A preparation method of posaconazole intermediate

Abstract

The present invention provides a preparation method of a posaconazole intermediate. In this method, 3-pentanone is used as the starting material, and the posaconazole intermediate is prepared through an asymmetric catalytic oxidation reaction, a substitution reaction and an asymmetric reductive amination reaction. The product obtained by this method has high purity and good yield. The preparation method has fewer steps, the raw materials are cheap and easily available, the operation is simple, the total yield is high, and it is more suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparation, and particularly relates to a preparation method of a posaconazole intermediate. Background Art

[0002] Posaconazole (Formula A), chemically named 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolane-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one, with the trade name Noxafil. It was developed by Schering-Plough Corporation in Germany and was approved for marketing by the European Union and the US FDA in October 2005. This drug has the characteristics of strong antibacterial efficacy and broad antifungal spectrum, and has a bactericidal effect on Aspergillus and other fungi. In particular, it is effective against polyene compounds and other triazole-resistant or invasive fungal infections. It is marketed in more than 70 countries around the world. Also, due to its good safety and tolerance, it has been used as a first-line prophylactic drug for invasive fungal infections for the treatment of various complex, rare, and refractory fungal infectious diseases.

[0003]

[0004] Posaconazole has 4 chiral centers, with a complex structure and relatively high preparation difficulty. Its preparation method has been reported in the literature. It mainly uses three intermediates, namely compound B (3S-cis)-[5-(2,4-difluorophenyl)-tetrahydro-5-(1,2,4-triazol-1-ylmethyl)-3-furanyl]-4-methyl-benzenesulfonic acid methyl ester, compound C 1-(4-hydroxyphenyl)-4-(4-aminophenyl)piperazine, and compound of formula (I) N'-(2S,3S)-2-(benzyloxy)-3-pentylformohydrazide, etc. as the main reaction raw materials, and is prepared through nucleophilic substitution, amine acylation, cyclization, and deprotection reactions. The structures of compound B, compound C, and the compound of formula (I) are as follows:

[0005]

[0006] Therefore, the compound of formula I N'-(2S,3S)-2-(benzyloxy)-3-pentylformohydrazide is a key intermediate for the preparation of posaconazole and has very important significance for the preparation of posaconazole.

[0007] For the synthesis of the compound of formula I, N'-(2S,3S)-2-(benzyloxy)-3-pentylformohydrazide, its synthetic methods have been reported in the literature. The representative and relatively optimized process is the one starting from ethyl S-lactate. The literature US5625064 and WO9633163 reported a method for synthesizing the compound of formula I starting from ethyl S-lactate, which realizes the synthesis through steps such as aminolysis, hydroxyl protection, Grignard reaction, carbonyl reduction, substitution, and resolution. The synthetic route is as follows:

[0008]

[0009] In the Grignard reaction of the process, strict anhydrous conditions are required, and the industrial operation is cumbersome; in the reduction reaction, lithium borohydride / zinc bromide is used as the reducing agent, and zinc borohydride is generated in situ for reduction. The reducing agent lithium borohydride has high activity, is prone to explosion and is subject to control, all of which are not suitable for industrialization. At the same time, in the process, after carbonyl reduction, it reacts with p-chlorobenzenesulfonyl chloride to form a sulfonate ester, and it further undergoes a substitution reaction with hydrazine hydrate. Since the sulfonate ester has low activity, the yield of this step is low; the formation of the chiral center is achieved through the resolution of D-dibenzoyl tartaric acid. The chiral resolution step will cause the waste of the other enantiomer, and the highest yield does not exceed 50%. Coupled with the fact that the process requires 7 steps and the process route is long, these all result in a low overall yield of the process.

[0010] The literature Bull Chem Soc Jpn, 1989, 62(9): 3038 - 3040 also uses ethyl S-lactate as the starting material and synthesizes the compound of formula I through 5 steps of reactions such as amidation, hydroxyl protection, reduction, condensation to form hydrazone, and Grignard reaction. The specific synthetic route is as follows:

[0011]

[0012] In the reduction reaction of this process, Red-Al is used as the reducing agent. Red-Al has high activity and requires low-temperature reaction; at the same time, even with low-temperature reaction, using highly active Red-Al for reduction may still lead to the generation of over-reduction impurities, and the quality of compound I is not easy to control.

[0013] The literature "World Clinical Drugs, 2007, 28(9): 40 - 45" reported that in the reduction step of this process, n-butyllithium is used as the reducing agent. n-butyllithium has relatively strict requirements for equipment and the environment, is relatively expensive, is not suitable for long-term storage, and the reaction needs to be carried out below -70 °C, making it difficult for industrial production.

[0014] CN201710204742 reported a synthetic method for preparing the compound of formula I by condensing S-2-benzyloxy-3-pentanone with formylhydrazine, followed by asymmetric reduction using Rh-[(I)-(R,R)-BDPCH]24 as the catalyst and sodium borohydride as the reducing agent. Although this method has a relatively short route, the starting materials of the reaction are expensive and difficult to obtain, and the asymmetric reduction reaction uses a catalyst Rh-[(I)-(R,R)-BDPCH] that is expensive and difficult to purchase. 24 As a result, the production cost is high.

