Preparation method of MK-A, used intermediate and synthesis method of MK-A

Abstract

According to the preparation method of the oral PCSK9 inhibitor intermediate, the used intermediate and the synthesis method of the intermediate, the key intermediates are innovatively designed and synthesized, the operation conditions of the steps are mild, the yield is high, the cost is low, toxic impurities are few, the steps are few, and industrial production is facilitated. The synthesis thought of the oral PCSK9 inhibitor intermediate MK-A is constructed through the key intermediates, the 5-bromo-1-pentene is innovatively used as the starting material, the reaction steps are shortened, the yield is obviously improved, the cost is reduced, and the method is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a preparation method of an oral PCSK9 inhibitor intermediate MK-A, an intermediate used therein and a synthesis method thereof. Background Art

[0002] MK-0616 is a macrocyclic peptide (a peptide structure with one or more rings spanning multiple amino acid residues) that binds to PCSK9 and inhibits the interaction between PCSK9 and the low-density lipoprotein receptor (LDL-R), thereby reducing LDL-C levels, elevated LDL-C being an important risk factor for cardiovascular disease.

[0003] The structure of MK-0616 is as follows:

[0004]

[0005] MK-A is an intermediate for synthesizing MK-0616. In the prior art, IN202017056126A discloses a method for preparing compound MK-A, which comprises reacting 4-(2-aminoethyl)benzylcarbamate hydrochloride to generate compound 77B through two steps of reaction, and then obtaining compound 81 (MK-A) from compound 77B through five steps of reaction (Step A-Step E). Seven steps of reaction are required, the steps are complicated, and the yield is low. Summary of the invention

[0006] Therefore, the technical problem to be solved by the present invention is to overcome the defects of the synthesis method of compound MK-A in the prior art, thereby providing a key intermediate used for oral PCSK9 inhibitor intermediate MK-A and a synthesis method of the intermediate.

[0007] To this end, the present invention provides the following technical solutions:

[0008] In a first aspect, the present invention provides an intermediate of an oral PCSK9 inhibitor intermediate MK-A.

[0009] The intermediate of the oral PCSK9 inhibitor intermediate MK-A is selected from the following formula I or formula II;

[0010]

[0011] Wherein, R1 is selected from BOC, CBZ, Trt or Fmoc. BOC is tert-butyloxycarbonyl, Cbz is benzyloxycarbonyl, FMOC is 9-fluorenylmethyloxycarbonyl, and Trt is trityl.

[0012] In a second aspect, the present invention provides a method for preparing the compound of formula I.

[0013] The preparation method of formula I comprises the following steps: adding a compound of formula III, a condensing agent, N,N-diisopropylethylamine, and monomethyl succinate to an organic solvent for mixing, quenching the mixed solution with an acidic aqueous solution and extracting to obtain an extract A, and purifying to obtain a compound of formula I;

[0014]

[0015] wherein R2 is selected from BOC, CBZ, Trt or Fmoc;

[0016] Optionally, the condensing agent is HATU; the organic solvent includes but is not limited to ethyl acetate.

[0017] In an optional embodiment, the molar ratio of the compound of formula III, the condensing agent, N, N-diisopropylethylamine, and monomethyl succinate is 4-6: 5-7: 9-11: 5-7. In some embodiments, the molar ratio of the compound of formula III, the condensing agent, N, N-diisopropylethylamine, and monomethyl succinate can be any one of 4: 7: 9: 7, 6: 5: 11: 5, 5: 6: 10: 6, 4: 5: 9: 5, 6: 7: 11: 7, or a range value between any two ratios.

[0018] In an optional embodiment, a compound of formula III, HATU, and N,N-diisopropylethylamine are added to an organic solvent, stirred, and then monomethyl succinate is added, and the reaction is carried out at room temperature for 3-5 hours. In some embodiments, the room temperature can be any one of 10°C, 15°C, 20°C, 25°C, and 30°C, or a range between any two values. The reaction time at room temperature can be any one of 3, 3.5, 4, 4.5, and 5 hours, or a range between any two values.

