermediate of posaconazole, which has the advantages of mild reaction conditions, simple reaction process, high total yield of the target product, high purity, etc., and is particularly suitable for industrial production. The present invention provides a novel method for synthesizing the compound of formula I ((3S,5R)-5-(halomethyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-carboxylic acid). To this end, in one aspect, the present invention provides a method for preparing a compound of formula I, which is an intermediate of posaconazole, comprising step (1) hydrolyzing a compound of formula II under alkaline conditions in a mixed solvent of an organic solvent and water, followed by treatment with an acid to obtain a compound of formula I.

[0019] [ka]

[0020] [Wherein, X is Cl, Br or I, and R1 is an ester protecting group.]

[0021] In some preferred embodiments, R1 is C 1-8 Alkyl groups of C 3-8 Cycloalkyl groups of C 6-10 Aryl groups of C 1-8 C substituted with alkyl groups 6-10 Aryl group, benzyl group, C 1-8 Benzyl group substituted with an alkyl group of C 1-8 and benzyl groups substituted with an alkoxy group, and benzyl groups substituted with a halogen atom, preferably, R1 is selected from the group consisting of C 1-8 Alkyl group, benzyl group, C 1-8 Benzyl group substituted with an alkyl group of C 1-8 a benzyl group substituted with an alkoxy group, and a benzyl group substituted with a halogen atom.

[0022] In some preferred embodiments, the hydrolysis in step (1) is carried out in the presence of one or more alkalis selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.

[0023] In some preferred embodiments, the acid treatment is a treatment in which the aqueous phase after the reaction is adjusted to pH=2-3 using one or more organic or inorganic acids, and preferably, an organic amine is added to the solution after the acid treatment to obtain an amine salt of the compound of formula I.

[0024] In some preferred embodiments, the compound of formula II is (2) reacting the compound of formula VI with formaldehyde or polyformaldehyde in an organic solvent in the presence of a chiral catalyst to obtain a compound of formula V; Step (3) of subjecting the compound of formula V to a Pinnick oxidation reaction with NaClO2 and NaH2PO4 in the presence of a scavenger to obtain a compound of formula IV; step (4) of reacting the compound of formula IV with a halogenated hydrocarbon R1-X under alkaline conditions to obtain a compound of formula III; and step (5) of halogenating or cyclizing the compound of formula III in the presence of a halogenating agent containing a halogen element X to obtain a compound of formula II, or, (2) reacting the compound of formula VI with formaldehyde or polyformaldehyde in an organic solvent in the presence of a chiral catalyst to obtain a compound of formula V; (3) subjecting the compound of formula V to a Pinnick oxidation reaction with NaClO2 and NaH2PO4 in the presence of a scavenger, followed by the addition of an organic amine compound to obtain an organic amine salt of the compound of formula IV; step (4) of reacting the organic amine salt of the compound of formula IV with a halogenated hydrocarbon R1-X under alkaline conditions to obtain a compound of formula III; Step (5) of halogenating and cyclizing the compound of formula III in the presence of a halogenating agent containing a halogen element X to obtain a compound of formula II; The present invention is produced by a method comprising the steps of:

[0025] [ka]

[0026] [In the formula, X and R1 are as defined above.]

[0027] In some preferred embodiments, the chiral catalyst used in step (2) is a compound represented by the following formula:

[0028] [ka]

[0029] [In the formula, R2 is selected from the group consisting of a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a triisopropylsilyl group, a benzyl group, a 4-methylbenzyl group, and a phenyl group, and Ph represents a phenyl group.]

[0030] In some preferred embodiments, the Pinnick oxidation reaction is carried out in an acetonitrile-water solution in the presence of NaClO2 and NaH2PO4, and preferably, the scavenger is one or more selected from the group consisting of resorcinol, sulfamic acid, 2-methyl-2-butylene, dimethyl sulfoxide, and hydrogen peroxide.

[0031] In some preferred embodiments, the halogenating reagent containing a halogen element X used in the step (5) is one or more selected from the group consisting of a halogen element, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-diiodo-5,5-dimethylhydantoin, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), and N-iodosuccinimide (NIS), and preferably, the organic amine is one or more selected from the group consisting of methylamine, ethylamine, propylamine, cyclopropylamine, n-butylamine, t-butylamine, n-pentylamine, isopentylamine, t-pentylamine, cyclopentylamine, hexylamine, cyclohexylamine, diethylamine, ethylenediamine, diisopropylethylamine, triethylamine, ethanolamine, aniline, phenylethylamine, and benzylamine.

[0032] In some preferred embodiments, the compound of formula VI is prepared by reducing a compound of formula X:

[0033] [ka]

[0034] Preferably, the reducing agent is one or more selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, and vitride.

[0035] In another embodiment, the present invention relates to a process for the preparation of a compound of formula I by hydrolyzing a compound of formula II under alkaline conditions in a mixture of an organic solvent and water, followed by treatment with an acid; (6) reducing the compound of formula I in an organic solvent in the presence of a reducing agent at a temperature of −5 to 5° C. to obtain a compound of formula VII; Step (7) of reacting the compound of formula VII with 1,2,4-triazole in an organic solvent in the presence of an alkali and a phase transfer catalyst to obtain a compound of formula VIII; Step (8) of reacting the compound of formula VIII with p-toluenesulfonyl chloride in an organic solvent under alkaline conditions to obtain the compound of formula IX; The present invention provides a process for preparing a compound of formula IX, which is a key intermediate of posaconazole, from a compound of formula II, comprising:

[0036] [ka]

[0037] [In the formula, X is Cl, Br or I, R1 is an ester protecting group, and Ts represents a p-toluenesulfonyl group.]

[0038] In some preferred embodiments, the reducing agent used in the step (6) is one or more selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, and vitrides. Preferably, the reducing agent is a combination of one or more selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, and vitrides and one or more selected from the group consisting of boron trifluoride diethyl etherate, aluminum chloride, iron chloride, and iodine.

[0039] In some preferred embodiments, the compound of formula II is prepared by the methods described above. In yet another aspect, the present invention provides a compound of formula II prepared by the above process.

[0040] [ka]

[0041] [In the formula, X and R1 are as defined above.]

[0042] In yet another aspect, the present invention provides compounds of formula II, formula III, formula IV, formula V and formula VI prepared by the above process.

[0043] [ka]

[0044] [In the formula, R1 is a benzyl group and X is Cl, Br or I.]

