Pyrone compound as well as preparation method and application thereof

Abstract

The invention provides a pyrone compound and a preparation method and application thereof, and belongs to the field of pharmaceutical chemicals, the preparation method comprises the following steps: carrying out aldoxime hydrolysis or oxidation on a product generated by oximation of 3-(benzyloxy)-2-methyl-4H-pyran-4-ketone and nitrite ester to form aldehyde, oxidizing the aldehyde into acid, and carrying out acid hydrolysis or oxidation on the acid to obtain a pyrone compound; the important intermediate 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid in the field of pharmaceutical and chemical engineering is obtained. The product obtained by the method disclosed by the invention is high in purity and high in yield; the method disclosed by the invention has the characteristics of low total cost, simplicity in operation and stable process.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemicals, and in particular to a pyrone compound and a preparation method and application thereof. Background Art

[0002] Xofluza (Baloxavir Marvoxil, formerly known as S-033188) is an innovative Cap-dependent nuclease inhibitor and one of the few new drugs in the world that can inhibit the proliferation of influenza viruses. It was developed by Shionogi Pharmaceutical Co., Ltd. of Japan and received accelerated approval. It was launched in Japan in February 2018. In October 2018, Swiss pharmaceutical giant Roche announced that the U.S. Food and Drug Administration (FDA) had approved Xofluza, a single-dose, oral drug for the treatment of acute, uncomplicated influenza in patients aged 12 years and above; Roche is currently confirming Xofluza's potential indications for the treatment and prevention of acute simple influenza in children aged 1-12 years with the FDA. This approval makes Xofluza the first influenza drug with a new mechanism of action in nearly 20 years. In clinical trials, a single treatment with Xofluza significantly reduced the duration of influenza symptoms and significantly reduced viral excretion in just one day. Xofluza was approved for marketing in the European Union and China in 2021; currently, Xofluza has been approved for the treatment of influenza A and B in more than 70 countries and regions.

[0003] The structural formula of Baloxavir Marvoxil is shown below:

[0004]

[0005] 3-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid is an important intermediate for the synthesis of Baloxavir Marvoxil; the structural formula of 3-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid is as follows:

[0006]

[0007] Among them, WO2006 / 116764 discloses a method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid; the synthesis route thereof is as follows:

[0008]

[0009] This route uses 3-6 times the equivalent of highly toxic selenium dioxide as an oxidant. Selenium dioxide is controlled by the public security department in accordance with the "Regulations on the Safety Management of Hazardous Chemicals". Its procurement, storage and use are very inconvenient, and its use poses a major threat to the health of researchers and the environment. In addition, the reaction needs to be carried out at a high temperature of about 160°C for 14-16 hours, which is energy-intensive and highly polluting, and is not suitable for large-scale industrial production.

[0010] Among them, WO2010 / 11816 discloses a method for synthesizing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid; the synthesis route thereof is as follows:

[0011]

[0012] This synthetic route uses 3-hydroxy-2-methyl-4H-pyran-4-one as a raw material, and undergoes benzyl protection, condensation, sulfonylation, elimination, double bond oxidation, and aldehyde oxidation to obtain a 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid compound. This route has a long number of steps and is cumbersome to operate; the third step uses highly toxic methylsulfonyl chloride, which is highly irritating to the mucous membranes, upper respiratory tract, eyes, and skin, and can cause burns. After inhalation, it can cause spasm, inflammation, and edema of the larynx and bronchi, chemical pneumonia, or pulmonary edema, and can cause death. After contact, a burning sensation, coughing, wheezing, laryngitis, shortness of breath, headache, nausea, and vomiting occur, and the environment is seriously polluted; the fifth step uses an expensive ruthenium catalyst and sodium periodate in combination for oxidation, which is costly.

[0013] In summary, in the prior art, there are few methods for preparing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid, and there are common technical problems such as the use of highly toxic reagents, complicated steps, high costs, environmental pollution, etc. It is urgent to develop a new process route with cheap raw materials, short steps, simple operation, high yield, and less waste. Summary of the invention

[0014] The purpose of the present invention is to solve the problems existing in the prior art, provide a compound represented by formula (III) and a preparation method of the compound represented by formula (III), and provide a preparation method of a compound represented by formula (V) which is an important intermediate in the field of pharmaceutical chemical industry; the preparation method disclosed by the present invention has short steps, high yield, less three wastes, and can obtain high-purity products without column purification.

