A method for preparing an opioid drug, oxaliplatin.

Abstract

This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing the opioid drug ocelidine. The invention sequentially synthesizes the target compound ocelidine through a Suzuki coupling reaction, a photocatalytic reaction, an etherification reaction, and a redox reaction. This method efficiently synthesizes ocelidine through four major reaction steps. The preparation method uses simple reaction substrates and relatively mild reaction conditions, avoiding the use of high temperatures, strong acids and bases, and sensitive reagents. It introduces a green and environmentally friendly photocatalytic synthesis method to synthesize the key compound, rapidly constructing a quaternary carbon center at the α-position of pyridine while simultaneously introducing two alkyl fragments, achieving high atom economy. Furthermore, the overall yield of the obtained target compound ocelidine is high (>15%).

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology. More specifically, it relates to a method for preparing an opioid drug, oxaliplatin. Background Technology

[0002] Opioids are the primary medications for treating moderate to severe pain and are the standard postoperative analgesics. They are several times more effective than aspirin and ibuprofen, making them the most important class of analgesics. However, traditional opioids such as morphine and fentanyl also have fatal drawbacks. In addition to being highly addictive, overdose of opioids can be life-threatening.

[0003] Oliceridine, developed by Trevena Pharmaceuticals in the United States, was approved by the FDA on August 7, 2020, for the treatment of moderate to severe acute pain. Oliceridine is a novel intravenous opioid agonist that selectively activates G protein signaling rather than β-inhibin [HSTan,ASHabib,J.Pain Res.,14(2021)969-979]. This differs from traditional opioids such as morphine and oxycodone, which typically bind to and activate μ-opioid receptors, stimulating β-inhibin-mediated downstream transduction (ERViscusi,F.Skobieranda,DGSoergel,E.Cook,DABurt,N.Singla,J.Pain Res.,12(2019)927-943). Trevena (D. Yamashita, D. Gotchev, P. Pitis, XTChen, G. Liu, CCKYuan, Opiooid Receptor Ligands and Methods of Using and Making Same. WO2012129495A1, 2012) first reported the synthesis of oliceridine, which involved seven purification steps, high preparation temperatures (up to 125°C), and the use of strong acids and bases such as sulfuric acid and sodium hydroxide, with an overall yield of only 3%. Furthermore, it required specific reagents, such as humidity-sensitive Grignard reagents and explosive LiAlH4, and the presence of scarce lithium metal in the reagents increased pharmaceutical costs, failing to meet market demands. Therefore, there is an urgent need to develop a green and efficient synthetic route for oliceridine. Summary of the Invention

[0004] The technical problem this invention aims to solve is to overcome the shortcomings and deficiencies of existing methods for synthesizing ocelidine, which involve multiple preparation steps, high preparation temperatures (up to 125°C), the need for strong acids and bases such as sulfuric acid and sodium hydroxide, low yields (<5%), and the use of specific reagents such as humidity-sensitive Grignard reagents and explosive LiAlH4. Furthermore, the presence of scarce lithium metal in these reagents increases pharmaceutical costs. This invention provides a method for preparing the opioid drug ocelidine. This method uses simple reaction substrates, has relatively mild reaction conditions, avoids high temperatures, strong acids and bases, and the use of sensitive reagents, and introduces a green and environmentally friendly photocatalytic synthesis method to synthesize the key compound. The target compound ocelidine is effectively synthesized through four separation steps, with a high overall yield (>15%).

[0005] The above-mentioned objective of this invention is achieved through the following technical solution:

[0006] This invention protects a method for preparing the opioid drug oxaliplatin, the synthetic route of which is shown below:

[0007]

[0008] The specific preparation method includes the following steps:

[0009] S1. Compound I, compound II, phosphorus ligand, palladium catalyst and basic reagent are added to an ether solvent or toluene and water, and the Suzuki coupling reaction is carried out at 75-85°C under an inert atmosphere. After the reaction is complete, the product is post-treated to obtain compound III.