[0045] The present invention provides a novel method for preparing an intermediate compound of posaconazole, in particular a novel method for preparing the compound of formula IX, which is a key intermediate of posaconazole, and these preparation methods have the advantages of mild reaction conditions, simple reaction procedures, high total yields of the target products and high purity, and are suitable for industrial production. In particular, in the method of the present invention, a chiral catalyst is used to carry out the cyclization reaction, and the compound of formula IX thus produced has a high chiral enantiomeric excess (ee) value of 99.5%, and thus has an extremely high chiral purity.

[0046] In addition, the total yield of the method of preparing the compound of formula I from the compound of formula VI provided by the present invention can reach about 45%, and the total yield of the method of preparing the compound of formula IX from the compound of formula I can reach about 66.0%, which is also high. In addition, the compound of formula IX, which is a key intermediate of posaconazole, produced by the process of the present invention has low impurity content and high purity, and other intermediate compounds produced by the process of the present invention also have low impurity content and high purity. In addition, the raw materials and auxiliary materials used in the method of the present invention are easy to obtain, low cost, the reaction conditions are mild, the operation is convenient, and it is easy to realize large-scale production. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] In order to address one or more, or even all, of the problems in the prior art, such as high impurity content, low purity, low yield, and harsh reaction conditions, which are unfavorable for industrial production, the inventors have conducted intensive research and found a novel method for preparing a compound which is an intermediate of posaconazole, in particular, a novel method for preparing the compound of formula IX, which is a key intermediate of posaconazole, and these preparation methods have the advantages of mild reaction conditions, simple reaction process, high total yield of the target product and high purity, which are suitable for industrial production. Based on this, the present invention provides a process for the preparation of the compound of formula I, which is an intermediate for the preparation of posaconazole.

[0048] [ka] The method includes the step (1) of hydrolyzing a compound of formula II under alkaline conditions in a mixture of an organic solvent and water, followed by treatment with an acid to obtain a compound of formula I.

[0049] [ka]

[0050] [Wherein, X is Cl, Br or I, and R1 is an ester protecting group.]

[0051] In the present invention, any ester protecting group known in the art may be used. Preferably, as an ester protecting group, R is C 1-8 Alkyl groups of C 3-8 Cycloalkyl groups of C 6-10 Aryl groups of C 1-8 C substituted with alkyl groups 6-10Aryl groups, benzyl groups (Bn), C 1-8 Benzyl group substituted with an alkyl group of C 1-8 More preferably, R1 is selected from the group consisting of a benzyl group substituted with an alkoxy group, and a benzyl group substituted with a halogen atom. 1-8 Alkyl group, benzyl group, C 1-8 Benzyl group substituted with an alkyl group of C 1-8 a benzyl group substituted with an alkoxy group, and a benzyl group substituted with a halogen atom.

[0052] As used herein, C 1-8 The alkyl group in refers to a linear or branched saturated hydrocarbon group having 1 to 8 carbon atoms, and examples thereof include, but are not limited to, a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a t-butyl group, a n-pentyl group, an isopentyl group, a n-hexyl group, a n-heptyl group, and a n-octyl group. 1-8 The alkoxy group is C 1-8 It refers to alkyl-O-. As used herein, C 3-8 The cycloalkyl group refers to a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms, and examples thereof include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a methylcyclobutyl group. As used herein, C 6-10 The aryl group in the above refers to a cyclic aryl group having 6 to 10 carbon atoms, and examples thereof include, but are not limited to, a phenyl group and a naphthyl group. 1-8 C substituted with alkyl groups 6-10 The aryl group is C 6-10 One or more hydrogen atoms on the aromatic ring of the aryl group are replaced by one or more C 1-8 It refers to a group substituted with an alkyl group. As used herein, a benzyl group refers to C6H5-CH2-. 1-8A benzyl group substituted with an alkyl group is one in which one or more hydrogen atoms on the benzene ring of the benzyl group are replaced with one or more C 1-8 Also, C 1-8 A benzyl group substituted with an alkoxy group or a benzyl group substituted with a halogen atom is a benzyl group in which one or more hydrogen atoms on the benzene ring of the benzyl group have been replaced with one or more C 1-8 This refers to a group substituted with an alkoxy group.

[0053] In the above method, the hydrolysis in step (1) may be carried out under any alkaline conditions known in the art. Preferably, the hydrolysis in step (1) is carried out in the presence of one or more alkalis selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. In the above method, the acid treatment may be a treatment using one or more organic acids or inorganic acids, and preferably, the acid treatment may be performed so that the aqueous phase after the reaction has a pH of 2 to 3.

[0054] More specifically, in the above method, the compound of formula II may be first dissolved in an organic solvent, and the one or more aqueous alkali solutions may be added thereto, and the reaction may be carried out by controlling the temperature to, for example, −10 to 20° C. After the reaction is completed, impurities are removed by extraction with an organic solvent, an acid is added to the aqueous phase to adjust the pH to 2 to 3, and further extraction with an organic solvent is carried out to concentrate the organic phase, thereby obtaining the compound of formula I as an oil. Alternatively, optionally, an acid may be added to the aqueous phase to adjust the pH to 2-3, an organic solvent may be added to extract the compound of formula I, and then an organic amine may be added to the organic phase to form an amine salt of the compound of formula I, which is precipitated in a solid form, and finally, the organic amine salt of the compound of formula I may be obtained by filtration. The method of forming an organic amine salt can effectively remove some impurities and improve the purity of the compound of formula I, while the amine salt can be precipitated in a solid form, which can facilitate the separation of the product, make the operability of industrial production stronger, and reduce the production cost.

[0055] In the above method, the organic solvent used is not particularly limited as long as it can dissolve the starting compound. Preferably, the organic solvent used may be one or more selected from the group consisting of toluene, hexane, n-heptane, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, isopropyl ether, methyl t-butyl ether, dichloromethane, acetone, methanol, ethanol, and isopropanol. In the above method, the water as the solvent is not limited, and is mainly used to dissolve the alkali in the reaction, for example, to form an alkaline aqueous solution. Preferably, drinking water, deionized water, distilled water, etc. may be used.

[0056] In the above method, the acid used is not particularly limited and may be any one or more organic acids or inorganic acids.Preferably, the acid used may be one or more selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, and trifluoroacetic acid. In the above method, the organic amine to be used is not particularly limited.Preferably, the organic amine to be used may be one or more selected from the group consisting of methylamine, ethylamine, propylamine, cyclopropylamine, n-butylamine, t-butylamine, n-pentylamine, isopentylamine, t-pentylamine, cyclopentylamine, hexylamine, cyclohexylamine, diethylamine, ethylenediamine, diisopropylethylamine, triethylamine, ethanolamine, aniline, phenylethylamine, and benzylamine.

