Method for preparing dexborneol derivative

Abstract

The present disclosure relates to a method for preparing a dexborneol derivative. Specifically, the method involved in the present disclosure introduces an intermediate which is convenient to purify in the preparation method, and the intermediate can be easily converted into a target product. Although process steps are additionally provided, the yield and product quality of the whole process are improved, and the working efficiency is improved.

Description

A method for preparing a dextroborneol derivative Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a method for preparing a dextroborneol derivative. Background Technology

[0002] Borneol is a norbornene derivative that selectively activates α2-GABA. A The receptor has a clear anti-cerebral ischemia effect and a good neuroprotective effect in the cerebral ischemia-reperfusion model (Journal of Biomedical Research, 2017, 31: 306-314). In addition, it also has anti-inflammatory, analgesic, anticoagulant, anti-myocardial ischemia, tumor drug resistance reversal and arousal and cognitive function improvement effects in rats that have been working continuously for a long time.

[0003] Compounds with hydroxyl functional groups are highly polar and often exist as oils, making them difficult to purify by recrystallization. They require distillation or column chromatography, but these methods are expensive and limited in large-scale production. Dextroborneol derivatives, such as fluorodextroborneol, show low yields and poor process controllability when purified by column chromatography. Summary of the Invention

[0004] This disclosure provides a method for preparing a dextroborneol derivative.

[0005] The method includes the step of converting a compound of formula DA into a compound of formula A.

[0006] Where R 1 R 2 Each is independently selected from hydrogen or halogen, and PG is a hydroxyl protecting group.

[0007] In some embodiments, the method further includes the step of reacting a crude compound of formula A with a hydroxyl protecting agent to form a compound of formula DA.

[0008] Where R 1 R 2 Each element is independently selected from hydrogen or halogen, with PG being a hydroxyl protecting group. In some embodiments, the reaction conditions for hydroxyl protection are known or can be confirmed by those skilled in the art, and can be referred to in "Protective Groups in Organic Synthesis", 5th. Ed. TW. Greene & P. ​​GMWuts, and the relevant content is incorporated herein by reference.

[0009] Compound A contains a hydroxyl functional group, is an oily substance, and has similar structural properties to other impurities, making it difficult to purify by recrystallization. Even with a high conversion rate in the synthesis of compound A, the actual yield of compound A remains low. Therefore, we designed a method to efficiently obtain high-purity compound A by introducing an easily purified intermediate that is also readily converted into compound A. Although this adds a process step, it improves the overall yield and product quality, and increases work efficiency.

[0010] In some embodiments, R in compound A 1 and R 2 Selected from hydrogen or fluorine.

[0011] In some embodiments, PG in the DA compound is selected from... In some embodiments, the compound of formula DA is a compound of formula DA-1. This intermediate is easy to purify, and its structure contains... It is easy to remove; the purified compound of formula DA-1 can be converted into compound of formula A under appropriate conditions, and the obtained compound of formula A has high purity, not less than 95.1%, 95.2%, 95.3%, 95.4%, 95.5%, 95.6%, 95.7%, 95.8%, 95.9%, 96.0%, 96.2%, 96.4%, 96.6%, 96.8%, 97.0%, 97.2%, 97.4%, 97.6%, 97.8%, 98.0%, 98.2%, 98.4%, 98.6%, 98.8%, 99.0% or higher; simultaneously, it can be purified by removing or eliminating the impurities. The method is also relatively simple. In some implementation schemes, the above... The group is, but is not limited to, an anhydride / base (3) condition, wherein the base (3) is selected from organic bases, such as triethylamine. De-oxidation The functional group can be established under appropriate alkaline conditions. In some embodiments, The group is released in the presence of a base (4), which is selected from sodium hydroxide or potassium hydroxide.

[0012] In some embodiments, the crude product of formula DA can be purified by recrystallization, resulting in a DA compound with a purity of not less than 96.0%, and may be 96%, 96.2%, 96.4%, 96.6%, 96.8%, 97.0%, 97.2%, 97.4%, 97.6%, 97.8%, 98.0%, 98.2%, 98.4%, 98.6%, 98.8%, 99.0%, or higher. In some embodiments, the solvent used for recrystallization of the crude DA compound is selected from at least one of esters, alkanes, cycloalkanes, alcohols, acetonitrile, or ether solvents. In some embodiments, the solvent used for recrystallization of the crude DA-1 compound is selected from acetonitrile.

[0013] In some embodiments, compound A is compound A-1. In some embodiments, the method for preparing compound A-1 includes the step of converting compound DA-1 into compound A-1.