[0015] SUMMARY OF THE INVENTION

[0016] In view of the deficiencies of the prior art, the present invention provides a method for preparing an intermediate of posaconazole.

[0017] The technical solution of the present invention is as follows: A method for preparing an intermediate of posaconazole, the structure of the intermediate of posaconazole is shown in formula I, and the method includes the following steps:

[0018]

[0019] (1) In the presence of CuX2 and oxygen, the compound shown in formula II undergoes an asymmetric oxidation reaction under the catalysis of chiral catalyst 1 to obtain the compound shown in formula III;

[0020] (2) The compound shown in formula III undergoes a substitution reaction with BnX to obtain the compound shown in formula IV;

[0021] (3) The compound shown in formula IV undergoes an asymmetric reductive amination reaction with NH2NH2CHO under the action of chiral catalyst 2, additive and hydrogen to obtain the compound shown in formula I.

[0022] Preferably, the chiral catalyst 1 in step 1 is [Pd2(MeCN)2(A1)(L1*)](BF4)2, where A1 is selected from HpT, PFHT or PHT, and the structural formulas of HpT, PFHT and PHT are:

[0023]

[0024] L1* is selected from S-BINAP, and the structure is L1 * = S-BINAP.

[0025] Preferably, the CuX2 in step (1) is CuI2, CuBr2 or CuCl2, and more preferably CuI2.

[0026] Preferably, the reaction solvent in step (1) is a mixture of THF and water, and the volume ratio of THF to water is 3 to 6:1.

[0027] Preferably, the molar ratio of CuX2, catalyst 1 and the compound of formula II in step (1) is 100: (2 - 6): 50.

[0028] Preferably, adding a strong acid in step (1) can accelerate the reaction, and the strong acid is preferably trifluoroacetic acid.

[0029] Preferably, the specific reaction steps of step (1) are as follows:

[0030] Add a mixture of 100 mmol CuI2, 5 mmol catalyst 1 [Pd2(MeCN)2(PFHT)(S - BINAP)](BF4)2 and 100 mL of THF - H2O (THF∶H2O = 4∶1) into a reaction flask, stir and mix evenly, then introduce oxygen and displace with oxygen twice. Add 50 mmol of the compound of formula II dissolved in 20 mL of THF and 0.5 mL of trifluoroacetic acid, and stir the reaction at room temperature after adding.

[0031] Preferably, BnX in step (2) is selected from BnCl or BnBr, and is preferably BnCl.

[0032] Preferably, the reaction steps of step (2) are as follows: Under N2 protection, add 60 mmol of sodium hydride and 20 mL of dry THF into a reaction flask, stir, cool to 0 °C in an ice bath, slowly dropwise add the compound of formula III dissolved in 20 mL of dry THF solution, control the reaction temperature not higher than 10 °C, and stir for 0.5 h. Dropwise add 55 mmol of benzyl chloride, and stir the reaction at room temperature for 3 h after dropping.

[0033] Preferably, the chiral catalyst 2 in step (3) is a metal iridium (I) complex with the structural formula Ir - L2*, which is in - situ generated from (1,5 - cyclooctadiene) iridium (I) chloride dimer and ligand L2* in the experiment. L2* is a chiral diphenylphosphine - phosphonamide ligand with the structure: Wherein, R1 is H, C1 - C4 alkyl; R2 is H, C1 - C4 alkyl or halogen.

[0034] Preferably, the additive in step (3) is selected from titanates, preferably isopropyl titanate, ethyl titanate, methyl titanate or isobutyl titanate, and more preferably isopropyl titanate.

[0035] Preferably, the hydrogen gas pressure in step (3) is 50 atmospheres, and the reaction temperature is 40 - 90 °C; preferably, the reaction temperature is 50 °C.

[0036] Preferably, the molar ratio of chiral catalyst 2, the compound of formula IV and formylhydrazine in step (3) is (0.25 - 1.25): 50: 55.

[0037] Preferably, the reaction steps of step (3) are as follows: Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH3, R2 = H), and 100 mL of toluene are added to a reaction kettle, stirred at room temperature for 15 min, then 50 mmol of the compound of formula IV and 55 mmol of formylhydrazine are respectively dissolved in 50 mL of toluene and added, then 20 mL of isopropyl titanate is added, replaced with hydrogen 3 times and then hydrogen is introduced to 50 atmospheres, heated to 50 °C with stirring, and kept stirring for reaction for 10 h.

[0038] Advantages of the present invention: The present invention provides a preparation method of a new posaconazole intermediate, N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine of formula I. The product prepared by this method has high purity and good yield. This method has few steps, the raw materials are cheap and easily available, the operation is simple, the total yield is high, and it is more suitable for industrial production.

[0039] Related definitions

[0040] [Ir(COD)Cl]2: (1,5-Cyclooctadiene)iridium(I) chloride dimer.

[0041] NH2NH2CHO: Formylhydrazine.

[0042] MTBE: Methyl tert-butyl ether. Brief description of the drawings

[0043] Figure 1 1H NMR spectrum of the compound of formula I

[0044] Figure 2 HPLC spectrum of the compound of formula I Detailed description of the invention

[0045] The following examples can enable those skilled in the art in this field to understand the present invention more comprehensively, but do not limit the present invention to the scope of the described examples.