[0057] In the above method, preferably the compound of formula II is (2) reacting the compound of formula VI with formaldehyde or polyformaldehyde in an organic solvent in the presence of a chiral catalyst to obtain a compound of formula V; Step (3) of subjecting the compound of formula V to a Pinnick oxidation reaction with NaClO2 and NaH2PO4 in the presence of a scavenger to obtain a compound of formula IV; step (4) of reacting the compound of formula IV with a halogenated hydrocarbon R1-X under alkaline conditions to obtain a compound of formula III; and step (5) of halogenating or cyclizing the compound of formula III in the presence of a halogenating agent containing a halogen element X to obtain a compound of formula II, or, (2) reacting the compound of formula VI with formaldehyde or polyformaldehyde in an organic solvent in the presence of a chiral catalyst to obtain a compound of formula V; (3) subjecting the compound of formula V to a Pinnick oxidation reaction with NaClO2 and NaH2PO4 in the presence of a scavenger, followed by the addition of an organic amine compound to obtain an organic amine salt of the compound of formula IV; step (4) of reacting the organic amine salt of the compound of formula IV with a halogenated hydrocarbon R1-X under alkaline conditions to obtain a compound of formula III; Step (5) of halogenating and cyclizing the compound of formula III in the presence of a halogenating agent containing a halogen element X to obtain a compound of formula II; The present invention is produced by a method comprising the steps of:

[0058] [ka]

[0059] [In the formula, X and R1 are as defined above.]

[0060] More specifically, in step (2), the compound of formula VI may be reacted with formaldehyde or polyformaldehyde in the presence of an alkali metal or alkaline earth metal hydroxide, carbonate, bicarbonate, phosphate, or hydrogen phosphate in toluene, chlorobenzene, ethyl acetate, isopropyl acetate, hexane, n-heptane, isopropyl ether, or methyl t-butyl ether solvent in the presence of a chiral catalyst to obtain the compound of formula V.

[0061] In step (3), the compound of formula V is reacted in NaClO2 / NaH2PO4 / acetonitrile-H2O solution in the presence of a scavenger at a temperature of 30°C or less, and then post-treated to obtain the compound of formula IV as an oil. Alternatively, optionally, in step (3), the compound of formula V is oxidized in the presence of NaClO2 / NaH2PO4, and then an organic amine is added to obtain the organic amine salt of the compound of formula IV, which is precipitated in a solid form, thereby effectively separating the compound of formula IV from the solvent and improving its purity.

[0062] In step (4), the compound of formula IV obtained in step (3) is reacted with a halogenating reagent containing a halogen element X under alkaline conditions while maintaining the temperature at 5 to 20°C. After completion of the reaction, a compound of formula III is obtained by post-treatment. Alternatively, optionally, the organic amine salt of the compound of formula IV obtained in step (3) is liberated by acid treatment, and then further reacted with a halogenating reagent containing a halogen element X under alkaline conditions while maintaining the temperature at 5 to 20°C. After completion of the reaction, a compound of formula III is obtained by post-treatment.

[0063] In the above process, preferably, the chiral catalyst used in step (2) may be a compound of the following formula:

[0064] [ka]

[0065] [In the formula, R2 may be selected from the group consisting of a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a triisopropylsilyl group, a benzyl group, a 4-methylbenzyl group, and a phenyl group, and Ph represents a phenyl group.]

[0066] In the above method, the chiral catalyst used may be prepared according to the method described in, for example, Bioorganic and Medicinal Chemistry, 2017, 5(18), 4996-5001, preferably by reacting (R)-diphenylprolinol with R2-X and then working up to obtain the chiral catalyst used in the above method.

[0067] In the above method, the hydroxide, carbonate, bicarbonate, phosphate, or hydrogen phosphate of an alkali metal or alkaline earth metal used in step (2) may preferably be one or more selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, calcium phosphate, calcium hydrogen phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate, and more preferably the alkali used in step (2) may be selected from the group consisting of a combination of sodium dihydrogen phosphate-disodium hydrogen phosphate or potassium dihydrogen phosphate-dipotassium hydrogen phosphate.

[0068] In the above method, the Pinnick oxidation reaction in step (3) preferably refers to an oxidation reaction using NaClO2 and NaH2PO4, and is preferably carried out in, for example, an acetonitrile-water solution, and the solvent used may be any other suitable solvent. More preferably, the scavenger used may be one or more selected from the group consisting of resorcinol, sulfamic acid, 2-methyl-2-butylene, dimethyl sulfoxide, and hydrogen peroxide.

[0069] In the above method, the organic amine used in step (3) may be one or more selected from the group consisting of methylamine, ethylamine, propylamine, cyclopropylamine, n-butylamine, t-butylamine, n-pentylamine, isopentylamine, t-pentylamine, cyclopentylamine, hexylamine, cyclohexylamine, diethylamine, ethylenediamine, diisopropylethylamine, triethylamine, ethanolamine, aniline, phenylethylamine, and benzylamine.

[0070] In the above method, the halogenated hydrocarbon R1-X used in step (4) is preferably benzyl chloride, benzyl bromide, chloroC 1-6 Alkyl group, bromo C 1-6 Alkyl or iodine C 1-6 It may be an alkyl group. In the above method, the alkali used in step (4) may preferably be one or more selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, triethylamine, diethylamine, methylamine, t-butylamine, and aniline. In the above method, the acid used in step (4) may be one or more selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and trifluoroacetic acid.

[0071] In the above method, the halogenating reagent containing a halogen element X used in step (5) may be one or more selected from the group consisting of a halogen element, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-diiodo-5,5-dimethylhydantoin, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), and N-iodosuccinimide (NIS). In the above process, the compound of formula VI used may be preferably prepared by subjecting a compound of formula X to a reduction reaction.

[0072] [ka]

[0073] More preferably, the reducing agent used herein may be one or more selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, and vitride.

[0074] In addition, the present invention is (1) hydrolyzing a compound of formula II under alkaline conditions in a mixed solvent of an organic solvent and water, followed by treatment with an acid to obtain a compound of formula I; (6) reducing the compound of formula I in an organic solvent in the presence of a reducing agent at a temperature of −5 to 5° C. to obtain a compound of formula VII; Step (7) of reacting the compound of formula VII with 1,2,4-triazole in an organic solvent in the presence of an alkali and a phase transfer catalyst to obtain a compound of formula VIII; Step (8) of reacting the compound of formula VIII with p-toluenesulfonyl chloride in an organic solvent under alkaline conditions to obtain the compound of formula IX; The present invention further provides a process for preparing a compound of formula IX, a key intermediate of posaconazole, from a compound of formula II, comprising:

[0075] [ka]

[0076] [In the formula, X is Cl, Br or I, R1 is an ester protecting group, and Ts represents a p-toluenesulfonyl group.]