[0010] S2. Dissolve the diphosphorus ligand, palladium catalyst, and photocatalyst in a polar organic solvent, add compound III obtained in step S1, allyl ester compound, compound IV, and alkaline reagent, and react fully under an inert atmosphere and blue light irradiation. After post-treatment, compound V is obtained.

[0011] S3. Dissolve compound V obtained in step S2 and p-toluenesulfonic acid in a chlorinated hydrocarbon solvent or toluene, and carry out an etherification reaction at 40-50°C until the reaction is complete. After post-treatment, compound VI is obtained.

[0012] S4. Dissolve compound VI obtained in step S3 in an aqueous solution of an ether solvent or an alcohol solvent, add an oxidizing agent, and carry out the first reaction at room temperature until the reaction is complete. After post-treatment, crude product 1 is obtained. Dissolve crude product 1 in an aqueous solution of an ether solvent or an alcohol solvent, add sodium periodate under ice bath conditions, and carry out the second reaction at room temperature until the reaction is complete. After post-treatment, crude product 2 is obtained. Dissolve crude product 2 and compound VII in a chlorinated hydrocarbon solvent, an ether solvent, or toluene, and carry out the third reaction at room temperature until the reaction is complete. After adding a boron reducing agent, add an alcohol solvent dropwise to carry out the fourth reaction until the reaction is complete. After post-treatment, the target compound ocelidine is obtained.

[0013] In compound I, R is a halogen, which is selected from bromine, iodine or chlorine.

[0014] To address the problems of existing methods for synthesizing ocelidine, such as numerous preparation steps, high preparation temperatures (up to 125°C), the need for strong acids and bases like sulfuric acid and sodium hydroxide, low yields (<5%), and the requirement for specific reagents like humidity-sensitive Grignard reagents and explosive LiAlH4, as well as the increased pharmaceutical costs due to the presence of scarce lithium metal in the reagents, the inventors' team creatively utilized the halopyridine shown in Formula I and the boronic ester shown in Formula II in the following synthetic route to perform a Suzuki coupling reaction to obtain the compound shown in Formula III (step S1); subsequently, a key three-component reaction was carried out using commercial α-hydroxycarboxylic acid IV as a free radical precursor, specifically using diphosphine ligands including Xantphos (4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene) as supporting ligands, and 4CzIPN (1,2,3,5-tetra(carbazole-9-yl)- The reagents, including 4,6-dicyanobenzene, are used as photocatalysts (4CzIPN is used as an example below). The reaction is completed under visible and blue light irradiation, followed by separation and purification to obtain compound V in a high yield (step S2). Then, p-toluenesulfonic acid (TsOH) is used to promote an efficient intramolecular etherification reaction to obtain spiro compound VI (step S3). Spiro compound VI is oxidized to an aldehyde by Os and NaIO4, and then reduced and aminationed with the compound shown in formula VII to obtain the target compound oliceridine (step S4). That is, the present invention effectively synthesizes oliceridine through four separation steps. The preparation method has simple reaction substrates and relatively mild reaction conditions, avoiding the use of high temperature, strong acid and strong base, and sensitive reagents. It introduces a green and environmentally friendly photocatalytic synthesis method to synthesize key compounds. The target compound oliceridine is effectively synthesized through four separation steps with a high overall yield (>15%).

[0015]

[0016] In summary, this invention yields the target compound ocelidine via a Suzuki coupling reaction, a photocatalytic reaction, an etherification reaction, and a redox reaction.

[0017] Preferably, in step S1, the phosphorus ligand is selected from 2-biscyclohexylphosphine-2',6'-dimethoxy-1,1'-bisphenyl (S-Phos), 1,1'-bis(diphenylphosphine)ferrocene (DPPF), 2-biscyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl (DavePhos), 1,2-bis(diphenylphosphino)ethane (DPPE), or triphenylphosphine, more preferably S-Phos.

[0018] Preferably, in step S2, the bisphosphine ligand is selected from 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xantphos), bis(2-diphenylphosphine) ether (DPEPhos), or 1,1'-bis(diphenylphosphine)ferrocene (DPPF), more preferably Xantphos.