[0046] The chiral diphenylphosphine-phosphonamide ligand can be purchased through commercial channels, and its preparation method is simple. Using chiral diphenol compounds as raw materials, first react with phosphorus trichloride to obtain phosphinous chloride, and then react with various amines to obtain it.

[0047] Example 1 Preparation of catalyst 1 [Pd2(MeCN)2(PHT)(S-BINAP)](BF4)2

[0048] Under N2 protection, 20 mmol of [Pd(CH3CN)4](BF4)2, 25 mmol of triethylamine and 300 mL of CH2Cl2 were added to a reaction flask. After stirring evenly, 10 mmol of PHT was slowly added dropwise, and the reaction solution immediately turned orange. After stirring the reaction at room temperature for 30 min, 10 mmol of (S)-(-)-BINAP dissolved in 50 ml of benzene was added, and then the reaction was stirred at room temperature for 12 h. The precipitated solid was filtered, and the filter cake was washed with ether (3×300 mL) and dried under reduced pressure. The obtained yellow-green solid was the title catalyst 1 with a yield of 93%.

[0049] Example 2 Preparation of catalyst 1 [Pd2(MeCN)2(HpT)(S-BINAP)](BF4)2

[0050] Replace PHT with HpT, and the rest was carried out according to the procedure for preparing [Pd2(MeCN)2(PHT)(S-BINAP)](BF4)2. The obtained yellow solid was the title catalyst 1 with a yield of 89%.

[0051] Example 3 Preparation of catalyst 1 [Pd2(MeCN)2(PFHT)(S-BINAP)](BF4)2

[0052] Replace PHT with PFHT, and the rest was carried out according to the procedure for preparing [Pd2(MeCN)2(PHT)(S-BINAP)](BF4)2. The obtained yellow solid was the title catalyst 1 with a yield of 91%.

[0053] Example 4 Preparation of Compound S-2-hydroxy-3-pentanone of Formula III

[0054] A mixture of 100 mmol of CuI2, 4 mmol of catalyst 1 [Pd2(MeCN)2(PFHT)(S-BINAP)](BF4)2 and 100 mL of THF-H2O (THF∶H2O = 4∶1) was added to a reaction flask. After stirring and mixing evenly, oxygen was introduced and replaced twice with oxygen. 50 mmol of the compound of Formula II dissolved in 20 mL of THF and 0.5 mL of trifluoroacetic acid were added. After addition, the reaction was stirred at room temperature. The reaction progress was monitored by TLC (developing agent: n-hexane∶ethyl acetate = 2∶1). After the reaction was completed, 200 mL of H2O was added and stirred for 10 min. The reaction solution was extracted with ether (3×100 mL). The ether layers were combined, washed with saturated sodium carbonate, the ether layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 50 mL of ethyl acetate was added to the residue, stirred to dissolve, and then 150 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain the compound of Formula III with a yield of 81% and an ee value of 91%. The structure was determined by 1Confirmed by \(^1\)H NMR and MS. ESI-LRMS m / z: 103.0831 [M+H] + , 1 \(^1\)H NMR (500 MHz, DMSO-d6) δ: 4.51 (q, J=11.4 Hz, 1H), 2.57 (q, J=13.4 Hz, 2H), 2.12 (s, 1H), 1.27 (d, J=11.4 Hz, 3H), 1.04 (t, J=13.4 Hz, 3H).

[0055] Example 5 Preparation of Compound III S-2-Hydroxy-3-pentanone

[0056] A mixture of 100 mmol of CuI2, 4 mmol of Catalyst 1 [Pd2(MeCN)2(PFHT)(S-BINAP)](BF4)2 and 100 mL of THF-H2O (THF∶H2O = 4∶1) was added to a reaction flask. After stirring and mixing evenly, oxygen was introduced and replaced twice with oxygen. 50 mmol of Compound II dissolved in 20 mL of THF was added. After addition, the reaction was stirred at room temperature. The reaction progress was monitored by TLC (developing solvent: n-hexane∶ethyl acetate = 2∶1). After the reaction was completed, 200 mL of H2O was added and stirred for 10 min. The reaction solution was extracted with ether (3×100 mL). The ether layers were combined, washed with saturated sodium carbonate, the ether layer was separated, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. 50 mL of ethyl acetate was added to the residue, stirred to dissolve, then 150 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain Compound III with a yield of 62% and an ee value of 93%.

[0057] Example 6 Preparation of Compound III S-2-Hydroxy-3-pentanone

[0058] A mixture of 100 mmol of CuBr2, 6 mmol of catalyst 1 [Pd2(MeCN)2(PFHT)(S-BINAP)](BF4)2 and 100 mL of THF-H2O (THF∶H2O = 5∶1) was added to a reaction flask. After stirring and mixing evenly, oxygen was introduced and the mixture was displaced with oxygen twice. 50 mmol of the compound of formula II dissolved in 20 mL of THF and 0.5 mL of trifluoroacetic acid were added. After addition, the reaction was stirred at room temperature. The reaction progress was monitored by TLC (developer: n-hexane∶ethyl acetate = 2∶1). After the reaction was completed, 200 mL of H2O was added and stirred for 10 min. The reaction solution was extracted with ether (3×100 mL). The ether layers were combined, washed with saturated sodium carbonate, the ether layer was separated, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. 50 mL of ethyl acetate was added to the residue, stirred to dissolve, then 150 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain the compound of formula III with a yield of 67% and an ee value of 81%.

