WO2023143158A1 - Phenol derivative, crystal form thereof, and preparation method therefor - Google Patents

Abstract

The present invention relates to a phenol derivative, a crystal form thereof, and a preparation method therefor, in particular to a solid intermediate used for preparing the phenol derivative, and specifically provides a compound shown in formula (I) or formula (II), a stereoisomer thereof, a crystal form thereof and a preparation method therefor.

Description

Phenol derivative, its crystal form and preparation method

This application claims the priority of the Chinese patent application with the application number 202210091223.8 submitted to the China Patent Office on January 26, 2022, and the title of the invention is "Phenol derivatives, their crystal forms and preparation methods", the entire contents of which are incorporated herein by reference In this application.

technical field

The invention relates to a phenol derivative, its crystal form and a preparation method, in particular to a solid intermediate for preparing the phenol derivative.

Background technique

Propofol activates multiple gamma-aminobutyric acid type A (GABA _A ) receptor subtypes and is widely used for induction and maintenance of general anesthesia. The remarkable pharmacokinetic and pharmacodynamic properties of propofol are rapid onset of action, short duration of action and rapid reversibility. After intravenous administration, propofol quickly enters hyperperfused areas such as the heart, lungs, and liver from the blood, and its high fat solubility makes it easy for propofol to cross the blood-brain barrier and enter the brain to exert general anesthesia.

In view of the many advantages of propofol, people have further developed a variety of propofol derivatives on the basis of the structure of propofol, hoping to obtain the structure of phenol derivatives with better effects and fewer side effects. Patent WO2014180305 describes a class of phenol derivatives and their preparation methods and uses in the central nervous system, some of which have stronger GABA _A agonistic activity than commercially available propofol, and can be predicted to have the effect of avoiding injection pain. Patent CN202111122520.6 describes another class of phenol derivatives and their application in medicine. Some compounds disclosed in it have stronger medicinal effects and lower side effects. However, at present, most of the compounds or synthetic intermediates obtained from phenol derivatives based on propofol structure improvement are basically in liquid or oil state, which is not conducive to the quality control and purification of intermediates or target products, and is also not conducive to large-scale production, as well as storage, The transportation process went smoothly.

Chinese patent CN201510255867.6 reports a solid intermediate for the synthesis of phenol derivatives, which has the structure shown in the following formula (VIII), which is obtained by introducing -N-((1R)-1-phenylethyl)aminomethyl The ester fragment was subjected to chiral resolution to obtain an optically pure solid intermediate formula (VIII), which was applied to the synthesis of chiral compound 2-((1R)-1-cyclopropylethyl)-6-isopropyl Base phenol (i.e. cycloporol).

The present invention provides another solid intermediate for synthesizing phenol derivatives, which has a structure shown in formula (I) or formula (II), wherein formula (II) is formed by introducing amino acid protecting groups and phenolic hydroxyl groups into esters The solid intermediate obtained, and the inventors of the present application have discovered through a large number of creative experiments that by introducing a specific configuration of amino acid protecting group fragments for chiral resolution, a solid intermediate with high optical purity can be obtained, and has Conducive to its further synthesis of high optical purity phenol derivatives. In the present invention, the solid intermediate formula (II) obtained by forming an ester of an amino acid protecting group and a phenolic hydroxyl group is compared with that obtained by forming a carbamate between (R)-(+)-1-phenylethyl isocyanate and a phenolic hydroxyl group in the prior art. The solid intermediate obtained by the present invention has a good resolution effect, and the obtained product has high optical purity, and the raw materials used for introducing amino acid protecting groups are relatively cheap, the production cost is low, and industrial production is easy to realize.

Contents of the invention

In order to improve the defects of the prior art, the present invention provides an intermediate for the synthesis of phenol derivatives through a large number of creative experiments by the researchers. After studying its solid state, we found a solid state with obvious powder X-ray diffraction pattern characteristics form. The intermediate provided by the invention has high optical purity, is more conducive to the synthesis of phenol derivatives with high optical purity, and has more industrial production value. The method for splitting synthetic intermediates provided by the invention reduces the difficulty of splitting, has high splitting purity and high yield, and the compound is stable during the splitting process, and the compound can be recycled and utilized many times to achieve the optimization of material utilization. The intermediate provided by the invention synthesizes the target product of the phenol derivative, and the cost is lower.