[0019] Preferably, in step S2, the photocatalyst is selected from 1,2,3,5-tetra(carbazole-9-yl)-4,6-dicyanophenylene (4CzIPN), 2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile, or [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridineN1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridylN]phenyl-C]iridium hexafluorophosphate(III), more preferably 4CzIPN.

[0020] Preferably, in steps S1 and S2, the palladium catalyst is selected from palladium acetate, palladium chloride, palladium dichloride (di(cyanobenzene)dichloride), palladium tri(dibenzylacetone)dipalladium, or palladium tetra(triphenylphosphine).

[0021] Preferably, in step S4, the oxidant is selected from a combination of potassium osmium tetroxide and N-methylmorpholine oxide or ozone, more preferably a combination of potassium osmium tetroxide and N-methylmorpholine oxide. Potassium osmium tetroxide and N-methylmorpholine oxide are generally used in combination as oxidants and have good oxidizing properties; while ozone alone has strong oxidizing properties.

[0022] Preferably, the allyl ester compound is selected from allyl methyl carbonate, allyl tert-butyl carbonate, or allyl acetate.

[0023] Preferably, in steps S1 and S2, the alkaline reagent is selected from potassium phosphate, potassium carbonate, or cesium carbonate.

[0024] Preferably, in steps S1 and S4, the ether solvent is selected from 1,4-dioxane, tetrahydrofuran, or ethylene glycol dimethyl ether.

[0025] Furthermore, the molar volume ratio of compound I to ether solvent or toluene is 1:(1-2)mol / L.

[0026] Furthermore, the molar ratio of compound I to water is 1:(5-6).

[0027] Preferably, in step S2, the polar organic solvent is selected from N,N-dimethylacetamide or N,N-dimethylformamide.

[0028] Preferably, in steps S3 and S4, the chlorinated hydrocarbon solvent is selected from dichloromethane or 1,2-dichloroethane.

[0029] Preferably, in step S4, the alcohol solvent is selected from tert-butanol and methanol.

[0030] Preferably, in step S1, the molar ratio of compound I to compound II is 1:(1.1 to 1.5).

[0031] Preferably, in step S1, the molar ratio of compound I, palladium catalyst, phosphorus ligand, and basic reagent is 1:(1%~2%):(2%~4%):(2~3).

[0032] Preferably, in step S1, the inert atmosphere gas is selected from nitrogen, argon, helium or neon.

[0033] Preferably, in step S1, the reaction takes 4 to 6 hours to complete.

[0034] Preferably, in step S1, the post-processing includes cooling, filtration, concentration, and purification.

[0035] Specifically, in step S1, the post-processing involves cooling the reaction mixture to room temperature, filtering it through diatomaceous earth, concentrating it under vacuum, and purifying the crude product using rapid column chromatography (silica, ethyl acetate: petroleum ether) to obtain a colorless oily compound III.

[0036] Preferably, in step S2, the molar ratio of compound III to compound IV is 1:(1.2 to 1.5).

[0037] Preferably, in step S2, the molar ratio of compound III, diphosphine ligand, palladium catalyst, photocatalyst, polar organic solvent, allyl ester compound and basic reagent is 1:(3%~4%):(2%~3%):(1%~2%):(0.10~0.12M):(1.2~1.5):(1.2~1.5).

[0038] Preferably, in step S2, the inert atmosphere gas is selected from nitrogen, argon, helium or neon.

[0039] Preferably, in step S2, the time for the complete reaction is 18 to 24 hours.

[0040] Specifically, in step S2, the post-treatment involves evaporating the mixture to remove the solvent after the reaction is complete, and purifying the residue by rapid chromatography on silica gel to obtain a colorless oily compound V.

[0041] Preferably, in step S3, the molar ratio of compound V to p-toluenesulfonic acid is 1:(2.0 to 2.2).

[0042] Preferably, in step S3, the reaction takes 10 to 12 hours to complete.

[0043] Preferably, in step S3, the post-processing includes quenching, extraction, filtration, concentration, and purification.

