Process for the preparation of resiquimod and intermediate compounds thereof

Abstract

The present invention relates to processes for the preparation of reslitrast and intermediate compounds thereof. In particular, the present invention relates to a process for the synthesis of reslitrast, key intermediates for the synthesis of reslitrast, solvates thereof and a process for the hydrolysis of reslitrast under basic conditions.

Description

[0001] This application is a divisional application of Chinese patent application No. 202111110390.4, filed on September 18, 2021, entitled "Method for preparing ristat and intermediate compounds thereof". Technical Field

[0002] This invention relates to the field of organic compound synthesis. Specifically, this invention relates to a method for synthesizing ristatin, a key intermediate for synthesizing ristatin, and a method for preparing the same. Background Technology

[0003] Lifitegrast, developed by Shire Pharmaceuticals, is a novel small-molecule integrin inhibitor that antagonizes lymphocyte-associated antigens, blocks their interaction with their homologous ligands, and interferes with the overexpression of integrin in corneal and conjunctival tissues that cause dry eye disease. It was approved for marketing in the United States by the U.S. Food and Drug Administration (FDA) on July 11, 2016.

[0004]

[0005] Common methods for preparing ristat include ester hydrolysis or hydrogenation of its precursors. As shown in Scheme 1, WO2009139817A2, WO2011050175A1, and WO2019096996A1 disclose the hydrogenation of compound II of formula on carbon under the catalysis of the noble metal palladium to obtain ristat. However, this route has noble metal residues and high production costs.

[0006]

[0007] As shown in Scheme 2, listatin can be obtained by alkaline hydrolysis of compound III using WO2019097547A1. Although this process seems simple, in actual production, chiral amino acid derivatives are prone to racemization under strongly alkaline conditions, resulting in impurity A, which is very detrimental to the purification of listatin.

[0008]

[0009] To address the shortcomings of existing methods, the inventors unexpectedly discovered a method suitable for the industrial production of ristatin during their research. This method not only effectively suppresses the formation of impurity A but also simplifies the operation and significantly reduces production costs. Furthermore, the inventors obtained a new crystalline form of a solvate of compound III. When using this crystalline form to prepare ristatin, the product purity can exceed 99.9%, with single impurities less than 0.1% or even zero. Moreover, the preparation method for this crystalline form is simple, thus reducing costs and overcoming the deficiencies of existing methods. Summary of the Invention

[0010] In this application, the following terms have the meanings described below:

[0011] “DMF” stands for N,N-dimethylformamide.

[0012] “DMA” stands for N,N-dimethylformamide.

[0013] “NMP” stands for N-methylpyrrolidone.

[0014] “DMSO” stands for dimethyl sulfoxide.

[0015] “DIPEA” stands for N,N-diisopropylethylamine.

[0016] "THF" stands for tetrahydrofuran.

[0017] The term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms. Preferably, the alkyl group has 1 to 10, for example, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. The term "C"... 1-10 "alkyl" and "C" 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 10 and 1 to 6 carbon atoms, respectively. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,3-dimethylbutyl, 3-methylpentane, cyclohexyl, n-heptyl, or n-octyl.

[0018] The term "alkoxy" indicates the group R'-O-, where R' is an alkyl group as described above. "C 1-6 "Alkoxy" indicates the group R'-O-, where R' is C as described above. 1-6 alkyl.

[0019] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0020] The term "haloalkyl" refers to the alkyl group described above, wherein one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are replaced by a halogen selected from fluorine, chlorine, bromine, and iodine. Preferably, the haloalkyl group is "C". 1-10 "Halogenated alkyl" or "C" 1-6 "Halogenated alkyl groups". Examples include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, -CH2CH2CF3 or -CF(CF3)2.

[0021] The term "haloalkoxy" refers to the alkoxy group described above, wherein one or more (e.g., 1, 2, 3, 4, or 5) hydrogen atoms are replaced by a halogen selected from fluorine, chlorine, bromine, and iodine. Preferably, the haloalkyl group is "C". 1-10 "Haloalkoxy" or "C" 1-6 "Haloalkoxy". Examples include, for example, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2CF3, -O-CH2Cl, or -O-CH2CH2CF3.

