CN115093415A - Method for removing residual metal palladium in pemetrexed disodium raw material medicine - Google Patents
Method for removing residual metal palladium in pemetrexed disodium raw material medicine Download PDFInfo
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- CN115093415A CN115093415A CN201910394525.0A CN201910394525A CN115093415A CN 115093415 A CN115093415 A CN 115093415A CN 201910394525 A CN201910394525 A CN 201910394525A CN 115093415 A CN115093415 A CN 115093415A
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 229910052763 palladium Inorganic materials 0.000 title claims abstract description 34
- NYDXNILOWQXUOF-UHFFFAOYSA-L disodium;2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)NC(CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-UHFFFAOYSA-L 0.000 title claims abstract description 25
- 229960003349 pemetrexed disodium Drugs 0.000 title claims abstract description 25
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 22
- 239000002184 metal Substances 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims abstract description 14
- 239000002994 raw material Substances 0.000 title claims abstract description 11
- 239000003814 drug Substances 0.000 title claims abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000000126 substance Substances 0.000 claims abstract description 21
- 238000007341 Heck reaction Methods 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000000706 filtrate Substances 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 239000012044 organic layer Substances 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000010410 layer Substances 0.000 claims description 7
- -1 palladium ions Chemical class 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 6
- DYUWQWMXZHDZOR-UHFFFAOYSA-N methyl 4-iodobenzoate Chemical compound COC(=O)C1=CC=C(I)C=C1 DYUWQWMXZHDZOR-UHFFFAOYSA-N 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 150000002500 ions Chemical group 0.000 claims description 4
- CZNGTXVOZOWWKM-UHFFFAOYSA-N methyl 4-bromobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1 CZNGTXVOZOWWKM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002351 wastewater Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims 3
- 229940088679 drug related substance Drugs 0.000 claims 3
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 7
- 239000013067 intermediate product Substances 0.000 abstract description 6
- 238000001914 filtration Methods 0.000 abstract description 5
- 239000012074 organic phase Substances 0.000 abstract description 5
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical group [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 abstract description 4
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 5
- SWELIMKTDYHAOY-UHFFFAOYSA-N 2,4-diamino-6-hydroxypyrimidine Chemical compound NC1=CC(=O)N=C(N)N1 SWELIMKTDYHAOY-UHFFFAOYSA-N 0.000 description 3
- ZSPTYLOMNJNZNG-UHFFFAOYSA-N 3-Buten-1-ol Chemical compound OCCC=C ZSPTYLOMNJNZNG-UHFFFAOYSA-N 0.000 description 3
- 108010022394 Threonine synthase Proteins 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000005497 Thymidylate Synthase Human genes 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000006933 Hydroxymethyl and Formyl Transferases Human genes 0.000 description 1
- 108010072462 Hydroxymethyl and Formyl Transferases Proteins 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 102000004419 dihydrofolate reductase Human genes 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- IAQLJCYTGRMXMA-UHFFFAOYSA-M lithium;acetate;dihydrate Chemical compound [Li+].O.O.CC([O-])=O IAQLJCYTGRMXMA-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- BXXLTVBTDZXPTN-UHFFFAOYSA-N methyl 2-iodobenzoate Chemical compound COC(=O)C1=CC=CC=C1I BXXLTVBTDZXPTN-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000006825 purine synthesis Effects 0.000 description 1
- 230000006824 pyrimidine synthesis Effects 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000010888 waste organic solvent Substances 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for removing residual metal palladium in a pemetrexed disodium raw material drug, which comprises the steps of dissolving organic substances by using N, N-dimethylformamide as a solvent in a first step Heck reaction of pemetrexed disodium, and adding water into reaction liquid to dissolve water-soluble substances after the reaction is finished; then filtering and absorbing to remove metal palladium and partial palladium ion groups, and then extracting and separating an organic phase and an aqueous layer. The combined removal process is adopted, so that the palladium content in the intermediate product and the final finished product pemetrexed disodium is extremely low, the useful organic phase is fully utilized, the yield is improved, and the removed metal palladium can be recycled.
Description
Technical Field
The invention relates to a technology for removing noble metal impurities from substances.
