Preparation method of 3-boron-L-phenylalanine or derivative thereof

Abstract

The invention provides a preparation method of 3-boron-L-phenylalanine or a derivative of 3-boron-L-phenylalanine. The preparation method provided by the invention comprises the step of preparing 3-boron-L-phenylalanine as shown in a formula (VI) or a derivative thereof by taking a compound as shown in a formula (III) as a raw material. The method has the advantages of mild reaction conditions, short route, high yield, few byproducts and low cost, and does not need an extremely low temperature condition process or complicated purification steps. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry. Specifically, the present invention relates to a method for preparing 3-boron-L-phenylalanine or its derivatives. Background Art

[0002] Boron neutron capture therapy (BNCT) is an effective method for treating tumors. In boron neutron capture therapy, BPA (Chinese name: p-dihydroxyboranophenylalanine or 4-boron-L-phenylalanine) is often used as a drug to treat patients. Through experiments, it is found that the solubility of 4-boron-L-phenylalanine is poor, and the solubility of 3-BPA (3-boron-L-phenylalanine, also known as (S)-2-amino-3-(3-boronophenyl)propanoic acid) is better than that of 4-boron-L-phenylalanine. It can be seen that 3-BPA has broad application prospects in boron neutron capture therapy.

[0003] However, the existing technology has less research on the preparation methods of 3-boron-L-phenylalanine and its derivatives, and the preparation methods of 3-boron-L-phenylalanine disclosed in the existing literature have defects such as long routes, difficult process amplification of preparation conditions, high material costs, and low yields.

[0004] Therefore, there is an urgent need to develop a new preparation method for 3-boron-L-phenylalanine or its derivatives. Summary of the Invention

[0005] In view of the disadvantages of the existing technology, such as too long process time and cumbersome process steps, the present invention provides a method for preparing 3-boron-L-phenylalanine or its derivatives that does not require complicated reaction steps and is environmentally friendly, effectively saving time and cost, and improving process efficiency. Accordingly, the 3-boron-L-phenylalanine prepared by the preparation method of the present invention also has advantages such as high chemical purity and high optical purity.

[0006] To achieve the above object, the present invention provides the following method for preparing 3-boron-L-phenylalanine or its derivatives.

[0007] The present invention provides a method for preparing 3-boron-L-phenylalanine or its derivatives, wherein the method comprises preparing 3-boron-L-phenylalanine or its derivatives represented by formula (VI) using a compound of formula (III) as a raw material:

[0008]

[0009] Wherein, R1 and R2 each independently selected from H or an amino protecting group; at least one of R1 and R2 is an amino protecting group; R3 is selected from H, an alkyl group having 1-3 carbon atoms or a cycloalkyl group having 3-7 carbon atoms.

[0010] According to some specific embodiments of the present invention, the method includes preparing a compound of formula (III) using a compound of formula (I) and a compound of formula (II) as raw materials, and then preparing 3-boron-L-phenylalanine or its derivative shown in formula (VI) using the compound of formula (III) as a raw material:

[0011]

[0012] Wherein,

[0013] R1 and R2 are each independently selected from H or an amino protecting group;

[0014] R3 is selected from H, an alkyl group having 1-3 carbon atoms or a cycloalkyl group having 3-7 carbon atoms;

[0015] R4 is selected from Br, Cl or I;

[0016] Each R5 is independently selected from an alkyl group having 1-10 carbon atoms, or an aryl group having 4-14 carbon atoms;

[0017] Each R 51 is independently selected from an alkyl group having 1-10 carbon atoms.

[0018] According to some specific embodiments of the present invention, the method includes: preparing a compound of formula (III) using a compound of formula (I) and a compound of formula (II) as raw materials;

[0019] wherein R1, R2, R3, R4 and R5 are as described above.

[0020] According to some specific embodiments of the present invention, wherein each R5 is independently selected from an alkyl group having 1-5 carbon atoms, or an aryl group having 6-10 carbon atoms; each R 51 is independently selected from an alkyl group having 1-5 carbon atoms.

[0021] According to some specific embodiments of the present invention, wherein R3 is H.

[0022] According to some specific embodiments of the present invention, wherein at least one of R1 and R2 is an amino protecting group. In some embodiments, R1 and R2 are respectively amino protecting groups. In other embodiments, one of R1 and R2 is an amino protecting group.

[0023] According to some specific embodiments of the present invention, wherein the amino protecting groups are each independently selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), trityl (Trt) or p-toluenesulfonyl (Tos).

[0024] In some embodiments, R1 and R2 are amino protecting groups, such as tert-butoxycarbonyl (Boc).

[0025] In some embodiments, R1 is H, and R2 is an amino protecting group, such as tert-butoxycarbonyl (Boc).

[0026] In some embodiments, R2 is H, and R1 is an amino protecting group, such as tert-butoxycarbonyl (Boc).

