Phenol derivatives, crystalline forms thereof and methods of preparation

Abstract

The present application relates to a kind of phenol derivatives, and its crystal form and preparation method, especially for the solid-state intermediate for preparing phenol derivative, specifically provide a kind of compound shown in formula (I) or formula (II) and its stereoisomer, crystal form and preparation method.

Description

[0001] This application claims priority to Chinese Patent Application No. 202210091223.8, filed on January 26, 2022, entitled "Phenol Derivatives, Crystal Forms Thereof and Preparation Methods Thereof", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to a phenol derivative, its crystal form and preparation method, and particularly to a solid intermediate for preparing a phenol derivative. Background Technology

[0003] Propofol can activate various γ-aminobutyric acid type A (GABA) compounds. A Propofol has a receptor subtype and is widely used for the induction and maintenance of general anesthesia. Its significant pharmacokinetic and pharmacodynamic properties include rapid onset of action, short duration of action, and rapid reversibility. After intravenous administration, propofol rapidly enters high-perfusion areas such as the heart, lungs, and liver from the bloodstream. Its high lipid solubility allows propofol to easily cross the blood-brain barrier and enter the brain to exert its general anesthetic effect.

[0004] Given the numerous advantages of propofol, various propofol derivatives have been developed based on its structure in hopes of obtaining phenol derivative structures with better efficacy and fewer side effects. Patent WO2014180305 describes a class of phenol derivatives, their preparation methods, and their uses in the central nervous system; some of these compounds possess a stronger GABA content than commercially available propofol. A It exhibits stimulating activity and predictable effects in avoiding injection pain. Patent CN202111122520.6 describes another class of phenol derivatives and their pharmaceutical applications, some of which disclose compounds with stronger efficacy and lower side effects. However, most phenol derivatives based on propofol structure modifications currently yield compounds or synthetic intermediates that are primarily in liquid or oil states. This hinders quality control and purification of intermediates or target products, as well as scale-up production and smooth storage and transportation processes.

[0005] Chinese patent CN201510255867.6 reports a solid intermediate for synthesizing phenol derivatives, having the structure shown in formula (VIII). This solid intermediate of optical purity was obtained by chiral resolution through the introduction of a -N-((1R)-1-phenylethyl)carbamate fragment, and was applied to the synthesis of the chiral compound 2-((1R)-1-cyclopropylethyl)-6-isopropylphenol (i.e., cyclopropanol).

[0006]

[0007] This invention provides another solid intermediate for synthesizing phenol derivatives, having a structure as shown in formula (I) or formula (II). Formula (II) is a solid intermediate obtained by introducing an amino acid protecting group and esterifying with a phenolic hydroxyl group. Furthermore, through extensive inventive experiments, the inventors have discovered that by introducing a specific configuration of an amino acid protecting group fragment for chiral resolution, a solid intermediate with high optical purity can be obtained, which is beneficial for further synthesis of high optical purity phenol derivatives. Compared to the solid intermediate obtained in the prior art by forming a carbamate from (R)-(+)-1-phenylethyl isocyanate and a phenolic hydroxyl group, the solid intermediate (Formula (II)) obtained by esterifying with an amino acid protecting group in this invention has better resolution, higher optical purity of the obtained product, and the raw materials used for introducing the amino acid protecting group are relatively inexpensive, resulting in lower production costs and easier industrial production. Summary of the Invention

[0008] To overcome the shortcomings of existing technologies, this invention, through extensive creative experiments by researchers, provides an intermediate for synthesizing phenol derivatives. Studies of its solid morphology revealed a solid form with distinct powder X-ray diffraction (PXRD) characteristics. The intermediate provided by this invention exhibits high optical purity, which is more conducive to the synthesis of high-optical-purity phenol derivatives and thus has greater value for industrial production. The resolution method for the synthetic intermediate provided by this invention reduces the difficulty of resolution, achieves high purity and high yield, ensures compound stability during resolution, and allows for multiple recycling of the compound, achieving optimal material utilization. Using the intermediate provided by this invention to synthesize the target phenol derivative product results in lower costs.

[0009] This invention provides a compound having formula (I) or formula (II), or a stereoisomer thereof:

[0010]

[0011] in:

[0012] R is a hydroxyl protecting group, wherein the hydroxyl protecting group is selected from amino acid protecting groups, and the amino acid protecting group is selected from Boc-amino acid protecting groups, Cbz-amino acid protecting groups, and Fmoc-amino acid protecting groups;

[0013] Or R can be the following structural formula:

[0014]

[0015] n is selected from 1, 2, and 3.

[0016] In some embodiments, the compound has the structure shown in formula (Ⅲ):

[0017]

[0018] Where n is selected from 1, 2, or 3.