Background
Pemetrexed disodium, chemically known as N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoyl ] -L-glutamic acid disodium salt, is a multi-targeted antifolate developed by Eli Lilly, USA, first marketed in the United states in 2004. The product can inhibit multiple folate dependent enzymes to exert anticancer effect, and inhibit multiple metabolic enzymes such as Thymidylate Synthase (TS), dihydrofolate reductase and glyceramide ribonucleotide transformylase to inhibit purine and pyrimidine synthesis. The structural formula is shown as the following (I):
the synthetic route of pemetrexed disodium reported in the U.S. Pat. No. 6,62262 has the best industrial production prospect, and the synthetic route takes methyl p-iodobenzoate, 3-butene-1-ol, palladium acetate and the like as raw materials, and the pemetrexed disodium is obtained by Heck reaction, alpha-bromination of aldehyde, cyclization, hydrolysis, acylation and salt formation after reaction with 2, 4-diamino-6-hydroxypyrimidine. According to the first step of the synthesis route, palladium acetate is used as a catalyst, superfine powdery metal palladium is generated after Heck reaction, if the metal palladium is not completely removed, the metal palladium is always carried into a final product of pemetrexed disodium, so that the palladium residue of the product is unqualified, and the standard requires that the palladium residue in the pemetrexed disodium is not more than 5 ppm. Removing palladium residue, wherein the common method comprises the steps of performing column chromatography on an intermediate product in a certain step, collecting eluent after the chromatography, distilling, crystallizing and filtering to obtain an intermediate, and controlling the palladium residue of the intermediate so as to control the palladium residue of a final product.
The method for removing palladium residue by column chromatography has long production period, is difficult to realize large-scale production, consumes a large amount of organic solvent, generates a large amount of waste chromatographic silica gel, and the waste organic solvent and the chromatographic silica gel must be subjected to harmless treatment according to dangerous wastes, so the method for column chromatography is increasingly not suitable for the current environmental protection requirement.
Disclosure of Invention
The purpose of the invention is as follows:
the method for removing the residual metal palladium in the pemetrexed disodium raw material medicine is simple to operate, less in waste discharge and high in metal palladium removal rate.
The technical scheme is as follows:
the preparation process of the pemetrexed disodium comprises the following steps:
the pemetrexed disodium is prepared by taking methyl p-iodobenzoate or methyl p-bromobenzoate, 3-buten-1-ol, palladium acetate and the like as raw materials, performing Heck reaction, reacting alpha-bromination of aldehyde with 2, 4-diamino-6-hydroxypyrimidine to form rings, and performing hydrolysis, acylation and salt formation.
Before the first step Heck reaction of the pemetrexed disodium, N-Dimethylformamide (DMF) is taken as a solvent, and organic substances are firstly dissolved; after the reaction is finished, adding water into the reaction solution, and dissolving the water-soluble substance; adding water in a volume ratio of at least 2-1: 1 to N, N-Dimethylformamide (DMF), and stirring for 5-10 min. In the Heck reaction, no water is added firstly, the concentration of palladium acetate is high, the catalytic efficiency is not influenced, and the Heck reaction speed is high. Moreover, the combined solvent and the adding sequence thereof enable water-soluble substances and oil-soluble substances to be dissolved and mixed without forming emulsion suspension, so that the subsequent filtration is convenient, most solid substances such as metal palladium and the like are filtered, and useful intermediate phases are basically remained in the filtrate to obtain primary filtrate.
The reason for using N, N-dimethylformamide is as follows: n, N-dimethyl formamide is a chemical substance, is colorless transparent liquid, is a chemical raw material with wide application and is an excellent solvent with wide application. The solvent belongs to a polar inert solvent, can be randomly mixed with water and most organic solvents except halogenated hydrocarbon, has good dissolving capacity and chemical stability for various organic compounds and inorganic compounds, ensures that metal palladium and ions thereof do not form a complex or other complex substances which are difficult to dissolve and separate with other organic substances, and can not dissolve the metal palladium or cause unknown chemical reaction with the organic solvent, thereby avoiding the metal palladium or ions thereof from migrating or doping into intermediate organic products.
And then, adding activated carbon, diatomite, silica gel or a combination of the activated carbon, the diatomite and the silica gel into the primary filtrate, wherein the added mass accounts for 0.5-2% of the mass of the p-iodobenzoic acid methyl ester or the p-bromobenzoic acid methyl ester serving as the initial raw material (the amount of the residual metal palladium simple substance and a small amount of palladium ion groups is met, and the filtration efficiency is not influenced by impurities brought by surplus.
