Preparation method of drug impurity 4-boron (10B) acid-phenylalanine butyl ester hydrochloride
The method for preparing 4-boron(10B) acid-phenylalanine butyl ester hydrochloride solves the problem of the lack of synthesis methods in the prior art, provides a basis for judging the impurities of L-10BPA drug, and realizes the preparation of high-purity target compounds.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-27
- Publication Date
- 2026-03-10
AI Technical Summary
The lack of existing methods for synthesizing the impurity 4-boron(10B) acid-phenylalanine butyl ester hydrochloride makes it impossible to provide a basis for determining impurities in L-10BPA drug research.
A method for preparing 4-boron(10B) acid-phenylalanine butyl ester hydrochloride is provided, wherein the target compound 6 is prepared by hydrolysis of compound 5 under acid IV and solvent IV, hydrocarbon boronization reaction of compound 3 and compound 4 under catalyst III and solvent III, protection group reaction of compound 2 under base II, and esterification reaction of compound 1 with n-butanol.
A synthetic route for 4-boron(10B) acid-phenylalanine butyl ester hydrochloride was successfully achieved. The reaction conditions were mild, the purity was high, the reaction time was short, the subsequent purification process was simple, and the product had high purity.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of boron drug impurity synthesis technology, specifically to a drug impurity 4-boron ( 10 B) Preparation method of phenylalanine butyl hydrochloride. Background Technology
[0002] Research revealed that impurity 4-boron ( 10 B) The chemical structure of phenylalanine butyl hydrochloride is as follows:
[0003]
[0004] In L- 10 In the preparation of BPA, 4-boron ( 10 B) Phenylalanine butyl hydrochloride is a byproduct of the reaction between compound BPA and n-butanol, causing this compound to exist as an impurity in drug L- 10 In BPA. Currently, the impurity compound 4-boron ( 10 There is limited research on B) phenylalanine butyl ester hydrochloride, and there is currently no information on this impurity compound 4-boron( 10 B) Research on the synthetic route of phenylalanine butyl hydrochloride, which leads to the development of L- 10 In BPA drug impurity studies, there is no strong basis for judgment. Therefore, there is an urgent need for a method for determining the impurity 4-boron (…). 10 B) A method for the synthesis and preparation of phenylalanine butyl hydrochloride, to facilitate the preparation of L- 10 BPA provides fundamental support for impurity research and drug research. Summary of the Invention
[0005] The purpose of this invention is to address the lack of information in the prior art regarding the impurity compound 4-boron ( 10 B) The synthesis method of phenylalanine butyl hydrochloride leads to the lack of appropriate detection methods and judgment criteria for the production and safe use of L-10BPA. The present invention provides the following technical solution:
[0006] A drug impurity 4-boron ( 10 B) Preparation method of phenylalanine butyl hydrochloride, 4-boron( 10 B) Acid-phenylalanine butyl ester hydrochloride (compound 6) is obtained by hydrolysis of compound 5 under acid IV and solvent IV conditions, as shown in the following reaction formula:
[0007]
[0008] Wherein, R1 is any one of the protecting bases Cbz, Boc, Pht, and Trt.
[0009] Compound 5 is obtained by reacting compound 3 and compound 4 under catalyst III and solvent III via a hydrocarbon borylation reaction, wherein compound 4 is one of the starting compounds. The specific reaction formula is as follows:
[0010]
[0011] Compound 3 was obtained from compound 2 under base II conditions via a protecting group reaction, as shown in the following reaction formula:
[0012]
[0013] Compound 2 was obtained by esterification of compound 1 and n-butanol, with compound 1 being the initial compound. The specific reaction formula is as follows:
[0014]
[0015] Acid IV is any one of concentrated hydrochloric acid, trifluoroacetic acid, and trifluoroformic acid.
[0016] The solvent IV is any one of tetrahydrofuran, 1,4-dioxane, acetone, dichloromethane, and water.
[0017] The molar ratio of compound 5 to acid IV is 1:(1-2).
[0018] Catalyst III is a methoxy(cyclooctadiene) iridium dimer.
[0019] Solvent III is any one of 2-methyltetrahydrofuran, tetrahydrofuran, and 1,4-dioxane.
[0020] The base II is any one of triethylamine, sodium carbonate, and potassium carbonate.