[0015] Specifically, in one aspect, the present invention provides a compound having a structure as shown in formula (III),

[0016]

[0017] in,

[0018] R 1For hydrogen, C 1-6 Alkyl, phenyl, phenyl-CH2-, C 1-6 Alkyl-C(=O)-, phenyl-C(=O)- or C 3-8 Cycloalkyl; wherein the C 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 halogens; the phenyl group is optionally substituted with 1, 2, 3, 4 or 5 halogens selected from halogen, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups;

[0019] R 2 and R 3 are each independently hydrogen.

[0020] R 1 For hydrogen, C 1-4 Alkyl, phenyl, phenyl-CH2-, C 1-4 Alkyl-C(=O)-, phenyl-C(=O)- or C 3-6 Cycloalkyl; wherein the C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 halogens; the phenyl group is optionally substituted with 1, 2, 3, 4 or 5 halogens selected from halogen, hydroxyl, cyano, nitro, carboxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl or C 1-4 Substitution of alkoxy groups;

[0021] R 2 and R 3 are each independently hydrogen.

[0022] Specifically, R 1 It is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH2CH(CH3)CH3, phenyl, phenyl-CH2-, CH3-C(=O)-, CH3CH2-C(=O)-, phenyl-C(=O)-, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0023] Preferably, R 1 It is phenyl-CH2-.

[0024] Preferably, the compound represented by formula (III) is

[0025] In another aspect, the present invention provides a method for preparing a compound as represented by formula (III), the method comprising:

[0026]

[0027] The compound represented by formula (I) and the compound represented by formula (II) are reacted at low temperature in a solvent under the action of an alkaline reagent to obtain a compound represented by formula (III);

[0028] Among them, R 4 C 1-6 alkyl;

[0029] R 1 , R 2 and R 3 It has the definition as described above in the present invention.

[0030] Specifically, R 4 is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2CH2CH2CH2CH3 or -CH2CH2CH(CH3)CH3.

[0031] Preferably, R 4 is -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2CH2CH2CH2CH3 or -CH2CH2CH(CH3)CH3.

[0032] Preferably, the compound represented by formula (I) is

[0033] Preferably, the compound represented by formula (II) is

[0034] Specifically, the alkaline reagent in the reaction of the compound represented by formula (I) with the compound represented by formula (II) is selected from KHMDS (potassium bis(trimethylsilyl)amide), NaHMDS (sodium bis(trimethylsilyl)amide) or LiHMDS (lithium bis(trimethylsilyl)amide).

[0035] Specifically, the solvent in the reaction between the compound represented by formula (I) and the compound represented by formula (II) is selected from aprotic solvents.

[0036] Specifically, the aprotic solvent is selected from THF (tetrahydrofuran), toluene or DCM (dichloromethane).

[0037] Specifically, the reaction of the compound represented by formula (I) and the compound represented by formula (II) is carried out under low temperature conditions, wherein the low temperature is -100 to -50°C; preferably -80 to -60°C.

[0038] Specifically, in the reaction of the compound represented by formula (I) and the compound represented by formula (II), the molar ratio of the compound represented by formula (I) to the compound represented by formula (II) is 1.0:2.0-4.0.

[0039] Specifically, in the reaction between the compound represented by formula (I) and the compound represented by formula (II), the molar ratio of the compound represented by formula (I) to the alkaline reagent is 1.0:2.0-4.0.

[0040] The compound represented by formula (III) of the present invention is an intermediate of the compound represented by formula (V), an important intermediate in the field of pharmaceutical chemical industry. The compound represented by formula (V) can be obtained by reacting the compound represented by formula (III) in two steps.

