A method for preparing PM-PBB3 and analogs thereof

Abstract

The application belongs to the field of organic synthesis and particularly relates to a preparation method of PM-PBB3 and analogs thereof, comprising the following steps: wherein represents a double bond or a triple bond, * F represents F or 18 F; the method comprises the following steps: step (1): compound 6 is reacted in the presence of epibromohydrin and an inorganic base to obtain compound 7; step (2): compound 7 is reacted in the presence of TBA * F, KH * F2 to obtain compound 8. The synthetic route of the application is simple, the reaction equipment requirement is low, the reaction condition is mild, the operation is simple, and the raw material is easy to obtain; a plurality of novel intermediates are obtained in the synthesis process, the intermediates have stable properties, good reusability and are easy to realize industrial scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to a PM-PBB3 and its analogs preparation method, belongs to the field of medicine and chemical technology. BACKGROUND

[0002] Alzheimer's disease (AD) and many other neurodegenerative diseases accumulate tau protein aggregates in brain cells, commonly known as tauopathy. In AD, tau protein aggregates called neurofibrillary tangles (NFTs) show a closer link to disease severity than senile plaques composed of beta-amyloid peptides (Aβ). In contrast to amyloid precursor protein (APP) Tg mice that do not reduce neurons but accumulate Aβ aggregates, tau Tg mice show a severe reduction in neurons. In vivo imaging methods such as positron emission tomography (PET), optical imaging, and nuclear magnetic resonance imaging can visualize Aβ deposits in AD patients and AD mouse models in vivo. As the molecular probes used at this time, WO2014097474A1 discloses the following representative compounds:

[0003]

[0004] The compound has good development prospects because it can specifically bind to the tau protein accumulated in the brain due to AD and non-AD tauopathy.

[0005] WO2014097474A1 discloses the preparation of the following compound, which will use 2-((tert-butyldimethylsilyl)oxy)-3-fluoropropan-1-ol, which is expensive and will use boron tribromide, which is strongly irritating and toxic, which is not conducive to industrial scale-up. The preparation method is as follows:

[0006]

[0007] Shenzhen Dingbang patent CN113402513A discloses the preparation of similar compounds, with a low two-step yield of 4.9% for substitution and ring opening, which is not conducive to industrial scale-up. The preparation method is as follows:

[0008] SUMMARY

[0009] In order to solve the technical problems existing in the above-mentioned reports, the present application provides a method for synthesizing PM-PBB3 and its analogs.

[0010] In order to overcome the defects of the prior art and realize the requirements of commercial scale-up production, the present application adopts the following preferred technical solutions:

[0011] The first aspect of the present application provides a method for preparing compound 8, the reaction formula is shown as follows:

[0012]

[0013] wherein represents a double bond or a triple bond, * F represents F or 18 F;

[0014] comprising the following steps:

[0015] Step (1): compound 6 is reacted in the presence of epibromohydrin and inorganic base to obtain compound 7;

[0016] Step (2): compound 7 is reacted in the presence of TBA * F, KH * F2 to obtain compound 8.

[0017] As a further improvement of the present application, including but not limited to, the step (1) reaction, comprising the following steps: compound 6 is reacted in the presence of epibromohydrin, inorganic base and catalyst in an organic solvent to obtain compound 7.

[0018] As a further improvement of the present application, including but not limited to, the catalyst of the step (1) reaction is selected from 15-crown-5 or 18-crown-6.

[0019] As a further improvement of the present application, including but not limited to, the inorganic base of the step (1) reaction is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably potassium carbonate.

[0020] As a further improvement of the present application, including but not limited to, the molar ratio of compound 6 to epibromohydrin in the step (1) is 1:(1-5), preferably 1:(2.5-3.5).

[0021] As a further improvement of the present application, including but not limited to, the molar ratio of compound 6 to inorganic base in the step (1) is 1:(1-5), preferably 1:(2.5-3.5).

[0022] As a further improvement of the present application, including but not limited to, the molar ratio of compound 6 to catalyst in the step (1) is 1:(0.01-0.5), preferably 1:(0.05-0.2).

[0023] As a further improvement of the present application, including but not limited to, the organic solvent of step (1) is selected from one or more of ethyl acetate, dichloromethane, dichloroethane, chloroform, acetone, tetrahydrofuran, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, preferably acetone.

[0024] As a further improvement of the present application, including but not limited to, the volume of the organic solvent of step (1) is 5-30 times, preferably 6-25 times, the mass of compound 6.

[0025] As a further improvement of the present application, including but not limited to, the reaction temperature of step (1) is 50-100℃, preferably 75-85℃.

[0026] As a further improvement of the present application, including but not limited to, the reaction time of step (1) is 9-32h, preferably 15-20h.

[0027] As a further improvement of the present application, the present inventors found that prolonging the reaction time and increasing the reaction temperature cannot make the raw materials react completely, and the impurities will increase, resulting in a decrease in yield.

[0028] As a further improvement of the present application, including but not limited to, the reaction of step (2) comprises the following steps: compound 7 is reacted with TBA * F, KH * in an organic solvent to obtain compound 8.

[0029] As a further improvement of the present application, including but not limited to, the molar ratio of compound 7 to TBA * F of step (2) is 1:(1-30), preferably 1:(5-15).

