Preparation method of the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole

Abstract

This invention belongs to the field of organic synthesis technology and relates to a method for preparing the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole. In an electrochemical cell, 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and methyl 2-bromo-3-isobutyryloxypropionate are reacted in the presence of a chiral nickel catalyst, followed by reduction to obtain the target product. This invention achieves asymmetric coupling of allyl and alkyl radicals through an electrochemical redox process catalyzed by a chiral nickel catalyst, constructing the core carbon skeleton and chiral center in one step. This avoids the cumbersome operations of multi-step functional group transformation and protection, and the target product exhibits high enantioselectivity and high overall yield, significantly reducing production costs and making it suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate, a key chiral intermediate of posaconazole. Background Technology

[0002] Posaconazole is a second-generation triazole antifungal drug with excellent therapeutic effects against various drug-resistant fungal infections. The preparation of the chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate is a crucial step in its synthesis. The compound is characterized by a pent-4-ene skeleton, with double bonds located between positions 4 and 5. A 2,4-difluorophenyl group is directly attached to the carbon at position 4, and the carbon at position 2 is the chiral center (S configuration), simultaneously connecting the hydroxymethyl group and the methyl group of the isobutyrate ester. Its structural formula is as follows:

[0003] .

[0004] In existing publicly available literature and patents, the methods for preparing this intermediate can be broadly categorized into several types:

[0005] The first type is palladium-catalyzed carpalladiumation reactions. For example, Chinese patent CN1147807A discloses a method for preparing an intermediate used in the synthesis of fungicides, using 2,4-difluorobromobenzene, diethyl malonate, and propadiene as raw materials, followed by a palladium-catalyzed next-step reaction to obtain the target skeleton. This method has a relatively short number of steps, but propadiene is a reactive gas, resulting in numerous impurities during the reaction process, making separation and purification difficult. The overall yield is approximately 45%, and the problems become more pronounced during industrial scale-up.

[0006]

[0007] The second type of method is the catalytic cross-coupling method. For example, Chinese patent CN102643194A discloses a method for preparing a posaconazole intermediate. First, 2,3-dichloropropene reacts with malonate diester, undergoing multiple steps of alkylation, reduction, and acylation. Then, it undergoes cross-coupling with 2,4-difluorophenyl magnesium bromide under iron salt catalysis. This process requires the use of Grignard reagents, demands high levels of anhydrous and oxygen-free conditions, and the iron-catalyzed system is prone to generating defluorination byproducts, affecting the purity of the final product.

[0008]

[0009] The third type of method is the chiral resolution method. For example, the world patent WO2011144657A1 utilizes the lipase Novozym435 or a chiral reagent to selectively acylate pre-chiral diols at low temperatures. While the enantioselectivity of enzyme-catalyzed methods is indeed very high, the enzymes themselves are expensive, sensitive to temperature and pH, and the reaction time can be as long as 24 hours, resulting in significant shortcomings in production efficiency.

[0010]

[0011] In summary, the existing technology for preparing this chiral intermediate faces three major bottlenecks: high reagent risk (such as propadiene and Grignard reagents), expensive catalytic systems (such as lipases), and complex process steps.

[0012] However, electrochemical synthesis, as an emerging green tool, can achieve efficient transformation under mild conditions by replacing redox reagents with controlled electron transfer, perfectly meeting the development needs of sustainable chemistry. It is worth mentioning that Liu et al. reported an electrochemically promoted nickel-catalyzed asymmetric reduction cross-coupling methodology in 2022 (Nature Communications, 2022, 13, 7318), achieving the asymmetric coupling of aryl bromides with α-chloro esters through a synergistic process of anodic oxidation to generate free radicals and cathodic reduction to regenerate the catalyst. C(sp...) was constructed through the oxidative addition of aryl bromides and the capture of alkyl free radicals. 2 )-C(sp 3 )key.