[0044] Specifically, in step S3, the post-treatment involves quenching the reaction with a saturated NaHCO3 aqueous solution, extracting the mixture with DCM, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and vacuum concentrating. The crude product is then purified using rapid column chromatography (silica, ethyl acetate: petroleum ether) to obtain a colorless oily compound VI.

[0045] Preferably, in step S4, the molar ratio of compound VI, compound VII, oxidant, potassium periodate, and boron reducing agent is 1:(1.2-1.3):(1%-2%):(2.0-2.2):(1.2-1.3).

[0046] Preferably, in step S4, the volume ratio of the ether solvent to water in the aqueous solution of the ether solvent is (2-2.5):1.

[0047] Preferably, in step S4, the time for the first reaction is 10 to 12 hours.

[0048] Preferably, in step S4, the second reaction takes 1.0 to 1.5 hours.

[0049] Preferably, in step S4, the time for the third reaction is 3.0 to 4.0 hours.

[0050] Preferably, in step S4, the fourth reaction takes 3 to 5 hours.

[0051] Further, in step S4, the post-treatment of the first reaction is to quench the reaction with a saturated Na2S2O3 aqueous solution, and to stir the mixture thoroughly (preferably for 1.0 to 1.2 h), to fully extract the organic phase with ethyl acetate, and to wash the combined extract with brine. The organic layer is dried with anhydrous sodium sulfate and the solvent is removed under vacuum to obtain crude product 1.

[0052] Specifically, in step S4, the post-treatment of the first reaction is to quench the reaction with a saturated Na2S2O3 aqueous solution, stir the mixture for 1 hour, extract the organic phase three times with ethyl acetate, wash the combined extracts with brine, dry the organic layer with anhydrous sodium sulfate, and remove the solvent under vacuum to obtain crude product 1.

[0053] Further, in step S4, the post-treatment of the second reaction involves filtering the mixture through a diatomaceous earth pad, extracting the filtrate with ethyl acetate, washing the organic layer with brine, and drying with anhydrous sodium sulfate. The solvent is then removed under vacuum to obtain crude product 2.

[0054] Further, in step S4, the post-treatment of the fourth reaction involves adding water, extracting the mixture with DCM, washing the organic layer with brine, drying it with anhydrous sodium sulfate, removing the solvent under vacuum, and purifying the crude product using rapid column chromatography to obtain the target compound ocelidine.

[0055] Compared with the prior art, the present invention has the following beneficial effects:

[0056] This invention yields the target compound ocelidine via a Suzuki coupling reaction, photocatalytic reaction, etherification reaction, and redox reaction. This method efficiently synthesizes ocelidine through four major reaction steps. The preparation method uses simple reaction substrates and relatively mild reaction conditions, avoiding the use of high temperatures, strong acids and bases, and sensitive reagents. It introduces a green and environmentally friendly photocatalytic synthesis method to synthesize the key compound, rapidly constructing a quaternary carbon center at the α-position of pyridine while simultaneously introducing two alkyl fragments, achieving high atom economy. Furthermore, the overall yield of the obtained target compound ocelidine is high (>15%). Detailed Implementation

[0057] The present invention will be further illustrated below with reference to specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in this technical field.

[0058] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0059] Table 1. English-Chinese comparison of reagents used in the examples.

[0060]

[0061] Example 1: A method for preparing an opioid drug, oxaliplatin.

[0062] The synthetic route of the opioid oxaliplatin is shown below:

[0063]

[0064] The preparation method of oxaliplatin specifically includes the following steps:

