CN115246828A - Palladium removal method for tedizolid phosphate intermediate - Google Patents
Palladium removal method for tedizolid phosphate intermediate Download PDFInfo
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 title claims abstract description 119
- 229910052763 palladium Inorganic materials 0.000 title claims abstract description 49
- 238000000034 method Methods 0.000 title claims abstract description 45
- QCGUSIANLFXSGE-GFCCVEGCSA-N tedizolid phosphate Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP(O)(O)=O)C2)=O)F)=N1 QCGUSIANLFXSGE-GFCCVEGCSA-N 0.000 title claims abstract description 27
- 229960003947 tedizolid phosphate Drugs 0.000 title claims abstract description 27
- 239000003463 adsorbent Substances 0.000 claims abstract description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 238000001914 filtration Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 10
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000002386 leaching Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 8
- 239000007787 solid Substances 0.000 abstract description 2
- 230000001376 precipitating effect Effects 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000001514 detection method Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- BARDROPHSZEBKC-OITMNORJSA-N fosaprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NC(=O)N(P(O)(O)=O)N1 BARDROPHSZEBKC-OITMNORJSA-N 0.000 description 4
- 229960002891 fosaprepitant Drugs 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 229940053194 antiepileptics oxazolidine derivative Drugs 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000002917 oxazolidines Chemical class 0.000 description 3
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 2
- JANKGNBDRWYWSN-UHFFFAOYSA-N 5-bromo-2-(2-methyltetrazol-5-yl)pyridine Chemical compound CN1N=NC(C=2N=CC(Br)=CC=2)=N1 JANKGNBDRWYWSN-UHFFFAOYSA-N 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- YLNSNVGRSIOCEU-ZCFIWIBFSA-N [(2r)-oxiran-2-yl]methyl butanoate Chemical compound CCCC(=O)OC[C@H]1CO1 YLNSNVGRSIOCEU-ZCFIWIBFSA-N 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- -1 2-methyl-2H-tetrazol-5-yl Chemical group 0.000 description 1
- QZVQQUVWFIZUBQ-UHFFFAOYSA-N 3-fluoroaniline Chemical compound NC1=CC=CC(F)=C1 QZVQQUVWFIZUBQ-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- YTMVYYAKOPIJCZ-UHFFFAOYSA-N 4-bromo-3-fluoroaniline Chemical compound NC1=CC=C(Br)C(F)=C1 YTMVYYAKOPIJCZ-UHFFFAOYSA-N 0.000 description 1
- 231100000111 LD50 Toxicity 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- NOQXXYIGRPAZJC-SECBINFHSA-N [(2r)-oxiran-2-yl]methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC[C@@H]1OC1 NOQXXYIGRPAZJC-SECBINFHSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- PWYPGEFOZYBWDP-UHFFFAOYSA-N boric acid;pyridine Chemical compound OB(O)O.C1=CC=NC=C1 PWYPGEFOZYBWDP-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- FXORZKOZOQWVMQ-UHFFFAOYSA-L dichloropalladium;triphenylphosphane Chemical compound Cl[Pd]Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FXORZKOZOQWVMQ-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- CAAULPUQFIIOTL-UHFFFAOYSA-M methyl hydrogen phosphate Chemical compound COP(O)([O-])=O CAAULPUQFIIOTL-UHFFFAOYSA-M 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention provides a method for reducing the palladium content in a tedizolid phosphate intermediate TD2, which comprises the following steps: preparing tedizolid phosphate intermediate TD2 solution, adding an adsorbent, separating the adsorbent, and then precipitating a solid from the solution to obtain the tedizolid phosphate intermediate TD2 (the palladium residue is less than 20 ppm), so that the palladium residue of the finished product of the tedizolid phosphate is less than 10ppm. The method has the advantages of simple operation, good repeatability and low cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for removing palladium from a tedizolid phosphate intermediate.
Background
Tedizolid phosphate is an oxazolidinone antibacterial drug useful for treating acute bacterial skin and skin structure infections (abssi) caused by susceptible strains of the following gram-positive microorganisms. Chemical name (IUPAC): [ (5R) - (3- {3-Fluoro-4- [6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl ] phenyl } -2-oxoazolidin-5-yl ] methylhydrogenphosphate, known as Tedizolidphosphate.