[0077] More specifically, step (1) is carried out in exactly the same manner as step (1) in the above-mentioned method.

[0078] In step (6), the reducing agent is dissolved in an organic solvent, the temperature is controlled to -5 to 5°C, and then the compound of formula I is added, preferably a solution of the compound of formula I dissolved in the same organic solvent is added dropwise, and the temperature is controlled to -5 to 5°C and maintained until the end of the reaction. More preferably, in step (6), the first reducing agent is dissolved in an organic solvent, the temperature is controlled to -5 to 5°C, and the solution of the compound of formula I is added dropwise, and the reaction is allowed to proceed for 20 to 30 minutes while maintaining the temperature. Then, the second reducing agent is added dropwise at the same temperature, and the temperature is controlled to -5 to 5°C and maintained until the end of the reaction.

[0079] In step (7), an alkali may be added to an organic solvent, the internal temperature may be controlled to ≦40° C., 1,2,4-triazole may be added in several batches, and the mixture may be stirred for 2.0 to 2.5 hours. Thereafter, the compound of formula VII and a phase transfer catalyst may be added, the mixture may be heated to 95 to 100° C., and the reaction may be continued while maintaining the temperature until the end of the reaction. Preferably, the phase transfer catalyst used in step (7) may be one or more selected from the group consisting of tetrabutylammonium iodide, tetrabutylammonium bromide, and tetrabutylammonium fluoride.

[0080] In step (8), the compound of formula VIII may be dissolved in an organic solvent, followed by adding an alkali and 4-dimethylaminopyridine (DMAP), controlling the temperature to 5 to 10°C, adding p-toluenesulfonyl chloride, and maintaining the temperature at 15 to 20°C until the reaction is completed after the addition.

[0081] In the above reaction, the organic solvent used in each step may be one or a combination of a plurality of organic solvents selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, t-butanol, 1,4-dioxane, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, sulfolane, tetrahydrofuran, methyltetrahydrofuran, toluene, chlorobenzene, dichloromethane, trichloromethane, ethyl acetate, isopropyl acetate, butyl acetate, acetonitrile, ethyl ether, isopropyl ether, methyl t-butyl ether, hexane, n-hexane, cyclohexane, and n-heptane.

[0082] Preferably, the organic solvent used in step (6) may be one or more selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, methyltetrahydrofuran, toluene, dichloromethane, ethyl acetate, and isopropyl acetate. Preferably, the organic solvent used in step (7) may be one or more selected from the group consisting of 1,4-dioxane, dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, and N,N-dimethylacetamide. Preferably, the organic solvent used in step (8) may be one or more selected from the group consisting of dichloromethane, trichloromethane, ethyl ether, isopropyl ether, methyl t-butyl ether, tetrahydrofuran, methyltetrahydrofuran, toluene, chlorobenzene, hexane, n-hexane, cyclohexane, n-heptane, and acetonitrile.

[0083] In the above reaction, the reducing agent is one or a combination of a plurality of agents selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, vitride, boron trifluoride diethyl etherate, aluminum chloride, iron chloride, and iodine. Preferably, the reducing agent (or the first and second reducing agents) used in step (6) may be one or more selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, and vitride. More preferably, the reducing agent (or the first and second reducing agents) used in step (6) may be a combination of one or more of the above reducing agents and one or more selected from the group consisting of boron trifluoride diethyl etherate, aluminum chloride, iron chloride, and iodine.

[0084] In the above reaction, the alkali is one or a combination of a plurality of alkalis selected from the group consisting of lithium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, triethylamine, diethylamine, methylamine, t-butylamine, and aniline. Preferably, the alkali used in step (7) may be one or more selected from the group consisting of sodium methoxide, sodium ethoxide, sodium t-butoxide, and potassium t-butoxide.

[0085] The present invention further provides the following several compounds. Compounds of Formula II:

[0086] [ka]

[0087] [In the formula, X is Cl, Br or I, and R1 is as defined above.]

[0088] More specifically, compounds of formula II can include the following compounds:

[0089] [ka]

[0090] [In the formula, Bn represents a benzyl group.]

[0091] Other intermediate compounds are namely the compound of formula III, where R1 is a benzyl group, and the compounds of formula IV, formula V and formula VI.

[0092] [ka] EXAMPLES

[0093] The method of the present invention will now be further described with reference to the following examples. It should be understood that the purpose of providing the following examples is not to limit the scope of the present invention in any manner, but merely to facilitate a better understanding of the present invention. Unless otherwise specified, the raw materials and reagents used in the examples of the present invention are all commercially available or obtained by existing methods and are used as is. The purity and chirality are detected by high performance liquid chromatography, and the confirmation of the target product is based on whether it matches the HPLC retention value of the standard.

[0094] Example 1: Preparation of Compound of Formula VI

[0095] [ka]

[0096] Under nitrogen gas protection, 40g of the compound of formula X and 200g of toluene were added to a 500mL reaction flask and dissolved by stirring. The temperature was lowered to about -80°C with liquid nitrogen, and 90g of a toluene solution of 1.5M diisobutylaluminum hydride (DIBAL-H) ​​was added dropwise. After the dropwise addition was completed, the reaction was carried out for about 2.0h while maintaining the temperature. The temperature was then controlled within the range of -5 to 20°C, and the reaction solution was gradually added to 400g of a 3M hydrochloric acid solution to quench the reaction. After the quenching was completed, the reaction solution was stirred for 3.0h, allowed to stand and separated into layers, and the organic layer was washed twice with water (80g x 2) to obtain a toluene solution of the compound of formula VI. The resulting solution was used as it was in the next reaction without being concentrated.

[0097] Example 2: Preparation of chiral catalyst (R-PDD-TMS)

[0098] [ka]

[0099] In a 500mL reaction flask, add 40g of R-diphenylprolinol (R-PDD), 400mL of dichloromethane, and 32.2g of imidazole, stir to dissolve, cool to 0℃, add 50mL of trimethylchlorosilane (TMSCl) dropwise, and after the dropwise addition, warm to 25℃ and react for 12h while maintaining the temperature. After the temperature is maintained, add 1000mL of methyl t-butyl ether, stir for 30 minutes while maintaining the temperature, filter, wash the filtrate with 500mL of water, wash with 1000mL of salt water, dry with anhydrous Na2SO4, and concentrate under reduced pressure to obtain 50g of oil. The yield was 97% and the HPLC purity was 98%.