[0027] In some embodiments, R1 is H, R2 is tert-butoxycarbonyl, and R3 is H.

[0028] According to some specific embodiments of the present invention, each R5 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trimethylsilyl or phenyl.

[0029] According to some specific embodiments of the present invention, the compound of formula (I) is selected from one or more of tributyl borate, trimethyl borate, triethyl borate, triisopropyl borate, tri-n-propyl borate, tri-tert-butyl borate, trimethylsilyl borate, and trimethylphenyl borate.

[0030] According to some specific embodiments of the present invention, the method includes using isopropylmagnesium chloride-lithium chloride as a Grignard reagent and using the compound of formula (I) and the compound of formula (II) as raw materials to prepare the compound of formula (III).

[0031] According to some specific embodiments of the present invention, the method includes sequentially adding isopropylmagnesium chloride-lithium chloride and the compound of formula (I) to the reaction system at a reaction system temperature less than or equal to 10 °C.

[0032] According to some specific embodiments of the present invention, the method includes sequentially adding isopropylmagnesium chloride-lithium chloride and the compound of formula (I) to the reaction system at a reaction system temperature less than or equal to 10 °C under the protection of an inert gas.

[0033] According to some specific embodiments of the present invention, the method includes adding the isopropylmagnesium chloride-lithium chloride solution or the compound of formula (I) dropwise under the protection of an inert gas at a reaction system temperature of -30 °C to 10 °C.

[0034] According to some specific embodiments of the present invention, the inert gas can be nitrogen, argon, or other conventional inert gases in the art.

[0035] According to some specific embodiments of the present invention, the method includes adding isopropylmagnesium chloride-lithium chloride dropwise to the reaction system at a reaction system temperature of -20 °C to 5 °C.

[0036] According to some specific embodiments of the present invention, the method includes adding isopropylmagnesium chloride-lithium chloride dropwise to the reaction system at a reaction system temperature of 0 °C.

[0037] According to some specific embodiments of the present invention, after adding isopropylmagnesium chloride-lithium chloride dropwise to the reaction system, stirring is carried out at a temperature less than or equal to 10 °C for 0.5 - 4 h; then the compound of formula (I) is added.

[0038] According to some specific embodiments of the present invention, the method includes adding the compound of formula (I) dropwise to the reaction system at a reaction system temperature of -10 °C to 0 °C. Further, the method includes adding the compound of formula (I) dropwise to the reaction system at a reaction system temperature of -10 °C to -5 °C.

[0039] According to some specific embodiments of the present invention, the method includes adding the compound of formula (I) dropwise to the reaction system at a reaction system temperature of 0 °C.

[0040] According to some specific embodiments of the present invention, after adding the compound of formula (I) dropwise to the reaction system, the reaction system is allowed to return to room temperature naturally and stirred for 4 - 20 h.

[0041] According to some specific embodiments of the present invention, after the reaction of preparing the compound of formula (III) using the compound of formula (I) and the compound of formula (II) as raw materials is completed, a saturated aqueous solution of ammonium chloride is added for quenching.

[0042] According to some specific embodiments of the present invention, during the process of adding the saturated aqueous solution of ammonium chloride for quenching, the temperature of the reaction system is controlled not to be higher than 10 °C.

[0043] According to some specific embodiments of the present invention, before adding the saturated aqueous solution of ammonium chloride dropwise, the temperature of the reaction system is cooled to not higher than 0 °C.

[0044] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (II) to isopropylmagnesium chloride-lithium chloride is 1:(3 - 6).

[0045] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (II) to the compound of formula (I) is 1:(1.2 - 3.0).

[0046] According to some specific embodiments of the present invention, the method includes using tetrahydrofuran (THF) as a solvent and using the compound of formula (I) and the compound of formula (II) as raw materials to prepare the compound of formula (III). Further, the mass ratio of the compound of formula (II) to the volume of tetrahydrofuran (THF) is 1:(4 - 10). Further, the mass-volume ratio (g / ml) of the compound of formula (II) to tetrahydrofuran (THF) is 1:(4 - 10). Furthermore, the tetrahydrofuran is anhydrous tetrahydrofuran (anhydrous THF).

[0047] According to some specific embodiments of the present invention, after the reaction of the compound of formula (I) and the compound of formula (II) is completed, an acid solution is added to the reaction system to adjust the pH of the reaction system to 2.5 - 3.5.

[0048] According to some specific embodiments of the present invention, after the reaction of the compound of formula (I) and the compound of formula (II) is completed, a saturated aqueous solution of ammonium chloride is added for quenching, and then an acid solution is added to the reaction system to adjust the pH of the reaction system to 2.5 - 3.5.