Structural formula (xvi):
the synthetic routes of tedizolid phosphate reported at present are various:
according to the report of document W02005058886Al, 3-fluoroaniline is used as a raw material, is subjected to Cbz protection, then reacts with (R) -glycidyl butyrate to obtain a compound, is iodinated and then is prepared into a tin reagent, and then reacts with 5-bromo-2- (2-methyl-2H-tetrazol-5-yl) -pyridine to generate suzuki coupling under the catalysis of triphenylphosphine palladium dichloride to obtain a key intermediate, wherein the reaction route is as follows:
the second method is that according to the report of document WO2010042887A2, 4-bromo-3-fluoroaniline is used as a starting material to synthesize borate, then the borate and 5-bromo-2- (2-methyl-2H-tetrazol-5-yl) -pyridine are subjected to Suzuki coupling through a palladium catalyst to generate an intermediate, and then the intermediate is reacted with (R) -glycidyl butyrate to generate an oxazolidinone intermediate, wherein the reaction route is as follows:
the third method is that 1-iodine-2-fluoro-phenyl isocyanate is selected as a starting material to react with (R) -p-toluenesulfonic acid glycidyl ester to generate oxazolidine derivatives, the oxazolidine derivatives are obtained through hydrolysis and esterification, and then the oxazolidine derivatives and pyridine boric acid are subjected to Suzuki coupling to obtain target compounds, as reported in document CN104327119A, the reaction route is as follows:
the fourth method is to produce the key intermediate TD2 by a suzuki reaction between TD4 and TD3 through a palladium catalyst according to the report of CN 105985331A.
The four synthesis methods inevitably use a palladium catalyst which is a key reagent in the suzuki reaction. In the pharmaceutical industry, palladium belongs to heavy metal (subgroup 2B) with high toxicity, and the residue of the palladium in the medicine needs to be strictly controlled, and according to the ICHQ3D guiding principle, the palladium residue limit is that the oral preparation does not exceed 10ppm, the injection does not exceed 1ppm, and the inhalant does not exceed 0.1ppm in terms of daily dosage of 10 g/day. The daily administration dosage of the tedizolid phosphate is 200 mg/day, and the tedizolid phosphate is in two dosage forms of tablets and freeze-dried powder injection for injection, and is temporarily free of inhalant. Therefore, the palladium residue of the oral preparation is estimated to be not more than 500ppm, and the palladium residue of the injection is not more than 50ppm.
The palladium used after completion of the Suzuki reaction is present in the reaction solution in the form of ions or atoms, and cannot be removed by filtration or liquid-separation extraction. Usually, a silica gel column chromatography method is used to leave palladium on the silica gel column. The method uses a large amount of organic solvent and is not suitable for industrial production.
The document CN101056672A provides a trialkyl phosphine method for removing palladium of fosaprepitant. In a specific example, tri-n-butylphosphine (20-100 uL/g Pd/C) is used. The used tri-n-butylphosphine is more, the anti-solvent is used during the subsequent recrystallization, the tri-n-butylphosphine is easy to remain, the tri-n-butylphosphine has medium toxicity, and the rat orally takes the semi-Lethal Dose (LD) 50 ) 750mg/kg, so the method has certain influence on the safety of the medicine. A similar document CN102838634A provides a combination of fosaprepitant, tributylphosphine and triphenylphosphine, but still has a potential safety hazard.
The document CN201610133979 provides palladium removal by a sulfydryl silica gel adsorption method of fosaprepitant. By using the method, the palladium residue of the TD2 intermediate can be reduced to be below 20ppm, but the mercapto silica gel adsorbs a part of products while adsorbing palladium, so that the yield is reduced, and in addition, the mercapto silica gel is expensive and is not easy to purchase at home.
The various methods for removing palladium by using fosaprepitant have some defects. The tedizolid phosphate urgently needs a safer, efficient, low-toxicity and economic palladium removal method.