And then, extracting the secondary filtrate by using ethyl acetate, separating an aqueous layer and an ethyl acetate organic layer, and performing waste water treatment on the aqueous layer, wherein the waste water contains residual palladium ions, so that the post treatment of the palladium ion solution is simple and does not bring the problem of environmental pollution. The organic layer has a very low palladium ion content. And washing the organic layer by using a saturated sodium chloride solution or a saturated sodium bromide solution (the saturated halogen ions can avoid the dissociation of the pemetrexed disodium intermediate product to generate bromide ions, the ionization reaction equation moves towards the left side, so that the yield of semi-finished products is kept at a higher level, the yield of products subjected to subsequent reaction and final finished products is higher, particularly sodium bromide is more suitable because bromide ions are generated at the same time and chloride ion impurities are not generated), distilling the organic layer under reduced pressure, evaporating ethyl acetate to constant weight to obtain a reddish brown viscous oily intermediate product, and measuring through component analysis of a testing instrument, wherein the palladium content is less than 5ppm, and the harm of residual heavy metals to medicine taking personnel is reduced to the greatest extent.
And (3) carrying out subsequent multi-step reaction on the intermediate product of the reddish brown viscous oily matter to finally obtain the pemetrexed disodium substance with higher yield and higher purity.
The simple substance of the metal palladium or the palladium ions can be respectively prepared into the palladium acetate by adopting respective proper reaction steps, and the palladium acetate is reused in the invention, so that the noble metal resources are recycled.
Has the advantages that:
after the first-step Heck reaction for synthesizing pemetrexed disodium is finished, fully dissolving and filtering are carried out, and metal palladium is removed in advance; then, carrying out secondary desorption on the filtrate by adopting an adsorbing material to remove the residual metal palladium simple substance; then, in the extraction process, the aqueous layer containing metallic palladium ions is discarded and the palladium ions in the organic phase are removed. The combined removal process results in very low palladium levels in the resulting semifinished and final products. And the useful organic phase in the middle can be fully utilized, and the yield is improved; the removed palladium simple substance and palladium ions can be respectively recovered and treated, and can be secondarily used in the invention, thereby saving resources, reducing cost and reducing emission.
Detailed Description
Example 1:
according to the method for removing the residual metal palladium in the pemetrexed disodium raw material medicine, before a Heck reaction in the first step of pemetrexed disodium synthesis, N-dimethylformamide is taken as a solvent, and organic substances are dissolved firstly; after Heck reaction is finished, adding water into the reaction solution, and dissolving the water-soluble substances; the volume ratio of the added water to the N, N-dimethylformamide is 1.5-2: 1; the reaction solution was then filtered, and a primary filtrate was obtained.
Adding powdered activated carbon or diatomite adsorbing material into the primary filtrate, wherein the added mass accounts for 1-2% of the mass of the starting raw material of the p-iodobenzoic acid methyl ester or the p-bromobenzoic acid methyl ester, adsorbing metal palladium or palladium-containing ion groups, and remaining the secondary filtrate.
Extracting the secondary filtrate with ethyl acetate to separate an aqueous layer and an ethyl acetate organic layer; the organic layer was washed with a saturated sodium chloride solution, the organic layer was distilled under reduced pressure, and ethyl acetate was evaporated to constant weight to give a reddish brown viscous oily intermediate.
The intermediate product of the reddish brown viscous oily matter is subjected to alpha-bromination of aldehyde and reacts with 2, 4-diamino-6-hydroxypyrimidine to form a ring, and then the ring is subjected to hydrolysis, acylation and salt formation to obtain the pemetrexed disodium.
Example 2:
in example 1, the specific equipment and amounts of materials used were as follows:
200g of methyl iodobenzoate, 86g of lithium acetate dihydrate, 96g of lithium chloride, 112g of tetrabutylammonium chloride and 80mL (0.8925 mol) of 3-buten-1-ol are added into a 3000mL four-neck round-bottom flask, stirred, heated (set temperature: 70 ℃) and added with 4.26g of palladium acetate when the temperature of the materials is raised to 60 ℃, and stirred for 20 hours at 65-70 ℃ after the addition. 350mL of drinking water and 350mL of ethyl acetate were added to the reaction mixture, and the mixture was stirred, cooled to room temperature, and then the reaction mixture was filtered under suction. The filtrate was poured into another clean 3000mL four-necked round-bottomed flask, 10g of powdered activated carbon was added thereto, stirred for 10 minutes, and filtered through a prepared filter.