[0049] According to some specific embodiments of the present invention, after adding an aqueous hydrochloric acid solution to adjust the pH of the reaction system to 2.5 - 3.5, it is left standing, and liquid separation is carried out to obtain an organic phase. The aqueous phase is extracted with an extraction solvent, and the organic phases are combined, and the extraction solvent and the organic solvent are removed to obtain a concentrate of the compound of formula (III).

[0050] According to some specific embodiments of the present invention, the acid solution can be selected from an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution.

[0051] According to some specific embodiments of the present invention, in the acid solution, H + has a concentration of 1M.

[0052] According to some specific embodiments of the present invention, the extraction solvent is selected from one or a mixture of more of ethyl acetate, dichloromethane, and chloroform.

[0053] According to some specific embodiments of the present invention, the method includes reacting the compound of formula (III) in the presence of hydrochloric acid to obtain the compound of formula (V); and then using the compound of formula (V) as a raw material to prepare 3-boron-L-phenylalanine or its derivative shown in formula (VI);

[0054]

[0055] According to some specific embodiments of the present invention, the compound of formula (III) reacts in the presence of hydrochloric acid at 20°C to 30°C to obtain the compound of formula (V).

[0056] In some embodiments, the acid is hydrochloric acid. That is, the compound of formula (V) is a hydrochloride compound.

[0057] According to some specific embodiments of the present invention, the method includes: mixing and reacting the compound of formula (III) with a dioxane solution of hydrochloric acid, precipitating, and filtering to obtain the hydrochloride compound represented by the compound of formula (V);

[0058]

[0059] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (III) to the hydrochloric acid is 1:(2 - 3).

[0060] According to some specific embodiments of the present invention, the solvent of the hydrochloric acid is dioxane. The hydrochloric acid is added to the reaction system in the form of a hydrochloric acid / dioxane solution.

[0061] According to some specific embodiments of the present invention, the concentration of hydrochloric acid in the hydrochloric acid / dioxane solution is 2 - 8 mol / L. For example, the concentration of hydrochloric acid in the hydrochloric acid / dioxane solution is 2 mol / L, 3 mol / L, 4 mol / L, 5 mol / L, 6 mol / L, or 8 mol / L.

[0062] According to some specific embodiments of the present invention, the solvent of the compound of formula (III) is dichloromethane (DCM).

[0063] Thus, it can be seen that the solvent of the reaction system for preparing the compound of formula (V) from the compound of formula (III) in the method is an organic solvent system. It can be imagined that hydrochloric acid is a strong acid, and there are safety hazards due to the violent reaction in an aqueous solvent, while the reaction of hydrochloric acid in an organic solvent is milder and the reaction is safer.

[0064] According to some specific embodiments of the present invention, the method includes subjecting the compound of formula (V) to an alkalization reaction to obtain 3-borono-L-phenylalanine or its derivative represented by formula (VI):

[0065]

[0066] According to some specific embodiments of the present invention, the alkalization reaction includes subjecting the compound of formula (V) to an alkalization reaction in the presence of a base to obtain 3-borono-L-phenylalanine or its derivative represented by formula (VI).

[0067] According to some specific embodiments of the present invention, the method includes: subjecting the compound of formula (V) to an alkalization reaction in the presence of a base, and after the reaction, adding acetone to the reaction system, precipitating, and filtering to obtain 3-boron-L-phenylalanine or its derivative shown in formula (VI).

[0068] According to some specific embodiments of the present invention, the method includes mixing the compound of formula (V) with a reaction solvent, then adding a base to the reaction system, and after the reaction, adding acetone to the reaction system, precipitating, and filtering to obtain 3-boron-L-phenylalanine or its derivative shown in formula (VI).

[0069] During the reaction of the hydrochloride compound shown by the formula (V) with the base, hydrochloric acid in the hydrochloride compound undergoes an acid-base neutralization reaction with the base, and thus 3-boron-L-phenylalanine or its derivative shown in formula (VI) is prepared.

[0070] According to some specific embodiments of the present invention, the reaction temperature for subjecting the compound of formula (V) to an alkalization reaction is 20 °C to 30 °C.

[0071] According to some specific embodiments of the present invention, in the alkalization reaction, the molar ratio of the compound of formula (V) to the base used is 1:(0.8 - 1.0). The molar ratio of the hydrogen ion of the compound of formula (V) to the hydroxide ion (OH - ) of the base is 1:(0.8 - 1.0).

[0072] The base used for alkalization can be a base commonly used in the art. In some embodiments, the base is selected from but not limited to metal hydroxides, such as hydroxides of alkali metals or alkaline earth metals, and further for example, at least one selected from sodium hydroxide (NaOH), potassium hydroxide (KOH), barium hydroxide (Ba(OH)2), and calcium hydroxide (Ca(OH)2).

[0073] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (V) to the base can be 1:0.8, 1:0.85, 1:0.9, 1:0.95, or 1:1.

[0074] According to some specific embodiments of the present invention, the base is added to the reaction system in the form of an aqueous solution of the base.

