Preparation method of PM-PBB3 and analogue thereof

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of PM-PBB3 and analogues thereof, which comprises the following steps: # imgabs0: # imgabs1 # represents a double bond or a triple bond, and * F represents F or 18F; comprising the following steps: (1) reacting a compound 6 in the presence of epoxy bromopropane and inorganic base to obtain a compound 7; and (2) reacting the compound 7 in the presence of TBA * F and KH * F2 to obtain a compound 8. The method has the advantages of simple synthetic route, low requirements on reaction equipment, mild reaction conditions, simple operation and easily available raw materials; a plurality of brand new intermediates are obtained in the synthesis process, and the intermediates are stable in property and good in reproducibility, so that industrial large-scale production is easy to realize.

Description

Technical Field

[0001] The invention relates to a preparation method of PM-PBB3 and analogs thereof, belonging to the technical field of medicine and chemistry. Background Art

[0002] In many neurodegenerative diseases including Alzheimer's disease (AD), Tau protein aggregates accumulate in brain cells, commonly known as Tau pathology. Tau protein aggregates, called neurofibrillary tangles (NFTs) in AD, show a closer relationship with the severity of the disease than senile plaques composed of β-amyloid peptide (Aβ). In contrast to amyloid precursor protein (APP) Tg mice, which do not lose 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 magnetic resonance imaging, can visualize Aβ deposits in AD patients and AD mouse models in vivo. As a molecular probe used at this time. WO2014097474A1 discloses the following representative compounds:

[0003]

[0004] This compound has good development prospects because it can specifically bind to Tau proteins accumulated in the brain due to AD and non-AD Tau lesions.

[0005] WO2014097474A1 discloses the preparation of the following compound, which uses 2-((tert-butyldimethylsilyl)oxy)-3-fluoropropan-1-ol, which is expensive, and uses boron tribromide, which is highly irritating and toxic, and 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. The yield of substitution and ring opening is low, only 4.9%, which is not conducive to industrial scale-up. The preparation method is as follows:

[0008] Summary of the invention

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

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

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

[0012]

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

[0014] The steps include:

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

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

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

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

[0019] As a further improvement of the present invention, including but not limited to, the inorganic base in 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 invention, including but not limited to, the molar ratio of compound 6 to epibromohydrin in step (1) is 1:(1-5), preferably 1:(2.5-3.5).

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

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

[0023] As a further improvement of the present invention, 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 acetone.

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

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

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

[0027] As a further improvement of the present invention, when the inventors use epichlorohydrin for the reaction, extending the reaction time and increasing the reaction temperature cannot completely react the raw materials, and the impurities will increase, resulting in a decrease in yield.

[0028] As a further improvement of the present invention, including but not limited to, the step (2) reaction comprises the following steps: compound 7 is reacted in an organic solvent with TBA * F, KH * The reaction is carried out in the presence of F2 to obtain compound 8.

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

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

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

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

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

[0034] As a further improvement of the present invention, when the inventors use only TBAF or use different fluorination agents in combination with KHF2 for the reaction, a large amount of raw materials will remain, resulting in a decrease in yield.

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

[0036]

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

[0038] The steps include:

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

[0040] Step (2): Compound 5 is reacted in the presence of a deprotecting agent 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, in TBA * F, KH * The reaction was carried out in the presence of 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 invention, including but not limited to, the reaction of step (1) comprises the following steps: compound 3 and compound 4 react in an organic solvent in the presence of a base to obtain compound 5.

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

[0046] As a further improvement of the present invention, 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 invention, 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 invention, 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 invention, including but not limited to, the volume amount of the organic solvent in step (1) mL is 2 to 30 times the mass amount of compound 3 g, preferably 6 to 20 times.

[0050] As a further improvement of the present invention, including but not limited to, step (1) comprises: dissolving compound 3 in an organic solvent, cooling, adding 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 invention, including but not limited to, the step (1) comprises: dissolving compound 3 in tetrahydrofuran, adding a base 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.

[0052] As a further improvement of the present invention, including but not limited to, the reaction of step (2) comprises: compound 5 reacts in an organic solvent in the presence of a deprotecting agent to obtain compound 6.