[0019] In some embodiments, the compound has the structure shown in formula (Ⅳ) or formula (IV-I) or its isomers:

[0020]

[0021] In some preferred embodiments, the compound has the structure shown in formula (Ⅲ-Ⅰ):

[0022]

[0023] The present invention also provides X-ray powder diffraction patterns of the crystalline form of compound (Ⅲ-Ⅰ), which in 2 θ The values ​​are: 7.280, 10.847, 10.954, 13.641, 14.304, 14.419, 15.161, 15.683, 16.556, 17.659, 18.501, 18.600, 19.301, 20.558, 20.663, 21.620, 22.060, 22.281, 22.663, 23.941, 25.461, 25.800, 26.500, 27.800, 28.079, 29.142, 29.498, 30.577, 30.819, 31.761, 34.979, 37.741, 42.400, and 44.257, where diffraction peaks are observed.

[0024] Furthermore, the X-ray powder diffraction pattern of the crystal form of the compound (Ⅲ-Ⅰ) is also shown in Figure 2. θ The values ​​are: 10.616, 15.583, 27.321, 29.902, 32.942, 33.503, 36.239, 39.601, 48.303. One or more of these values ​​have diffraction peaks.

[0025] The present invention also provides X-ray powder diffraction patterns of the crystal form of the compound of formula (Ⅳ) or its isomers, which are in 2 θ The values ​​are: 9.316, 12.121, 13.097, 13.599, 15.158, 16.037, 17.222, 18.239, 18.659, 20.142, 20.519, 20.858, 21.279, 22.261, 23.123, 24.182, 25.002, 25.301, 25.981, and 34.839, with diffraction peaks.

[0026] Furthermore, the X-ray powder diffraction patterns of the crystal forms of compound formula (Ⅳ) or its isomers are also shown in 2.θ The values ​​are: 15.780, 19.499, 21.899, 27.542, 28.122, 35.338, 36.001. One or more of these values ​​have diffraction peaks.

[0027] On the other hand, the present invention also provides a method for preparing the compound represented by formula (III), wherein the compound is prepared by esterification reaction of the compound of formula (V) with a cyclic anhydride;

[0028]

[0029] Preferably, a solvent is used in the reaction, the solvent being selected from any one or a mixture of several of the following in any proportion: dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, and acetone.

[0030] The reaction is carried out with a catalyst selected from DMAP;

[0031] The reaction involves the addition of an alkaline reagent, which is selected from any one or a mixture of several of the following: triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, lithium carbonate, potassium fluoride, potassium phosphate, potassium bicarbonate, and sodium bicarbonate.

[0032] On the other hand, the present invention also provides a method for preparing the compound represented by formula (Ⅳ), wherein the compound is prepared by condensing the compound of formula (Ⅵ) with Boc-D-alanine to form an ester;

[0033]

[0034] Preferably, the solvent used in the reaction is selected from any one or a mixture of several of the following in any proportion: dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, and acetone.

[0035] A condensing agent is added to the reaction, and the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and 2-(7-azobenzotriazole).

[0036] Any one of -N,N,N',N'-tetramethylurea hexafluorophosphate and 1-hydroxybenzotriazole;

[0037] More preferably, the condensing agent is selected from any one of N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;

[0038] The reaction involves the addition of an alkaline reagent, which is selected from any one of the following bases: DMAP, triethylamine, N,N-diisopropylethylamine, and pyridine.

[0039] Preferably, the method for preparing the compound represented by formula (VI) includes the following steps:

[0040] Step a: Hydrolyze compound (III-1) under alkaline conditions to generate compound (V);

[0041] Step b: The compound of formula (V) is reduced to produce the compound of formula (VI);

[0042]

[0043] In step a, an alkaline reagent and a reaction solvent are used. The alkaline reagent is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate, and potassium carbonate. The reaction solvent is selected from any one or a mixture of several of methanol, ethanol, tetrahydrofuran, and water in any proportion.

[0044] In step b, a reducing agent and a catalyst are used. The reducing agent is hydrogen, and the catalyst is (4R,5R)-(+)-O-[1-benzyl-1-(5-methyl-2-phenyl-4,5-dihydrooxazol-4-yl)-2-phenylethyl](dicyclohexylphosphine)(1,5-cyclopentadiene)iridium(I)tetra(3,5-bis(trifluoromethyl)phenylboronic acid ester).

[0045] On the other hand, the present invention also provides a method for purifying the compound represented by formula (Ⅲ).

[0046] The purification method is to purify the crude product of compound (III) by pulping in an organic solvent, wherein the organic solvent is selected from any one or a mixture of several of the following: alkanes, cycloalkanes, aromatics, and ethers.

[0047] Preferably, the organic solvent is selected from a single solvent of hexane, heptane, or toluene;

[0048] More preferably, the organic solvent is selected from the mixed solvents n-hexane and methyl tert-butyl ether, n-heptane and methyl tert-butyl ether, or toluene and methyl tert-butyl ether.

[0049] On the other hand, the present invention also provides a method for purifying the compound represented by formula (Ⅳ).

[0050] The purification method involves recrystallizing the crude product of the compound shown in formula (Ⅳ) in an organic solvent, wherein the organic solvent is selected from any one or a mixture of several alkanes and cycloalkanes in any proportion; preferably, the organic solvent is n-hexane or n-heptane.