[0019] In an optional embodiment, the acidic aqueous solution is a hydrochloric acid aqueous solution; the concentration of the hydrochloric acid aqueous solution is 1wt%-5wt%. In some embodiments, the concentration of the hydrochloric acid aqueous solution can be any one of 1wt%, 2wt%, 3wt%, 4wt%, 5wt% or a range between any two values.

[0020] In an optional embodiment, before the purification, the extract A is dried and concentrated using Na2SO4;

[0021] In an optional embodiment, the extract A is purified by silica gel chromatography to obtain a compound having a structure shown in Formula I;

[0022] In an optional embodiment, petroleum ether is added to the extract A to precipitate solids, and the solid-liquid separation is performed to obtain a compound with a structure shown in Formula I.

[0023] In an optional embodiment, during the purification of the extract A by silica gel chromatography, a mixture of ethyl acetate and chloroform, and a mixture of ethyl acetate, chloroform and methanol are used as eluents in sequence, and the eluents of each stage are collected, and the same and similar components are combined to obtain a compound with a structure shown in Formula I;

[0024] In an optional embodiment, the volume ratio of ethyl acetate to chloroform in the mixture of ethyl acetate and chloroform is 5-7:4-6. The volume ratio of ethyl acetate to chloroform can be any one of 5:4, 7:6, 5:6, 7:4, 6:5 or a range between any two ratios.

[0025] In an optional embodiment, the volume ratio of ethyl acetate, chloroform and methanol in the mixture of ethyl acetate, chloroform and methanol is 5-7:4-6:1-2. The volume ratio of ethyl acetate, chloroform and methanol can be any one of 5:4:1, 7:6:2, 5:6:1, 7:4:2, 6:5:1, 6:5:2 or a range between any two ratios.

[0026] In an optional embodiment, the preparation method of the compound of the structure shown in Formula III is as follows: in an organic solvent, the compound of the structure shown in Formula VI and 5-bromo-1-pentene are mixed, base-catalyzed, and extracted, quenched and extracted to obtain an extract B, and purified to obtain a compound of the structure shown in Formula III;

[0027]

[0028] wherein R3 is selected from BOC, CBZ, Trt or Fmoc;

[0029] The CAS number of the compound represented by the structure of Formula VI is 1094689-12-9.

[0030] In some embodiments, the molar ratio of the compound of the structure shown in Formula VI to 5-bromo-1-pentene is 9-11: 11-13. In some embodiments, the molar ratio of the compound of the structure shown in Formula VI to 5-bromo-1-pentene can be any one of 9:11, 9:12, 9:13, 10:11, 10:12, 10:13, 11:11, 11:12, 11:13, or a range value between any two ratios.

[0031] In some embodiments, after the compound of the structure represented by Formula VI and 5-bromo-1-pentene are mixed, a base catalyst is added, and the base catalyst is selected from triethylamine and / or potassium carbonate;

[0032] In some embodiments, the base-catalyzed reaction conditions are: cooling the compound of the structure shown in Formula VI and the mixed solution of 5-bromo-1-pentene to 0-4°C, adding a base catalyst, heating to room temperature (10-30°C), and reacting for 1-3 hours. In some embodiments, the cooling step can be cooled to any one of 0°C, 1°C, 2°C, 3°C, and 4°C or a range between any two values. In some embodiments, the room temperature can be any one of 10°C, 15°C, 20°C, 25°C, and 30°C or a range between any two values. In some embodiments, the reaction time can be any one of 1 hour, 1.5 hours, 2 hours, 2.5 hours, and 3 hours or a range between any two values.

