Process for the preparation of dihydroisoflavone derivatives

Abstract

This invention discloses a method for preparing dihydroisoflavone derivatives. Specifically, this invention provides a method for preparing compound 16, which includes the following steps: in an organic solvent, in the presence of an alkoxide, a catalyst, and a ligand, compound 12 and compound 15 undergo a Suzuki-Miyaura reaction to obtain compound 16; the catalyst is Pd(OAc)2; and the ligand is PPh3. This application designs and synthesizes the target natural product (compound 1) through a total synthesis method. This research provides a basis for the total synthesis of dihydroisoflavone alcohol compounds containing chiral centers.

Description

Technical Field

[0001] This invention belongs to the field of medicine. Specifically, this invention relates to a method for preparing a class of dihydroisoflavone derivatives. Background Technology

[0002] (S,E)-3-(2,4-dihydroxy-3-(7-hydroxy-3,7-dimethyloct-2-en-1-yl)phenyl)-3,5,7-trihydroxybenzopyran-4-one (compound 1) is derived from the roots of *Hymenochloa crus-galli*. *Hymenochloa crus-galli* is a subtropical plant native to China, and its roots have medicinal value, used in Traditional Chinese Medicine to treat menstrual disorders, dysmenorrhea, bleeding, and gastric ulcers. Flavonoids isolated from its roots have immunosuppressive effects. Compound 1 is a class of chiral tertiary alcohol flavonoids, typically obtained from natural products; its synthesis has not yet been reported. Summary of the Invention

[0003] The technical problem this invention aims to solve is overcoming the deficiency in the prior art regarding the synthesis of compound 1, thereby providing a method for preparing dihydroisoflavone derivatives. This invention, through the design of a synthetic route, can obtain this natural product in large quantities, solving the problem of low yield and difficulty in obtaining further natural products, thus satisfying the needs of further research.

[0004] This invention provides a method for preparing compound 16, comprising the following steps: in an organic solvent, in the presence of an alkoxide, a catalyst, and a ligand, compound 12 and compound 15 undergo a Suzuki-Miyaura reaction to obtain compound 16; the catalyst is Pd(OAc)2; and the ligand is PPh3.

[0005]

[0006] In one embodiment, the organic solvent may be an amide solvent; the amide solvent may be N,N-dimethylformamide (DMF); preferably anhydrous DMF.

[0007] In one embodiment, the volume-to-mass ratio of the organic solvent to compound 12 may be (5-100):1 mL / g, for example, 25.5:1 mL / g.

[0008] In one embodiment, the molar ratio of compound 15 to compound 12 may be (1-5):1, for example, 2:1.

[0009] In one embodiment, the molar ratio of the catalyst to the compound 12 may be (0.01-0.1):1, for example, 0.04:1.

[0010] In one embodiment, the molar ratio of the ligand to the compound 12 may be (0.01-0.1):1, for example, 0.04:1.

[0011] In one embodiment, the molar ratio of the catalyst to the ligand may be (1-5):1, for example, 1:1.

[0012] In one embodiment, the alkoxide may be a lithium salt, sodium salt, or potassium salt, such as t-BuOLi.

[0013] In one embodiment, the molar ratio of the alkoxide to compound 12 may be (1-6):1, for example, 2:1.

[0014] The reaction temperature of the Suzuki-Miyaura reaction is the conventional temperature for this type of reaction in the art, for example, 50-120°C, preferably 90°C.

[0015] The progress of the Suzuki-Miyaura reaction is monitored using conventional methods in the art (e.g., TLC, HPLC, LCMS, or NMR), and the reaction endpoint is generally defined as the disappearance of compound 12 or the cessation of the reaction. The reaction time of the Suzuki-Miyaura reaction is the conventional reaction time for this type of reaction in the art, for example, 3-10 hours, preferably 4 hours.

[0016] The preparation method of compound 16 may further include post-processing, wherein the post-processing operations are conventional post-processing operations in this type of preparation method in the art. For example, the preparation method further includes the following steps after the Suzuki-Miyaura reaction is completed: extraction, drying, concentration, and purification.

[0017] The quenching is preferably performed using ethyl acetate and water. The drying is preferably performed using anhydrous sodium sulfate. The purification is preferably performed using column chromatography; the eluent for the column chromatography can be PE:EA = 4:1.