[0100] Example 3: Preparation of Compound of Formula V

[0101] [ka]

[0102] 1.5g of chiral catalyst R-PDD-TMS, 2.0g of KH2PO4, and 3.1g of K2HPO4 were added to the toluene solution of the compound of formula VI prepared in Example 1 above, and stirred for 10 to 15 min. Then, 15g of 37% formaldehyde solution was added, and the internal temperature was raised to about 20°C, and the reaction was carried out for 12 h while maintaining the temperature. 100g of water was added to the reaction solution, and after stirring, the layers were separated, the aqueous layer was extracted with 50g of toluene, the aqueous layer was discarded, and the organic phase was combined and concentrated under reduced pressure until dry, to obtain 40g of the compound of formula V. The yield was 88% and the HPLC purity was 85%.

[0103] Example 4: Preparation of Compound of Formula IV

[0104] [ka]

[0105] 35g of the compound of formula V and 200g of acetonitrile were added to a reaction flask, and after stirring to dissolve, the temperature was lowered so that the internal temperature was within the range of -5 to 5°C, and 100g of 30% hydrogen peroxide solution was added dropwise. After the completion of the dropwise addition, the temperature was controlled to less than 15°C, and 333g of NaClO2 / NaH2PO4 / H2O solution (40g of NaClO2, 39g of NaH2PO4, and 254g of water) was added dropwise, and after the completion of the dropwise addition, the mixture was stirred for 1.0h, heated to room temperature, and reacted for 2.0h while maintaining the temperature. The temperature was controlled to ≦30°C, and 25g of sodium hydrogen sulfite was added to quench, stirred for 1.5h, and allowed to stand for layer separation. The aqueous layer was extracted with an appropriate amount of methyl t-butyl ether, and the organic layers were combined and concentrated under reduced pressure until dry. Add 100g of water, add liquid caustic soda to adjust the pH to 8.0-10.0, add an appropriate amount of methyl t-butyl ether, stir and stand to separate, discard the organic layer, add concentrated hydrochloric acid to the alkaline aqueous solution layer to adjust the pH to 2-4, add 100g of methyl t-butyl ether, stir and stand to separate, discard the aqueous layer, wash the organic layer twice with water (60g x 2), and concentrate the organic layer to obtain 26.5g of oily compound of formula IV. The yield was 80% and the HPLC purity was 85%.

[0106] Example 5: Preparation of the amine salt of the compound of formula IV

[0107] [ka]

[0108] 37 g of methyl t-butyl ether was added to the compound of formula IV obtained in Example 4, the temperature was raised to 50-55°C, and the solution was stirred until it became clear, and 8.5 g (1.2 eq.) of cyclopropylamine was added dropwise, and after the completion of the dropwise addition, the reaction was carried out for 1.0 h while maintaining the temperature, and the temperature was further lowered to 10-15°C, and the reaction was carried out for 2 h while maintaining the temperature, and the mixture was suction filtered to obtain 26.5 g of cyclopropylamine salt of the compound of formula IV. The yield was 81%, and the HPLC purity was 95%.

[0109] Example 6: Preparation of the amine salt of the compound of formula IV

[0110] [ka]

[0111] 35g of the compound of formula V and 200g of acetonitrile were added to a reaction flask, and after stirring to dissolve, the temperature was lowered so that the internal temperature was in the range of -5 to 5°C, and 100g of 30% hydrogen peroxide solution was added dropwise. After the completion of the dropwise addition, the temperature was controlled to less than 15°C, and 333g of NaClO2 / NaH2PO4 / H2O solution (40g of NaClO2, 39g of NaH2PO4, and 254g of water) was added dropwise, and after the completion of the dropwise addition, the mixture was stirred for 1.0h, heated to room temperature, and reacted for 2.0h while maintaining the temperature. The temperature was controlled to ≦30°C, and 25g of sodium hydrogen sulfite was added to quench, stirred for 1.5h, and allowed to stand for layer separation. The aqueous layer was extracted with an appropriate amount of methyl t-butyl ether, and the organic layers were combined and concentrated under reduced pressure until dry. 100g of water was added, and liquid caustic soda was added to adjust the pH to 8.0-10.0, and an appropriate amount of methyl t-butyl ether was added and stirred, and the mixture was allowed to stand to separate into layers, and the organic layer was discarded, and concentrated hydrochloric acid was added to the alkaline aqueous solution layer to adjust the pH to 2-4, and 100g of methyl t-butyl ether was added and stirred, and the mixture was allowed to stand to separate into layers, and the organic layer was washed twice with water (60g x 2). While stirring, 14.8g of cyclohexylamine was dropped into the organic phase, and the mixture was stirred for 1 hour, and the temperature was further lowered to 10-15°C, and the mixture was stirred for 2 hours while maintaining the temperature, and the mixture was suction filtered to obtain 39.6g of the cyclohexylamine salt of the compound of formula IV.

[0112] Example 7: Preparation of compounds of formula III (R1 is a benzyl group (Bn))

[0113] [ka]

[0114] 35g of N,N-dimethylformamide and 8.48g of the compound of formula IV were added to a reaction flask, and the solution was stirred until it became clear. 4.5g of sodium carbonate and 6.0g of benzyl bromide were added, and the reaction temperature was controlled to 5-20°C. The reaction was allowed to proceed for 3.0h while maintaining the temperature. After the temperature was maintained, 120g of methyl t-butyl ether was added, and the mixture was stirred for about 10-15min and filtered. The filtrate was washed with water three times (60g x 3), separated into layers, the aqueous layer was discarded, and the organic layer was concentrated to dryness to obtain 10.5g of the compound of formula III. The yield was 90% and the HPLC purity was 90%.

[0115] Example 8: Preparation of a compound of formula III (R1 is an ethyl group (Et))

[0116] [ka]

[0117] 70g of N,N-dimethylformamide and 17g of the compound of formula IV were added to a reaction flask, and the solution was stirred until it became clear. 9g of sodium carbonate and 7.8g of ethyl bromide were added, and the reaction temperature was controlled to 5-20°C. The reaction was allowed to proceed for 3.0 hours while maintaining the temperature. After the temperature was maintained, 240g of methyl t-butyl ether was added, and the mixture was stirred for about 30 minutes and filtered. The filtrate was washed with water three times (120g x 3), separated into layers, the aqueous layer was discarded, and the organic layer was concentrated to dryness to obtain 16.5g of the compound of formula III. The yield was 87%.

