Preparation method of upatinib intermediate and intermediate thereof

Abstract

The invention discloses a preparation method of an upatinib intermediate and the upatinib intermediate. The preparation method of the upatinib intermediate and the compound I comprises the following steps: removing ester groups from a compound V to generate the compound I. The compound V is obtained by taking an existing compound II as a raw material, reacting with malonic acid diester and then brominating. The preparation method of the compound I, provided by the invention, has the advantages of low price of used reagents, simple operation of each step of reaction and high yield, and is suitable for industrial large-scale production. In the imgabs0 #, R is an amino protecting group or a trifluoroethylamine carbonyl group, and R1 and R2 are respectively and independently C1-6 alkyl groups.

Description

Technical Field

[0001] The present invention belongs to the field of organic compound synthesis, and specifically relates to a preparation method of an Upadacitinib intermediate and the intermediate thereof. Background Art

[0002] Upadacitinib is a novel JAK1 inhibitor developed by AbbVie. It was first approved for marketing in the United States in August 2019 for the treatment of adult patients with moderate to severe active rheumatoid arthritis (RA) who have an insufficient response or intolerance to methotrexate (MTX). AbbVie has also evaluated the potential of Upadacitinib in the treatment of other immune diseases, including psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), Crohn's disease (CD), atopic dermatitis (AD), ulcerative colitis (UC), giant cell arteritis (GCA), etc.

[0003] The chemical structural formula of Upadacitinib is as follows:

[0004]

[0005] Compound I is a key intermediate in the preparation of Upadacitinib, and its structural formula I is as follows:

[0006]

[0007] In Structural formula 1, R is an amine protecting group such as benzyl, benzyloxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, etc. or trifluoroethylamine carbonyl.

[0008] When R in Structural formula I is benzyloxycarbonyl and trifluoroethylamine carbonyl, the structural formula of Compound I is as follows:

[0009]

[0010] Currently, the main methods for preparing intermediate Compound I (Compound I-a or Compound I-b) are as follows:

[0011] The prior art WO2017066775A1 discloses a method for preparing Compound I-a (Route 1), as shown below:

[0012]

[0013] In Route 1, Compound A reacts with trimethylsulfoxonium chloride to form Compound B, and Compound B then reacts with lithium bromide to form Compound I-a. Since trimethylsulfoxonium chloride is a sulfur-containing compound, it and its reaction by-products have obvious odors, making the operating environment unfriendly. In addition, the yields of the two-step reactions in Route 1 are 82% and 70% respectively, and the reaction yields are relatively low, resulting in high production costs for this route.

[0014] Another method (Route 2) for preparing Compound I-a is disclosed in the prior art CN110872250A, as follows:

[0015]

[0016] In Route 2, in the process of synthesizing Intermediate E from Intermediate C and Intermediate D, it is necessary to react with methyllithium at -60 °C. The reaction conditions are harsh and not suitable for industrial production. Moreover, the reaction reagent methyllithium used is flammable, resulting in greater potential safety hazards for the entire method.

[0017] The prior art WO2020202183A1 discloses a method (Route 3) for preparing Compound I-a similar to CN110872250A. This route uses methylmagnesium chloride to react with Intermediate C or Intermediate D at 0 - 5 °C to synthesize Intermediate E. The methylmagnesium chloride used is air-sensitive and relatively expensive. In addition, when preparing Intermediate Compound I-a from Compound E, dibromo substitution by-products are generated, resulting in a relatively low reaction yield.

[0018] The prior art WO2021005484A1 discloses a method (Route 4) for preparing Intermediate Compound I-b, as follows:

[0019]

[0020] Route 4 uses methylmagnesium bromide which is air-sensitive and relatively expensive. Moreover, in the last step, dibromo by-products are generated during the bromination reaction, resulting in a relatively low reaction yield.

[0021] Therefore, there is an urgent need in the art to develop a new method for preparing the intermediate compound I of Upadacitinib that is environmentally friendly, has lower costs, higher yields, mild and simple operating conditions, and is suitable for large-scale industrial production. Summary of the Invention

[0022] In view of the defects in the prior art methods for preparing the intermediate compound I of Upadacitinib, on the one hand, the present invention provides a method for preparing Compound I, the preparation method comprising the following step: removing the ester group from Compound V to generate Compound I, and the reaction formula is as follows:

[0023] Among them, R is an amino protecting group or trifluoroethylamine carbonyl, and R1 and R2 are each independently C 1～6 alkyl group.

