CN116768901A - Preparation method of pemetrexed disodium - Google Patents
Preparation method of pemetrexed disodium Download PDFInfo
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- CN116768901A CN116768901A CN202210216746.0A CN202210216746A CN116768901A CN 116768901 A CN116768901 A CN 116768901A CN 202210216746 A CN202210216746 A CN 202210216746A CN 116768901 A CN116768901 A CN 116768901A
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- pemetrexed disodium
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- 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 19
- 229960003349 pemetrexed disodium Drugs 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000005185 salting out Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 230000009471 action Effects 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 229940033654 pemetrexed disodium heptahydrate Drugs 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 claims description 3
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 claims description 2
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 239000012043 crude product Substances 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 abstract description 10
- 230000008569 process Effects 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 238000009835 boiling Methods 0.000 abstract description 2
- 238000009749 continuous casting Methods 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 208000006178 malignant mesothelioma Diseases 0.000 description 5
- 201000005282 malignant pleural mesothelioma Diseases 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 3
- 229960005079 pemetrexed Drugs 0.000 description 3
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- WSEQLMQNPBNMSL-FJXQXJEOSA-N diethyl (2s)-2-aminopentanedioate;hydron;chloride Chemical compound Cl.CCOC(=O)CC[C@H](N)C(=O)OCC WSEQLMQNPBNMSL-FJXQXJEOSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 230000009946 DNA mutation Effects 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 240000007695 Nandina domestica Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- GDEKSBCRJKAARB-UHFFFAOYSA-N methyl 4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CCC1=CNC2=C1C(=O)N=C(N)N2 GDEKSBCRJKAARB-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to a preparation method of pemetrexed disodium, which is characterized in that only water is used as a solvent in the preparation process, a one-pot boiling method is adopted, three steps of continuous casting are adopted, methyl 4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2,3-d ] pyrimidine-5-yl) ethyl ] benzoate is used as a starting material, after hydrolysis, the methyl 4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2,3-d ] pyrimidine-5-yl) ethyl ] benzoate is directly condensed with L-diethyl glutamate hydrochloride, and then the high-purity pemetrexed disodium is obtained after hydrolysis and salting out. Compared with the method reported in the prior literature, the reaction process does not need to separate the intermediate, does not use an organic solvent, does not need to purify the intermediate by salifying p-toluenesulfonic acid, avoids the generation of mutation-causing impurities, and is more environment-friendly in the whole process.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of pemetrexed disodium.
Background
Pemetrexed disodium (Pemetrexed disodium) was first to obtain FDA approval for treatment of Malignant Pleural Mesothelioma (MPM) in combination with cisplatin for treatment of Malignant Pleural Mesothelioma (MPM) patients not amenable to surgical excision, as the first to obtain FDA approval for treatment of malignant pleural mesothelioma, month 2 2004. 8 months 2004 it was FDA approved as a second line therapeutic drug for non-small cell lung cancer. According to the unique action mechanism of pemetrexed and the clinical research results obtained by the pemetrexed in two aspects of expanding the indication, the pemetrexed has great application potential in the anti-tumor field and has wide prospect in the aspect of tumor treatment and application.
In pharmaceutical synthesis, sulfonic acid or sulfonyl halide reagents are often used as alkylating agents and catalysts, and are also often used in purification or salification steps of pharmaceutical synthesis. The presence of any residual alcohol during the synthesis reaction or recrystallization step may lead to sulfonate formation. Clinical studies have found that sulfonates are capable of direct alkylation with biological macromolecules (DNAs, RNAs and proteins), potentially leading to DNA mutations. P-toluenesulfonates have been shown to be genotoxic and pose a threat to human health.
In the prior art, a large number of synthesis processes of pemetrexed disodium are reported, most of which are prepared from methyl 4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2,3-d ] pyrimidine-5-yl) ethyl ] benzoate or ethyl 4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2,3-d ] pyrimidine-5-yl) ethyl ] benzoate by ester hydrolysis, condensation, hydrolysis and other reactions, and the difference is mainly that the intermediate purification modes are different: firstly, p-toluenesulfonic acid is used for purification, as reported in patent WO2011/064256A1 and journal of Chinese pharmaceutical chemistry (2008,18 (6): 445-448); and secondly, the purification is carried out by recrystallization using mixed solvents, as reported, for example, in J.Nandina.China (2007,16 (2): 134-137) and J.Heteromycin chem.,2015,52 (5): 1565-1569. Thirdly, purification is carried out using column chromatography, as reported, for example, in organic chemistry (2006, 26 (4): 546-550).
The above route needs to separate the intermediate in the reaction process, and also uses various organic solvents, even needs to purify the intermediate by salifying p-toluenesulfonic acid, the preparation process is complex in steps, more waste liquid is generated, mutation-causing impurities are possibly generated, and the industrial production is not facilitated.
