CN116283797A - Synthesis method of oxaagoli sodium - Google Patents
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- CN116283797A CN116283797A CN202211739577.5A CN202211739577A CN116283797A CN 116283797 A CN116283797 A CN 116283797A CN 202211739577 A CN202211739577 A CN 202211739577A CN 116283797 A CN116283797 A CN 116283797A
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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Abstract
The invention discloses a synthesis method of oxaagole sodium, and belongs to the technical field of organic synthesis. The technical scheme is as follows: brominating the compound 4 with N-bromosuccinimide to obtain an intermediate 5; then reacting with (R) -2-phenyl aziridine under the action of alkali metal and Lewis acid to obtain an intermediate 6; then reacting with sodium 4-bromobutyrate to obtain an intermediate 7; and finally, carrying out a Suzuki coupling reaction with 2-fluoro-3-methoxyphenylboronic acid to obtain the oxaragrolidine sodium. The invention avoids the conventional alkaline hydrolysis reaction, shortens the route steps, improves the route efficiency and greatly reduces the process cost.
Description
Technical Field
The invention relates to a synthetic method of oxaagole sodium, and belongs to the technical field of organic synthesis.
Background
Endometriosis is a common and frequently occurring disease of gynaecology, is a benign invasive disease common to women in childbearing period, and belongs to one of the gynaecological difficult and complicated diseases. The oxaagoli (Elagolix) sodium salt was approved by the FDA for marketing 7 in 2018, which was the first new oral drug approved by the FDA for endometriosis for 10 years. The oxagolide is not marketed in China at present, but is listed in the "second encouragement imitation medicine catalogue" list in month 12 of 2020, and the market potential in the future is huge.
The structural formula of the oxarogoli and its sodium salt is as follows:
the oxa-agole and its sodium salt have been described and protected in patent EP1646389B, using 2-fluoro-6-trifluoromethyl benzonitrile as raw material, firstly reducing cyano group with borane, then condensing with urea under the action of hydrochloric acid, then performing cyclization reaction with ketene dimer, then performing Suzuki coupling reaction with 2-fluoro-3-methoxyphenylboronic acid after bromination and aminoalkylation reaction, and acidolysis to remove Boc protecting group to obtain key intermediate, and finally condensing with 4-bromo-n-butyric acid to obtain the final product. The synthetic route reported in this patent is as follows:
in the above synthetic route, 1) the step of reducing the nitrile group by borane requires a strictly anhydrous environment and presents a safety hazard due to the possible generation of hydrogen; 2) Toxic and explosive diketene is used, so that the production safety risk is high; 3) The light-delay reaction reagent triphenylphosphine, which generates a byproduct triphenylphosphine oxide, is difficult to remove in the industrial production by using a common purification mode; 4) The aryl coupling reaction adopts tetrakis (triphenylphosphine) palladium as a catalyst, post-treatment requires column chromatography purification, purification is difficult, and the risk of heavy metal residue is high, so that the quality control of the API is difficult.
The original company further developed a proprietary route to synthesize this compound, the route of which is described in patent WO2009062087a as follows:
the method is characterized in that the process is improved on the basis of a compound patent, but the problem of purification of an aryl coupling intermediate still cannot be solved, in addition, in the process, iodine chloride serving as a strong poison is used for iodination, chlorinated impurities are generated in the reaction process, the purification is difficult, in addition, the patent adopts substitution reaction with chiral amino alcohol methyl sulfonate to prepare the oxa-golide intermediate, and byproduct methyl sulfonate possibly undergoes esterification reaction with alcohol used in the subsequent process or generated in the reaction to generate methyl sulfonate, and the methyl sulfonate is a compound with potential genotoxicity, so that the process route provides additional and higher requirements for quality control and test of a final product and is unfavorable for production of bulk drugs.
Therefore, a new synthesis process of the sodium salt of oxagolide needs to be studied to overcome the disadvantages of the above processes.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a novel synthesis method of the oxaagole sodium, which has a simple process route and is suitable for industrial production.