[0024] In another more preferred example, R is benzyloxycarbonyl, Boc, Fmoc or trifluoroethylamine carbonyl.

[0025] In another more preferred example, R is benzyloxycarbonyl or trifluoroethylamine carbonyl

[0026] In another preferred example, R1 and R2 are each independently methyl, ethyl, propyl, isopropyl or tert-butyl.

[0027] In another more preferred example, R1 and R2 are each independently tert-butyl.

[0028] In another preferred example, the de-esterification of compound V is carried out under acidic conditions, and the acid is selected from inorganic acids or organic acids.

[0029] In another preferred example, the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof. In another preferred example, the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, or a combination thereof.

[0030] In another preferred example, the amount of the acid used is such that its molar ratio to compound V is 2 to 10:1.

[0031] In another preferred example, the solvent used for the de-esterification reaction is selected from dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, toluene or a combination thereof.

[0032] In another preferred example, the temperature of the de-esterification reaction is 0 to 50 °C, more preferably 4 to 40 °C, and most preferably 15 to 30 °C.

[0033] In another preferred example, in the preparation method of compound I, the preparation method of compound V includes the following steps:

[0034] Compound IV reacts with a brominating reagent to form compound V, and the reaction formula is as follows:

[0035] Among them, R is an amino protecting group or trifluoroethylamine carbonyl, and R1 and R2 are each independently C 1～6 alkyl group.

[0036] In another preferred example, the brominating reagent is selected from N-bromosuccinimide (NBS), bromine, dibromohydantoin, pyridinium tribromide, or a combination thereof, more preferably NBS.

[0037] In another preferred example, the molar ratio of compound IV to the brominating reagent is 1:1.0 to 3.0, more preferably 1:1.2 to 1.8.

[0038] In another preferred example, the solvent used in the reaction is selected from methanol, ethanol, isopropanol, tert-butanol, or a combination thereof.

[0039] In another preferred example, the reaction temperature is 0 to 50 °C, more preferably 4 to 40 °C, and most preferably 15 to 30 °C.

[0040] In another preferred example, in the preparation method of compound I, the preparation method of compound IV includes the following steps:

[0041] Compound II reacts with compound III to form compound IV, and the reaction formula is as follows:

[0042] Wherein, R is an amino protecting group or trifluoroethylamine carbonyl, and R1 and R2 are each independently a C 1～6 alkyl group.

[0043] In another preferred example, the molar ratio of compound II to compound III is 1:1.0 to 1.5, more preferably 1:1.1 to 1.2.

[0044] In another preferred example, the reaction of compound II with compound III to form compound IV includes the following steps:

[0045] (a) Compound II reacts with a chlorinating reagent to form an acyl chloride compound II-a,

[0046] (b) After stirring and mixing compound III, an organic base, and an inorganic salt in a reaction vessel, a solution containing the acyl chloride compound II-a prepared in step (a) is added dropwise, and the reaction forms compound IV.

[0047] In another preferred example, the chlorinating reagent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, or a combination thereof. In another more preferred example, the chlorinating reagent is selected from thionyl chloride.

[0048] In another preferred example, the organic base is selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N,N-dimethylformamide, pyridine, or a combination thereof. In another more preferred example, the organic base is selected from triethylamine.

[0049] In another more preferred example, the inorganic salt is selected from MgCl2, MgBr2, MgI2, CaCl2, CaBr2, CaI2, or a combination thereof. In another more preferred example, the inorganic salt is selected from MgCl2.

[0050] In another preferred example, in step (a), the molar ratio of compound II to the chlorinating reagent is 1:1 to 3, more preferably 1:1.2 to 1.5.

[0051] In another preferred example, the reaction temperature in step (a) is 4 to 60 °C.

[0052] In another preferred example, the solvent used in the reaction of step (a) is selected from dichloromethane, toluene, xylene, halogenated benzene, or a combination thereof.

[0053] In another preferred example, in step (b), the molar ratio of compound III, the organic base, and the inorganic salt is 1:1.0 to 3.0:1.0 to 1.5:, more preferably 1:1.1 to 2.5:1.0 to 1.2.