[0021] The present invention has the following advantages:
[0022] (1) This invention discloses for the first time the synthetic route and method of 4-boron(10B) acid-phenylalanine butyl ester hydrochloride, providing support for subsequent research on 4-boron(10B) acid-phenylalanine butyl ester hydrochloride.
[0023] (2) The preparation method of 4-boron(10B) acid-phenylalanine butyl hydrochloride provided by the present invention uses L-phenylalanine as the starting material and reacts with n-butanol to generate compound 2. Compound 2 undergoes a protecting group reaction under alkaline conditions to generate compound 3. Compound 3 reacts with pinacolboron(10B) alkyl in the presence of a relevant catalyst through a hydrocarbon boronization reaction. After post-treatment, compound 5 is obtained. Compound 5 is hydrolyzed under acidic conditions to obtain compound 6, namely 4-boron(10B) acid-phenylalanine butyl hydrochloride. The reaction conditions are mild, the reaction purity is high, the reaction time is short, the subsequent purification process is simple, and the purified product has high purity. Attached Figure Description
[0024] Figure 1 A reaction route diagram for one embodiment;
[0025] Figure 2 The NMR spectrum of compound 6 is shown below.
[0026] Figure 3 This is the mass spectrum of compound 6. Detailed Implementation
[0027] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.
[0028] Therefore, the following detailed description of embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely illustrates some embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.
[0029] It should be noted that, unless otherwise specified, the embodiments and features and technical solutions in the present invention can be combined with each other.
[0030] It should be noted that similar reference numerals and letters in the following figures indicate similar items. Therefore, once an item is defined in one figure, it does not need to be further defined and explained in subsequent figures. In the description of this invention, it should be noted that the terms "upper," "lower," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the figures, or the orientation or positional relationship commonly used when the product of the invention is in use, or the orientation or positional relationship commonly understood by those skilled in the art. These terms are only for the convenience of describing the invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on the invention. Furthermore, the terms "first," "second," etc., are only used to distinguish descriptions and should not be construed as indicating or implying relative importance.
[0031] Example 1:
[0032] The reaction route of Example 1 is as follows:
[0033]
[0034] I. Preparation of Compound 2:
[0035] Add 100 ml of methanol to a 250 ml three-necked flask, place it in an ice bath, and slowly add thionyl chloride (12.98 g, 0.109 mol, 1.8 eq) dropwise over 30 min. Continue stirring for 1.5 h, then add compound 1 (10.0 g, 0.06 mol, 1.0 eq), and reflux for 7 h. After the reaction is complete, distill the reaction solution under reduced pressure at 45 °C. After the reaction solution is evaporated to dryness, add 50 ml of water to the three-necked flask to dissolve the solution. Wash the aqueous phase formed by dissolving the solution twice with 30 ml of ethyl acetate. Then, adjust the pH of the aqueous phase to 9-10 with sodium carbonate aqueous solution. A white solid precipitates out. Stir to crystallize for 2-3 h, filter the crystals, and obtain 211.89 g of compound, with a yield of 89.66%.
[0036] II. Preparation of Compound 3:
[0037] Compound 2 (10.0 g, 0.045 mol, 1.0 eq) was added to a clean 250 ml three-necked flask. 50 ml of tetrahydrofuran (THF) and 50 ml of water (H2O) were added and stirred to dissolve. Then, triethylamine (5.48 g, 0.054 mol, 1.2 eq) and di-tert-butyl dicarbonate (11.83 g, 0.054 mol, 1.2 eq) were added. The mixture was placed in a water bath at 45 °C and reacted for 2.5 h. After the reaction was monitored by TLC (thin-layer chromatography), the reaction solution was concentrated under reduced pressure at 45 °C. 150 ml of petroleum ether was added to the crude product after the reduced-distillation process, and the mixture was slurried. After filtration, 313.5 g of compound was obtained, with a yield of 93.4%.
[0038] III. Preparation of Compound 5:
[0039] At room temperature, compound 3 (10.0 g, 0.031 mol, 1.0 eq) was placed in a three-necked flask, and pinacol boron ( 10 B) Alkane (4.95 g, 0.039 mol, 1.25 eq) was dissolved in 100 ml of 2-methyltetrahydrofuran, followed by the addition of methoxy(cyclooctadiene)iridium dimer (CAS: 12148-71-9) (2.05 g, 0.0031 mol, 0.1 eq) and 3,4,7,8-tetramethyl-1,10-phenanthroline (CAS: 1660-93-1) (1.46 g, 0.0062 mol, 0.1 eq). 2 eq) of nitrogen gas was introduced into a single-necked flask and purged three times. Under nitrogen protection, the temperature was controlled at 80℃ and the reaction was carried out for 3.5 h. The reaction was monitored by TLC plate spotting until the reaction was complete. The reaction solution was concentrated under reduced pressure at (45-60)℃. The concentrated product was purified by column chromatography using silica gel column chromatography with ethyl acetate:petroleum ether = 1:6 (volume ratio) as the eluent. The eluent was concentrated to obtain 68.5 g of the compound, with a yield of 61.59%.