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

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

[0055] As a further improvement of the present invention, 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 invention, including but not limited to, the volume amount of the organic solvent in step (2) mL is 2 to 40 times the mass amount of compound 5 g, preferably 6 to 25 times.

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

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

[0059] The preparation methods of steps (3) to (4) in this scheme are as described above in the first aspect of the present invention.

[0060] As a further improvement of the present invention, including but not limited to, in the reaction of step (5), the acidic reagent 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 invention, including but not limited to, the volume amount mL of the acidic reagent in step (5) is 6 to 60 times the mass amount g of compound 8.

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

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

[0064] The third aspect of the present invention provides a method for preparing compound 3, and the reaction formula is as follows:

[0065]

[0066] Including R 1 The next step is to select a methyl or ethyl group;

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

[0068] Step (7): Compound 2 is reacted in the presence of O,O-dialkylphosphoryl chloride and a base to obtain compound 3.

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

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

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

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

[0073] As a further improvement of the present invention, including but not limited to, the organic solvent in 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 invention, including but not limited to, the volume amount of the organic solvent in step (6) mL is 5 to 20 times the mass amount of compound 1 g, preferably 6 to 15 times.

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

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

[0077] As a further improvement of the present invention, including but not limited to, the reaction of step (7) comprises 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.

[0078] As a further improvement of the present invention, including but not limited to, the O,O-dialkyl phosphorus oxychloride in step (7) is selected from O,O-dimethyl phosphorus oxychloride or O,O-diethyl phosphorus oxychloride.

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

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

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

[0082] As a further improvement of the present invention, 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 invention, including but not limited to, the volume amount of the organic solvent in step (7) mL is 3 to 20 times the mass amount of compound 2 g, preferably 4 to 10 times.

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

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

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

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

[0088]

[0089] in As mentioned in the first aspect above, * F is as described in the first aspect above;

[0090] As a further improvement of the present invention, the compound structure is as follows:

[0091]

[0092] The present invention has the following beneficial effects:

[0093] (1) The synthesis route of the present invention is simple, the requirements for reaction equipment are low, the reaction conditions are mild, the operation is simple, the raw materials are readily available, and the use of boron tribromide, which is highly irritating and toxic, can be avoided, and the present invention is suitable for industrial scale-up production.

[0094] (2) When the inventors used epichlorohydrin for the reaction, no matter how the reaction time was extended or the reaction temperature was increased, the raw materials could not be completely reacted, and more by-products were produced, resulting in a low yield. When the epibromohydrin of the present invention was used, the yield could be increased by 20 to 30%, thus solving the problem of low yield of epichlorohydrin in the prior art and being more conducive to industrialized scale-up production.

[0095] (3) When the inventors used only TBAF or used different fluorination agents in combination with KHF2 for the reaction, a large amount of raw materials would remain, resulting in a reduced yield. However, when TBAF was combined with KHF2 for epoxygenation under the conditions of the present invention, the yield could be increased by 28 to 38%, thus solving the problem of low epoxygenation yield in the prior art and facilitating large-scale industrial production.

[0096] (4) The preparation method of the present invention obtains multiple new intermediates during the synthesis process, and the intermediates have stable properties and good reproducibility. The intermediate compounds of the present invention are judged according to the method for producing subsequent API products or the resulting products:

[0097] The novel intermediate compound of the present invention contributes to a creative method for producing subsequent API products therefrom, and the preparation method of the novel intermediate compound of the present invention is simple to operate, has a high yield, good product quality, and is easy to realize large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] Figure 1 For the compound 5-2 of Example 4 of the present invention 1 H-NMR spectrum;

[0099] Figure 2 is the compound 6-2 of Example 6 of the present invention 1 H-NMR spectrum;

[0100] Figure 3 is the compound 7-2 of Example 8 of the present invention 1 H-NMR spectrum;

[0101] Figure 4 is the compound 8-2 of Example 10 of the present invention 1 H-NMR spectrum. DETAILED DESCRIPTION

[0102] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0103] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods; the reagents, materials, etc. used in the following examples, unless otherwise specified, can be obtained from commercial channels.