[0054] In another preferred example, in step (b), the solvent used in the reaction is selected from toluene, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.

[0055] In another preferred example, in step (b), the reaction temperature is 0 to 50 °C, more preferably 4 to 40 °C, and most preferably 15 to 30 °C.

[0056] In another preferred example, in step (b), the time for stirring and mixing is preferably 1 to 4 hours, more preferably 1 to 2 hours.

[0057] In another preferred example, the solvent of the solution containing compound II-a is the same as the solvent for dissolving compound III in step (b).

[0058] In another preferred example, for the compound I provided by the present invention, wherein R is an amine protecting group or trifluoroethylamine carbonyl, the preparation method comprises the following steps:

[0059] Compound IV reacts with a brominating reagent to form compound V, and the reaction formula is as follows:

[0060] wherein R is an amine protecting group or trifluoroethylamine carbonyl, and R1 and R2 are each independently C 1～6 alkyl.

[0061] In another preferred example, the brominating reagent is selected from N-bromosuccinimide (NBS), bromine, dibromohydantoin, pyridinium tribromide, or a combination thereof. More preferably, NBS.

[0062] In another preferred example, for the compound I provided by the present invention, wherein R is an amine protecting group or trifluoroethylamine carbonyl, the preparation method comprises the following steps:

[0063] (a) Compound II reacts with compound III to form compound IV, and the reaction formula is as follows:

[0064] wherein R is an amino protecting group or trifluoroethylamine carbonyl, and R1 and R2 are each independently selected from C 1～6 alkyl groups.

[0065] (b) Compound IV reacts with a brominating reagent to form Compound V, and the reaction formula is as follows:

[0066] wherein R is an amino protecting group or trifluoroethylamine carbonyl, and R1 and R2 are each independently selected from C 1～6 alkyl groups.

[0067] In another preferred example, the brominating reagent is selected from N-bromosuccinimide (NBS), bromine, dibromohydantoin, pyridinium tribromide, or a combination thereof. More preferably, NBS.

[0068] In another preferred example, the method for preparing Compound I provided by the present invention comprises the following steps:

[0069] (1) Compound II reacts with Compound III-1 to form Compound IV-1;

[0070] (2) Compound IV-1 reacts with a brominating reagent to form Compound V-1;

[0071] (3) Compound V-1 is de-esterified to form Compound I,

[0072] and the reaction formula is as follows:

[0073] wherein R is Cbz or trifluoroethylamine carbonyl.

[0074] On the other hand, the present invention provides a compound, the structural formula of which is shown in Formula IV or Formula V as follows:

[0075] wherein R is an amino protecting group, and R1 and R2 are each independently selected from C 1～6 alkyl groups, wherein R is an amino protecting group, and R1 and R2 are each independently selected from C 1～6 alkyl groups.

[0076] On yet another aspect, the present invention provides a method for preparing Compound IV, comprising the following steps:

[0077] Compound II reacts with Compound III to form Compound IV, and the reaction formula is as follows:

[0078] wherein R is an amino protecting group, and R1 and R2 are each independently selected from C 1～6 alkyl groups.

[0079] In another aspect, the present invention provides a method for preparing Compound V, comprising the following steps:

[0080] (a) Compound II reacts with Compound III to form Compound IV, and the reaction formula is as follows:

[0081] wherein R is an amino protecting group or trifluoroethylamine carbonyl, and R1 and R2 are each independently selected from C 1～6 alkyl;

[0082] (b) Compound IV reacts with a brominating reagent to form Compound V, and the reaction formula is as follows:

[0083] In Structural Formulas II and IV, R is an amino protecting group, and R1 and R2 are each independently selected from C 1～6 alkyl.

[0084] In another preferred example, the brominating reagent is selected from N-bromosuccinimide (NBS), bromine, dibromohydantoin, pyridinium tribromide, or a combination thereof.