[0075] According to some specific embodiments of the present invention, the concentration of the aqueous solution of the base is 30 - 50%. For example, the concentration can be 30%, 35%, 40%, 45%, or 50%.

[0076] According to some specific embodiments of the present invention, after the compound of formula (V) is mixed with the reaction solvent, the concentration of the resulting solution of the compound of formula (V) is 1.5 - 2.5 mol / L.

[0077] According to some specific embodiments of the present invention, the reaction solvent of the compound of formula (V) is water.

[0078] According to some specific embodiments of the present invention, the compound of formula (V) is an acid salt, such as hydrochloride or sulfate.

[0079] According to some specific embodiments of the present invention, the molar ratio of the hydrogen ion of hydrochloric acid of the compound of formula (V) to the hydroxide ion (OH - ) of the base is 1:(0.8 - 1.0).

[0080] According to some specific embodiments of the present invention, the method includes basifying the compound of formula (V), adding acetone, stirring to precipitate, and filtering to obtain the compound of formula (VI).

[0081] According to some specific embodiments of the present invention, the volume of acetone used is 8 - 15 times the volume of the reaction system containing the compound of formula (V) before adding the base.

[0082] The reaction system containing the compound of formula (V) before adding the base refers to the reaction system after adding the compound of formula (V) to the reaction solvent and before adding the base.

[0083] According to some specific embodiments of the present invention, the volume of acetone used is 8 - 15 times the volume of the aqueous solution of the compound of formula (V). For example, it can be 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times or 15 times.

[0084] According to some specific embodiments of the present invention, the method further includes stirring for 0.5 - 2 h after adding acetone, and then filtering to obtain the compound of formula (VI).

[0085] Currently, since the selected boron ester is enriched with 10B, and most of the boron esters enriched with 10B are not commercially available compounds, the process complexity is high and the time consumed is long, resulting in the inability to prepare 3 - BPA or its derivatives with high yield. And this problem is solved by adopting the above method of the present invention.

[0086] According to some specific embodiments of the present invention, the method further includes preparing the compound of formula (I) using the compound of formula (IV) as a raw material:

[0087]

[0088] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (IV) to R5OH is 1:3 - 5. Further, the molar ratio of the compound of formula (IV) to R5OH can be 1:3, 1:4 or 1:5.

[0089] According to some specific embodiments of the present invention, the selection of R5 in R5OH can refer to the previous description.

[0090] According to some specific embodiments of the present invention, sulfuric acid is added to the reaction solution containing the compound of formula (IV) (boric acid - 10 B) and R5OH, and the mixture is stirred at 120 - 150 °C for 10 - 14 h; after the reaction is completed, the compound shown in formula (I) is obtained.

[0091] According to some specific embodiments of the present invention, the reaction solvent in the reaction solution of the compound of formula (IV) is selected from toluene.

[0092] According to some specific embodiments of the present invention, the molar ratio of the compound of formula (IV) to the sulfuric acid (H2SO4) is 1:0.01 - 0.03. For example, the molar ratio of the compound of formula (IV) to the sulfuric acid (H2SO4) can be 1:0.01, 1:0.02 or 1:0.03.

[0093] According to some specific embodiments of the present invention, after the reaction is completed, the remaining R5OH is distilled out, the crude product is distilled, and then the product is collected to obtain the compound shown in formula (I).

[0094] According to some specific embodiments of the present invention, to the solution system of toluene and R5OH of boric acid - 10 B, H2SO4 is added; the mixture is stirred at 120 - 150 °C for 10 - 14 h; after the reaction is completed, the remaining R5OH is distilled out, and the crude product is distilled in an oil pump until the temperature of the mixture reaches 120 - 130 °C; then the product is collected to obtain the borate compound shown in formula (I).

[0095] According to some specific embodiments of the present invention, the method comprises the following steps:

[0096] Under an inert gas atmosphere, isopropylmagnesium chloride - lithium chloride solution is added dropwise to the organic solvent solution of the compound of formula (II), stirred, and then the compound of formula (I) is added dropwise and stirred to react to obtain the compound of formula (III);

[0097] Hydrochloric acid dioxane solution is added to the compound of formula (III) to react to obtain the compound of formula (V);

[0098] The compound of formula (V) is alkalized, acetone is added for precipitation, and the compound of formula (VI) is obtained by filtration;

[0099] Wherein, during the alkalization process, the molar ratio of the compound of formula (V) to the base used is 1:0.8 - 1.0;

[0100]

[0101] According to some specific embodiments of the present invention, among them, the configuration of the compound of formula (VI) is the same as that of the compound of formula (II).

[0102] According to some specific embodiments of the present invention, among them, referring to the foregoing preparation steps, when R3 is selected from H, it is the preparation method of 3-boro-L-phenylalanine. When R3 is selected from other groups, it is the preparation method of 3-boro-L-phenylalanine derivatives.