[0022] The term "cycloalkyl" refers to a monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic non-aromatic saturated monovalent hydrocarbon ring structure with a specified number of ring atoms. Cycloalkyl groups can have 3 to 12 carbon atoms (i.e., C3-C4). 12 Cycloalkyl groups, for example, having 3 to 10, 3 to 8, 3 to 7, 3 to 6, or 5 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0023] The term "aryl" refers to a monovalent aromatic hydrocarbon group derived by removing a hydrogen atom from a single carbon atom in an aromatic ring system. Specifically, an aryl refers to a monocyclic or fused polycyclic aromatic ring structure having a specified number of ring atoms. For example, aryl includes groups containing 6 to 14, for example 6 to 10, preferably 6 ring atoms. Examples of aryl groups include C... 6-14 Aryl or C 6-10 Aryl, such as phenyl or naphthyl, preferably phenyl.

[0024] The term "aralkyl" refers to an alkyl group as described above, substituted with an aryl group as described above, for example, C6-C. 10 Aryl-C 1-6 Alkyl groups, such as benzyl groups.

[0025] The term "optionally substituted" means that the group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, or 5 or more) substituents, which may be the same or different.

[0026] "Optionally substituted cycloalkyl" means optionally substituted with one, two, or three identical or different cycloalkyl groups selected from C10. 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 The cyclic alkyl group substituted by the halogenated alkoxy group, such as C 3-8 Cycloalkyl groups, for example, C-shaped groups substituted with one, two, or three substituents selected from halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, and ethoxy. 3-8 Cycloalkyl.

[0027] "Optionally substituted aryl" refers to an aryl group that is optionally replaced by one, two, or three identical or different aryl groups selected from C. 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 The aryl group substituted by the halogenated alkoxy group, for example, C6-C 10 Aryl, such as phenyl, for example, a phenyl group substituted with one, two or three substituents selected from halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy and ethoxy.

[0028] "Optionally substituted aralkyl group" means optionally substituted with one, two, or three identical or different aralkyl groups selected from C10. 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl groups and C 1-6 The aralkyl group substituted by the halogenated alkoxy group, for example, C6-C 10 Aryl-C 1-6 Alkyl groups, such as benzyl, are substituted with one, two, or three substituents selected from halogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxy, and ethoxy.

[0029] In a first aspect, the present invention provides a method for preparing ristatin, the method comprising:

[0030] The compound of formula I or its salt or solvate is hydrolyzed under alkaline conditions to obtain ristat.

[0031]

[0032] R is selected from alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted aralkyl, preferably C. 1-10 Alkyl, C 6-10 Aryl, or C 6-10 Aryl-C 1-10 Alkyl, such as C 1-6 Alkyl or C 6-10 Aryl-C 1-6 Alkyl groups, particularly preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or benzyl, and

[0033] The alkaline conditions described refer to hydrolysis occurring in the presence of both inorganic and organic bases.

[0034] In a preferred embodiment, the inorganic base is selected from hydroxides, carbonates, bicarbonates, hydrides, or any combination thereof of alkali metals or alkaline earth metals, such as any one or any combination of two or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, Ba(OH)2, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, and calcium hydride.

[0035] In a preferred embodiment, the organic base is selected from alkoxides, organic amines, or any combination thereof, such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, ethylamine, n-propylamine, isopropylamine, n-butylamine, ethylenediamine, dimethylethylenediamine, trimethylethylenediamine, tetramethylethylenediamine, trimethylamine, triethylamine, triethanolamine, DIPEA, pyridine, 4-dimethylaminopyridine, imidazole, methylimidazolium, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, piperazine, N-methylpiperazine, tetrabutylammonium hydroxide, N,N-dimethylaniline, N,N-dimethylcyclohexylamine, and hexamethylphosphoric triamine, or any combination of two or more of them.

[0036] The salt of the compound of formula I is selected from salts formed with organic or inorganic acids, preferably pharmaceutically acceptable salts, such as hydrochloride, sulfate, phosphate, nitrate, acetate or benzoate.

[0037] In a preferred embodiment, the solvate of the compound of formula I is selected from solvates formed by the compound of formula I or its salt with an organic solvent such as methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, toluene, acetonitrile, acetone or butanone, preferably the solvate described in the second aspect below.

