Preparation method of dihydroisoflavone derivative

Abstract

The invention discloses a preparation method of a dihydroisoflavone derivative. Specifically, the invention provides a preparation method of a compound 16, which comprises the following steps: in an organic solvent, in the presence of alkoxide, a catalyst and a ligand, carrying out Suzuki-Miyaura reaction on a compound 12 and a compound 15 to obtain the compound 16, the catalyst is Pd (OAc) 2; and the ligand is PPh3. A target natural product (compound 1) is designed and synthesized through a total synthesis method, and the research provides a basis for total synthesis of a dihydroisoflavonol compound containing a chiral center. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine and specifically relates to a preparation method of a class of dihydroisoflavone derivatives. Background Art

[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 tip of the Rhizoma Cynoglossi. The Rhizoma Cynoglossi is a plant distributed in the subtropical regions of China. Its roots have medicinal value and are used in traditional Chinese medicine to treat menstrual disorders, dysmenorrhea, bleeding, gastric ulcers, etc. The flavonoids isolated from its roots have immunosuppressive effects. Compound 1 is a class of flavonoids containing chiral tertiary alcohols, which are usually isolated from natural products. There are no reports on its synthesis. Summary of the invention

[0003] The technical problem to be solved by the present invention is to overcome the defect of the prior art that compound 1 is lacking in synthesis, thereby providing a method for preparing dihydroisoflavone derivatives. The present invention can obtain a large amount of the natural product by designing a synthetic route, solving the problem that the natural product is difficult to obtain due to its low content, so as to meet further research.

[0004] The present invention provides a method for preparing compound 16, which comprises 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; the ligand is PPh3;

[0005]

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

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

[0008] In one embodiment, the molar ratio of the compound 15 to the compound 12 can 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 can 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, a sodium salt or a potassium salt, such as t-BuOLi.

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

[0014] The reaction temperature of the Suzuki-Miyaura reaction is a conventional temperature for such reactions in the art, such as 50-120°C, preferably 90°C.

[0015] The progress of the Suzuki-Miyaura reaction is monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, LCMS or NMR), and the end point of the reaction is generally when compound 12 disappears or no longer reacts. The reaction time of the Suzuki-Miyaura reaction is the conventional reaction time of this type of reaction in the art, such as 3-10 hours, preferably 4 hours.

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

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

[0018] The preparation method of the compound 16 further comprises the following steps: in an organic solvent, in the presence of a catalyst, compound 14 and biboric acid pinacol ester are subjected to a hydroxyl protection reaction to obtain compound 15;

[0019]

[0020] In a certain 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 a certain embodiment, the mass volume ratio of the 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 biboric acid pinacol ester to the compound 14 can be (1-6):1, for example, 1.5:1.

[0023] In one embodiment, the catalyst may be divalent palladium, such as palladium(II)tetrakis(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 of the hydroxyl protection reaction is a conventional temperature for such reactions in the art, such as 0-50°C, preferably 0°C.

[0026] The progress of the hydroxyl protection reaction is monitored by conventional monitoring methods in the art (eg, TLC, HPLC, LCMS or NMR), and the disappearance or no-reaction of compound 12 is generally regarded as the reaction endpoint.

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

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

[0029] The present invention also provides a method for preparing compound 15, which comprises the following steps: in an organic solvent, in the presence of a catalyst, compound 14 and biboric acid pinacol ester undergo a hydroxyl protection reaction to obtain compound 15;

[0030]

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

[0032] The present invention also provides a method for preparing compound 1, which comprises 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 a certain 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 a certain embodiment, the mass volume ratio of the compound 16 to the solvent can be (2-8):1 mg / ml, for example 3.75:1 mg / ml.

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

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

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

[0039] The reaction temperature of the debenzylation reaction is a conventional temperature for such reactions in the art, such as 50-120°C, preferably 80°C.

[0040] The progress of the debenzylation reaction is monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, LCMS or NMR), and the reaction endpoint is generally when compound 16 disappears or no longer reacts. The reaction time of the debenzylation reaction is the conventional reaction time of this type of reaction in the art, for example, 1-5 h, preferably 2 h.