[0030] As a further improvement of the present application, including but not limited to, the molar ratio of compound 7 to KH * F2 of step (2) is 1:(1-5), preferably 1:(1.5-2.5).

[0031] As a further improvement of the present application, including but not limited to, the organic solvent of step (2) is selected from one or more of tetrahydrofuran, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, n-heptane, preferably n-heptane.

[0032] As a further improvement of the present application, including but not limited to, the reaction temperature of step (2) is 80-120℃, preferably 100-110℃.

[0033] As a further improvement of the present application, including but not limited to, the reaction time of step (2) is 10-24h, preferably 15-20h.

[0034] As a further improvement of the present application, when the present inventors only use TBAF or use different fluorinated reagents in combination with KHF2, a large amount of starting material remains, resulting in a reduced yield.

[0035] The second aspect of the present application provides a method for preparing compound 9, the reaction formula is shown as follows:

[0036]

[0037] Wherein As described in the first aspect above, * F As described in the first aspect above, R1 is selected from methyl or ethyl;

[0038] Comprising the following steps:

[0039] Step (1): compound 3 and compound 4 are reacted in the presence of a base to obtain compound 5;

[0040] Step (2): compound 5 is reacted in the presence of a deprotection reagent to obtain compound 6;

[0041] Step (3): compound 6 is reacted in the presence of epibromohydrin and an inorganic base to obtain compound 7;

[0042] Step (4): compound 7 is reacted in the presence of TBA * F, KH * F2 to obtain compound 8;

[0043] Step (5): compound 8 is reacted in the presence of an acidic reagent to obtain compound 9.

[0044] As a further improvement of the present application, including but not limited to, the reaction of step (1) comprises the following steps: compound 3 and compound 4 are reacted in an organic solvent in the presence of a base to obtain compound 5.

[0045] As a further improvement of the present application, including but not limited to, the base of the reaction of step (1) is selected from one or more of lithium hexamethyldisilazide, sodium hydride, potassium tert-butoxide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium tert-butoxide, sodium methoxide, and butyllithium, preferably sodium hydride.

[0046] As a further improvement of the present application, including but not limited to, the molar ratio of compound 3 to compound 4 in step (1) is 1:(1-3), preferably 1:(1.1-1.5).

[0047] As a further improvement of the present application, including but not limited to, the molar ratio of compound 3 to base in step (1) is 1: (1-5), preferably 1: (1.1-1.5).

[0048] As a further improvement of the present application, including but not limited to, the organic solvent in step (1) is selected from one or more of ethyl acetate, dichloromethane, dichloroethane, chloroform, acetone, tetrahydrofuran, dioxane, toluene, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, preferably tetrahydrofuran.

[0049] As a further improvement of the present application, including but not limited to, the volume of the organic solvent in step (1) is 2-30 times, preferably 6-20 times, the mass of compound 3.

[0050] As a further improvement of the present application, including but not limited to, step (1) includes: dissolving compound 3 in an organic solvent, cooling, adding to a base, stirring for a period of time, then adding compound 4, and reacting at room temperature to obtain compound 5.

[0051] As a further improvement of the present application, including but not limited to, step (1) includes: dissolving compound 3 in tetrahydrofuran, adding to a base at -5-5°C, stirring for 20-50 minutes, then adding compound 4, and reacting at room temperature for 0.5-2 hours to obtain compound 5.

[0052] As a further improvement of the present application, including but not limited to, the reaction in step (2) includes: compound 5 is reacted in an organic solvent in the presence of a deprotection reagent to obtain compound 6.

[0053] As a further improvement of the present application, including but not limited to, the deprotection reagent in step (2) is selected from TBAF.

[0054] As a further improvement of the present application, including but not limited to, the molar ratio of compound 5 to deprotection reagent in step (2) is 1: (1-10), preferably 1: (4-5).

[0055] As a further improvement of the present application, including but not limited to, the organic solvent in step (2) is selected from one or more of toluene, methanol, ethanol, tetrahydrofuran, ethyl acetate, dichloromethane, dioxane, acetonitrile, preferably tetrahydrofuran.

[0056] As a further improvement of the present application, including but not limited to, the volume of the organic solvent in step (2) is 2-40 times, preferably 6-25 times, the mass of compound 5.

[0057] As a further improvement of the present application, including but not limited to, the reaction temperature of step (2) is 10-40℃, preferably 15-30℃.

[0058] As a further improvement of the present application, including but not limited to, the reaction time of step (2) is 0.5-5h, preferably 0.5-2h.

[0059] The preparation method of steps (3)-(4) in the present scheme is as described above in the first aspect of the present application.

[0060] As a further improvement of the present application, including but not limited to, the acid reagent of step (5) is selected from one or more of trifluoroacetic acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, hydrochloric acid / methanol solution, and hydrochloric acid, preferably trifluoroacetic acid.

[0061] As a further improvement of the present application, including but not limited to, the volume of the acid reagent of step (5) is 6-60 times the mass of compound 8.

[0062] As a further improvement of the present application, including but not limited to, the reaction temperature of step (5) is 10-40℃, preferably 15-30℃.

[0063] As a further improvement of the present application, including but not limited to, the reaction time of step (5) is 0.5-5h, preferably 0.5-3h.