[0014] In some embodiments, the compound of formula DA-1 is reacted in the presence of a base (4) to form the compound of formula A-1, wherein the base (4) is selected from potassium hydroxide or sodium hydroxide.

[0015] In other embodiments, the method for preparing compound A-1 further includes the step of reacting the crude product of compound A-1 with a hydroxyl protecting agent to form compound DA-1.

[0016] In some embodiments, the crude product of compound A-1 is reacted with phthalic anhydride in the presence of a base (4) to form compound DA-1, wherein the base (4) is selected from triethylamine.

[0017] In some embodiments, the molar ratio of the crude compound of formula A-1 to phthalic anhydride is 1:1.5 to 1:4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.0, or any value between the two numbers. In some implementation schemes, the molar ratio of the crude compound of formula A-1 to the base (4) is 1:2 to 1:6, including 1:2.0, 1:2.2, 1:2.4, 1:2.6, 1:2.8, 1:3.0, 1:3.2, 1:3.4, 1:3.6, 1:3.8, 1:4.0, 1:4.2, 1:4.4, 1:4.6, 1:4.8, 1:5.0, 1:5.2, 1:5.4, 1:5.6, 1:5.8, 1:6.0 or any value between two numbers.

[0018] In some embodiments, the reaction of the crude compound of formula A-1 with phthalic anhydride further contains a condensing agent, including but not limited to 4-dimethylaminopyridine. In some embodiments, the molar ratio of the crude compound of formula A-1 to the condensing agent is 1:0.1 to 1:0.4, including 1:0.1, 1:0.2, 1:0.3, 1:0.4, or any two of these values.

[0019] In some embodiments, the solvent used to react the crude product of formula A-1 with phthalic anhydride is selected from dimethylmethane.

[0020] In some embodiments, the method for preparing compound A-1 includes reacting a crude product of compound A-1 with a hydroxyl protecting agent to form compound DA-1, and converting compound DA-1 into compound A-1.

[0021] On the other hand, the crude product of compound A-1 is formed by the reaction of compound 1 with a fluorinating agent to form compound 2, and the reaction of compound 2 in the presence of a reducing agent to form the crude product of compound A-1.

[0022] The preferred fluorinating agent is N-fluorobis(benzene)sulfonamide or SulfoxFluor. In some embodiments, the reducing agent is selected from sodium dihydrobis(2-methoxyethoxy)aluminate or sodium borohydride. In some embodiments, the molar ratio of compound 1 to a fluorinating agent such as N-fluorobisbenzenesulfonamide is 1:1 to 1:3, including 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, or any two values ​​between them. In some embodiments, the molar ratio of compound 1 to a fluorinating agent such as N-fluorobisbenzenesulfonamide is 1:1.1 to 1:1.2.

[0023] In some embodiments, the molar ratio of compound 2 to the reducing agent is 1:1 to 1:2, including 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, or any value between two such numbers. In some embodiments, the molar ratio of compound 2 to the reducing agent, such as red aluminum, is 1:1 to 1:1.5.

[0024] In some embodiments, the solvent used to convert compound 2 into compound A-1 is selected from aprotic solvents, such as dichloromethane.

[0025] In some embodiments, compound 1 reacts with a fluorinating agent in the presence of a base (1) to form compound B, and compound B is converted to compound 2 in the presence of a base (2).

[0026] In some embodiments, the base (1) is selected from lithium diisopropylamino, lithium n-butyl, or lithium tert-butyl. In some embodiments, the base (2) is selected from sodium bis(trimethylsilyl)amino or lithium di(trimethylsilyl)amino.

[0027] In some embodiments, the molar ratio of compound 1 to base (1) is 1:1 to 1:2, including 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, or any value between any two numbers. In some embodiments, the molar ratio of compound 1 to base (1), such as lithium diisopropylamino, is 1:1 to 1:1.5.

[0028] In some embodiments, the molar ratio of compound B to base (2) is 1:1 to 1:2, including 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, or any value between any two numbers. In some embodiments, the molar ratio of compound B to base (2), such as sodium bis(trimethylsilyl)amino, is 1:1 to 1:1.5.

[0029] In some embodiments, the solvent used to convert compound 1 to compound B is selected from polar aprotic solvents, such as tetrahydrofuran.

[0030] In some embodiments, the solvent used to convert compound B into compound 2 is selected from polar aprotic solvents, such as tetrahydrofuran.

[0031] This disclosure also provides a method for preparing compound A-1.