[0040] IV. Preparation of Compound 6:
[0041] Compound 5 (5.0 g, 0.011 mol, 1.0 eq) was dissolved in 25 ml of acetone in a 100 ml three-necked flask by stirring. Then, 25 ml of water and concentrated hydrochloric acid (2.84 g, 0.028 mol, 2.5 eq) were added. The mixture was heated to 50 °C and stirred for 3 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure at 45 °C to obtain a crude product. 20 ml of water was added to the crude product to dissolve it, and the aqueous phase was used as the aqueous phase. The aqueous phase was washed and extracted twice with 25 ml of n-butanol. The n-butanol phase was concentrated under reduced pressure and evaporated to dryness. After drying, 62.5 g of the compound was obtained, with a yield of 74.4% and a purity of 98.5%.
[0042] The HNMR data for compound 6 are as follows:
[0043] 1 H-NMR(400MHZ D2O / CF3COOD), δ7.52 (d, J=7.5Hz, 2H), δ7.08 (d, J=7.5Hz, 2H), δ4.17 (t, J=7.5Hz, 1H), δ3.94 (t, J=7Hz, 2H ), δ3.06 (d, J=7.5Hz, 2H), δ1.26-1.3 (m, J=7.0Hz, 2H), δ0.91-0.97 (m, J=7.0Hz, 2H), δ0.58 (t, J=7Hz, 3H).
[0044] The mass spectrometry data for compound 6 are as follows:
[0045] m / z(ESI-)=299.2(MH)
[0046] Impurity 4-boron ( 10 B) The molecular formula of phenylalanine butyl ester is C 13 H 20 10 BNO4·HCl, average molecular weight 300.78, exact molecular weight 300.13. Test sample ESI. - The model mass spectrometer shows a peak at m / z = 299.2, which is the MH quasi-molecular ion peak.
[0047] NMR and mass spectrometry data indicate that compound 6 is related to the target compound 4-boron ( 10 B) The structure of phenylalanine butyl ester is consistent.
[0048] The purity of compound 6 was determined by HPLC, and quantitative analysis was performed by the area normalization method. The specific detection conditions are as follows:
[0049] Chromatographic conditions:
[0050] Detector: Ultraviolet detector
[0051] Column: Polar-terminated octadecyl-bonded (fully porous silica gel packing) (Horizon)
[0052] (C18 / AQUA, 4.6mm × 250mm, 5µm or equivalent column)
[0053] Column temperature: 40℃
[0054] Flow rate: 1.0 mL / min
[0055] Mobile phase: Mobile phase A: 0.1% phosphoric acid solution (mix 1 mL of phosphoric acid with 1000 mL of water).
[0056] Mobile phase B: Methanol
[0057] Injection volume: 10 μL
[0058] Running time: 35 minutes
[0059] Gradient elution procedure:
[0060]
[0061] Example 2:
[0062] The reaction route of Example 1 is as follows:
[0063]
[0064] I. Preparation of Compound 2:
[0065] Add 100 ml of methanol to a 250 ml three-necked flask, place it in an ice bath, and slowly add thionyl chloride (12.96 g, 0.109 mol, 1.8 eq) dropwise over 30 min. Continue stirring for 1 h, then add compound 1 (10.0 g, 0.06 mol, 1.0 eq), and reflux for 6 h. After the reaction is complete, distill the reaction solution under reduced pressure at 40 °C. After the reaction solution is evaporated to dryness, add 50 ml of water to the three-necked flask to dissolve the solution. Wash the aqueous phase formed by dissolving the solution twice with 30 ml of ethyl acetate. Then, adjust the pH of the aqueous phase to 9-10 with sodium carbonate aqueous solution. A white solid precipitates out. Stir to crystallize for 2-3 h, filter the crystals, and obtain 212.09 g of compound 2, with a yield of 90.22%.
