Preparation method of (S)-3-hydroxy-4-methoxy-5-methyl phenylalaninol

Abstract

The invention relates to a preparation method of (S)-3-hydroxy-4-methoxy-5-methyl phenylalaninol and a preparation method of the (S)-3-hydroxy-4-methoxy-5-methyl phenylalaninol. Specifically, 5-bromo-2-methoxy-3-methylphenol is taken as a starting raw material, (S)-3-hydroxy-4-methoxy-5-methyl phenylalaninol is prepared through a five-step reaction, a chiral center is introduced through a key step a1, a chiral product is high in yield and good in purity, reaction conditions are mild, a route is short, and industrial production is easy.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and in particular relates to a method for preparing (S)-3-hydroxy-4-methoxy-5-methylphenylalaninol. Background Art

[0002] Trabectedin, isolated from the marine organism Ascidian, is a complex tetrahydroisoquinoline alkaloid with highly potent antitumor activity. In 2007, trabectedin received EU approval for the treatment of soft tissue sarcomas. In 2015, trabectedin received FDA approval for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have received anthracycline therapy. Lurbectedin, an ascidian derivative independently developed by the Spanish company PharmaMar, was approved by the FDA in 2020 for the treatment of small cell lung cancer. (S)-3-Hydroxy-4-methoxy-5-methylphenylalaninol is an important intermediate in the synthesis of the antitumor drugs trabectedin and rubectedin.

[0003] The synthesis of (S)-3-hydroxy-4-methoxy-5-methylphenylalaninol has been reported in numerous publications. The paper [J.Org.Chem. 2005, 70, 4397] reports a nine-step synthesis of (S)-3-hydroxy-4-methoxy-5-methylphenylalaninol from 3-methylcatechol. This method utilizes asymmetric alkylation to create the key chiral center, but the chiral purity of the catalytic reaction does not exceed 99%, requiring additional purification steps to achieve high chiral purity, resulting in low efficiency. Furthermore, two steps in this route utilize hazardous reducing agents such as sodium borohydride and lithium borohydride, respectively, placing high demands on production equipment and conditions.

[0004] The paper [Tetrahedron: Asymmetry, 2010, 21, 39] reports the synthesis of (S)-3-hydroxy-4-methoxy-5-methylphenylalaninol from natural L-tyrosine via an eight-step reaction. This route uses a chiral center introduced from a natural product, resulting in mostly oily intermediates that are difficult to separate. Each step requires column purification, making industrial production difficult. Furthermore, the ester group must be reduced using hazardous sodium borohydride.

[0005] Therefore, there is an urgent need in the art to develop a method for preparing (S)-3-hydroxy-4-methoxy-5-methylphenylalaninol with a short route, mild reaction conditions, high product yield and good purity, and more suitable for industrial production. Summary of the Invention

[0006] The present invention aims to provide a method for preparing (S)-3-hydroxy-4-methoxy-5-methylphenylalaninol, which has a short route, low safety risk, mild reaction conditions, high product yield and good purity, and is easy for industrial production.

[0007] The first aspect of the present invention provides a method for preparing a compound of formula I, comprising the following steps:

[0008] (a1) In an inert solvent, in the presence of a base, the compound of formula V undergoes an epoxy ring-opening reaction with compound Y to obtain a compound of formula IV having a chiral structure;

[0009] (b) the compound of formula IV is prepared through a multi-step reaction to obtain the compound of formula I;

[0010]

[0011] in,

[0012] Compound Y is selected from the group consisting of (R)-benzyloxymethyloxirane, (R)-p-methoxybenzyloxymethyloxirane, and (R)-tert-butyloxymethyloxirane.

[0013] X is selected from the group consisting of benzyl, p-methoxybenzyl, and tert-butyl.

[0014] In another preferred embodiment, compound Y is (R)-benzyloxymethyloxirane.

[0015] In another preferred embodiment, X is benzyl.

[0016] In another preferred embodiment, the important intermediate compound of formula IV has the following structure:

[0017]

[0018] Wherein, X is defined as in claim 1.

[0019] In another preferred embodiment, the compound of formula IV is

[0020] In another preferred embodiment, the preparation method of the compound of formula V is as follows:

[0021] (a0) In an inert solvent, in the presence of a base, the compound of formula VI undergoes a substitution reaction with a benzyl halide to prepare a compound of formula V.

[0022]

[0023] In another preferred embodiment, the benzyl halide is selected from the group consisting of benzyl bromide, benzyl chloride, or a combination thereof; preferably benzyl bromide.