Therefore, the invention improves the preparation process of pemetrexed disodium, the improved process condition is mild, the operation is simple and easy to implement, no organic solvent is used in the reaction process, the intermediate is not required to be separated, the intermediate is not required to be purified by salifying p-toluenesulfonic acid, the generation of mutation-causing impurities is avoided, the whole process is more environment-friendly, and the industrial production is easy.
Disclosure of Invention
1. The invention aims to overcome the defects of the prior art and provide a method for industrially producing pemetrexed disodium.
The reaction equation is as follows:
2. the invention solves the technical problems by adopting the following technical scheme:
in water, compound 1 is hydrolyzed under the action of sodium hydroxide, is directly condensed with L-diethyl glutamate hydrochloride under the action of a condensing agent without post-treatment, and is hydrolyzed under the action of sodium hydroxide without post-treatment to generate pemetrexed disodium. The specific operation steps are as follows:
(1) Synthesis of Compound 2:
in water, compound 1 is hydrolyzed under the action of sodium hydroxide, and the molar ratio of compound 1 to sodium hydroxide is 1:3-5, preferably 1:4; the reaction is carried out at 40-60 ℃ for 1-2 h, preferably 1h; after the reaction, the pH=6 to 8 is adjusted by concentrated hydrochloric acid, and the next reaction is directly carried out without post-treatment.
(2) Synthesis of Compound 3:
condensing the reaction solution of the compound 2 with L-diethyl glutamate hydrochloride under the action of a condensing agent, wherein the molar ratio of the compound 2 to the L-diethyl glutamate hydrochloride to the N-methylmorpholine to the 4- (4, 6-dimethoxy triazine-2-yl) -4-methylmorpholine hydrochloride is 1:1-1.5:1.5-2.5:1-1.5, preferably 1:1.2:2:1.2; or the mol ratio of the compound 1 to the L-glutamic acid diethyl ester hydrochloride, the N-methylmorpholine and the 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine is 1:1-1.5:2.5-3.5:1-1.5, preferably 1:1.2:3:1.2; the reaction is carried out at 10-30 ℃ for 1-3 h, preferably 2h; and directly carrying out the next reaction without post-treatment after the reaction is finished.
(3) Synthesis of pemetrexed disodium:
the reaction solution of the compound 3 is hydrolyzed under the action of sodium hydroxide, and the molar ratio of the compound 3 to the sodium hydroxide is 1:3-5, preferably 1:4; the reaction is carried out at 10-30 ℃ for 1-2 h, preferably 1h; after the reaction is finished, the pH=7 to 9 is regulated by concentrated hydrochloric acid, and then 10 to 20 percent of sodium chloride aqueous solution is added for salting out, preferably 15 percent; salting out is carried out by stirring at 10-30℃for 1-4 hours, preferably 2 hours.
3. The solvent of the reaction is water.
4. The invention has the beneficial effects that:
compared with the prior literature report method, the method has the advantages that only water is used as a solvent for reaction, a one-pot boiling method is adopted, three steps of continuous casting are adopted to obtain high-purity pemetrexed disodium, and the obtained product is refined in one step to obtain the pemetrexed disodium heptahydrate with the grade of bulk drug. The reaction process does not need to separate the intermediate, does not use an organic solvent, does not need to purify the intermediate by salifying p-toluenesulfonic acid, avoids the generation of mutation-causing impurities, and is more environment-friendly in the whole process.
Drawings
The accompanying drawings are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification.
FIG. 1 shows the product of Messaging disodium H 1 -NMR spectrum.
FIG. 2 is an HPLC chart of the obtained product pemetrexed disodium.
Fig. 3 is an HPLC profile of the resulting refined pemetrexed disodium heptahydrate.
Detailed Description
The present invention will be described in further detail with reference to the following specific embodiments, but it should not be construed that the scope of the present invention is limited to the following examples.
The process equipment or devices not specifically identified in the examples below are all conventional in the art; all reagents were commercially available.
Case (B)
Purified water (25.0 kg) is added into a 100L reaction kettle at normal temperature, stirring is started, sodium hydroxide (1.3 kg,32.0 mol) is added into the 100L reaction kettle, stirring is carried out for dissolution, methyl 4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2,3-d ] pyrimidin-5-yl) ethyl ] benzoate (2.5 kg,8.0 mol) is added into the 100L reaction kettle under the protection of nitrogen, the reaction temperature is maintained at 40-60 ℃ for 1 hour, then the temperature is reduced to 10-30 ℃, and concentrated hydrochloric acid is added dropwise into the reaction solution until the pH is 6-8.
N-methylmorpholine (1.6 kg,16.0 mol) and 4- (4, 6-dimethoxy-triazin-2-yl) -4-methylmorpholine hydrochloride (2.6 kg,9.6 mol) are continuously added into the reaction kettle under the protection of nitrogen at the temperature of 10-30 ℃, and the reaction system is maintained at the temperature of 10-30 ℃ and stirred for 1h. L-glutamic acid diethyl ester hydrochloride (2.3 kg,9.6 mol) was added in portions, the reaction temperature was maintained at 10 to 30℃and the reaction was stirred for 2 hours.