[0066] II. Preparation of Compound 3:
[0067] Compound 2 (10.0 g, 0.045 mol, 1.0 eq) was added to a clean 250 ml three-necked flask, followed by 50 ml of tetrahydrofuran (THF) and 50 ml of water (H2O) and stirred until dissolved. Then, sodium carbonate (5.75 g, 0.054 mol, 1.2 eq) and benzylformyl chloride (9.2 g, 0.054 mol, 1.2 eq) were added, and the mixture was placed in a water bath at 45 °C for 1 h. After the reaction was monitored by TLC, the reaction solution was concentrated under reduced pressure at 45 °C. The crude product after reduced evaporation was mixed with 150 ml of n-heptane and slurried. After filtration, 317.3 g of compound was obtained, with a yield of 90.24%.
[0068] III. Preparation of Compound 5:
[0069] At room temperature, compound 3 (10.0 g, 0.028 mol, 1.0 eq) was placed in a three-necked flask, and pinacol boron ( 10B) Alkane (3.58 g, 0.028 mol, 1.0 eq) was dissolved in 100 ml of tetrahydrofuran, followed by the addition of methoxy(cyclooctadiene)iridium dimer (CAS: 12148-71-9) (2.05 g, 0.0031 mol, 0.1 eq) and 3,4,7,8-tetramethyl-1,10-phenanthroline (CAS: 1660-93-1) (1.46 g, 0.0062 mol, 0.1 eq). 2 eq) of nitrogen gas was introduced into a single-necked flask and purged three times. Under nitrogen protection, the temperature was controlled at 80℃ and the reaction was carried out for 3 h. The reaction was monitored by TLC thin-layer chromatography until the reaction was complete. The reaction solution was concentrated under reduced pressure at (45-60)℃. The concentrated product was purified by column chromatography using silica gel column chromatography with ethyl acetate:petroleum ether = 1:6 (volume ratio) as the eluent. The eluent was concentrated to obtain 68.4 g of the compound, with a yield of 62.2%.
[0070] IV. Preparation of Compound 6:
[0071] Compound 5 (5.0 g, 0.011 mol, 1.0 eq) and 1,4-dioxane (25 ml) were dissolved in a 100 ml three-necked flask by stirring. Then, 25 ml of water and a hydrogen bromide acetic acid solution (5.394 g, 0.022 mol, 2 eq) were added. The mixture was heated to 40 °C and stirred for 2 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure at 50 °C to obtain a crude product. 20 ml of water was added to the crude product to dissolve it, and the resulting aqueous phase was washed twice with 25 ml of n-butanol. The aqueous phase was separated and retained. The pH of the aqueous phase was adjusted to 6–7 with 20% sodium hydroxide strips, and crystallization was carried out at 0–10 °C for 2–3 h. The crystals were filtered, dried, and the resulting solid was adjusted to pH 1–2 with dilute hydrochloric acid. The solid was then evaporated under reduced pressure at 60 °C and dried to obtain 62.8 g of the compound, with a yield of 89.74% and a purity of 99.4%.
[0072] The HNMR data for compound 6 are as follows:
[0073] 1 H-NMR(400MHZ D2O / CF3COOD), δ7.51 (d, J=7.5Hz, 2H), δ7.07 (d, J=7.5Hz, 2H), δ4.18 (t, J=7.5Hz, 1H), δ3.95 (t, J=7Hz, 2H ), δ3.05 (d, J=7.5Hz, 2H), δ1.25-1.3 (m, J=7.0Hz, 2H), δ0.91-0.97 (m, J=7.0Hz, 2H), δ0.58 (t, J=7Hz, 3H).
[0074] The mass spectrometry data for compound 6 are as follows:
[0075] m / z(ESI-)=299.3(MH)
[0076] NMR and mass spectrometry data indicate that compound 6 is related to the target compound 4-boron ( 10 B) The structure of phenylalanine butyl ester is consistent.
[0077] Example 2 uses the same HPLC detection method as Example 2 to detect the purity of compound 6.