[0013] Although the methods reported above involve the basic paradigm of electrochemical nickel-catalyzed reduction cross-coupling, the substrate types are limited to aryl-alkyl coupling systems, the catalytic cycle is based on the Ni(II) / Ni(I) / Ni(III) pathway, and the key intermediate is an aryl nickel complex. However, the synthesis of the chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate belongs to the allyl-alkyl carbon skeleton construction, involving η 3 The formation of π-allyl nickel complexes and the facet-selective stereocontrol of π-allyl systems differ greatly in catalytic cycle pathways, key intermediate structures, and enantioselectivity-determining steps. Therefore, the method described in this literature cannot be directly applied to the synthesis of key chiral intermediates of posaconazole.

[0014] Therefore, there is an urgent need to develop an electrochemical synthesis route that combines ease of operation, cost competitiveness, and excellent stereoselectivity, providing highly promising technical support for the large-scale production of posaconazole. Summary of the Invention

[0015] To address the technical problems of cumbersome synthesis steps, poor enantioselectivity, and high cost in existing technologies, this invention provides a method for preparing the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole. Using 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and methyl 2-bromo-3-isobutyryloxypropionate as raw materials, and under the catalysis of a chiral nickel catalyst, the asymmetric coupling of allyl and alkyl radicals is achieved through an electrochemical redox process, thereby constructing the core carbon skeleton and chiral center in one step.

[0016] The technical solution adopted by this invention to solve its technical problem is: a method for preparing the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole, comprising the following steps: in an electrochemical cell, using 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and methyl 2-bromo-3-isobutyryloxypropionate as raw materials, an electrochemical reaction is carried out in the presence of a chiral nickel catalyst to generate the key intermediate. After further reduction with a reducing agent, (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate is obtained.

[0017] Furthermore, the chiral nickel catalyst is generated by in-situ reaction of nickel salt and chiral ligand, with a molar ratio of nickel salt to chiral ligand of 1:1.1-1.3.

[0018] Furthermore, the nickel salt is NiCl2·glyme, NiBr2·glyme, or Ni(OAc)2.

[0019] Furthermore, the chiral ligand is (S,S)-Ph-BPE or (S,S)-Me-DuPhos.

[0020] Furthermore, the electrochemical cell is a non-separated electrolytic cell, with the anode being zinc, magnesium, aluminum, or iron; and the cathode being platinum or carbon.

[0021] Furthermore, the energizing mode during the energizing reaction is a constant current mode, with a current of 10-30mA and an energizing reaction time of 5-7h.

[0022] Furthermore, a supporting electrolyte is added to the electrochemical cell. The supporting electrolyte is tetrabutylammonium tetrafluoroborate, and the molar ratio of the supporting electrolyte to 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene is 0.9-1.1:1.

[0023] Further, the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to methyl 2-bromo-3-isobutyryloxypropionate is 1:1.1-1.3, and the molar ratio of nickel to 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene in the chiral nickel catalyst is 0.08-0.10:1.

[0024] Furthermore, the reducing agent is lithium borohydride, the reduction temperature is 20-30℃, and the reduction time is 3-5h.

[0025] Specifically, the preparation method of the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole in this invention is based on the following reaction principle:

[0026] (1) Electrochemical asymmetric reduction cross-coupling reaction

[0027] Using 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene (Formula II) and methyl 2-bromo-3-isobutyryloxypropionate (Formula III) as raw materials, a key intermediate (Formula IV) is first generated by electrolysis in a non-separated electrolytic cell in the presence of a chiral nickel catalyst.

[0028] .

[0029] This process belongs to an electrochemically promoted nickel-catalyzed asymmetric reduction cross-coupling system, which includes three synergistic processes: anodic oxidation, cathodic reduction, and nickel catalytic cycling.

[0030] The specific reaction mechanism is as follows:

[0031] .

[0032] 1) Anodizing process:

[0033] In a non-separated electrolytic cell, the sacrificial anode (such as zinc) undergoes an oxidation reaction, releasing electrons: Zn → Zn 2+ +2e - ;

[0034] Meanwhile, methyl 2-bromo-3-isobutyryloxypropionate (Formula III) in the solution can undergo a single electron transfer on the anode surface to generate a free radical positive ion intermediate, which then loses the bromide anion to produce an α-ester-substituted free radical intermediate A.