[0018] The preparation method of compound 16 further includes the following steps: in an organic solvent, in the presence of a catalyst, compound 14 undergoes a hydroxyl protection reaction with pinacol diboronate to obtain compound 15;

[0019]

[0020] In one embodiment, the organic solvent may be an alcohol solvent and / or a sulfoxide solvent; the alcohol solvent may be one or more of methanol, ethanol, and isopropanol, preferably methanol; the sulfoxide solvent may be dimethyl sulfoxide; the organic solvent is preferably an alcohol solvent and a sulfoxide solvent, such as methanol and dimethyl sulfoxide; when the organic solvent is an alcohol solvent and a sulfoxide solvent, the volume ratio of the alcohol solvent to the sulfoxide solvent is (1-5):1, for example, 1:1.

[0021] In one embodiment, the mass-to-volume ratio of compound 14 to the organic solvent may be (0.5-0.05):1 g / ml, for example, 0.116:1 g / ml.

[0022] In one embodiment, the molar ratio of the pinacol diboronate to the compound 14 may be (1-6):1, for example, 1.5:1.

[0023] In one embodiment, the catalyst may be divalent palladium, such as palladium(II) tetra(acetonitrile)tetrafluoroborate (Pd(BF4)2(MeCN)4).

[0024] In one embodiment, the molar ratio of the catalyst to the compound 14 may be (0.01-0.2):1, for example, 0.05:1.

[0025] The reaction temperature for the hydroxyl protection reaction is the conventional temperature for this type of reaction in the art, for example, 0-50°C, preferably 0°C.

[0026] The progress of the hydroxyl protection reaction is detected using conventional monitoring methods in the art (e.g., TLC, HPLC, LCMS or NMR), and the reaction endpoint is generally defined as the disappearance of compound 12 or the cessation of the reaction.

[0027] The preparation method of compound 15 may further include post-processing, wherein the post-processing operations are conventional post-processing operations in this type of preparation method in the art. For example, after the hydroxyl protection reaction is completed, the preparation method may further include the following steps: quenching, extraction, drying, concentration, and purification.

[0028] The quenching is preferably performed using ethyl acetate and a saturated sodium chloride aqueous solution. The drying is preferably performed using anhydrous sodium sulfate. The purification is preferably performed using column chromatography; the eluent for the column chromatography can be PE:EA = 1:9.

[0029] The present invention also provides a method for preparing compound 15, which includes the following steps: in an organic solvent, in the presence of a catalyst, compound 14 undergoes a hydroxyl protection reaction with pinacol diboronate to obtain compound 15;

[0030]

[0031] In one embodiment, the reaction conditions and steps for preparing compound 15 are as described in the previous preparation method.

[0032] The present invention also provides a method for preparing compound 1, which includes the following steps: in a solvent, in the presence of a hydrogen donor and a catalyst, compound 16 undergoes a debenzylation reaction to obtain compound 1;

[0033]

[0034] In one embodiment, the solvent may be an alcohol solvent; the alcohol solvent may be one or more of methanol, ethanol, and isopropanol, preferably isopropanol.

[0035] In one embodiment, the mass-to-volume ratio of compound 16 to solvent may be (2-8):1 mg / ml, for example, 3.75:1 mg / ml.

[0036] In one embodiment, the hydrogen donor may be ammonium formate and / or 1,4-cyclohexadiene, preferably 1,4-cyclohexadiene.

[0037] In one embodiment, the mass-to-volume ratio of compound 16 to the hydrogen donor may be 1:(1-5) mg / μL, for example: 1:2 mg / μL.

[0038] In one embodiment, the catalyst is Pd / C and / or Pd(OH)2, preferably 10% Pd / C and Pd(OH)2. When the catalyst is Pd / C and Pd(OH)2, the mass ratio of Pd / C to Pd(OH)2 is (2-6):1, for example, 4:1.

[0039] The reaction temperature for the debenzylation reaction is the conventional temperature for this type of reaction in the art, for example, 50-120°C, preferably 80°C.

[0040] The progress of the debenzylation reaction is monitored using conventional methods in the art (e.g., TLC, HPLC, LCMS, or NMR), and the reaction endpoint is generally defined as the disappearance of compound 16 or the cessation of the reaction. The reaction time for the debenzylation reaction is the conventional reaction time for this type of reaction in the art, for example, 1-5 hours, preferably 2 hours.

[0041] The preparation method of compound 1 may further include post-processing, wherein the post-processing operations are conventional post-processing operations in this type of preparation method in the art. For example, after the debenzylation reaction is completed, the preparation method further includes the following steps: cooling, filtration, concentration, and purification.

[0042] The purification is preferably performed by column chromatography; the column chromatography is preferably performed by reversed-phase column chromatography; the eluent for the column chromatography can be a water:methanol system.