[0033] In some embodiments, the molar ratio of the compound of the structure shown in Formula VI, 5-bromo-1-pentene and the base catalyst is 9-11: 11-13: 15-20. In some embodiments, the molar ratio of the compound of the structure shown in Formula VI, 5-bromo-1-pentene and the base catalyst can be any one of 9:11:15, 9:12:18, 9:13:20, 10:11:15, 10:12:18, 10:13:20, 11:11:20, 11:12:18, 11:13:15, 10:12:20, 10:12:15, or a range value between any two ratios.

[0034] In an optional embodiment, the extract B is purified by silica gel chromatography.

[0035] In an optional embodiment, before the purification, the extract B is dried and concentrated using Na2SO4;

[0036] In an optional embodiment, the volume of extract B is concentrated to less than 20%.

[0037] In an optional embodiment, during the purification of extract B by silica gel chromatography, a mixture of ethyl acetate and n-hexane is used as the eluent, the eluates of each stage are collected, and the same and similar components are combined to obtain a compound of the structure shown in Formula III;

[0038] In an optional embodiment, the volume ratio of n-hexane to ethyl acetate is (1-3): 1. In an optional embodiment, the volume ratio of n-hexane to ethyl acetate can be any one of 1:1, 1:2, 1:3 or a range between any two values.

[0039] In some optional embodiments, the organic solvent includes but is not limited to dichloromethane.

[0040] In a third aspect, the present invention provides a method for preparing a compound of formula II using a compound of formula I.

[0041] The method for preparing a compound of formula II using a compound of formula I comprises the following steps: taking the compound of formula I and deprotecting it to obtain a compound of formula II;

[0042]

[0043] Wherein, R1 is selected from BOC, CBZ, Trt or Fmoc.

[0044] In an optional embodiment, the compound of formula I is dissolved in an organic solvent, and then a mixture of hydrochloric acid and dioxane is added, mixed and reacted to obtain the compound of formula II.

[0045] In an optional embodiment, the molar ratio of the compound of formula I to dioxane is 1:(3-10); the content of hydrochloric acid in the mixed solution of hydrochloric acid and dioxane is 3-5 mol / L. In some embodiments, the molar ratio of the compound of formula I to dioxane can be any one of 1:3, 1:5, 1:7, 1:9, 1:10 or a range between any two ratios. In some embodiments, the content of hydrochloric acid in the mixed solution of hydrochloric acid and dioxane can be any one of 3, 3.5, 4, 4.5, 5 mol / L or a range between any two values.

[0046] Optionally, the organic solvent includes but is not limited to dichloromethane. The molar volume ratio of the compound of formula I to the dichloromethane is 30 mmol: (50-70) ml.

[0047] In a third aspect, the present invention provides a method for preparing MK-A using the compound of formula II.

[0048] The method for preparing MK-A using the compound of formula II comprises the following steps:

[0049]

[0050] Dissolve the compound of formula II in an organic solvent or its aqueous solution, add NaHCO3, dropwise add the compound of formula V, react overnight at room temperature, and purify to obtain a compound of formula MK-A;

[0051]

[0052] In an optional embodiment, the molar ratio of the compound of formula II, NaHCO3, and the compound of formula V is 1:(1-5):(1-1.5). In some embodiments, the molar ratio of the compound of formula II, NaHCO3, and the compound of formula V can be any one of 1:1:1.5, 1:5:1, 1:3:1.2, 1:1:1, 1:5:1.5, 1:2:1.1, 1:2:1.25, or a range value between any two ratios.

[0053] And / or, in the mixed solution of the compound of formula V and tetrahydrofuran, the molar ratio of the compound of formula V to tetrahydrofuran is 20-25:10-20, mmol / mL.

[0054] Purification was carried out by silica gel chromatography using a gradient from a 20:1 volume ratio of dichloromethane to methanol to a 8:1 volume ratio of dichloromethane to methanol as the eluent.