The invention provides a synthetic method of oxaagole sodium, which adopts the following technical scheme:
s1: brominating the compound 4 with N-bromosuccinimide to obtain an intermediate 5;
s2: reacting the intermediate 5 with (R) -2-phenyl aziridine under the action of alkali metal and Lewis acid to obtain an intermediate 6;
s3: reacting the intermediate 6 with sodium 4-bromobutyrate to obtain an intermediate 7;
s4: and carrying out Suzuki coupling reaction on the intermediate 7 and 2-fluoro-3-methoxyphenylboronic acid to obtain the oxaragrolidine sodium.
The reaction equation is expressed as follows:
further, in the above technical solution, the step S1: the bromination reaction is carried out in a solvent selected from ethyl acetate, methyl acetate, acetonitrile, dichloromethane, tetrahydrofuran, and more preferably ethyl acetate.
Further, in the above technical solution, the step S1: the mol ratio of the compound 4 to NBS is 1:1-1.5.
Further, in the above technical solution, the step S2: the alkali metal is an alkali metal carbonate such as sodium carbonate, potassium carbonate, lithium carbonate, etc., and sodium carbonate is further preferable.
Further, in the above technical solution, the step S2: the lewis acid is triphenylborane or tris (pentafluorophenyl) borane.
Further, in the above technical solution, the step S2: the reaction temperature is 80-120 ℃.
Further, in the above technical solution, the step S2: the molar ratio of the intermediate 5 to the (R) -2-phenyl aziridine is 1:1-1.5.
Further, in the above technical solution, the step S3: the reaction is carried out in the presence of an acid-binding agent, which is anhydrous sodium carbonate, anhydrous potassium carbonate, or the like, and further preferably anhydrous sodium carbonate.
Further, in the above technical solution, the step S3: the molar ratio of the intermediate 6 to the sodium 4-bromobutyrate is 1:1-1.5.
Further, in the above technical solution, the step S3: the reaction temperature is 50-80 ℃.
Further, in the above technical solution, step S4: and (3) carrying out temperature-rising reaction on Suzuki coupling under alkaline conditions in the presence of a palladium catalyst and a phosphorus ligand. The palladium catalyst is PdCl 2 dppf、Pd(OAc) 2 、PdCl 2 、Pd(PPh 4 ) 3 、PdCl 2 (CH 3 CN) 2 Etc., the phosphorus ligands are dppf, tricyclohexylphosphorus-tetrafluoroborate, tri-tert-butylphosphorus, tri-tert-butyl phosphorusButyl phosphorus tetrafluoroborate and the like.
Further, in the above technical solution, step S4: and after the reaction is finished, filtering, adding water and isopropyl acetate into the filtrate, stirring and mixing uniformly, and layering. Cooling the water layer to 5-10deg.C, adding hydrochloric acid to separate out material, and filtering to obtain wet material filter cake. And (3) uniformly stirring the wet material filter cake with water, sequentially adding a sodium hydroxide solution and methyl isobutyl ketone, uniformly stirring, separating a liquid, extracting a water layer with the methyl isobutyl ketone, merging organic phases, washing with saturated brine, separating the liquid, concentrating the filtrate under reduced pressure, eluting with n-heptane, and drying under reduced pressure to obtain the oxaagoli sodium.