[0051] On the other hand, the present invention also provides a compound represented by formula (VII), or an isomer thereof of formula (VII-I) or formula (VII-II):

[0052]

[0053] Furthermore, the present invention also provides a method for preparing the compound shown in formula (VII), comprising the following steps:

[0054] Step c: Hydrolyze compound (IV-I) under alkaline conditions to generate compound (VI);

[0055] Step d: Acylation of compound (VI) to generate compound (VII);

[0056]

[0057] Preferably, in the method for preparing the compound shown in formula (VII), a basic reagent and a reaction solvent are used in step c. The basic reagent is selected from sodium hydroxide, and the reaction solvent is selected from methanol and tetrahydrofuran, methanol and water, or a mixture of any one or several of these in any proportion.

[0058] In step d, an acylation reagent, a catalyst, and a basic reagent are used. The acylation reagent is selected from paraformaldehyde, the catalyst is selected from magnesium chloride, and the basic reagent is selected from triethylamine.

[0059] The present invention also provides a method for preparing the compound shown in formula (XI), the preparation process comprising the following steps:

[0060] Step e: The compound of formula (VII) undergoes a Grignard reaction to produce the compound of formula (IX);

[0061] Step f: React compound (IX) with ethanethiol to generate compound (X);

[0062] Step g: Oxidize compound (X) to produce compound (XI);

[0063]

[0064] Preferably, in step e, a Grignard reagent is used, wherein the Grignard reagent is selected from magnesium methyl chloride;

[0065] In step f, an acid reagent is used, and the acid reagent is selected from hydrochloric acid;

[0066] In step g, an oxidizing agent is used, which is selected from m-chloroperoxybenzoic acid.

[0067] The "amino acid protecting group" referred to in this invention refers to the group formed after a carboxylic acid undergoes a reaction between an amino acid and a hydroxyl group, resulting in the removal of the hydroxyl group. The Boc-amino acid protecting group, Cbz-amino acid protecting group, and Fmoc-amino acid protecting group are the groups formed after a Boc-amino acid, Cbz-amino acid, and Fmoc-amino acid react with a hydroxyl group, respectively, to remove the hydroxyl group from the carboxylic acid.

[0068] Boc-amino acids include, but are not limited to, N-(tert-butoxycarbonyl)-L-glutamic acid-1-benzyl ester, Boc-L-proline, N-Boc-O-benzyl-L-serine, S-acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N2-[tert-butoxycarbonyl]-N-(triphenylmethyl)-D-aspartamide, Boc-D-alanine, N-Boc-N-nitro-L-arginine, tert-butoxycarbonyl-L-2,4-diaminobutyric acid, (S)-3-amino-2-(tert-butoxycarbonylamino)propionic acid, Boc-glycine, N-tert-butoxycarbonyl-L-glutamic acid-5-benzyl ester, N-Boc-N'-triphenylmethyl-L-histidine, Boc-L-4-nitrophenylalanine, Boc-D-proline, and Boc-3-(2-naphthyl)-D-alanine.

[0069] Cbz-amino acids include, but are not limited to, N-benzyloxycarbonyl-L-arginine cyclohexylamine salt, N-benzyloxycarbonyl-glycine, N-benzyloxycarbonyl-D-leucine, N-benzyloxycarbonyl-L-glutamic acid-5-tert-butyl ester, N-benzyloxycarbonyl-L-leucine, N-[(benzyloxy)carbonyl]-1-(triphenylmethyl)-L-histidine, N-alpha-benzyloxycarbonyl-L-2,3-diaminopropionic acid, Cbz-L-phenylglycine, N-benzyloxycarbonyl-O-tert-butyl-L-serine, Cbz-glycine methyl ester, N-benzyloxycarbonyl-L-tryptophan, Cbz-L-tyrosine, benzyloxycarbonyl-L-alanine, N-benzyloxycarbonyl-L-aspartic acid-1-methyl ester, and N-benzyloxycarbonyl-L-aspartic acid-1-benzyl ester.

[0070] Fmoc-amino acids include, but are not limited to, fluorenemethoxycarbonyl-O-tert-butyl-L-threonine, Fmoc-L-aspartic acid-beta-tert-butyl ester, Fmoc-O-tert-butyl-L-glutamic acid, Fmoc-O-tert-butyl-L-tyrosine, N-alpha-fluorenemethoxycarbonyl-N-epsilon-tert-butyloxycarbonyl-L-lysine, Fmoc-Pbf-arginine, N-alpha-fluorenemethoxycarbonyl-N-in-tert-butyloxycarbonyl-L-tryptophan, Fmoc-L-proline, N-fluorenemethoxycarbonyl-L-alanine, Fmoc-L-valine, Fmoc-L-methionine, Fmoc-L-phenylalanine, Fmoc-L-leucine, Fmoc-L-isoleucine, and Fmoc-S-triphenylmethyl-L-cysteine. Attached Figure Description

[0071] The accompanying drawings, which are provided to further illustrate this application and form part of this application, illustrate exemplary embodiments of this application and are used to explain this application, but do not constitute an undue limitation of this application.

[0072] Figure 1 The XRD pattern of the crystal form of compound (Ⅲ-Ⅰ) is shown.

[0073] Figure 2 The XRD pattern of the crystal form of compound (Ⅳ) is shown.