[0032] The method includes the step of reacting compound 1 with a fluorinating agent to form compound 2.

[0033] The preferred fluorinating agent is N-fluorobis(benzene)sulfonamide or SulfoxFluor.

[0034] In some embodiments, the method for preparing compound A-1 includes reacting compound 1 with a fluorinating agent in the presence of a base (1) to form compound B, and converting compound B into compound 2 in the presence of a base (2).

[0035] In some embodiments, the base (1) is selected from n-butyllithium or tert-butyllithium. In some embodiments, the base (2) is selected from sodium bis(trimethylsilyl)amino or lithium di(trimethylsilyl)amino.

[0036] In some embodiments, the molar ratio of compound 1 to the fluorinating agent, such as N-fluorobisbenzenesulfonamide, is 1:1 to 1:3, including 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, or any value between any two numbers. In some embodiments, the molar ratio of compound 1 to the fluorinating agent, such as N-fluorobisbenzenesulfonamide, is 1:1.1 to 1:1.2.

[0037] In some embodiments, the molar ratio of compound 1 to base (1) is 1:1 to 1:2, including 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, or any value between any two numbers. In some embodiments, the molar ratio of compound 1 to base (1), such as lithium diisopropylamino, is 1:1 to 1:1.5.

[0038] In some embodiments, the molar ratio of compound B to base (2) is 1:1 to 1:2, including 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, or any value between any two numbers. In some embodiments, the molar ratio of compound B to base (2), such as sodium bis(trimethylsilyl)amino, is 1:1 to 1:1.5.

[0039] In other embodiments, the method for preparing compound A-1 includes reacting compound 2 in the presence of a reducing agent to form compound A-1.

[0040] Furthermore, in some embodiments, the method for preparing compound A-1 further includes the steps of reacting the crude product of compound A-1 with a hydroxyl protecting agent to form compound DA-1, and converting compound DA-1 into compound A-1.

[0041] This disclosure also provides compound DA-1 or a salt thereof.

[0042] The compound salts or pharmaceutically acceptable salts described in this disclosure may be selected from inorganic or organic salts. These include acid addition salts and base addition salts. For example, salts formed by an acid-base reaction with a basic group (amino group), wherein the acid includes organic or inorganic acids.

[0043] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations.

[0044] In the chemical structure of the compounds described in this disclosure, the bonds... No configuration is specified, meaning it can be Z configuration, E configuration, or both configurations.

[0045] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also called proton transfer tautomers) include interconversions via proton migration, such as compounds of this disclosure comprising tautomer changes between formulas A and B as shown below:

[0046] All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0047] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0048] Terminology Explanation:

[0049] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0050] The term "SulfoxFluor" refers to a selective fluorine reagent.

[0051] The term "LDA" refers to lithium diisopropylaminodimethylamine.

[0052] The term "NaHMDS" refers to sodium bis(trimethylsilyl)amino.

[0053] The term "LiHMDS" refers to lithium bis(trimethylsilyl)amino. Detailed Implementation

[0054] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0055] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0056] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4). The internal standard was tetramethylsilane (TMS).

[0057] HPLC determination was performed using an Agilent 1100 high-performance liquid chromatograph, a GAS15B DAD UV detector, and a Water Vbridge C18 150*4.6mm 5um column.

[0058] MS measurements were performed using an Agilent 6120 triple quadrupole mass spectrometer with a G1315D DAD detector and a Waters Xbridge C18 4.6*50mm, 5µm column, in positive / negative ion mode, with a mass scan range of 80–1200.

[0059] The silica gel plates used for thin-layer chromatography are Yantai Huanghai HSGF254 silica gel plates. The silica gel plates used in thin-layer chromatography (TLC) have a size of 0.2mm ± 0.03mm, and the size used for thin-layer chromatography separation and purification of products is 0.4mm-0.5mm.

[0060] Rapid column purification systems use either the Combiflash Rf150 (TELEDYNE ISCO) or Isolara One (Biotage).

[0061] Normal column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh as the carrier, or Changzhou Santai pre-filled ultrapure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0062] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Bid Pharmaceuticals.

[0063] Unless otherwise specified in the examples, all reactions can be carried out under a nitrogen atmosphere.

[0064] A nitrogen atmosphere refers to a reaction flask connected to a nitrogen balloon with a volume of approximately 1L.

[0065] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0066] Hydrogen was produced by the QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instruments Co., Ltd.

[0067] Nitrogen or hydrogen atmospheres are typically evacuated and then filled with nitrogen or hydrogen gas, and this process is repeated three times.