[0041] The preparation method of compound 1 may further include post-treatment, and the post-treatment operation is a conventional post-treatment operation in the preparation method of this type in the art. For example, the preparation method may further include the following steps after the debenzylation reaction is completed: cooling, filtering, concentrating, and purifying.

[0042] The purification is preferably performed by column chromatography; the column chromatography is preferably a reverse phase column; the eluent of 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 the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0048] The reagents and raw materials used in the present invention are commercially available.

[0049] The positive progressive effect of the present invention is that the target natural product (Compound 1) is designed and synthesized by a total synthesis method, and this study provides a basis for the total synthesis of dihydroisoflavonol compounds containing chiral centers. DETAILED DESCRIPTION

[0050] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[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 Compounds

[0054] Compound 3-11 was synthesized according to the method 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, solvent toluene was added, and the mixture was quickly backfilled with nitrogen three times. After reacting at room temperature for 30 minutes under nitrogen protection, triethylamine (4.5 mg, 0.04 mmol) was added, and the mixture was reacted at room temperature for 24 hours under nitrogen atmosphere, and 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 over anhydrous sodium sulfate, concentrated under pressure, purified by column chromatography (PE:EA=7:1), and dried to obtain a light yellow solid product 12 (141 mg, 40.3%).

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

[0057] Compound 14 (M = 172.27, 696 mg, 4.0 mmol) and bipyraclostrobin (1.5 g, 6.0 mmol) were weighed into a round-bottom flask, and solvent methanol: dimethyl sulfoxide (volume ratio = 1:1, 6 mL) were added, and then the catalyst tetrakis(acetonitrile)tetrafluoroborate palladium (II) (Pd(BF4)2(MeCN)4, 88.8 mg, 0.2 mmol) was added at 0°C and monitored by TLC (PE:EA = 4:1). After the reaction was completed, water was added to dilute, 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 separated and purified by column chromatography (PE:EA = 1:9) to obtain 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 (101 MHz, 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: C 16 H 31 BO3Na[M+Na] + 304.2295, detection 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. ol) were added into a microwave tube in sequence, dissolved with anhydrous DMF (4 ml), the air in the microwave tube was removed with nitrogen, the microwave tube was quickly sealed under a nitrogen atmosphere, placed at 90°C for reaction for 4 h, cooled to room temperature, and monitored by TLC (PE: EA = 2: 1) spot plate. After the reaction was completed, ethyl acetate and water were added for extraction, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography (PE: EA = 4: 1). After drying, a light yellow solid product 16 (M = 819.01, 112.0 mg, 68.5%) was obtained.

[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 solvent was added, 60 μL of 1,4-cyclohexadiene (1:2, raw material weight mg: 1,4-cyclohexadiene μL) was added in batches, 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 reacted at 80°C, and LC-MS was detected every 30 minutes. After two hours, the reaction did not change any more, and the reaction was stopped. The reaction was cooled to room temperature and filtered, concentrated under reduced pressure, purified by a reverse phase column (water: methanol system), and freeze-dried to obtain a 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, and ethanol solvent was added, and then an appropriate amount of catalyst Pd / C was added, and the air in the reaction was discharged, and the reaction was carried out at room temperature for 6 h under a hydrogen atmosphere, and monitored by LC-MS. After the reaction was completed, the filtrate was concentrated and dried to obtain a 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, HPLC analysis and determination). (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): Weigh compound 12 (100 mg, 0.13 mmol) into a round-bottom flask, add solvent ethanol, and then add an appropriate amount of catalyst Pd / C, expel the air in the reaction, react at 40°C for 10 h under a hydrogen atmosphere, monitor with LC-MS, filter after completion of the reaction, concentrate the filtrate, and then purify with a reverse phase column (water: methanol system) and freeze-dry to obtain a white solid 22 (30 mg, 82.2%). 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), the 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 Suzuki-Miyaura reaction conditions

[0066]