[0043] The present invention also provides a compound 15,

[0044]

[0045] The present invention also provides a compound 16,

[0046]

[0047] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0048] The reagents and raw materials used in this invention are all commercially available.

[0049] The positive and progressive effects of this invention are as follows: This application designs and synthesizes the target natural product (compound 1) through a total synthesis method, which provides a basis for the total synthesis of dihydroisoflavone alcohol compounds containing chiral centers. Detailed Implementation

[0050] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0051]

[0052] a:K2CO3,BnBr,DMF;b:Py,(OAc)2O;c:(1)TATBA,OH(CH)3OH,CH(OCH2CH3)3;(2)MeOH / K2CO3; d: I2 / KIO3; e: BnBr, MeCN, K2CO3, rf; f: Br2, Et2O; g: (1) DMF, K2CO3, rt; (2) CH 3COOH,H2O;h:CatA,Et3N,tuluene,rt,12h;i:Pd / C,H2:k:Cat,(Bpin)2,DMSO.MeOH;L:Pd(OAc)2,PPh3,t-BuOLi,DMF,90℃;m:Pd / C,Pd(OH)2,1,4-cyclohexadiene,IPA,80℃

[0053] Example 1: Synthesis of the compound

[0054] Compound 3-11 was synthesized according to the method described in Du, Zhi Teng, et al. "Study on the Synthesis of Dihydroflavonol Compounds." Pharmaceutical Fronts. DOI:10.1055 / s-0043-1764226.

[0055] Synthesis of compound (12): Compound 11 (350 mg, 0.44 mmol) and catalyst (31 mg, 0.07 mmol) were weighed into a round-bottom flask, toluene was added as solvent, and nitrogen was quickly backfilled three times. After reacting at room temperature for 30 minutes under nitrogen protection, triethylamine (4.5 mg, 0.04 mmol) was added, and the reaction was carried out at room temperature for 24 h under nitrogen atmosphere. The reaction was monitored by TLC (PE:EA = 2:1). After the reaction was complete, water was added to quench the reaction, toluene was evaporated, and the mixture was extracted three times with ethyl acetate and saturated sodium chloride aqueous solution. The organic layer was collected, dried with anhydrous sodium sulfate, concentrated under pressure, and purified by column chromatography (PE:EA = 7:1). After drying, a pale yellow solid product 12 (141 mg, 40.3%) was obtained.

[0056] Synthesis of compound (15): Synthesis of 2,6-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)oct-6-en-2-ol

[0057] Compound 14 (M = 172.27, 696 mg, 4.0 mmol) and pinacol diborate ester (1.5 g, 6.0 mmol) were weighed into a round-bottom flask. The solvent methanol:dimethyl sulfoxide (v / v = 1:1, 6 mL) was added, and then the catalyst palladium(II) tetra(acetonitrile)tetrafluoroborate (Pd(BF4)2(MeCN)4, 88.8 mg, 0.2 mmol) was added at 0 °C. The reaction was monitored by TLC (PE:EA = 4:1). After the reaction was complete, water was added for dilution, and the mixture was extracted with ethyl acetate and saturated sodium chloride aqueous solution. The organic layer was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 1:9) to give a colorless liquid product 15 (654 mg, 58.0%). 1 H NMR (400MHz, DMSO) δ5.17–5.10(m,1H),4.06(s,1H),1.90(t,J=7.1Hz,2H),1.50(s,3H),1.47(d,J=7. 7Hz, 2H), 1.36 (ddd, J=14.4, 6.6, 2.3Hz, 2H), 1.27 (dd, J=7.5, 3.2Hz, 2H), 1.17 (s, 12H), 1.05 (s, 6H). 13C NMR (101MHz, DMSO) δ 134.45, 119.15, 83.12, 69.12, 43.47, 29.77, 25.00, 24.93, 22.62, 15.92. HR-ESI-MS: Calculated values: C 16 H 31 BO3Na[M+Na] + 304.2295, Detected value: 304.2291.

