CN103254196B - Preparation method of pemetrexed diacid - Google Patents
Preparation method of pemetrexed diacid Download PDFInfo
- Publication number
- CN103254196B CN103254196B CN201310202316.4A CN201310202316A CN103254196B CN 103254196 B CN103254196 B CN 103254196B CN 201310202316 A CN201310202316 A CN 201310202316A CN 103254196 B CN103254196 B CN 103254196B
- Authority
- CN
- China
- Prior art keywords
- preparation
- butyl
- pemetrexed diacid
- pidolidone
- benzoyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229960005079 pemetrexed Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 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 title claims abstract 12
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 28
- -1 L-glutamic acid diester Chemical class 0.000 claims abstract description 16
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- 230000026030 halogenation Effects 0.000 claims abstract description 3
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 3
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- SWELIMKTDYHAOY-UHFFFAOYSA-N 2,4-diamino-6-hydroxypyrimidine Chemical class NC1=CC(=O)N=C(N)N1 SWELIMKTDYHAOY-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 230000002140 halogenating effect Effects 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000001475 halogen functional group Chemical group 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- RIRBAVAYPRSMRH-UHFFFAOYSA-N 2,4-dimethoxy-1,3,5-triazine Chemical compound COC1=NC=NC(OC)=N1 RIRBAVAYPRSMRH-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- 150000003818 basic metals Chemical class 0.000 claims description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 claims description 2
- 239000012433 hydrogen halide Substances 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 229910001507 metal halide Inorganic materials 0.000 claims description 2
- 150000005309 metal halides Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- NAYYNDKKHOIIOD-UHFFFAOYSA-N phthalamide Chemical compound NC(=O)C1=CC=CC=C1C(N)=O NAYYNDKKHOIIOD-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims 1
- 150000001342 alkaline earth metals Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-Glutamic acid Natural products OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 239000005711 Benzoic acid Substances 0.000 abstract 1
- 235000010233 benzoic acid Nutrition 0.000 abstract 1
- 229960002989 glutamic acid Drugs 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-L pemetrexed(2-) 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-L 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 7
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 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 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229960003349 pemetrexed disodium Drugs 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- JFKUBRAOUZEZSL-UHFFFAOYSA-N 4-butylbenzoic acid Chemical class CCCCC1=CC=C(C(O)=O)C=C1 JFKUBRAOUZEZSL-UHFFFAOYSA-N 0.000 description 2
- GUQDPZIUUZLCGX-UHFFFAOYSA-N 4-chloro-2,6-dimethyl-1H-triazine Chemical compound ClC1=NN(NC(=C1)C)C GUQDPZIUUZLCGX-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 2
- 238000006987 Nef reaction Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229940110282 alimta Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 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 2
- 208000006178 malignant mesothelioma Diseases 0.000 description 2
- 201000005282 malignant pleural mesothelioma Diseases 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- ZSPTYLOMNJNZNG-UHFFFAOYSA-N 3-Buten-1-ol Chemical compound OCCC=C ZSPTYLOMNJNZNG-UHFFFAOYSA-N 0.000 description 1
- DENKGPBHLYFNGK-UHFFFAOYSA-N 4-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Br)C=C1 DENKGPBHLYFNGK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- YEJSPQZHMWGIGP-YFKPBYRVSA-N L-glutamic acid, dimethyl ester Chemical compound COC(=O)CC[C@H](N)C(=O)OC YEJSPQZHMWGIGP-YFKPBYRVSA-N 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- FRFXLISGFDQWEY-UHFFFAOYSA-N but-1-ene;ethanol Chemical compound CCO.CCC=C FRFXLISGFDQWEY-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 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
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- YEJSPQZHMWGIGP-UHFFFAOYSA-N dl-glutamic acid dimethyl ester Natural products COC(=O)CCC(N)C(=O)OC YEJSPQZHMWGIGP-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000002390 hyperplastic effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000004944 pyrrolopyrimidines Chemical group 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of pemetrexed diacid (I). The preparation method comprises the following steps of carrying out condensation reaction on 4-[(4, 4-dimethoxy-3- hydroxyl) butyl] benzoic acid (II) and L-glutamic acid diester (III) to generate 4-[(4, 4-dimethoxy-3- hydroxyl) butyl] benzoyl-L-glutamic acid diester (IV); carrying out halogenation and acidolysis on the compound (IV) to obtain 4-[(4-oxo-3-halogenated) butyl] benzoyl-L-glutamic acid diester (V); and carrying out cyclization and basic hydrolysis on the intermediate (V) and 2,4-diamino-6- hydroxypyrmidine (VI) to obtain the pemetrexed diacid (I). The preparation method has the advantages that raw materials are easily available and the process is simple; and the preparation method is economical and environment-friendly and is suitable for industrial production.