[0059] Example 7 Preparation of Compound III S-2-Hydroxy-3-pentanone

[0060] A mixture of 100 mmol of CuCl2, 6 mmol of catalyst 1 [Pd2(MeCN)2(PFHT)(S-BINAP)](BF4)2 and 100 mL of THF-H2O (THF∶H2O = 4∶1) was added to a reaction flask. After stirring and mixing evenly, oxygen was introduced and the mixture was displaced with oxygen twice. 50 mmol of the compound of formula II dissolved in 20 mL of THF and 0.5 mL of trifluoroacetic acid were added. After addition, the reaction was stirred at room temperature. The reaction progress was monitored by TLC (developer: n-hexane∶ethyl acetate = 2∶1). After the reaction was completed, 200 mL of H2O was added and stirred for 10 min. The reaction solution was extracted with ether (3×100 mL). The ether layers were combined, washed with saturated sodium carbonate, the ether layer was separated, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. 50 mL of ethyl acetate was added to the residue, stirred to dissolve, then 150 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain the compound of formula III with a yield of 61% and an ee value of 70%.

[0061] Example 8 Preparation of Compound III S-2-Hydroxy-3-pentanone

[0062] 100 mmol of CuI2, 4 mmol of catalyst 1 [Pd2(MeCN)2(PHT)(S-BINAP)](BF4)2 and a mixture of 100 mL of THF-H2O (THF∶H2O = 4∶1) were added to a reaction flask. After stirring and mixing evenly, oxygen was introduced and the system was purged with oxygen twice. 50 mmol of the compound of formula II dissolved in 20 mL of THF and 0.5 mL of trifluoroacetic acid were added. After addition, the reaction was stirred at room temperature. The reaction progress was monitored by TLC (developing solvent: n-hexane∶ethyl acetate = 2∶1). After the reaction was completed, 200 mL of H2O was added and stirred for 10 min. The reaction solution was extracted with ether (3 × 100 mL). The ether layers were combined, washed with saturated sodium carbonate, the ether layer was separated, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. 50 mL of ethyl acetate was added to the residue, stirred until dissolved, then 150 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain the compound of formula III with a yield of 80% and an ee value of 85%.

[0063] Example 9 Preparation of Compound S-2-Hydroxy-3-pentanone of Formula III

[0064] 100 mmol of CuI2, 4 mmol of catalyst 1 [Pd2(MeCN)2(HpT)(S-BINAP)](BF4)2 and a mixture of 100 mL of THF-H2O (THF∶H2O = 4∶1) were added to a reaction flask. After stirring and mixing evenly, oxygen was introduced and the system was purged with oxygen twice. 50 mmol of the compound of formula II dissolved in 20 mL of THF and 0.5 mL of trifluoroacetic acid were added. After addition, the reaction was stirred at room temperature. The reaction progress was monitored by TLC (developing solvent: n-hexane∶ethyl acetate = 2∶1). After the reaction was completed, 200 mL of H2O was added and stirred for 10 min. The reaction solution was extracted with ether (3 × 100 mL). The ether layers were combined, washed with saturated sodium carbonate, the ether layer was separated, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. 50 mL of ethyl acetate was added to the residue, stirred until dissolved, then 150 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain the compound of formula III with a yield of 76% and an ee value of 79%.

[0065] Example 10 Preparation of Compound S-2-Hydroxy-3-pentanone of Formula III

[0066] 100 mmol of CuI2, 2 mmol of catalyst 1 [Pd2(MeCN)2(PFHT)(S-BINAP)](BF4)2 and a mixture of 100 mL of THF-H2O (THF∶H2O = 4∶1) were added to a reaction flask. After stirring and mixing evenly, oxygen was introduced and the system was purged with oxygen twice. 50 mmol of the compound of formula II dissolved in 20 mL of THF and 0.5 mL of trifluoroacetic acid were added. After addition, the reaction was stirred at room temperature. The reaction progress was monitored by TLC (developing solvent: n-hexane∶ethyl acetate = 2∶1). After the reaction was completed, 200 mL of H2O was added and stirred for 10 min. The reaction solution was extracted with ether (3 × 100 mL). The ether layers were combined, washed with saturated sodium carbonate, the ether layer was separated, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. 50 mL of ethyl acetate was added to the residue, stirred to dissolve, then 150 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain the compound of formula III with a yield of 73% and an ee value of 76%.

[0067] Example 11 Preparation of Compound S-2-hydroxy-3-pentanone of Formula III

[0068] 100 mmol of CuI2, 5 mmol of catalyst 1 [Pd2(MeCN)2(PHT)(S-BINAP)](BF4)2 and a mixture of 100 mL of THF-H2O (THF∶H2O = 4∶1) were added to a reaction flask. After stirring and mixing evenly, oxygen was introduced and the system was purged with oxygen twice. 50 mmol of the compound of formula II dissolved in 20 mL of THF and 0.5 mL of trifluoroacetic acid were added. After addition, the reaction was stirred at room temperature. The reaction progress was monitored by TLC (developing solvent: n-hexane∶ethyl acetate = 2∶1). After the reaction was completed, 200 mL of H2O was added and stirred for 10 min. The reaction solution was extracted with ether (3 × 100 mL). The ether layers were combined, washed with saturated sodium carbonate, the ether layer was separated, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. 50 mL of ethyl acetate was added to the residue, stirred to dissolve, then 150 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain the compound of formula III with a yield of 81% and an ee value of 87%.