The beneficial effects of the invention are that
The invention provides a novel synthesis method of oxarogridinium, which comprises the following steps: the compound 5 is reacted with (R) -2-phenyl aziridine to obtain a compound 6, then the compound 6 is reacted with 4-bromosodium butyrate to obtain a compound 7, and then the compound 7 is subjected to coupling reaction with 2-fluoro-3-methoxyphenylboric acid to directly obtain the oxagolide sodium, so that the conventional alkaline hydrolysis reaction is avoided, the route steps are shortened, the route efficiency is improved, and the process cost is greatly reduced.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Into a 500mL reaction flask, 50g (0.165 mol) of 1- (2-fluoro-6- (trifluoromethyl) benzyl) -6-methylpyrimidine-2, 4 (1H, 3H) -dione (compound 4) solid and 200mL of ethyl acetate were charged, the mixture was stirred uniformly, the temperature was lowered by a cold bath, 30.9g (0.174 mol) of N-bromosuccinimide was charged into the reaction system at 0℃and the mixture was stirred uniformly, and then the mixture was allowed to react at room temperature for 2 hours, followed by filtration. The filter cake was rinsed with 50mL of water and dried to give 5-bromo-1- [ 2-fluoro-6- (trifluoromethyl) benzyl]-6-methylpyrimidine-2, 4 (1H, 3H) -dione (compound 5) 61g, white solid, HPLC content 99.8%. 1 H-NMR(400MHz,DMSO-d 6 ):δ11.89(s,1H),7.68-7.66(d,1H),7.61-7.52(m,2H),5.37(s,2H),4.11-4.15(m,1H),4.02-3.89(m,2H),2.45(s,3H)。
Example 2
Into a 500mL reaction flask was charged 38g (0.1 mol) of 5-bromo-1- [ 2-fluoro-6- (trifluoromethyl) benzyl]-6-methylpyrimidine-2, 4 (1H, 3H) -dione (compound 5), 11.1g (0.105 mol) sodium carbonate and 75mL DMF were warmed up toStirring at 60deg.C for 1 hr, adding 13.1g (0.11 mol) of R-2-phenylaziridine and 26.6g (0.11 mol) of triphenylborane into a reaction bottle, stirring uniformly, heating to 110deg.C, keeping the temperature for 8 hr until the raw materials are completely reacted, cooling to 25deg.C, adding 200mL of ethyl acetate into the reaction bottle, stirring for 1 hr, filtering insoluble substances, stirring and dripping 15g of concentrated hydrochloric acid into the filtrate at room temperature to precipitate solid, stirring and precipitating at the same temperature for 2 hr, filtering, stirring the filter cake uniformly with 250mL of ethyl acetate, neutralizing to pH=8-9 with 5% sodium carbonate solution, separating out water phase, saturated brine washing the organic phase, drying anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to 60mL of residual ethyl acetate, cooling to 5deg.C, stirring and crystallizing for 2 hr, filtering, and oven drying to obtain 5-bromo-1- [ 2-fluoro-6- (trifluoromethyl) benzyl]-6-methyl-3- [2 (R) -amino-2-phenethyl]45.6g of pyrimidine-2, 4 (1H, 3H) -dione (compound 6), white solid, HPLC content 99.80%. 1 H-NMR(400MHz,DMSO-d 6 ):δ7.66(d,1H),7.60-7.49(m,2H),7.30-7.17(m,5H),5.37(dd,2H),4.11-4.15(m,1H),4.02-3.89(m,2H),2.52(s,3H),1.80(s,2H)。
Example 3
To a 500mL reaction flask were charged 38g (0.1 mol) of 5-bromo-1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methylpyrimidine-2, 4 (1H, 3H) -dione (compound 5), 11.1g (0.105 mol) of sodium carbonate and 75mL of DMF, stirred at 60℃for 1 hour, 12.5g (0.105 mol) of (R) -2-phenylaziridine and 26.6g (0.11 mol) of triphenylborane, stirred uniformly, warmed to 80℃for 8 hours until the starting material was completely reacted, cooled to 25℃and 200mL of ethyl acetate was added to the reaction flask, stirred for 1 hour, insoluble matters were filtered, 15g of concentrated hydrochloric acid was added dropwise to the filtrate at room temperature, stirred and precipitated solid at the same temperature for 2 hours, filtered, the cake was stirred uniformly with 250mL of ethyl acetate, 5% sodium carbonate solution and pH=8-9, aqueous phase was removed, saturated brine of the organic phase was washed, dried with anhydrous magnesium sulfate, filtered, ethyl acetate was dried to 60℃until the remaining ethyl acetate was concentrated to 3H-3H (3H) of 5- [ 2-fluoro-6- [2- (3H, 3H) -benzyl ] -2-methyl-2, 3H) -2-fluoro-1- [2- (3H) -1-methyl-ethyl-6- (3H) -dione, 3-methyl-2-ethyl-3-methyl-3-2-methyl-2-hydroxy-3-methyl-2-ethyl-2-methyl-ketone (compound, 3H-ethyl acetate was obtained.