Description
Technical field
The invention belongs to organic synthetic route design and bulk drug thereof and Intermediate Preparation technical field, particularly a kind of preparation method of pemetrexed diacid.
Background technology
Pemetrexed disodium (Pemetrexed disodium) is a kind of novel many target position folic acid retarding agent containing pyrrolopyrimidine group.Multiple enzyme required in cancer cell division and hyperplastic process can be blocked, thus reach antineoplastic effect.This medicine is developed by Lilly (Eli Lilly) company, and in 2004 in U.S.'s Initial Public Offering, be approved for and treat malignant pleural mesothelioma and nonsmall-cell lung cancer with Cisplatin, commodity are called Alimta (Alimta).In December, 2005, this medicine was in Discussion on Chinese Listed, and the indication of approval is malignant pleural mesothelioma.
The active pharmaceutical ingredients of pemetrexed disodium is pemetrexed diacid, chemistry N-by name [4-[2-(amino-4,7-dihydro-4-oxygen-1H-pyrroles [2, the 3-d] pyrimidine-5-bases of 2-) ethyl] benzoyl]-Pidolidone, and its structural formula is:
About pemetrexed and Intermediate Preparation have more report, it has two principal synthetic routes: Article 1 route is by 4-butylbenzoic acid derivative and 2,4-diamino-6-hydroxy pyrimidine first cyclization generates 4-[2-(2-amino-4,7-dihydro-4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-base) ethyl] phenylformic acid, then obtain pemetrexed diacid and disodium salt thereof with Pidolidone or its ester condensation; Article 2 route obtains 4-[(4-oxo-3-halo) butyl] benzoyl-Pidolidone or its ester by 4-butylbenzoic acid derivative and Pidolidone or its ester condensation, this compound generates pemetrexed diacid and disodium salt thereof with the cyclization of 2,4-diamino-6-hydroxy pyrimidine again.
No. CN1821219Ath, Chinese patent and No. CN1821220A report and a kind ofly utilize above-mentioned Article 2 route to prepare the operational path of pemetrexed: take parabromobenzoyl chloride as raw material, intermediate 4-Bromophenacyl-Pidolidone diethyl ester (VII) is generated with Pidolidone diethyl ester acylation reaction, intermediate (VII) and 3-butene-1-ol react through Heck and generate intermediate 4-(4-oxo butyl) benzoyl-Pidolidone diethyl ester (VIII), intermediate (VIII) generates 4-(3-bromo-4-oxo butyl) benzoyl-Pidolidone diethyl ester (IX) through bromo, intermediate (IX) and 2, 4-diamino-6-hydroxy pyrimidine (VI) cyclization through being hydrolyzed obtained pemetrexed diacid (I).
No. CN101333173Ath, Chinese patent reports the similar preparation method of a kind of and above-mentioned technique, difference is that the halogen bromine of Benzoyl chloride contraposition has changed iodine into, glutamate diethyl ester has changed glutamic acid dimethyl ester into, when intermediate (VIII) halo becomes intermediate (IX), instead of the bromine in previous process by halogens chlorine.