[0058] Synthesis of compound (16): Compound 12 (M = 790.65, 157 mg, 0.2 mmol), compound 15 (M = 282.23, 112 mg, 0.4 mmol), PPh3 (triphenylphosphine, M = 262.29, 2.1 mg, 0.008 mmol), Pd(OAc)2 (palladium acetate, palladium acetate, M = 224.51, 1.8 mg, 0.008 mmol) and t-BuOLi (lithium tert-butoxide, M = 80.05, 32 mg, 0.4 mmol) were weighed separately. The organic and organic layers were added sequentially to a microwave tube, dissolved in anhydrous DMF (4 ml), and the air in the microwave tube was removed with nitrogen. The microwave tube was then quickly sealed under a nitrogen atmosphere and reacted at 90 °C for 4 h. After cooling to room temperature, the reaction was monitored by TLC (PE:EA = 2:1). After the reaction was complete, ethyl acetate and water were added for extraction. The organic layers were combined, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 4:1). The product was a pale yellow solid, product 16 (M = 819.01, 112.0 mg, 68.5%).

[0059] 1H NMR (400MHz, CDCl3) δ7.42(d,J=7.3Hz,2H),7.34–7.25(m,14H),7.22–7.20(m,2H),7.18(d,J=6.3Hz,2H),7.02(d,J=8.7Hz, 1H),6.54(d,J=8.7Hz,1H),6.06(d,J=2.1Hz,1H),5.97(d,J=2.1Hz,1H),5.17(s,1H),5.05(s,1H),5.02(d,J=2.0Hz,1H),4. 97(d,J=9.3Hz,3H),4.90(d,J=9.1Hz,3H),4.78(d,J=11.3Hz,1H),4.40(s,1H),4.13(d,J=11.3Hz,1H),3.39(dd,J=15.0,6. 2Hz,1H),3.29(dd,J=15.1,5.7Hz,1H),1.85(t,J=6.4Hz,2H),1.41(s,3H),1.28(d,J=4.5Hz,2H),1.18(s,2H),1.05(s,6H). 13 C NMR (101MHz, CDCl3) δ192.07,165.19,164.53,160.81,158.48,157.16,137.87,137.17,136.34 ,135.73,135.39,128.75,128.56,128.51,128.44,128.21,127.79,127.71,127.67,127.48,12 7.41,127.05,126.56,125.19,125.13,123.31,107.27,104.92,94.93,94.50,76.46,73.51,73 .36,70.94,70.37,70.20,69.92,43.53,39.91,29.74,29.18,23.70,22.61,16.14.HR-ESI-MS:C 53 H 54 O8Na[M+Na] + Calculated value: 841.3711, Detected value: 841.3709.

[0060] Synthesis of compound (1): Compound 16 (30 mg, 0.04 mmol) was weighed into a reaction flask, 8 mL of isopropanol was added, 60 μL of 1,4-cyclohexadiene was added in portions (1:2, starting material weight mg: 1,4-cyclohexadiene μL), 12 mg of 10% Pd / C catalyst was added, and 3 mg of Pd(OH)2 was added at the same time. The reaction was carried out at 80 °C, and LC-MS was detected every 30 minutes. After two hours, the reaction stopped and the reaction was stopped. After cooling to room temperature, the mixture was filtered, concentrated under reduced pressure, purified by reverse phase column (water: methanol system), and freeze-dried to obtain white solid 1 (5 mg, 30.0%) with an ee value of 55.28% (column: IE3 0.46×25 cm, 3 μm; mobile phase: n-hexane / isopropanol = 80 / 20 v / v%; UV: 214 nm; flow rate: 0.7 mL / min). (c 0.15, MeOH) 1 H NMR (400MHz, MeOD) δ6.87(d,J=8.6Hz,1H),6.18(dd,J=8.6,3.7Hz,1H),5.76(d,J=2.1Hz,1H),5.72(s,1H),5.12(t,J=6.7Hz,1H),4.58(d,J=11 .5Hz,1H),4.13(d,J=11.5Hz,1H),3.24(d,J=9.2Hz,2H),1.85(t,J=6.9 Hz,2H),1.65(s,3H),1.40–1.32(m,2H),1.31–1.25(m,2H),1.04(s,6H). 13 C NMR(101MHz,MeOD)δ194.29,174.63,170.06,162.80,156.36,154.59,133.91,124.05,122.92,116.25 ,115.18,106.09,95.25,73.91,73.40,70.08,42.85,39.88,27.75,22.24,21.70,14.75.HR-ESI-MS:C 25 H 30 O8Na[M+Na] + Calculated value: 458.1941, Detected value: 458.1939.

