Preparation method of intermediates of parovir and boceprevir

Abstract

The present invention relates to a method for preparing a compound represented by formula (V) (intermediates of parovir and boceprevir). The method comprises: subjecting the compound represented by formula (I) to a hydroxyl protection reaction to obtain a compound represented by formula (II); subjecting the compound represented by formula (II) to an elimination reaction to obtain a compound represented by formula (III); subjecting the compound represented by formula (III) to a cyclopropanation reaction to obtain a compound represented by formula (V); wherein R in the compound represented by formula (II) is a hydroxyl protection group. The method has the advantages of a short synthetic route and mild reaction conditions, simple operation and no special requirements for equipment, and is easy to realize large-scale production; and the synthesized compound represented by formula (I) has the advantages of high yield and high chiral purity.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology. Specifically, the present invention relates to a method for preparing a parovide and boceprevir intermediate. More specifically, the present invention relates to a (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride and a preparation method thereof and a preparation method of parovide or boceprevir. Background Art

[0002] Paxlovid is an oral small molecule novel coronavirus treatment for the treatment of mild to moderate novel coronavirus pneumonia (COVID-19) in adults with high risk factors for progression to severe illness, such as advanced age, chronic kidney disease, diabetes, cardiovascular disease or chronic lung disease. Paxlovid has been reported to be 89% effective in preventing hospitalization and death in high-risk patients. Paxlovid is an oral combination of PF-07321332 and ritonavir. PF-07321332 has the activity of blocking SARS-CoV-2-3CL protease, which is an enzyme required for coronavirus replication; PF-07321332 is used in combination with low-dose antiretroviral drug ritonavir to help slow the metabolism or decomposition of PF-07321332, allowing it to remain active in the body at higher concentrations for a longer time to help fight the virus. The structural formula of PF-07321332 is shown below:

[0003]

[0004] The chemical name of Boceprevir is (1R,2S,5S)-N-(4-amino-1-cyclobutyl-3,4-dioxobutane-2-yl)-3-[(2S)-2-(tert-butylcarbamoylamino)-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, which is used in combination with pegylated interferon α and ribavirin to treat chronic hepatitis of CHC genotype I. The three drugs can cure more than 60% of patients, which is 2 to 3 times the cure rate of pegylated interferon or ribavirin alone, and Boceprevir can improve the cure rate and shorten the treatment time. The structural formula of Boceprevir is as follows:

[0005]

[0006] (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride is an important intermediate of parovird and boceprevir, and has a huge application market.

[0007] Therefore, it is urgent to develop a method for efficiently preparing (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride. Summary of the invention

[0008] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. To this end, the present invention provides a method for preparing (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride, which has the advantages of short synthesis route, high yield and high chiral purity.

[0009] The present invention is accomplished based on the following findings of the inventors:

[0010] Currently, for the preparation of paroviride and boceprevir, (1R, 2S, 5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid methyl ester hydrochloride (INTA, i.e., the compound shown in formula (V)) is the key intermediate with the highest cost in the synthesis process;

[0011]

[0012] However, the existing methods for synthesizing the compound represented by formula (V) have the disadvantages of extremely complicated steps and long reaction time, or expensive catalysts or highly toxic potassium cyanide are used in the synthesis process, which increases the production cost or fails to meet environmental protection requirements, and is not conducive to industrialization.

[0013] However, in one aspect of the present invention, the present invention provides a method for preparing a compound represented by formula (V). According to an embodiment of the present invention, the method comprises: subjecting the compound represented by formula (I) to a hydroxyl protection reaction to obtain a compound represented by formula (II); subjecting the compound represented by formula (II) to an elimination reaction to obtain a compound represented by formula (III); subjecting the compound represented by formula (III) to a cyclopropanation reaction to obtain a compound represented by formula (V);

[0014]

[0015] Wherein, R is a hydroxyl protecting group.

[0016] The raw materials in the method according to the embodiment of the present invention are easily available and cheap, the synthesis route of the method is short and the reaction conditions are mild, the method has the advantages of simple operation and no special requirements for equipment, and is easy to achieve large-scale production; and the synthesized compound represented by formula (I) has the advantages of high yield and high chiral purity, among which the yield can reach more than 66%, and the optical purity ee% can reach 95%.

[0017] In another aspect of the present invention, the present invention provides a compound represented by formula (V). According to an embodiment of the present invention, the compound represented by formula (V) is obtained according to the aforementioned method. The compound represented by formula (I) of the present invention has the advantages of high yield and high chiral purity.