[0035] 2) Cathode reduction process:

[0036] A reduction reaction occurs at the cathode, reducing the chiral nickel catalyst (such as NiBr2·glymeL, which is generated in situ from NiBr2·glyme and (S,S)-Ph-BPE) to the zero-valent nickel active species Ni(0)L. At the same time, the chiral ligand L coordinates with the nickel center to form a catalytically active chiral nickel complex Ni(0)L*(Int-1).

[0037] 3) Nickel catalytic cycle: includes three steps: oxidative addition, free radical capture, and reductive elimination.

[0038] ①Oxidative addition

[0039] The Ni(0)L* (Int-1) generated at the cathode undergoes oxidative addition with 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene (Formula II). This process begins with the oxidative addition of the C-Br bond, followed by the formation of an η³-allyl nickel(II) complex (Int-2). Throughout the process, the chiral ligand L* remains coordinated to the nickel center, creating an asymmetric spatial environment that lays the foundation for subsequent stereoselective control.

[0040] ② Free radical capture (enantioselectivity determination step)

[0041] The radical intermediate A, generated at the anode, diffuses and attacks the terminal carbon of the allyl group in the η³-allyl nickel(II) complex (Int-2). In the asymmetric spatial environment created by the chiral ligand L*, radical intermediate A preferentially attacks the anti-side of the terminal carbon, thereby controlling the absolute configuration of the final product. This step generates a trivalent nickel intermediate (Int-3), in which both an allyl group and an alkyl group are simultaneously attached to the nickel.

[0042] ③Reduction and elimination

[0043] The high-valence trivalent nickel intermediate (Int-3) undergoes a rapid reductive elimination reaction, where the terminal carbon of the allyl group directly couples with the alkyl group R to form a new carbon-carbon bond, generating the target coupling intermediate (Formula IV), while simultaneously regenerating the chiral nickel complex Ni(0)L* (Int-1), thus completing the nickel catalytic cycle.

[0044] (2) Selective reduction

[0045] The key intermediate (Formula IV) was reduced by a reducing agent to reduce the methyl ester group to hydroxymethyl, yielding the target product (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate (Formula I).

[0046] .

[0047] The process uses lithium borohydride to selectively reduce the key intermediate (Formula IV) to reduce the methyl ester group (-COOMe) to hydroxymethyl (-CH2OH), yielding the target product (Formula I). ​​During this reduction process, the chiral center configuration is maintained.

[0048] It should be noted that the absolute configuration of the chiral center of the key coupling intermediate (Formula IV) obtained in step (1) is (S)-configuration. However, due to the Cahn-Ingold-Prelog (CIP) nomenclature rules, it is named as the R-configuration. In the reduction reaction of step (2), since the methyl ester group is reduced to hydroxymethyl, the priority order of the substituents on the chiral carbon is reversed. Therefore, the absolute configuration name of the target product (Formula I) is correspondingly changed to (S)-configuration.

[0049] The beneficial effects of this invention are as follows:

[0050] (1) Innovative mechanism: For the first time, electrochemically promoted nickel-catalyzed asymmetric reduction cross-coupling is applied to the synthesis of posaconazole intermediates. This mechanism generates free radicals through anodic oxidation and regenerates the catalyst through cathodic reduction, achieving synergy between electrochemistry and transition metal catalysis, which is fundamentally different from the thermocatalytic mode of existing technologies.

[0051] (2) It is green and environmentally friendly. It is driven by electrochemistry and does not require the addition of chemical oxidants or reducing agents. It has high atom economy, less waste, and conforms to the concept of green chemistry.

[0052] (3) The raw materials are simple, using 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and methyl 2-bromo-3-isobutyryloxypropionate as raw materials. There is no need to prepare active metal reagents or sensitive intermediates in advance. The raw materials are readily available and the cost is controllable.

[0053] (4) The steps are concise. Starting from two simple electrophilic reagents, the core carbon skeleton and chiral center are constructed by a single-step electrochemical reaction, avoiding the cumbersome operation of multi-step functional group transformation and protection.

[0054] (5) It has good enantioselectivity. Through rational screening of chiral ligands, the ee value can reach more than 99.5%, which meets the quality requirements of pharmaceutical intermediates.

[0055] (6) It has extremely high stereoselectivity and controllable configuration. Using the specific chiral ligands of this invention, the target product with the S configuration of posaconazole can be constructed with high selectivity and precision.