[0103]

[0104] The present invention uses boron-10 ( 10 B) element. It can be imagined that the method of the present invention can prepare 10 B compounds, and can also prepare natural boron compounds.

[0105] In summary, the present invention provides a preparation method of 3-boro-L-phenylalanine or its derivatives. The preparation method of the present invention has the following advantages:

[0106] The preparation method of 3-borono-L-phenylalanine or its derivatives provided by the present invention uses amino-protected 3-halo-L-phenylalanine or its derivatives as starting materials, selects isopropylmagnesium chloride-lithium chloride for reaction, and then drops a boronic acid ester compound for reaction to obtain an intermediate amino-protected 3-boro-L-phenylalanine or its derivatives; then deprotects to form a hydrochloride salt, and then alkalizes to obtain the target product. Using the route and reagents of the present invention, the reaction conditions are mild, extremely low temperature conditions are not required, and there is no need for complicated purification steps. The route is short, the yield is high, the by-products are few, and the cost is low.

[0107] The 3-borono-L-phenylalanine or its derivatives prepared by the preparation method of the present invention also have the advantages of high chemical purity, high optical purity, and high isotope purity. Detailed implementation mode

[0108] The following details the implementation process and beneficial effects of the present invention through specific examples, aiming to help readers better understand the essence and characteristics of the present invention, and shall not be used as a limitation on the scope of implementation of this case.

[0109] Example 1:

[0110]

[0111] Synthesis of Intermediate 1:

[0112]

[0113] To boric acid- 10 H2SO4 (1.61 g, 16.4 mmol, 873 μL, 0.02 eq) was added to a solution of B (50.0 g, 819 mmol, 1.00 eq) in toluene (350 mL) and n-butanol (300 mL, 4.00 eq). The mixture was stirred at 135 °C for 12 h. TLC (DCM / MeOH = 10 / 1, Rf = 0.21) showed that the starting materials were completely consumed and 1 new spot was formed. TLC showed a clean reaction. The 2 reactions were combined for inspection. The remaining n-butanol was distilled off, and the crude product was distilled in an oil pump until the temperature of the mixture reached 120 - 130 °C. Then the product was collected as a clear colorless liquid to obtain Intermediate 1 (170 g, 741 mmol, 45.2%).

[0114] 1 1H NMR (400 MHz, CHLOROFORM-d) δ 3.78 (t, J = 6.54 Hz, 6H), 1.25 - 1.65 (m, 12H), 0.93 (t, J = 7.34 Hz, 9H).

[0115] Synthesis of Intermediate 2:

[0116]

[0117] Under a nitrogen atmosphere, 160 ml of anhydrous THF and Boc-D-3-iodophenylalanine (40.0 g, 102 mmol, 1.00 eq) were added, stirred and dissolved, and cooled to below 0 °C. Isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution (1.3 M, 240 mL, 3.00 eq) was slowly added. During the addition, the temperature inside the reactor was controlled below 5 °C. After the addition was complete, stirring was continued at this temperature for 3 h. Intermediate 1 (47.2 g, 204 mmol, 2 eq) was added dropwise. During the addition, the temperature was controlled at -10 °C to -5 °C. After the addition was complete, the temperature was allowed to return to room temperature naturally and stirring was continued overnight. LC-MS showed that the reactants were completely consumed and the required mass was detected. After cooling to 0 °C, the reaction was quenched with saturated aqueous ammonium chloride solution (500 ml) and the mixture was adjusted to pH = 3 with 1 M hydrochloric acid. Then it was extracted with EtOAc (300 mL × 5). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 20 / 1 to 10 / 1) to obtain a yellow solid, giving Intermediate 2 (27.4 g, 89 mmol, 87.4%).

[0118] 11H NMR (400 MHz, METHANOL-d4) δ 7.46 (s, 2H), 7.23 (d, J = 3.63 Hz, 2H), 4.18 - 4.40 (m, 1H), 2.72 - 3.18 (m, 2H), 1.21 - 1.43 (m, 9H).

[0119] Synthesis of Intermediate 3:

[0120]

[0121] Intermediate 2 (60.0 g, 195 mmol, 1.00 eq) was dissolved in dichloromethane (DCM) (420 mL) at 10 °C, and then 4 mol / L dioxane hydrochloride solution (120 mL) was added dropwise to the mixture at 10 °C. The mixture was stirred at 25 °C for 12 h. LC-MS showed that the reactant was completely consumed and the desired mass was detected. The reaction mixture was filtered to obtain a filter cake, and the filter cake was dried under reduced pressure to give an off-white solid, obtaining Intermediate 3 (46.0 g, 188 mmol, 96.6%).

[0122] 1 1H NMR (400 MHz, METHANOL-d4) δ 7.46 (s, 2H), 7.23 (d, J = 3.63 Hz, 2H), 4.18 - 4.40 (m, 1H), 2.72 - 3.18 (m, 2H), 1.21 - 1.43 (m, 9H).