[0038] In a more preferred embodiment, the method includes one or more of the following steps:

[0039] (1) Add the compound of formula I or its salt or solvate to the reaction solvent and stir until dissolved;

[0040] (2) Add inorganic base and organic base to purified water, stir to dissolve, control the reaction temperature from -10 to 60℃, add the solution prepared in step (1) dropwise to the aqueous solution of base, and stir until the reaction is complete;

[0041] (3) The reaction mixture was concentrated under reduced pressure to remove the reaction solvent, extracted with an organic solvent, and the pH was adjusted to 1-4 with acid to precipitate a solid, thus obtaining ristat.

[0042] In one specific implementation, after the solid precipitates in step (3), it is filtered, washed with water, and dried at 20-70°C to obtain the ristat product. Its yield is ≥94.5%, purity ≥99.8%, ee value ≥99.8%, and single impurity ≤0.1%.

[0043] In step (1), the reaction solvent is selected from water, organic solvents or mixtures thereof, such as any one or any combination of two or more of methanol, ethanol, n-propanol, isopropanol, THF, methyltetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, isopropyl formate, toluene, xylene, acetonitrile, DMF, DMA, NMP, DMSO, acetone, butanone, n-hexane, cyclohexane, n-heptane and purified water.

[0044] In step (2), the inorganic base and organic base are as described above.

[0045] In step (3), the organic solvent for extraction is selected from aprotic organic solvents, such as any one or any combination of two or more of toluene, methyl formate, ethyl formate, isopropyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-hexane, cyclohexane, n-heptane, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, and chloroform.

[0046] In step (3), the acid is selected from organic or inorganic acids, such as any one or any combination of two or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and benzoic acid.

[0047] In step (1), the salt of the compound of formula I is selected from salts formed with organic or inorganic acids, preferably pharmaceutically acceptable salts, such as hydrochlorides, sulfates, phosphates, nitrates, acetates, or benzoates. The solvate is selected from solvates formed by the compound of formula I or its salt with organic solvents such as methanol, ethanol, isopropanol, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, methyl tert-butyl ether, toluene, acetonitrile, acetone, and butanone. In a preferred embodiment, the solvate of the compound of formula I is the solvate described in the second aspect below.

[0048] In a second aspect, the present invention provides solvates of the compounds represented by Formula IV.

[0049]

[0050] In a preferred embodiment, the compound of formula IV is in crystalline form, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.12±0.2°, 20.12±0.2° and 20.94±0.2°, expressed in terms of 2θ diffraction angles.

[0051] In a more preferred embodiment, the compound of formula IV is in crystalline form, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.12±0.2°, 17.40±0.2°, 17.70±0.2°, 20.12±0.2°, 20.94±0.2° and 22.5±0.2°, expressed in terms of 2θ diffraction angles.

[0052] In a more preferred embodiment, the compound of formula IV is in crystalline form, characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.12±0.2°, 17.40±0.2°, 17.70±0.2°, 20.12±0.2°, 20.94±0.2°, 22.5±0.2°, 22.78±0.2°, 26.14±0.2°, 26.74±0.2° and 26.98±0.2°, expressed in 2θ diffraction angles.

[0053] In a more preferred embodiment, the compound of formula IV is in crystalline form, characterized by having the following properties: Figure 1 The X-ray powder diffraction pattern shown is shown.

[0054] The crystalline form of the compound of formula IV, when using Cu-Kα When performing continuous θ-2θ scanning with radiation, tube voltage 40KV, tube current 250mA, scanning speed 5° / min, step width 0.02°, and scanning range 3-50° (2θ), it exhibits the following characteristics: Figure 1 The X-ray powder diffraction pattern is shown. The main characteristic diffraction lines, expressed in terms of the 2θ diffraction angle, are shown in Table 1.

[0055] Table 1: Main Characteristic Diffraction Lines of Compounds of Formula IV

[0056]

[0057] The single-crystal structure data of the compound of formula IV described in this invention are shown in Table 2. The atomic coordinates and isotropic temperature factors of the molecule of compound IV are shown in Table 3. The stereoscopic structure diagram of the molecule of compound IV (solvent molecules ignored) is shown in Table 3. Figure 2 As shown, the layered stacking diagram of the molecules of Formula IV compound (along the ac direction) is as follows. Figure 3 As shown.