[0056] (7) Scalability: Electrochemical methods are easy to scale up, and continuous flow electrochemical technology can be directly applied to industrial production, with good industrialization prospects.

[0057] In summary, this invention uses 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and methyl 2-bromo-3-isobutyryloxypropionate as raw materials. Under the catalysis of a chiral nickel catalyst, an electrochemical redox process is used to achieve the asymmetric coupling of allyl and alkyl radicals, constructing the core carbon skeleton and chiral center in one step, avoiding the cumbersome operations of multi-step functional group transformation and protection. The target product has advantages such as high enantioselectivity (ee value ≥ 99.5%), simple steps, overall yield of over 65%, and easy operation, significantly reducing production costs and making it suitable for industrial production. Attached Figure Description

[0058] Figure 1 This is a schematic diagram of the electrochemical / nickel co-catalytic asymmetric reduction cross-coupling reaction mechanism of the present invention.

[0059] Figure 2 It is the intermediate (Formula IV) prepared in step (1) of Example 1. 1 H NMR spectrum.

[0060] Figure 3 It is the (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate prepared in step (2) of Example 1. 1 H NMR spectrum.

[0061] Figure 4 It is the (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate prepared in step (2) of Example 1. 13 C NMR spectrum.

[0062] Figure 5 This is the HPLC chromatogram of (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate prepared in step (2) of Example 1.

[0063] Figure 6 It is the methyl 2-bromo-3-isobutyryloxypropionate (Formula III) of this invention. 1 H NMR spectrum.

[0064] Figure 7 It is the methyl 2-bromo-3-isobutyryloxypropionate (Formula III) of this invention. 13 C NMR spectrum. Detailed Implementation

[0065] The following are specific embodiments of the present invention, which further describe the technical solution of the present invention. However, the scope of protection of the present invention is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present invention are included within the scope of protection of the present invention.

[0066] The raw material 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene (Formula II) used in this invention has the CAS number 159276-58-1 and was purchased from Aibisin (Shanghai) Biotechnology Co., Ltd.

[0067] In this invention, the raw material methyl 2-bromo-3-isobutyryloxypropionate (Formula III) is prepared from methyl 2-bromo-3-hydroxypropionate and isobutyryl chloride. The preparation method is based on the method disclosed in Example 3 of Chinese Patent Publication No. CN103124759B. This patent document discloses the reaction of methyl 2-bromo-3-hydroxypropionate with acetyl chloride in anhydrous diethyl ether in the presence of triethylamine to obtain the corresponding methyl 3-acetoxy-2-bromopropionate. Based on the hydroxylation reaction conditions disclosed in the aforementioned patent document, the methyl 2-bromo-3-isobutyryloxypropionate (Formula III) of this invention is prepared by replacing the acetyl chloride in Example 3 of the aforementioned patent document with isobutyryl chloride. Specifically, following the reaction conditions in the aforementioned patent document, 25 mmol of methyl 2-bromo-3-hydroxypropionate is used as the raw material, and reacted with isobutyryl chloride in the presence of triethylamine to obtain 4.207 g of methyl 2-bromo-3-isobutyryloxypropionate (Formula III), with a yield of 64.5%. methyl 2-bromo-3-isobutyryloxypropionate 1 H NMR image as follows Figure 6 As shown, 13 C NMR spectrum as shown Figure 7 As shown, the specific data is as follows:

[0068] 1 HNMR(500MHz,CDCl3)δ4.93(t,J=6.4Hz,1H),4.79(dd,J=12.5,6.3Hz,1H),4.54(dd,J =12.6,6.4Hz,1H),3.71(s,3H),2.52(hept,J=7.4Hz,1H),1.16(dd,J=7.3,2.2Hz,6H). 13 CNMR (125MHz, CDCl3) δ176.66,169.30,64.61,53.06,43.17,34.24,19.04.

[0069] Example 1

[0070] (1) Preparation of key intermediate (Formula IV)

[0071] In a separate electrolytic cell, NiBr2·glyme (30.8 mg, 0.1 mmol), chiral ligand L1 ((S,S)-Ph-BPE, 0.12 mmol), tetrabutylammonium tetrafluoroborate (nBu4NBF4, 1.0 mmol), and anhydrous DMF (10 mL) were added sequentially. The solids were stirred to dissolve, and then 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene (II, 233 mg, 1.0 mmol) and methyl 2-bromo-3-isobutyryloxypropionate (III, 303.6 mg, 1.2 mmol) were added.