[0061] Synthesis of compound (2): Compound 12 (100 mg, 0.13 mmol) was weighed into a round-bottom flask, ethanol was added as solvent, and an appropriate amount of catalyst Pd / C was added. The air in the reaction was removed, and the reaction was carried out at room temperature for 6 h under a hydrogen atmosphere. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and dried to obtain white solid 2 (50.0 mg, 91.9%). The ee value was 46% (separated by chiral chromatography, chiral stationary phase IE3 0.46 × 25 cm, 3 μm, mobile phase n-hexane / isopropanol = 80 / 20 (v / v%), UV: 214 nm, flow rate: 0.7 mL / min, determined by HPLC). (c 0.15, MeOH). 1 H NMR(400MHz,MeOD)δ7.30(d,J=8.5Hz,1H),6.33(dd,J=8.5,2.4Hz,1H),6.27(d,J=2.3Hz,1H) ,5.90(d,J=2.2Hz,1H),5.88(d,J=2.2Hz,1H),4.79(d,J=11.9Hz,1H),4.09(d,J=11.9Hz,1H). 13 C NMR(101MHz,MeOD)δ195.12,166.78,165.01,162.97,158.46,155.08,127.9 5,115.70,106.16,102.65,100.70,95.84,94.61,73.88,73.43.HR-ESI-MS:C 15 H 12 O7Na[M+Na] + Calculated value: 327.0475, Detected value: 327.0475.

[0062] Synthesis of compound (22): Compound 12 (100 mg, 0.13 mmol) was weighed into a round-bottom flask, ethanol was added as solvent, and an appropriate amount of catalyst Pd / C was added. The air in the reaction was removed, and the reaction was carried out at 40 °C for 10 h under a hydrogen atmosphere. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and then purified by reverse-phase column chromatography (water: methanol system). After freeze-drying, a white solid 22 (30 mg, 82.2%) was obtained. 1 H NMR(400MHz,MeOD)δ6.84(d,J=8.3Hz,1H),6.32(d,J=2.3Hz,1H),6.25(dd,J=8.3,2.4Hz,1H),5.9 0–5.85(m,2H),4.53(t,J=10.8Hz,1H),4.37(dd,J=10.9,5.4Hz,1H),4.18(dd,J=10.7,5.4Hz,1H).13 C NMR (126MHz, MeOD) δ197.61,166.23,163.88,163.34,157.33,155.76,130.05,112.08,105.90,101.99,101.89,94.05,69.68,46.16.HR-ESI-MS:C 15 H 12 O7Na[M+Na] + Calculated value: 311.0526, Detected value: 311.0527.

[0063] Comparative Example

[0064] 1. Referring to the synthesis of compound (16), commonly used catalysts / ligands Pd(PPh3)4, Pd(dppf)Cl2, Pd(pda)3+PCy, Pd(OAc)2+PPh3, and XPhos-G2 were selected to explore the Suzuki-Miyaura reaction conditions under different alkaline conditions (Table 1).

[0065] Table 1. Reaction conditions for Suzuki-Miyaura

[0066]

[0067] a: Using microwave reaction

[0068] eq. equivalent to the amount of a compound

[0069] We initially used Pd(dppf)Cl2 as a catalyst and an inorganic base, CsCO3, at 90°C. LC-MS analysis showed no product formation; the main new product was deiodination byproduct 21 (serial number 1). At the end of the reaction, TLC analysis revealed a large amount of unreacted alkylboronate. We speculated that the failure to couple was due to the high reactivity of iodine, which, at high temperatures and prolonged reaction times, led to premature deiodination, thus preventing coupling with the alkylboronate. We then lowered the reaction temperature and used a microwave reactor to accelerate the reaction, but the result was the same (serial number 2). Next, we used CsF as a base and reacted at 80°C. LC-MS showed product formation (serial number 3), but the reaction progress was limited, and the yield was extremely low. Under these circumstances, we optimized the conditions by changing the catalyst. After switching to Pd(PPh3)4, no product was formed; only byproduct 21 (serial number 4) was observed. Under Pd(PPh3)4 catalyst conditions, replacing CsCO3 with CsCO3 and changing the reaction temperature resulted in product formation, but in very small quantities, almost invisible on TLC-MS. Only LC-MS analysis revealed the molecular weight of the product (numbers 5 and 6). Under the same catalyst, reaction with NaOH at 90°C under microwave conditions produced new spots on TLC-MS, which were later identified as product 16 by LC-MS. After separation and purification, this was confirmed as the product, but the reaction yield was low (numbers 7 and 8).