Disclosure of Invention
The invention provides a method for removing palladium from a tedizolid phosphate intermediate, which is suitable for industrial production. The method has the advantages of simple operation, good repeatability and low cost, and is suitable for industrial production.
The structure of the tedizolid phosphate intermediate (TD 2) is as follows:
the invention relates to a method for removing palladium from a tedizolid phosphate intermediate suitable for industrial production, which aims at TD4 and TD3 in the presence of a palladium catalyst Pd (dppf) Cl 2 TD2 produced by suzuki reaction in the presence of the following reaction formula
The invention provides a method for removing palladium from a tedizolid phosphate intermediate, which comprises the following steps:
1) Carrying out a suzuki reaction on TD4 and TD3 in the presence of a palladium catalyst to generate a TD2 intermediate, cooling and crystallizing after the reaction is finished, filtering, leaching and drying to obtain a TD2 crude product;
2) Heating and dissolving the TD2 crude product by using a solvent, adding an adsorbent, and stirring for a period of time while keeping the temperature;
3) Thermally filtering and separating the adsorbent and the TD2 solution;
4) Cooling and crystallizing the TD2 solution, separating and drying to obtain a TD2 intermediate.
One embodiment of the present invention provides a method for preparing crude TD2 in step 1): stirring TD4, TD3, tetrahydrofuran and a potassium carbonate aqueous solution in a reaction bottle, and replacing nitrogen for three times; rapid addition of Pd (dppf) Cl 2 Replacing nitrogen for three times; keeping the external temperature at 85 +/-5 ℃ under the protection of nitrogen, carrying out reflux reaction for 16-20 h, adding water, and slowly cooling to 25 +/-5 ℃. Filtering, leaching a filter cake with water, and drying by blowing at 65 +/-5 ℃ to obtain a crude product of TD2.
The solvent suitable in step 2) of the above method is selected from one or two of acetonitrile, tetrahydrofuran, ethanol and isopropanol, and a mixed solvent of water, preferably a mixed solution of acetonitrile and water, wherein the ratio of acetonitrile: volume ratio of water = 17; the choice of solvent for TD2 recrystallization is a complex and difficult process due to solubility issues of the intermediate TD2. The use of a solvent with poor solubility leads to a large solvent consumption, which is not suitable for industrial production; when a solvent with good solubility is used, the yield of TD2 recrystallization is low, and long-term tests show that the ratio of acetonitrile: water volume ratio = 17. The detailed data are shown in the table I:
the adsorbent in the step 2) of the method is activated carbon. The activated carbon is a common solid adsorbent, is low in price and easy to purchase, is widely applied to the aspects of chemical industry, medicine, environment and the like, and is used for decoloring, reducing heavy metal ions, adsorbing oil stains, purifying water or purifying air; the solvents used are wide in the pH range and can be used in both aqueous and organic solutions.
The dosage of the adsorbent in the step 2) of the method is 5-20%, preferably 10% of the dosage of TD2.
The temperature of the heat preservation is 60-80 ℃ after the adsorbent is added in the step 2) of the method, and the time is 1-3 h; the reflux temperature is preferably 78. + -. 2 ℃.
The hot filtering temperature in the step 3) of the method is 60-70 ℃; TD2 is easy to precipitate at a low temperature, and the solvent is easy to volatilize at a high temperature.
The temperature for cooling and crystallizing in the step 4) of the method is 20-30 ℃ and the time is 2-4 h;
the separation and drying in the step 4) of the method can be carried out according to the conventional method in the field, and the forced air drying at 55-65 ℃ is preferably carried out for 12-24 h;
and D2, if the palladium residue of the TD2 prepared in the step 4) of the method is unqualified, dissolving the TD2 in acetonitrile: and (3) continuing the steps 2) to 4) for 1 to 2 times in the mixed solvent of water = 17.
The method for removing the palladium from the TD2 crude product is simple to operate, good in repeatability and low in cost, and is suitable for industrial production. The content of the TD2 intermediate palladium prepared by the method is lower than 20ppm, and the product quality is uniform and stable. Compared with an organophosphorus reagent, the palladium removing method provided by the invention is safer; compared with the method for removing palladium by using sulfydryl silica gel, the method is lower in cost; the invention has good repeatability and is more suitable for industrial production of TD2.