The present invention provides a compound represented by formula (I) or formula (II), or a stereoisomer thereof:

in:

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

Or R is the following structural formula:

n is selected from 1,2,3.

In some embodiments, the compound has the structure shown in the following formula (III):

Wherein n is selected from 1, 2, 3.

In some embodiments, the compound has the structure shown in the following formula (IV) or formula (IV-I) or its isomer formula:

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

The present invention also provides the X-ray powder diffraction pattern of the crystal form of compound formula (Ⅲ-I), whose values at ^2θ 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, 3 Diffraction peaks at 0.819, 31.761, 34.979, 37.741, 42.400, 44.257 .

Further, the X-ray powder diffraction pattern of the crystal form of the compound formula (III-I) also has a ^2θ value of: 10.616, 15.583, 27.321, 29.902, 32.942, 33.503, 36.239, 39.601, 48.303 or There are many diffraction peaks.

The present invention also provides the X-ray powder diffraction pattern of the structure shown in compound formula (IV) or the crystal form of its isomer formula, and its value at ^2θ is: 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, 34.839 have diffraction peaks.

Further, the X-ray powder diffraction pattern of the crystal form of the compound formula (IV) or its isomer formula also has a ^2θ value of: 15.780, 19.499, 21.899, 27.542, 28.122, 35.338, 36.001 or There are many diffraction peaks.

On the other hand, the present invention also provides a preparation method of the compound represented by the formula (III), the method is obtained by the formula (Ⅴ) The compound is prepared by esterification with cyclic acid anhydride;

Preferably, a solvent is used in the reaction, and the solvent is selected from any one of methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, and acetone one or a mixture of several proportions;

Described reaction adds catalyst, and catalyst is selected from DMAP;

An alkaline reagent is added to the reaction, and the alkaline reagent is selected from triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, lithium carbonate, potassium fluoride, potassium phosphate, potassium bicarbonate, Any one or a mixture of any of sodium bicarbonate.

On the other hand, the present invention also provides a preparation method of the compound represented by formula (IV), which is prepared by performing condensation reaction between the compound of formula (VI) and Boc-D-alanine to form an ester;

Preferably, a solvent is used in the reaction, and the solvent is selected from any one of dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, and acetone one or a mixture of several proportions;

A condensing agent is added in the reaction, and the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 2-(7-azobenzotriazole)-N,N, Any of N',N'-tetramethylurea hexafluorophosphate, 1-hydroxybenzotriazole;

More preferably, the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-(3- Any one of dimethylaminopropyl)-3-ethylcarbodiimide;

An alkaline reagent is added to the reaction, and the alkaline reagent is selected from the bases: any one of DMAP, triethylamine, N,N-diisopropylethylamine, and pyridine.

Preferably, the preparation method of the compound represented by the formula (VI) comprises the following steps:

Step a: hydrolyzing the compound of formula (III-1) under basic conditions to generate the compound of formula (V);

Step b: reducing the compound of formula (V) to generate the compound of formula (VI);

Use alkaline reagent and reaction solvent in described step a, described basic reagent is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate, potassium carbonate, described reaction solvent Any one selected from methanol, ethanol, tetrahydrofuran, water or a mixture of any ratio;

A reducing agent and a catalyst are used in the step b, 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)tetrakis(3, 5-Bis(trifluoromethyl)phenyl borate.

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

The purification method is that the crude product of the compound of formula (Ⅲ) is subjected to beating and purification in an organic solvent, and the organic solvent is selected from alkanes, Any one of cycloalkanes, aromatic hydrocarbons, and ether solvents or a mixture of any ratio;

Preferably, the organic solvent is selected from a single solvent of n-hexane, n-heptane or toluene;

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

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

The purification method is that the crude product of the compound shown in formula (IV) is recrystallized in an organic solvent, and the organic solvent is selected from any one or a mixture of any ratio in alkane and cycloalkane solvents; preferably, the organic solvent For n-hexane or n-heptane.