[0070] Although the steric hindrance of aryl iodides has a less significant impact on coupling reactions than that of boron esters, there are two benzyl groups at the ortho position of the aryl iodide in the starting material, and successful cases of sterically hindered aryl iodides directly participating in coupling reactions are rare. Therefore, we tried using catalyst systems suitable for steric hindrance, Pd(dba)3+PCy3 and XPhos-G2, but the reaction results were still unsatisfactory (items 9 and 10). We then switched to a catalyst / phosphine ligand Pd(OAc)2+PPh3 system, using the organic base t-BuOLi, and reacted in a microwave at 90°C for 3 hours, with the main product being coupling compound 16 (item 11). Because the single sample feed volume of the microwave reaction is limited, it could not meet the product quantity required for our experiment. Therefore, we tried to extend the reaction time without using a microwave reactor under the same conditions, and the reaction effect was similar, and the yield was stable with increased sample feed volume.

[0071] The Suzuki-Miyaura cross-coupling requires very specific reaction conditions, including isolation from air and water, use of ultra-dry solvents, and removal of air from the reaction flask through special treatment. The reaction must be carried out in a sealed system under nitrogen protection. Based on the above experiments, we found the optimal conditions for the reaction of sterically hindered aryl iodides and alkyl borate esters: catalyst / ligand Pd(OAc)2 / PPh3, base t-BuOLi, and solvent anhydrous DMF (number 12).

[0072] 2. Exploration of debenzylation reaction conditions

[0073] For the protection of phenolic hydroxyl groups, electron-donating methyl groups can be used as protecting groups, and electron-withdrawing acetyl groups can also be used. However, demethylation protection involves the use of acidic reagents such as boron tribromide and aluminum trichloride, which are highly toxic, difficult to control, and have complicated post-treatment processes. Acetyl protection is unstable and prone to hydrolysis. After comprehensive consideration, this paper ultimately chose benzyl to protect the phenolic hydroxyl group. In studying the debenzylation reaction of compound 16, considering that the compound has many active sites, including multiple phenolic hydroxyl groups, tertiary alcohol structures, and unsaturated double bonds, we attempted acidolysis or catalytic hydrogenolysis to remove the benzyl group.

[0074] 2.1. Hydrogenation-catalyzed debenzylation

[0075] Catalytic hydrogenation is the most commonly used method for benzyl removal, but due to the presence of multiple benzyl-protected phenolic hydroxyl groups in the structure of compound 16 and the presence of easily reduced carbon-carbon double bonds in the side chain, successfully removing multiple benzyl groups using catalytic hydrogenation is very difficult. Therefore, we need to explore reaction conditions for catalytic hydrogenation without affecting other groups such as the carbon-carbon double bonds in the side chain (Table 2). When Pd / C is used as the catalyst and ammonium formate is used as the hydrogen source (serial number 1), LC-MS monitoring revealed that the reduction of the side chain double bonds and incomplete benzyl removal occurred simultaneously in the reaction, and the product and reduction byproduct had similar polarities, making them difficult to separate and purify.

[0076] To preserve the carbon-carbon double bonds in the side chain, a milder catalyst, Pd(OH)₂, was used in the experiment, with ammonium formate as the hydrogen source. LC-MS monitoring revealed that some benzyl groups could not be completely removed, and the main product was still the carbon-carbon double bond reduction product (item 2). Benzylic groups could not be removed under Pd-CaCO₃-PdO formic acid or ammonium formate conditions, and heating to 40℃-60℃ did not show significant changes (items 3 and 4).

[0077] Under Pd / C and 1,4-cyclohexadiene conditions, LC-MS monitoring revealed that increasing the temperature favored the reaction. At 45℃ and after 12 hours, a significant amount of product was observed, with less reduction product, but the main product was an intermediate with an unremoved benzyl group (serial number 5). Therefore, the conditions were further optimized by increasing the temperature to 60℃, 70℃, 80℃, and 90℃ (serial numbers 6-8). Increasing the temperature resulted in a decrease in the 1,4-cyclohexadiene content in the solvent, possibly due to two reasons: firstly, higher temperatures lead to increased volatility of 1,4-cyclohexadiene, resulting in a reduction; secondly, 1,4-cyclohexadiene is unstable. Therefore, multiple additions of 1,4-cyclohexadiene were necessary. LC-MS monitoring also showed that the debenzylation reaction rate was related to the concentration of 1,4-cyclohexadiene in the solvent, the reaction temperature, and the reaction time. During the experiment, LC-MS monitoring also revealed the formation of methylation byproducts when methanol was used as the solvent. Therefore, ethanol or isopropanol were used instead of methanol. After repeated experiments, suitable conditions were finally found: the reaction temperature was controlled at 80℃, and 1,4-cyclohexadiene was added in a 1:2 ratio (starting material weight mg: 1,4-cyclohexadiene μL). Pd / C was used as a catalyst, and a small amount of Pd(OH)₂ (serial number 9) was added simultaneously. The reaction was monitored every 30 minutes using LC-MS, and the reaction was stopped when no further change was observed. The disadvantage of this method is that it cannot completely remove all benzyl groups from the structure of compound 16; the amount of intermediate with one remaining benzyl group is roughly equivalent to the amount of product formed. However, these reaction conditions have virtually no effect on other groups in the structure of compound 16, and the carbon-carbon double bond reduction product averages less than 3%.