[0068] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0069] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0070] In the examples, the reaction process was monitored using thin-layer chromatography (TLC). The volume ratio of the developing solvent used in the reaction, the eluent system used for column chromatography to purify the compound, and the developing solvent system for TLC were adjusted according to the different polarities of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0071] Example 1

[0072] Step 1: Weigh 20.0 g (131.37 mmol, 1.0 eq) of D-camphor into a 1 L three-necked flask, purge with nitrogen three times, add 200 mL of anhydrous THF, stir to dissolve, cool to below -60 °C, add LDA (78.8 mL, 157.65 mmol, 1.2 eq) dropwise, and stir to react for 1 hour. Add NFSI (49.7 g, 157.65 mmol, 1.2 eq) / THF dropwise. The reaction is basically complete under GC control. Quench the reaction by adding 100 mL of 2 M dilute hydrochloric acid to the reaction system, concentrate, and extract three times with petroleum ether (200 mL × 3). Combine the organic phases, wash successively with water, saturated sodium bicarbonate, dry with anhydrous sodium sulfate, filter, and concentrate to obtain 22.1 g of compound 1a (of which compound 1a-1 content is 41.1% and compound 1a-2 content is 53.7%).

[0073] Step 2: Compound 1a (20.0 g, 117.49 mmol, 1.0 eq) was added to a 1 L three-necked flask, followed by 200 mL of THF and stirring to dissolve. The mixture was cooled to below -60 °C and a tetrahydrofuran solution of NaHMDS (76.4 mL, 152.74 mmol, 1.3 eq) was added dropwise. The mixture was stirred for 1 hour. The reaction was basically complete under GC control (1.9% of compounds 1a-2 were not converted). The reaction was quenched by adding 200 mL of 2M dilute hydrochloric acid to the reaction system. The mixture was extracted with MTBE, washed successively with water (60 mL), saturated sodium bicarbonate (60 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure (≤35 °C) to obtain compound 1b with a purity of 90.8%.

[0074] Step 3: Add 50 mL of dichloromethane to a 500 mL three-necked flask, slowly add (21.82 mL, 76.37 mmol, 1.3 eq) of sodium dihydrobis(2-methoxyethoxy)aluminate toluene solution, purge three times with nitrogen, cool to below -60 °C, add 50 mL of 1b (10.0 g, 58.75 mmol, 1.0 eq) / DCM solution, maintain the temperature for 1 hour, and the reaction is basically complete under GC control. Dilute the reaction system with 100 mL of dichloromethane, then quench the reaction with 150 mL of 2M dilute hydrochloric acid, raise the temperature to room temperature, separate the phases, extract the aqueous phase with 100 mL of dichloromethane, combine the organic phases, wash successively with saturated sodium bicarbonate and saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain 10.6 g of compound 1c with a purity of 91.4% and a yield of 104%.

[0075] Example 2

[0076] Step 1: Weigh compound 1c (theoretical amount 10.12 g, 58.76 mmol, 1.0 eq) into a 500 mL single-necked flask, add 100 mL of anhydrous DCM, stir to dissolve, and then add DMAP (1.44 g, 11.75 mmol, 0.2 eq), triethylamine (29.73 g, 293.78 mmol, 5.0 eq), phthalic anhydride (17.41 g, 117.51 ​​mmol, 2.0 eq), and nitrogen in sequence. The reaction was purged three times with gas, heated to 40°C and stirred. TLC analysis showed the reaction was almost complete. 100 mL of 10% sodium chloride aqueous solution was added to the reaction solution, and the mixture was concentrated. 100 mL of ethyl acetate was added and stirred to separate the layers. The aqueous phase was extracted with 100 mL of ethyl acetate, washed with 50 mL of saturated brine, 50 mL of 1M dilute hydrochloric acid, and 30 mL of saturated brine once. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 15.2 g of crude product with an HPLC purity of 90.0%.

[0077] Add 60 mL of acetonitrile to the crude product, heat to 60 °C and stir, then allow to cool naturally to room temperature and stir again. Filter to obtain 11.87 g of white powder solid with a purity of 99.1%. The total yield from D-camphor to compound 1d in four steps was 63.1%.

[0078] Step 2: Weigh compound 1d (11.33 g, 35.37 mmol, 1.0 eq) into a 500 mL single-necked flask, add 110 mL of dichloromethane and 110 mL of 25% KOH aqueous solution, stir at room temperature for 18 h, and LCMS detect that the reaction is basically complete. Concentrate, add 110 mL of MTBE and stir to separate the layers. Wash the organic phase with 30 mL of 25% KOH aqueous solution (3V), 30 mL of 1M hydrochloric acid (3V), and 30 mL of saturated brine (3V). Collect the organic phase, dry it with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 6.09 g of white solid 1c product with a purity of 99.3% and a yield of 100%.