In addition, No. CN1827604Ath, Chinese patent reports the Article 3 route of a kind of preparation method of pemetrexed of similar above-mentioned Article 2 route: adopt and introduce nitro functions, becomes during ring and utilizes Nef reaction to prepare pemetrexed diacid (I).
Analyze above-mentioned operational path, front two lines all have employed the substrate that 3-butene-1-ethanol reacts as Heck, and will use expensive palladium metal catalyst.Article 3 route, due to the introducing of nitro functions, adds the probability that Genotoxic produces.Meanwhile, be embodied as ring owing to finally carrying out Nef reaction, the use of strong acid and strong base too increases the possibility of side reaction generation, have impact on industrialized use.
Summary of the invention
The object of the invention is to for defect of the prior art, provide a kind of and have that raw material is easy to get, concise in technology and the preparation method of pemetrexed diacid with low cost.
For achieving the above object, present invention employs following main technical schemes: the preparation method of a kind of pemetrexed diacid (I),
Described preparation method, its preparation process comprises: 4-[(4,4-dimethoxy-3-hydroxyl) butyl) there is condensation reaction and generate 4-[(4,4-dimethoxy-3-hydroxyl) butyl] benzoyl-Pidolidone diester (IV) in phenylformic acid (II) and Pidolidone diester (III); 4-[(4,4-dimethoxy-3-hydroxyl) butyl] benzoyl-Pidolidone diester (IV) obtains 4-[(4-oxo-3-halo) butyl] benzoyl-Pidolidone diester (V) through halogenating reaction and acidolysis; There is ring-closure reaction and obtain pemetrexed diacid (I) through basic hydrolysis in 4-[(4-oxo-3-halo) butyl] benzoyl-Pidolidone diester (V) and 2,4-diamino-6-hydroxy pyrimidines (VI).
In addition, the present invention also proposes following attached technical scheme:
Described Pidolidone diester (III) or 4-[(4,4-dimethoxy-3-hydroxyl) butyl] alkyl R in benzoyl-Pidolidone diester (IV) is phenyl, preferable methyl or the ethyl of methyl, ethyl, propyl group, sec.-propyl, allyl group, butyl, isobutyl-, the tertiary butyl, phenyl or replacement.
The condensing agent of described condensation reaction is dimethoxy s-triazine, benzothiazole mercaptan, phthalic diamide, 1-hydroxy benzo triazole or benzotriazole, preferred dimethoxy s-triazine.
The acid binding agent of described condensation reaction is sodium hydroxide, sodium methylate, sodium bicarbonate, potassium hydroxide, triethylamine, pyridine, N-methylpyrrole, N-methyl piperidine or N-methylmorpholine, preferred N-methylmorpholine.
The halogenating agent of described halogenating reaction is elemental halogen, hydrogen halide, metal halide, Phosphorates phosphorus Halides, halogenation oxygen phosphorus, halocarbon or thionyl chloride, preferred phosphorus tribromide.
The acid binding agent of described halogenating reaction is triethylamine, diisopropylamine, pyridine, salt of wormwood, saleratus, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methylate or potassium tert.-butoxide, preferred triethylamine or pyridine.
The solvent of described ring-closure reaction is methyl alcohol, ethanol, Virahol, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran (THF), toluene, water or water and the mixed solvent wherein between any one organic solvent, particular methanol and water (volume ratio 1: 1).
Described hydrolysis reaction is alkaline hydrolysis, and its alkali is the oxyhydroxide of metal on basic metal or alkali, alkali-metal carbonate, alkali-metal supercarbonate or alkali alcoholate, preferred sodium hydroxide or potassium hydroxide.
Compared to prior art, the preparation method of pemetrexed intermediate involved in the present invention, has the features such as raw material is easy to get, concise in technology, cost are lower and quality controllable, so be beneficial to the suitability for industrialized production of this bulk drug, promotes the development of its economic technology.