[0118] Example 9: Preparation of compound of formula III (R1 is a methyl group (Me))

[0119] [ka]

[0120] 75g of N,N-dimethylformamide and 20g of the compound of formula IV were added to a reaction flask, and the solution was stirred until it became clear. 10.5g of sodium carbonate and 11.95g of iodomethane were added, and the reaction temperature was controlled to 5-20°C. The reaction was allowed to proceed for 3.0 hours while maintaining the temperature. After the temperature was maintained, 240g of methyl t-butyl ether was added, and the mixture was stirred for about 30 minutes and filtered. The filtrate was washed with water three times (120g x 3), separated into layers, the aqueous layer was discarded, and the organic layer was concentrated to dryness to obtain 19.4g of the compound of formula III. The yield was 91.5%.

[0121] Example 10: Preparation of compounds of formula III (R1 is a benzyl group (Bn))

[0122] [ka]

[0123] 10.48g of the cyclopropylamine salt of the compound of formula IV and 50g of water were added to a reaction flask, and after uniform stirring, concentrated hydrochloric acid was added to adjust the pH to 1 to 3, 50g of methyl t-butyl ether was added, and the mixture was left to stand for layer separation, the aqueous layer was extracted with 20g of methyl t-butyl ether, the organic layer was combined, washed with water (50g x 2), the aqueous layer was discarded, and the organic layer was concentrated under reduced pressure until it became dry. 35g of N,N-dimethylformamide was added to the concentrate, and the mixture was stirred until the solution became clear, 4.5g of sodium carbonate and 6.0g of benzyl bromide were added, and the reaction temperature was controlled to 5 to 20°C, and the reaction was carried out for 3.0h while maintaining the temperature. After the temperature was maintained, 120g of methyl t-butyl ether was added, and the mixture was stirred for about 10 to 15min, and filtered. The filtrate was washed with water three times (60 g x 3), the layers were separated, the aqueous layer was discarded, and the organic layer was concentrated to dryness to give 10.5 g of compound of formula III in 90.3% yield and 95.5% HPLC purity.

[0124] Example 11: Preparation of compounds of formula II, where R1 is a benzyl group (Bn) and X is Br.

[0125] [ka]

[0126] Into a reaction flask, 68.6 g of the compound of formula III, 1170 g of tetrahydrofuran, and 50 g of water were added, and the solution was stirred until it became clear. The temperature was controlled in the range of -5 to 5°C, and 41.2 g of N-bromosuccinimide (NBS) was added in several portions, and the reaction was carried out for 3.0 h while maintaining the temperature. After the temperature was maintained, 500 g of 10% NaHSO3 was added to the reaction solution, and the mixture was stirred for 30 min, and then concentrated under reduced pressure until it became dry. 210 g of methyl t-butyl ether was added, washed with water (100 g x 2), the aqueous layer was discarded, and the organic layer was concentrated until it became dry, to obtain 68 g of the compound of formula II. The yield was 80.1%, and the HPLC purity was 90.5%.

[0127] Example 12: Preparation of a compound of formula II, where R1 is an ethyl group (Et) and X is Br.

[0128] [ka]

[0129] 56.8g of the compound of formula III, 1170g of tetrahydrofuran, and 50g of water were added to a reaction flask, and the solution was stirred until it became clear. The temperature was controlled to -5 to 5°C, and 41.2g of N-bromosuccinimide (NBS) was added in several portions, and the reaction was carried out for 3.0h while maintaining the temperature. After the temperature was maintained, 500g of 10% NaHSO3 was added to the reaction solution, and the mixture was stirred for 30min, and then concentrated under reduced pressure until it became dry. 210g of methyl t-butyl ether was added, washed with water (100g x 2), the aqueous layer was discarded, and the organic layer was concentrated until it became dry, to obtain 60.8g of the compound of formula II. The yield was 83%.

[0130] Example 13: Preparation of compound of formula II (R1 is a methyl group (Me) and X is Br)

[0131] [ka]

[0132] 53.1g of the compound of formula III, 1170g of tetrahydrofuran, and 50g of water were added to a reaction flask, and the solution was stirred until it became clear. The temperature was controlled to -5 to 5°C, and 41.2g of N-bromosuccinimide (NBS) was added in several portions, and the reaction was carried out for 3.0h while maintaining the temperature. After the temperature was maintained, 500g of 10% NaHSO3 was added to the reaction solution, and the solution was stirred for 30min, and then concentrated under reduced pressure until it became dry. 210g of methyl t-butyl ether was added, washed with water (100g x 2), the aqueous layer was discarded, and the organic layer was concentrated until it became dry, to obtain 56.7g of the compound of formula II. The yield was 81.8%.

[0133] Example 14: Preparation of compounds of formula I (X is Br)

[0134] [ka]

[0135] In a reaction flask, 73g of the compound of formula II, 170g of tetrahydrofuran, and 13.2g of water were added, the temperature was lowered to 0-5°C, 65.7mL of 20% LiOH solution was added dropwise, and after the completion of the dropwise addition, the mixture was stirred for 0.5h, and reacted for 7h while maintaining the temperature at about 2°C, and extracted with 146g of ethyl acetate, allowed to stand for layer separation, the aqueous layer was extracted with ethyl acetate (73g x 2), and the ethyl acetate phase was discarded. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 2-3, 73g of ethyl acetate was added, stirred, allowed to stand for layer separation, the aqueous layer was back-extracted with ethyl acetate (73g x 2), the ethyl acetate layers were combined, and further washed once with 146g of water, and the organic layer was concentrated under reduced pressure to obtain 50g of the compound of formula I as an oil. The yield was 87.7% and the HPLC purity was 91%.

[0136] Example 15: Preparation of compounds of formula I (X is Br)

[0137] [ka]

[0138] In a reaction flask, 62g of the compound of formula II, 170g of tetrahydrofuran, and 13.2g of water were added, and the temperature was lowered to 0-5°C. 73g of 30% NaOH solution was added dropwise. After the completion of the dropwise addition, the mixture was stirred for 0.5h, and reacted for 5h while maintaining the temperature at about 3°C. The mixture was extracted with 150g of ethyl acetate, allowed to stand for layer separation, the aqueous layer was extracted with ethyl acetate (50g x 2), and the ethyl acetate phase was discarded. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 2-3, 50g of ethyl acetate was added, stirred, allowed to stand for layer separation, the aqueous layer was back-extracted with ethyl acetate (50g x 2), the ethyl acetate layer was combined, and further washed once with 150g of water. The organic layer was concentrated under reduced pressure to obtain 51.3g of the compound of formula I as an oil. The yield was 90% and the HPLC purity was 92%.