[0064] The third aspect of the present application provides a preparation method of compound 3, the reaction formula is as shown below:

[0065]

[0066] including R 1 optionally substituted with methyl or ethyl;

[0067] Step (6): Compound 1 is subjected to protection reaction in the presence of tert-butyldiphenylsilyl chloride and an organic base to obtain compound 2.

[0068] Step (7): Compound 2 is subjected to reaction in the presence of O,O-dialkyl phosphorus oxychloride and a base to obtain compound 3.

[0069] As a further improvement of the present application, including but not limited to, the reaction of step (6) comprises the following steps: compound 1 is subjected to protection reaction in the presence of tert-butyldiphenylsilyl chloride and an organic base in an organic solvent to obtain compound 2.

[0070] As a further improvement of the present application, including but not limited to, the organic base of the step (6) is selected from one or more of triethylamine, diisopropylethylamine, pyridine, imidazole, DBU, preferably imidazole.

[0071] As a further improvement of the present application, including but not limited to, the molar ratio of compound 1 to the organic base of the step (6) is 1:(1~5), preferably 1:(1.5~2.5).

[0072] As a further improvement of the present application, including but not limited to, the molar ratio of compound 1 to the tert-butyldiphenylsilyl chloride of the step (6) is 1:(1~2), preferably 1:(1.01~1.3).

[0073] As a further improvement of the present application, including but not limited to, the organic solvent of the step (6) is selected from one or more of dichloromethane, tetrahydrofuran, dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, preferably N,N-dimethylformamide.

[0074] As a further improvement of the present application, including but not limited to, the volume of the organic solvent of the step (6) is 5~20 times, preferably 6~15 times, of the mass of compound 1.

[0075] As a further improvement of the present application, including but not limited to, the reaction temperature of the step (6) is 10~40℃, preferably 15~25℃.

[0076] As a further improvement of the present application, including but not limited to, the reaction time of the step (6) is 2~10h, preferably 4~6h.

[0077] As a further improvement of the present application, including but not limited to, the step (7) reaction comprises the following step: compound 2 is reacted in an organic solvent in the presence of O,O-dialkylphosphoryl chloride and a base to obtain compound 3.

[0078] As a further improvement of the present application, including but not limited to, the O,O-dialkylphosphoryl chloride of the step (7) is selected from O,O-dimethylphosphoryl chloride or O,O-diethylphosphoryl chloride.

[0079] As a further improvement of the present application, including but not limited to, the base of the step (7) is selected from one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, preferably lithium diisopropylamide.

[0080] As a further improvement of the present application, including but not limited to, the molar ratio of compound 2 to base in step (7) is 1: (1-5), preferably 1: (2.5-3.5).

[0081] As a further improvement of the present application, including but not limited to, the molar ratio of compound 2 to O, O-dialkyl phosphoryl chloride in step (7) is 1: (1-5), preferably 1: (2.5-3.5).

[0082] As a further improvement of the present application, including but not limited to, the organic solvent in step (7) is selected from one or more of ethyl acetate, acetone, dichloromethane, tetrahydrofuran, dioxane, toluene, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, preferably tetrahydrofuran.

[0083] As a further improvement of the present application, including but not limited to, the volume of the organic solvent in step (7) is 3-20 times, preferably 4-10 times, the amount of compound 2.

[0084] As a further improvement of the present application, including but not limited to, the reaction time in step (7) is 0.5-5h, preferably 1-3h.

[0085] As a further improvement of the present application, including but not limited to, the reaction in step (7) comprises the following steps: dissolving the base in the organic solvent, cooling, adding a solution of compound 2, maintaining the temperature and reacting for 20-60 minutes; adding a solution of O, O-dialkyl phosphoryl chloride dropwise to the reaction system, reacting at room temperature for 0.5-2.5h to obtain compound 3.

[0086] As a further improvement of the present application, including but not limited to, the reaction in step (7) comprises the following steps: dissolving lithium diisopropylamide in tetrahydrofuran, cooling to -65℃ to -55℃, adding a tetrahydrofuran solution of compound 2, maintaining the temperature and reacting for 20-60 minutes; adding a tetrahydrofuran solution of O, O-dialkyl phosphoryl chloride dropwise to the reaction system, reacting at room temperature for 0.5-2.5h to obtain compound 3.

[0087] The fourth aspect of the present application provides a compound 5, a compound 6, a compound 7 and a compound 8, the structures of which are as follows:

[0088]

[0089] wherein As described in the first aspect above, * F As described in the first aspect above;

[0090] As a further improvement of the present application, the compound has the following structure:

[0091]

[0092] The present application has the following advantages:

[0093] (1) The synthetic route of the present application is simple, the reaction equipment requirement is low, the reaction condition is mild, the operation is simple, the raw material is easy to obtain, and the use of boron tribromide with strong irritation and toxicity can be avoided, which is suitable for industrial scale production.

[0094] (2) When the present inventors use epichlorohydrin, neither prolonging the reaction time nor increasing the reaction temperature can make the raw material react completely, and there are more by-products and lower yield. When the present application is used, the yield can be increased by 20-30%, solving the problem of low yield of epichlorohydrin in the prior art, and being more conducive to industrial scale production.