[0018] In another aspect of the present invention, the present invention provides a method for preparing parovir or boceprevir. According to an embodiment of the present invention, the preparation method comprises: preparing the parovir or boceprevir using the compound represented by the aforementioned formula (V). The preparation method according to the embodiment of the present invention can prepare parovir and boceprevir.

[0019] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:

[0021] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the compound represented by formula (V) synthesized in Example 1 of the present invention;

[0022] Figure 2 It is a liquid chromatogram of the compound represented by formula (V) synthesized in Example 1 of the present invention. DETAILED DESCRIPTION

[0023] 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 understood as limiting the present invention.

[0024] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, the features defined as "first" and "second" may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, the meaning of "plurality" is two or more.

[0025] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0026] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0027] As used herein, the terms "optionally", "optional" or "optionally" generally mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0028] The present invention provides a compound represented by formula (V) and a preparation method thereof, and a preparation method of parovird or boceprevir, which will be described in detail below.

[0029] Method for preparing the compound represented by formula (V)

[0030] In one aspect of the present invention, the present invention provides a method for preparing a compound represented by formula (V). According to an embodiment of the present invention, the method comprises: subjecting the compound represented by formula (I) to a hydroxyl protection reaction to obtain a compound represented by formula (II); subjecting the compound represented by formula (II) to an elimination reaction to obtain a compound represented by formula (III); subjecting the compound represented by formula (III) to a cyclopropanation reaction to obtain a compound represented by formula (V);

[0031]

[0032] Wherein, R is a hydroxyl protecting group.

[0033] The raw materials in the method according to the embodiment of the present invention are easily available and cheap, the synthetic route of the method is short and the reaction conditions are mild, it has the advantages of simple operation and no special requirements for equipment, and it is easy to achieve large-scale production; and the compound shown in the synthesized formula (I) has the advantages of high yield and high chiral purity. Therefore, the method of the present invention is of great significance and practical value for realizing the industrial production of parovir and boceprevir.

[0034] According to an embodiment of the present invention, the hydroxyl protection reaction is achieved by: performing a first mixing treatment on the compound represented by formula (I) with a first base and a hydroxyl protection agent to obtain the compound represented by formula (II). Thus, the hydroxyl group of the compound represented by formula (I) can be protected by the first base and the hydroxyl protection agent, which is beneficial to the subsequent elimination reaction.

[0035] According to an embodiment of the present invention, the first mixing treatment is performed at 20 to 30° C. for 3 to 6 hours, thereby facilitating the hydroxyl protection reaction and ensuring the yield of the compound represented by formula (II).

[0036] According to an embodiment of the present invention, the hydroxyl protecting agent includes at least one selected from methanesulfonyl chloride, p-chlorobenzenesulfonyl chloride or p-toluenesulfonyl chloride.

[0037] According to an embodiment of the present invention, R is

[0038] According to an embodiment of the present invention, the first base includes at least one selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and triethylenediamine (DABCO).

[0039] According to an embodiment of the present invention, the molar ratio of the compound represented by formula (I), the first base and the hydroxyl protecting agent is 1.0: (1.0-2.0): (1.0-2.0), preferably 1.0: (1.0-1.5): (1.0-1.5). The above ratio is conducive to the hydroxyl protecting reaction, thereby ensuring the yield of the compound represented by formula (II).

[0040] According to an embodiment of the present invention, before the first mixing process, the compound represented by formula (I) is dissolved in a first solvent in advance.

[0041] According to an embodiment of the present invention, the first solvent includes at least one selected from tetrahydrofuran, toluene, methyl tert-butyl ether and dichloromethane.

[0042] According to an embodiment of the present invention, before the elimination reaction, the first mixed treatment product and the first acid are subjected to a second mixed treatment in advance; the organic phase of the second mixed treatment product is sequentially washed, dried and concentrated to obtain the compound represented by formula (II). Thus, the purity of the compound represented by formula (II) can be improved, thereby ensuring the yield of the final product (i.e., the compound represented by formula (II)).

[0043] According to an embodiment of the present invention, the first acid is a citric acid solution, preferably a citric acid solution with a mass percentage of 5 to 30%.

[0044] According to an embodiment of the present invention, the elimination reaction is achieved by: subjecting the compound represented by formula (II) to a first heating treatment with a second base; subjecting the first heating treatment product to a third mixing treatment with a methylating agent to obtain the compound represented by formula (II). Thus, the elimination reaction can be carried out under alkaline conditions to avoid acidic conditions affecting the stability of the amino group and the carboxylic acid methyl ester of the compound represented by formula (II).