[0104] Example 1 Synthesis of Compound 2:

[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, the temperature was lowered to 0°C, TBDPSCl (83 g, 301 mmol, 1.05 eq) was added dropwise, and the reaction was carried out at room temperature for 5 h. The reaction was completed after the plate was detected. The reaction solution was added to water and extracted with ethyl acetate to obtain compound 2 (65 g, yield 57%).

[0107] Example 2 Synthesis of Compound 3-1:

[0108]

[0109] Dissolve lithium diisopropylamide (14 mL, 2 mol / L) in tetrahydrofuran (14 mL), cool to -60°C, add a solution of compound 2 (4.0 g, 9.9 mmol) in tetrahydrofuran (14 mL), maintain the temperature and react for 40 minutes; add a solution of O,O-dimethylphosphoryl chloride (4.3 g, 29.7 mmol) in tetrahydrofuran (14 mL) dropwise to the reaction system, react at room temperature for 1 hour, and the reaction is complete after spot plate detection. Add the reaction solution to water, extract with ethyl acetate, evaporate to dryness, and purify by column to obtain compound 3-1 (3.2 g, yield 63.1%).

[0110] Example 3 Synthesis of Compound 5-1:

[0111]

[0112] 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, and stirred at room temperature for 30 minutes, followed by compound 4-1 (1.23 g, 4.69 mmol, 1.2 eq), stirred for 1 h, and the reaction was completed by spot plate detection. The reaction solution was added to water, extracted with ethyl acetate, evaporated to dryness, and purified by column to obtain compound 5-1 (1.6 g, yield 63.2%).

[0113] Example 4 Synthesis of Compound 5-2:

[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 minutes, compound 4-2 (1.22 g, 4.69 mmol, 1.2 eq) was added, stirred for 1 h, and the reaction was completed by spot plate detection. The reaction solution was added to water, extracted with ethyl acetate, evaporated to dryness, and purified by column to obtain compound 5-2 (1.6 g, yield 63.4%). 1 H-NMR spectrum Figure 1 shown.

[0116] Example 5 Synthesis of Compound 6-1:

[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 completed after the plate detection. The reaction solution was added to water, extracted with ethyl acetate, evaporated and concentrated, and purified to obtain the product compound 6-1 (5.5 g, yield 87%).

[0119] Example 6 Synthesis of Compound 6-2:

[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 completed after the plate detection. The reaction solution was added to water, extracted with ethyl acetate, evaporated and concentrated, and purified to obtain compound 6-2 (5.3 g, yield 84%). 1 H-NMR spectrum Figure 2 shown.

[0122] Example 7 Synthesis of Compound 7-1:

[0123]

[0124] Compound 6-1 (2 g, 4.88 mmol, 1 eq) was dissolved in acetone (50 mL), and 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 in sequence, and the reaction was refluxed at 80°C overnight, and the reaction was completed by spot plate detection. The mixture was evaporated to dryness and concentrated, and purified to obtain compound 7-1 (1.2 g, yield 52.8%).

[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 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 in sequence, and the reaction was refluxed at 80°C overnight, and the reaction was completed by spot plate detection. The mixture was evaporated to dryness and concentrated, and purified to obtain compound 7-2 (1.2 g, yield 52.7%). 1 H-NMR spectrum Figure 3 shown.

[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), KHF2 (335.5 mg, 4.3 mmol, 2 eq) and TBAF (21.5 mL, 1 mol / L tetrahydrofuran solution, 10 eq) were added, and the reaction was carried out at 105°C overnight. The reaction was completed by spot plate detection. The reaction solution was taken into water, extracted with ethyl acetate, evaporated to dryness, concentrated, and purified to obtain compound 8-1 (600 mg, yield 57.5%).

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

[0132]

[0133] Compound 7-2 (1 g, 2.15 mmol, 1 eq) was dissolved in 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 mixture was reacted at 105°C overnight. The reaction was completed by spot plate detection. The reaction solution was taken into water, extracted with ethyl acetate, evaporated to dryness, and purified to obtain compound 8-2 (600 mg, yield 57.5%). 1 H-NMR spectrum Figure 4 shown.

[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), reacted at room temperature for 2 h, and the reaction was completed by spot plate detection. The reaction solution 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), evaporated and concentrated to obtain the product. The reaction solution was placed in a bottle, ethyl acetate was added and stirred for 0.5 h, and filtered to obtain compound 9-1 (500 mg, yield 63%).