[0024] In another preferred embodiment, the specific steps of preparing the compound of formula I from the compound of formula IV are as follows:

[0025] (b1) in an inert solvent, in the presence of a phosphine reagent and phthalimide, the compound of formula IV is subjected to a substitution reaction with an azodicarbonyl reagent to prepare a compound of formula III;

[0026] (b2) removing the protecting group of the compound of formula III to obtain the compound of formula II;

[0027] (b3) In an inert solvent, in the presence of a catalyst, the compound of formula II is subjected to a hydrogenation reaction to prepare a compound of formula I.

[0028]

[0029] In another preferred embodiment, the amount of the phosphine reagent used is 1-5 times, preferably 1.5 times, of the compound represented by formula IV.

[0030] In another preferred embodiment, the azodicarbonyl reagent is selected from the group consisting of DEAD, DIAD, ADDP, DBAD, TMAD, or a combination thereof; preferably DIAD.

[0031] In another preferred embodiment, the inert solvent in step a1 is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ethylene glycol dimethyl ether, or a combination thereof; preferably tetrahydrofuran.

[0032] In another preferred embodiment, the base in step a1 is selected from the group consisting of n-butyllithium, isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride, 2,2,6,6-tetramethylpiperidiniummagnesium chloride, or a combination thereof; preferably isopropylmagnesium chloride lithium chloride.

[0033] In another preferred embodiment, the amount of compound Y is 0.5-5.0 times the molar mass of the compound of formula V, preferably 1.0 times that of compound V.

[0034] In another preferred embodiment, the amount of the inert solvent in step a1 is 1-20 times, preferably 10 times, of the compound of formula V.

[0035] In another preferred embodiment, the amount of the base used in step a1 is 1-5 times the molar mass of the compound of formula V, preferably 1.2 times.

[0036] In another preferred embodiment, the reaction temperature of step a1 is -80-30°C, preferably 0-10°C.

[0037] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0038] After extensive and in-depth research, the inventors unexpectedly discovered that the epoxy ring-opening reaction of compound V with compound Y can stably produce a chiral compound. This allows the preparation of compound I with high chiral purity after a series of reactions. The method of the present invention features a short synthesis process, high product yield, mild reaction conditions, simple purification procedures, and ease of industrial production. Based on this, the inventors completed the present invention.

[0039] the term

[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0041] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."

[0042] As used herein, the terms "the method of the present invention", "the preparation method of the present invention" and "the industrial preparation method of the present invention" can be used interchangeably to refer to the method described in the first aspect of the present invention.

[0043] The compound of formula I described in the present invention is (S)-3-hydroxy-4-methoxy-5-methylphenylalaninol, and its structural formula is as follows:

[0044]

[0045] The -Bn group of the present invention is a benzyl group, and the structure is

[0046] The "inert solvent" described in the present invention refers to a solvent that does not react with the compounds in the reaction system.

[0047] Preparation method

[0048] Typically, the preparation method of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.

[0049] The present invention provides a method for preparing (S)-3-hydroxy-4-methoxy-5-methylphenylalaninol, comprising the following five steps:

[0050]

[0051] Specifically, the preparation method of the present invention comprises the following steps:

[0052] (a0) Add the compound of formula VI, a base, and a benzyl halide to an inert solvent and react at a certain temperature. After the reaction is complete, add acid water to quench the reaction, extract with an organic solvent, wash with water, and concentrate to dryness to obtain the compound of formula V.

[0053]

[0054] The inert solvent is selected from the group consisting of dichloromethane, acetonitrile, toluene, DMF, DMAc, DMSO, NMP, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ethylene glycol dimethyl ether and other ether solvents, methanol, ethanol, isopropanol and other alcohol solvents, or a combination thereof.

[0055] Preferably, the inert solvent is dichloromethane.

[0056] The benzyl halide is selected from the group consisting of benzyl bromide, benzyl chloride, or a combination thereof.

[0057] Preferably, the benzyl halide is benzyl bromide.

[0058] The base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium phosphate, cesium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, pyridine, tri-n-propylamine, N,N-dimethylaniline, 2-methylpyridine, 2,6-lutidine, or a combination thereof.

[0059] Preferably, the base is triethylamine.

[0060] The amount of the inert solvent is 1-20 times that of the compound of formula VI, preferably 10 times.

[0061] The amount of the benzyl halide used is 0.5-5.0 times the molar mass of the compound of formula VI, preferably 1.1 times the molar mass of the compound of formula VI.