Embodiment
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.Wherein 4-[(4,4-dimethoxy-3-hydroxyl) butyl) synthesis of phenylformic acid (II) refers to No. 2013101996871st, the Chinese patent of the applicant's application.
Embodiment one:
Under drying and nitrogen atmosphere, N-methylmorpholine (2.0g is added in there-necked flask, 20mmol) with 4-chloro-2,6-dimethyltriazine (3.5g, 20mmol) and 4-[(4,4-dimethoxy-3-hydroxyl) butyl) phenylformic acid (II) (2.54g, 10mmol) and N, dinethylformamide 50mL, stirring at room temperature 1 hour.Add Pidolidone dimethyl ester hydrochloride (2.75g, 13mmol) and N-methylmorpholine (1.5g, 15mmol), continue stirring 3 hours, TLC detection reaction completes.By in reaction solution impouring water, add dichloromethane extraction.Organic phase washed with water, anhydrous sodium sulfate drying.Decompression and solvent recovery, gained residue with Ethyl acetate and normal hexane (1: 1) recrystallization obtain off-white color solid 4-[(4,4-dimethoxy-3-hydroxyl) butyl] benzoyl-Pidolidone dimethyl ester (IV) 3.5g, yield 85.2%.
Embodiment two:
Under drying and nitrogen atmosphere, N-methylmorpholine (2.0g is added in there-necked flask, 20mmol) with 4-chloro-2,6-dimethyltriazine (3.5g, 20mmol) and 4-[(4,4-dimethoxy-3-hydroxyl) butyl) phenylformic acid (II) (2.54g, 10mmol) and N, dinethylformamide 50mL, stirring at room temperature 1 hour.Add Pidolidone diethyl ester hydrochloride (3.1g, 13mmol) and N-methylmorpholine (1.5g, 15mmol), continue stirring 3 hours, TLC detection reaction completes.By in reaction solution impouring water, add dichloromethane extraction.Organic phase washed with water, anhydrous sodium sulfate drying.Decompression and solvent recovery, gained residue with Ethyl acetate and normal hexane (1: 1) recrystallization obtain off-white color solid 4-[(4,4-dimethoxy-3-hydroxyl) butyl] benzoyl-Pidolidone diethyl ester (IV) 3.8g, yield 86.5%.
Embodiment three:
4-[(4,4-dimethoxy-3-hydroxyl) butyl] benzoyl-Pidolidone diethyl ester (IV) (2.20g, 5mmol), pyridine (1.2g, 15mmol) and methylene dichloride 25mL is added in there-necked flask.Be cooled to 0 DEG C, under stirring, drip phosphorus tribromide (2.7g, 10mmol), drip and finish, room temperature reaction 4 hours, TLC detection reaction terminates.Solids removed by filtration, mother liquor uses water and brine It successively, vacuum distillation recovered solvent.Gained resistates adds trifluoracetic acid, room temperature reaction 2 hours.Washing, toluene extracts, and concentrated faint yellow thick solid 4-[(4-oxo-3-bromine) butyl] benzoyl-Pidolidone diethyl ester (V) 1.7g obtained, yield is 74.7%.
Embodiment four:
4-[(4-oxo-3-bromine) butyl] benzoyl-Pidolidone diethyl ester (V) (2.28g is added in reaction flask, 5mmol), 2,4-diamino-6-hydroxy pyrimidine (VI) (0.77g, 6mmol), first alcohol and water (1: 1) mixed solvent 50mL, be stirred to down and add sodium-acetate (0.82g, 10mmol), be warming up to 45 DEG C, react 5 hours, TLC detection reaction completes.Cooling, has solid to separate out, and filters.Gained solid adds 1M sodium hydroxide solution 25mL, room temperature reaction 3 hours.Regulate pH=2-3 with hydrochloric acid, have solid to separate out, filter, gained solid acetone recrystallization obtains off-white color solid pemetrexed diacid (I) 1.73g, yield 80.8%.