[0078] Example 3:
[0079] The reaction route of Example 1 is as follows:
[0080]
[0081] I. Preparation of Compound 2:
[0082] Add 100 ml of methanol to a 250 ml three-necked flask, place it in an ice bath, and slowly add thionyl chloride (12.96 g, 0.109 mol, 1.8 eq) dropwise over 30 min. Continue stirring for 2 h, then add compound 1 (10.0 g, 0.06 mol, 1.0 eq), and reflux for 8 h. After the reaction is complete, distill the reaction solution under reduced pressure at 65 °C. After the reaction solution is evaporated to dryness, add 50 ml of water to the three-necked flask to dissolve the solution. Wash the aqueous phase formed by dissolving the solution twice with 30 ml of ethyl acetate. Then, adjust the pH of the aqueous phase to 9-10 with sodium carbonate aqueous solution. A white solid precipitates out. Stir to crystallize for 2-3 h, filter the crystals, and obtain 212.03 g of compound, with a yield of 89.7%.
[0083] II. Preparation of Compound 3:
[0084] Compound 2 (10.0 g, 0.045 mol, 1.0 eq) was added to a clean 250 ml three-necked flask. 50 ml of tetrahydrofuran (THF) and 50 ml of water (H2O) were added and stirred to dissolve. Then, potassium carbonate (7.46 g, 0.054 mol, 1.2 eq) and triphenylchloromethane (15.14 g, 0.054 mol, 1.2 eq) were added. The mixture was placed in a water bath at 45 °C and reacted for 4 h. After the reaction was monitored by TLC (thin-layer chromatography), the reaction solution was concentrated under reduced pressure at 45 °C. The crude product was then mixed with 150 ml of petroleum ether and slurried. The mixture was filtered, and the filter cake was washed with 150 ml of water, filtered again, and dried to obtain 315.6 g of compound, with a yield of 78%.
[0085] III. Preparation of Compound 5:
[0086] At room temperature, compound 3 (10 g, 0.023 mol, 1.0 eq) was placed in a three-necked flask, and pinacol boron ( 10B) Alkane (4.3 g, 0.034 mol, 1.5 eq) was dissolved in 100 ml of 1,4-dioxane, followed by the addition of methoxy(cyclooctadiene)iridium dimer (CAS: 12148-71-9) (2.05 g, 0.0031 mol, 0.1 eq) and 3,4,7,8-tetramethyl-1,10-phenanthroline (CAS: 1660-93-1) (1.46 g, 0.0062 mol, 0.1 eq). 2 eq) of nitrogen gas was introduced into a single-necked flask and purged three times. Under nitrogen protection, the temperature was controlled at 80℃ and the reaction was carried out for 4 h. The reaction was monitored by TLC until the reaction was complete. The reaction solution was concentrated under reduced pressure at (45-60)℃. The concentrated product was purified by column chromatography using silica gel column chromatography with ethyl acetate:petroleum ether = 1:6 (volume ratio) as the eluent. The eluent was concentrated to obtain 65.1 g of the compound, with a yield of 39.8%.
[0087] IV. Preparation of Compound 6:
[0088] Compound 5 (5g, 0.009mol, 1.0eq) was dissolved in a 100ml three-necked flask by stirring. 50ml of acetic acid was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure at 60℃ to obtain a crude product. The crude product was dissolved in 50ml of water, and the pH was adjusted to 6-7 with 20% sodium hydroxide. Crystallization was carried out at 0-10℃ for 2-3 hours to obtain the product. After drying, 50ml of water was added, and the pH was adjusted to 1-2 with dilute hydrochloric acid. The mixture was then evaporated under reduced pressure at 60℃. After drying, 62.3g of the compound was obtained, with a yield of 90.2% and a purity of 97.8%.
[0089] The HNMR data for compound 6 are as follows:
[0090] 1 H-NMR(400MHZ D2O / CF3COOD), δ7.52 (d, J=7.5Hz, 2H), δ7.07 (d, J=7.5Hz, 2H), δ4.17 (t, J=7.5Hz, 1H), δ3.95 (t, J=7Hz, 2H ), δ3.04 (d, J=7.4Hz, 2H), δ1.25-1.3 (m, J=7.0Hz, 2H), δ0.92-0.98 (m, J=7.0Hz, 2H), δ0.58 (t, J=7Hz, 3H).
[0091] The mass spectrometry data for compound 6 are as follows:
[0092] m / z(ESI-)=299.2(MH)
[0093] NMR and mass spectrometry data indicate that compound 6 is related to the target compound 4-boron ( 10 B) The structure of phenylalanine butyl ester is consistent.
[0094] Example 2 uses the same HPLC detection method as Example 2 to detect the purity of compound 6.