[0062] The amount of the base used is 1-5 times the molar mass of the compound of formula VI, preferably 1.5 times.

[0063] The reaction temperature is preferably 0-80°C, more preferably 0-10°C.

[0064] (a1) Add the compound represented by formula V to an inert solvent, add a base dropwise at a certain temperature, and then add compound Y dropwise. After the reaction is complete, quench with water, extract with an organic solvent, wash with water, and concentrate to dryness to obtain the compound represented by formula IV.

[0065]

[0066] wherein X is as defined above.

[0067] Compound Y is selected from the group consisting of (R)-benzyloxymethyloxirane, (R)-p-methoxybenzyloxymethyloxirane, and (R)-tert-butyloxymethyloxirane.

[0068] Preferably, compound Y is (R)-benzyloxymethyloxirane.

[0069] The inert solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ethylene glycol dimethyl ether, or a combination thereof; preferably tetrahydrofuran.

[0070] The amount of the inert solvent used is 1-20 times that of the compound of formula V, preferably 10 times.

[0071] The amount of compound Y used is 0.5-5.0 times the molar mass of the compound of formula V, preferably 1.0 times the molar mass of the compound of formula V.

[0072] The base is selected from the group consisting of n-butyl lithium, isopropyl magnesium chloride, isopropyl magnesium chloride lithium chloride, 2,2,6,6-tetramethylpiperidinium magnesium chloride, or a combination thereof; preferably isopropyl magnesium chloride lithium chloride.

[0073] The amount of the base used is 1-5 times the molar mass of the compound of formula V, preferably 1.2 times.

[0074] The reaction temperature is -80-30°C, preferably 0-10°C.

[0075] (b1) Compound IV, phthalimide, and a phosphine reagent are dissolved in a certain organic solvent, and an azodicarbonyl reagent is added dropwise at a certain temperature. After the reaction is completed, water is added to quench the reaction, and the mixture is washed with water, concentrated to dryness, and then recrystallized to obtain a compound represented by Formula III.

[0076]

[0077] Wherein, X is defined as above.

[0078] The inert solvent is selected from the group consisting of dichloromethane, acetonitrile, toluene, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ethylene glycol dimethyl ether, or a combination thereof; preferably dichloromethane.

[0079] The amount of the inert solvent used is 1-20 times, preferably 12 times, of the compound of formula IV.

[0080] The amount of phthalimide used is 0.5-5.0 times the molar mass of the compound IV, preferably 1.5 times that of compound IV.

[0081] The phosphine reagent is selected from the group consisting of triphenylphosphine, tri-n-butylphosphine, or a combination thereof; preferably tri-n-butylphosphine.

[0082] The amount of the phosphine reagent used is 1-5 times, preferably 1.5 times, of the compound of formula IV.

[0083] The reaction temperature is 20-80°C, preferably 10-20°C.

[0084] The azodicarbonyl reagent is selected from the group consisting of DEAD, DIAD, ADDP, DBAD, TMAD, or a combination thereof; preferably DIAD.

[0085] The dosage of the azodicarbonyl reagent is 1-5 times, preferably 1.2 times, of the compound represented by formula IV.

[0086] (b2) The compound represented by formula III is dissolved in a certain volume of an inert solvent, a certain amount of hydrazine hydrate is added, and the mixture is reacted at a certain temperature. After the reaction is completed, water is added to quench the reaction, the layers are separated, and the mixture is extracted and concentrated with an organic solvent to obtain the compound represented by formula II.

[0087]

[0088] wherein X is as defined above.

[0089] The inert solvent is selected from the group consisting of C1-C8 alcohol solvents, ether solvents, DMF, DMAc, acetonitrile, or a combination thereof.

[0090] In another preferred embodiment, the alcohol solvent is selected from the group consisting of methanol, ethanol, isopropanol, isobutanol, n-butanol, or a combination thereof; the ether solvent is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, or a combination thereof.

[0091] Preferably, the inert solvent is methanol, ethanol, or a combination thereof.

[0092] The amount of hydrazine hydrate used is 0.5-5.0 times the molar mass of the compound III, preferably 2.0 times that of compound III.

[0093] The amount of the inert solvent used is 1-20 times, preferably 5 times, of the compound of formula III.

[0094] The reaction temperature is 20-80°C, preferably 40-50°C.