[0123] Synthesis of Product 4:

[0124]

[0125] NaOH (16.9 g, 169 mmol, 40% concentration, 0.90 eq) was added to a solution of Intermediate 3 (46.0 g, 188 mmol, 1.00 eq) in H2O (92.0 mL). The mixture was stirred at 20 °C for 12 h. 920 ml of acetone was added to the reaction solution, and stirring was continued for 1 h. The reaction mixture was filtered to obtain a white solid, which is Product 4 (29.5 g, 113 mmol, yield 98.3%, ee value 100%).

[0126] Example 2:

[0127]

[0128] Under a nitrogen atmosphere, 40 mL of anhydrous THF and Boc-D-3-iodophenylalanine (4.0 g, 10 mmol, 1.00 eq) were added, stirred until dissolved, and cooled to below 0 °C. Isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution (1.3 M, 40 mL, 5.00 eq) was slowly added while controlling the temperature inside the reactor below 5 °C during the addition. After the addition was complete, stirring was continued at this temperature for 3 hours. Tri-n-butyl borate- 10 B (4.7 g, 20 mmol, 2 eq) was added while controlling the temperature at -10 °C to -5 °C during the addition. After the addition was complete, the mixture was allowed to warm to room temperature naturally and stirred overnight. LC-MS showed that the reactants were completely consumed and the desired mass was detected. After cooling to 0 °C, the reaction was quenched with saturated aqueous ammonium chloride solution (50 mL) and the mixture was adjusted to pH = 3 with 1 M hydrochloric acid. Then it was extracted with EtOAc (30 mL × 5). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 20 / 1 to 10 / 1) to obtain a yellow solid, (S)-3-(3-(borono- 10 B)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (2.45 g, 8 mmol, 78%).

[0129] Example 3:

[0130]

[0131] Under a nitrogen atmosphere, 16 mL of anhydrous THF and Boc-D-3-iodophenylalanine (4.0 g, 10 mmol, 1.00 eq) were added, stirred until dissolved, and cooled to below 0 °C. Isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution (1.3 M, 40 mL, 5.00 eq) was slowly added while controlling the temperature inside the reactor below 5 °C during the addition. After the addition was complete, stirring was continued at this temperature for 3 hours. Tri-n-butyl borate- 10 B (4.7 g, 20 mmol, 2 eq) was added while controlling the temperature at -10 °C to -5 °C during the addition. After the addition was complete, the mixture was allowed to warm to room temperature naturally and stirred overnight. LC-MS showed that the reactants were completely consumed and the desired mass was detected. After cooling to 0 °C, the reaction was quenched with saturated aqueous ammonium chloride solution (50 mL) and the mixture was adjusted to pH = 3 with 1 M hydrochloric acid. Then it was extracted with EtOAc (30 mL × 5). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 20 / 1 to 10 / 1) to obtain a yellow solid, (S)-3-(3-(borono- 10B)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (2.46 g, 8 mmol, 80%).

[0132] In this example, a higher yield can be achieved with less solvent.

[0133] Example 4

[0134]

[0135] To a solution of intermediate 3 (4.6 g, 18.8 mmol, 1.00 eq) in H2O (9.2 mL) was added NaOH (1.7 g, 16.9 mmol, 40% purity, 0.90 eq). The mixture was stirred at 20 °C for 12 h. 92 ml of methanol was added to the reaction solution, and stirring was continued for 1 h. The reaction mixture was filtered to obtain a white solid, which is product 4 (0.378 g, 1.47 mmol, 12.8%).

[0136] Example 5

[0137]

[0138] To a solution of intermediate 3 (4.6 g, 18.8 mmol, 1.00 eq) in H2O (9.2 mL) was added NaOH (1.7 g, 16.9 mmol, 40% purity, 0.90 eq). The mixture was stirred at 20 °C for 12 h. 92 ml of ethanol was added to the reaction solution, and stirring was continued for 1 h. The reaction mixture was filtered to obtain a white solid, which is product 4 (0.17 g, 0.64 mmol, 5.6%).

[0139] Example 6

[0140]

[0141] To a solution of intermediate 3 (4.6 g, 18.8 mmol, 1.00 eq) in H2O (9.2 mL) was added NaOH (1.7 g, 16.9 mmol, 40% purity, 0.90 eq). The mixture was stirred at 20 °C for 12 h. 92 ml of tetrahydrofuran was added to the reaction solution, and stirring was continued for 1 h. The reaction mixture was filtered to obtain a white solid, which is product 4 (1.46 g, 5.62 mmol, 48.9%).