On the other hand, the present invention also provides a compound represented by formula (VII), or its isomer formula (VII-I) or formula (VII-II):

Further, the present invention also provides a preparation method of the compound represented by formula (VII), comprising the following steps:

Step c: hydrolyzing the compound of formula (IV-I) under basic conditions to generate the compound of formula (VI);

Step d: acylation of the compound of formula (VI) to generate the compound of formula (VII);

Preferably, in the preparation method of the compound represented by the formula (VII), an alkaline reagent and a reaction solvent are used in the step c, the alkaline reagent is selected from sodium hydroxide, and the reaction solvent is selected from methanol and Tetrahydrofuran, methanol and water in any one or a mixture of several ratios;

In the step d, an acylating agent, a catalyst and an alkaline agent are used, the acylating agent is selected from paraformaldehyde, the catalyst is selected from magnesium chloride, and the alkaline agent is selected from triethylamine.

The present invention also provides a preparation method of the compound shown in formula (XI), the preparation process comprising the following steps:

Step e: Grignard reaction of the compound of formula (VII) to generate the compound of formula (IX);

Step f: reacting the compound of formula (IX) with ethanethiol to generate the compound of formula (X);

Step g: oxidizing the compound of formula (X) to generate the compound of formula (XI);

Preferably, a Grignard reagent is used in the step e, and the Grignard reagent is selected from methylmagnesium chloride;

An acid reagent is used in the step f, and the acid reagent is selected from hydrochloric acid;

Use oxidizing agent in the described step g, described oxidizing agent is selected from m-chloroperoxybenzoic acid.

The term "amino acid protecting group" in the present invention refers to the group after amino acid reacts with hydroxyl group and carboxylic acid removes hydroxyl group. Boc-amino acid protecting group, Cbz-amino acid protecting group, and Fmoc-amino acid protecting group are respectively Boc-amino acid, Cbz-amino acid, Fmoc-amino acid reacting with hydroxyl group after the carboxylic acid removes the hydroxyl group.

Boc-amino acids include, but are not limited to, N-(tert-butoxycarbonyl)-L-glutamate-1-benzyl ester, Boc-L-proline, N-Boc-O-benzyl-L-serine, S- Acetamidomethyl-N-tert-butoxycarbonyl-L-cysteine, N2-[tert-butoxycarbonyl]-N-(trityl base)-D-asparagine, 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'-triphenyl Methyl-L-histidine, Boc-L-4-nitrophenylalanine, Boc-D-prolinol, Boc-3-(2-naphthyl)-D-alanine.

Cbz-amino acids include but are not limited to N-benzyloxycarbonyl-L-arginine cyclohexylamine salt, N-benzyloxycarbonyl-glycyl-glycine, N-benzyloxycarbonyl-D-leucine, N-benzyloxycarbonyl Oxycarbonyl-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 , N-Benzyloxycarbonyl-L-aspartic acid-1-benzyl ester.

Fmoc-amino acids include, but are not limited to, Fmoc-O-tert-butyl-L-threonine, Fmoc-L-aspartic acid-beta-tert-butyl ester, Fmoc-O-tert-butyl-L-glutamine Amino acid, Fmoc-O-tert-butyl-L-tyrosine, N-alpha-fluorenylmethoxycarbonyl-N-epsilon-tert-butoxycarbonyl-L-lysine, Fmoc-Pbf-arginine, N -alpha-Fmoc-N-in-tert-Butoxycarbonyl-L-Tryptophan, Fmoc-L-Proline, N-Fmoc-L-Alanine, Fmoc-L-Valine acid, Fmoc-L-methionine, Fmoc-L-phenylalanine, Fmoc-L-leucine, Fmoc-L-isoleucine, Fmoc-S-trityl-L-cysteine.