[0095] (3) When the present inventors use only TBAF or use different fluorinated reagents combined with KHF2, a large amount of raw material remains, resulting in a decrease in yield. However, when the present application is used, the yield can be increased by 28-38% when TBAF is combined with KHF2 to open the epoxide, solving the problem of low yield of opening the epoxide in the prior art, and being easy to realize industrial scale production.

[0096] (4) The preparation method of the present application obtains a plurality of novel intermediates in the synthesis process, and the intermediates have stable properties and good reproducibility. The intermediate compounds in the present application are judged according to the method of producing subsequent API products or the obtained products:

[0097] The novel intermediate compounds of the present application contribute to the creative method of producing subsequent API products, and the preparation method of the novel intermediate compounds is simple to operate, has high yield, good product quality, and is easy to realize industrial scale production. BRIEF DESCRIPTION OF DRAWINGS

[0098] Figure 1 The H-NMR spectrum of the compound 5-2 of Example 4 of the present application is as follows: 1 H-NMR spectrum;

[0099] Figure 2 The H-NMR spectrum of the compound 6-2 of Example 6 of the present application is as follows: 1 H-NMR spectrum;

[0100] Figure 3 The H-NMR spectrum of the compound 7-2 of Example 8 of the present application is as follows: 1 H-NMR spectrum;

[0101] Figure 4 The H-NMR spectrum of the compound 8-2 of Example 10 of the present application is as follows: 1 H-NMR spectrum. DETAILED DESCRIPTION

[0102] The application will be further described in connection with the specific embodiments. It should be understood that these embodiments are only used to illustrate but not to limit the scope of the application.

[0103] The experimental methods used in the following examples are conventional methods unless otherwise specified; the reagents, materials, etc. used in the following examples are commercially available unless otherwise specified.

[0104] Synthesis of compound 2 in Example 1:

[0105]

[0106] Compound 1 (47 g, 284.48 mmol, 1 eq) was dissolved in DMF (560 mL), imidazole (39 g, 568.96 mmol, 2 eq) was added, and the temperature was lowered to 0°C, and TBDPSCl (83 g, 301 mmol, 1.05 eq) was added dropwise. The reaction was carried out at room temperature for 5 h, and the completion of the reaction was detected by spotting on a plate. The reaction solution was added to water, and ethyl acetate was used for extraction to obtain compound 2 (65 g, yield 57%).

[0107] Synthesis of compound 3-1 in Example 2:

[0108]

[0109] Lithium diisopropylamine (14 mL, 2 mol / L) was dissolved in tetrahydrofuran (14 mL), and the temperature was lowered to -60°C. Compound 2 (4.0 g, 9.9 mmol) was dissolved in tetrahydrofuran (14 mL), and the temperature was maintained for 40 min. O,O-dimethyl phosphorochloridate (4.3 g, 29.7 mmol) was dissolved in tetrahydrofuran (14 mL), and the solution was added dropwise to the reaction system. The reaction was carried out at room temperature for 1 h, and the completion of the reaction was detected by spotting on a plate. The reaction solution was added to water, and ethyl acetate was used for extraction. After being evaporated and concentrated, column purification was performed to obtain compound 3-1 (3.2 g, yield 63.1%).

[0110] Synthesis of compound 5-1 in Example 3:

[0111]

[0112] Compound 3-1 (2.0 g, 3.91 mmol, 1 eq) was dissolved in tetrahydrofuran (39 mL), and the temperature was lowered to 0°C. 60% NaH (187.6 mg, 4.69 mmol, 1.2 eq) was added, and the temperature was maintained at room temperature for 30 min. Then, compound 4-1 (1.23 g, 4.69 mmol, 1.2 eq) was added, and the reaction was carried out for 1 h. The completion of the reaction was detected by spotting on a plate. The reaction solution was added to water, and ethyl acetate was used for extraction. After being evaporated and concentrated, column purification was performed to obtain compound 5-1 (1.6 g, yield 63.2%).

[0113] Synthesis of compound 5-2 in Example 4:

[0114]

[0115] Compound 3-1 (2.0 g, 3.91 mmol, 1 eq) was dissolved in tetrahydrofuran (39 mL), cooled to 0 °C, 60% NaH (187.6 mg, 4.69 mmol, 1.2 eq) was added, stirred at room temperature for 30 min, compound 4-2 (1.22 g, 4.69 mmol, 1.2 eq) was added, stirred for 1 h, and the reaction was detected by spotting on a plate. The reaction was added to water, extracted with ethyl acetate, concentrated by evaporation, and purified by column to obtain compound 5-2 (1.6 g, yield 63.4%). 1 The H-NMR spectrum is shown in Figure 1 .

[0116] Synthesis of compound 6-1 in Example 5:

[0117]

[0118] Compound 5-1 (10 g, 15.43 mmol, 1 eq) was dissolved in tetrahydrofuran (250 mL), TBAF (76 mL, 4.9 eq, 1 mol / L tetrahydrofuran solution) was added, and the reaction was carried out at room temperature for 1 h. The reaction was added to water, extracted with ethyl acetate, concentrated by evaporation, and purified to obtain product compound 6-1 (5.5 g, yield 87%).