[0069] Example 12 Preparation of Compound S-2-hydroxy-3-pentanone of Formula III

[0070] 100 mmol of CuI2, 5 mmol of catalyst 1 [Pd2(MeCN)2(PFHT)(S-BINAP)](BF4)2 and a mixture of 100 mL of THF-H2O (THF∶H2O = 4∶1) were added to a reaction flask. After stirring and mixing evenly, oxygen was introduced and the mixture was displaced with oxygen twice. 50 mmol of the compound of formula II dissolved in 20 mL of THF and 0.5 mL of trifluoroacetic acid were added. After the addition, the reaction was stirred at room temperature. The reaction progress was monitored by TLC (developing agent: n-hexane∶ethyl acetate = 2∶1). After the reaction was completed, 200 mL of H2O was added and stirred for 10 min. The reaction solution was extracted with ether (3×100 mL). The ether layers were combined, washed with saturated sodium carbonate, the ether layer was separated, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. 50 mL of ethyl acetate was added to the residue, stirred until dissolved, then 150 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain the compound of formula III with a yield of 81% and an ee value of 92%.

[0071] Example 13 Preparation of Compound of Formula IV S-2-Benzyloxy-3-pentanone

[0072] Under N2 protection, 60 mmol of sodium hydride and 20 mL of dry THF were added to a reaction flask, stirred, cooled to 0 °C in an ice bath, and 50 mmol of the compound of formula III obtained in Example 12 dissolved in 20 mL of dry THF solution was slowly added dropwise, controlling the reaction temperature not to exceed 10 °C, and stirred for 0.5 h. 55 mmol of benzyl chloride was added dropwise. After the addition, the reaction was stirred at room temperature for 3 h. The reaction progress was monitored by TLC (developing agent: n-hexane∶ethyl acetate = 3∶1). After the reaction was completed, 1 N hydrochloric acid was added to the reaction solution to terminate the reaction, the pH was adjusted to 3 - 4, then 30 mL of MTBE was added and stirred until dissolved completely. The layers were separated, the organic phase was washed with 30 mL of saturated brine, dried, and the solvent was removed under reduced pressure to dryness to obtain a crude solid. 50 mL of MTBE was added to the crude solid, then 150 mL of petroleum ether was added, stirred, and left at room temperature for 0.5 h. The precipitated solid was filtered and dried under reduced pressure to obtain the compound of formula IV with a yield of 90% and an ee value of 94%. This solid can be directly used for the next experiment without further purification.

[0073] Example 14 Preparation of Compound of Formula I N'-(2S,3S)-2-(Benzyloxy)-3-pentylformohydrazide

[0074] Under N2 protection, 0.25 mmol of [Ir(COD)Cl]2, 0.55 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH3, R2 = H), and 100 mL of toluene were added to a reaction kettle, stirred at room temperature for 15 min, and then 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added, and then 20 mL of isopropyl titanate was added. After replacing with hydrogen 3 times, hydrogen was introduced to 50 atmospheres, the temperature was raised to 40 °C under stirring, and the reaction was stirred and maintained for 10 h. The hydrogen was slowly released, and the mixture was cooled to room temperature. The reaction mixture was discharged, filtered, and the organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine, dried, and the solvent was distilled off under reduced pressure. 200 mL of MTBE and 200 mL of 1N HCl were added to the residue, stirred, and the layers were separated. The organic phase was separated, and the organic phase was washed again with 200 mL of 1N HCl. The aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3, extracted with 200 mL of MTBE, the organic phases were combined, dried, and the solvent was distilled off under reduced pressure to obtain a yellow oily compound of formula I with a yield of 60% and a purity of 98.2%. The structure was confirmed by 1 1H NMR and 13 13C NMR. 1 1H NMR (500 MHz, DMSO-d6) δ: 9.39 (s, 1H), 8.77 (d, J = 10.7 Hz, 1H), 8.02 (s, 1H), 7.49 - 7.20 (m, 5H), 4.59 (dd, J = 11.8, 5.9 Hz, 1H), 4.44 (dd, J = 11.8, 2.6 Hz, 1H), 3.76 - 3.46 (m, 1H), 2.75 (dd, J = 53.4, 3.9 Hz, 1H), 1.66 - 1.51 (m, 1H), 1.41 - 1.26 (m, 1H), 1.24 - 1.12 (m, 3H), 0.95 (dt, J = 12.8, 7.4 Hz, 3H); 13 13C NMR (126 MHz, DMSO) δ: 166.97, 159.70, 139.40, 128.70, 128.55, 75.10, 70.37, 65.15, 20.79, 15.30, 10.34.