[0065] S1. In a 100 mL round-bottom flask dried in an oven equipped with a reflux condenser, add compound I (10 mmol), compound II (1.1 equivalents), Pd(OAc)₂ (2 mol%, i.e., 0.02 equivalents), S-Phos (4 mol%), and K₃PO₄ (3.0 equivalents). Cap the flask and purge with nitrogen. Add 1,4-dioxane (20 mL) and water (5.0 equivalents), and stir the reaction mixture at 80 °C for 6 hours. Then cool the mixture to room temperature, filter through diatomaceous earth, and concentrate under vacuum. Purify the crude product using rapid column chromatography (silica, ethyl acetate: petroleum ether) to give compound III as a colorless oil. 1.19 g, yield 80%. 1 H NMR (400MHz, CDCl3) δ8.48(d,J=4.8Hz,1H),7.65(td,J=7.6,1.8Hz,1H),7.55(dt,J=8.0,1.2Hz,1H),7 .22–7.08(m,1H),5.65(s,1H),5.37(s,1H),4.93(s,1H),3.81(t,J=5.6Hz,2H),2.76(t,J=5.6Hz,2H). 13 C NMRδ158.6,147.9,147.5,137.1,122.3,121.0,118.0,63.6,38.1.HRMS(ESI):Calcd for C9H 11 NO[M+H] + :150.0910.Found:150.0913.

[0066] S2. A magnetic stir bar, Xantphos (3 mol%, 1.8 mg), PdCl2 (2.5 mol%, 0.4 mg), 4CzIPN (2 mol%, 1.6 mg), and dry DMA (0.1 M) were placed in a flame-dried 10 mL vial. The system was placed under an argon atmosphere and stirred at room temperature for 10 min. Then, compound III (0.10 mmol, 14.9 mg), allyl methyl carbonate (0.15 mmol, 17.3 mg), compound IV (0.15 mmol, 19.5 mg), and Cs2CO3 (0.15 mmol, 48.8 mg) obtained in step S1 were added. The mixture was stirred for 24 h at room temperature under 20 W blue LED irradiation. After the reaction was complete, the mixture was evaporated to remove the solvent. The residue was purified by rapid chromatography on silica gel to give 15.1 mg of a colorless oily compound V, in 55% yield. 1H NMR (400MHz, CDCl3) δ8.55(d,J=4.8Hz,1H),7.67(td,J=8.0,2.0Hz,1H),7.40(d,J=8.0Hz,1H),7 .19–7.11(m,1H),5.66–5.54(m,1H),5.10–4.97(m,2H),3.80–3.72(m,1H),3.68–3.61(m,1H),2.7 9(dd,J=14.2,6.8Hz,1H),2.65(dd,J=14.2,7.6Hz,1H),2.37–2.23(m,3H),2.14(d,J=15.2Hz,1H ),1.69–1.58(m,2H),1.54–1.41(m,3H),1.38–1.31(m,1H),1.28–1.23(m,1H),1.18–1.09(m,1H). 13 C NMR (101MHz, CDCl3) δ166.0,148.2,137.0,134.6,122.0,121.6,118.2,82.1,59.2,49.5,46.7,43.7,42.4,41.4,39.3,23.6,23.2.HRMS(ESI): Calcd for C 20 H 25 N[M+H] + :276.1958.Found:276.1960.

[0067] S3. In a 10 mL round-bottom flask dried in an oven equipped with a reflux condenser, add compound V (0.1 mmol) and TsOH (2.0 equivalents) obtained in step S2. Cap the flask and purge with N2. Add dichloromethane (DCM, 1 mL) and stir at 40 °C for 12 hours. Quench the reaction with a saturated aqueous solution of NaHCO3. Extract the mixture with DCM. Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate under vacuum. Purify the crude product using rapid column chromatography (silica, ethyl acetate: petroleum ether) to give 21.1 mg of the desired compound VI in a colorless oil, yield 82%. 1H NMR(400MHz,CDCl3)δ8.59(d,J=3.6Hz,1H),7.62(td,J=7.6,2.0Hz,1H),7.26–7.24(m,1H),7.10(dd,J=7.6,4.8Hz,1H),5.41–5.29(m,1H),4.91–4.81(m,2H),3.82–3.73(m,2H),2.50(dd,J=13.6,6.8Hz,1H),2.41–2.33(m,2H),2.23(dd,J=13.6,6.8Hz,1H),1.91(d,J=13.6Hz,1H),1.79–1.61(m,3H),1.57–1.46(m,3H),1.45–1.36(m,1H),1.17–1.09(m,1H),0.78–0.69(m,1H). 13 C NMR(101MHz,CDCl3)δ164.9,149.0,135.9,133.9,121.4,121.0,117.6,83.2,59.5,49.8,44.9,42.4,41.0,34.4,33.2,24.1,22.7.HRMS(ESI):Calcd for C 17 H 23 NO[M+H] + :258.1852.Found:258.1848.