It is pointed out that above-described embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (8)
1. a preparation method for pemetrexed diacid (I),
It is characterized in that described preparation method, its preparation process comprises: 4-[(4,4-dimethoxy-3-hydroxyl) butyl) there is condensation reaction and generate 4-[(4,4-dimethoxy-3-hydroxyl) butyl] benzoyl-Pidolidone diester (IV) in phenylformic acid (II) and Pidolidone diester (III); Described 4-[(4,4-dimethoxy-3-hydroxyl) butyl] benzoyl-Pidolidone diester (IV) obtains 4-[(4-oxo-3-halo) butyl] benzoyl-Pidolidone diester (V) through halogenating reaction and acidolysis; There is ring-closure reaction and obtain pemetrexed diacid (I) through basic hydrolysis in described 4-[(4-oxo-3-halo) butyl] benzoyl-Pidolidone diester (V) and 2,4-diamino-6-hydroxy pyrimidines (VI).
2. the preparation method of pemetrexed diacid (I) as claimed in claim 1, is characterized in that: the structure of described 4-[(4,4-dimethoxy-3-hydroxyl) butyl] benzoyl-Pidolidone diester (IV) is shown below,
Wherein R is the phenyl of methyl, ethyl, propyl group, sec.-propyl, allyl group, butyl, isobutyl-, the tertiary butyl, phenyl or replacement.
3. the preparation method of pemetrexed diacid (I) as claimed in claim 1, is characterized in that: the condensing agent of described condensation reaction is dimethoxy s-triazine, benzothiazole mercaptan, phthalic diamide, 1-hydroxy benzo triazole or benzotriazole.
4. the preparation method of pemetrexed diacid (I) as claimed in claim 1, is characterized in that: the acid binding agent of described condensation reaction is sodium hydroxide, sodium methylate, sodium bicarbonate, potassium hydroxide, triethylamine, pyridine, N-methylpyrrole, N-methyl piperidine or N-methylmorpholine.
5. the preparation method of pemetrexed diacid (I) as claimed in claim 1, is characterized in that: the halogenating agent of described halogenating reaction is elemental halogen, hydrogen halide, metal halide, Phosphorates phosphorus Halides, halogenation oxygen phosphorus, halocarbon or thionyl chloride.
6. the preparation method of pemetrexed diacid (I) as claimed in claim 1, is characterized in that: the acid binding agent of described halogenating reaction is triethylamine, diisopropylamine, pyridine, salt of wormwood, saleratus, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methylate or potassium tert.-butoxide.
7. the preparation method of pemetrexed diacid (I) as claimed in claim 1, is characterized in that: the solvent of described ring-closure reaction is methyl alcohol, ethanol, Virahol, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran (THF), toluene, water or water and the mixed solvent wherein between any one organic solvent.