[0041] Specifically, in another aspect, the present invention provides a method for preparing a compound represented by formula (V), wherein the preparation method uses a compound represented by formula (III) as a raw material;

[0042]

[0043] The first step: the compound of formula (III) undergoes a hydrolysis reaction or an oxidation reaction under the action of an oxidant to obtain a compound of formula (IV);

[0044] Step 2: The compound of formula (IV) is oxidized under the action of an oxidant to obtain a compound of formula (V);

[0045] Among them, R 1 , R 2 and R 3 It has the definition as described above in the present invention.

[0046] Specifically, in the first step reaction, the hydrolysis reaction is carried out in an acidic environment, and the acidic environment is preferably hydrochloric acid or sulfuric acid.

[0047] Specifically, the oxidant in the first step reaction is selected from Dess-Martin periodinane.

[0048] Specifically, the oxidant in the second step reaction is selected from sodium chlorite.

[0049] Specifically, the molar ratio of the compound of formula (III) to the Dess-Martin periodinane is 1.0:1.0-4.0.

[0050] Specifically, the molar ratio of the compound of formula (IV) to sodium chlorite is 1.0:1.0-4.0;

[0051] Specifically, in the second step reaction, TEMPO is further included; the amount of TEMPO is a catalytic amount;

[0052] Specifically, the solvent for the first step reaction is selected from DCM (dichloromethane).

[0053] Specifically, the solvent for the second step reaction is selected from a mixture of THF and water; wherein the volume ratio of THF to water is 1:5.

[0054] Specifically, the first step reaction is carried out at room temperature.

[0055] Preferably, the room temperature is 10-35°C.

[0056] Specifically, the second step reaction is carried out at 0°C.

[0057] Preferably, the compound of formula (IV) is

[0058] Preferably, the compound of formula (V) is

[0059] Specifically, the present invention provides a method for preparing 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid, and the synthetic route of the method is as follows:

[0060] The route uses 3-(benzyloxy)-2-methyl-4H-pyran-4-one as a starting material, and obtains the target product 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid after oximation reaction, hydrolysis of aldoxime to aldehyde or oxidation to aldehyde, and oxidation of aldehyde to acid. After comparing the mass spectrum of the target product obtained by the route with the mass spectrum of the standard, it is confirmed that the target product is 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. The route has short steps, a single reaction, avoids the use of highly toxic reagents and polluting reagents, uses cheap and easily available reagents to save costs, avoids high-temperature reactions, and can obtain a product with higher purity by preliminary purification of the crude product, avoiding column purification, which is conducive to industrial production.

[0061] Definitions and general terms

[0062] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0063] Unless otherwise indicated, the following definitions used in the present invention shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0064] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at each position in the same or different manner.

[0065] In addition, it should be noted that, unless explicitly stated otherwise, the description methods used in the present invention, "each... is independently" and "... are each independently" and "... are independently" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0066] In various parts of this specification, substituents of compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly noted that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C1-C6 alkyl" or "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl as disclosed independently.

[0067] The term "alkyl" or "alkyl group" used in the present invention refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms; wherein the alkyl group is optionally substituted with one or more substituents described in the present invention. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in one embodiment, the alkyl group contains 1-8 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1-4 carbon atoms; in another embodiment, the alkyl group contains 1-3 carbon atoms.

[0068] Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-butyl (n-Bu, -CH2CH2CH2CH3), Pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), and the like.

[0069] The term "haloalkyl" means an alkyl group substituted by one or more halogen atoms, such examples include, but are not limited to, -CF3, -CHF2, -CH2Cl, -CH2CF3, -CH2CHF2, -CH2CH2CF3 and the like.

[0070] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), and the like.

[0071] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. In one embodiment, the cycloalkyl contains 3-10 carbon atoms; in another embodiment, the cycloalkyl contains 3-8 carbon atoms; in yet another embodiment, the cycloalkyl contains 3-6 carbon atoms. The cycloalkyl group is optionally substituted with one or more substituents described herein. Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[0072] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0073] KHMDS refers to potassium bis(trimethylsilyl)amide; NaHMDS refers to sodium bis(trimethylsilyl)amide; LiHMDS refers to lithium bis(trimethylsilyl)amide;

[0074] THF refers to tetrahydrofuran; DCM refers to dichloromethane; EA refers to ethyl acetate;

[0075] TEMPO means: 2,2,6,6-tetramethylpiperidinyloxide. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 This is the hydrogen spectrum of 3-(benzyloxy)-4-keto-4H-pyran-2-carbaldehyde oxime obtained in Example 1.