[0045] According to an embodiment of the present invention, the first heating treatment is performed at 30-50° C. for 3-6 hours, which is beneficial to the elimination reaction, thereby ensuring the yield of the final product.

[0046] According to an embodiment of the present invention, the third mixing process is performed at room temperature, which is conducive to the elimination reaction, thereby ensuring the yield of the final product.

[0047] According to an embodiment of the present invention, the second base includes at least one selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and triethylenediamine (DABCO).

[0048] According to an embodiment of the present invention, the methylating agent includes at least one selected from methyl iodide, methyl bromide, dimethyl sulfate and dimethyl carbonate. Thus, the elimination reaction is facilitated, thereby ensuring the yield of the final product.

[0049] According to an embodiment of the present invention, the molar ratio of the compound represented by formula (II), the second base and the methylating agent is 1.0: (1.0-4.0): (0.6-2.0), preferably 1.0: (2.0-3.0): (0.8-1.5). The above ratio is conducive to the elimination reaction, thereby ensuring the yield of the final product.

[0050] According to an embodiment of the present invention, before the first heating treatment, the compound represented by formula (II) is dissolved in a second solvent in advance.

[0051] According to an embodiment of the present invention, the second solvent includes at least one selected from tetrahydrofuran, toluene, methyl tert-butyl ether and dichloromethane.

[0052] According to an embodiment of the present invention, before the cyclopropanation reaction, the third mixed treatment product and the second acid are subjected to a fourth mixed treatment in advance; the organic phase of the fourth mixed treatment product is sequentially washed, dried and concentrated to obtain the compound represented by formula (III). Thus, the purity of the compound represented by formula (III) can be improved, thereby ensuring the yield of the final product.

[0053] According to an embodiment of the present invention, the second acid is a citric acid solution, preferably a citric acid solution with a mass percentage of 5 to 30%.

[0054] According to an embodiment of the present invention, the cyclopropanation reaction is achieved by the following method: subjecting the compound represented by formula (III) to a second heating treatment with a metal catalyst, a metal activator, a metal additive and a cyclopropanation agent to obtain the compound represented by formula (V). The inventors have found through experiments that the use of a metal catalyst, a metal activator and a metal additive at the same time can effectively promote the cyclopropanation reaction between the double bond of the compound represented by formula (V) and the cyclopropanation agent, thereby improving the yield and chiral purity of the compound represented by formula (V).

[0055] According to an embodiment of the present invention, the second heating treatment is performed at 30-50° C. for 8-12 hours. This is beneficial to the cyclopropanation reaction and can further improve the yield and chiral purity of the final product.

[0056] According to an embodiment of the present invention, the metal catalyst includes at least one selected from a cobalt catalyst, a copper catalyst, an iron catalyst, a nickel catalyst and a palladium catalyst.

[0057] According to an embodiment of the present invention, the cobalt catalyst is [2-t-Bu PDI]CoBr2.

[0058] According to an embodiment of the present invention, the copper catalyst is [2-t-Bu PDI]CuBr2.

[0059] According to an embodiment of the present invention, the iron catalyst is [2-t-Bu PDI]FeBr3.

[0060] According to an embodiment of the present invention, the nickel catalyst is [2-t-Bu PDI]NiBr2.

[0061] According to an embodiment of the present invention, the palladium catalyst is [2-t-Bu PDI]PdBr2.

[0062] According to an embodiment of the present invention, the metal activator includes at least one selected from cobalt powder, copper powder, iron powder, nickel powder and palladium carbon.

[0063] According to an embodiment of the present invention, the metal additive includes at least one selected from the group consisting of cobalt bromide, cobalt chloride, copper chloride, copper bromide, ferric chloride, ferric bromide, nickel bromide and nickel chloride.

[0064] According to an embodiment of the present invention, the cyclopropanation agent includes at least one selected from 2,2-dichloropropane, 2,2-dibromopropane and 2,2-diiodopropane.

[0065] According to an embodiment of the present invention, the molar ratio of the compound represented by formula (III), the metal catalyst, the metal activator, the metal additive and the cyclopropanation agent is 1.0: (0.001-1.0): (0.6.0-2.0): (1.0-2.5): (0.5-3.0), preferably 1.0: (0.001-0.1): (0.8-1.8): (1.0-2.0): (1.0-1.5), more preferably 1.0: (0.001-0.01): (0.8-1.8): (1.0-2.0): (1.0-1.5). The above ratio is conducive to the cyclopropanation reaction and can further improve the yield and chiral purity of the final product.