[0119] Synthesis of compound 6-2 in Example 6:

[0120]

[0121] Compound 5-2 (10 g, 15.48 mmol, 1 eq) was dissolved in tetrahydrofuran (250 mL), TBAF (76 mL, 4.9 eq, 1 mol / L tetrahydrofuran solution) was added, and the reaction was carried out at room temperature for 1 h. The reaction was added to water, extracted with ethyl acetate, concentrated by evaporation, and purified to obtain compound 6-2 (5.3 g, yield 84%). 1 The H-NMR spectrum is shown in Figure 2 .

[0122] Synthesis of compound 7-1 in Example 7:

[0123]

[0124] Compound 6-1 (2 g, 4.88 mmol, 1 eq) was dissolved in acetone (50 mL), and then epibromohydrin (2 g, 14.66 mmol, 3.0 eq), potassium carbonate (2 g, 14.65 mmol, 3 eq), 18-crown-6 (0.2 g, 0.75 mmol, 0.15 eq) were added successively. The reaction was refluxed at 80 °C overnight, and the reaction completion was detected by spotting on a plate. The reaction solution was concentrated by evaporation, and compound 7-1 (1.2 g, yield 52.8%) was obtained by purification.

[0125] Example 8 Synthesis of compound 7-2:

[0126]

[0127] Compound 6-2 (2 g, 4.91 mmol, 1 eq) was dissolved in acetone (50 mL), and then epibromohydrin (2 g, 14.66 mmol, 3.0 eq), potassium carbonate (2 g, 14.72 mmol, 3 eq), 18-crown-6 (0.2 g, 0.75 mmol, 0.15 eq) were added successively. The reaction was refluxed at 80 °C overnight, and the reaction completion was detected by spotting on a plate. The reaction solution was concentrated by evaporation, and compound 7-2 (1.2 g, yield 52.7%) was obtained by purification. 1 H-NMR spectrum is shown in Figure 3

[0128] Example 9 Synthesis of compound 8-1:

[0129]

[0130] Compound 7-1 (1 g, 2.15 mmol, 1 eq) was dissolved in n-heptane (50 mL), and then KHF2 (335.5 mg, 4.3 mmol, 2 eq) and TBAF (21.5 mL, 1 mol / L tetrahydrofuran solution, 10 eq) were added. The reaction was carried out at 105 °C overnight, and the reaction completion was detected by spotting on a plate. The reaction solution was extracted with ethyl acetate, and then concentrated by evaporation. Compound 8-1 (600 mg, yield 57.5%) was obtained by purification.

[0131] Example 10 Synthesis of compound 8-2:

[0132]

[0133] ​Compound 7-2 (1 g, 2.15 mmol, 1 eq) was added to 50 mL of n-heptane, KHF2 (335.5 mg, 4.3 mmol, 2 eq) and TBAF (21.6 mL, 1 mol / L tetrahydrofuran solution, 10 eq) were added, and the reaction was reacted at 105 °C overnight. The reaction was detected by spotting on a plate to determine completion. The reaction was taken up in water, extracted with ethyl acetate, and concentrated by evaporation to dryness. Purification yielded compound 8-2 (600 mg, 57.5% yield). 1 H-NMR spectrum is shown in Figure 4

[0134] Example 11 Synthesis of compound 9-1:

[0135]

[0136] Compound 8-1 (1 g, 2.06 mmol) was added to trifluoroacetic acid (60 mL) and reacted at room temperature for 2 h. The reaction was detected by spotting on a plate to determine completion. The reaction was added to water, the pH was adjusted to 8.5 with dilute sodium hydroxide aqueous solution, extracted with ethyl acetate (60 mL) and methanol (10 mL), and concentrated by evaporation to dryness to obtain the product. The reaction was placed in a bottle, ethyl acetate was added and stirred for 0.5 h, and the product 9-1 (500 mg, 63% yield) was obtained by suction filtration.

[0137] Example 12 Synthesis of compound 9-2:

[0138]

[0139] Compound 8-2 (1 g, 2.07 mmol, 1 eq) was added to trifluoroacetic acid (60 mL) and reacted at room temperature for 2 h. The reaction was detected by spotting on a plate to determine completion. The reaction was added to water, the pH was adjusted to 8.5 with dilute sodium hydroxide aqueous solution, extracted with ethyl acetate (60 mL) and methanol (10 mL), and concentrated by evaporation to dryness to obtain the product. The reaction was placed in a bottle, ethyl acetate was added and stirred for 0.5 h, and the product 9-2 (500 mg, 63% yield) was obtained by suction filtration.

[0140] Comparative Example 1 Synthesis of compound 7-2:

[0141]

[0142] ​Compound 6-2 (400 mg, 0.98 mmol, 1 eq) was dissolved in 18 mL of acetone. The reaction was protected with argon, and (136 mg, 1.47 mmol, 1.5 eq) of epichlorohydrin was added, followed by potassium carbonate (204 mg, 1.47 mmol, 1.5 eq), and 18-crown-6 (20 mg, 0.07 mmol, 0.07 eq). The reaction solution turned a light red color. The reaction was refluxed at 65 °C overnight. Spot plate testing showed that there was some starting material left and less product. The reaction solution was added to 50 mL of water, and extracted twice with 50 mL of ethyl acetate. The organic phase was combined and concentrated by evaporation to dryness to obtain a crude product, which was purified to obtain compound 7-2 (0.1 g, yield 22%), and 0.3 g of starting material was recovered.