[0077] Figure 2 This is the hydrogen spectrum of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid obtained in Example 3. DETAILED DESCRIPTION

[0078] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used that do not specify the manufacturer are all conventional products that can be obtained commercially.

[0079] To describe the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0080] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0081] The test conditions of the nuclear magnetic resonance hydrogen spectrum of the present invention are: at room temperature, a Bruker 400MHz or 600MHz nuclear magnetic spectrometer is used, with CDC13, d 6 -DMSO, CD3OD or d 6 - Acetone is the solvent (reported in ppm), TMS (0 ppm) or chloroform (7.26 ppm) is used as the reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0082] The mass spectrometry test conditions used in the present invention are: the conditions for low-resolution mass spectrometry (MS) data determination are: Agilent 6120 Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1x 30mm, 3.5μm, 6min, flow rate of 0.6mL / min, mobile phase: 5%-95% (CH3CN containing 0.1% formic acid) in (H2O containing 0.1% formic acid)), UV detection at 210 / 254nm, using electrospray ionization mode (ESI).

[0083] Example

[0084] Example 1: Synthesis of 3-(Benzyloxy)-4-keto-4H-pyran-2-carbaldehyde oxime

[0085]

[0086] KHMDS (1M THF solution, 40 mL) (2-4 equivalents) was added to the flask. Under nitrogen protection, the temperature was lowered to -70°C with stirring. A solution of 3-(benzyloxy)-2-methyl-4H-pyran-4-one (4.3 g, 19.89 mmol) (1 equivalent) in THF (20 mL) was added dropwise. After the addition was complete, the mixture was stirred at -70°C for 30 minutes. Isoamyl nitrite (7.0 g, 59.75 mmol) (2-4 equivalents) was then added dropwise. The mixture was stirred at -70°C for 3 hours. After the reaction was completed, the reaction solution was heated to 0°C, saturated aqueous ammonium chloride solution (100 mL) was added dropwise to quench, and dichloromethane (100 mL×3) was added to extract three times. The mixture was separated and the organic phase was collected. The organic phase was concentrated under reduced pressure at 35°C to obtain 4.9 g of a brown oil with a yield of 89%.

[0087] LC-MS: m / z(ESI):246(M+H)+.

[0088] 1 H NMR (400MHz, CDCl3) δ (ppm): 9.65 (s, 1H), 8.10 (s, 1H), 7.64 (s, 1H), 7.38 (d, J = 51.5Hz, 5H), 6.52 (s, 1H), 5.32 (s, 2H).

[0089] Example 2: Synthesis of 3-(Benzyloxy)-4-keto-4H-pyran-2-carbaldehyde

[0090]

[0091] 3-(Benzyloxy)-4-one-4H-pyran-2-carbaldehyde oxime (4.9 g, 19.98 mmol), 50 mL of DCM and Dess-Martin periodinane (9.3 g, 21.93 mmol) were added to the flask and reacted at room temperature (25°C) for 4 hours. After the reaction, 5% aqueous sodium hydroxide solution (40 mL) was added to quench the reaction, and then washed once with 40 mL of water. The DCM phase was concentrated under reduced pressure at 35°C to obtain 4.4 g of a brown oil with a yield of 95%.

[0092] LC-MS: m / z(ESI):231(M+H)+.

[0093] Example 3: Synthesis of 3-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid

[0094]

[0095] 3-(Benzyloxy)-4-one-4H-pyran-2-carbaldehyde (4.6 g, 19.98 mmol) was added to the flask, followed by 10 mL of THF and 50 mL of water, TEMPO (0.31 g, 1.98 mmol) and sodium chlorite (2.2 g, 24.32 mmol). The mixture was stirred at 0 °C for 10 h. After the reaction was completed, sodium sulfite (5.04 g) was added to quench the reaction. After the starch potassium iodide paper detected that the reaction did not change color, 60 mL of EA was added for extraction. 4 mol / L hydrochloric acid (20 mL) was added to the aqueous layer. The temperature was lowered to 5 °C for crystallization and filtration. The mixture was dried in vacuo at 50 °C to obtain 4.6 g of an off-white solid with a yield of 94%.