[0142] Example 7

[0143]

[0144] To a solution of intermediate 3 (4.6 g, 18.8 mmol, 1.00 eq) in H2O (9.2 mL) was added NaOH (1.7 g, 16.9 mmol, 40% purity, 0.90 eq). The mixture was stirred at 20 °C for 12 h. 92 mL of isopropanol was added to the reaction solution, and stirring was continued for 1 h. The reaction mixture was filtered to obtain a white solid, which was product 4 (1.76 g, 6.74 mmol, 58.6%).

[0145] In Examples 4 to 7 of the present invention, methanol, ethanol, tetrahydrofuran, and isopropanol were respectively added to precipitate the product, and the yields were 12.8%, 5.6%, 48.9%, and 58.6% respectively; while in Example 1, acetone was used to precipitate the product, and the yield was 98.3%. Thus, it can be seen that the yield of Example 1 is significantly higher than that of Examples 4 to 7.

[0146] Comparative Example 1:

[0147]

[0148] Under a nitrogen atmosphere, 16 mL of a mixed solvent of toluene / THF (1:1) and Boc-D-3-iodophenylalanine (4.0 g, 10 mmol, 1.00 eq) were added, stirred and dissolved, and cooled to below 0 °C. Isopropylmagnesium chloride-lithium chloride tetrahydrofuran solution (1.3 M, 40 mL, 5.00 eq) was slowly added dropwise, and the temperature inside the reactor was controlled below 5 °C during the dropping process. After the dropping was completed, stirring was continued at this temperature for 3 hours. Tri-n-butyl borate - 10 B (4.7 g, 20 mmol, 2 eq) was added dropwise, and the temperature was controlled at -10 °C to -5 °C during the dropping process. After the dropping was completed, the temperature was allowed to return to room temperature naturally, and stirring was carried out overnight. LC-MS showed that the reactants were completely consumed and the required mass was detected. After cooling to 0 °C, the reaction was quenched with saturated aqueous ammonium chloride solution (50 mL) and the mixture was adjusted to pH = 3 with 1 M hydrochloric acid. Then it was extracted with EtOAc (30 mL × 5). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 20 / 1 to 10 / 1) to obtain a yellow solid, and (S)-3-(3-(borono-10B)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.32 g, 4.4 mmol, 43%) was obtained.

[0149] In this Comparative Example 1, a mixed solvent of toluene / THF (1:1) was used, and the yield was only 43%, which was much lower than that of Example 1.

[0150] Comparative Example 2:

[0151]

[0152] Under a nitrogen atmosphere, 16 mL of anhydrous THF and Boc-D-3-iodophenylalanine (4.0 g, 10 mmol, 1.00 eq) were added, stirred until dissolved, and cooled to below 0 °C. 60% sodium hydride (0.4 g, 10 mmol, 1.00 eq) was slowly added, and stirring was continued for 30 minutes. Then, a solution of tert-butylmagnesium chloride in THF (1.7 M, 29 mL, 5.00 eq) was slowly added while controlling the temperature inside the reactor below 5 °C. After the addition was complete, stirring was continued at this temperature for 3 hours. Tri-n-butyl borate - 10 B (4.7 g, 20 mmol, 2 eq) was added while controlling the temperature at -10 °C to -5 °C. After the addition was complete, the mixture was allowed to warm to room temperature naturally and stirred overnight. LC-MS showed that the reactants were completely consumed and the desired mass was detected. After cooling to 0 °C, the reaction was quenched with saturated aqueous ammonium chloride solution (50 mL), and the mixture was adjusted to pH = 3 with 1 M hydrochloric acid. Then, it was extracted with EtOAc (30 mL × 5). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 20 / 1 to 10 / 1) to obtain a yellow solid, (S)-3-(3-(borono- 10 B)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.10 g, 3.5 mmol, 35%).

[0153] Compared with Example 1, the format reagent was changed in Comparative Example 2, and its yield was only 35%, which was much lower than that of Example 1.

[0154] Comparative Example 3:

[0155]

[0156] Under a nitrogen atmosphere, 16 mL of anhydrous THF and Boc-D-3-iodophenylalanine (4.0 g, 10 mmol, 1.00 eq) were added, stirred until dissolved, and cooled to below -35 °C. A solution of isopropylmagnesium chloride - lithium chloride in THF (1.3 M, 40 mL, 5.00 eq) was slowly added while controlling the temperature inside the reactor below -35 °C. After the addition was complete, stirring was continued at this temperature for 3 hours. Stirring was continued at -35 °C for 1 hour, and a solid precipitated and solidified, making it completely impossible to stir. The reaction could not proceed.

[0157] Comparative Example 4:

[0158]

[0159] Weigh 2.0 g of the intermediate N-Boc-3-borono-L-phenylalanine, add 16 ml of acetone and 1.5 ml of water to the intermediate, then add 1.5 ml of concentrated hydrochloric acid. After stirring evenly at room temperature, heat it up to 50 - 55 °C and react for 2 h. Then distill off the acetone. When the temperature of the remaining reaction solution drops below 10 °C, adjust the pH to about 6.2 with sodium hydroxide solution. The system is a light yellow oily substance and no obvious solid precipitates.