[0055] The preparation method of the compound of the structure shown in formula V:

[0056]

[0057] Using 1-tert-butoxycarbonyl-(R)-2-methylpyrrolidine-2-carboxylic acid (CAS: 166170-15-6) as raw material, 1-tert-butoxycarbonyl-(R)-2-methylpyrrolidine-2-carboxylic acid (1 mmol) and DCC (0.8-1.3 mmol, dicyclohexylcarbodiimide) are dissolved in 20-40 mL of dichloromethane, and stirred at 0°C for 0.5-3 h. HOSU (0.8-1.3 mmol, N-hydroxysuccinimide) is added to the above solution, reacted at 0°C for 8 h, filtered, and the filtrate is spin-dried to obtain a compound of formula V.

[0058] The technical solution of the present invention has the following advantages:

[0059] 1. The key intermediates of the oral PCSK9 inhibitor intermediate MK-A provided by the present invention are innovatively designed and synthesized, and the operating conditions of each step are mild, the yield is high, the cost is low, the toxic impurities are small, and the steps are few, which is conducive to industrial production.

[0060] 2. The preparation of the oral PCSK9 inhibitor intermediate MK-A provided by the present invention constructs a synthetic idea of ​​the oral PCSK9 inhibitor intermediate MK-A through these key intermediates. 5-bromo-1-pentene is innovatively used as the starting material, and MK-A can be prepared in only four steps, which shortens the reaction steps, significantly improves the yield, reduces the cost, and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0062] Figure 1 is the mass spectrum of the compound of formula III prepared in Example 1 of the present invention;

[0063] Figure 2 is the mass spectrum of the compound of formula I prepared in Example 3 of the present invention;

[0064] Figure 3 is the mass spectrum of the compound of formula II obtained in Example 5 of the present invention;

[0065] Figure 4 It is the mass spectrum of the compound of formula MK-A prepared in Example 7 of the present invention. DETAILED DESCRIPTION

[0066] The following examples are provided for a better understanding of the present invention, but are not intended to limit the best mode of implementation, nor to limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the inspiration of the present invention or by combining the features of the present invention with other prior arts shall fall within the protection scope of the present invention.

[0067] If no specific experimental steps or conditions are specified in the examples, the conventional experimental steps or conditions described in the literature in the field can be used. If no manufacturer is specified for the reagents or instruments used, they are all conventional reagent products that can be obtained commercially.

[0068] In the following experiments, the silica gel in the silica gel column was purchased from Qingdao Ocean Chemical Plant; the silica gel particle size was 100-200 mesh.

[0069] Shimadzu LC-MS mass spectrometry parameters: positive ion mode; scan 200-2000 m / z; scan speed 1875 u / sec; interface temperature 350°C; desolvation tube (DL) temperature 250°C; nebulizer gas flow rate 1.5 L / min; heating block temperature 200°C; dryer flow rate 15 L / min.

[0070] Example 1

[0071] This embodiment provides a compound of formula III, and its reaction equation and preparation method are as follows:

[0072]

[0073] In a three-necked flask filled with 200 ml of DCM (dichloromethane), 100 mmol of the compound of formula VI (CAS: 1094689-12-9) and 120 mmol of 5-bromo-1-pentene were added, mixed and stirred to clarify; the temperature was lowered to about 0°C, 200 mmol of triethylamine was added dropwise, and after stirring for 0.5 h, the temperature was raised to room temperature (25°C) and the reaction was continued for 2 h; 200 ml of water was added to quench, and the mixture was extracted, dried with Na2SO4, and concentrated. The concentrate was purified by a silica gel column, and 29.3 g of the compound of formula III was obtained by rotary evaporation, with a yield of 92%, and MS=320.1 (M+H + ). Silica gel column purification method: ethyl acetate: n-hexane = 1:3 (V:V), the required volume is 830 ml, then ethyl acetate: n-hexane = 1:1 (V:V), the required volume is 360 ml; the volume of the solution containing the target compound eluate is 276 ml.

[0074] The compound of formula III obtained in Example 1 was qualitatively detected by high performance liquid phase tandem mass spectrometry. The MS (mass spectrum) of the compound of formula III is as follows: Figure 1 shown.