[0096] LC-MS: m / z(ESI):247(M+H)+.

[0097] 1 H NMR (400MHz, d 6 -DMSO)δ(ppm):8.22(d,J=5.6Hz,1H),7.45(d,J=6.7Hz,2H),7.41–7.31(m,3H),6.56(d,J=5.6Hz,1H),5.13(s,2H).

[0098] In the description of this specification, the description with reference to the terms "one embodiment", "an embodiment", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, unless they are contradictory.

[0099] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound having a structure as shown in formula (III), in, R 1 For hydrogen, C 1-6 Alkyl, phenyl, phenyl-CH2-, C 1-6 Alkyl-C(=O)-, phenyl-C(=O)- or C 3-8 Cycloalkyl; wherein the C 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 halogens; the phenyl group is optionally substituted with 1, 2, 3, 4 or 5 halogens selected from halogen, hydroxyl, cyano, nitro, carboxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl or C 1-6 Substitution of alkoxy groups; R 2 and R 3 are each independently hydrogen.

2. The compound according to claim 1, wherein R 1 is hydrogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH2CH(CH3)CH3, phenyl, phenyl-CH2-, CH3-C(=O)-, CH3CH2-C(=O)-, phenyl-C(=O)-, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R 2 and R 3 are each independently hydrogen.

3. A method for preparing a compound of formula (III) as claimed in claim 1 or 2, characterized in that: The method comprises: The compound represented by formula (I) and the compound represented by formula (II) are reacted at low temperature in a solvent under the action of an alkaline reagent to obtain a compound represented by formula (III); Among them, R 1 , R 2 and R 3 Having R as in claim 1 or 2 1 , R 2 and R 3 Same meaning; R 4 C 1-6 alkyl; Best choice, R 4 -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CH(CH3)CH3, -C(CH3)3, -CH2CH2CH2CH2CH3 or -CH2CH2CH(CH3)CH3.

4. The preparation method according to claim 3, characterized in that: The alkaline agent is selected from KHMDS, NaHMDS or LiHMDS.

5. The preparation method according to claim 3, characterized in that: The solvent is selected from an aprotic solvent; preferably the aprotic solvent is selected from THF, toluene or DCM.

6. The preparation method according to claim 3, characterized in that: The low temperature is -100 to -50°C, preferably -80 to -60°C.

7. The preparation method according to claim 3, characterized in that: The molar ratio of the compound represented by formula (I) to the compound represented by formula (II) is 1.0:2.0-4.

0.

8. The preparation method according to claim 3, characterized in that: The molar ratio of the compound represented by formula (I) to the alkaline agent is 1.0:2.0-4.

0.

9. A method for preparing a compound represented by formula (V), characterized in that: The first step: the compound of formula (III) undergoes a hydrolysis reaction or an oxidation reaction under the action of an oxidant to obtain a compound of formula (IV); Step 2: The compound of formula (IV) is oxidized under the action of an oxidant to obtain a compound of formula (V); Among them, R 1 , R 2 and R 3 Having R as in claim 1 or 2 1 , R 2 and R 3 Same meaning.

10. The preparation method according to claim 9, characterized in that: The oxidant in the first step reaction is selected from Dess-Martin oxidant; the oxidant in the second step reaction is selected from sodium chlorite; in, The molar ratio of the compound of formula (III) to the Dess-Martin periodinane is 1.0:1.0-4.0; The molar ratio of the compound of formula (IV) to sodium chlorite is 1.0:1.0-4.0; The solvent of the first step reaction is selected from DCM; The solvent for the second step reaction is selected from a mixture of THF and water; wherein the volume ratio of THF to water is 1:5; The first step reaction is carried out at room temperature; the second step reaction is carried out at 0°C.

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