[0066] According to an embodiment of the present invention, before the second heating treatment, the compound represented by formula (III) is dissolved in a third solvent in advance.

[0067] According to an embodiment of the present invention, the third solvent includes at least one selected from tetrahydrofuran, toluene, methyl tert-butyl ether or dichloromethane.

[0068] According to an embodiment of the present invention, the method further comprises: filtering and concentrating the second heating treatment product, sequentially performing a fifth mixing treatment on the concentrated product with a third acid, a fourth base and an organic ether; and sequentially washing, drying and concentrating the organic phase of the fifth mixing treatment product to obtain the compound represented by formula (V). Thus, the purity of the compound represented by formula (V) can be improved.

[0069] According to an embodiment of the present invention, the third acid is hydrochloric acid.

[0070] According to an embodiment of the present invention, the fourth alkali is sodium hydroxide.

[0071] According to an embodiment of the present invention, the organic ether is methyl tert-butyl ether.

[0072] In another aspect of the present invention, the present invention provides a compound represented by formula (V). According to an embodiment of the present invention, the compound represented by formula (V) is obtained according to the aforementioned method. The compound represented by formula (I) of the present invention has the advantages of high yield and high chiral purity.

[0073] In another aspect of the present invention, the present invention provides a method for preparing parovir or boceprevir. According to an embodiment of the present invention, the preparation method comprises: preparing the parovir or boceprevir using the compound represented by the aforementioned formula (V). The preparation method according to the embodiment of the present invention can prepare parovir and boceprevir.

[0074] The scheme of the present invention will be explained below in conjunction with the embodiments. It will be appreciated by those skilled in the art that the following embodiments are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not indicated 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 are not indicated by the manufacturer and are all conventional products that can be obtained commercially.

[0075] Preparation Example 1: Preparation of cobalt catalyst

[0076] The cobalt catalyst in the embodiment of the present invention is [2-t-Bu PDI] CoBr2, and the specific synthesis is as follows:

[0077]

[0078] 1. Preparation of intermediate INT1: Dissolve diacetylpyridine SM1 (1.50 g, 9.2 mmol) in anhydrous ethanol (25 mL) and add 2,6-diisopropylaniline SM2 (3.46 mL, 18.4 mmol). After the addition, add a few drops of glacial acetic acid and reflux the solution overnight. After the spot plate reaction is complete, cool to room temperature, filter the product from ethanol, wash the yellow solid with cold ethanol and dry it in a vacuum oven (50 ° C) overnight to obtain 3.54 g of INT1 (yield 80%).

[0079] 2. Preparation of cobalt catalyst [2-tBu PDI] CoBr2: In a three-necked flask filled with nitrogen, INT1 (3.54 g, 8.31 mmol, 1.0 eq) and CoBr2 (anhydrous) (1.97 g, 8.31 mmol, 1.0 eq) were added to dry THF (15 mL). The mixture was stirred at 20-30° C. for 24 hours. After 24 hours, the mixture was concentrated to dryness under vacuum to produce 5.51 g (yield 100%) of mustard yellow solid, which was the cobalt catalyst [2-t-Bu PDI] CoBr2.

[0080] Embodiment 1:

[0081]

[0082] N-Boc-trans-4-hydroxy-L-proline methyl ester (SM for short) (490 g, 2 mol) and dichloromethane (1.5 L) were added to a 3 L three-necked flask, and then triethylamine (262.6 g, 2.6 mol) was added and stirred evenly. Methanesulfonyl chloride (251.9 g, 2.2 mol) was slowly added dropwise under an ice-water bath, and the temperature was naturally raised to 25°C. The mixture was stirred for 2 hours. The reaction was completed when detected by TLC. 10% by mass citric acid water (1 L) was added dropwise, and the mixture was stirred for 0.5 hour. The mixture was allowed to stand for stratification. The aqueous phase was extracted once with dichloromethane (0.3 L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5 L). The organic phase was separated, dried with anhydrous magnesium sulfate (20 g), and concentrated to obtain intermediate INT2 (640.3 g, yield 99%).