Example 4
To a 500mL reaction flask were charged 38g (0.1 mol) of 5-bromo-1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methylpyrimidine-2, 4 (1H, 3H) -dione (compound 5), 11.1g (0.105 mol) of sodium carbonate and 75mL of DMF, stirred at 60℃for 1 hour, 17.9g (0.15 mol) of (R) -2-phenylaziridine and 26.6g (0.11 mol) of triphenylborane, stirred uniformly, warmed to 120℃for 8 hours until the starting material was completely reacted, cooled to 25℃and 200mL of ethyl acetate was added to the reaction flask, stirred for 1 hour, insoluble matters were filtered, 15g of concentrated hydrochloric acid was added dropwise to the filtrate at room temperature, stirred and precipitated solid at the same temperature for 2 hours, filtered, 250mL of ethyl acetate was stirred uniformly, 5% sodium carbonate solution was stirred until pH=8-9, aqueous phase was removed, saturated salt, anhydrous magnesium sulfate was dried, filtered, and concentrated ethyl acetate was dried at reduced pressure until the temperature was about 60℃until the residual ethyl acetate was reached, and crystalline ethyl acetate was cooled to 5- [ 2-fluoro-6- [2- (3H, 3H) -2- [ 2-methyl-1H ] -2, 3H ] -benzyl-2- (3H) -dione (compound was obtained by cooling to 5.5 mol).
Example 5
Into a 500mL reaction flask, 38g (0.1 mol) of 5-bromo-1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methylpyrimidine-2, 4 (1H, 3H) -dione (compound 5), 11.1g (0.105 mol) of sodium carbonate and 75mL of DMF were charged, the mixture was stirred at 60℃for 1 hour, 13.1g (0.11 mol) of R-2-phenylaziridine and 56.3g (0.11 mol) of tris (pentafluorophenyl) borane were charged into the reaction flask, the mixture was stirred uniformly, the temperature was raised to 110℃and kept for 8 hours until the reaction of the starting materials was completed, the temperature was lowered to 25℃and 200mL of ethyl acetate was added to the reaction flask, the mixture was stirred for 1 hour, and insoluble matters were filtered, the filtrate was stirred at room temperature to precipitate a solid by dropwise adding 15g of concentrated hydrochloric acid, stirring the precipitate at the same temperature for 2 hours, filtering, neutralizing the filter cake with 250mL of ethyl acetate uniformly, separating the aqueous phase, washing with saturated brine, drying with anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to about 60mL of the remaining ethyl acetate, cooling to 5 ℃ and crystallizing for 2 hours with heat preservation, filtering, and drying to obtain 45.1g of 5-bromo-1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methyl-3- [2 (R) -amino-2-phenethyl ] -pyrimidine-2, 4 (1H, 3H) -dione (compound 6) as a white solid with an HPLC purity of 99.5%.