[0074] Figure 3 The diagram shows the ellipsoid of the molecular structure of compound (Ⅳ). Detailed Implementation

[0075] The following detailed embodiments illustrate the implementation process and beneficial effects of the present invention, aiming to help readers better understand the essence and characteristics of the invention, and are not intended to limit the scope of the invention. The known starting materials of the present invention can be synthesized using methods known in the art, or can be purchased commercially.

[0076] As used in this article, room temperature (rt) refers to approximately 20-30°C; 1M, 1N: 1 mol / L; eq: equivalent; ee: enantiomer excess; yield = actual product mass / theoretical product mass × 100%; chemical purity test: the chemical purity of the product was determined by high performance liquid chromatography (HPLC); optical purity test: chrial-HPLC test.

[0077] Example 1

[0078] Synthesis of 4-(2-(1-cyclopropylvinyl)phenoxy)-4-oxobutyric acid (compound III-I)

[0079]

[0080] Compound V (47.0 g, 293.75 mmol, 1.0 eq), 4-dimethylaminopyridine (DMAP, 15 mg, catalytic amount), and triethylamine (TEA, 29.7 g, 293.75 mmol, 1.0 eq) were added to 250 mL of dichloromethane (DCM), followed by succinic anhydride (29.4 g, 293.75 mmol, 1.0 eq). The mixture was stirred at room temperature for 1 h. Thin-layer chromatography (TLC) was used to monitor the reaction until the reactants were almost completely reacted. The reaction mixture was then stopped, and the reaction solution was poured into 100 mL of water. The pH was adjusted to 3 with 2 M hydrochloric acid. The mixture was separated, and the aqueous phase was extracted with DCM (100 mL × 2). The organic phases were combined and evaporated to dryness to obtain compound III-1. The mixture was slurried twice with 250 mL of a mixed solvent of n-hexane and methyl tert-butyl ether at a volume ratio of 15:1 to obtain compound III-I (white solid, 62.4 g, yield: 81.7%).

[0081] 1 H NMR (400MHz, Chloroform-d) δ7.35-7.29 (m, 2H), 7.27-7.19 (m, 1H), 7.10-7.03 (m, 1H), 5.07 (d, J=1.4 Hz, 1H), 4.92 (d, J=1.4Hz, 1H), 2.92-2.77 (m, 4H), 1.60 (m, 1H), 0.79-0.66 (m, 2H), 0.59-0.47 (m, 2H).

[0082] Powder X-ray diffraction (XRD) test: The characteristic powder X-ray diffraction (XRD) peaks of the III-I crystal form of the compound prepared in Example 1 are shown in Table 1; the powder X-ray diffraction pattern is shown in... Figure 1 As shown.

[0083] Table 1

[0084]

[0085]

[0086] Example 2

[0087] Synthesis of (R)-2-(1-cyclopropylvinyl)phenyl-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-phenylpropionate (Compound 1)

[0088]

[0089] Compound V (35.2 g, 220 mmol, 1.0 eq) and Fmoc-D-phenylalanine (85.2 g, 220 mmol, 1.0 eq) were dissolved in DCM (250 mL). The reaction solution was placed in an ice bath. Then, DMAP (269 mg, 2.2 mmol, 0.01 eq) and N,N'-dicyclohexylcarbodiimide (DCC, 45.3 g, 220 mmol, 1.0 eq) were added to the reaction solution sequentially. The reaction solution was then stirred at room temperature for 2 hours. When most of the starting material was consumed by TLC, the reaction was stopped. The reaction solution was evaporated to dryness, and 200 mL of methyl tert-butyl ether was added and stirred for 5 min. After filtering off the solid, the filtrate was evaporated to dryness to obtain the crude product. The crude product was slurried with 150 mL of a mixed solvent of n-hexane and methyl tert-butyl ether at a volume ratio of 15:1 to obtain compound 1 (white solid, 75.0 g, yield: 70.8%).

[0090] [M+Na] + :552.1; 1 H NMR (400MHz, CD3Cl) δ7.76 (m, 2H), 7.55 (m, 2H), 7.42-7.20 (m, 12H), 6.98 (m, 1H), 5.28 (m, 1H), 5.04 (s, 1H), 4.89 (m, 2H), 4.47-4.19 (m, 3H), 3.36-3.15 (m, 2H), 1.57 (m, 1H), 0.69 (m, 2H), 0.45 (m, 2H).

[0091] Example 3

[0092] Synthesis of 2-(1-cyclopropylvinyl)phenyl(tert-butoxycarbonyl)-D-alanine ester (compound 2)

[0093]

[0094] Compound V (5.0 g, 31.25 mmol, 1.0 eq) and Boc-D-alanine (6.2 g, 32.81 mmol, 1.05 eq) were dissolved in DCM (50 mL). The reaction solution was placed in an ice bath. Then, DMAP (38 mg, 0.31 mmol, 0.01 eq) and DCC (6.4 g, 31.25 mmol, 1.0 eq) were added to the reaction solution sequentially. The reaction solution was then stirred at room temperature for 2 hours. When most of the starting material was consumed, the reaction was stopped by TLC. The reaction solution was evaporated to dryness, and 50 mL of methyl tert-butyl ether was added and stirred for 5 min. After filtering off the solid, the filtrate was evaporated to dryness to obtain the crude product. The crude product was slurried with 50 mL of a mixed solvent of n-hexane and methyl tert-butyl ether at a volume ratio of 15:1 to obtain compound 2 (white solid, 6.2 g, yield: 59.9%).