Description of drawings

The drawings described here are used to provide a further understanding of the application and constitute a part of the application. The schematic embodiments and descriptions of the application are used to explain the application and do not constitute an improper limitation to the application.

Fig. 1 is the XRD pattern of formula (Ⅲ-I) compound crystal form;

Fig. 2 is the XRD pattern of formula (IV) compound crystal form;

Fig. 3 is an ellipsoid diagram of the three-dimensional molecular structure of the compound of formula (IV).

Detailed ways

The implementation process and the beneficial effects of the present invention are described in detail below through specific examples, aiming at helping readers better understand the essence and characteristics of the present invention, and not as limiting the applicable scope of the present invention. The starting materials known in the present invention may be employed or synthesized according to methods known in the art, or may be purchased commercially.

As used herein, room temperature (rt) refers to about 20-30°C; 1M, 1N: 1mol/L; eq: equivalent; ee: enantiomeric excess; yield=actual synthetic product mass/theoretical synthetic product mass×100% ; Chemical purity test: adopt high performance liquid chromatography (HPLC) to detect the chemical purity of the product; Optical purity test: chrial-HPLC test.

Example 1

Synthesis of 4-(2-(1-cyclopropylvinyl)phenoxy)-4-oxobutanoic acid (compound Ⅲ-Ⅰ)

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), then add succinic anhydride (29.4g, 293.75mmol, 1.0eq) and stir at room temperature for 1h, thin-layer chromatography (TLC) monitors that the basic reaction of the raw materials is complete, stop the reaction, pour the reaction solution into 100mL water, and use 2M Adjust the pH to 3 with hydrochloric acid, separate the liquids, extract the aqueous phase with DCM (100mL×2), combine the organic phases, and spin dry to obtain compound III-1. The volume ratio of n-hexane: methyl tert-butyl ether is 15:1 250 mL of mixed solvent was beaten twice to obtain compound III-I crystal form (white solid, 62.4 g, yield: 81.7%).

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=1.4Hz, 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).

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

Table 1

Example 2

(R)-2-(1-cyclopropylvinyl)phenyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-phenylpropionate (compound 1 )Synthesis

After compound V (35.2g, 220mmol, 1.0eq) and Fmoc-D-phenylalanine (85.2g, 220mmol, 1.0eq) were dissolved in DCM (250mL), the reaction solution was placed in an ice bath, and then poured into the reaction solution DMAP (269mg, 2.2mmol, 0.01eq) and N,N'-dicyclohexylcarbodiimide (DCC, 45.3g, 220mmol, 1.0eq) were added sequentially to the mixture, and the reaction solution was stirred at room temperature for 2 hours, and monitored by TLC. Most of the raw materials are consumed, stop the reaction, spin the reaction solution to dryness, add 200mL methyl tert-butyl ether and stir for 5min, filter off the solid, spin the filtrate to obtain the crude product, and use the volume ratio of n-hexane:methyl tert-butyl ether as 150 mL of a 15:1 mixed solvent was slurried to obtain compound 1 (white solid, 75.0 g, yield: 70.8%).

[M+Na] ⁺ :552.1; ¹ H NMR (400MHz, CD ₃ Cl) 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).

Example 3

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

After compound V (5.0g, 31.25mmol, 1.0eq) and Boc-D-alanine (6.2g, 32.81mmol, 1.05eq) were dissolved in DCM (50mL), the reaction solution was placed in an ice bath, and then the reaction DMAP (38mg, 0.31mmol, 0.01eq) and DCC (6.4g, 31.25mmol, 1.0eq) were added successively to the solution, and then the reaction solution was stirred at room temperature for 2 hours. TLC monitored that most of the raw materials were consumed, and the reaction was stopped. Spin to dry, add 50mL of methyl tert-butyl ether and stir for 5min, filter out the solid, spin the filtrate to obtain the crude product, use 50mL of a mixed solvent with a volume ratio of n-hexane: methyl tert-butyl ether to be 15:1 for beating, and obtain compound 2 (White solid, 6.2 g, yield: 59.9%).

¹ H NMR (400MHz, CD ₃ Cl) 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).