Example 6
Into a 250mL reaction flask was charged 25g (50 mmol) of 5-bromo-1- [ 2-fluoro-6- (trifluoromethyl) benzyl]-6-methyl-3- [2 (R) -amino-2-phenethyl]Pyrimidine-2, 4 (1H, 3H) -dione (compound 6) solid, 10.6g (0.1 mol) anhydrous sodium carbonate and 30mL DMF were stirred at 25℃for 1 hour, 11.35g (60.1 mmol) of sodium 4-bromobutyrate was slowly added, and the temperature was raised to 60℃and the reaction was continued at 16 hours. Cooling to room temperature, adding 250mL of dichloromethane into the reaction solution, stirring at room temperature for 2 hours, filtering, concentrating the filtrate under reduced pressure to be almost dry, adding 90mL of dichloromethane, continuously concentrating the filtrate under reduced pressure until the residual dichloromethane is about 50mL, filtering by using a microporous filter, slowly dropwise adding the filtrate into 200mL of n-heptane cooled to 20 ℃, stirring and crystallizing for 2 hours. Filtering n-heptane, leaching, vacuum drying to obtain 4- (R-2- [ 5-bromo-3- (2-fluoro-6-trifluoromethyl-phenyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidine-1-yl)]-1-phenyl-ethylamino) -butyric acid sodium salt (compound 7) 28g, white solid. 1 H-NMR(400MHz,DMSO-d 6 ):δ7.64-7.63(d,J=7.6Hz,1H),7.57-7.51(m,2H),7.23-7.17(m,5H),5.37-5.28(dd,2H),4.02-3.97(m,1H),3.92-3.85(m,2H),2.25-2.15(m,2H),1.94(s,3H),1.54-1.44(m,2H),1.43-1.24(m,2H)。
Example 7
Into a 250mL reaction flask were charged 25g (50 mmol) of 5-bromo-1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methyl-3- [2 (R) -amino-2-phenethyl ] -pyrimidine-2, 4 (1H, 3H) -dione (compound 6) as a solid, 10.6g (0.1, mol) of anhydrous sodium carbonate and 30mL of DMF, stirred at 25℃for 1 hour, 10.4g (55 mmol) of sodium 4-bromobutyrate was slowly added, and the mixture was warmed to 50℃and reacted at 16 hours. After cooling to room temperature, 250mL of methylene chloride was added to the reaction solution, stirred at room temperature for two hours, filtered, the filtrate was concentrated under reduced pressure to almost dryness, and the additional 90mL of methylene chloride was continuously concentrated under reduced pressure to 50mL of the remaining methylene chloride, which was filtered using a microporous filter, and slowly added dropwise to L-n-heptane cooled to 20℃for 200m, stirred and crystallized for 2 hours, filtered, and eluted with n-heptane, and vacuum-dried at 45℃to give 27.4g of 4- (R-2- [ 5-bromo-3- (2-fluoro-6-trifluoromethyl-phenyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid sodium salt (compound 7) as a white solid.
Example 8
Into a 250mL reaction flask were charged 25g (50 mmol) of 5-bromo-1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methyl-3- [2 (R) -amino-2-phenethyl ] -pyrimidine-2, 4 (1H, 3H) -dione (compound 6) as a solid, 10.6g (01 mol) of anhydrous sodium carbonate and 30mL of DMF, stirred at 25℃for 1 hour, 13.2g (70 mmol) of sodium 4-bromobutyrate was slowly added, and the mixture was warmed to 75℃and reacted at 16 hours. After cooling to room temperature, 250mL of methylene chloride was added to the reaction solution, stirred at room temperature for 2 hours, filtered, the filtrate was concentrated under reduced pressure to almost dryness, and the additional 90mL of methylene chloride was continuously concentrated under reduced pressure to 50mL of the remaining methylene chloride, which was filtered using a microporous filter, and slowly added dropwise to 200mL of n-heptane cooled to 20℃for 2 hours with stirring, filtering, eluting with n-heptane, and vacuum-drying at 45℃to give 27.7g of 4- (R-2- [ 5-bromo-3- (2-fluoro-6-trifluoromethyl-phenyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid sodium salt (compound 7) as a white solid.
Example 9
Into a 500mL reaction flask were charged 25g (0.041 mol) of 4- (R-2- [ 5-bromo-3- (2-fluoro-6-trifluoromethyl-phenyl) -4-methyl-2, 6-dioxo-3, 6-dihydro-2H-pyrimidin-1-yl ] -1-phenyl-ethylamino) -butyric acid sodium salt (compound 7), 13.1g (0.124 mol) of anhydrous sodium carbonate, 9.78g (0.058 mol) of 2-fluoro-3-methoxyphenylboric acid, 1.2g (4.1 mmol) of tri-tert-butyltetrafluoroborate and 300mL of a 1:1 dioxane/water mixture by volume ratio, and the oxygen was removed by nitrogen bubbling for 1 hour. Into the reaction flask, 0.28g (1.2 mmol) of palladium acetate was charged, and the reaction was continued at 90℃for 2 hours until the reaction of the raw materials was completed. Cooled to room temperature, 25g of diatomite is added, stirred and mixed evenly, then filtered, 150mL of water and 150mL of isopropyl acetate are added to the filtrate, stirred and mixed evenly, and layered. The aqueous layer was cooled to 10 ℃, hydrochloric acid precipitation was added dropwise, and filtration was carried out to obtain 47g of wet cake.