[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), reacted at room temperature for 2 h, and the reaction was completed by spot plate detection. The reaction solution 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), evaporated and concentrated to obtain the product. The reaction solution was placed in a bottle, ethyl acetate was added and stirred for 0.5 h, and the product 9-2 (500 mg, yield 63%) 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 epichlorohydrin (136 mg, 1.47 mmol, 1.5 eq) was added, potassium carbonate (204 mg, 1.47 mmol, 1.5 eq) was added, and 18-crown-6 (20 mg, 0.07 mmol, 0.07 eq) was added. The color of the reaction solution deepened and turned light red. The reaction was refluxed at 65 ° C overnight. The plate was tested and there was residual raw material and less product. The reaction solution was added to 50 mL of water, extracted twice with 50 mL of ethyl acetate, and the organic phases were combined and evaporated to dryness and concentrated to obtain a crude product. Compound 7-2 (0.1 g, yield 22%) was purified and 0.3 g of raw material was recovered.

[0143] Comparative Example 2 Synthesis of Compound 7-2:

[0144]

[0145] Compound 6-2 (400 mg, 0.98 mmol, 1 eq) was dissolved in 18 mL of acetone, and the reaction was protected with argon. Epichlorohydrin (272 mg, 2.94 mmol, 3 eq) was added, potassium carbonate (407 mg, 2.94 mmol, 3 eq) was added, and 18-crown-6 (0.06 g, 0.21 mmol, 0.21 eq) was added. The color of the reaction solution deepened and turned light red. The reaction was refluxed at 80 ° C overnight. The plate was tested and there was residual raw material and less product. Epichlorohydrin (272 mg, 2.94 mmol, 3 eq) was added and the reaction was continued for 6 h. The plate was tested and the change was not significant. The reaction solution was added to 50 mL of water, extracted twice with 50 mL of ethyl acetate, and the organic phases were combined and evaporated to dryness and concentrated to obtain a crude product. Compound 7-2 (0.15 g, yield 33%) was obtained by column purification, and 0.2 g of raw material was recovered.

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

[0147]

[0148] Compound 7-2 (200 mg, 0.43 mmol, 1 eq) was dissolved in 6 mL of toluene, and 1.3 mL of tetrabutylammonium fluoride (1.3 mmol, 1 mol / L, 3 eq) of tetrahydrofuran solution was added, and the mixture was reacted at 95°C overnight. The plate was tested and a large amount of raw materials remained and a small amount of products were produced. The reaction solution was added to 30 mL of water, extracted twice with 30 mL of ethyl acetate, evaporated and concentrated, and purified by column to obtain compound 8-2 (40 mg, yield 19.2%), and 0.12 g of raw materials were recovered.

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

[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. A 50% dichloroethane solution of tetra-n-butylammonium dihydrogen trifluoride (0.6 g, 1.0 mmol, 2.3 eq) was added. The reaction was heated to 100 ° C overnight. The plate was tested. The remaining raw material was large and a small amount of product was obtained. The reaction solution was added to 30 mL of water, extracted twice with 30 mL of ethyl acetate, evaporated and concentrated, and purified by column to obtain compound 8-2 (60 mg, yield 28.8%), and 0.1 g of raw material was recovered.

Claims

1. A method for preparing compound 8, characterized in that: The reaction formula is as follows: in represents a double bond or a triple bond, * F means F or 18 F; The steps include: Step (1): Compound 6 is reacted in the presence of epibromopropane and an inorganic base to obtain compound 7; Step (2): Compound 7 is reacted in the presence of TBA * F, KH * The reaction is carried out in the presence of F2 to obtain compound 8.