[0083] INT2 (485.1 g, 1.5 mol) and tetrahydrofuran (1.5 L) were added to a 3L three-necked flask and stirred evenly. Sodium methoxide (243 g, 4.5 mol) was added under an ice-water bath. The temperature was slowly raised to 35°C for reaction for 6 h. There was almost no residual raw material on TLC. The temperature was lowered to 25°C, acetic acid (270 g, 4.5 mol) was added dropwise, potassium carbonate powder (276 g, 2 mol) was added dropwise, dimethyl sulfate (189 g, 1.5 mol) was added dropwise, and the mixture was stirred until the reaction was complete. After the reaction was completed, 10% by mass citric acid water (1 L) was added, and the mixture was allowed to stand for stratification. The aqueous phase was extracted once with methyl tert-butyl ether (0.3 L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5 L). The organic phase was separated, dried with anhydrous magnesium sulfate (20 g), and concentrated to obtain the intermediate INT3 (313.3 g, yield 92%).

[0084] INT3 (227.3 g, 1.0 mol) and dry tetrahydrofuran (0.65 L) were added to a 1 L three-necked flask, and then the cobalt catalyst (2.27 g, 0.0035 mol) and zinc bromide (225.2 g, 1.0 mol) obtained in Preparation Example 1 were added in sequence. The atmosphere was replaced with nitrogen. Zinc powder (97.5 g, 1.5 mol) was added under stirring. The reaction mixture was stirred at room temperature for about 15 minutes. The solution turned dark purple. 2,2-dichloropropane (135.6 g, 1.2 mol) was added dropwise, and then the temperature was raised to 45 ° C for reaction for 8-10 hours. The raw materials were completely consumed, and the filtrate was concentrated to dryness. The oil was spin-dried under ice-water bath. 3N hydrochloric acid (0.5L) was added dropwise to the solid, and the mixture was stirred at room temperature for 2 hours. Under an ice-water bath, 6N aqueous sodium hydroxide solution was added dropwise to a pH of 9-9.5, methyl tert-butyl ether (0.5L) was added and stirred for 10 minutes, and the organic phase was separated by standing. The aqueous phase was extracted once with methyl tert-butyl ether (0.5L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5L), the organic phase was separated, and dried over anhydrous magnesium sulfate (20g). 4N propanol solution of hydrogen chloride (0.3L) was added dropwise to the organic phase under stirring to precipitate a solid, which was filtered and dried to obtain the product as a white solid INTA (135.8g, yield 66%, optical purity ee% 98.0%). 1 H NMR(300MHz, CDCl3)10.80(d,1H,NH,J=0.06Hz),9.64(s,1H),4.21(t,1H,J=0.06Hz),4.00(m,1H),3.87( s, 3H), 3.31 (t, 1H, J = 0.06Hz), 1.84 (d, 1H, J = 0.06Hz), 1.74 (t, 1H, J = 0.06Hz), 1.24 (s, 3H), 1.09 (s, 3H).

[0085] It should be noted that the hydrogen nuclear magnetic resonance spectra and liquid chromatograms of the white solid INTA obtained in Examples 2, 3 and 4 are similar to those in Example 1 and will not be presented one by one in the following.

[0086] Embodiment 2:

[0087]

[0088] N-Boc-trans-4-hydroxy-L-proline methyl ester (SM for short) (490 g, 2 mol) and dichloromethane (1.5 L) were added to a 3 L three-necked flask, and then triethylamine (232.3 g, 2.3 mol) was added and stirred evenly. Methanesulfonyl chloride (240.5 g, 2.1 mol) was slowly added dropwise under an ice-water bath, and the temperature was naturally raised to 25°C. The mixture was stirred for 2 hours. The reaction was completed when detected by TLC. 10% by mass citric acid water (1 L) was added dropwise, and the mixture was stirred for 0.5 hour. The mixture was allowed to stand for stratification. The aqueous phase was extracted once with dichloromethane (0.3 L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5 L). The organic phase was separated, dried with anhydrous magnesium sulfate (20 g), and concentrated to obtain intermediate INT2 (633.3 g, yield 97.9%).