8. the preparation method of pemetrexed diacid (I) as claimed in claim 1, it is characterized in that: described hydrolysis reaction is alkaline hydrolysis, its alkali is the oxyhydroxide of basic metal or alkaline-earth metal, alkali-metal carbonate, alkali-metal supercarbonate or alkali alcoholate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310202316.4A CN103254196B (en) | 2013-05-28 | 2013-05-28 | Preparation method of pemetrexed diacid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310202316.4A CN103254196B (en) | 2013-05-28 | 2013-05-28 | Preparation method of pemetrexed diacid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103254196A CN103254196A (en) | 2013-08-21 |
| CN103254196B true CN103254196B (en) | 2015-02-18 |
Family
ID=48958459
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310202316.4A Expired - Fee Related CN103254196B (en) | 2013-05-28 | 2013-05-28 | Preparation method of pemetrexed diacid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103254196B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114262332A (en) * | 2020-09-16 | 2022-04-01 | 齐鲁制药有限公司 | Novel crystal form of pemetrexed diacid and preparation method thereof |
| CN114539353B (en) * | 2020-11-26 | 2024-08-30 | 南京碳硅人工智能生物医药技术研究院有限公司 | Pemetrexed polyglutamic acid metabolite and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI377063B (en) * | 2006-08-14 | 2012-11-21 | Sicor Inc | Crystalline forms of pemetrexed diacid and processes for the preparation thereof |
| CN100509814C (en) * | 2007-07-06 | 2009-07-08 | 吴洪流 | Pemetrexed intermediate and preparation method thereof |
| WO2011064256A1 (en) * | 2009-11-24 | 2011-06-03 | Azad Pharmaceutical Ingredients Ag | A new crystalline form of pemetrexed disodium |
| EP2654795B1 (en) * | 2010-12-21 | 2018-03-07 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of pemetrexed-based compounds |
| CN102827168A (en) * | 2012-09-24 | 2012-12-19 | 苏州立新制药有限公司 | Preparation method of pemetrexed intermediate |
-
2013
- 2013-05-28 CN CN201310202316.4A patent/CN103254196B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN103254196A (en) | 2013-08-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106478641B (en) | The synthetic method of Rui Boxini intermediates | |
| CN103254179B (en) | Preparation method of Avanafil | |
| CN103265534B (en) | Method for preparing avanafil | |
| EP3004047B1 (en) | Compounds of '3-(5-substituted oxy-2,4-dinitro-phenyl)-2-oxo-propionic acid ester', process and applications thereof | |
| KR102212496B1 (en) | Method for producing 5R-benzyloxyamino piperidine-2S-formic acid or derivatives thereof | |
| CN107207519B (en) | Yi Bu replaces the preparation method of Buddhist nun | |
| CN103254196B (en) | Preparation method of pemetrexed diacid | |
| CN103254180B (en) | Preparation method of Avanafil | |
| CN104520278A (en) | A process for the preparation of an intermediate for a triazolopyrimidine carbonucleoside | |
| CN103288758B (en) | Preparation method of dacomitinib (I) | |
| CN105198821A (en) | Preparation method of Rociletinib | |
| CN105985294A (en) | Preparation method for olaparib | |
| CN108373468B (en) | Preparation method of N-2-pyridine-5-pyrimidine methylamine | |
| US20160362400A1 (en) | Avanafil preparation method | |
| CN103274962B (en) | N-[4-(1-(2-propinyl)-3, 4-dioxo-n-butyl) benzoyl]-L-glutamic dialkyl ester and preparation method thereof | |
| CN103265482A (en) | Preparation method of bosutinib | |
| CN103333117B (en) | The preparation method of a kind of 4 [(the chloro-2-pyrimidyl of 4-) is amino] cyanophenyl | |
| CN105130887A (en) | Regorafenib preparation method | |
| CN103265428B (en) | Method for preparing 4-[(3-halogenate-4-oxo) butyl] benzoic acid | |
| CN104011029A (en) | An improved process for the preparation of bendamustine hydrochloride | |
| CN108409557A (en) | Bu Waxitan new intermediates and its synthetic method and application | |
| CN104086553B (en) | One prepares the method for 7-bromine imidazo [2,1-f] [1,2,4] triazine-4-amine | |
| CN107353291A (en) | Her a kind of cloth replaces the refined preparation method of Buddhist nun | |
| CN103664951B (en) | A kind of preparation method treating chronic myelocytic leukemia medicine | |
| CN104592222A (en) | Preparation method for antiplatelet medicine AZD6482 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191223 Address after: 064400 floor 1, no.25-8, Jinshui Haoting community, Yongshun sub district office, Qian'an City, Tangshan City, Hebei Province Patentee after: Qian'an Keheng Material Distribution Office Address before: 215000 Jiangsu Province, Suzhou City Industrial Park Commercial Plaza Building 1 room 1305 Lianfeng Co-patentee before: Xu Xuenong Patentee before: SUZHOU MIRACPHARMA TECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150218 |