[0068] S4. Add K2OsO4·2H2O (2.0 mol%, 0.7 mg) to a solution of VI (0.10 mmol, 25.7 mg) and NMO (0.12 mmol, 14.1 mg) obtained in step S3 in THF-H2O (5:2, 0.7 mL), and stir the reaction mixture overnight (12 h) at room temperature. Quench the reaction with a saturated aqueous solution of Na2S2O3, and stir the mixture for 1 h. Extract the organic phase three times with ethyl acetate, and wash the combined extracts with brine. Dry the organic layer with anhydrous sodium sulfate and remove the solvent under vacuum. Use the residue for the next step without further purification. Dissolve the crude product in THF-H2O (2:1, 0.6 mL), add NaIO4 (43.2 mg, 0.20 mmol) in an ice bath, and stir the reaction mixture for 1 h at room temperature. Filter the mixture through a diatomaceous earth mat, and extract the filtrate with ethyl acetate. Wash the organic layer with brine and dry with anhydrous sodium sulfate. Remove the solvent under vacuum. The residue was used in the next step without further purification. A mixture of the crude product, anhydrous sodium sulfate (30 mg), and compound VII (0.12 mmol, 17 mg) in DCM (1 ml) was stirred overnight at room temperature. Sodium borohydride (0.12 mmol, 7.6 mg) was added, followed by dropwise addition of methanol (0.3 ml), avoiding a vigorous exothermic reaction. After stirring at room temperature for 4 hours, water (1 ml) was added, and the mixture was extracted with DCM. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the crude product was purified by rapid column chromatography to obtain a light beige oily target compound—the racemic oligomeric oliceridine. 21.6 mg, yield 56%. The final overall yield of the target compound obtained through the four steps was 20%. 1 H NMR (600MHz, CDCl3) δ8.53(d,J=4.8Hz,1H),7.63(t,J=7.8Hz,1H),7.33–7.28(m,1H),7.19–7. 03(m,2H),6.77(d,J=6.0Hz,1H),3.87–3.69(m,7H),2.67–2.59(m,1H),2.44–2.38(m,1H),2.32 –2.27(m,1H),2.25–2.18(m,1H),2.03–1.96(m,1H),1.89(d,J=13.8Hz,1H),1.83–1.73(m,2H), 1.72–1.60(m,2H),1.52–1.43(m,3H),1.41–1.34(m,1H),1.13–1.06(m,1H),0.70–0.63(m,1H). 13C NMR (150MHz, CDCl3) δ164.6,155.2,148.8,136.5,123.1,121.4,121.3,116.1,83.0,59 .5,58.8,45.6,43.9,43.5,43.4,41.6,40.9,34.3,33.8,24.1,22.6.HRMS(ESI):Calcd for C 22 H 30 N₂O₂S[M+Na] + :409.1920.Found:409.1904.

[0069] Example 2: A method for preparing an opioid drug, oxaliplatin.

[0070] The preparation method of oxalidin differs from that of Example 1 in that: in step S1, the reactants are stirred at 85°C for 4 hours, while the other steps, reagents, and parameters are the same as in Example 1.

[0071] The yield of compound III obtained in step S1 was 78%, the yield of compound V obtained in step S2 was 55%, the yield of compound VI obtained in step S3 was 82%, and the yield of the target compound Oliceridine obtained in step S4 was 56%, with a total yield of 20%.

[0072] Example 3: A method for preparing an opioid drug, oxaliplatin.

[0073] The preparation method of oxalidin differs from that of Example 1 in that: in step S1, the reactants are stirred at 75°C for 6 hours, while the other steps, reagents, and parameters are the same as in Example 1.