[0072] Using a zinc sheet as the sacrificial anode and a platinum sheet as the cathode, the mixture was stirred and energized at room temperature for 6 hours in constant current mode (10 mA). The electrochemical / nickel co-catalyzed asymmetric reduction cross-coupling reaction mechanism is as follows: Figure 1 As shown. After the reaction, the electrolyte was diluted with ethyl acetate, washed successively with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give 248 mg of a pale yellow oily coupling key intermediate (formula IV), with a yield of 76% and an ee value of 99.7%. 1 H NMR image as follows Figure 2 .

[0073] ¹HNMR(400MHz, CDCl3)δ7.18-7.11(m,1H),6.82-6.72(m,2H),5.19-5.14(m,1H),5.04(dt,J=2.0,1.1Hz,1H),4.47-4.42(m,1 H),4.33-4.23(m,1H),3.59(s,3H),3.08-3.00(m,2H),2.73-2.63(m,1H),2.52(h,J=7.4Hz,1H),1.16(dd,J=7.3,2.2Hz,6H).

[0074] (2) Preparation of (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate

[0075] The key intermediate obtained in step (1) (formula IV, 124 mg, 0.38 mmol) was dissolved in anhydrous THF (5 mL) and cooled to -20 °C. A lithium borohydride THF solution (1.0 M, 0.57 mL, 0.57 mmol) was slowly added dropwise, maintaining the system temperature at approximately 0 °C during the addition. After the addition was complete, the temperature was slowly raised to 20-30 °C and stirred for 4 hours. After the reaction was monitored by TLC to ensure complete reaction, water (0.03 mL), 15% NaOH solution (0.03 mL), and water (0.09 mL) were added slowly in an ice bath to quench the reaction. Anhydrous sodium sulfate was added for drying, and the mixture was filtered and the filtrate concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1 → 3:1) to obtain 105.4 mg of the white solid target product (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate (Formula I), with a yield of 93.0%, purity of 99.5%, and ee value retention of 99.7%. The HPLC chromatogram is shown below. Figure 5 .

[0076] That 1 H NMR image as follows Figure 3 , 13 C NMR spectrum as shown Figure 4 The specific data is as follows:

[0077] Structural confirmation of target product I: ¹H NMR (400MHz, CDCl₃) δ 7.17–7.09 (m, 1H), 6.81–6.72 (m, 2H), 5.17 (q, J = 1.7 Hz, 1H), 5.04 (dt, J = 2.4, 1.3 Hz, 1H), 4.24 (dd, J = 11.5, 7.1 Hz, 1H), 4.02 (dd, J = 11.5, 7.1 Hz, 1H), 3.65 (ddd, J = 12.2, 6.8, 5.5 Hz, 1H), 3.47 (ddd, J = 12.1, 6.8, 5.7 Hz, 1H) ,3.29(t,J=5.5Hz,1H),2.99(ddt,J=14.3,8.0,1.4Hz,1H),2.74(ddt,J=14.3,8.0,1.3Hz, 1H), 2.52(dq,J=14.9,7.4Hz,1H),2.39(tp,J=8.0,7.0Hz,1H),1.16(dd,J=7.4,2.2Hz,6H).

[0078] 13CNMR (125MHz, CDCl3) δ177.25,165.42,165.31,163.45,163.34,161.83,161 .73,159.84,159.74,143.63,130.86,130.80,130.79,130.73,124.86,124. 84,124.76,124.73,114.21,114.19,111.32,111.28,111.14,111.10,104.42,104.23,104.21,104.01,67.19,64.77,39.98,34.28,33.68,33.66,19.04.

[0079] Example 2

[0080] Replace “(S,S)-Ph-BPE” in step (1) of Example 1 with (S,S)-Me-DuPhos, and follow the same steps as in Example 1. A pale yellow, oily coupling key intermediate (Formula IV) was obtained with a yield of 72% and an ee value of 99.6%. The target product, (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate (Formula I), was obtained with a yield of 73% and an ee value of 99.5%.