[0143] Synthesis of compound 7-2 in Comparative Example 2:

[0144]

[0145] Compound 6-2 (400 mg, 0.98 mmol, 1 eq) was dissolved in 18 mL of acetone. The reaction was protected with argon, and (136 mg, 1.47 mmol, 1.5 eq) of epichlorohydrin was added, followed by potassium carbonate (204 mg, 1.47 mmol, 1.5 eq), and 18-crown-6 (20 mg, 0.07 mmol, 0.07 eq). The reaction solution turned a light red color. The reaction was refluxed at 65 °C overnight. Spot plate testing showed that there was some starting material left and less product. The reaction solution was added to 50 mL of water, and extracted twice with 50 mL of ethyl acetate. The organic phase was combined and concentrated by evaporation to dryness to obtain a crude product, which was purified to obtain compound 7-2 (0.1 g, yield 22%), and 0.3 g of starting material was recovered.

[0146] Synthesis of compound 8-2 in Comparative Example 3:

[0147]

[0148] Compound 7-2 (200 mg, 0.43 mmol, 1 eq) was dissolved in 6 mL of toluene, and 1.3 mL of a solution of tetrabutylammonium fluoride (1.3 mmol, 1 mol / L, 3 eq) in tetrahydrofuran was added. The reaction was refluxed at 95 °C overnight. Spot plate testing showed that there was a large amount of starting material left and a small amount of product was produced. The reaction solution was added to 30 mL of water, and extracted twice with 30 mL of ethyl acetate. The organic phase was concentrated by evaporation to dryness, and purified by column chromatography to obtain compound 8-2 (40 mg, yield 19.2%), and 0.12 g of starting material was recovered.

[0149] Synthesis of compound 8-2 in Comparative Example 4:

[0150]

[0151] Compound 7-2 (200 mg, 0.43 mmol, 1 eq) was dissolved in n-heptane (6 mL), the product was insoluble, KHF2 (60 mg, 0.86 mmol, 2 eq) was added, 50% tetra-n-butylammonium dihydrogen trifluoride in dichloroethane solution (0.6 g, 1.0 mmol, 2.3 eq) was added, the reaction was heated to 100 °C overnight, spot plate detection, there was more raw material left, and a small amount of product was obtained. The reaction was added to 30 mL of water, extracted with 30 mL of ethyl acetate twice, concentrated by evaporation, and purified by column to obtain compound 8-2 (60 mg, yield 28.8%), and 0.1 g of recovered raw material.

Claims

1. A method for preparing compound 8, characterized in that, The reaction formula is shown below: in Indicates a double or triple bond. * F represents F or 18 F; Includes the following steps: Step (1): Compound 6 is reacted in the presence of epichlorohydrin and an inorganic base to give compound 7; Step (2): Compound 7 is reacted in TBA * F, KH * The reaction proceeds in the presence of F2 to give compound 8.

2. A method for preparing compound 9, characterized in that, The reaction formula is shown below: in Indicates a double or triple bond. * F represents F or 18 F and R1 are selected from methyl or ethyl; Includes the following steps: Step (1): Compound 3 and compound 4 react in the presence of a base to give compound 5; Step (2): Compound 5 was reacted in the presence of a deprotecting agent to give compound 6; Step (3): Compound 6 is reacted in the presence of epoxybromopropane and an inorganic base to give compound 7; Step (4): Compound 7, in TBA * F, KH * The reaction proceeded in the presence of F2 to give compound 8; Step (5): Compound 8 is reacted in the presence of an acidic reagent to give compound 9.

3. The preparation method according to claim 1 or 2, characterized in that, The reaction of step (1) of claim 1 or step (3) of claim 2 includes the following steps: compound 6 is reacted in an organic solvent in the presence of epoxybromopropane, an inorganic base and a catalyst to obtain compound 7; The reaction in step (1) of claim 1 or step (3) of claim 2 satisfies one or more of the following conditions: 1) The catalyst for the reaction is selected from 15-crown-5 or 18-crown-6; 2) The inorganic base in the reaction is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, and potassium hydroxide; 3) The molar ratio of the reactant compound 6 to epichlorohydrin is 1:(1-5); 4) The molar ratio of the reactant compound 6 to the inorganic base is 1:(1-5); 5) The molar ratio of the reaction compound 6 to the catalyst is 1:(0.01~0.5); 6) The organic solvent used in the reaction is selected from ethyl acetate, dichloromethane, dichloroethane, chloroform, acetone, tetrahydrofuran, etc. One or more of dioxane, toluene, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide; 7) The volume (mL) of the organic solvent used in the reaction is 5 to 30 times the mass (g) of compound 6; 8) The reaction temperature is 50–100°C; 9) The reaction time is 9 to 32 hours.

4. The preparation method according to claim 3, characterized in that, 1) The inorganic base in the reaction is potassium carbonate; 2) The molar ratio of the reactant compound 6 to epichlorohydrin is 1:(2.5-3.5); 3) The molar ratio of the reactant compound 6 to the inorganic base is 1:(2.5-3.5); 4) The molar ratio of the reaction compound 6 to the catalyst is 1:(0.05~0.2); 5) The organic solvent used in the reaction is acetone; 6) The volume (mL) of the organic solvent used in the reaction is 6 to 25 times the mass (g) of compound 6; 7) The reaction temperature is 75–85°C; 8) The reaction time is 15-20 hours.