[0078] Table 2 Hydrogenated Debenzylation

[0079]

[0080] Note: “—” in the table indicates that no compound 1 was generated, and the yield was zero.

[0081] 2.2. Acid-induced debenzylase

[0082] While attempting debenzylation under catalytic hydrogenation conditions, we also explored debenzylation via acidolysis. The acids used included boron tribromide, boron trichloride, trimethyliodosilane, and trimethylbromosilane, with reaction conditions shown in Table 3. The strength of the acid significantly affected the debenzylation reaction; excessively strong acids easily led to the dehydration of tertiary alcohols, while insufficiently strong acids failed to break the CO bond. Furthermore, if the nucleophile in the system was too strong, the carbocation would form a neutral molecule, causing electrophilic addition to the carbon-carbon double bond in the side chain.

[0083] When the acidolysis reaction was carried out under boron tribromide conditions, no debenzylide product was detected by LC-MS monitoring. Based on the molecular weight and polarity, the reaction mainly produced a byproduct (number 1) containing an unremoved benzyl group, dehydration of the tertiary alcohol, and an additional bromine atom. Other impurity peaks were also generated, indicating a complex reaction process.

[0084] Under aluminum trichloride conditions, LC-MS monitoring revealed that the main peak was a byproduct (number 2) containing unremoved benzyl groups and tertiary alcohols undergoing dehydration. Although the molecular weight of the target product could be observed, the product peak was not prominent, and there were many other impurity peaks around the product peak. Under these conditions, the yield was extremely low and purification was difficult.

[0085] Under the conditions of trimethyliodosilane, LC-MS analysis showed that the reactants reacted completely, but the main peak was not the target product (number 4). When trimethylbromosilane was used instead, LC-MS analysis showed that the main peak was a byproduct formed by the substitution of hydrogen atoms of the tertiary alcohol with bromine; similarly, no target product was observed (number 3).

[0086] Table 3 Acid-derived benzyl groups

[0087]

[0088] Note: “—” in the table indicates that no compound 1 was generated, and the yield was zero.

Claims

1. A method for preparing compound 16, characterized in that, The process includes the following steps: in an organic solvent, in the presence of an alkoxide, a catalyst, and a ligand, compound 12 and compound 15 undergo a Suzuki-Miyaura reaction to obtain compound 16; the catalyst is Pd(OAc)2; and the ligand is PPh3. 。 2. The preparation method according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The organic solvent is an amide solvent; (2) The volume-to-mass ratio of the organic solvent to compound 12 is (5-100): 1 mL / g; (3) The molar ratio of compound 15 to compound 12 is (1-5):1; (4) The molar ratio of the catalyst to compound 12 is (0.01-0.1):1; (5) The molar ratio of the ligand to compound 12 is (0.01-0.1):1; (6) The molar ratio of the catalyst to the ligand is (1-5):1; (7) The alkoxide is a lithium salt, sodium salt, or potassium salt; (8) The molar ratio of the alkoxide to compound 12 is (1-6):1; (9) The reaction temperature of the Suzuki-Miyaura reaction is 50-120℃; The reaction time of the Suzuki-Miyaura reaction described in (10) is 3-10 h.

3. The preparation method according to claim 2, characterized in that, It meets one or more of the following conditions: (1) The amide solvent is N,N-dimethylformamide; (2) The volume-to-mass ratio of the organic solvent to compound 12 is 25.5:1 mL / g; (3) The molar ratio of compound 15 to compound 12 is 2:1; (4) The molar ratio of the catalyst to compound 12 is 0.04:1; (5) The molar ratio of the ligand to compound 12 is 0.04:1; (6) The molar ratio of the catalyst to the ligand is 1:1; (7) The alkoxide is t-BuOLi; (8) The molar ratio of the alkoxide to compound 12 is 2:1; (9) The reaction temperature of the Suzuki-Miyaura reaction is 90°C; The reaction time for the Suzuki-Miyaura reaction described in (10) is 4 h.