[0075] Example 2

[0076]

[0077] Into a three-necked flask filled with 200 ml of DCM, 100 mmol of the compound of formula VI and 120 mmol of 5-bromo-1-pentene were added, and the mixture was stirred to clarify; the temperature was lowered to about 0°C, 150 mmol of potassium carbonate was added, and after stirring for 0.5 h, the temperature was raised to room temperature (25°C) and the reaction was continued for 2 h; 200 ml of water was added to quench, and the mixture was extracted, dried over Na2SO4, and concentrated. The concentrate was purified by a silica gel column, and 27.6 g of the compound of formula III was obtained by rotary evaporation, with a yield of 87%, and MS=319.4 (M+H + Silica gel column purification method: ethyl acetate: n-hexane = 1:3 (V:V), the required volume is 860 ml; then ethyl acetate: n-hexane = 1:1 (V:V), the required volume is 330 ml; the volume of the eluate containing the target compound is collected to be 265 ml.

[0078] Example 3

[0079]

[0080] Into a three-necked flask filled with 150 ml of ethyl acetate, 50 mmol of the compound of formula III (prepared in Example 1), 60 mmol of HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, CAS registration number 148893-10-1), and 100 mmol of DIPEA (N,N-diisopropylethylamine) were added, and after stirring at room temperature (25°C), 60 mmol of monomethyl succinate was added; after reacting at room temperature (25°C) for 4 hours, 200 ml of 5 wt% aqueous hydrochloric acid solution was added to quench, and the mixture was extracted, dried over Na2SO4, and concentrated. The concentrate was purified by a silica gel column and rotary evaporated to obtain 16.5 g of the compound of formula I, with a yield of 76.3%, MS=434.3 (M+H + Silica gel column purification method: ethyl acetate: chloroform = 6:5 (V:V), the required volume is 480 ml; then ethyl acetate: chloroform: methanol = 6:5:1 (V:V:V), the required volume is 340 ml; the volume of the eluate containing the target compound is collected to 240 ml.

[0081] The MS of the product formula I compound is as follows: Figure 2 shown.

[0082] Example 4

[0083]

[0084] To a three-necked flask containing 150 ml of ethyl acetate, add 50 mmol of the compound of formula III, 60 mmol of HATU, and 100 mmol of DIPEA; after stirring at room temperature, add 60 mmol of monomethyl succinate, react at room temperature for 4 hours, add 200 ml of 5 wt% aqueous hydrochloric acid solution to quench, extract, and dry with Na2SO4. Take out 140 ml of ethyl acetate solution containing the compound of formula I, and add it dropwise to 1400 ml of petroleum ether, stir well, filter, rinse twice with petroleum ether, and dry to obtain 18.8 g of the compound of formula I, with a yield of 86.9%, MS=434.3 (M+H + ).

[0085] Example 5

[0086]

[0087] 30 mmol of the compound of formula I was placed in 60 ml of 0.5 mmol / ml DCM solution, a mixture of HCl / dioxane was added (hydrochloric acid was added to 150 mmol 1,4-dioxane to a concentration of 4 mol / L), and the resulting solution was stirred at room temperature overnight. The mixture was concentrated to obtain 9.2 g of the compound of formula II, with a yield of 92.2%, MS = 334.2 (M+H +).

[0088] MS of product II compound is as follows Figure 3 shown.