[0058] The above results indicate that the crystal of compound IV belongs to the monoclinic crystal system, space group C2(5#), and its unit cell parameters are: β=97.039(2)°, Z = 4, Molecular formula: C 30 H 26Cl₂N₂O₇S₀.₅(C₄H₈O), crystal density d = 1.403 g / cm³ 3 Its smallest asymmetric unit contains a compound molecule of formula IV (structural formula as shown in the image). Figure 3 (As shown) and half a tetrahydrofuran molecule. There is no hydrogen bond between the tetrahydrofuran molecule and the compound IV molecule. The two compound IV molecules are linked together by intermolecular hydrogen bonds NH…O to form a molecular dimer. The weak intermolecular interactions connect this molecular dimer into a layered stacked structure, with the THF molecule located in the middle of the compound IV molecular layer.

[0059] Table 2 shows the single-crystal structure data and structure correction data for compounds of formula IV.

[0060]

[0061]

[0062] Table 3 shows the atomic coordinates and isotropic temperature factors of compounds of formula IV.

[0063]

[0064]

[0065] The DSC curve of the crystal of compound IV of the present invention is as follows: Figure 4 As shown, this indicates that its melting point is 146.5℃.

[0066] The DSC-TGA curves of the crystals of the formula IV compound of the present invention are as follows: Figure 5 As shown, this indicates that its structure contains approximately 5.3% solvent. This is consistent with the results of single-crystal diffraction analysis. The single-crystal diffraction results show that the cross-linking intermediate of compound IV is a THF solvate, meaning its structure contains half a tetrahydrofuran molecule, with the molecular formula: C 30 H 26 C l2 N2O7S·0.5(C4H8O) has a molecular weight of 665.57. The weight percentage of half a tetrahydrofuran is: 36.06 / 665.57*100%=5.4% (the molecular weight of tetrahydrofuran is 72.11, and half a tetrahydrofuran is 36.06).

[0067] Thirdly, the present invention provides a method for preparing a solvate of formula IV, the method comprising:

[0068] (a) The crude product of compound III was added to a crystallization solvent, dissolved, and then cooled to crystallize, yielding the crystalline form of compound IV.

[0069]

[0070] In one specific implementation, step (a) involves adding the crude product of formula III to a crystallization solvent, heating to dissolve it, then cooling to crystallize it, filtering and drying it to obtain the crystalline form of compound IV.

[0071] The crystallization solvent is selected from tetrahydrofuran, or a mixture of tetrahydrofuran and any two or more solvents selected from methanol, ethanol, propanol, isopropanol, toluene, xylene, chlorobenzene, acetonitrile, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, isopropyl ether, methyl tert-butyl ether, hexane, n-hexane, cyclohexane, and n-heptane.

[0072] In one specific implementation, the dissolution temperature is 20-100℃.

[0073] In one specific implementation, the cooling crystallization process is a programmed cooling crystallization, for example, cooling at a rate of 5-15°C per hour.

[0074] In one specific embodiment, when the temperature drops to -10 to 25°C, crystallization is carried out at this temperature for 0.5 to 10 hours, followed by filtration to obtain a white wet product. This white wet product is then dried at a temperature of 10 to 70°C to obtain the crystalline form of compound IV.

[0075] Fourthly, the present invention provides a method for preparing ritalact, the method comprising hydrolyzing a solvate of formula IV under alkaline conditions to obtain ritalact.

[0076]

[0077] The alkaline conditions mentioned above refer to hydrolysis occurring in the presence of both inorganic and organic bases.

[0078] In a preferred embodiment, the inorganic base is selected from hydroxides, carbonates, bicarbonates, hydrides, or any combination thereof of alkali metals or alkaline earth metals, such as any one or any combination of two or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydride, and calcium hydride.

[0079] In a preferred embodiment, the organic base is selected from alkoxides, organic amines, or any combination thereof, such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, ethylamine, n-propylamine, isopropylamine, n-butylamine, ethylenediamine, dimethylethylenediamine, trimethylethylenediamine, tetramethylethylenediamine, trimethylamine, triethylamine, triethanolamine, DIPEA, pyridine, 4-dimethylaminopyridine, imidazole, methylimidazolium, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, piperazine, N-methylpiperazine, tetrabutylammonium hydroxide, N,N-dimethylaniline, N,N-dimethylcyclohexylamine, and hexamethylphosphoric triamine, or any combination of two or more of them.

[0080] In a more preferred embodiment, the method includes one or more of the following steps:

[0081] (1') Add the solvate crystal of formula IV to the reaction solvent and stir until dissolved;

[0082] (2') Add the inorganic base and organic base to purified water, stir to dissolve, control the reaction temperature from -10 to 60°C, add the solution prepared in step (1') dropwise to the aqueous solution of the base, and stir until the reaction is complete;

[0083] (3') The reaction mixture was concentrated under reduced pressure to remove the reaction solvent, extracted with an organic solvent, and the pH was adjusted to 1-4 with acid to precipitate a solid, thus obtaining ristat.