[0067] a: Use microwave reaction

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

[0069] We first used Pd(dppf)Cl2 as a catalyst, used an inorganic base CsCO3, reacted at 90°C, and detected by LC-MS. No product was generated, and the main new point generated was the deiodination byproduct 21 (serial number 1). At the end of the reaction, the spot plate was detected, and a large amount of alkyl borate esters were not reacted. It is speculated that the reason for the failure of coupling may be due to the high activity of iodine. At high temperature, long-term reaction leads to deiodination first, so the coupling with alkyl borate esters fails. So the reaction temperature was lowered and a microwave reactor was used to accelerate the reaction, but the result was the same (serial number 2). Then CsF was used as a base and the reaction was carried out at 80°C. LC-MS detected that there was a product (serial number 3), but the reaction progress was limited and the yield was extremely low. In this case, the conditions were optimized in the direction of changing the catalyst. After the reaction was replaced with the catalyst Pd(PPh3)4, no product was generated, and only the byproduct 21 (serial number 4) was observed. Under the conditions of Pd(PPh3)4 catalyst, CsCO3 was used and the reaction temperature was changed. Although there was product generated, it was very little and could hardly be seen on the spot plate. The molecular weight of the product could only be seen by LC-MS detection (No. 5, 6). Under this catalyst, NaOH was used to react at 90°C in a microwave. A new spot was detected on the spot plate. LC-MS detected the new spot as product 16. After separation and purification, it was confirmed to be the product, but the reaction yield was low (No. 7, 8).

[0070] Although the steric hindrance of aryl iodine does not have as great an effect on the coupling reaction as that of boron ester, there are two benzyl groups at the ortho position of the raw material aryl iodine, and there are few successful cases of large steric hindrance aryl iodide directly participating in the coupling reaction. Therefore, we tried to use a catalyst system suitable for large steric hindrance, Pd(dba)3+PCy3, XPhos-G2, but the reaction situation was still not ideal (serial number 9, 10). We used the catalyst / phosphine ligand Pd(OAc)2+PPh3 system instead, used the organic base t-BuOLi, and reacted for 3 hours at 90°C in the microwave. The main product was coupling compound 16 (serial number 11). Because the single sample injection amount of the microwave reaction is limited, it cannot meet the product amount required for our experiment. Therefore, we tried not to use a microwave reactor under the same conditions and extended the reaction time. The reaction effect was similar, and the yield was stable with large-scale injection.

[0071] Suzuki-Miyaura cross-coupling has very high requirements for reaction conditions. It needs to be isolated from air and water, use ultra-dry solvents, and remove the air in the reaction bottle after special treatment. The reaction is carried out in a sealed system protected by nitrogen. Combining the above experiments, we found that the optimal conditions for the reaction of large sterically hindered aryl iodide and alkyl borate are Pd(OAc)2 / PPh3 as catalyst / ligand, t-BuOLi as base, and anhydrous DMF as solvent (No. 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, when demethylating the protection group, acidic reagents such as boron tribromide and aluminum trichloride are used, and they are highly toxic, the reaction is difficult to control, and the post-processing is cumbersome. The use of acetyl groups for protection is unstable and prone to hydrolysis. After comprehensive consideration, this paper finally chose benzyl groups to protect phenolic hydroxyl groups. In studying the debenzylation reaction of compound 16, considering that the compound has many active sites, contains multiple phenolic hydroxyl groups, tertiary alcohol structures, and unsaturated double bond structures, we tried to perform acidolysis or catalytic hydrogenolysis to debenzylate.

[0074] 2.1. Hydrogenation catalytic debenzylation

[0075] Catalytic hydrogenation is the most commonly used method for debenzylation, but since compound 16 contains multiple benzyl-protected phenolic hydroxyl groups and the side chain contains a carbon-carbon double bond that is easily reduced, it is very difficult to successfully remove multiple benzyl groups using catalytic hydrogenation. Therefore, we need to explore the reaction conditions for catalytic hydrogenation without affecting other groups such as the side chain carbon-carbon double bond (Table 2). When Pd / C is used as a catalyst and ammonium formate is used as a hydrogen source (No. 1), LC-MS monitoring found that the side chain double bond reduction and incomplete debenzylation coexist in the reaction, and the product and the reduction byproduct have similar polarity, making it difficult to separate and purify.