[0089] INT2 (485.1 g, 1.5 mol) and tetrahydrofuran (1.5 L) were added to a 3L three-necked flask and stirred evenly. Sodium methoxide (226.8 g, 4.2 mol) was added under an ice-water bath. The temperature was slowly raised to 35°C for reaction for 6 h. There was almost no residual raw material on TLC. The temperature was lowered to 25°C, acetic acid (270 g, 4.5 mol) was added dropwise, potassium carbonate powder (276 g, 2 mol) was added dropwise, dimethyl sulfate (189 g, 1.5 mol) was added dropwise, and the mixture was stirred until the reaction was complete. After the reaction was completed, 10% by mass citric acid water (1 L) was added, and the mixture was allowed to stand for stratification. The aqueous phase was extracted once with methyl tert-butyl ether (0.3 L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5 L). The organic phase was separated, dried with anhydrous magnesium sulfate (20 g), and concentrated to obtain the intermediate INT3 (309.3 g, yield 90.7%).

[0090] INT3 (227.3 g, 1.0 mol) and dry tetrahydrofuran (0.65 L) were added to a 1 L three-necked flask, and then the cobalt catalyst (2.27 g, 0.0035 mol) and zinc bromide (225.2 g, 1.0 mol) obtained in Preparation Example 1 were added in sequence. The atmosphere was replaced with nitrogen, and zinc powder (97.5 g, 1.5 mol) was added under stirring. The reaction mixture was stirred at room temperature for about 15 minutes. The solution turned dark purple. 2,2-dibromopropane (242.3 g, 1.2 mol) was added dropwise, and then the temperature was raised to 45 ° C for reaction for 8-10 hours. The raw materials were completely consumed, and the filtrate was concentrated to dryness. Under an ice-water bath, the mixture was added to a spin-dried oily 3N hydrochloric acid (0.5L) was added dropwise to the mixture, and the mixture was stirred at room temperature for 2 hours. Under an ice-water bath, 6N aqueous sodium hydroxide solution was added dropwise to a pH of 9-9.5, methyl tert-butyl ether (0.5L) was added and stirred for 10 minutes, and the organic phase was separated by standing. The aqueous phase was extracted once with methyl tert-butyl ether (0.5L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5L), the organic phase was separated, and dried over anhydrous magnesium sulfate (20g). 4N propanol solution of hydrogen chloride (0.3L) was added dropwise to the organic phase under stirring, and a solid was precipitated. The solid was filtered and dried to obtain the product as a white solid INTA (139.5g, yield 67.8%, optical purity ee% 97.8%).

[0091] Embodiment 3:

[0092]

[0093] N-Boc-trans-4-hydroxy-L-proline methyl ester (SM for short) (490 g, 2 mol) and dichloromethane (1.5 L) were added to a 3 L three-necked flask, and then triethylamine (262.6 g, 2.6 mol) was added and stirred evenly. Methanesulfonyl chloride (251.9 g, 2.2 mol) was slowly added dropwise under an ice-water bath, and the temperature was naturally raised to 25°C. The mixture was stirred for 2 hours. The reaction was completed when detected by TLC. 10% by mass citric acid water (1 L) was added dropwise, and the mixture was stirred for 0.5 hour. The mixture was allowed to stand for stratification. The aqueous phase was extracted once with dichloromethane (0.3 L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5 L). The organic phase was separated, dried with anhydrous magnesium sulfate (20 g), and concentrated to obtain intermediate INT2 (620.9 g, yield 96%).

[0094] INT2 (485.1 g, 1.5 mol) and tetrahydrofuran (1.5 L) were added to a 3L three-necked flask and stirred evenly. Sodium methoxide (243 g, 4.5 mol) was added under an ice-water bath. The temperature was slowly raised to 35°C for reaction for 6 h. There was almost no residual raw material on TLC. The temperature was lowered to 25°C, acetic acid (270 g, 4.5 mol) was added dropwise, potassium carbonate powder (276 g, 2 mol) was added, and dimethyl sulfate (189 g, 1.5 mol) was added dropwise. The mixture was stirred until the reaction was complete. After the reaction was completed, 10% by mass of citric acid water (1 L) was added, and the mixture was allowed to stand for stratification. The aqueous phase was extracted once with methyl tert-butyl ether (0.3 L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5 L). The organic phase was separated, dried with anhydrous magnesium sulfate (20 g), and concentrated to obtain the intermediate INT3 (310.3 g, yield 91%).