[0075] Preparation of the compound of formula I N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine in Example 15

[0076] Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH3, R2 = H), and 100 mL of toluene were added to a reaction kettle, stirred at room temperature for 15 min, then 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added, and then 20 mL of isopropyl titanate was added. After purging with hydrogen three times, hydrogen was introduced to 50 atmospheres, the temperature was raised to 40 °C with stirring, and the reaction was stirred and maintained for 10 h. The hydrogen was slowly released, and the mixture was cooled to room temperature. The reaction mixture was discharged, filtered, and the organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine, dried, the solvent was removed under reduced pressure, 200 mL of MTBE and 200 mL of 1N HCl were added to the residue, stirred, separated, and the organic phase was separated. The organic phase was washed again with 200 mL of 1N HCl, the aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3, extracted with 200 mL of MTBE, the combined organic phases were dried and the solvent was removed under reduced pressure to obtain the yellow oily compound of formula I with a yield of 68% and a purity of 99.0%.

[0077] Preparation of the compound of formula I N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine in Example 16

[0078] Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH3, R2 = H), and 100 mL of toluene were added to a reaction kettle, stirred at room temperature for 15 min, then 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added, and then 20 mL of isopropyl titanate was added. After purging with hydrogen three times, hydrogen was introduced to 50 atmospheres, the temperature was raised to 50 °C with stirring, and the reaction was stirred and maintained for 10 h. The hydrogen was slowly released, and the mixture was cooled to room temperature. The reaction mixture was discharged, filtered, and the organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine, dried, the solvent was removed under reduced pressure, 200 mL of MTBE and 200 mL of 1N HCl were added to the residue, stirred, separated, and the organic phase was separated. The organic phase was washed again with 200 mL of 1N HCl, the aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3, extracted with 200 mL of MTBE, the combined organic phases were dried and the solvent was removed under reduced pressure to obtain the yellow oily compound of formula I with a yield of 74% and a purity of 99.1%.

[0079] Preparation of the compound of formula I N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine in Example 17

[0080] Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH3, R2 = H), and 100 mL of toluene were added to a reaction kettle, stirred at room temperature for 15 min, and then 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added. Then, 20 mL of isopropyl titanate was added. After purging with hydrogen three times, hydrogen was introduced to 50 atmospheres. The temperature was raised to 90 °C with stirring and kept stirring for reaction for 10 h. The hydrogen was slowly released and cooled to room temperature. The reaction mixture was discharged, filtered, and the organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine, dried, and the solvent was distilled off under reduced pressure. 200 mL of MTBE and 200 mL of 1N HCl were added to the residue, stirred, and separated. The organic phase was separated, and the organic phase was washed once again with 200 mL of 1N HCl. The aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3. It was extracted with 200 mL of MTBE. The combined organic phases were dried and the solvent was distilled off under reduced pressure to obtain the yellow oily compound of formula I with a yield of 81% and a purity of 96.4%.

[0081] Preparation of the compound of formula I N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine in Example 18

[0082] Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = H, R2 = H), and 100 mL of toluene were added to a reaction kettle, stirred at room temperature for 15 min, and then 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added. Then, 20 mL of isopropyl titanate was added. After purging with hydrogen three times, hydrogen was introduced to 50 atmospheres. The temperature was raised to 50 °C with stirring and kept stirring for reaction for 10 h. The hydrogen was slowly released and cooled to room temperature. The reaction mixture was discharged, filtered, and the organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine, dried, and the solvent was distilled off under reduced pressure. 200 mL of MTBE and 200 mL of 1N HCl were added to the residue, stirred, and separated. The organic phase was separated, and the organic phase was washed once again with 200 mL of 1N HCl. The aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3. It was extracted with 200 mL of MTBE. The combined organic phases were dried and the solvent was distilled off under reduced pressure to obtain the yellow oily compound of formula I with a yield of 75% and a purity of 92.4%.

[0083] Preparation of the compound of formula I N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine in Example 19

[0084] Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH2CH3, R2 = CH3), and 100 mL of toluene were added to a reaction kettle, stirred at room temperature for 15 min, then 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added, and then 20 mL of isopropyl titanate was added. After purging with hydrogen three times, hydrogen was introduced to 50 atmospheres, the temperature was raised to 50 °C with stirring, and the reaction was stirred and maintained for 10 h. The hydrogen was slowly released, and the mixture was cooled to room temperature. The reaction mixture was discharged, filtered, and the organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine respectively, dried, and the solvent was evaporated under reduced pressure. 200 mL of MTBE and 200 mL of 1N HCl were added to the residue, stirred, and the layers were separated. The organic phase was separated, and the organic phase was washed again with 200 mL of 1N HCl. The aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3, extracted with 200 mL of MTBE, and the combined organic phases were dried and the solvent was evaporated under reduced pressure to obtain the yellow oily compound of formula I with a yield of 56% and a purity of 98.9%.