[0095] Example 4:
[0096] The reaction route of Example 1 is as follows:
[0097]
[0098] I. Preparation of Compound 2:
[0099] Add 100 ml of methanol to a 250 ml three-necked flask, place it in an ice bath, and slowly add thionyl chloride (12.96 g, 0.109 mol, 1.8 eq) dropwise over 30 min. Continue stirring for 2 h. Then add compound 1 (10.0 g, 0.06 mol, 1.0 eq) and reflux for 6.5 h. After the reaction is complete, distill the reaction solution under reduced pressure at 50 °C. After the reaction solution is evaporated to dryness, add 50 ml of water to the three-necked flask to dissolve the solution. Wash the aqueous phase formed by dissolving the solution twice with 30 ml of ethyl acetate. Then adjust the pH of the aqueous phase to 9-10 with sodium carbonate aqueous solution. A white solid precipitates out. Stir to crystallize for 2-3 h. Filter the crystals to obtain 211.75 g of compound, with a yield of 87.75%.
[0100] II. Preparation of Compound 3:
[0101] Compound 2 (10.0 g, 0.045 mol, 1.0 eq) was added to a clean 250 ml three-necked flask, followed by 100 ml of tetrahydrofuran (THF) and stirring to dissolve. Then, triethylamine (5.48 g, 0.054 mol, 1.2 eq) and trimethylsilylethoxymethyl chloride (9.0 g, 0.054 mol, 1.2 eq) were added and the mixture was allowed to react at room temperature for 3 h. After the reaction was monitored by TLC, the reaction solution was concentrated under reduced pressure at 45 °C. The crude product after reduced evaporation was mixed with 150 ml of petroleum ether and slurried. After filtration, 313.5 g of compound was obtained, with a yield of 71.42%.
[0102] III. Preparation of Compound 5:
[0103] At room temperature, compound 3 (10.0 g, 0.0285 mol, 1.0 eq) was placed in a three-necked flask, and pinacol boron ( 10B) Alkane (4.34 g, 0.034 mol, 1.2 eq) was dissolved in 100 ml of 2-methyltetrahydrofuran, followed by the addition of methoxy(cyclooctadiene)iridium dimer (CAS: 12148-71-9) (2.05 g, 0.0031 mol, 0.1 eq) and 3,4,7,8-tetramethyl-1,10-phenanthroline (CAS: 1660-93-1) (1.46 g, 0.0062 mol, 0.1 eq). 2 eq) of nitrogen gas was introduced into a single-necked flask and purged three times. Under nitrogen protection, the temperature was controlled at 80℃ and the reaction was carried out for 3.5 h. The reaction was monitored by TLC plate spotting until the reaction was complete. The reaction solution was concentrated under reduced pressure at (45-60)℃. The concentrated product was purified by column chromatography using silica gel column chromatography with ethyl acetate:petroleum ether = 1:6 (volume ratio) as the eluent. The eluent was concentrated to obtain 66.3 g of the compound, with a yield of 46.4%.
[0104] IV. Preparation of Compound 6:
[0105] Compound 5 (5.0 g, 0.01 mol, 1.0 eq), dichloromethane (50 ml), and trifluoroformic acid (3.23 g, 0.028 mol, 2.7 eq) were added to a 100 ml three-necked flask and stirred at room temperature for 2.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure at 45 °C to obtain a crude product. 20 ml of water was added to the crude product to dissolve it, and the aqueous phase was used as the aqueous phase. The aqueous phase was washed and extracted twice with 25 ml of n-heptane, separated, and the aqueous phase was retained. The pH of the aqueous phase was adjusted to 6-7 with 20% sodium hydroxide, and crystallized at 0-10 °C for 2-3 h. After filtration and drying, 50 ml of water was added to the product, and the pH was adjusted to 1-2 with dilute hydrochloric acid. After drying under reduced pressure at 60 °C, 62.5 g of compound was obtained, with a yield of 79.37% and a purity of 99.1%.
[0106] The HNMR data for compound 6 are as follows:
[0107] 1 H-NMR(400MHZ D2O / CF3COOD), δ7.53 (d, J=7.5Hz, 2H), δ7.08 (d, J=7.5Hz, 2H), δ4.18 (t, J=7.5Hz, 1H), δ3.95 (t, J=7Hz, 2H ), δ3.07 (d, J=7.5Hz, 2H), δ1.26-1.4 (m, J=7.0Hz, 2H), δ0.92-0.98 (m, J=7.0Hz, 2H), δ0.58 (t, J=7Hz, 3H).