2. A method for preparing compound 9, characterized in that: The reaction formula is as follows: in represents a double bond or a triple bond, * F means F or 18 F, R1 is selected from methyl or ethyl; The steps include: Step (1): Compound 3 and compound 4 react in the presence of a base to obtain compound 5; Step (2): Compound 5 is reacted in the presence of a deprotecting agent to obtain compound 6; Step (3): Compound 6 is reacted in the presence of epibromohydrin and an inorganic base to obtain compound 7; Step (4): Compound 7, in TBA * F, KH * The reaction was carried out in the presence of F2 to obtain compound 8; Step (5): Compound 8 is reacted in the presence of an acidic reagent to obtain 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 comprises the following steps: compound 6 is reacted in an organic solvent in the presence of epibromohydrin, an inorganic base and a catalyst to obtain compound 7; Furthermore, the reaction of step (1) of claim 1 or step (3) of claim 2 satisfies one or more of the following conditions: 1) The catalyst of the reaction is selected from 15-crown-5 or 18-crown-6; 2) The inorganic base of 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, potassium hydroxide, preferably potassium carbonate; 3) The molar ratio of the reaction compound 6 to epibromohydrin is 1:(1-5), preferably 1:(2.5-3.5); 4) The molar ratio of the reaction compound 6 to the inorganic base is 1:(1-5), preferably 1:(2.5-3.5); 5) The molar ratio of the reaction compound 6 to the catalyst is 1:(0.01-0.5), preferably 1:(0.05-0.2); 6) The organic solvent of the reaction is selected from ethyl acetate, dichloromethane, dichloroethane, chloroform, acetone, tetrahydrofuran, One or more of dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, preferably acetone; 7) The volume of the organic solvent used in the reaction is 5 to 30 times, preferably 6 to 25 times, the mass of compound 6. 8) The reaction temperature of the reaction is 50-100°C, preferably 75-85°C; 9) The reaction time of the reaction is 9 to 32 hours, preferably 15 to 20 hours.

4. The preparation method according to claim 1 or 2, characterized in that: The reaction of step (2) of claim 1 or step (4) of claim 2 comprises the following steps: compound 7 is reacted in an organic solvent with TBA * F, KH * The reaction was carried out in the presence of F2 to obtain compound 8; Furthermore, the reaction of step (2) of claim 1 or step (4) of claim 2 satisfies one or more of the following conditions: 1) Compound 7 of the reaction and TBA * The molar ratio of F is 1:(1-30), preferably 1:(5-15); 2) Compound 7 of the reaction and KH * The molar ratio of F2 is 1:(1-5), preferably 1:(1.5-2.5); 3) The organic solvent of the reaction is selected from tetrahydrofuran, dioxane, toluene, acetonitrile, N,N-dimethylformamide, One or more of N,N-dimethylacetamide and n-heptane, preferably n-heptane; 4) The reaction temperature of the reaction is 80-120°C, preferably 100-110°C; 5) The reaction time of the reaction is 10 to 24 hours, preferably 15 to 20 hours.

5. The preparation method according to claim 2, characterized in that: The reaction of step (1) comprises the following steps: Compound 3 and Compound 4 react in an organic solvent in the presence of a base to obtain Compound 5; Furthermore, the reaction in step (1) of claim 2 satisfies one or more of the following conditions: 1) The base of the reaction is selected from one or more of lithium hexamethyldisilazide, sodium hydrogen hydride, potassium tert-butoxide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium tert-butoxide, sodium methoxide, and butyl lithium, preferably sodium hydrogen hydride; 2) The molar ratio of compound 3 to compound 4 in the reaction is 1:(1-3), preferably 1:(1.1-1.5); 3) The molar ratio of the compound 3 to the base in the reaction is 1:(1-5), preferably 1:(1.1-1.5); 4) The organic solvent of the reaction is selected from ethyl acetate, dichloromethane, dichloroethane, chloroform, acetone, tetrahydrofuran, One or more of dioxane, toluene, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, Tetrahydrofuran is preferred; 5) The volume of the organic solvent used in the reaction is 2 to 30 times, preferably 6 to 20 times, the mass of compound 3. 6) The step (1) comprises: dissolving compound 3 in an organic solvent, cooling, adding a base, stirring for a period of time, Then compound 4 was added and reacted at room temperature to obtain compound 5; 7) The step (1) comprises: dissolving compound 3 in tetrahydrofuran, adding a base 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.