[0095] (b3) Compound II is subjected to hydrogenation in an inert solvent in the presence of a catalyst and hydrogen pressure. After the reaction, the catalyst is filtered off and the mixture is concentrated to dryness to obtain Compound I.

[0096]

[0097] wherein X is as defined above.

[0098] The inert solvent is selected from the following group: C1-C8 alcohol solvents, ester solvents, ether solvents, or a combination thereof.

[0099] In another preferred embodiment, the alcohol solvent is selected from the following group: methanol, ethanol, isopropanol, isobutanol, n-butanol, or a combination thereof; the ester solvent is selected from the following group: ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate, or a combination thereof; the ether solvent is selected from the following group: tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, or a combination thereof.

[0100] Preferably, the inert solvent is methanol, ethanol, or a combination thereof.

[0101] The catalyst is selected from the group consisting of palladium-carbon, ruthenium-carbon, rhodium-carbon, platinum-carbon, or a combination thereof;

[0102] Preferably, the catalyst is palladium on carbon.

[0103] The amount of the catalyst used is 1%-50% of the mass of the compound of formula II, preferably 5% of the mass of the compound of formula II.

[0104] The amount of the inert solvent is 1-20 times that of the compound of formula II, preferably 10 times.

[0105] The hydrogen pressure is 0.1-2.0 MPa, preferably 0.5 MPa.

[0106] The temperature of the hydrogen reaction is 20-80°C, preferably 40-50°C.

[0107] The main advantages of the present invention are:

[0108] 1. The present invention provides a method for preparing (S)-3-hydroxy-4-methoxy-5-methylphenylalaninol with short synthesis steps, high synthesis efficiency, high yield and good purity.

[0109] 2. Compound Y in step a1 of the present invention has high chiral purity. A chiral center is introduced by an epoxy ring-opening reaction between compound V and compound Y, and compound IV is prepared in high yield and high purity.

[0110] 3. The method of the present invention does not involve low-temperature reactions and avoids dangerous reactions of reducing agents such as sodium borohydride. The reaction conditions are relatively mild and easy to industrialize.

[0111] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0112] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0113] In the present invention, the structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR measurements are performed using a Bruker AVANCE-400 nuclear magnetic spectrometer. LCMS measurements are performed using a Waters 2695 liquid chromatography-mass spectrometer (MS model: Micromass ZQ).

[0114] HPLC determination was performed using an Agilent 1100 high pressure liquid chromatograph (ZORBAX SP-C18 250×4.6 mm column, Eclipse Plus-C18 250×4.6 mm column).

[0115] Unless otherwise stated, the following examples were carried out under normal pressure.

[0116] Preparation of Compound V

[0117]

[0118] Example 1

[0119] 5-Bromo-2-methoxy-3-methylphenol (Compound VI) (200 g, 0.92 mol), benzyl bromide (173 g, 1.01 mol), triethylamine (140 g, 1.38 mol), and dichloromethane (2000 g) were added to the reaction flask and reacted at 0-10 degrees for 5 hours. After the reaction, dilute hydrochloric acid (500 g) was added to quench the reaction. The mixture was extracted and separated, and concentrated to dryness to obtain Compound V (277 g, 0.90 mol) with a yield of 98%.

[0120] Example 2

[0121] 5-Bromo-2-methoxy-3-methylphenol (Compound III) (200 g, 0.92 mol), benzyl chloride (128 g, 1.01 mol), triethylamine (140 g, 1.38 mol), and dichloromethane (2000 g) were added to the reaction flask and reacted at 0-10 degrees for 5 hours. After the reaction, dilute hydrochloric acid (500 g) was added to quench the reaction. The mixture was extracted and separated, and concentrated to dryness to obtain Compound V (270 g, 0.88 mol) with a yield of 96%.

[0122] 1 H NMR (400MHz, Chloroform-d) δ7.46–7.29(m,5H),6.94(d,J=2.4Hz,1H),6.93(d,J=2.2Hz,1H),5.06(s,2H),3.80(s,3H),2.24(d,J=0.7Hz,3H).

[0123] Preparation of Compound IV

[0124]

[0125] Example 1

[0126] Isopropylmagnesium chloride and lithium chloride (1.3 M solution in tetrahydrofuran) (452 ​​mL, 0.59 mol) was added dropwise to a solution of compound V (150 g, 0.49 mol) in tetrahydrofuran (1500 g) at 0-10 degrees. After half an hour, a solution of (R)-benzyloxymethyloxirane (80 g, 0.49 mol) in tetrahydrofuran (150 g) was added dropwise. The reaction was continued at 0-10 degrees for 10 hours. After the reaction was complete, water (1000 g) was added to quench the reaction. The mixture was extracted twice with ethyl acetate (500 g). The organic phases were combined, washed with water, and concentrated to dryness to give compound IV (173 g, 0.44 mol) with a yield of 90%, a purity of 96.0%, and an ee value of 99.5%.