[0084] In a preferred embodiment, after the solid precipitates in step (3'), it is filtered, washed with water, and dried at 20-70°C to obtain ristat. Its yield is ≥97.2%, purity ≥99.8%, ee value ≥99.8%, and single impurity ≤0.1%.

[0085] In a preferred embodiment, the reaction solvent is as described in the first aspect above.

[0086] In a preferred embodiment, the inorganic base and organic base described in step (2') are as described in the first aspect above.

[0087] In a preferred embodiment, the extraction solvent is as described in the first aspect above.

[0088] In another embodiment, the method further includes step (a) of the third aspect described above.

[0089] In a preferred embodiment, the method includes:

[0090] (a) The crude product of compound III is added to a crystallization solvent, dissolved, and then cooled to crystallize, yielding the solvate of compound IV in crystalline form; and

[0091] (b) Dissolving the solvate crystal of formula IV in a reaction solvent and hydrolyzing it under alkaline conditions yields ristat.

[0092]

[0093] The alkaline conditions mentioned above refer to hydrolysis occurring in the presence of both inorganic and organic bases.

[0094] In a preferred embodiment, step (a) is as described in the third aspect above.

[0095] In a preferred embodiment, the reaction solvent in step (b) is selected from water, organic solvents or mixtures thereof, such as any one or any combination of two or more of methanol, ethanol, n-propanol, isopropanol, THF, methyltetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, isopropyl formate, toluene, xylene, acetonitrile, DMF, DMA, NMP, DMSO, acetone, butanone, n-hexane, cyclohexane, n-heptane, and purified water.

[0096] In a more preferred embodiment, step (b) includes steps (1'), (2') and (3') described above.

[0097] The conditions for steps (1'), (2'), and (3') are as described in the corresponding implementation schemes of the first to third aspects above for steps (1), (2), and (3), respectively.

[0098] This invention unexpectedly reveals a method for preparing ristat by hydrolysis of compounds of formula I or IV in the presence of organic and inorganic bases. Surprisingly, this method offers advantages such as high product purity, excellent ee value, and minimal impurities, overcoming the problems of low purity and ee value in existing technologies. In particular, when using solvates of formula IV to prepare ristat, product purity can exceed 99.9%, with single impurities less than 0.1% or even zero. Furthermore, the method is simple, highly suitable for industrial production, and can significantly reduce costs. Attached Figure Description

[0099] Figure 1 The image shows the XRPD diagram of the crystal of compound IV.

[0100] Figure 2 This is a stereoscopic diagram of the crystal structure of compound IV (solvent molecules are ignored).

[0101] Figure 3 This is a diagram showing the layered stacking of the crystals of Formula IV compound (along the ac direction).

[0102] Figure 4 The figure shows the DSC curve of the crystal of compound IV.

[0103] Figure 5 The DSC-TGA curves of the crystals of compound IV are shown. Detailed Implementation

[0104] The method of the present invention will be further illustrated by the following embodiments. It should be understood that the purpose of providing the following embodiments is merely to enable a better understanding of the present invention, and not to limit the scope of the present invention in any way.

[0105] Example 1: Preparation method of compound of formula III

[0106]

[0107] Method 1:

[0108] 46 g of compound VI, 4.5 g of compound V1, and 34.2 g of HATU were dissolved in 460 g of DMF, and the solution was cooled to -5 to 5 °C. 9.6 g of triethylamine was added dropwise, and the mixture was kept at this temperature for 4–6 hours after the addition was complete. Once the reaction was complete, the reaction solution was quenched dropwise in 500 g of ice water and filtered. The filter cake was dissolved in 300 g of dichloromethane and washed with water. The organic layer was collected and concentrated to dryness to give 55.5 g of crude compound III (100% yield, 95.6% purity).

[0109] Method 2:

[0110] 4.2 g of compound V and 0.1 g of DMF were dissolved in 45 g of dichloromethane, heated to reflux, and 10.8 g of thionyl chloride was added dropwise. After the reaction was complete, the solution was concentrated to dryness, and 30 g of dichloromethane was added to dissolve it. Then, the solution was added dropwise to a pre-prepared 400 g dichloromethane solution containing 45 g of compound VI. After the reaction was complete, the solution was washed twice with 100 g of water, separated, and the organic phase was concentrated to dryness to obtain 54.3 g of crude compound III, with a yield of 100% and a purity of 95.5%.