[0160] In Comparative Example 4, a treatment method different from that in Example 1 was adopted, specifically, the treatment method of 4-boro-L-phenylalanine was used. It can be seen that for the preparation method of 3-boro-L-phenylalanine, if the treatment method of 4-boro-L-phenylalanine is adopted, the target product (3-borono-L-phenylalanine) cannot be obtained quickly and effectively.

[0161] In summary, through the preparation method of the present invention, the target product with a high yield can be prepared, and it has the characteristics of a short reaction route, mild reaction and cost reduction, and has excellent application prospects.

[0162] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can still be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing 3-boron-L-phenylalanine or a derivative thereof, wherein: The method comprises using a compound of formula (III) as a raw material to prepare 3-boron-L-phenylalanine or a derivative thereof represented by formula (VI): Wherein, R1 and R2 are each independently selected from H or an amino protecting group; at least one of R1 and R2 is an amino protecting group; and R3 is selected from H, an alkyl group having 1 to 3 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms.

2. The preparation method according to claim 1, wherein The method comprises using the compound of formula (I) and the compound of formula (II) as raw materials to prepare the compound of formula (III), and then using the compound of formula (III) as raw material to prepare 3-boron-L-phenylalanine or its derivatives represented by formula (VI); in, R1 and R2 are each independently selected from H or an amino protecting group; at least one of R1 and R2 is an amino protecting group; R3 is selected from H, an alkyl group having 1 to 3 carbon atoms, or a cycloalkyl group having 3 to 7 carbon atoms; R4 is selected from Br, Cl or I; Each R5 is independently selected from an alkyl group having 1 to 10 carbon atoms, or an aromatic group having 4 to 14 carbon atoms; each R 51 Each is independently selected from an alkyl group having 1 to 10 carbon atoms.

3. The preparation method according to claim 1 or 2, wherein The method comprises reacting a compound of formula (III) in the presence of hydrochloric acid to obtain a compound of formula (V); and then using the compound of formula (V) as a raw material to prepare 3-boron-L-phenylalanine or a derivative thereof represented by formula (VI); 4. The preparation method according to claim 3, wherein The solvent of the hydrochloric acid is dioxane; and / or The solvent of the compound of formula (III) is dichloromethane; and / or The molar ratio of the compound of formula (III) to the hydrochloric acid is 1:(2-3).

5. The preparation method according to claim 3, wherein: The method comprises: mixing a compound of formula (III) with a dioxane solution of hydrochloric acid for reaction, precipitating, and filtering to obtain a hydrochloride compound represented by a compound of formula (V).

6. The preparation method according to claim 3, wherein: The method comprises: mixing the compound of formula (V) with a base to carry out an alkalization reaction to prepare 3-boron-L-phenylalanine or a derivative thereof represented by formula (VI); or The method comprises: adding a base to the compound represented by the formula (V) to carry out an alkalization reaction, then adding acetone, precipitating, and filtering to obtain the 3-boron-L-phenylalanine represented by the formula (VI) or a derivative thereof.

7. The preparation method according to claim 6, wherein: The molar ratio of the compound of formula (V) to the base is 1:(0.8-1.0); and / or The volume of the acetone is 8 to 15 times the volume of the reaction system containing the compound of formula (V) before the addition of the base.

8. The preparation method according to claim 1 or 2, wherein: The amino protecting groups are each independently selected from tert-butyloxycarbonyl, benzyloxycarbonyl, benzyl, trityl or p-toluenesulfonyl; and / or Each R5 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trimethylsilyl or phenyl.

9. The preparation method according to claim 2, wherein: The method comprises using isopropylmagnesium chloride-lithium chloride as a Grignard reagent and using a compound of formula (I) and a compound of formula (II) as raw materials to prepare a compound of formula (III); and / or The method comprises using tetrahydrofuran as solvent and using the compound of formula (I) and the compound of formula (II) as raw materials to prepare the compound of formula (III); the mass ratio of the compound of formula (II) to the volume of tetrahydrofuran is 1:(4-10); preferably, the tetrahydrofuran is anhydrous tetrahydrofuran; and / or The method also includes preparing a compound of formula (I) using a compound of formula (IV) as a raw material:

10. The preparation method according to claim 9, wherein: The method comprises sequentially dropping isopropylmagnesium chloride-lithium chloride and a compound of formula (I) into a reaction system at a temperature of the reaction system of less than or equal to 10°C; and / or The molar ratio of the compound of formula (II) to isopropylmagnesium chloride-lithium chloride is 1:(3-6); and / or The molar ratio of the compound of formula (II) to the compound of formula (I) is 1:(1.2-3.0).

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