[0081] Examples 3-4

[0082] In step (1) of Example 1, the nickel salt “NiBr2·glyme” was replaced with NiCl2·glyme and Ni(OAc)2, respectively, and the remaining steps were the same as in Example 1. The specific yield and ee value data of nickel salt, product formula IV and formula I are shown in Table 1.

[0083] Table 1. Yields and ee values ​​of specific nickel salts, products of formula IV and formula I.

[0084] Example Nickel salts Product form IV yield (%) Product-type IVee value (%) Product Formula I Yield (%) Product type Iee value (%) Product I configuration Example 3 <![CDATA[NiCl2·glyme]]> 70 99.6 94.2 99.6 S Example 4 <![CDATA[Ni(OAc)2]]> 73 99.5 93.6 99.5 S

[0085] Examples 5-6

[0086] Based on NiBr2·glyme (30.8 mg, 0.1 mmol), the molar ratio of NiBr2·glyme to (S,S)-Ph-BPE was changed, and the remaining steps were the same as in Example 1. The specific dosage ratios, yields of products of formula IV and formula I, and ee values ​​are shown in Table 2.

[0087] Table 2. Specific dosage ratios, yields of products of formula IV and formula I, and ee values.

[0088] Example <![CDATA[NiBr2·glyme:(S,S)-Ph-BPE (molar ratio)]]> Product form IV yield (%) Product-type IVee value (%) Product Formula I Yield (%) Product type Iee value (%) Product I configuration Example 5 1:1.1 75 99.5 92.7 99.5 S Example 6 1:1.3 74 99.7 93.1 99.6 S

[0089] Examples 7-10

[0090] The electrode materials of the anode and cathode in the unseparated electrolytic cell were changed, and the remaining steps were the same as in Example 1. Specific electrode materials, yields of products of formula IV and formula I, and ee values ​​are shown in Table 3.

[0091] Table 3. Yields and ee values ​​of specific electrode materials, products of formula IV and formula I.

[0092] Example anode cathode Product form IV yield (%) Product-type IVee value (%) Product Formula I Yield (%) Product type Iee value (%) Product I configuration Example 7 Zn C (graphite) 76 99.7 92.4 99.6 S Example 8 Mg Pt 72 99.3 93.3 99.5 S Example 9 Al Pt 73 99.5 92.8 99.5 S Example 10 Fe C (graphite) 74 99.4 93.1 99.6 S

[0093] Examples 11-14

[0094] Replace "current 10mA" in step (1) of Example 1 with 15mA, 20mA, 25mA, and 30mA respectively, and the remaining steps are the same as in Example 1. The current magnitude, yield of product formula IV and formula I, and ee value data of specific examples are shown in Table 4.

[0095] Table 4 shows the specific current magnitude, yield of product formula IV and formula I, and ee value data.

[0096] Example Current magnitude (mA) Power-on time (h) Product form IV yield (%) Product-type IVee value (%) Product Formula I Yield (%) Product type Iee value (%) Product I configuration Example 11 15 7 74 99.7 92.8 99.6 S Example 12 20 6.5 75 99.5 92.2 99.5 S Example 13 25 5.5 73 99.4 92.6 99.6 S Example 14 30 5 72 99.6 93.1 99.5 S

[0097] Examples 15-17

[0098] The amount of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene (II, 233 mg, 1.0 mmol) remained unchanged, only the amounts of NiBr2·glyme, tetrabutyltetrafluoroborate ammonium, and methyl 2-bromo-3-isobutyryloxypropionate were changed, and the remaining steps were the same as in Example 1. The specific amounts of substances, the yields of products of formula IV and formula I, and the ee values ​​are shown in Table 5.

[0099] Table 5. Specific substance dosages, yields of products of formula IV and formula I, and ee values.