5. The preparation method according to claim 1 or 2, characterized in that, The reaction described in step (2) of claim 1 or step (4) of claim 2 includes the following steps: Compound 7 in organic solvents, TBA * F, KH * The reaction proceeded in the presence of F2 to give compound 8; The reaction in step (2) of claim 1 or step (4) of claim 2 satisfies one or more of the following conditions: 1) The reaction of compound 7 with TBA * The molar ratio of F is 1:(1~30); 2) The reaction of compound 7 with KH * The molar ratio of F2 is 1:(1~5); 3) The organic solvent used in the reaction is selected from tetrahydrofuran, dioxane, toluene, acetonitrile, N,N-dimethylformamide, One or more of N,N-dimethylacetamide and n-heptane; 4) The reaction temperature is 80–120°C; 5) The reaction time is 10 to 24 hours.

6. The preparation method according to claim 5, characterized in that, The reaction in step (2) of claim 1 or step (4) of claim 2 satisfies one or more of the following conditions: 1) The reaction of compound 7 with TBA * The molar ratio of F is 1:(5~15); 2) The reaction of compound 7 with KH * The molar ratio of F2 is 1:(1.5~2.5); 3) The organic solvent used in the reaction is n-heptane; 4) The reaction temperature is 100–110℃; 5) The reaction time is 15-20 hours.

7. The preparation method according to claim 2, characterized in that, The reaction in step (1) includes the following steps: Compound 3 and Compound 4 react in an organic solvent in the presence of a base to obtain Compound 5; The reaction in step (1) satisfies one or more of the following conditions: 1) The base used in the reaction is selected from one or more of hexamethyldisilamide lithium, sodium hydrogen, potassium tert-butoxide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, sodium tert-butoxide, sodium methoxide, and butyllithium; 2) The molar ratio of compound 3 to compound 4 in the reaction is 1:(1-3); 3) The molar ratio of compound 3 to the base in the reaction is 1:(1-5); 4) The organic solvent used in the reaction is selected from ethyl acetate, dichloromethane, dichloroethane, chloroform, acetone, tetrahydrofuran, etc. One or more of dioxane, toluene, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide; 5) The volume (mL) of the organic solvent used in the reaction is 2 to 30 times the mass (g) of compound 3; 6) Step (1) includes: dissolving compound 3 in an organic solvent, cooling, adding alkali, and stirring for a period of time. Then compound 4 was added, and the reaction was carried out at room temperature to give compound 5; 7) Step (1) includes: dissolving compound 3 in tetrahydrofuran, adding alkali at -5 to 5°C, stirring for 20 to 50 minutes, then adding compound 4, and reacting at room temperature for 0.5 to 2 hours to obtain compound 5.

8. The preparation method according to claim 7, characterized in that, The reaction in step (1) satisfies one or more of the following conditions: 1) The base in the reaction is sodium hydrogen; 2) The molar ratio of compound 3 to compound 4 in the reaction is 1:(1.1 to 1.5); 3) The molar ratio of compound 3 to the base in the reaction is 1:(1.1~1.5); 4) The organic solvent used in the reaction is tetrahydrofuran; 5) The volume of the organic solvent used in the reaction (mL) is 6 to 20 times the mass (g) of compound 3.

9. The preparation method according to claim 2, characterized in that, The reaction in step (2) includes the following steps: compound 5 is reacted in an organic solvent in the presence of a deprotecting agent to obtain compound 6; The reaction in step (2) satisfies one or more of the following conditions: 1) The deprotecting agent in the reaction is TBAF; 2) The molar ratio of compound 5 to the deprotecting reagent in the reaction is 1:(1-10); 3) The organic solvent used in the reaction is selected from one or more of toluene, methanol, ethanol, tetrahydrofuran, ethyl acetate, dichloromethane, dioxane, and acetonitrile; 4) The volume (mL) of the organic solvent used in the reaction is 2 to 40 times the mass (g) of compound 5; 5) The reaction temperature is 10–40°C; 6) The reaction time is 0.5 to 5 hours.

10. The preparation method according to claim 9, characterized in that, The reaction in step (2) satisfies one or more of the following conditions: 1) The molar ratio of compound 5 to the deprotecting reagent in the reaction is 1:(4-5); 2) The organic solvent used in the reaction is tetrahydrofuran; 3) The volume (mL) of the organic solvent used in the reaction is 6 to 25 times the mass (g) of compound 5; 4) The reaction temperature is 15–30°C; 5) The reaction time is 0.5 to 2 hours.

11. The preparation method according to claim 2, characterized in that, The reaction in step (5) satisfies one or more of the following conditions: 1) The acidic reagent in the reaction is selected from one or more of the following: trifluoroacetic acid, hydrochloric acid / ethyl acetate solution, hydrochloric acid / dioxane solution, hydrochloric acid / ethanol solution, hydrochloric acid / methanol solution, and hydrochloric acid. 2) The volume (mL) of the acidic reagent used in the reaction is 6 to 60 times the mass (g) of compound 8; 3) The reaction temperature is 10–40°C; 4) The reaction time is 0.5 to 5 hours.