Drawings
FIG. 1 (0.5% Pd (dppf) Cl 2 Using crude TD2, palladium residue 820.586 ppm)
FIG. 2 (0.5% Pd (dppf) Cl 2 Using TD2 crude product to remove palladium once, and palladium residue 16.235 ppm)
FIG. 3 (0.3% Pd (dppf) Cl 2 Using crude TD2, palladium residue 487.439 ppm)
FIG. 4 (0.3% Pd (dppf) Cl 2 Using TD2 crude product to remove palladium once, and palladium residue 14.081 ppm)
FIG. 5 (0.5% Pd (dppf) Cl 2 Twice palladium removal by using TD2 crude product, palladium residue 3.484 ppm)
Watch 1
Table one is a screening table of TD2 recrystallization solvent;
Detailed Description
In order that those skilled in the art may better understand the present invention, the following embodiments further illustrate the present invention. It should be understood that the following examples are given for better illustration of the present invention and are not intended to limit the scope of the present invention.
Example 1:
A5L reaction flask was charged with TD4 (110.00 g), TD3 (120.87 g), tetrahydrofuran (1500 mL) and aqueous potassium carbonate (172.51 g potassium carbonate +200mL water). Stirring, nitrogen displacement three times, rapid addition of Pd (dppf) Cl 2 (1.52 g), nitrogen gas was replaced three times. Keeping (weak) nitrogen flow, heating to 80-85 ℃ at the external temperature, and carrying out reflux reaction for 16h to finish the reaction.
Adding water (1500 mL) into the reaction liquid drop, stirring and pulping, slowly cooling to 25 +/-5 ℃, and stirring for 1.0h. Filtering, rinsing the filter cake with water (200 mL), and then blowing and drying at 65 +/-5 ℃ to obtain crude TD2 product 140.32g (the palladium residue is 820.586ppm, and the detection data are shown in the attached figure 1).
A1L reaction flask was charged with crude TD2 (20 g, palladium residue 820.586 ppm) and acetonitrile: water = 17. The mixture was heated to reflux (78 ℃ C.) with stirring, and after dissolution activated carbon (2.00 g) was added, the reflux was maintained for 1 hour. The internal temperature is reduced to 60 to 70 ℃, and the mixture is filtered when the mixture is hot. The temperature of the filtrate is slowly reduced to 25 +/-5 ℃, and the temperature is maintained and the stirring is carried out for 2 hours. Filtration, cake filtration with acetonitrile: mixed solvent (40 mL) of water =17, and air-dried at 60 ± 5 ℃ for 20 hours to obtain TD2 (17.82 g, palladium residue 16.235ppm, see fig. 2 for detection data).
Example 2:
A5L reaction flask was charged with TD4 (110.00 g), TD3 (120.87 g), tetrahydrofuran (1500 mL) and aqueous potassium carbonate (172.51 g potassium carbonate +200mL water). Stirring, nitrogen displacement three times, rapid addition of Pd (dppf) Cl 2 (0.92 g), nitrogen gas was replaced three times. Keeping (weak) nitrogen flow, heating to 80-85 ℃ at the external temperature, and carrying out reflux reaction for 20h to finish the reaction.
Adding water (1500 mL) into the reaction solution drop by drop, stirring and pulping, slowly cooling to 25 +/-5 ℃, and stirring for 0.5h. The solution is filtered, and a filter cake is rinsed by water (200 mL) and then is blown and dried at 65 +/-5 ℃ to obtain 137.82g of TD2 crude product (the palladium residue is 487.439ppm, and the detection data is shown in figure 3).
A500 mL reaction flask was charged with crude TD2 (10 g, palladium residual 487.439 ppm) and acetonitrile: water = 17. The mixture was heated to reflux (78 ℃ C.) with stirring, and after dissolution activated carbon (1.00 g) was added, the reflux was maintained for 1 hour. The internal temperature is reduced to 60 to 70 ℃, and the mixture is filtered when the mixture is hot. The temperature of the filtrate is slowly reduced to 25 +/-5 ℃, and the temperature is maintained and the stirring is carried out for 2 hours. Filtration, cake filtration with acetonitrile: water =17, mixed solvent (20 mL) was rinsed and air dried at 60 ± 5 ℃ for 20 hours to give TD2 (8.90 g, palladium residue 14.081ppm, see fig. 4 for assay data).