6. The preparation method according to claim 2, characterized in that: The reaction of step (2) comprises the following steps: compound 5 is reacted in an organic solvent in the presence of a deprotection agent to obtain compound 6; Furthermore, the reaction in step (2) of claim 2 satisfies one or more of the following conditions: 1) The deprotection reagent of the reaction is selected from TBAF; 2) The molar ratio of the compound 5 in the reaction to the deprotection agent is 1:(1-10), preferably 1:(4-5); 3) The organic solvent of the reaction is selected from one or more of toluene, methanol, ethanol, tetrahydrofuran, ethyl acetate, dichloromethane, dioxane, acetonitrile, preferably tetrahydrofuran; 4) The volume of the organic solvent used in the reaction is 2 to 40 times, preferably 6 to 25 times, the mass of compound 5. 5) The reaction temperature of the reaction is 10 to 40°C, preferably 15 to 30°C; 6) The reaction time of the reaction is 0.5 to 5 h, preferably 0.5 to 2 h.

7. 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 of the reaction 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; 2) The volume of the acidic reagent used in the reaction is 6 to 60 times the mass of compound 8; 3) The reaction temperature of the reaction is 10 to 40°C, preferably 15 to 30°C; 4) The reaction time of the reaction is 0.5 to 5 hours, preferably 0.5 to 3 hours.

8. The preparation method according to claim 1 or 2, characterized in that: The preparation method of compound 3 is as follows: Wherein R1 is selected from methyl or ethyl; The steps include: Step (6): Compound 1 is subjected to an upper protection reaction in the presence of tert-butyldiphenylsilyl 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 obtain compound 3.

9. The preparation method according to claim 8, characterized in that: The reaction of step (6) comprises the following steps: Compound 1 is subjected to an upper protection reaction in an organic solvent in the presence of tert-butyldiphenylsilyl chloride and an organic base to obtain Compound 2; Furthermore, 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, preferably imidazole; 2) The molar ratio of compound 1 to the organic base in step (6) is 1:(1-5), preferably 1:(1.5-2.5); 3) The molar ratio of compound 1 to tert-butyldiphenylsilyl chloride in step (6) is 1:(1-2), preferably 1:(1.01-1.3); 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, preferably N,N-dimethylformamide; 5) The volume of the organic solvent in step (6) is 5 to 20 times, preferably 6 to 15 times, the mass of compound 1. 6) The reaction temperature of step (6) is 10-40°C, preferably 15-25°C; 7) The reaction time of step (6) is 2 to 10 hours, preferably 4 to 6 hours; And / or, preferably, the reaction of step (7) comprises 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; a) the O,O-dialkyl phosphorus oxychloride in step (7) is selected from O,O-dimethyl phosphorus oxychloride or O,O-diethyl phosphorus oxychloride; b) the base in step (7) is selected from one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, lithium diisopropylamide, butyl lithium, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, preferably lithium diisopropylamide; c) the molar ratio of compound 2 to the base in step (7) is 1:(1-5), preferably 1:(2.5-3.5); d) the molar ratio of compound 2 to O,O-dialkylphosphoryl chloride in step (7) is 1:(1-5), preferably 1:(2.5-3.5); 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, N,N-dimethylacetamide, preferably tetrahydrofuran; f) The volume of the organic solvent in step (7) is 3 to 20 times, preferably 4 to 10 times, the mass of compound 2 in mL; g) The reaction time of step (7) is 0.5 to 5 hours, preferably 1 to 3 hours; h) the reaction of step (7) comprises the following steps: dissolving a base in an organic solvent, cooling, adding a solution of compound 2, and maintaining the temperature for reaction for 20-60 minutes; dropping a solution of O,O-dialkylphosphoryl chloride into the reaction system, and reacting at room temperature for 0.5-2.5 hours to obtain compound 3; i) The reaction of step (7) comprises the following steps: dissolving lithium diisopropylamide in tetrahydrofuran, cooling to -65°C to -55°C, adding a tetrahydrofuran solution of compound 2, and maintaining the temperature for reaction for 20-60 minutes; dropping a tetrahydrofuran solution of O,O-dialkylphosphoryl chloride into the reaction system, and reacting at room temperature for 0.5-2.5 hours to obtain compound 3.

10. Compound 5, Compound 6, Compound 7 and Compound 8, the structures of which are as follows: in represents a double bond or a triple bond, * F means F or 18 ; The following structure is preferred:

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