[0100] Example 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene (mmol) Methyl 2-bromo-3-isobutyryloxypropionate (mmol) <![CDATA[NiBr2·glyme(mmol)]]> Tetrabutyltetrafluoroborate ammonium (mmol) Product form IV yield (%) Product-type IVee value (%) Product Formula I Yield (%) Product type Iee value (%) Product I configuration Example 15 1 1.1 0.08 0.9 74 99.7 92.8 99.6 S Example 16 1 1.3 0.09 0.95 70 99.5 93.5 99.5 S Example 17 1 1.2 0.10 0.9 73 99.4 93.0 99.6 S

[0101] Comparative Example 1

[0102] The difference from step (1) in Example 1 is that no power is applied; the remaining steps are the same as in Example 1. Specifically:

[0103] In a separate electrolytic cell, NiBr2·glyme (30.8 mg, 0.1 mmol), chiral ligand L1 ((S,S)-Ph-BPE, 0.12 mmol), tetrabutylammonium tetrafluoroborate (nBu4NBF4, 1.0 mmol), and anhydrous DMF (10 mL) were added sequentially. The solids were stirred to dissolve, and then 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene (II, 233 mg, 1.0 mmol) and methyl 2-bromo-3-isobutyryloxypropionate (III, 303.6 mg, 1.2 mmol) were added.

[0104] Using a zinc sheet as the sacrificial anode and a platinum sheet as the cathode, the reaction was carried out at room temperature with stirring for 6 hours without power. After the reaction, the electrolyte was diluted with ethyl acetate, washed successively with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give 13.42 mg of a pale yellow oily coupling key intermediate (formula IV), with a yield of 4.5%. Due to the extremely low conversion rate, its ee value was not determined.

[0105] Compared to Example 1, in Comparative Example 1, the reaction hardly proceeded and the yield of the target product was <5% without the application of electricity. This indicates that electrochemical driving is an indispensable condition for this reaction.

[0106] Comparative Example 2

[0107] The difference from step (1) in Example 1 is that the chiral ligand L1 ((S,S)-Ph-BPE) is not added; the remaining steps are the same as in Example 1. Specifically:

[0108] In a separate electrolytic cell, NiBr2·glyme (30.8 mg, 0.1 mmol), tetrabutylammonium tetrafluoroborate (nBu4NBF4, 1.0 mmol), and anhydrous DMF (10 mL) were added sequentially. The mixture was stirred to dissolve the solids, and then 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene (II, 233 mg, 1.0 mmol) and methyl 2-bromo-3-isobutyryloxypropionate (III, 303.6 mg, 1.2 mmol) were added.

[0109] Using a zinc sheet as the sacrificial anode and a platinum sheet as the cathode, the reaction was carried out under constant current mode (10 mA) at room temperature with stirring for 6 hours. After the reaction was completed, the electrolyte was diluted with ethyl acetate, washed successively with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give 146.18 mg of a pale yellow oily coupling key intermediate (formula IV), with a yield of 49% and an ee value of 0%.

[0110] Compared with Example 1, Comparative Example 2 did not add a chiral ligand, which not only reduced the reaction yield but also completely racemed the product (ee value of 0%). This fully demonstrates that the chiral ligand plays a decisive role in controlling the stereoselectivity of asymmetric cross-coupling.

[0111] Comparative Example 3

[0112] The difference from step (1) in Example 1 is that NiBr2·glyme is not added; the remaining steps are the same as in Example 1. Specifically:

[0113] In a separate electrolytic cell, chiral ligand L1 ((S,S)-Ph-BPE, 0.12 mmol), tetrabutylammonium tetrafluoroborate (nBu4NBF4, 1.0 mmol), and anhydrous DMF (10 mL) were added sequentially. The mixture was stirred to dissolve the solids, and then 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene (II, 233 mg, 1.0 mmol) and methyl 2-bromo-3-isobutyryloxypropionate (III, 303.6 mg, 1.2 mmol) were added.

[0114] Using a zinc sheet as the sacrificial anode and a platinum sheet as the cathode, the reaction was carried out under constant current mode (10 mA) at room temperature with stirring for 6 hours. After the reaction was completed, the electrolyte was diluted with ethyl acetate, washed successively with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give a pale yellow oily coupling key intermediate (formula IV) in yield <1%, and the ee value was not determined.

[0115] Compared with Example 1, Comparative Example 3 did not add NiBr2·glyme, and the reaction basically did not occur, indicating that nickel salt is the core active center of the catalytic cycle and is indispensable.