[0127] Example 2

[0128] Isopropylmagnesium chloride (2M solution in tetrahydrofuran) (295 mL, 0.59 mol) was added dropwise to a solution of compound V (150 g, 0.49 mol) in tetrahydrofuran (1500 g) at 0-10 degrees. Half an hour later, a solution of (R)-benzyloxymethyloxirane (80 g, 0.49 mol) in tetrahydrofuran (150 g) was added dropwise. The reaction was continued at 0-10 degrees for 10 hours. After the reaction was complete, water (1000 g) was added to quench the reaction. The mixture was extracted twice with ethyl acetate (500 g). The organic phases were combined, washed with water, and concentrated to dryness to obtain compound IV (155 g, 0.39 mol) with a yield of 81%.

[0129] 1H NMR(400MHz,Chloroform-d)δ7.47(d,J=7.5Hz,2H),7.44–7.31(m,8H),6.70(d,J=2.1Hz,1H),6.66(d,J=2.0Hz,1H),5.11(s,2H),4.5 7(s,2H),4.08–3.98(m,1H),3.86(s,3H),3.52(dd,J=9.5,3.6Hz,1H),3.41(dd,J=9.5,6.9Hz,1H),2.72(d,J=6.6Hz,2H),2.28(s,3H).

[0130] Preparation of Compound III

[0131]

[0132] Example 1

[0133] Dichloromethane (1200 g), compound IV (100 g, 0.25 mol), phthalimide (56 g, 0.38 mol), and tri-n-butylphosphine (77 g, 0.38 mol) were added to the reaction flask, and the temperature was lowered to 10-20 ° C. DIAD (61 g, 0.30 mol) was added dropwise under temperature control. After reacting for 6 hours, water (1000 g) was added to quench the reaction. The layers were separated, the organic phase was washed with water, concentrated to dryness, and then recrystallized from ethyl acetate and n-heptane to obtain the compound of formula III (122 g, 0.23 mol) with a yield of 91%.

[0134] Example 2

[0135] Dichloromethane (1200 g), compound IV (100 g, 0.25 mol), phthalimide (56 g, 0.38 mol), and tri-n-butylphosphine (77 g, 0.38 mol) were added to the reaction flask, and the temperature was lowered to 10-20 ° C. DIAD (52 g, 0.30 mol) was added dropwise under temperature control. After reacting for 6 hours, water (1000 g) was added to quench the reaction. The layers were separated, the organic phase was washed with water, concentrated to dryness, and then recrystallized from ethyl acetate and n-heptane to obtain the compound of formula III (115 g, 0.22 mol) with a yield of 87%.

[0136] 1H NMR(400MHz,Chloroform-d)δ7.76(dd,J=5.5,3.0Hz,2H),7.67(dd,J=5.5,3.1Hz,2H),7.41–7.27( m,5H),7.22(dq,J=7.0,4.1,3.0Hz,5H),6.62(d,J=2.1Hz,1H),6.59(d,J=2.0Hz,1H),4.98–4.86(m ,2H),4.77(tt,J=9.4,5.9Hz,1H),4.54(d,J=12.1Hz,1H),4.44(d,J=12.1Hz,1H),4.05(t,J=9.5Hz ,1H),3.74(s,3H),3.73–3.70(m,1H),3.16(dd,J=14.0,9.8Hz,1H),3.07–2.97(m,1H),2.14(s,3H).

[0137] Preparation of Compound II

[0138]

[0139] Example 1

[0140] Compound III (151 g, 0.29 mol), ethanol (550 g), and 50% hydrazine hydrate (59 g, 0.59 mol) were added to the reaction flask and heated to 40-50 degrees for 2 hours. After the reaction, water (750 g) was added to quench the reaction, the layers were separated, and the mixture was extracted twice with ethyl acetate (800 g). The mixture was concentrated to give a colorless oily compound II (101 g, 0.26 mol) with a yield of 88%.