[0085] In another aspect, the present invention provides a compound, and its structural formula is as follows:

[0086] Description of the Drawings

[0087] Figure 1 is the 1H NMR spectrum (solvent CDCl3) of Compound IV-2 obtained in Example 1;

[0088] Figure 2 is the high performance liquid chromatography of Compound IV-2 obtained in Example 1;

[0089] Figure 3 is the 1H NMR spectrum (solvent CDCl3) of Compound IV-3 obtained in Example 3;

[0090] Figure 4 is the high performance liquid chromatography of Compound IV-3 obtained in Example 3;

[0091] Figure 5 is the 1H NMR spectrum (solvent CDCl3) of Compound V-2 obtained in Example 4;

[0092] Figure 6 is the high performance liquid chromatography of Compound V-2 obtained in Example 4;

[0093] Figure 7 is the 1H NMR spectrum (solvent CDCl3) of Compound V-3 obtained in Example 5;

[0094] Figure 8It is the high performance liquid chromatography of Compound V-3 obtained in Example 5.

[0095] Figure 9 It is the 1H NMR spectrum (solvent CDCl3) of Compound I-a obtained in Example 7;

[0096] Figure 10 It is the 1H NMR spectrum (solvent DMSO) of Compound I-b obtained in Example 8. Specific Embodiments

[0097] In view of the defects existing in the preparation process of Compound I, a key intermediate of Upadacitinib, in the prior art, the inventors of the present application have conducted in-depth research and found that a method using the existing Compound II as a raw material, reacting it with diethyl malonate and a brominating reagent in sequence, and then removing the ester group to obtain the target Compound I uses reagents with stable properties, low prices, easy operation, and high yields in each step, which is suitable for large-scale industrial production. Based on this, the present invention has been completed.

[0098] Preparation of Compound I

[0099] In some specific embodiments of the present invention, the preparation method of Compound I provided by the present invention includes the following steps:

[0100] (1) React Compound II with Compound III to form Compound IV,

[0101] (2) React Compound IV with a brominating reagent to form Compound V,

[0102] (3) Remove the ester group from Compound V to form Compound I,

[0103] The reaction formula is as follows:

[0104]

[0105] Wherein R is an amino protecting group, and R1 and R2 are each independently selected from C 1～6 alkyl.

[0106] In some specific embodiments of the present invention, in step (1), the reaction of Compound II with Compound III includes two steps:

[0107] (a) React Compound II with a chlorinating reagent to form an acyl chloride compound II-a,

[0108] (b) After fully stirring Compound III, an organic base, an inorganic salt, and a solvent in a reaction vessel, add dropwise a solution containing the acyl chloride compound II-a prepared in step (a), and react to form Compound IV.

[0109] Step (a): The acyl chloride compound is prepared by following the conventional methods for such reactions in the art. The chlorinating reagents used include but are not limited to thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene, etc. The solvents used include but are not limited to dichloromethane, toluene, xylene, halogenated benzene, etc. The amount of the solvent used is the conventional amount for such reactions.

[0110] In step (b), the reaction of compound III with the acyl chloride compound prepared in step (a) is carried out by following the conventional methods for such reactions in the art. The organic bases used include but are not limited to triethylamine, N,N - diisopropylethylamine, N - methylmorpholine, N,N - dimethylformamide, pyridine, etc. The inorganic salts play a catalytic role, and the inorganic salts that can be used in the present invention include but are not limited to MgCl2, MgBr2, MgI2, CaCl2, CaBr2, CaI2, etc. The solvents used include but are not limited to toluene acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tetrahydrofuran, 2 - methyltetrahydrofuran, etc. The amount of the solvent used is the conventional amount for such reactions. In this step, the solution of compound III, the organic base, and the inorganic salt is preferably stirred and mixed in the reaction vessel for 1 - 4 hours, such as 1 - 2 hours, 1.5 - 2 hours, and the stirring temperature is room temperature. The purpose of sufficient stirring is to form an active intermediate, which then reacts with the acyl chloride compound II - a. During the process of dropping the solution containing the acyl chloride compound II - a into the solution of compound III, the organic base, and the inorganic salt, the system temperature is maintained not higher than room temperature, such as 30°C.

[0111] In some specific embodiments of the present invention, after the reaction in step (b) is completed, the reaction solution is cooled to 0 - 10°C and then adjusted to acidic with an acidic aqueous solution, separated by liquid - liquid extraction. The organic phase is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, and then concentrated to obtain the target compound.

[0112] In some specific embodiments of the present invention, in step (2), the brominating groups used for the reaction of compound IV with the brominating reagent include but are not limited to N - bromosuccinimide, bromine, dibromohydantoin, pyridinium tribromide, etc. The solvents used for the reaction include but are not limited to methanol, ethanol, isopropanol, tert - butanol. The amount of the solvent used is the conventional amount for such reactions. For example, the weight - volume ratio of compound V to the solvent is 1 g / 2 mL - 20 mL, more preferably 1 g / 4 mL - 10 mL.