[0139] Example 16: Preparation of compounds of formula I (X is Br)

[0140] [ka]

[0141] In a reaction flask, 59.5g of the compound of formula II, 170g of tetrahydrofuran, and 13.2g of water were added, the temperature was lowered to 0-5°C, 73g of 30% NaOH solution was added dropwise, and after the completion of the dropwise addition, the mixture was stirred for 0.5h, and reacted for 5h while maintaining the temperature at about 3°C, and extracted with 150g of ethyl acetate, allowed to stand for layer separation, the aqueous layer was extracted with ethyl acetate (50g x 2), and the ethyl acetate phase was discarded. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 2-3, 50g of ethyl acetate was added, stirred, allowed to stand for layer separation, the aqueous layer was back-extracted with ethyl acetate (50g x 2), the ethyl acetate layer was combined, and further washed once with 150g of water. The organic layer was concentrated under reduced pressure to obtain 50.7g of the compound of formula I as an oil. The yield was 89% and the HPLC purity was 95.5%.

[0142] Example 17: Preparation of cyclohexylamine salts of compounds of formula I (X is Br)

[0143] [ka]

[0144] 75 g of methyl t-butyl ether was added to the compound of formula I obtained in Example 14, the temperature was raised to a range of 50 to 55°C, and the solution was stirred until it became clear, 15.4 g of cyclohexylamine was added dropwise, and after the completion of the dropwise addition, the reaction was carried out for 1.0 h while maintaining the temperature, and the temperature was further lowered to about 10 to 15°C, and the reaction was stirred for 3 h while maintaining the temperature, and the mixture was suction filtered and dried by heating to obtain 55 g of cyclohexylamine salt of the compound of formula I. The yield was 84.6%, the HPLC purity was 97%, and the ee value detected by normal phase HPLC was 98%.

[0145] Example 18: Preparation of cyclopropylamine salts of compounds of formula I (X is Br)

[0146] [ka]

[0147] 80 g of methyl t-butyl ether was added to the compound of formula I obtained in Example 15, the temperature was raised to within a range of 50 to 55°C, and the solution was stirred until it became clear, 9.12 g of cyclopropylamine was added dropwise, and after the completion of the dropwise addition, the reaction was carried out for 1.0 h while maintaining the temperature, and the temperature was further lowered to about 10 to 15°C, and the reaction was stirred for 3 h while maintaining the temperature, and the mixture was suction filtered and dried by heating to obtain 52 g of cyclohexylamine salt of the compound of formula I. The yield was 86%, the HPLC purity was 96.5%, and the ee value detected by normal phase HPLC was 98%.

[0148] Example 19: Preparation of the compound of formula IX, a key intermediate for posaconazole, from the compound of formula I (X is Br)

[0149] [ka]

[0150] (1) Preparation of Compound VII: Under nitrogen gas protection, 100g of THF and 14.4g of NaBH4 were added to a 1L reaction flask, the reaction temperature was controlled to be in the range of -5 to 5°C, 350g of a THF solution containing 116g of the compound of formula I was added dropwise, and after the addition was completed, the internal temperature was controlled to be in the range of -5 to 5°C, the temperature was maintained for 30min, and 42.6g of boron trifluoride diethyl ether was added dropwise over 1 to 2h while controlling the internal temperature to be in the range of -5 to 5°C. After the addition was completed, the internal temperature was controlled to be in the range of -5 to 5°C, the temperature was maintained for about 2h, and the reaction was completed. The reaction solution was gradually added to 400g of 10% HCl solution (40g HCl+360g drinking water) pre-cooled to 0-5℃, the temperature was controlled in the range of 10-25℃, stirred for 30min, phase separated, the THF layer was prepared for use, the aqueous layer was extracted with toluene (100g×2 times), phase separated, the aqueous layer was discarded, the organic layer was combined, 200g of saturated NaHCO3 was added for washing, phase separated, the organic layer was washed with 200g of water, the aqueous layer was separated, the organic phase was controlled at an external temperature≦60℃, and concentrated under reduced pressure until dry to obtain 108.7g of compound of formula VII. The yield was 98% and the HPLC purity was >95%.

[0151] (2) Preparation of Compound VIII: Under nitrogen gas protection, 264g of DMSO and 121.7g of potassium t-butoxide were added to a dry and clean reaction flask, and after the addition, the internal temperature was controlled to ≦40°C, and 77.0g of 1,2,4-triazole was added in several portions, and after the addition, the internal temperature was controlled to 20-40°C and reacted for 2 hours. After the temperature was maintained, 118g of the compound of formula VII, 8.6g of tetrabutylammonium iodide, and 7.3g of 18-crown ether-6 were added, and the temperature was gradually increased to 95-100°C, and the internal temperature was controlled to 95-100°C and reacted for 36 hours. After the temperature was maintained, the mixture was cooled to less than 30°C, quenched by adding 600g of drinking water, and extracted with 600g of methyl t-butyl ether. The methyl t-butyl ether layer was washed with drinking water, and added with 30g of anhydrous Na2SO4 and 4g of activated carbon, dried and decolorized for 1h, suction filtered, and washed with methyl t-butyl ether (30g x 2 times). The filtrate was combined, and the external temperature was controlled to ≦60°C. The mixture was concentrated to dryness to obtain 85g of compound of formula VIII. The yield was about 75% and the HPLC purity was 96.7%.

[0152] (3) Preparation of Compound IX: Under nitrogen gas protection, 240g of DCM, 1.5g of DMAP, 35.5g of the compound of formula VIII, and 30.8g of triethylamine were added to a dry and clean reaction flask, cooled to 5-10°C, and the internal temperature was controlled within the range of 5-10°C. 23.3g of p-toluenesulfonyl chloride was added in several portions, and after the addition was completed, the internal temperature was controlled within the range of 15-20°C to react. After the reaction was completed, the reaction was quenched by adding 300g of water, and the layers were separated. The DCM layer was further washed with Na2CO3 solution, 10% HCl solution, and water in this order, and the layers were separated and the aqueous layer was discarded. The DCM layer was concentrated under reduced pressure until it became dry under the condition of controlling the external temperature to ≦60°C. 300g of isopropanol was added, the temperature was raised to 50℃, and the solution was stirred until it became clear, and the temperature was gradually lowered to 0-5℃ for 2h to precipitate, and the solution was filtered by suction to obtain 48.5g of the compound of formula IX. The yield was 89.8%, the HPLC purity was 99.0%, and the ee value was 99.5%.