[0108] The mass spectrometry data for compound 6 are as follows:
[0109] m / z(ESI-)=299.1(MH)
[0110] Example 4 uses the same HPLC detection method as in Example 1 to detect the purity of compound 6.
[0111] In summary, the method for preparing 4-boron(10B) acid-phenylalanine butyl hydrochloride provided by this invention uses L-phenylalanine as the starting material and proceeds sequentially through esterification, protecting group addition, hydrocarbon borylation, and hydrolysis to obtain 4-boron(10B) acid-phenylalanine butyl hydrochloride. This reaction route requires only four steps to obtain the target compound 6. The reaction conditions are mild, the reaction purity is high, the reaction time is short, the subsequent purification process is simple, and the purified product has high purity.
[0112] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.
Claims
1. A pharmaceutical impurity 4-borono- 10 B) A process for the preparation of acid-phenylalanine butyl ester hydrochloride characterized by, 4-boronic acid 10 B) Acid-phenylalanine butyl ester hydrochloride (Compound 6) was obtained from Compound 5 under the condition of acid IV and solvent IV by hydrolysis reaction, and the specific reaction formula was as follows: Wherein, R1 is any one of Cbz, Fmoc, Boc, Alloc, SEM, Tos, Pht, Trt, Dmb.
2. A pharmaceutical impurity 4-boron( 1) -10-deoxy carbapenam-2-carboxylic acid phenylalanine ester hydrochloride according to claim 1. 10 B) A process for the preparation of acid-phenylalanine butyl ester hydrochloride characterized in that, The compound 5 is obtained by the reaction of the compound 3 with the compound 4 under the catalyzer III, the solvent III, wherein the compound 4 is one of the starting compounds, and the specific reaction formula is as follows:
3. A pharmaceutical impurity 4-boro 10 B) Process for the preparation of acid-phenylalanine butyl ester hydrochloride, characterized in that, The compound 3 is obtained by reacting the compound 2 with a protecting group under the condition of a base II, and the specific reaction formula is as follows:
4. A pharmaceutical impurity 4-boron(3) -acid-phenylalanine butyl ester hydrochloride according to claim 3. 10 B) Process for the preparation of acid-phenylalanine butyl ester hydrochloride, characterized in that, The compound 2 is obtained by esterification reaction of the compound 1 and n-butanol, and the compound 1 is an initial compound, and the specific reaction formula is as follows:
5. A pharmaceutical impurity 4-boro 10 B) A process for the preparation of acid-phenylalanine butyl ester hydrochloride characterized by, The acid IV is any one of concentrated hydrochloric acid, trifluoroacetic acid and trifluoromethane acid.
6. A pharmaceutical impurity 4-boron( 1) -10-deoxy carbapenam-2-carboxylic acid phenylalanine butyl ester hydrochloride according to claim 1. 10 B) A process for the preparation of acid-phenylalanine butyl ester hydrochloride characterized in that, The solvent IV is any one of tetrahydrofuran, 1,4-dioxane, acetone, dichloromethane and water.
7. A pharmaceutical impurity 4-boron( 1) -10-deoxy carbapenam-2- carboxylic acid phenylalanine ester according to claim 1. 10 B) A process for the preparation of acid-phenylalanine butyl ester hydrochloride characterized in that, The molar ratio of the compound 5 to the acid IV is 1:(1-2).
8. A pharmaceutical impurity 4-boron( 1) -10-deoxy carbapenam-2-carboxylic acid phenylalanine ester hydrochloride according to claim 2. 10 B) A process for the preparation of acid-phenylalanine butyl ester hydrochloride characterized in that, The catalyst III is methoxy(cyclooctadiene)iridium dimer and 3,4,7,8-tetramethyl-1,10-phenanthroline.
9. A pharmaceutical impurity 4-boron( 1) -10-deoxy carbapenam-2-carboxylic acid phenylalanine butyl ester hydrochloride according to claim 2. 10 B) A process for the preparation of acid-phenylalanine butyl ester hydrochloride characterized in that, The solvent III is any one of 2-methyl-tetrahydrofuran, tetrahydrofuran and 1.4-dioxane.
10. A pharmaceutical impurity 4-boron (as described in claim 3) 10 B) A method for preparing phenylalanine butyl hydrochloride, characterized in that, The base II is any one of triethylamine, sodium carbonate and potassium carbonate.