If the TD2 product palladium residue is not qualified, the TD2 intermediate can be dissolved in acetonitrile: the above operation of removing palladium was repeated 1 to 2 times in the mixed solvent of water =17 and 7, and an intermediate having a palladium content of less than 20ppm was obtained.
A500 mL reaction flask was charged with TD2 (10 g, palladium residue 16.235 ppm) and acetonitrile: water = 17. The mixture was heated to reflux (78 ℃ C.) with stirring, and after dissolution activated carbon (1.00 g) was added, the reflux was maintained for 1 hour. The internal temperature is reduced to 60 to 70 ℃, and the mixture is filtered when the mixture is hot. The temperature of the filtrate is slowly reduced to 25 +/-5 ℃, and the temperature is maintained and the stirring is carried out for 2 hours. Filtration, cake filtration with acetonitrile: mixed solvent (20 mL) of water =17, and air-dried at 60 ± 5 ℃ for 20 hours to obtain TD2 (8.93 g, palladium residue 3.484ppm, see fig. 5 for detection data).
The detection method of the palladium content comprises the following steps: ICP-MS (inductively coupled plasma Mass Spectrometry detection method).
Claims (10)
1. A method for removing palladium from a tedizolid phosphate intermediate is characterized by comprising the following steps;
1) Carrying out a suzuki reaction on TD4 and TD3 in the presence of a palladium catalyst to generate a TD2 intermediate, cooling and crystallizing after the reaction is finished, filtering, leaching and drying to obtain a TD2 crude product;
2) Heating and dissolving the TD2 crude product by using a solvent, adding an adsorbent, and stirring for a period of time while keeping the temperature;
3) Thermally filtering and separating the adsorbent and the TD2 solution;
4) Cooling and crystallizing the TD2 solution, separating and drying to obtain a TD2 intermediate.
2. The method for removing palladium from tedizolid phosphate intermediate according to claim 1, wherein in the step 2), the suitable solvent is selected from one or two of acetonitrile, tetrahydrofuran, ethanol and isopropanol, and a mixed solvent of water, preferably a mixed solution of acetonitrile and water, wherein the volume ratio of acetonitrile to water is =17: 7.
3. The method for removing palladium from tedizolid phosphate intermediate according to claim 1, wherein in the step 2), the adsorbent is activated carbon.
4. The method for removing palladium from tedizolid phosphate intermediate according to claim 1, wherein in the step 2), the dosage of the adsorbent is 5% to 20% of the dosage of TD2.
5. The method for removing palladium from tedizolid phosphate intermediate according to claim 1, wherein in the step 2), the dosage of the adsorbent is 10% of the dosage of TD2.
6. The method for removing palladium from the tedizolid phosphate intermediate according to claim 1, wherein the temperature of the step 2) after the adsorbent is added is 60-80 ℃ and the time is 1-3 hours.
7. The method for removing palladium from tedizolid phosphate intermediate according to claim 1, wherein the hot filtration temperature in the step 3) is 60 to 70 ℃.
8. The method for removing palladium from the tedizolid phosphate intermediate according to claim 1, wherein the temperature for cooling and crystallizing in the step 4) is 20-30 ℃ and the time is 2-4 h.
9. The method for removing palladium from the tedizolid phosphate intermediate according to claim 1, wherein the drying in the step 4) is performed by air blast drying at 55-65 ℃ for 12-24 h.
10. The method for removing palladium from the tedizolid phosphate intermediate according to claim 1, wherein the TD2 prepared in the step 4) is dissolved in a mixed solvent of acetonitrile: water =17:7 to continue the steps 2) -4) for 1-2 times if palladium remains unqualified.
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| CN114105968A (en) * | 2020-08-28 | 2022-03-01 | 河北明吉化工科技有限公司 | Method for removing palladium residue of tedizolid |
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