[0153] The specific embodiments and examples described above further illustrate the objectives, technical solutions and beneficial effects of the present disclosure, and it should be understood that the specific embodiments and examples described above are merely specific examples of the present disclosure and do not limit the scope of the contents of the present disclosure. Any modifications, equivalent replacements, improvements, etc. made without departing from the spirit and principles of the present disclosure should be included within the scope of protection of the contents of the present disclosure.

Claims

1. A method for producing a compound of formula I, which is an intermediate of posaconazole, comprising the steps of: (1) hydrolyzing a compound of formula II under alkaline conditions in a mixed solvent of an organic solvent and water, and then treating with an acid to obtain a compound of formula I. 【Chemistry 41】 [Wherein, X is Cl, Br or I, and R １ is an ester protecting group.

2. R １ is C １－８ Alkyl groups of C ３－８ a cycloalkyl group of C ６－１０ an aryl group of C １－８ C substituted with an alkyl group of ６－１０ an aryl group, a benzyl group, １－８ a benzyl group substituted with an alkyl group of the formula C １－８ and benzyl groups substituted with an alkoxy group represented by R １ is C １－８ alkyl group, benzyl group, C １－８ a benzyl group substituted with an alkyl group of the formula C １－８ 2. The method according to claim 1, wherein the aryl group is selected from the group consisting of benzyl groups substituted with an alkoxy group and benzyl groups substituted with a halogen atom.

3. 2. The method according to claim 1, wherein the hydrolysis in the step (1) is carried out in the presence of one or more alkalis selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.

4. The method according to claim 1, characterized in that the acid treatment is a treatment using one or more organic or inorganic acids to adjust the pH of the aqueous phase after the reaction to 2-3, and preferably an organic amine is added to the solution after the acid treatment to obtain an amine salt of the compound of formula I.

5. The compound of formula II is (2) reacting the compound of formula VI with formaldehyde or polyformaldehyde in an organic solvent in the presence of a chiral catalyst to obtain a compound of formula V; In the presence of a scavenger, the compound of formula V is reacted with NaClO ２ and NaH ２ P.O. ４ to obtain a compound of formula IV; and Compounds of formula IV are reacted with halogenated hydrocarbons R １ -X to obtain a compound of formula III; and step (5) of halogenating or cyclizing the compound of formula III in the presence of a halogenating agent containing a halogen element X to obtain a compound of formula II; or, (2) reacting the compound of formula VI with formaldehyde or polyformaldehyde in an organic solvent in the presence of a chiral catalyst to obtain a compound of formula V; In the presence of a scavenger, the compound of formula V is reacted with NaClO ２ and NaH ２ P.O. ４ and then adding an organic amine compound to obtain an organic amine salt of the compound of formula IV. Under alkaline conditions, the organic amine salt of the compound of formula IV is reacted with a halogenated hydrocarbon R １ -X to obtain a compound of formula III; Step (5) of halogenating and cyclizing the compound of formula III in the presence of a halogenating reagent containing a halogen element X to obtain a compound of formula II; The method of claim 1, characterized in that the composition is produced by a process comprising: 【Chemistry 42】 [Wherein, X and R １ is as defined above.]

6. The method according to claim 5, wherein the chiral catalyst used in step (2) is a compound represented by the following formula: 【Chemistry 43】 [In the formula, R ２ is selected from the group consisting of a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a triisopropylsilyl group, a benzyl group, a 4-methylbenzyl group, and a phenyl group, and Ph represents a phenyl group.

7. The Pinnick oxidation reaction is carried out using NaClO ２ and NaH ２ P.O. ４ The method according to claim 5, wherein the method is carried out in an acetonitrile-aqueous solution in the presence of, preferably, the scavenger is one or more selected from the group consisting of resorcin, sulfamic acid, 2-methyl-2-butylene, dimethyl sulfoxide, and hydrogen peroxide.

8. The method according to claim 5, wherein the halogenating reagent containing a halogen element X used in the step (5) is one or more selected from the group consisting of a halogen element, 1,3-dichloro-5,5-dimethylhydantoin, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-diiodo-5,5-dimethylhydantoin, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), and N-iodosuccinimide (NIS), and preferably the organic amine is one or more selected from the group consisting of methylamine, ethylamine, propylamine, cyclopropylamine, n-butylamine, t-butylamine, n-pentylamine, isopentylamine, t-pentylamine, cyclopentylamine, hexylamine, cyclohexylamine, diethylamine, ethylenediamine, diisopropylethylamine, triethylamine, ethanolamine, aniline, phenylethylamine, and benzylamine.

9. The compound of formula VI is prepared by reducing a compound of formula X, 【Chemistry 44】 The method according to claim 5, characterized in that the reducing agent is one or more selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, and vitride.

10. Step (1) of hydrolyzing a compound of formula II under alkaline conditions in a mixed solvent of an organic solvent and water, followed by treatment with an acid to obtain a compound of formula I; Step (6) of reducing the compound of formula I in the presence of a reducing agent in an organic solvent at a temperature of −5 to 5° C. to obtain a compound of formula VII; Step (7) of reacting the compound of formula VII with 1,2,4-triazole in the presence of an alkali and a phase transfer catalyst in an organic solvent to obtain a compound of formula VIII; Step (8) of reacting the compound of formula VIII with p-toluenesulfonyl chloride in an organic solvent under alkaline conditions to obtain the compound of formula IX; A process for preparing a compound of formula IX, which is a key intermediate of posaconazole, from a compound of formula II, comprising: 【Chemistry 45】 [Wherein, X is Cl, Br or I; R １ is an ester protecting group, and Ts represents a p-toluenesulfonyl group.

11. The method according to claim 10, characterized in that the reducing agent used in the step (6) is one or more selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, and vitride, and preferably the reducing agent is a combination of one or more selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, borane, lithium aluminum hydride, diisobutylaluminum hydride, and vitride with one or more selected from the group consisting of boron trifluoride diethyl etherate, aluminum chloride, iron chloride, and iodine.

12. The method according to claim 10, characterized in that the compound of formula II is prepared by the method according to claim 5, preferably the compound of formula II is prepared by the method according to claim 9.

13. 6. A compound of formula II prepared by the process of claim 5. 【Chemistry 46】 [Wherein, X and R １ is as defined above.]

14. 10. A compound of formula II, formula III, formula IV, formula V and formula VI prepared by the process of claim 9. 【Chemistry 47】 [In the formula, R １ is a benzyl group and X is Cl, Br or I.

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