[0089] Example 6

[0090]

[0091] Using 1-tert-butoxycarbonyl-(R)-2-methylpyrrolidine-2-carboxylic acid (CAS: 166170-15-6) as raw material, 1-tert-butoxycarbonyl-(R)-2-methylpyrrolidine-2-carboxylic acid (1 mmol) and DCC (1.1 mmol, dicyclohexylcarbodiimide) were dissolved in 30 mL of dichloromethane, and stirred at 0°C for 1 h. HOSU (1.1 mmol, N-hydroxysuccinimide) was added to the above solution, reacted at 0°C for 8 h, filtered, and the filtrate was spin-dried to obtain a compound of formula V. Dissolve 20 mmol of the compound of formula II in 40 ml of tetrahydrofuran aqueous solution (the volume ratio of THF:H2O is 1:1), add 40 mmol of solid NaHCO3, and stir until clear; add dropwise 15 mL of THF solution containing 22 mmol of the compound of formula V, wherein the molar volume ratio of the compound of formula V to THF is 22:15, mmol / mL; after the addition is complete, continue stirring at room temperature (25°C) overnight. The mixture is concentrated and then purified by silica gel column to obtain 8.3 g of MK-A, with a yield of 76.3%, MS=544.3 (M+H + ). Silica gel column purification method: dichloromethane:methanol=20:1 (V:V), then dichloromethane:methanol=8:1 (V:V).

[0092] Example 7

[0093]

[0094] Using 1-tert-butoxycarbonyl-(R)-2-methylpyrrolidine-2-carboxylic acid (CAS: 166170-15-6) as raw material, 1-tert-butoxycarbonyl-(R)-2-methylpyrrolidine-2-carboxylic acid (1 mmol) and DCC (1.1 mmol, dicyclohexylcarbodiimide) were dissolved in 30 mL of dichloromethane, and stirred at 0°C for 1 h. HOSU (1.1 mmol, N-hydroxysuccinimide) was added to the above solution, reacted at 0°C for 8 h, filtered, and the filtrate was spin-dried to obtain a compound of formula V. Then, 20 mmol of PIA-03 (Formula II) was dissolved in 40 ml of THF aqueous solution (the volume ratio of THF:H2O was 1:1), 40 mmol of solid NaHCO3 was added, and stirred until clear; a THF solution containing 25 mmol of the compound of Formula V was added dropwise, wherein the molar volume ratio of the compound of Formula V to THF was 25:10, mmol / mL; after the addition was completed, stirring was continued at room temperature overnight. The mixture was concentrated and then purified by a silica gel column to obtain 9.3 g of MK-A, with a yield of 85.5%, MS = 544.3 (M+H + ). Silica gel column purification method: dichloromethane:methanol=20:1 (V:V), then dichloromethane:methanol=8:1 V:V).

[0095] The MS of the product MK-A compound is as follows Figure 4 shown.

[0096] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the scope of protection of the invention.

Claims

1. An intermediate of an oral PCSK9 inhibitor intermediate MK-A, characterized in that: It is selected from the following formula I or formula II; Wherein, R1 is selected from BOC, CBZ, Trt or Fmoc.

2. The preparation method of formula (I) according to claim 1, characterized in that: The method comprises the following steps: adding a compound having a structure shown in formula III, a condensing agent, N,N-diisopropylethylamine and monomethyl succinate into an organic solvent and mixing them, quenching the mixed solution with an acidic aqueous solution and extracting to obtain an extract A, and purifying to obtain a compound having a structure shown in formula I; wherein R2 is selected from BOC, CBZ, Trt or Fmoc; Optionally, the condensation agent is HATU; and the organic solvent includes ethyl acetate.

3. The preparation method of formula (I) according to claim 2, characterized in that: The molar ratio of the compound of formula III, the condensing agent, N,N-diisopropylethylamine and monomethyl succinate is 4-6:5-7:9-11:5-7; And / or, adding a compound of formula III, HATU, and N,N-diisopropylethylamine to an organic solvent, stirring, and then adding monomethyl succinate, and reacting at room temperature for 3-5 hours; And / or, the acidic aqueous solution is a hydrochloric acid aqueous solution; the concentration of the hydrochloric acid aqueous solution is 1wt%-5wt%; And / or, before the purification, the extract A is dried and concentrated using Na2SO4; And / or, purifying the extract A by silica gel chromatography to obtain a compound with a structure shown in Formula I; Alternatively, petroleum ether is added to the extract A to precipitate solids, and the solid-liquid separation is performed to obtain a compound with a structure shown in Formula I.