[0076] In order to retain the carbon-carbon double bond in the side chain, the experiment used a milder catalyst Pd(OH)2 and selected ammonium formate as the hydrogen source. LC-MS monitoring found that some benzyl groups could not be completely removed, and the main product was still the carbon-carbon double bond reduction product (No. 2). The benzyl group could not be removed under the conditions of Pd-CaCO3-PdO formic acid or ammonium formate, and there was no obvious change when heated to 40℃-60℃ (No. 3 and 4).

[0077] Under the conditions of Pd / C and 1,4-cyclohexadiene, LC-MS monitoring found that increasing the temperature was conducive to the reaction. When the temperature was raised to 45°C and the reaction was carried out for 12 hours, more products were observed to be generated, and fewer reduction products were observed, but the main product was an intermediate with a benzyl group left (serial number 5). So on this basis, the conditions were further optimized, and the temperature was raised to 60°C, 70°C, 80°C, and 90°C (serial numbers 6-8). It was found that the content of 1,4-cyclohexadiene in the solvent would decrease as the temperature increased. There are two possible reasons: one is that the higher the temperature, the more volatile 1,4-cyclohexadiene is, resulting in a decrease; the other is that 1,4-cyclohexadiene is unstable. Therefore, 1,4-cyclohexadiene needs to be added multiple times. At the same time, under LC-MS monitoring, it was found that the rate of debenzylation reaction is related to the concentration of 1,4-cyclohexadiene in the solvent, the reaction temperature, and the reaction time. During the experiment, it was also found that when methanol was used as a solvent, LC-MS monitoring found that methylation byproducts were generated. So the solvent was changed to ethanol or isopropanol. After repeated experiments, we finally found the most suitable conditions. The reaction temperature was controlled at 80°C, 1,4-cyclohexadiene was added in a ratio of 1:2 (raw material weight mg: 1,4-cyclohexadiene μL), Pd / C was used as a catalyst, and a small amount of Pd(OH)2 (No. 9) was added. LC-MS was used to detect every 30 minutes. If the reaction no longer changed, the reaction was stopped. The disadvantage of this method is that it cannot completely remove all benzyl groups in the structure of compound 16. The intermediate with one benzyl group is equivalent to the amount of product generated. However, the reaction conditions have little effect on other groups in the structure of compound 16, and the average reduction product of carbon-carbon double bond is less than 3%.

[0078] Table 2 Hydrogenation debenzylation

[0079]

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

[0081] 2.2. Acid debenzylation

[0082] While trying to debenzylate under catalytic hydrogenation conditions, we also tried to debenzylate by acid hydrolysis. The acids used were boron tribromide, boron trichloride, trimethylsilyl iodide, and trimethylsilyl bromide, and the reaction conditions are shown in Table 3. The acidity of the acid used has a great influence on the debenzylation reaction. If the acidity is too strong, it will easily lead to the dehydration of tertiary alcohol; if the acidity is too weak, the CO bond cannot be broken. If the nucleophilicity of the nucleophilic reagent in the system is too strong, the carbon cation forms a neutral molecule, which will cause electrophilic addition to the side chain carbon-carbon double bond.

[0083] When the acid hydrolysis reaction was carried out under the condition of boron tribromide, no debenzylation product was found by LC-MS monitoring. From the molecular weight and polarity, it was inferred that the reaction mainly produced a by-product (serial number 1) in which a benzyl group was not removed, the tertiary alcohol was dehydrated, and a bromine atom was added to the structure. At the same time, other impurity peaks were generated, and the reaction situation was very complicated.

[0084] Under aluminum chloride conditions, LC-MS monitoring revealed that the main peak was a byproduct (serial number 2) in which the benzyl group was not removed and the tertiary alcohol was dehydrated. Although the molecular weight of the target product could be observed, the product peak was not obvious, and there were many other impurity peaks around the product peak. The yield under this condition was extremely low and difficult to purify.

[0085] Under the condition of trimethylsilyl iodide, the raw material can be completely reacted through LC-MS detection, but the main peak is not the target product (No. 4). When trimethylsilyl bromide is used for the reaction, the main peak is the by-product generated by the replacement of tertiary alcohol hydrogen atoms and bromine through LC-MS detection, and the target product is also not observed (No. 3).