The wet material filter cake is stirred evenly by 100mL of water, 44g of sodium hydroxide solution (the mass fraction is 50%), 100mL of methyl isobutyl ketone is mixed and stirred evenly, the mixture is separated, the water layer is extracted by 100mL of methyl isobutyl ketone, the organic phase is combined, the mixture is washed by 25mL of saturated brine, the separated mixture is concentrated to the residual methyl isobutyl ketone of 50mL under reduced pressure, the mixture is filtered by a microporous filter, and n-heptane which is cooled to 20 ℃ in advance is added dropwiseDuring this time, stirring was carried out for 2 hours, filtration, rinsing with a little n-heptane and drying under reduced pressure gave Li Na 21.5.5 g of oxa-agon, a white solid with an HPLC content of 99.87%. 1 H-NMR(400MHz,DMSO-d 6 ):δ7.64-7.62(d,J=8Hz,1H),7.55-7.51(m,2H),7.21-7.11(m,7H),6.73-6.57(m,1H),5.35-5.26(dd,2H),4.02-3.96(m,1H),3.94-3.88(m,2H),3.85(s,3H),2.24-2.22(m,2H),2.07(s,3H),1.96-1.94(m,2H),1.51-1.44(m,2H)。
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by making equivalents and modifications to the technical solution and the inventive concept thereof.
Claims (9)
1. A method for synthesizing oxaagole sodium, which is characterized by comprising the following steps:
s1: brominating the compound 4 with N-bromosuccinimide to generate an intermediate 5;
s2: reacting intermediate 5 with (R) -2-phenyl aziridine in the presence of a lewis acid and a base to form intermediate 6;
s3: reacting the intermediate 6 with sodium 4-bromobutyrate to generate an intermediate 7;
s4: and carrying out Suzuki coupling reaction on the intermediate 7 and 2-fluoro-3-methoxyphenylboronic acid to obtain the oxarogolisodium.
2. The synthetic method of the oxarogoli sodium according to claim 1, characterized in that: in step S1, the bromination reaction is carried out in a solvent selected from the group consisting of ethyl acetate, methyl acetate, acetonitrile, methylene chloride, tetrahydrofuran.
3. The synthetic method of the oxarogoli sodium according to claim 1, characterized in that: in the step S1, the molar ratio of the compound 4 to the NBS is 1:1-1.5.
4. The synthetic method of the oxarogoli sodium according to claim 1, characterized in that: in step S2, the base is selected from sodium carbonate, potassium carbonate or lithium carbonate.
5. The synthetic method of the oxarogoli sodium according to claim 1, characterized in that: in step S2, the lewis acid is selected from triphenylborane or tris (pentafluorophenyl) borane.
6. The synthetic method of the oxarogoli sodium according to claim 1, characterized in that: in the step S2, the mol ratio of the intermediate 5 to the (R) -2-phenyl aziridine is 1:1-1.5, and the reaction temperature is 80-120 ℃.
7. The synthetic method of the oxarogoli sodium according to claim 1, characterized in that: in the step S3, the reaction is carried out in the presence of an acid binding agent, wherein the acid binding agent is sodium carbonate or potassium carbonate.
8. The synthetic method of the oxarogoli sodium according to claim 1, characterized in that: in the step S3, the molar ratio of the intermediate 6 to the sodium 4-bromobutyrate is 1:1-1.5, and the reaction temperature is 50-80 ℃.
9. The synthetic method of the oxarogoli sodium according to claim 1, characterized in that: in the step S4, the Suzuki coupling is heated to react under alkaline conditions in the presence of a palladium catalyst and a phosphorus ligand.
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