[0113] In some specific embodiments of the present invention, after the reaction is completed, the reaction solution is concentrated to dryness. An extraction organic solvent and an aqueous solution of sodium bisulfite are added to the residue, separated by liquid - liquid extraction. The organic phase is washed with an aqueous solution of sodium chloride and then concentrated to obtain the target compound.

[0114] In some specific embodiments of the present invention, in step (3), the de-esterification of compound V under acidic conditions is carried out according to the conventional methods in the art for carrying out such reactions. The acids that can be used in this step include but are not limited to hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, acetic acid, trifluoroacetic acid, etc. The solvents used in the reaction include but are not limited to methyl, ethyl, propyl, isopropyl, tert-butyl, etc. The amount of the solvent used is the conventional amount for carrying out such reactions. For example, the weight-volume ratio of compound V to the solvent is 1 g / 2 mL to 20 mL, and more preferably 1 g / 4 mL to 10 mL.

[0115] In some embodiments of the present invention, in this step, after the reaction is completed, an alkaline solution is directly added to the reaction solution, and liquid separation is carried out. The organic phase is washed with an aqueous sodium chloride solution and then concentrated to obtain the target compound.

[0116] As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4 - 40 °C, preferably 25 ± 5 °C.

[0117] The term "alkyl", by itself or as part of another substituent, refers to a straight-chain or branched-chain hydrocarbon group having the specified number of carbon atoms. C1-C6 alkyl represents an alkyl group containing 1 - 6 carbons. Examples of such include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0118] Compared with the prior art, the advantageous effects of the method for preparing the upadacitinib intermediate of the present invention are as follows:

[0119] (1) The raw materials and reaction reagents used are all readily available and inexpensive;

[0120] (2) Each step has mild reaction conditions, simple operation, high yield, and is suitable for industrial production;

[0121] (3) Each step has no sulfide emissions, does not involve flammable and explosive reagents, and is safe and environmentally friendly in operation.

[0122] The method for using intermediate compound I-a to prepare upadacitinib can be carried out according to the method disclosed in the prior art CN108368121A. The reaction formula is as follows:

[0123]

[0124] The method for using intermediate compound I-b to prepare upadacitinib can be carried out according to the method disclosed in the prior art WO2021005484A1. The reaction formula is as follows:

[0125]

[0126] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight. The reagents and raw materials used in the following embodiments are generally commercially available without special instructions.

[0127] In the following embodiments, the reaction raw materials or reagents used, if not specifically stated, are commercially available or can be prepared according to the methods described in the prior art.

[0128] Example 1 Preparation of Compound IV-2

[0129]

[0130] To the first reaction flask, compound II-1 (10.0 g, 36.1 mmol), dichloromethane (100 mL) were added successively, and thionyl chloride (6.4 g, 54 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to the reflux temperature of dichloromethane and reacted for 7-8 hours. After detecting that the raw material compound II-1 had completely reacted, heating was stopped, and the reaction solution was concentrated to dryness, then toluene (40 mL) was added to obtain a solution containing the acyl chloride active intermediate compound.

[0131] To the second reaction flask, magnesium chloride (4.1 g, 43 mmol), toluene (60 mL), triethylamine (8.8 g, 87 mmol) and di-tert-butyl malonate (9.4 g, 43.6 mmol) were added, and the reaction was stirred at room temperature for 2 hours.

[0132] The solution containing the acyl chloride compound was added dropwise to the second reaction flask. During the addition process, the system temperature was maintained not higher than 30 °C. After the addition was complete, the reaction was carried out at room temperature for 2-3 hours until the reaction was completed. The reaction solution was cooled to 0-10 °C, and 1N hydrochloric acid (50 mL) was added dropwise. After the addition was complete, the mixture was warmed to room temperature, and liquid separation was carried out. The organic phase was washed successively with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL), then concentrated, and the solvent was removed completely to obtain 16.5 g of an oily substance with a molar yield of 94.7% and an HPLC purity of 98.53%. The 1H NMR spectrum and HPLC chromatogram are shown in Figure 1 and Figure 2 . This oily substance was directly used in the next step of the reaction without purification.