12. The preparation method according to claim 11, characterized in that, The reaction in step (5) satisfies one or more of the following conditions: 1) The acidic reagent in the reaction is trifluoroacetic acid; 2) The reaction temperature is 15–30°C; 3) The reaction time is 0.5 to 3 hours.

13. The preparation method according to claim 1 or 2, characterized in that, The preparation method of compound 3 is as follows: R1 is selected from methyl or ethyl; Includes the following steps: Step (6): Compound 1 undergoes an upprotection reaction in the presence of tert-butyldiphenylsilane chloride and an organic base to obtain compound 2; Step (7): Compound 2 is reacted in the presence of O,O-dialkylphosphoryl chloride and a base to give compound 3.

14. The preparation method according to claim 13, characterized in that, The reaction in step (6) includes the following steps: Compound 1 undergoes an up-protection reaction in an organic solvent in the presence of tert-butyldiphenylsilane chloride and an organic base to obtain Compound 2; Step (6) satisfies one or more of the following conditions: 1) The organic base in step (6) is selected from one or more of triethylamine, diisopropylethylamine, pyridine, imidazole, and DBU; 2) The molar ratio of compound 1 to organic base in step (6) is 1:(1-5); 3) The molar ratio of compound 1 to tert-butyldiphenylsilane chloride in step (6) is 1:(1-2); 4) The organic solvent in step (6) is selected from one or more of dichloromethane, tetrahydrofuran, dioxane, toluene, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide; 5) The volume of the organic solvent used in step (6) is 5 to 20 times the mass of compound 1 (g); 6) The reaction temperature in step (6) is 10–40°C; 7) The reaction time of step (6) is 2 to 10 hours.

15. The preparation method according to claim 13, characterized in that, The reaction in step (7) includes the following steps: Compound 2 is reacted in an organic solvent in the presence of O,O-dialkylphosphoryl chloride and a base to obtain Compound 3; Step (7) satisfies one or more of the following conditions: a) The O,O-dialkylphosphoryl chloride in step (7) is selected from O,O-dimethylphosphoryl chloride or O,O-diethylphosphoryl chloride; b) The base in step (7) is selected from one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamino, butyllithium, lithium bis(trimethylsilylamino)amine, sodium bis(trimethylsilylamino)amine, and potassium bis(trimethylsilylamino)amine. c) The molar ratio of compound 2 to base in step (7) is 1:(1-5); d) The molar ratio of compound 2 to O,O-dialkylphosphochloride in step (7) is 1:(1-5); e) The organic solvent in step (7) is selected from one or more of ethyl acetate, acetone, dichloromethane, tetrahydrofuran, dioxane, toluene, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide; f) The volume of the organic solvent used in step (7) is 3 to 20 times the mass of compound 2 (g); g) The reaction time of step (7) is 0.5 to 5 hours; h) The reaction in step (7) includes the following steps: dissolving the base in an organic solvent, cooling, adding a solution of compound 2, and maintaining the temperature for 20-60 minutes; adding a solution of O,O-dialkylphosphoyl chloride dropwise to the reaction system and reacting at room temperature for 0.5-2.5 hours to obtain compound 3; i) The reaction in step (7) includes the following steps: dissolving diisopropylaminolithium in tetrahydrofuran, cooling to -65℃ to -55℃, adding a tetrahydrofuran solution of compound 2, and maintaining the temperature for 20-60 minutes; adding a tetrahydrofuran solution of O,O-dialkylphosphoyl chloride dropwise to the reaction system, and reacting at room temperature for 0.5-2.5 hours to obtain compound 3.

16. The preparation method according to claim 14, characterized in that, Step (6) satisfies one or more of the following conditions: 1) The organic base in step (6) is imidazole; 2) The molar ratio of compound 1 to organic base in step (6) is 1:(1.5-2.5); 3) The molar ratio of compound 1 to tert-butyldiphenylsilane chloride in step (6) is 1:(1.01~1.3); 4) The organic solvent in step (6) is N,N-dimethylformamide; 5) The volume of the organic solvent used in step (6) is 6 to 15 times the mass of compound 1 (g); 6) The reaction temperature in step (6) is 15-25℃; 7) The reaction time of step (6) is 4 to 6 hours.

17. The preparation method according to claim 15, characterized in that, Step (7) satisfies one or more of the following conditions: a) The base in step (7) is lithium diisopropylamino; b) The molar ratio of compound 2 to the base in step (7) is 1:(2.5-3.5); c) The molar ratio of compound 2 to O,O-dialkylphosphochloride in step (7) is 1:(2.5-3.5); d) The organic solvent in step (7) is tetrahydrofuran; e) The volume of the organic solvent used in step (7) is 4 to 10 times the mass of compound 2 (g); f) The reaction time for step (7) is 1 to 3 hours.

18. A compound 7 has the following structure: in Indicates a double or triple bond. * F represents F or F 18 .

19. A compound 8 has the following structure: in Indicates a double or triple bond. * F represents F or F 18 .

20. A compound 7, selected from the following structures:

21. A compound 8, selected from the following structures:

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