4. The preparation method of formula (I) according to claim 3, characterized in that: In the process of purifying the extract A by silica gel chromatography, a mixture of ethyl acetate and chloroform, and a mixture of ethyl acetate, chloroform and methanol are used as eluents in sequence, and the eluents of each stage are collected, and the same and similar components are combined to obtain a compound with a structure shown in Formula I; Optionally, the volume ratio of ethyl acetate to chloroform in the mixture of ethyl acetate and chloroform is 5-7:4-6, and the volume ratio of ethyl acetate, chloroform and methanol in the mixture of ethyl acetate, chloroform and methanol is 5-7:4-6:1-2.

5. The preparation method of formula (I) according to claim 2, characterized in that: The preparation method of the compound of formula III comprises: mixing the compound of formula VI and 5-bromo-1-pentene in an organic solvent, catalyzing with base, quenching and extracting to obtain extract B, and purifying to obtain the compound of formula III; wherein R3 is selected from BOC; Optionally, the molar ratio of the compound of the structure shown in Formula VI to 5-bromo-1-pentene is 9-11:11-13; Optionally, after the compound of the structure shown in Formula VI and 5-bromo-1-pentene are mixed, a base catalyst is added, and the base catalyst is selected from triethylamine and / or potassium carbonate; Optionally, the base-catalyzed reaction conditions are: cooling the mixed solution of the compound of the structure represented by Formula VI and 5-bromo-1-pentene to 0-4° C., adding a base catalyst, heating to room temperature, and reacting for 1-3 hours; Optionally, the molar ratio of the compound of the structure shown in Formula VI, 5-bromo-1-pentene and the base catalyst is 9-11:11-13:15-20.

6. The preparation method of formula (I) according to claim 5, characterized in that: Extract B was purified by silica gel chromatography; And / or, before the purification, the extract B is dried and concentrated using Na2SO4; Optionally, the volume of extract B is concentrated to less than 20%.

7. The preparation method of formula (I) according to claim 6, characterized in that: In the process of purifying the extract B by silica gel chromatography, a mixture of ethyl acetate and n-hexane is used as the eluent, the eluates of each stage are collected, and the same and similar components are combined to obtain a compound with a structure shown in Formula III; Optionally, the volume ratio of n-hexane to ethyl acetate is (1-3):

1.

8. A method for preparing a compound of formula II using a compound of formula I, characterized in that: The method comprises the following steps: taking a compound of formula I and subjecting it to deprotection to obtain a compound of formula II; Wherein, R1 is selected from BOC, CBZ, Trt or Fmoc.

9. The method for preparing the compound of formula II according to claim 8, characterized in that: Dissolving the compound of formula I in an organic solvent, adding a mixture of hydrochloric acid and dioxane, mixing and reacting to obtain a compound of formula II; Optionally, the molar ratio of the compound of formula I to dioxane is 1:(3-10); Optionally, the content of hydrochloric acid in the mixed solution of hydrochloric acid and dioxane is 3-5 mol / L.

10. A method for preparing MK-A using a compound of formula II, characterized in that: The steps include: Dissolve the compound of formula II in an organic solvent or its aqueous solution, add NaHCO3, dropwise add the compound of formula V, react at room temperature overnight, and purify to obtain a compound of formula MK-A; Optionally, the molar ratio of the compound of formula II, NaHCO3, and the compound of formula V is 1:(1-5):(1-1.5); and / or, in the mixed solution of the compound of formula V and tetrahydrofuran, the molar volume ratio of the compound of formula V to tetrahydrofuran is 20-25:10-20, mmol / mL; Purification was carried out by silica gel chromatography using a gradient from a 20:1 volume ratio of dichloromethane to methanol to a 8:1 volume ratio of dichloromethane to methanol as the eluent.

Images