[0116] Comparative Example 4

[0117] The difference from step (1) in Example 1 is the addition of a free radical scavenger; the remaining steps are the same as in Example 1. Specifically:

[0118] In a separate electrolytic cell, NiBr2·glyme (30.8 mg, 0.1 mmol), chiral ligand L1 ((S,S)-Ph-BPE, 0.12 mmol), tetrabutylammonium tetrafluoroborate (nBu4NBF4, 1.0 mmol), anhydrous DMF (10 mL), and 2.0 equivalents of radical scavenger TEMPO were added sequentially. The solids were stirred until dissolved, and then 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene (II, 233 mg, 1.0 mmol) and methyl 2-bromo-3-isobutyryloxypropionate (III, 303.6 mg, 1.2 mmol) were added.

[0119] Using a zinc sheet as the sacrificial anode and a platinum sheet as the cathode, the reaction was carried out at room temperature for 6 hours under constant current mode (10 mA) with stirring. After the reaction was completed, the electrolyte was diluted with ethyl acetate, washed successively with saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1), and no pale yellow oily coupling key intermediate (Formula IV) was obtained.

[0120] Compared to Example 1, in Comparative Example 4, with the addition of a free radical scavenger, free radical intermediate A was captured by the scavenger TEMPO, the reaction was completely inhibited, and the target product was not detected. This confirms that a free radical intermediate did indeed occur during the reaction.

[0121] Comparative Example 5: Comparison with Existing Solutions

[0122] According to the routes disclosed in the literature (such as CN105732311A and CN115448912A), the target product is obtained through 5 reaction steps, with an overall yield of only 48.6%. In contrast, the method of the present invention requires only 2 steps and achieves a higher overall yield (>70% in Example 1) and comparable or even better enantioselectivity (ee>99.7%) without the need for expensive biological enzymes, significantly shortening the process route.

[0123] This invention is not limited to the above-described embodiments. Anyone should know that any structural changes made under the guidance of this invention, and any technical solutions that are the same as or similar to this invention, fall within the protection scope of this invention.

[0124] The technologies, shapes, and structures not described in detail in this invention are all known technologies.

Claims

1. A method for preparing the key chiral intermediate of posaconazole, (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate, characterized in that, In an electrochemical cell, 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and methyl 2-bromo-3-isobutyryloxypropionate were reacted in the presence of a chiral nickel catalyst to generate a key intermediate. After further reduction with a reducing agent, (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate is obtained.

2. The method for preparing the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole according to claim 1, characterized in that, The chiral nickel catalyst is generated by in-situ reaction of nickel salt and chiral ligand, with a molar ratio of nickel salt to chiral ligand of 1:1.1-1.

3.

3. The method for preparing the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole according to claim 2, characterized in that, The nickel salt is NiCl2·glyme, NiBr2·glyme, or Ni(OAc)2.

4. The method for preparing the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole according to claim 2, characterized in that, The chiral ligand is (S,S)-Ph-BPE or (S,S)-Me-DuPhos.

5. The method for preparing the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole according to claim 1, characterized in that, The electrochemical cell is a non-separated electrolytic cell, with the anode being zinc, magnesium, aluminum, or iron; and the cathode being platinum or carbon.

6. The method for preparing the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole according to claim 1, characterized in that, The energizing mode during the energizing reaction is constant current mode, with a current of 10-30mA and an energizing reaction time of 5-7h.

7. The method for preparing the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole according to claim 1, characterized in that, The electrochemical cell also contains a supporting electrolyte, which is tetrabutylammonium tetrafluoroborate, and the molar ratio of the supporting electrolyte to 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene is 0.9-1.1:

1.

8. The method for preparing the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole according to claim 1, characterized in that, The molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to methyl 2-bromo-3-isobutyryloxypropionate is 1:1.1-1.3, and the molar ratio of nickel to 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene in the chiral nickel catalyst is 0.08-0.10:

1.

9. The method for preparing the key chiral intermediate (S)-4-(2,4-difluorophenyl)-2-(hydroxymethyl)pent-4-en-1-yl isobutyrate of posaconazole according to claim 1, characterized in that, The reducing agent is lithium borohydride, the reduction temperature is 20-30℃, and the reduction time is 3-5h.

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