[0095] 1 H NMR (400MHz, CD3Cl) δ7.36-7.29 (m, 2H), 7.27-7.19 (m, 1H), 7.10-7.03 (m, 1H), 5.11 (d, J=7.1Hz, 1H), 5.07 (d, J=1.3Hz, 1H), 4. 92 (d, J=1.4Hz, 1H), 4.62-4.54 (m, 1H), 1.60 (m, 1H), 1.57 (d, J=7.2Hz, 3H), 1.49 (s, 9H), 0.78-0.66 (m, 2H), 0.60-0.48 (m, 2H).

[0096] Example 4

[0097] Synthesis of 2-((R)-1-cyclopropylethyl)phenyl(tert-butoxycarbonyl)-L-phenylalanine ester (compound 3)

[0098]

[0099] Compound VI (15.0 g, 92.6 mmol, 1.0 eq) and Boc-L-phenylalanine (25.8 g, 97.23 mmol, 1.05 eq) were dissolved in dichloromethane, followed by the sequential addition of DMAP (113 mg, 0.93 mmol, 0.1 eq) and DCC (20.1 g, 97.23 mmol, 1.05 eq). The mixture was stirred at room temperature for 2 hours and monitored by TLC. After the starting material had completely reacted, the mixture was concentrated to dryness under reduced pressure. Add 80 mL of methyl tert-butyl ether, stir for 5 min, filter, wash the filter cake with methyl tert-butyl ether, concentrate the filtrate to obtain 38.5 g of pale yellow viscous substance; add n-hexane (577.5 mL, 15 mL / g), heat to 40 °C and stir to dissolve, then slowly cool to -10 °C and stir for 1 hour, filter to obtain 28.0 g of white solid; repeat recrystallization in the same way until optical purity ≥99.5% to obtain compound 3 (18.5 g, yield 47.5%).

[0100] 1H NMR (400MHz, CD3Cl) δ7.42 (dt, J=7.4Hz, 2.3Hz, 1H), 7.37-7.32 (m, 2H), 7.31-7.28 (m, 1H), 7.27 (d, J=1.7Hz, 1H), 7.25 (t, J=1.9 Hz, 1H), 7.23-7.16 (m, 2H), 6.86 (t, J=7.4Hz, 1H), 5.02 (d, J=7.1Hz, 1H), 4.81 (d, J=8.4Hz, 1H), 3.27 (dd, J=13.9Hz, 6.0Hz, 1H), 3 .17 (dt, J=13.7Hz, 6.3Hz, 1H), 2.15-2.07 (m, 1H), 1.43 (s, 9H), 1.22 (dd, J=7.0Hz, 4.2Hz, 3H), 0.94 (dddd, J=14.3Hz, 8.2Hz, 6.1 Hz, 4.2Hz, 1H), 0.55-0.49 (m, 1H), 0.36 (tt, J=8.9Hz, 4.7Hz, 1H), 0.17 (dq, J=9.9Hz, 4.7Hz, 1H), 0.07 (dq, J=15.1Hz, 5.0Hz, 1H).

[0101] Example 5

[0102] Synthesis of 2-((R)-1-cyclopropylethyl)phenyl(tert-butoxycarbonyl)-D-alanine ester (compound IV)

[0103]

[0104] Step 1: Synthesis of 2-(1-cyclopropylvinyl)phenol (V)

[0105] Compound III-I (62.4 g, 240 mmol, 1.0 eq) was dissolved in 300 mL of methanol (MeOH) and 100 mL of water, and then sodium hydroxide (24.0 g, 600 mmol, 2.5 eq) was added. The reaction was carried out at 25 °C for 5 hours. After the reactants were completely reacted, methanol was removed by rotary evaporation, and the mixture was extracted with n-hexane (150 mL × 3). The organic phase was washed with 100 mL of saturated sodium bicarbonate solution and then evaporated to dryness to give compound V (pale yellow liquid, 38.0 g, yield 99.0%).

[0106] 1H NMR (400MHz, Chloroform-d) δ7.24-7.10 (m, 2H), 6.99-6.83 (m, 2H), 5.60 (s, 1H), 5.32 (d , J=1.4Hz, 1H), 5.07 (d, J=1.5Hz, 1H), 1.67 (m, 1H), 0.87-0.74 (m, 2H), 0.61-0.50 (m, 2H).