[0095] INT3 (227.3 g, 1.0 mol) and dry tetrahydrofuran (0.65 L) were added to a 1 L three-necked flask, and then the cobalt catalyst (2.47 g, 0.0038 mol) and zinc bromide (225.2 g, 1.0 mol) obtained in Preparation Example 1 were added in sequence. Nitrogen was replaced, and copper powder (95.3 g, 1.5 mol) was added under stirring. The reaction mixture was stirred at room temperature for about 15 minutes. The solution turned dark purple. 2,2-dichloropropane (135.6 g, 1.2 mol) was added dropwise, and then the temperature was raised to 45 ° C for reaction for 8-10 hours. The raw materials were completely consumed, and the filtrate was concentrated to dryness. Under an ice-water bath, the mixture was added to a spin-dried oily 3N hydrochloric acid (0.5L) was added dropwise to the mixture, and the mixture was stirred at room temperature for 2 hours. Under an ice-water bath, 6N aqueous sodium hydroxide solution was added dropwise to a pH of 9-9.5, methyl tert-butyl ether (0.5L) was added and stirred for 10 minutes, and the organic phase was separated by standing. The aqueous phase was extracted once with methyl tert-butyl ether (0.5L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5L), the organic phase was separated, and dried over anhydrous magnesium sulfate (20g). 4N propanol solution of hydrogen chloride (0.3L) was added dropwise to the organic phase under stirring to precipitate a solid, which was filtered and dried to obtain the product as a white solid INTA (43.8g, yield 21.3%, optical purity ee% 95.0%).

[0096] Embodiment 4:

[0097]

[0098] N-Boc-trans-4-hydroxy-L-proline methyl ester (SM for short) (490 g, 2 mol) and dichloromethane (1.5 L) were added to a 3 L three-necked flask, and then triethylamine (262.6 g, 2.6 mol) was added and stirred evenly. Methanesulfonyl chloride (251.9 g, 2.2 mol) was slowly added dropwise under an ice-water bath, and the temperature was naturally raised to 25°C. The mixture was stirred for 2 hours. The reaction was completed when detected by TLC. 10% by mass citric acid water (1 L) was added dropwise, and the mixture was stirred for 0.5 hour. The mixture was allowed to stand for stratification. The aqueous phase was extracted once with dichloromethane (0.3 L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5 L). The organic phase was separated, dried with anhydrous magnesium sulfate (20 g), and concentrated to obtain intermediate INT2 (635.6 g, yield 98.3%).

[0099] INT2 (485.1 g, 1.5 mol) and tetrahydrofuran (1.5 L) were added to a 3L three-necked flask and stirred evenly. Sodium methoxide (243 g, 4.5 mol) was added under an ice-water bath. The temperature was slowly raised to 35°C for reaction for 6 h. There was almost no residual raw material on TLC. The temperature was lowered to 25°C, acetic acid (270 g, 4.5 mol) was added dropwise, potassium carbonate powder (276 g, 2 mol) was added, and dimethyl sulfate (189 g, 1.5 mol) was added dropwise. The mixture was stirred until the reaction was complete. After the reaction was completed, 10% by mass citric acid water (1 L) was added, and the mixture was allowed to stand for stratification. The aqueous phase was extracted once with methyl tert-butyl ether (0.3 L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5 L). The organic phase was separated, dried with anhydrous magnesium sulfate (20 g), and concentrated to obtain the intermediate INT3 (304.8 g, yield 89.4%).

[0100] INT3 (227.3 g, 1.0 mol) and dry tetrahydrofuran (0.65 L) were added to a 1 L three-necked flask, and then the cobalt catalyst (2.00 g, 0.0031 mol) and zinc chloride (136.3 g, 1.0 mol) obtained in Preparation Example 1 were added in sequence. The atmosphere was replaced with nitrogen. Zinc powder (97.5 g, 1.5 mol) was added under stirring. The reaction mixture was stirred at room temperature for about 15 minutes. The solution turned dark purple. 2,2-dichloropropane (135.6 g, 1.2 mol) was added dropwise, and then the temperature was raised to 45 ° C for reaction for 8-10 hours. The raw materials were completely consumed, and the filtrate was concentrated to dryness. Under an ice-water bath, the mixture was added to a spin-dried oil. 3N hydrochloric acid (0.5L) was added dropwise to the mixture, and the mixture was stirred at room temperature for 2 hours. Under an ice-water bath, 6N aqueous sodium hydroxide solution was added dropwise to a pH of 9-9.5, methyl tert-butyl ether (0.5L) was added and stirred for 10 minutes, and the organic phase was separated by standing. The aqueous phase was extracted once with methyl tert-butyl ether (0.5L), the organic phases were combined, and the organic phases were washed with saturated sodium chloride water (0.5L), the organic phase was separated, and dried over anhydrous magnesium sulfate (20g). 4N propanol solution of hydrogen chloride (0.3L) was added dropwise to the organic phase under stirring to precipitate a solid, which was filtered and dried to obtain the product as a white solid INTA (70.3g, yield 34.3%, optical purity ee% 96.0%).