Example 4

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

Compound VI (15.0g, 92.6mmol, 1.0eq) and Boc-L-phenylalanine (25.8g, 97.23mmol, 1.05eq) were dissolved in dichloromethane, and DMAP (113mg, 0.93mmol, 0.1 eq) and DCC (20.1g, 97.23mmol, 1.05eq), then stirred and reacted at room temperature for 2 hours, monitored by TLC, after the reaction of raw materials was complete; concentrated to dryness under reduced pressure, added methyl tert-butyl ether (80mL), stirred for 5min, Suction filtration, and wash the filter cake with methyl tert-butyl ether, concentrate the filtrate to obtain 38.5 g of light yellow sticky substance; add n-hexane (577.5 mL, 15 mL/g), heat to 40 ° C and stir to dissolve, then slowly cool down to Stir at -10°C for another 1 hour, and filter with suction to obtain 28.0 g of a white solid; repeated recrystallization by the same method to optical purity ≥ 99.5% to obtain compound 3 (18.5 g, yield 47.5%).

¹ H NMR (400MHz, CD ₃ Cl) 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=1.9Hz, 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, 6.1Hz, 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).

Example 5

2-((R)-1-cyclopropylethyl)phenyl(tert-butoxycarbonyl)-D-alanine ester(tert-butoxycarbonyl)-D-alanine Synthesis of Esters (Compound IV)

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

Dissolve compound III-I (62.4g, 240mmol, 1.0eq) in 300mL of methanol (MeOH) and 100mL of water, then add sodium hydroxide (24.0g, 600mmol, 2.5eq), and react at 25°C for 5 hours. , spin to remove methanol, then extract with n-hexane (150mL×3), the organic phase was washed with 100mL saturated sodium bicarbonate solution, and then spin-dried to obtain compound V (light yellow liquid, 38.0g, yield 99.0%).

¹ H 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).

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

Compound V (47.0g, 293.8.0mmol, 1.0eq) and 150mL DCM were added to a 500mL hydrogenation kettle, and then the catalyst ((4R,5R)-(+)-O-[1-benzyl-1-( 5-Methyl-2-phenyl-4,5-dihydrooxazol-4-yl)-2-phenylethyl](dicyclohexylphosphine)(1,5-cyclopentadiene)iridium(I ) Tetrakis(3,5-bis(trifluoromethyl)phenyl borate, CAS: 880262-14-6) (400mg, 0.23mmol, 0.00078eq), reacted at 35°C under a hydrogen pressure of 4.5MPa for 5 hours, Raw materials reacted Finally, the reaction solution was poured into 50mL of water, the organic phase was separated, spin-dried to obtain the crude product dissolved in n-hexane, suction filtered, short silica gel (compound V: silica gel = 1g: 1.5g, silica gel height 8-10cm), silica gel Rinse with about 1.5 L of n-hexane until there is no product in the filtrate, and the filtrate is spin-dried to obtain compound VI (light yellow liquid, 45.5 g, yield 95.6%).

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).

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

Compound VI (57g, 351mmol) and Boc-D-alanine (70g, 369mmol) were dissolved in dichloromethane, then DMAP (4.3g, 35mmol) and DCC (80g, 386mmol) were added successively, and the reaction was stirred at room temperature After 2 hours, TLC monitoring showed that the reaction of compound VI was complete; concentrated to dryness under reduced pressure, added methyl tert-butyl ether (500mL), stirred for 5min, filtered with suction, washed the filter cake with methyl tert-butyl ether, and concentrated the filtrate to obtain compound IV (pale yellow viscous substance, 110g); add n-hexane (1650mL, 15mL/g), heat to 40°C and stir to dissolve, then slowly cool down to -10°C and stir for 1 hour, and suction filter to obtain 88g of white solid; The same method was used to repeat the recrystallization until the optical purity was ≥ 99.5%, and the crystal form of compound IV was obtained (white solid, 65 g, yield 55.5%).