[0133] Example 2 Preparation of Compound IV-2

[0134]

[0135] To the first reaction flask, compound II-1 (10.0 g, 36.1 mmol), dichloromethane (100 mL) were added successively, and oxalyl chloride (6.9 g, 54 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to the reflux temperature of dichloromethane and reacted for 5 - 6 hours. After detecting that the starting compound II-1 had completely reacted, heating was stopped, the reaction solution was concentrated to remove the solvent, and toluene (40 mL) was added to obtain a solution containing the acyl chloride active intermediate compound.

[0136] To the second reaction flask, calcium chloride (4.8 g, 43 mmol), toluene (60 mL), N,N-diisopropylethylamine (11.2 g, 87 mmol) and di-tert-butyl malonate (9.4 g, 43 mmol) were added, and the reaction was stirred at room temperature for 2 hours.

[0137] The solution containing the acyl chloride compound was added dropwise to the second reaction flask. During the addition, the system temperature was maintained not higher than 30 °C. After the addition was complete, the reaction was carried out at room temperature for 1 - 2 hours, and the reaction was completed. The reaction solution was cooled to 0 - 10 °C, 1N hydrochloric acid (50 mL) was added dropwise thereto. After the addition was complete, the mixture was warmed to room temperature, separated, and the organic phase was washed successively with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride (50 mL), then concentrated and the solvent was removed completely to obtain 15.9 g of an oily substance with a molar yield of 90.9% and an HPLC purity of 98.15%. This oily substance was used directly in the next reaction without purification.

[0138] Example 3: Preparation of Compound IV-3

[0139]

[0140] To the first reaction flask, compound II-2 (8.6 g, 32.1 mmol), dichloromethane (43 mL) were added successively, and thionyl chloride (5.7 g, 48.1 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to the reflux temperature of dichloromethane and reacted for 7 - 8 hours. After detecting that the starting compound II-1 had completely reacted, heating was stopped, the reaction solution was concentrated to remove the solvent, and dichloromethane (43 mL) was added to obtain a solution containing the acyl chloride active intermediate compound.

[0141] To the second reaction flask, magnesium chloride (3.7 g, 38.5 mmol), dichloromethane (43 mL), triethylamine (7.8 g, 76.9 mmol) and di-tert-butyl malonate (8.3 g, 38.5 mmol) were added, and the reaction was stirred at room temperature for 2 hours.

[0142] The solution containing the acyl chloride compound was dropped into the second reaction flask. During the dropping process, the temperature of the system was maintained not to exceed 30 °C. After the dropping was completed, the reaction was carried out at room temperature for 4 - 5 hours, and the reaction was completed. The reaction solution was cooled to 0 - 10 °C, and 1N hydrochloric acid (50 mL) was dropped into it. After the dropping was completed, the mixture was warmed to room temperature, and liquid separation was carried out. The organic phase was washed successively with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL), and then concentrated and the solvent was removed thoroughly to obtain 15.7 g of an oily substance. The molar yield was 92.4%, and the HPLC purity was 88.11% (the sum of two main peaks). The 1H NMR spectrum and HPLC chromatogram are respectively shown in Figure 3 and Figure 4 (Both of the two main peaks in the HPLC chromatogram are product peaks and are enol tautomerism peaks). This oily substance was directly used in the next reaction without purification.

[0143] Example 4: Preparation of Compound V-2

[0144]

[0145] Compound IV-2 (17.0 g, 35.2 mmol, purity about 98.53%) and methanol (85 mL) were successively added into the reaction flask. NBS (7.6 g, 43 mmol) was added in batches, and the reaction was carried out at room temperature for 4 - 5 hours. After the reaction was completed, the reaction solution was concentrated to dryness without solvent, and dichloromethane (170 mL) was added to it. The organic phase was washed successively with 10% sodium bisulfite solution (85 mL) and saturated sodium chloride solution (85 mL), and then concentrated to dryness to obtain 20.2 g of an oily substance. The molar yield was 97.6%, and the HPLC purity was 94.30%. The 1H NMR spectrum and HPLC chromatogram are respectively shown in Figure 5 and Figure 6 . The product obtained in this example was directly used in the next reaction without purification.