[0101] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "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, without contradiction.

[0102] 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 method for preparing a compound represented by formula (V), characterized in that: include: The compound represented by formula (I) is subjected to a hydroxyl protection reaction to obtain a compound represented by formula (II); The compound represented by formula (II) is subjected to elimination reaction to obtain a compound represented by formula (III); The compound represented by the formula (III) is subjected to a cyclopropanation reaction to obtain the compound represented by the formula (V); in, The cyclopropanation reaction is achieved by the following method: The compound represented by the formula (III) is subjected to a second heating treatment with [2-t-Bu PDI]CoBr2, zinc powder, zinc bromide and 2,2-dibromopropane to obtain the compound represented by the formula (V); The second heating treatment is performed at 30-50° C. for 8-12 hours; The molar ratio of the compound represented by formula (III), [2-t-Bu PDI]CoBr2, zinc powder, zinc bromide and 2,2-dibromopropane is 1.0: (0.001-0.1): (0.8-1.8): (1.0-2.0): (1.0-1.5); R is ; The elimination reaction is achieved in the following manner: Preliminarily dissolving the compound represented by formula (II) in a second solvent, wherein the second solvent is selected from tetrahydrofuran; The compound represented by formula (II) is subjected to a first heating treatment with a second base, wherein the first heating treatment is carried out at 30-50° C. for 3-6 hours, and the second base is selected from sodium methoxide; The first heating product is subjected to a third mixing treatment with a methylating agent to obtain the compound represented by the formula (III), wherein the third mixing treatment is carried out at room temperature, and the methylating agent is selected from dimethyl sulfate; The molar ratio of the compound represented by formula (II), the second base and the methylating agent is 1.0:(2.0-3.0):(0.8-1.5).

2. The method according to claim 1, characterized in that The hydroxyl protection reaction is achieved in the following manner: Performing a first mixing treatment on the compound represented by formula (I), a first base and a hydroxyl protecting agent to obtain the compound represented by formula (II); Optionally, the first mixing treatment is performed at 20-30° C. for 3-6 hours; Optionally, the hydroxyl protecting agent is selected from methanesulfonyl chloride; Optionally, the first base is selected from at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and triethylenediamine; Optionally, the molar ratio of the compound represented by formula (I), the first base and the hydroxyl protecting agent is 1.0:(1.0-2.0):(1.0-2.0).

3. The method according to claim 2, characterized in that Before the first mixing process, the compound represented by formula (I) is dissolved in a first solvent in advance; Optionally, the first solvent is selected from at least one of tetrahydrofuran, toluene, methyl tert-butyl ether and dichloromethane.

4. The method according to claim 2, characterized in that The molar ratio of the compound represented by formula (I), the first base and the hydroxyl protecting agent is 1.0: (1.0-1.5): (1.0-1.5).

5. The method according to claim 2, characterized in that: Before the elimination reaction, the first mixed treatment product and the first acid are subjected to a second mixed treatment in advance; The organic phase of the second mixed treatment product is sequentially washed, dried and concentrated to obtain the compound represented by formula (II); Optionally, the first acid is a citric acid solution with a mass percentage of 5 to 30%.

6. The method according to claim 1, characterized in that Before the cyclopropanation reaction, the third mixed treatment product and the second acid are subjected to a fourth mixed treatment in advance; The organic phase of the fourth mixed treatment product is sequentially washed, dried and concentrated to obtain the compound represented by formula (III); Optionally, the second acid is a citric acid solution with a mass percentage of 5 to 30%.

7. The method according to claim 1, characterized in that Before the second heating treatment, the compound represented by formula (III) is dissolved in a third solvent in advance; Optionally, the third solvent is selected from at least one of tetrahydrofuran, toluene, methyl tert-butyl ether or dichloromethane.

8. The method according to claim 7, characterized in that Further including: The second heating treatment product is filtered and concentrated, and the concentrated product is sequentially subjected to a fifth mixing treatment with a third acid, a fourth base and an organic ether; The organic phase of the fifth mixed treatment product is washed, dried and concentrated in sequence to obtain the compound represented by formula (V); Optionally, the third acid is hydrochloric acid; Optionally, the fourth base is sodium hydroxide; Optionally, the organic ether is methyl tert-butyl ether.

Images