¹ H NMR (400MHz, CD ₃ Cl) 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 = 7.0 Hz, 3H), 1.01 (m, 1H), 0.63-0.52 (m, 1H), 0.39 (m, 1H), 0.23 (m, 1H), 0.10 (m, 1H).

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.

Table 2

Example 6

Synthesis of (2-(1-cyclopropylethyl)-6-(1-(ethylsulfonate)ethyl)phenol) (compound XI)

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

Compound IV-I (164g, 492mmol) was dissolved in methanol (410mL) and tetrahydrofuran (THF, 410mL), and then 4M aqueous sodium hydroxide solution (246mL, 984mol) was added, and the reaction was stirred at room temperature for 1 hour, monitored by TLC, and the reaction of the raw materials was complete Add water (600mL) to the reaction solution, extract with ethyl acetate (700mL×2), then wash the organic phase with water and saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound VI (light yellow liquid, 79.5 g, yield 99.6%, chemical purity 98.24%).

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

Add compound VI (79.5g, 490mmol), acetonitrile (ACN, 795mL), paraformaldehyde (73.6g, 2450mmol), magnesium chloride (140g, 1470mmol) and triethylamine (247.9g, 2450mmol) into the flask, and heat to 65°C Stir the reaction for 2 hours, monitor by TLC, the reaction of the raw materials is complete; slowly add 2N HCl solution at 0°C to adjust the pH=3~4, extract with ethyl acetate (600mL×2), then wash the organic phase with water and saturated brine successively, and dry Dry over sodium sulfate, filter through silica gel, and concentrate the filtrate to obtain compound VII (dark red liquid, 86.0 g, chemical purity: 96.97%).

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

Compound VII (86.0g, 452mmol) was dissolved in tetrahydrofuran (430mL), nitrogen was replaced and protected, the temperature was lowered to 0°C, 3M methylmagnesium chloride (331.5mL, 994.4mol) was slowly added dropwise, and the reaction was stirred at room temperature for 1 hour after the addition was complete , TLC monitoring, the reaction of the raw materials is complete; under stirring, the reaction solution is slowly added to saturated ammonium chloride solution (600mL), extracted with ethyl acetate (700mL), and then the organic phase is washed with water and saturated brine successively, and 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%).

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

Compound IX (1.0g, 4.85mmol) was dissolved in acetonitrile (ACN, 10mL), ethanethiol (361mg, 5.81mmol, 1.2eq) was added under nitrogen protection, and hydrochloric acid (229mg , 6.30mmol, 1.3eq), the reaction system was stirred at 15°C for 10 hours, TLC (V _n-hexane :V _{ethyl acetate} =5:1) detected that most of the raw materials were consumed, and the reaction was stopped. The reaction solution was diluted with water, extracted with ethyl acetate (50mL×3), the organic phases were combined, and saturated Washed with brine, concentrated, and the crude product was purified by column chromatography, eluting with polarity V _n-hexane : V _{ethyl acetate} = 50:1-20:1 to obtain compound X (yellow oil, 700 mg, yield 57.7%).

¹ H NMR (400MHz, CD ₃ Cl) 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).

Step 5: Synthesis of (2-(1-cyclopropylethyl)-6-(1-(ethylsulfonate)ethyl)phenol) (XI)

Under nitrogen protection, compound X (200mg, 0.798mmol) was dissolved in DCM (10mL) and m-chloroperoxybenzoic acid (m-CPBA, 325mg, 1.60mmol, 2.0 eq) was added to the reaction, and the reaction was allowed to react at 10°C for 0.5 hours. TLC (V _n-hexane : V _{ethyl acetate} = 1:1) detected that the raw materials were consumed, stopped the reaction, diluted the reaction solution with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution, combined the organic phases, washed with saturated salt Washed with water, the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography, the eluent was V _n-hexane : V _{ethyl acetate} = 1:1, to obtain compound XI (light yellow oil, 180.0mg , yield 82%).

¹ H NMR (400MHz, CD ₃ Cl) 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).