[0074] The yield of compound III obtained in step S1 was 75%, the yield of compound V obtained in step S2 was 55%, the yield of compound VI obtained in step S3 was 82%, and the yield of the target compound Oliceridine obtained in step S4 was 56%, with a total yield of 19%.

[0075] Example 4: A method for preparing an opioid drug, oxaliplatin.

[0076] The preparation method of oxalidin differs from that of Example 1 in that: in step S1, the phosphorus ligand S-Phos is replaced with triphenylphosphine, while the other steps, reagents, and parameters are the same as in Example 1.

[0077] The yield of compound III obtained in step S1 was 65%, the yield of compound V obtained in step S2 was 55%, the yield of compound VI obtained in step S3 was 82%, and the yield of the target compound Oliceridine obtained in step S4 was 56%, with a total yield of 16%.

[0078] Example 5: A method for preparing an opioid drug, oxaliplatin.

[0079] The preparation method of oxalidin differs from that of Example 1 in that: in step S1, the solvent 1,4-dioxane is replaced with toluene, while the other steps, reagents, and parameters are the same as in Example 1.

[0080] The yield of compound III obtained in step S1 was 60%, the yield of compound V obtained in step S2 was 55%, the yield of compound VI obtained in step S3 was 82%, and the yield of the target compound Oliceridine obtained in step S4 was 56%, with a total yield of 15%.

[0081] Example 6: A method for preparing an opioid drug, oxaliplatin.

[0082] The preparation method of oxalidin differs from that of Example 1 in that: in step S2, the solvent DMA is replaced with DMF, while the other steps, reagents, and parameters are the same as in Example 1.

[0083] The yield of compound III obtained in step S1 was 80%, the yield of compound V obtained in step S2 was 50%, the yield of compound VI obtained in step S3 was 82%, and the yield of the target compound Oliceridine obtained in step S4 was 56%, with a total yield of 18%.

[0084] Example 7: A method for preparing an opioid drug, oxaliplatin.

[0085] The preparation method of oxalidin differs from that of Example 1 in that: in step S2, the diphosphine ligand Xantphos is replaced with 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, while the other steps, reagents, and parameters are the same as in Example 1.

[0086] The yield of compound III obtained in step S1 was 80%, the yield of compound V obtained in step S2 was 45%, the yield of compound VI obtained in step S3 was 82%, and the yield of the target compound Oliceridine obtained in step S4 was 56%, with a total yield of 16%.

[0087] Example 8: A method for preparing an opioid drug, oxaliplatin.

[0088] The preparation method of ozetin differs from that of Example 1 in that: in step S2, the photocatalyst 4CzIPN is replaced with [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridineN1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridylN]phenyl-C]iridium hexafluorophosphate(III), while the other steps, reagents, and parameters are the same as in Example 1.

[0089] The yield of compound III obtained in step S1 was 80%, the yield of compound V obtained in step S2 was 49%, the yield of compound VI obtained in step S3 was 82%, and the yield of the target compound Oliceridine obtained in step S4 was 56%, with a total yield of 18%.

[0090] Example 9: A method for preparing an opioid drug, oxaliplatin.

[0091] The preparation method of oxalidin differs from that of Example 1 in that: in step S3, the reaction is stirred at 50°C for 10 hours, while the other steps, reagents, and parameters are the same as in Example 1.

[0092] The yield of compound III obtained in step S1 was 80%, the yield of compound V obtained in step S2 was 55%, the yield of compound VI obtained in step S3 was 80%, and the yield of the target compound Oliceridine obtained in step S4 was 56%, with a total yield of 20%.

[0093] Example 10: A method for preparing an opioid drug, oxaliplatin.

[0094] The preparation method of oxalidin differs from that of Example 1 in that: in step S4, THF is replaced with tert-butanol, while the other steps, reagents, and parameters are the same as in Example 1.