[0107] Step 2: Synthesis of 2-(1-cyclopropylethyl)phenol (VI)

[0108] Compound V (47.0 g, 293.8 mmol, 1.0 eq) and 150 mL of DCM were added to a 500 mL hydrogenation reactor, followed by the addition of catalyst ((4R,5R)-(+)-O-[1-benzyl-1-(5-methyl-2-phenyl-4,5-dihydrooxazol-4-yl)-2-phenylethyl](dicyclohexylphosphine)(1,5-cyclopentadiene)iridium(I)tetra(3,5-bis(trifluoromethyl)phenylboronic acid ester, CAS: 880262-14-6) (400 mg, 0.23 mmol, 0.00078 e The reaction was carried out at 35°C for 5 hours under a hydrogen pressure of 4.5 MPa. After the reactants were completely reacted, the reaction solution was poured into 50 mL of water, the organic phase was separated, and the solution was evaporated to dryness to obtain the crude product. The crude product was dissolved in n-hexane, filtered, and filtered through short silica gel (compound V: silica gel = 1 g: 1.5 g, silica gel height 8-10 cm). The silica gel was washed with about 1.5 L of n-hexane until there was no product in the filtrate. The filtrate was evaporated to dryness to obtain compound VI (pale yellow liquid, 45.5 g, yield 95.6%).

[0109] 1 H NMR (400MHz, Chloroform-d) δ7.31 (dd, J=7.6Hz, 1.7Hz, 1H), 7.11 (td, J=7.7Hz, 1. 7Hz, 1H), 6.95 (td, J=7.5Hz, 1.3Hz, 1H), 6.77 (dd, J=7.9Hz, 1.3Hz, 1H), 4.75 (s, 1H ), 2.46 (dd, J=8.4Hz, 6.8Hz, 1H), 1.33 (d, J=7.0Hz, 3H), 1.08 (qt, J=8.2Hz, 5.0Hz, 1H), 0.67-0.51 (m, 1H), 0.46 (tdd, J=8.0Hz, 5.1Hz, 4.0Hz, 1H), 0.33-0.13 (m, 2H).

[0110] Step 3: Synthesis of 2-((R)-1-cyclopropylethyl)phenyl(tert-butoxycarbonyl)-D-alanine ester (Ⅳ)

[0111] Compound VI (57 g, 351 mmol) and Boc-D-alanine (70 g, 369 mmol) were dissolved in dichloromethane, followed by the addition of DMAP (4.3 g, 35 mmol) and DCC (80 g, 386 mmol). The mixture was stirred at room temperature for 2 hours, and TLC monitoring showed that compound VI reacted completely. The mixture was concentrated to dryness under reduced pressure, and methyl tert-butyl ether (500 mL) was added. The mixture was stirred for 5 min, filtered, and the filter cake was washed with methyl tert-butyl ether. The filtrate was concentrated to give compound IV (pale yellow viscous substance, 110 g). Hexane (1650 mL, 15 mL / g) was added, and the mixture was heated to 40 °C and stirred until dissolved. The mixture was then slowly cooled to -10 °C and stirred for 1 hour. The mixture was filtered to give 88 g of white solid. The same recrystallization method was repeated until the optical purity was ≥99.5% to obtain compound IV (white solid, 65 g, yield 55.5%).

[0112] 1 H NMR (400MHz, CD3Cl) δ7.46 (dd, J=7.3Hz, 2.2Hz, 1H), 7.28-7.18 (m, 2H), 7.05-6.98 (m, 1H), 5.11 (d, J=7.1Hz, 1H), 4.62-4.54 (m, 1H), 2.19 (dq, J=9. 1Hz, 6.9Hz, 1H), 1.57 (d, J=7.2Hz, 3H), 1.49 (s, 9H), 1.27 (d, J=7.0Hz, 3H ), 1.01 (m, 1H), 0.63-0.52 (m, 1H), 0.39 (m, 1H), 0.23 (m, 1H), 0.10 (m, 1H).

[0113] Powder X-ray diffraction (XRD) test: The characteristic powder X-ray diffraction (XRD) peaks of the compound IV crystal form prepared in Example 5 are shown in Table 2; the powder X-ray diffraction pattern is shown in... Figure 2 As shown.

[0114] Table 2

[0115]

[0116]

[0117] Example 6

[0118] Synthesis of (2-(1-cyclopropylethyl)-6-(1-(ethylsulfonic acid)ethyl)phenol) (compound XI)

[0119]

[0120] Step 1: Synthesis of 2-(1-cyclopropylethyl)phenol (VI)

[0121] Compound IV-I (164 g, 492 mmol) was dissolved in methanol (410 mL) and tetrahydrofuran (THF, 410 mL), and then 4M sodium hydroxide aqueous solution (246 mL, 984 mol) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by TLC. The reaction proceeds were completely reacted. Water (600 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (700 mL × 2). The organic phase was then washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound VI (pale yellow liquid, 79.5 g, yield 99.6%, chemical purity 98.24%).

[0122] Step 2: Synthesis of 3-(1-cyclopropylethyl)-2-hydroxybenzaldehyde (VII)

[0123] Compound VI (79.5 g, 490 mmol), acetonitrile (ACN, 795 mL), paraformaldehyde (73.6 g, 2450 mmol), magnesium chloride (140 g, 1470 mmol), and triethylamine (247.9 g, 2450 mmol) were added to a flask. The mixture was heated to 65 °C and stirred for 2 hours. TLC monitoring showed that the starting material reacted completely. The pH was adjusted to 3-4 by slowly adding 2N HCl solution at 0 °C. The mixture was extracted with ethyl acetate (600 mL × 2), and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered through silica gel, and the filtrate was concentrated to obtain compound VII (deep red liquid, 86.0 g, chemical purity 96.97%).