[0086] Table 3 Acid removal of benzyl groups

[0087]

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

Claims

1. A method for preparing compound 16, characterized in that: The method comprises the following steps: in an organic solvent, in the presence of an alkoxide, a catalyst and a ligand, compound 12 and compound 15 undergo Suzuki-Miyaura reaction to obtain compound 16; the catalyst is Pd(OAc)2; 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; the amide solvent may be N,N-dimethylformamide (DMF); preferably anhydrous DMF; (2) The volume mass ratio of the organic solvent to the compound 12 is (5-100):1 mL / g, for example 25.5:1 mL / g; (3) The molar ratio of the compound 15 to the compound 12 is (1-5):1, for example 2:1; (4) The molar ratio of the catalyst to the compound 12 is (0.01-0.1):1, for example 0.04:1; (5) The molar ratio of the ligand to the compound 12 is (0.01-0.1):1, for example 0.04:1; (6) The molar ratio of the catalyst to the ligand is (1-5):1, for example 1:1; (7) The alkoxide is a lithium salt, a sodium salt or a potassium salt, such as t-BuOLi; (8) The molar ratio of the alkoxide to the compound 12 is (1-6):1, for example 2:1; (9) The reaction temperature of the Suzuki-Miyaura reaction is 50-120°C, preferably 90°C; and (10) The reaction time of the Suzuki-Miyaura reaction is 3-10 h, preferably 4 h.

3. The preparation method according to claim 1, characterized in that: The preparation method of the compound 16 further comprises the following steps: in an organic solvent, in the presence of a catalyst, compound 14 and biboric acid pinacol ester undergo a hydroxyl protection reaction to obtain compound 15; 4. The preparation method according to claim 3, 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; 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 preferably (1-5):1, such as 1:1; (2) The mass volume ratio of the compound 14 to the organic solvent is (0.5-0.05):1 g / ml, for example 0.116:1 g / ml; (3) The molar ratio of the biboric acid pinacol ester to the compound 14 is (1-6):1, for example 1.5:1; (4) The catalyst is divalent palladium, such as palladium (II) tetrakis(acetonitrile)tetrafluoroborate (Pd(BF4)2(MeCN)4; (5) The molar ratio of the catalyst to the compound 14 is (0.01-0.2):1, for example 0.05:1; and (6) The reaction temperature of the hydroxyl protection reaction is 0-50°C, preferably 0°C.

5. A method for preparing compound 15, comprising the following steps: In an organic solvent, in the presence of a catalyst, compound 14 is reacted with biboric acid pinacol ester to undergo a hydroxyl protection reaction to obtain compound 15; 6. The preparation method according to claim 5, characterized in that: The reaction conditions and steps of the hydroxyl protection reaction are as described in claim 3 or 4.

7. 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 obtain compound 1; 8. The preparation method according to claim 7, characterized in that: It meets one or more of the following conditions: (1) The solvent is an alcohol solvent; (2) The mass volume ratio of the 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 volume ratio of the compound 16 to the hydrogen donor is 1: (1-5) mg / μL; (5) The catalyst is Pd / C and / or Pd(OH)2, and the Pd / C is preferably 10% Pd / C and Pd(OH)2; (6) When the catalyst is Pd / C and Pd(OH)2, the mass ratio of Pd / C and Pd(OH)2 is (2-6):1; (7) The reaction temperature of the debenzylation reaction is 50-120° C.; and (8) The reaction time of the debenzylation reaction is 1-5h.

9. The preparation method according to claim 8, 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, preferably isopropanol; (2) The mass volume ratio of the compound 16 to the solvent is 3.75:1 mg / ml; (3) The hydrogen donor is 1,4-cyclohexadiene; (4) The mass volume ratio of the compound 16 to the hydrogen donor is 1:2 mg / μL; (5) The catalyst is preferably 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 4:1; (7) The reaction temperature of the debenzylation reaction is 80° C.; and (8) The reaction time of the debenzylation reaction is 2 h.

10. A compound, which is compound 15 or compound 16,

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