4. The preparation method according to claim 3, characterized in that, The amide solvent is anhydrous DMF.

5. The preparation method according to claim 1, characterized in that, The preparation method of compound 16 further includes the following steps: in an organic solvent, in the presence of a catalyst, compound 14 undergoes a hydroxyl protection reaction with pinacol diboronate to obtain compound 15; 。 6. The preparation method according to claim 5, characterized in that, The preparation method of compound 15 satisfies one or more of the following conditions: (1) The organic solvent is an alcohol solvent and / or a sulfoxide solvent; (2) The mass-to-volume ratio of compound 14 to the organic solvent is (0.5-0.05):1 g / ml; (3) The molar ratio of the pinacol diboronate to the compound 14 is (1-6):1; (4) The catalyst is divalent palladium; (5) The molar ratio of the catalyst to compound 14 is (0.01-0.2):1; The reaction temperature for the hydroxyl protection reaction described in (6) is 0-50℃.

7. The preparation method according to claim 6, characterized in that, The preparation method of compound 15 satisfies one or more of the following conditions: (1) The organic solvents are alcohol solvents and sulfoxide solvents; (2) The mass-to-volume ratio of compound 14 to the organic solvent is 0.116:1 g / ml; (3) The molar ratio of the pinacol diboronate to the compound 14 is 1.5:1; (4) The catalyst is palladium(II) tetra(acetonitrile)tetrafluoroborate; (5) The molar ratio of the catalyst to compound 14 is 0.05:1; The reaction temperature for the hydroxyl protection reaction described in (6) is 0°C.

8. The preparation method according to claim 7, characterized in that, The preparation method of compound 15 satisfies one or more of the following conditions: (1) The alcohol solvent is one or more of methanol, ethanol and isopropanol; (2) The sulfoxide solvent is dimethyl sulfoxide; (3) When the organic solvent is an alcohol solvent and a sulfoxide solvent, the volume ratio of the alcohol solvent to the sulfoxide solvent is (1-5):

1.

9. The preparation method according to claim 8, characterized in that, The preparation method of compound 15 satisfies one or more of the following conditions: (1) The alcohol solvent is methanol; (2) The organic solvents are methanol and dimethyl sulfoxide; (3) When the organic solvent is an alcohol solvent and a sulfoxide solvent, the volume ratio of the alcohol solvent to the sulfoxide solvent is 1:

1.

10. A method for preparing compound 15, comprising the following steps: In an organic solvent, in the presence of a catalyst, compound 14 undergoes a hydroxyl protection reaction with pinacol diboronic acid ester to obtain compound 15. 。 11. The preparation method according to claim 10, characterized in that, The reaction conditions for the hydroxyl protection reaction are as described in any one of claims 6-9.

12. A method for preparing compound 1, comprising the following steps: In a solvent, in the presence of a hydrogen donor and a catalyst, compound 16 undergoes a debenzylation reaction to yield compound 1. 。 13. The preparation method according to claim 12, characterized in that, It meets one or more of the following conditions: (1) The solvent is an alcohol solvent; (2) The mass-to-volume ratio of compound 16 to the solvent is (2-8):1 mg / ml; (3) The hydrogen donor is ammonium formate and / or 1,4-cyclohexadiene; (4) The mass-to-volume ratio of compound 16 to the hydrogen donor is 1:(1-5) mg / μL; (5) The catalyst is Pd / C and / or Pd(OH)2; (6) The reaction temperature for the debenzylation reaction is 50-120℃; The reaction time for the debenzylation reaction described in (7) is 1-5 h.

14. The preparation method according to claim 13, characterized in that, It meets one or more of the following conditions: (1) The alcohol solvent is one or more of methanol, ethanol and isopropanol; (2) The mass-to-volume ratio of compound 16 to the solvent is 3.75:1 mg / ml; (3) The hydrogen donor is 1,4-cyclohexadiene; (4) The mass-to-volume ratio of compound 16 to the hydrogen donor is 1:2 mg / μL; (5) The catalyst is 10% Pd / C and Pd(OH)2; (6) When the catalyst is Pd / C and Pd(OH)2, the mass ratio of Pd / C to Pd(OH)2 is (2-6):1; (7) The reaction temperature for the debenzylation reaction is 80°C; The reaction time for the debenzylation reaction described in (8) is 2 h.

15. The preparation method according to claim 14, characterized in that, It meets one or two of the following conditions: (1) The alcohol solvent is isopropanol; (2) When the catalyst is Pd / C and Pd(OH)2, the mass ratio of Pd / C and Pd(OH)2 is 4:

1.

16. A compound, said compound being compound 15 or compound 16, ， 。

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