[0124] Step 3: Synthesis of 2-(1-cyclopropylethyl)-6-(1-hydroxyethyl)phenol (IX)

[0125] Compound VII (86.0 g, 452 mmol) was dissolved in tetrahydrofuran (430 mL), purged with nitrogen for protection, and cooled to 0 °C. 3M methyl magnesium chloride (331.5 mL, 994.4 mol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour. TLC monitoring showed that the starting material reacted completely. The reaction solution was then slowly added to a saturated ammonium chloride solution (600 mL) with stirring. The mixture was extracted with ethyl acetate (700 mL), and the organic phase was washed successively with water and saturated brine. The solution was dried over anhydrous sodium sulfate, filtered through silica gel, and the filtrate was concentrated to obtain compound IX (yellow liquid, 92.4 g, chemical purity 91.93%).

[0126] Step 4: Synthesis of (2-(1-cyclopropylethyl)-6-(1-(ethylthio)ethyl)phenol (X)

[0127] Compound IX (1.0 g, 4.85 mmol) was dissolved in acetonitrile (ACN, 10 mL), and ethanethiol (361 mg, 5.81 mmol, 1.2 eq) was added under nitrogen protection. Hydrochloric acid (229 mg, 6.30 mmol, 1.3 eq) was then slowly added dropwise to the reaction mixture. The reaction system was stirred at 15 °C for 10 hours. TLC (V1) was performed. 正己烷 V 乙酸乙酯 =5:1) Stop the reaction when most of the raw materials have been consumed. Dilute the reaction solution with water, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine, concentrate, and purify the crude product by column chromatography with an eluent polarity V. 正己烷 V 乙酸乙酯 =50:1 to 20:1, to obtain compound X (yellow oil, 700 mg, yield 57.7%).

[0128] 1 H NMR (400MHz, CD3Cl) δ7.50 (d, J=8.0Hz, 1H), 7.27-7.25 (m, 1H), 6.93-6.91 (m, 1H), 6.86-6.83 (m, 1H), 4.18-4.12 (m, 1H), 2.58-2.52 (m, 1H), 2.40-2. 34(m, 2H), 1.64(d, J=8.0Hz, 3H), 1.31-1.28(m, 3H), 1.19-1.15(m, 3H), 1. 05-0.97 (m, 1H), 0.55-0.54 (m, 1H), 0.35-0.30 (m, 1H), 0.20-0.16 (m, 2H).

[0129] Step 5: Synthesis of (2-(1-cyclopropylethyl)-6-(1-(ethylsulfonic acid)ethyl)phenol)(XI)

[0130] Under nitrogen protection, compound X (200 mg, 0.798 mmol) was dissolved in DCM (10 mL). While maintaining the system temperature at -5 to 0 °C, m-chloroperoxybenzoic acid (m-CPBA, 325 mg, 1.60 mmol, 2.0 eq) was slowly added to the reaction mixture, and the reaction was allowed to proceed at 10 °C for 0.5 hours. TLC (V 正己烷 V 乙酸乙酯 =1:1) Once the raw materials are consumed, stop the reaction. Dilute the reaction solution with dichloromethane (10 mL), wash with saturated sodium bicarbonate solution, combine the organic phases, wash with saturated brine, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify the crude product by column chromatography using V as the eluent. 正己烷 V 乙酸乙酯 =1:1, to obtain compound XI (pale yellow oil, 180.0 mg, yield 82%).

[0131] 1 H NMR (400MHz, CD3Cl) δ7.38-7.33(m, 1H), 7.12-7.10(m, 2H), 6.99-6.96(m, 1H), 4.59-4.55(m, 1H), 2.94-2.88(m, 2H), 2.58-2.54(m, 1H), 1.83 (d, J=8.0Hz, 3H), 1.34-1.32 (m, 3H), 1.30-1.27 (m, 3H), 1.05-1.01 (m, 1H), 0.58-0.56 (m, 1H), 0.42-0.40 (m, 1H), 0.23-0.15 (m, 2H).

[0132] Example 7

[0133] X-ray single-crystal diffraction analysis of 2-((R)-1-cyclopropylethyl)phenyl(tert-butoxycarbonyl)-D-alanine ester (Ⅳ)

[0134]

[0135] Crystal data

[0136]

[0137] After integrating and restoring the diffraction data using the SAINT program, empirical absorption correction was performed using the SADABS program. The single-crystal structure was analyzed using the SHELXT2014 software via the direct method, and the structure was refined using the least squares method. The hydrogen atom refinement process was obtained by isotropic calculation, and the hydrogen atoms on CH were obtained by calculated hydrogen addition, and the structure was refined using the riding model. The Flack constant was 0.14(11), the chirality was confirmed, and C7 and C13 were R configurations ( Figure 3 ).