[0111] Example 2: Preparation of Compound IV

[0112]

[0113] Method 1:

[0114] Weigh 20g of the crude compound of formula III into a round-bottom flask, add 30g of tetrahydrofuran, heat to reflux and dissolve, then add 10g of methyl tert-butyl ether, keep warm for 20-30 minutes, allow to cool naturally to crystallize, and continue stirring for 1.0-1.5h at 5-10℃. Filter to obtain a white crystalline powder solid. Dry at 45-55℃ to obtain 18.9g, yield 94.5%, purity 99.7%, maximum single impurity less than 0.1%.

[0115] Method 2:

[0116] Weigh 30g of the crude compound of formula III and place it in a reaction flask. Add 30g of tetrahydrofuran and 30g of isopropyl ether, heat and stir until dissolved, continue stirring for 10-20 minutes, and then proceed with a programmed cooling process to crystallize. Decrease the temperature by 5-10°C per hour, and maintain the temperature at 30-40°C for 1 hour. Then continue cooling and stirring to crystallize, and continue stirring to crystallize at 0-5°C for 1.0-1.5 hours. Filter, dry at 45-50°C, and obtain 28.5g of white crystalline powder solid, with a yield of 95.0%, purity of 99.7%, and a maximum single impurity of less than 0.1%.

[0117] Method 3:

[0118] Weigh 30g of the crude compound of formula III into a reaction flask, add 35g of tetrahydrofuran and 15g of n-heptane, stir, heat under reflux until completely dissolved, continue stirring for 10-20 minutes, and allow crystallization to occur by programmed cooling, decreasing the temperature by 5-15°C per hour. After cooling to 0-10°C, continue stirring to allow crystallization to occur for 1.0-1.5 hours, filter, wash with n-heptane, and dry at 45-55°C to obtain 28.6g of white crystalline powder solid, with a yield of 95.3%, a purity of 99.8%, and a maximum single impurity of less than 0.1%.

[0119] Example 3: Preparation of ristatin from compound II (i.e., R = Bn in compound I)

[0120]

[0121] Method 1 (Inorganic Base):

[0122] 70.6 g of compound II was added to 600 g of acetonitrile and stirred until dissolved. 11.2 g of potassium hydroxide was added to 1000 g of purified water and stirred until dissolved. The reaction temperature was controlled between -10 and 30 °C. The prepared reaction solution was added dropwise to the sodium hydroxide aqueous solution, and the mixture was stirred until the reaction was complete. The reaction solvent was removed by vacuum concentration. The concentrate was extracted with 2 × 200 g of isopropyl acetate, and the pH was adjusted to 1-4 with hydrochloric acid. The precipitated solid was filtered, washed with 1000 g of water, and dried at 50-60 °C to obtain 55.6 g of ristatin, with a yield of 90.4%, purity of 95.8%, ee value of 95.6%, and impurity A of 4.4%.

[0123] Method 2 (Inorganic base + Organic base):

[0124] 70.6 g of compound II was added to 600 g of acetonitrile and stirred until dissolved. 11.2 g of potassium hydroxide and 15.0 g of triethylamine were added to 1000 g of purified water and stirred until dissolved. The reaction temperature was controlled between -10 and 30 °C. The prepared reaction solution was added dropwise to the sodium hydroxide aqueous solution, and the mixture was stirred until the reaction was complete. The reaction solvent was removed by vacuum concentration. The concentrate was extracted with 2 × 200 g of isopropyl acetate, and the pH was adjusted to 1-4 with hydrochloric acid. The precipitated solid was filtered, washed with 1000 g of water, and dried at 50-60 °C to obtain 58.3 g of ristatin, with a yield of 94.8%, purity of 99.8%, ee value of 99.8%, and impurity A of 0.02%.