[0079] Example 3

[0080] Step 1: Compound 1a (3.0 g, 17.62 mmol) was added to a flask, and 30 mL of anhydrous tetrahydrofuran was added and stirred to dissolve. The system was protected under nitrogen atmosphere and cooled to -78 °C. LDA (1.0 M, 35.25 mL) was added dropwise, and the reaction was allowed to proceed until complete. The mixture was quenched with 30 mL of saturated ammonium chloride solution, extracted three times with 30 mL of MTBE each time, and the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA = 50:1-20:1) to obtain 1.5 g of compound 1b (yield: 50%).

[0081] 1 H NMR (400MHz, CDCl3): δ4.83~4.97(m,1H), 2.40~2.42(m,1H), 1.74~1.88(m,3H), 1.26~1.58(m,1H), 0.84~1.12(m,9H).

[0082] Step 2: Compound 1b (300 mg, 1.76 mmol) was added to a flask, and 10 mL of anhydrous tetrahydrofuran was added and stirred to dissolve. The system was protected under nitrogen, cooled to -78 °C, and lithium aluminum hydride (1.0 M, 2.29 mL) was added dropwise until the reaction was complete. The mixture was quenched with 20 mL of saturated ammonium chloride solution, extracted three times with 30 mL of MTBE each time, and the organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography (PE:EA = 50:1-20:1) to obtain 120 mg of compound 1c (yield: 40%).

[0083] 1H NMR(400MHz,CDCl3):δ4.92~5.10(m,1H),3.83~3.89(m,1H),1.98~2.06(m,2H),1.68~1.82(m,2H),1.49~1.54(m,1H),1.23~1.30(m,1H),0.84~0.93(m,9H)。

Claims

1. A method for preparing compound A or a pharmaceutically acceptable salt thereof, The method comprises: The steps to convert a compound of formula DA into a compound of formula A. wherein R 1 , R 2 are each independently selected from hydrogen or halogen, and PG is a hydroxyl protecting group.

2. The method according to claim 1, further comprising the step of reacting the crude product of formula A with a hydroxyl protecting agent to form a compound of formula DA. wherein R 1 , R 2 are each independently selected from hydrogen or halogen, and PG is a hydroxyl protecting group.

3. The method of claim 1 or 2, wherein R 1 and R 2 are selected from hydrogen or fluorine.

4. The method of claim 1 or 2, wherein PG in the compound of formula DA is selected from Preferably, the compound of formula DA has the structure:

5. The method according to any one of claims 1-4, wherein the method further comprises a step of recrystallizing the crude product of formula DA, wherein the solvent used for recrystallization is selected from at least one of esters, alkanes, cycloalkanes, alcohols, acetonitrs, or ethers.

6. The method of claim 1, wherein the compound of Formula A is a compound of Formula A-1 The method of preparing a compound of Formula A-1 includes the step of converting a compound of Formula DA-1 to a compound of Formula A-1, Further, the process for preparing the compound of formula A-1 preferably comprises the steps of reacting the crude product of formula A-1 with a hydroxyl protecting agent to form a compound of formula DA-1, 7. The method according to claim 6, further comprising the step of reacting compound 1 with a fluorinating agent to form compound 2, and reacting compound 2 in the presence of a reducing agent to form the crude product of compound A-1. The preferred fluorinating agent is N-fluorobis(benzene)sulfonamide or SulfoxFluor.

8. A method for preparing compound A-1, The method includes the step of reacting compound 1 with a fluorinating agent to form compound 2. The preferred fluorinating agent is N-fluorobis(benzene)sulfonamide or SulfoxFluor.

9. The process of claim 8, wherein the process comprises the steps of reacting Compound 1 with a fluorinating reagent in the presence of a base (1) to form Compound B, and converting Compound B to Compound 2 in the presence of a base (2), 10. The method according to claim 9, wherein the base (1) is selected from n-butyllithium or tert-butyllithium; and the base (2) is selected from sodium bis(trimethylsilyl)amino or lithium bis(trimethylsilyl)amino.

11. The process according to any one of claims 8-10, wherein further comprising the step of converting the compound of formula DA-1 to the compound of formula A-1, 12. The compound DA-1 or a salt thereof,

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