[0095] The yield of compound III obtained in step S1 was 80%, the yield of compound V obtained in step S2 was 55%, the yield of compound VI obtained in step S3 was 82%, and the yield of the target compound Oliceridine obtained in step S4 was 50%, with a total yield of 18%.

[0096] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A method for preparing an opioid drug, oxaliplatin, characterized in that, The synthesis route is shown below: The specific preparation method includes the following steps: S1. Compound I, compound II, phosphorus ligand, palladium catalyst and basic reagent are added to an ether solvent or toluene and water, and the Suzuki coupling reaction is carried out at 75-85°C under an inert atmosphere. After the reaction is complete, the product is post-treated to obtain compound III. S2. Dissolve the diphosphorus ligand, palladium catalyst, and photocatalyst in a polar organic solvent, add compound III obtained in step S1, allyl ester compound, compound IV, and alkaline reagent, and react fully under an inert atmosphere and blue light irradiation. After post-treatment, compound V is obtained. S3. Dissolve compound V obtained in step S2 and p-toluenesulfonic acid in a chlorinated hydrocarbon solvent or toluene, and carry out an etherification reaction at 40-50°C. After the reaction is complete, perform post-treatment to obtain compound VI. S4. Dissolve compound VI obtained in step S3 in an aqueous solution of an ether solvent or an alcohol solvent, add an oxidizing agent, and carry out the first reaction at room temperature until the reaction is complete. After post-treatment, crude product 1 is obtained. Dissolve crude product 1 in an aqueous solution of an ether solvent or an alcohol solvent, add sodium periodate under ice bath conditions, and carry out the second reaction at room temperature until the reaction is complete. After post-treatment, crude product 2 is obtained. Dissolve crude product 2 and compound VII in a chlorinated hydrocarbon solvent, an ether solvent, or toluene, and carry out the third reaction at room temperature until the reaction is complete. After adding a boron reducing agent, add an alcohol solvent dropwise to carry out the fourth reaction until the reaction is complete. After post-treatment, the target compound ocelidine is obtained. In compound I, R is a halogen, which is selected from bromine, iodine or chlorine; The oxidant is selected from a combination of potassium osmium tetroxide and N-methylmorpholine oxide.

2. The preparation method according to claim 1, characterized in that, In step S1, the phosphorus ligand is selected from 2-biscyclohexylphosphine-2',6'-dimethoxy-1,1'-bisphenyl, 1,1'-bis(diphenylphosphine)ferrocene, 2-biscyclohexylphosphine-2'-(N,N-dimethylamino)biphenyl, 1,2-bis(diphenylphosphino)ethane, or triphenylphosphine.

3. The preparation method according to claim 1, characterized in that, In step S2, the bisphosphine ligand is selected from 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, bis(2-diphenylphosphine) ether, or 1,1'-bis(diphenylphosphine)ferrocene.

4. The preparation method according to claim 1, characterized in that, In step S2, the photocatalyst is selected from 1,2,3,5-tetra(carbazole-9-yl)-4,6-dicyanobenzene, 2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile, or [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridineN1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridylN]phenyl-C]iridium(III) hexafluorophosphate.

5. The preparation method according to claim 1, characterized in that, In steps S1 and S2, the palladium catalyst is selected from palladium acetate, palladium chloride, palladium dichloride (di(cyanobenzene)dichloride), palladium tri(dibenzylacetone)dipalladium, or palladium tetra(triphenylphosphine).

6. The preparation method according to claim 1, characterized in that, In step S2, the allyl ester compound is selected from allyl methyl carbonate, allyl tert-butyl carbonate, or allyl acetate.

7. The preparation method according to claim 1, characterized in that, In steps S1 and S4, the ether solvent is selected from 1,4-dioxane, tetrahydrofuran, or ethylene glycol dimethyl ether.

8. The preparation method according to claim 1, characterized in that, In step S2, the polar organic solvent is selected from N,N-dimethylacetamide or N,N-dimethylformamide.

9. The preparation method according to claim 1, characterized in that, In steps S3 and S4, the chlorinated hydrocarbon solvent is selected from dichloromethane or 1,2-dichloroethane.

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