[0125] Example 4: Preparation of ristatin from compound III (i.e., compound I in which R = Me)

[0126]

[0127] Method 1 (Inorganic Base):

[0128] Add 63.0 g of compound III to 600 g of acetone and stir until dissolved. Add 10.0 g of sodium hydroxide to 1000 g of purified water and stir until dissolved. Controlling the reaction temperature from -5 to 25 °C, add the prepared reaction solution dropwise to the sodium hydroxide aqueous solution. After the addition is complete, stir until the reaction is finished. Concentrate under reduced pressure to remove the reaction solvent. Extract the concentrated solution with 2 × 150 g of ethyl acetate. Adjust the pH to 1-4 with hydrochloric acid to precipitate the solid. Filter, wash with 1000 g of water, and dry at 55-65 °C to obtain 56.4 g of ritaxel, yield 91.7%, purity 96.2%, ee value 94.8%, impurity A 5.2%.

[0129] Method 2 (Inorganic base + Organic base):

[0130] Add 63.0 g of compound III to 600 g of acetone and stir until dissolved. Add 10.0 g of sodium hydroxide and 19.4 g of DIPEA to 1000 g of purified water and stir until dissolved. Controlling the reaction temperature from -5 to 25 °C, add the prepared reaction solution dropwise to the sodium hydroxide aqueous solution. After the addition is complete, stir until the reaction is finished. Concentrate under reduced pressure to remove the reaction solvent. Extract the concentrated solution with 2 × 150 g of ethyl acetate. Adjust the pH to 1-4 with hydrochloric acid to precipitate the solid. Filter, wash with 1000 g of water, and dry at 55-65 °C to obtain 58.6 g of ritaxel, yield 95.3%, purity 99.8%, ee value 99.9%, impurity A 0.01%.

[0131] Example 5: Preparation of Rittalact from Compound IV

[0132]

[0133] Method 1 (Inorganic Base):

[0134] Add 66.6 g of compound IV to 800 g of tetrahydrofuran and stir until dissolved. Add 10.0 g of sodium hydroxide to 1000 g of purified water and stir until dissolved. Controlling the reaction temperature between -5 and 20 °C, add the prepared reaction solution dropwise to the sodium hydroxide aqueous solution. After addition, stir until the reaction is complete. Concentrate under reduced pressure to remove the reaction solvent. Extract the concentrate with 2 × 190 g of toluene. Adjust the pH to 1-4 with hydrochloric acid to precipitate the solid. Filter, wash with 1100 g of water, and dry at 50-70 °C to obtain 56.8 g of ritaxel, yield 92.4%, purity 96.5%, ee value 96.7%, impurity A 3.3%.

[0135] Method 2 (Inorganic base + Organic base):

[0136] Add 66.6 g of compound IV to 800 g of tetrahydrofuran, stir until dissolved, and set aside. Add 10.0 g of sodium hydroxide and 15.5 g of N-methylpiperidine to 1000 g of purified water, stir until dissolved. Control the reaction temperature to -5 to 20 °C, and add the above-prepared reaction solution dropwise to the sodium hydroxide aqueous solution. After the addition is complete, stir until the reaction is finished. Concentrate under reduced pressure to remove the reaction solvent, extract the concentrate with 2 × 190 g of toluene, adjust the pH to 1-4 with hydrochloric acid, precipitate the solid, filter, wash with 1100 g of water, and dry at 50-70 °C to obtain 59.8 g of ritaxel, yield 97.2%, purity 99.9%, ee value 100%, impurity A 0%.

Claims

1. The compound shown in Formula IV 2. The compound according to claim 1, wherein the compound of formula IV is in crystalline form, characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.12±0.2°, 20.12±0.2° and 20.94±0.2°, expressed in terms of 2θ diffraction angles.

3. The compound according to claim 1, wherein the compound of formula IV is in crystalline form, characterized in that, Its X-ray powder diffraction pattern has characteristic diffraction peaks at 6.12±0.2°, 17.40±0.2°, 17.70±0.2°, 20.12±0.2°, 20.94±0.2° and 22.5±0.2°, expressed in terms of 2θ diffraction angles.

4. A method for preparing the compound of formula IV according to claim 1, the method comprising: (a) The crude product of compound III was added to a crystallization solvent, dissolved, and then cooled to crystallize, yielding the crystalline form of compound IV.

5. The method according to claim 4, wherein the crystallization solvent is selected from tetrahydrofuran, or a mixture of tetrahydrofuran and any two or more solvents selected from methanol, ethanol, propanol, isopropanol, toluene, xylene, chlorobenzene, acetonitrile, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, ethyl acetate, isopropyl ether, methyl tert-butyl ether, hexane, cyclohexane, and n-heptane.

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