[0085] Preparation of the compound of formula I in Example 20, N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine

[0086] Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH3, R2 = Cl), and 100 mL of toluene were added to a reaction kettle, stirred at room temperature for 15 min, then 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added, and then 20 mL of isopropyl titanate was added. After purging with hydrogen three times, hydrogen was introduced to 50 atmospheres, the temperature was raised to 50 °C with stirring, and the reaction was stirred and maintained for 10 h. The hydrogen was slowly released, and the mixture was cooled to room temperature. The reaction mixture was discharged, filtered, and the organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine respectively, dried, and the solvent was evaporated under reduced pressure. 200 mL of MTBE and 200 mL of 1N HCl were added to the residue, stirred, and the layers were separated. The organic phase was separated, and the organic phase was washed again with 200 mL of 1N HCl. The aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3, extracted with 200 mL of MTBE, and the combined organic phases were dried and the solvent was evaporated under reduced pressure to obtain the yellow oily compound of formula I with a yield of 60% and a purity of 96.8%.

[0087] Preparation of the compound of formula I in Example 21, N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine

[0088] Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH3, R2 = Br), and 100 mL of toluene were added to a reaction kettle, stirred at room temperature for 15 min, then 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added, and then 20 mL of isopropyl titanate was added. After replacing with hydrogen 3 times, hydrogen was introduced to 50 atmospheres, the temperature was raised to 50 °C with stirring, and the reaction was stirred and maintained for 10 h. The hydrogen was slowly released, and the mixture was cooled to room temperature. The reaction mixture was discharged, filtered, the organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine respectively, dried, the solvent was distilled off under reduced pressure, 200 mL of MTBE and 200 mL of 1N HCl were added to the residue, stirred, separated, the organic phase was separated, the organic phase was washed once again with 200 mL of 1N HCl, the aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3, extracted with 200 mL of MTBE, the organic phases were combined, dried, and the solvent was distilled off under reduced pressure to obtain the yellow oily compound of formula I with a yield of 53% and a purity of 96.1%.

[0089] Preparation of the compound of formula I, N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine, in Example 22

[0090] Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH2CH2CH3, R2 = H), and 100 mL of toluene were added to a reaction kettle, stirred at room temperature for 15 min, then 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added, and then 20 mL of isopropyl titanate was added. After replacing with hydrogen 3 times, hydrogen was introduced to 50 atmospheres, the temperature was raised to 50 °C with stirring, and the reaction was stirred and maintained for 10 h. The hydrogen was slowly released, and the mixture was cooled to room temperature. The reaction mixture was discharged, filtered, the organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine respectively, dried, the solvent was distilled off under reduced pressure, 200 mL of MTBE and 200 mL of 1N HCl were added to the residue, stirred, separated, the organic phase was separated, the organic phase was washed once again with 200 mL of 1N HCl, the aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3, extracted with 200 mL of MTBE, the organic phases were combined, dried, and the solvent was distilled off under reduced pressure to obtain the yellow oily compound of formula I with a yield of 69% and a purity of 98.5%.

[0091] Preparation of the compound of formula I, N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine, in Example 23

[0092] Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH3, R2 = H), and 100 mL of toluene were added to a reaction kettle. Stir at room temperature for 15 min. Then, 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added. Then, 20 mL of methyl titanate was added. After purging with hydrogen three times, hydrogen was introduced to 50 atmospheres. Stir and heat up to 50 °C, and keep stirring and reacting for 10 h. Slowly release hydrogen and cool to room temperature. Discharge the reaction mixture. Filter. The organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine respectively, dried, and the solvent was removed under reduced pressure. 200 mL of MTBE and 200 mL of 1N HCl were added to the residue. Stir and separate the layers. The organic phase was separated, and the organic phase was washed again with 200 mL of 1N HCl. The aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3. Extracted with 200 mL of MTBE. The combined organic phases were dried and the solvent was removed under reduced pressure to obtain a yellow oily compound of formula I, with a yield of 62% and a purity of 95.4%.

[0093] Preparation of the compound of formula I N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine in Example 24

[0094] Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH3, R2 = H), and 100 mL of toluene were added to a reaction kettle. Stir at room temperature for 15 min. Then, 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added. Then, 20 mL of ethyl titanate was added. After purging with hydrogen three times, hydrogen was introduced to 50 atmospheres. Stir and heat up to 50 °C, and keep stirring and reacting for 10 h. Slowly release hydrogen and cool to room temperature. Discharge the reaction mixture. Filter. The organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine respectively, dried, and the solvent was removed under reduced pressure. 200 mL of MTBE and 200 mL of 1N HCl were added to the residue. Stir and separate the layers. The organic phase was separated, and the organic phase was washed again with 200 mL of 1N HCl. The aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3. Extracted with 200 mL of MTBE. The combined organic phases were dried and the solvent was removed under reduced pressure to obtain a yellow oily compound of formula I, with a yield of 66% and a purity of 97.4%.