Example 7

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

Crystal data

After integrating and restoring the diffraction data using the SAINT program, the SADABS program was used to perform empirical absorption correction on the data; the SHELXT2014 software was used to analyze the single crystal structure by the direct method, and the structure was refined by the least square method. The isotropic calculation process is obtained, and the hydrogen atoms on C-H are obtained by calculation hydrogenation, and the riding model is used to refine it. The Flack constant is 0.14 (11), the chirality can be confirmed, and C7 and C13 are R configurations (Figure 3).

Example 8

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

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

Compound IV (164g, 492mmol) was dissolved in methanol (410mL) and tetrahydrofuran (410mL), and then 4M aqueous sodium hydroxide solution (246mL, 984mol) was added, and the reaction was stirred at room temperature for 1 hour, monitored by TLC, and the reaction of the raw materials was complete; Add water (600mL), extract with ethyl acetate (700mL×2), then wash the organic phase with water and saturated brine successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 4 (light yellow liquid, 79.5g, yield 99.6%, optical purity 99.32%, chemical purity 98.24%).

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

Add compound 4 (79.5g, 490mmol), acetonitrile (795mL), paraformaldehyde (73.6g, 2450mmol), magnesium chloride (140g, 1470mmol) and triethylamine (247.9g, 2450mmol) into the flask, heat to 65°C and stir the reaction After 2 hours, TLC monitoring showed that the reaction of the raw materials was complete; at 0°C, slowly add 2N HCl solution to adjust the pH=3~4, extract with ethyl acetate (600mL×2), then wash the organic phase with water and saturated brine successively, and anhydrous sodium sulfate Dry, filter through silica gel, and concentrate the filtrate to obtain compound VII-I (dark red liquid, 86.0 g, chemical purity: 96.97%).

Comparative Example 1

Synthesis of 2-((1R)-1-cyclopropylethyl)phenyl N-((1R)-1-phenylethyl)carbamate (Compound 5)

The preparation process of Compound V and Compound VI in Comparative Example 1 was consistent with that in Example 5.

Compound VI (4.0g, 24.8mmol, 1.0eq), (R)-(+)-1-phenylethylisocyanate (3.97g, 27.0mmol, 1.05eq), triethylamine (2.6g, 27.0mmol , 1.05eq) and tetrahydrofuran (30mL), heated to 60°C and stirred for 3 hours. TLC monitors that the reaction of the raw materials is complete. The reaction solution is poured into 15 mL of water, extracted with dichloromethane (30 mL × 3), the organic phase is collected, spin-dried, and purified by column chromatography. The eluent is V _n-hexane : V _{ethyl acetate Ester} =10:1, 7.8g of white solid product was obtained.

Take 2.0g of the product and recrystallize it with 20mL of n-hexane or n-heptane, and heat it to reflux. Most of the product is not dissolved and cannot be recrystallized. Instead, use 20mL of n-hexane to make slurry at room temperature, and suction filter to obtain 1.6g of white solid (yield: 80 %), test results: the ratio of compound 5 and its diastereoisomer 5-1 is 51.77%: 48.23%, (compound 5: ee value 3.54%), basically no resolution effect;

Get 2.0g product and recrystallize with 20mL isopropanol, obtain white solid 1.2g (yield: 60%), detection result: Compound 5 and its diastereoisomer 5-1 are listed as 51.41%: 48.59%, (Compound 5: ee value 2.82%), basically no resolution effect;

Get 2.0g product and recrystallize with 8mL toluene, obtain white solid 1.0g (yield: 50%), detection result: compound 5 and its diastereoisomer 5-1 ratio are listed as 52.45%: 47.55%, (compound 5: ee value 4.90%), basically no splitting effect. Subsequent failure to find a good solvent for beating or recrystallization resolution, this compound is difficult to resolve.

¹ HNMR (400MHz, CD ₃ Cl) 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).