Under the protection of nitrogen, maintaining the reaction temperature at 10-30 ℃, adding sodium hydroxide solution (1.3 kg of sodium hydroxide is dissolved in 13.0kg of water), continuing to react for 1h after the addition, and dripping concentrated hydrochloric acid into the reaction solution until the pH is 7-9.
Under the protection of nitrogen, 15% sodium chloride solution (3.0 kg sodium chloride is dissolved in 17.0kg water) is added at 10-30 ℃, and after the addition, the mixture is stirred and crystallized for 2 hours. The mixture was filtered off and the filter cake was rinsed with 15% sodium chloride solution (1.5 kg sodium chloride in 8.5kg water). And (3) drying the filter cake in vacuum for 18 hours (50 ℃ and the vacuum degree is-0.1 MPa) to obtain 2.4kg of pemetrexed disodium. The total yield was 63.6% and the purity was 99.817%.
Refining: under the protection of nitrogen, at 20-30 ℃, the crude pemetrexed disodium (2.4 kg,5.1 mol) and purified water (14.4 kg) are added into a reaction kettle, stirred and dissolved. Adding active carbon (0.024 kg), stirring for decolorizing for 0.5 hours, press-filtering to another reaction kettle, heating to 40-60 ℃, dropwise adding acetone (45.5 kg), slowly precipitating a large amount of white solid, cooling to 20-30 ℃, continuously stirring for crystallizing for 1 hour, carrying out throwing filtration, and washing a filter cake with acetone (2.4 kg). Drying with wet nitrogen to obtain 2.7kg of white solid pemetrexed disodium heptahydrate with the yield of 88.8% and the purity: 99.962%, moisture: 21.4%.
The above embodiments are provided to illustrate the technical concept and features of the present invention and are intended to enable those skilled in the art to understand the content of the present invention and implement the same, and are not intended to limit the scope of the present invention. All equivalent changes or modifications made according to the spirit of the invention should be construed to be included in the scope of the present invention.
Claims (4)
1. A method for preparing pemetrexed disodium, which is characterized by comprising the following steps:
(1) Synthesis of Compound 2:
in water, the compound 1 is hydrolyzed under the action of sodium hydroxide, the molar ratio of the compound 1 to the sodium hydroxide is 1:3-5, the reaction is carried out for 1-2 h at 40-60 ℃, and after the reaction is finished, the pH is regulated by concentrated hydrochloric acid, and the next reaction is directly carried out;
(2) Synthesis of Compound 3:
condensing the reaction solution of the compound 2 with L-diethyl glutamate hydrochloride under the action of a condensing agent, wherein the molar ratio of the compound 2 to the L-diethyl glutamate hydrochloride to the N-methylmorpholine to the 4- (4, 6-dimethoxy triazine-2-yl) -4-methylmorpholine hydrochloride is 1:1-1.5:1.5-2.5:1-1.5, or the molar ratio of the compound 1 to the L-diethyl glutamate hydrochloride to the N-methylmorpholine to the 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine is 1:1-1.5, and the reaction is carried out for 1-3 h at the temperature of 10-30 ℃; after the reaction is finished, no post-treatment is carried out, and the next reaction is directly carried out;
(3) Synthesis of pemetrexed disodium:
the reaction solution of the compound 3 is hydrolyzed under the action of sodium hydroxide, the mol ratio of the compound 3 to the sodium hydroxide is 1:3-5, and the reaction is carried out for 1-2 h at the temperature of 10-30 ℃; after the reaction is finished, regulating the pH value by using concentrated hydrochloric acid, and then adding 10-20% sodium chloride aqueous solution for salting out, wherein the salting out is carried out by stirring for 1-4 h at 10-30 ℃;
(4) Synthesis of pemetrexed disodium heptahydrate:
and refining the pemetrexed disodium crude product by water and acetone to obtain the pemetrexed disodium heptahydrate.
2. The method of manufacturing according to claim 1, characterized in that: the reaction solvents in the step (1), the step (2) and the step (3) are all water.
3. The method of manufacturing according to claim 1, characterized in that:
the condensing agent in step (2) is selected from the group consisting of: n-methylmorpholine and 4- (4, 6-dimethoxytriazin-2-yl) -4-methylmorpholine hydrochloride or N-methylmorpholine and 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine.
4. The production process according to claim 1, wherein the pH of the adjustment in step (1) is=6 to 8; and (3) regulating the pH value to be 7-9.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210216746.0A CN116768901A (en) | 2022-03-07 | 2022-03-07 | Preparation method of pemetrexed disodium |
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| CN202210216746.0A CN116768901A (en) | 2022-03-07 | 2022-03-07 | Preparation method of pemetrexed disodium |
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| Publication Number | Publication Date |
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| CN116768901A true CN116768901A (en) | 2023-09-19 |
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