[0095] Preparation of the compound of formula I N'-(2S,3S)-2-(benzyloxy)-3-pentylformylhydrazine in Example 25

[0096] Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH3, R2 = H), and 100 mL of toluene were added to a reaction kettle, stirred at room temperature for 15 min, and then 50 mmol of the compound of formula IV obtained in Example 13 and 55 mmol of formylhydrazine were respectively dissolved in 50 mL of toluene and added, and then 20 mL of isobutyl titanate was added. After purging with hydrogen three times, hydrogen was introduced to 50 atmospheres, the temperature was raised to 50 °C with stirring, and the reaction was stirred and maintained for 10 h. The hydrogen was slowly released, and the mixture was cooled to room temperature. The reaction mixture was discharged, filtered, and the organic phase was washed once with 100 mL of saturated ammonium chloride and 200 mL of brine, dried, and the solvent was evaporated under reduced pressure. 200 mL of MTBE and 200 mL of 1N HCl were added to the residue, stirred, and the layers were separated. The organic phase was washed once again with 200 mL of 1N HCl. The aqueous phases were combined, and the pH was adjusted to about 8 with saturated Na2CO3. The mixture was extracted with 200 mL of MTBE. The organic phases were combined, dried, and the solvent was evaporated under reduced pressure to obtain a yellow oily compound of formula I with a yield of 70% and a purity of 98.9%.

Claims

1. A preparation method of a posaconazole intermediate, the structure of the posaconazole intermediate is shown in Formula I, and the method comprises the following steps: (1) In the presence of CuX2 and oxygen, the compound shown in Formula II undergoes an asymmetric oxidation reaction with oxygen under the catalysis of chiral catalyst 1 to obtain the compound shown in Formula III; (2) The compound shown in Formula III undergoes a substitution reaction with BnX to obtain the compound shown in Formula IV; (3) The compound shown in Formula IV undergoes an asymmetric reductive amination reaction with NH2NH2CHO under the action of chiral catalyst 2, an additive and hydrogen to obtain the compound shown in Formula I; The chiral catalyst 1 in step (1) is [Pd2(MeCN)2(A1)(L1*)](BF4)2, where A1 is selected from HpT, PFHT or PHT, and the structural formulas of HpT, PFHT and PHT are: L1* is selected from S-BINAP, and the structure is: The chiral catalyst 2 in step (3) is a metal iridium (I) complex, and the structural formula is Ir-L2*, which is generated in situ in the experiment from (1,5-cyclooctadiene) iridium (I) chloride dimer and ligand L2*, and L2* is a chiral diphenylphosphine-phosphonamide ligand, and the structure is: Among them, R1 is H, an alkyl group with 1 to 4 carbon atoms; R2 is H, an alkyl group with 1 to 4 carbon atoms or a halogen.

2. The preparation method of the posaconazole intermediate according to claim 1, characterized in that, The CuX2 in step (1) is CuI2, CuBr2 or CuCl2.

3. The preparation method of the posaconazole intermediate according to claim 1, wherein The reaction solvent in step (1) is a mixture of THF and water, and the volume ratio of THF to water is 3 to 6:

1.

4. The preparation method of the posaconazole intermediate according to claim 1, wherein, The molar ratio of CuX2, catalyst 1 and the compound of Formula II in step (1) is 100:(2 to 6):

50.

5. The preparation method of the posaconazole intermediate according to claim 1, wherein, Adding a strong acid in step (1) can accelerate the reaction, and the strong acid is trifluoroacetic acid.

6. The preparation method of the posaconazole intermediate according to claim 1, wherein, The specific reaction steps of step (1) are as follows: Add 100 mmol of CuI2, 5 mmol of catalyst 1 [Pd2(MeCN)2(PFHT)(S-BINAP)](BF4)2 and 100 mL of a mixture of THF-H2O with a volume ratio of 4:1 into a reaction flask, stir and mix evenly, then introduce oxygen and displace it twice with oxygen. Add 50 mmol of the compound of Formula II dissolved in 20 mL of THF and 0.5 mL of trifluoroacetic acid, and stir and react at room temperature after adding.

7. The preparation method of the posaconazole intermediate according to claim 1, characterized in that, The reaction steps of step (2) are as follows: Under the protection of N2, add 60 mmol of sodium hydride and 20 mL of dry THF into a reaction flask, stir, cool to 0 °C in an ice bath, slowly dropwise add the compound of Formula III dissolved in 20 mL of dry THF solution, control the reaction temperature not higher than 10 °C, stir for 0.5 h, dropwise add 55 mmol of benzyl chloride, and stir and react at room temperature for 3 h after dropping.

8. The preparation method of the posaconazole intermediate according to claim 1, characterized in that, The hydrogen pressure in step (3) is 50 atmospheres, and the reaction temperature is 50 °C; the molar ratio of chiral catalyst 2, the compound of Formula IV and formylhydrazine in step (3) is (0.25 to 1.25):50:

55.

9. The preparation method of the posaconazole intermediate according to claim 1, wherein, The additive in step (3) is selected from isopropyl titanate, ethyl titanate, methyl titanate or isobutyl titanate.

10. The preparation method of the posaconazole intermediate according to claim 1, wherein, The reaction procedure of step (3) is as follows: Under N2 protection, 1.25 mmol of [Ir(COD)Cl]2, 2.75 mmol of chiral phosphine-phosphonamide ligand L2* (R1 = CH3, R2 = H), and 100 mL of toluene are added to a reaction kettle, stirred at room temperature for 15 min, then 50 mmol of the compound of formula IV and 55 mmol of formylhydrazine are respectively dissolved in 50 mL of toluene and added, and then 20 mL of isopropyl titanate is added. After three replacements with hydrogen, hydrogen is introduced to 50 atmospheres, the temperature is raised to 50 °C with stirring, and the reaction is stirred and maintained for 10 h.

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