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims (15)

1. A compound represented by formula (I) or formula (II), or a stereoisomer thereof:
   

   in:

   R is a hydroxyl protecting group, and the hydroxyl protecting group is selected from amino acid protecting groups;

   The amino acid protecting group is selected from Boc-amino acid protecting group, Cbz-amino acid protecting group, Fmoc-amino acid protecting group;

   Or the R is the following structural formula:
   

   n is selected from 1,2,3.
2. The compound according to claim 1, characterized in that the compound has the structure shown in the following formula (III):
   
   

   Wherein n is selected from 1, 2, 3.
3. The compound according to claim 1, characterized in that, the compound has the structure shown in the following formula (IV) or formula (IV-I) or its isomer formula:
   
4. The compound according to claim 2, characterized in that the compound has the structure shown in the following formula (III-I):
   
5. The compound according to claim 4, wherein the X-ray powder diffraction pattern of the crystal form of the compound formula (III-I) has a value of 7.280, 10.847, 10.954, 13.641, 14.304, 14.419, 15.161 at ^2θ values , 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, 2 8.079, 29.142, 29.498, 30.577, 30.819, 31.761, 34.979, 37.741 , 42.400, 44.257 have diffraction peaks.
6. The compound according to claim 5, wherein the X-ray powder diffraction pattern of the crystal form of the compound formula (III-I) also has ^2θ values: 10.616, 15.583, 27.321, 29.902, 32.942, 33.503, One or more of 36.239, 39.601, and 48.303 have diffraction peaks.
7. The compound according to claim 3, wherein the X-ray powder diffraction pattern of the structure shown in the compound formula (IV) or its isomer formula is 9.316, 12.121, 13.097, 13.599 at ^2θ values. , 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, 34.839 have diffraction peaks.
8. The compound according to claim 7, characterized in that, the X-ray powder diffraction pattern of the structure shown in the compound formula (IV) or its isomer formula is also 2 ^theta values: 15.780, 19.499, 21.899, One or more of 27.542, 28.122, 35.338, and 36.001 have diffraction peaks.
9. A method for preparing a compound represented by formula (III), characterized in that it is prepared by esterification of a compound of formula (V) with a cyclic acid anhydride;
   
10. The preparation method of the compound according to claim 9, is characterized in that,

    Use solvent in the described reaction, described solvent is selected from any one in dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, acetone Or a mixture of any ratio;

    Described reaction adds catalyzer, and described catalyzer is selected from DMAP;

    The reaction adds an alkaline reagent, and the alkaline reagent is selected from triethylamine, N,N-diisopropylethylamine, pyridine, carbonic acid Any one or a mixture of any of potassium, sodium carbonate, lithium carbonate, potassium fluoride, potassium phosphate, potassium bicarbonate, and sodium bicarbonate.
11. A method for preparing a compound represented by formula (IV), characterized in that it is prepared by performing a condensation reaction between a compound of formula (VI) and Boc-D-alanine to form an ester;
    
12. The preparation method of the compound according to claim 11, is characterized in that,

    Use solvent in the described reaction, described solvent is selected from any one in dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, toluene, acetone Or a mixture of any ratio;

    A condensing agent is added in the reaction, and the condensing agent is selected from N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride , 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Any of urea hexafluorophosphate, 1-hydroxybenzotriazole, preferably N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl Any one of carbodiimide hydrochloride and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide;

    An alkaline reagent is added to the reaction, and the alkaline reagent is selected from any one of bases selected from DMAP, triethylamine, N,N-diisopropylethylamine, and pyridine.
13. The preparation method of the compound according to claim 11, is characterized in that, the preparation method of the compound shown in formula (VI) comprises the following steps:

    Step a: hydrolyzing the compound of formula (III-1) under basic conditions to generate the compound of formula (V);

    Step b: reducing the compound of formula (V) to generate the compound of formula (VI);
    
14. A preparation method for the compound shown in formula (VII), characterized in that it is prepared by the compound of formula (IV-I), comprising the following steps:

    Step c: hydrolyzing the compound of formula (IV-I) under basic conditions to generate the compound of formula (VI);

    Step d: acylation of the compound of formula (VI) to generate the compound of formula (VII);
    
15. A compound represented by formula (VII), or its isomer formula (VII-I) or formula (VII-II):