[0141] Example 2

[0142] Compound III (151 g, 0.29 mol), methanol (550 g), and 50% hydrazine hydrate (59 g, 0.59 mol) were added to the reaction flask and heated to 40-50 degrees for 2 hours. After the reaction, water (750 g) was added to quench the reaction, the layers were separated, and the mixture was extracted twice with ethyl acetate (800 g). The mixture was concentrated to dryness to obtain compound II (98 g, 0.25 mol) with a yield of 85%.

[0143] 1H NMR(400MHz,Chloroform-d)δ7.50–7.31(m,10H),6.66(dd,J=12.7,2.0Hz,2H),5.12(s,2H),4.55(d,J=1.8Hz,2H),3.86(s,3H),3.50(d d,J=9.0,4.0Hz,1H),3.36(dd,J=9.1,6.9Hz,1H),3.25(s,1H),2.73(dd,J=13.4,5.2Hz,1H),2.50(dd,J=13.4,8.3Hz,1H),2.28(s,3H).

[0144] Preparation of Compound I

[0145]

[0146] Example 1

[0147] Compound II (80 g, 0.20 mol), ethanol (800 g), and palladium carbon (4 g) were added to a hydrogenation kettle, and the mixture was reacted at a hydrogen pressure of 0.5 MPa and 40-50 degrees for 2 hours. After the reaction, the palladium carbon was filtered off and the mixture was concentrated to dryness to obtain compound I (40 g, 0.18 mol) with a yield of 92%, a purity of 97.6%, and an ee value of 99.5%.

[0148] Example 2

[0149] Compound II (80 g, 0.20 mol), ethanol (800 g), and palladium carbon (1 g) were added to a hydrogenation kettle, and the mixture was reacted at a hydrogen pressure of 0.5 MPa and 40-50 degrees for 8 hours. After the reaction, the palladium carbon was filtered off and the mixture was concentrated to dryness to obtain compound I (41 g, 0.19 mol) with a yield of 95%, a purity of 97.0%, and an ee value of 99.5%.

[0150] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A method for preparing a compound of formula I, comprising the following steps: (a1) In an inert solvent, in the presence of a base, the compound of formula V undergoes an epoxy ring-opening reaction with compound Y to obtain a compound of formula IV having a chiral structure; (b) the compound of formula IV is prepared through a multi-step reaction to obtain the compound of formula I; in, Compound Y is selected from the group consisting of (R)-benzyloxymethyl oxirane, (R)-p-methoxybenzyloxymethyl oxirane, and (R)-tert-butyloxymethyl oxirane; preferably, compound Y is (R)-benzyloxymethyl oxirane; X is selected from the group consisting of benzyl, p-methoxybenzyl, and tert-butyl.

2. The preparation method according to claim 1, wherein The important intermediate compound of formula IV has the following structure: Wherein, X is defined as in claim 1.

3. The preparation method according to claim 1, wherein The preparation method of the compound of formula V is as follows: (a0) In an inert solvent, in the presence of a base, the compound of formula VI undergoes a substitution reaction with a benzyl halide to prepare a compound of formula V.

4. The preparation method according to claim 1, wherein The specific steps of preparing the compound of formula I from the compound of formula IV are as follows: (b1) in an inert solvent, in the presence of a phosphine reagent and phthalimide, the compound of formula IV is subjected to a substitution reaction with an azodicarbonyl reagent to prepare a compound of formula III; (b2) removing the protecting group of the compound of formula III to obtain the compound of formula II; (b3) In an inert solvent, in the presence of a catalyst, the compound of formula II is subjected to a hydrogenation reaction to prepare a compound of formula I.

5. The preparation method according to claim 1, wherein The inert solvent in step a1 is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, ethylene glycol dimethyl ether, or a combination thereof; preferably tetrahydrofuran.

6. The preparation method according to claim 1, wherein The base in step a1 is selected from the group consisting of n-butyllithium, isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride, 2,2,6,6-tetramethylpiperidiniummagnesium chloride, or a combination thereof; preferably isopropylmagnesium chloride lithium chloride.

7. The preparation method according to claim 1, wherein The amount of compound Y used is 0.5-5.0 times the molar mass of the compound of formula V, preferably 1.0 times that of compound V.

8. The preparation method according to claim 1, wherein The amount of the inert solvent in step a1 is 1-20 times, preferably 10 times, of the compound of formula V.

9. The preparation method according to claim 1, wherein The amount of the base used in step a1 is 1-5 times the molar mass of the compound of formula V, preferably 1.2 times.

10. The preparation method according to claim 1, wherein The reaction temperature of step a1 is -80-30°C, preferably 0-10°C.

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