[0146] Example 5: Preparation of Compound V-2

[0147]

[0148] Compound IV-2 (10.0 g, 20.7 mmol, purity about 98.53%) and methanol (50 mL) were successively added into the reaction flask. Liquid bromine (4.0 g, 24.8 mmol) was dropped in, and the reaction was carried out at room temperature for 4 - 5 hours. After the reaction was completed, dichloromethane (100 mL) was added to it. The organic phase was washed successively with 10% sodium bisulfite solution (100 mL) and saturated sodium chloride solution (100 mL), and then concentrated to dryness to obtain 10.5 g of an oily substance. The molar yield was 87.5%, and the HPLC purity was 95.61%. This oily substance was directly used in the next reaction without purification.

[0149] Example 6: Preparation of Compound V-3

[0150]

[0151] To the reaction flask, compound IV-3 (5.1 g, 9.6 mmol, calculated according to a purity of 88.11%) was added successively, followed by magnesium chloride (0.2 g, 1.9 mmol) and methanol (23 mL). NBS (2.1 g, 11.6 mmol) was added in portions, and the reaction was carried out at room temperature for 4 - 5 hours. After the reaction was completed, the reaction solution was concentrated to dryness without solvent, and dichloromethane (45 mL) was added thereto. The organic phase was washed successively with 10% sodium bisulfite solution (45 mL) and saturated sodium chloride solution (45 mL), and then concentrated to dryness to obtain 5.0 g of an oily substance with a molar yield of 86.3%. The HPLC purity was 90.33%. The 1H NMR spectrum and HPLC chromatogram are shown in Figure 7 and Figure 8 . This oily substance was directly used in the next reaction without purification.

[0152] Example 7: Preparation of Compound I-a

[0153]

[0154] To the reaction flask, V-2 (19.5 g, 33.16 mmol, purity approximately 94.30%) was added successively, followed by dichloromethane (100 mL) and acetic acid (12.6 g, 210 mmol). The reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was washed successively with 5% sodium bicarbonate solution (140 mL) and saturated sodium chloride solution (100 mL), and then concentrated to obtain 11.0 g of an oily substance with a molar yield of 84.8% and an HPLC purity of 90.50%. MS(ESI+) m / z 354.2 [M + H] + . The 1H NMR spectrum is shown in Figure 9 .

[0155] Example 8: Preparation of Compound I-b

[0156]

[0157] To the reaction flask, V-3 (20.0 g, 33.8 mmol, purity approximately 92.1%) was added successively, followed by dichloromethane (100 mL) and acetic acid (19.4 g, 323 mmol). The reaction was carried out overnight at room temperature. After the reaction was completed, the reaction solution was washed successively with 5% sodium bicarbonate solution (140 mL) and saturated sodium chloride solution (100 mL), and then concentrated to obtain 11.1 g of an oily substance. 9.6 g of an off-white solid was obtained by column chromatography with a yield of 78.6% and an HPLC purity of 95.5%. MS(ESI+) m / z 344.9 [M + H] +。The proton nuclear magnetic resonance spectrum is shown in Figure 10 。

[0158] All documents mentioned in the present invention are incorporated herein by reference as if each individual document was specifically and individually incorporated by reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. A method for preparing Compound I, characterized in that, The preparation method comprises the following steps: The de-esterification of compound V to generate compound I, and the reaction formula is as follows: Among them in I, R is an amino protecting group or trifluoroethylamine carbonyl, and R1 and R2 are each independently C 1～6 alkyl group.

2. The preparation method of Compound I according to Claim 1, characterized in that, R is Cbz, Boc, Fmoc or trifluoroethylamine carbonyl, more preferably Cbz or trifluoroethylamine carbonyl, and / or R1 and R2 are each independently methyl, ethyl, propyl, isopropyl or tert-butyl, more preferably tert-butyl, and / or The de-esterification of compound V is carried out under acidic conditions, and the acid is selected from inorganic acids or organic acids. Preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof, and the organic acid is selected from formic acid, acetic acid, trifluoroacetic acid, or a combination thereof.

3. The preparation method of compound I according to claim 1 or 2, characterized in that, The preparation method of compound V comprises the following steps: Compound IV reacts with a brominating reagent to generate compound V, and the reaction formula is as follows: wherein R, R1 and R2 are as defined in claim 1, Preferably, the brominating reagent is selected from N-bromosuccinimide, bromine, dibromohydantoin, pyridinium tribromide, or a combination thereof, more preferably N-bromosuccinimide.