The filtrate was transferred to a separatory funnel, and 400mL of ethyl acetate was added for extraction. The aqueous layer was extracted 3 times with 400mL portions of ethyl acetate. The organic phases are combined, washed once with 400mL of saturated saline, concentrated under reduced pressure at a temperature not exceeding 45 ℃ and the ethyl acetate is evaporated off to constant weight. A reddish brown viscous oil was obtained which had a palladium content of 1 ppm.
Claims (4)
1. A method for removing residual metal palladium in a pemetrexed disodium raw material medicine is characterized by comprising the following steps: before a first step Heck reaction for synthesizing pemetrexed disodium, N-dimethylformamide is taken as a solvent, and organic substances are dissolved; after Heck reaction is finished, adding water into the reaction solution, and dissolving the water-soluble substances; the volume ratio of the added water to the N, N-dimethylformamide is 1-2: 1; the reaction solution was then filtered to remove the metallic palladium solid, leaving a primary filtrate.
2. The method for removing residual metallic palladium in a pemetrexed disodium drug substance as claimed in claim 1, wherein: adding active carbon, diatomite, silica gel or their combined adsorbing material into the primary filtrate, the added mass accounting for 0.5-2% of the mass of the initial raw material of methyl p-iodobenzoate or methyl p-bromobenzoate, adsorbing metal palladium or palladium-containing ion groups, and the rest of the secondary filtrate.
3. The method for removing residual metallic palladium in a pemetrexed disodium drug substance as claimed in claim 2, wherein: powdered activated carbon is used as an adsorbing material.
4. The method for removing residual metallic palladium in a pemetrexed disodium drug substance according to claim 2 or 3, wherein: extracting the secondary filtrate with ethyl acetate to separate an aqueous layer and an ethyl acetate organic layer; the water layer is treated with wastewater, and palladium ions in the wastewater are recovered; the organic layer was washed with saturated sodium chloride solution or sodium bromide solution, the organic layer was distilled under reduced pressure, and ethyl acetate was evaporated to constant weight to give a reddish brown viscous oily intermediate.
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| CN201910394525.0A CN115093415A (en) | 2019-05-13 | 2019-05-13 | Method for removing residual metal palladium in pemetrexed disodium raw material medicine |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101560215A (en) * | 2009-05-27 | 2009-10-21 | 复旦大学 | Method for removing residual palladium of faropenem sodium |
| US20110124861A1 (en) * | 2008-05-30 | 2011-05-26 | Jinliang Li | Process for Preparing Pemetrexed Disodium and Its Intermediate, 4-(4-Carbomethoxyphenyl) Butanal |
| CN102887902A (en) * | 2012-10-10 | 2013-01-23 | 北京莱瑞森医药科技有限公司 | Preparation process for synthesizing high-purity Pemedolac |
| CN104230991A (en) * | 2014-08-25 | 2014-12-24 | 亿腾药业（泰州）有限公司 | Method for controlling palladium residue in fosaprepitant dimeglumine |
-
2019
- 2019-05-13 CN CN201910394525.0A patent/CN115093415A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110124861A1 (en) * | 2008-05-30 | 2011-05-26 | Jinliang Li | Process for Preparing Pemetrexed Disodium and Its Intermediate, 4-(4-Carbomethoxyphenyl) Butanal |
| CN101560215A (en) * | 2009-05-27 | 2009-10-21 | 复旦大学 | Method for removing residual palladium of faropenem sodium |
| CN102887902A (en) * | 2012-10-10 | 2013-01-23 | 北京莱瑞森医药科技有限公司 | Preparation process for synthesizing high-purity Pemedolac |
| CN104230991A (en) * | 2014-08-25 | 2014-12-24 | 亿腾药业（泰州）有限公司 | Method for controlling palladium residue in fosaprepitant dimeglumine |
Non-Patent Citations (1)
| Title |
|---|
| 马彦琴 等: "培美曲塞二钠的合成", 《中国新药杂志》, vol. 16, no. 2, 31 December 2007 (2007-12-31), pages 134 - 137 * |
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