[0138] Example 8

[0139] Synthesis of 3-((1R)-1-cyclopropylethyl)-2-hydroxybenzaldehyde (compound VII-I)

[0140]

[0141] Step 1: Synthesis of 2-((1R)-1-cyclopropylethyl)phenol (4)

[0142] Compound IV (164 g, 492 mmol) was dissolved in methanol (410 mL) and tetrahydrofuran (410 mL), and then 4M sodium hydroxide aqueous solution (246 mL, 984 mol) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by TLC. The reaction proceeds were completely reacted. Water (600 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (700 mL × 2). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 4 (pale yellow liquid, 79.5 g, yield 99.6%, optical purity 99.32%, chemical purity 98.24%).

[0143] Step 2: Synthesis of 3-((1R)-1-cyclopropylethyl)-2-hydroxybenzaldehyde (VII-I)

[0144] Compound 4 (79.5 g, 490 mmol), acetonitrile (795 mL), paraformaldehyde (73.6 g, 2450 mmol), magnesium chloride (140 g, 1470 mmol), and triethylamine (247.9 g, 2450 mmol) were added to a flask. The mixture was heated to 65 °C and stirred for 2 hours. TLC monitoring showed that the starting material reacted completely. The pH was adjusted to 3-4 by slowly adding 2N HCl solution at 0 °C. The mixture was extracted with ethyl acetate (600 mL × 2), and the organic phase was washed successively with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered through silica gel, and the filtrate was concentrated to obtain compound VII-I (deep red liquid, 86.0 g, chemical purity 96.97%).

[0145] Comparative Example 1

[0146] Synthesis of 2-((1R)-1-cyclopropylethyl)phenyl N-((1R)-1-phenylethyl)carbamate (compound 5)

[0147]

[0148] The preparation processes of compounds V and VI in Comparative Example 1 are the same as those in Example 5.

[0149] Compound VI (4.0 g, 24.8 mmol, 1.0 eq), (R)-(+)-1-phenylethyl isocyanate (3.97 g, 27.0 mmol, 1.05 eq), triethylamine (2.6 g, 27.0 mmol, 1.05 eq), and tetrahydrofuran (30 mL) were added to a flask. The mixture was heated to 60 °C and stirred for 3 hours. TLC monitoring showed that the reactants had reacted completely. The reaction mixture was poured into 15 mL of water and extracted with dichloromethane (30 mL × 3). The organic phase was collected, evaporated to dryness, and purified by column chromatography using V as the eluent. 正己烷 V 乙酸乙酯 =10:1, yielding 7.8g of white solid product.

[0150] 2.0g of the product was recrystallized with 20mL of n-hexane or n-heptane and heated to reflux. Most of the product did not dissolve and recrystallization could not be performed. Instead, 20mL of n-hexane was used to slurry the product at room temperature and filtered to obtain 1.6g of white solid (yield: 80%). The test results showed that the ratio of compound 5 to its diastereomer 5-1 was 51.77%:48.23% (compound 5: ee value 3.54%), indicating that there was basically no resolving effect.

[0151] 2.0 g of the product was recrystallized from 20 mL of isopropanol to obtain 1.2 g of white solid (yield: 60%). The test results showed that the ratio of compound 5 to its diastereomer 5-1 was 51.41%:48.59% (compound 5: ee value 2.82%), indicating that there was basically no separation effect.

[0152] 2.0 g of the product was recrystallized from 8 mL of toluene to obtain 1.0 g of white solid (yield: 50%). Analysis showed that the ratio of compound 5 to its diastereomer 5-1 was 52.45%:47.55% (compound 5: ee value 4.90%), indicating virtually no resolution effect. No suitable solvent was found for further separation by pulping or recrystallization; this compound is difficult to resolve.

[0153] 1 HNMR (400MHz, CD3Cl) δ7.44-7.30 (m, 6H), 7.23-7.18 (m, 2H), 7.08 (dd, J=6.2, 3.2Hz, 1H), 5.29 (s, 1H), 4.95 (p, J=7.1Hz, 1H), 2.24-2.18 (m, 1H), 1.59 (d, J=5.6Hz, 3H), 1.26 (dd, J=13.4, 7.0Hz, 3H), 1.02-0.98 (m, 1H), 0.58-0.50 (m, 1H), 0.40-0.34 (m, 1H), 0.21-0.04 (m, 2H).

[0154] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing a compound represented by formula (Ⅳ), characterized in that, It is prepared by condensation reaction of compound (VI) with Boc-D-alanine to form an ester; （Ⅵ） （Ⅳ）。 2. The method for preparing the compound according to claim 1, characterized in that, The reaction uses a solvent selected from any one or a mixture of several of the following in any proportion: dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, and acetone. A condensing agent is added to the reaction, and the condensing agent is selected from any one of N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, and 1-hydroxybenzotriazole, with preference given to any one of N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction involves the addition of an alkaline reagent, which is selected from any one of DMAP, triethylamine, N,N-diisopropylethylamine, and pyridine.

3. The method for preparing the compound according to claim 1, characterized in that, The method for preparing the compound shown in formula (VI) includes the following steps: Step a: Hydrolyze the compound of formula (III-1) under alkaline conditions to generate the compound of formula (V); Step b: The compound of formula (V) is reduced to produce the compound of formula (VI); (III-I) (V) (VI).

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