4. The preparation method of Compound I according to claim 3, characterized in that, The preparation method of compound IV comprises the following steps: Compound II reacts with compound III to generate compound IV, and the reaction formula is as follows: Wherein, R, R1 and R2 are as defined in claim 1.

5. The preparation method of Compound I according to claim 4, characterized in that, The reaction of compound II with compound III to generate compound IV comprises the following steps: (a) Compound II reacts with a chlorinating reagent to form acyl chloride compound II-a, (b) After compound III, an organic base and an inorganic salt are sufficiently stirred in a reaction vessel, a solution containing the acyl chloride compound II-a prepared in step (a) is added dropwise, and compound IV is generated by reaction. Preferably, the chlorinating reagent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, triphosgene or a combination thereof, more preferably thionyl chloride, and / or Preferably, the organic base is selected from triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N,N-dimethylformamide, pyridine or a combination thereof, more preferably triethylamine, and / or Preferably, the inorganic salt is selected from MgCl2, MgBr2, MgI2, CaCl2, CaBr2, CaI2 or a combination thereof.

6. A compound I, wherein R is an amine protecting group or trifluoroethylamine carbonyl, the preparation method thereof is characterized in that, The preparation method comprises the following steps: Compound IV reacts with a brominating reagent to generate compound V, and the reaction formula is as follows: Wherein, R is an amino protecting group or trifluoroethylamine carbonyl, and R1 and R2 are each independently C 1～6 alkyl Preferably, the brominating reagent is selected from N-bromosuccinimide (NBS), bromine, dibromohydantoin, pyridinium tribromide, or a combination thereof.

7. A compound I, wherein, A preparation method of R being an amino protecting group or trifluoroethylamine carbonyl, characterized in that the preparation method comprises the following steps: (a) Compound II reacts with compound III to generate compound IV, and the reaction formula is as follows: wherein R is an amino protecting group or trifluoroethylcarbonyl, and R1 and R2 are each independently selected from C 1～6 alkyl; (b) Compound IV reacts with a brominating reagent to generate compound V, and the reaction formula is as follows: wherein R is an amino protecting group or trifluoroethylaminocarbonyl, and R1 and R2 are each independently selected from C 1～6 alkyl Preferably, the brominating reagent is selected from N-bromosuccinimide (NBS), bromine, dibromohydantoin, pyridinium tribromide, or a combination thereof.

8. A method for preparing Compound I, characterized in that, The preparation method comprises the following steps: (1) Compound II reacts with compound III-1 to generate compound IV-1. (2) Compound IV-1 reacts with a brominating reagent to generate compound V-1. (3) The de-esterification of compound V-1 generates compound I. The reaction formula is as follows: wherein R is Cbz or trifluoroethylamine carbonyl.

9. A compound, the structural formula of which is shown as formula IV or formula V below: wherein R is the amino protecting group trifluoroethylcarbonyl, and R1 and R2 are each independently selected from C 1～6 alkyl wherein R is an amino protecting group or trifluoroethylaminocarbonyl, and R1 and R2 are each independently selected from C 1～6 alkyl groups.

10. A method for preparing Compound IV, characterized in that, The preparation method comprises the following steps: Compound II reacts with compound III to generate compound IV, and the reaction formula is as follows: wherein R is an amino protecting group or trifluoroethylaminocarbonyl, and R1 and R2 are each independently selected from C 1～6 alkyl groups.

11. A method for preparing compound V, characterized in that, The preparation method comprises the following steps: (a) Compound III reacts with Compound III to form Compound IV, and the reaction formula is as follows: wherein R is an amino protecting group or trifluoroethylaminocarbonyl, and R1 and R2 are each independently selected from C 1～6 alkyl; (b) Compound IV reacts with a brominating reagent to form Compound V, and the reaction formula is as follows: wherein R is an amino protecting group or trifluoroethylcarbonyl, and R1 and R2 are each independently selected from C 1～6 alkyl Preferably, the brominating reagent is selected from N-bromosuccinimide (NBS), bromine, dibromohydantoin, pyridinium tribromide, or a combination thereof.

12. A compound, the structural formula of which is as follows:

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