CN102344452B - The new method of synthesis pemetrexed disodium - Google Patents
The new method of synthesis pemetrexed disodium Download PDFInfo
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- CN102344452B CN102344452B CN201110204375.6A CN201110204375A CN102344452B CN 102344452 B CN102344452 B CN 102344452B CN 201110204375 A CN201110204375 A CN 201110204375A CN 102344452 B CN102344452 B CN 102344452B
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- pemetrexed
- diethylester
- mixture
- polar organic
- aqueous solution
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- NYDXNILOWQXUOF-GXKRWWSZSA-L pemetrexed disodium Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-GXKRWWSZSA-L 0.000 title abstract description 16
- 229960003349 pemetrexed disodium Drugs 0.000 title abstract description 16
- 230000002194 synthesizing Effects 0.000 title abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title description 11
- 238000003786 synthesis reaction Methods 0.000 title description 10
- 229960005079 pemetrexed Drugs 0.000 claims abstract description 46
- 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 claims abstract description 45
- 239000000203 mixture Substances 0.000 claims abstract description 38
- 239000003495 polar organic solvent Substances 0.000 claims abstract description 19
- 239000007864 aqueous solution Substances 0.000 claims abstract description 15
- 238000001556 precipitation Methods 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 239000000243 solution Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000000634 powder X-ray diffraction Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 229960000935 Dehydrated Alcohol Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N 1,2-dihydrobenzotriazol-4-one Chemical compound O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- -1 iodate pyrrole ring Chemical group 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 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 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N N,N′-Dicyclohexylcarbodiimide Substances C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000560222 Mibora minima Species 0.000 description 2
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 description 2
- 108009000071 Non-small cell lung cancer Proteins 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- ODHCTXKNWHHXJC-VKHMYHEASA-N Pyroglutamic acid Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000037348 biosynthesis Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000004059 degradation Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 229950008597 drug INN Drugs 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000001738 genotoxic Effects 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 239000004519 grease Substances 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- 238000011068 load Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 1
- VORLTHPZWVELIX-UHFFFAOYSA-N 1-methyl-2H-quinoline Chemical compound C1=CC=C2N(C)CC=CC2=C1 VORLTHPZWVELIX-UHFFFAOYSA-N 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-M 2-methylpropanimidate Chemical compound CC(C)C([O-])=N WFKAJVHLWXSISD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N Dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000259 anti-tumor Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000008365 aromatic ketones Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000000711 cancerogenic Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001472 cytotoxic Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 201000005282 malignant pleural mesothelioma Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- ZXDUPDQEFOYLOM-UHFFFAOYSA-O propylideneazanium Chemical group [CH2-]CC=[NH2+] ZXDUPDQEFOYLOM-UHFFFAOYSA-O 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
Abstract
The invention discloses a kind of new method synthesizing pemetrexed disodium.The present invention relates to prepare the new method of pemetrexed diethylester 2Described method includes being purified by aprotic organic solvent, can promote in the presence of the chemical agent that peptide bond is formed, the step of the mixture that compound 1 and 1a reaction obtains,It is characterized in that, this mixture stands following steps: a) wash with alkaline aqueous solution；B) organic facies is concentrated；C) polar organic solvent and/or the mixture of polar organic solvent are added；D) precipitation pemetrexed diethylester 2.The method that the invention still further relates to prepare disodium salt 5It includes the above-mentioned method preparing pemetrexed diethylester 2.The further subject matter of the present invention is the crystal form of pemetrexed diethylester 2.
Description
Technical field
The present invention relates to prepare the new method of pemetrexed diethylester 2
Described method includes being purified by aprotic organic solvent, can promote depositing of chemical agent that peptide bond is formed
Under, the step of the mixture that compound 1 and 1a reaction obtains,
It is characterized in that, this mixture stands following steps:
A) wash with alkaline aqueous solution；
B) organic facies is concentrated；
C) polar organic solvent and/or the mixture of polar organic solvent are added；
D) precipitation pemetrexed diethylester 2.
The method that the invention still further relates to prepare disodium salt 5
Described method includes the above-mentioned method preparing pemetrexed diethylester 2.
The further subject matter of the present invention is the crystal form of pemetrexed diethylester 2.
Background technology
Pemetrexed is that [[(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] is phonetic for 2-for 4-for active component N-
Pyridine-5-base) ethyl] benzoyl]-Pidolidone, the International Non-Proprietary Name (INN) of compound 4:
Relevant disodium salt, compound 5,
It is special medicament (pharmaceutical speciality)In the active component that contains, this medicine
Product are widely used in treatment nonsmall-cell lung cancer (NSCLC) and malignant pleural mesothelioma, and are in being applied to other tumors
In the research of the treatment of pathology.
Pemetrexed belongs to many targeting antifol class, i.e. works under the level of some folate-dependant enzymes systems
Those anti-tumor active ingredients, this folate-dependant enzymes system relates to the life of the biosynthesis of purine and pyrimidine, purine and pyrimidine
Thing synthesis is the biosynthesis starting point of DNA and RNA.
The synthesis of pemetrexed is described in US 5,344,932 first.This synthesis originates in compound 2-amino-7H-pyrroles
And [2,3-d] pyrimidine-4-alcohol, it is at protection amino with subsequently after iodate pyrrole ring, with (S)-2-(4-acetenyl benzene carbon amide
Base) reaction of pentane acid dimethyl.After a series of simple reactions, the product of this reaction changes into pemetrexed.
According to nearest US 5,416,211, it is incorporated herein by, pemetrexed can according to scheme 1 below, by
From the 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base) of the formula 1 that simple precursor obtains
Ethyl] benzoic acid synthesis:
Scheme 1
This second method seems to be additionally operable to the industrially prepared of this active component.It is true that the synthetic schemes of same type
It is also described in C.J.Barnett, T.W.Wilson and M.E.Kobierski, Org.Proc.Res.&Develop., 1999,3,
184-188, wherein EXPERIMENTAL EXAMPLE is suitable for the magnitude scale of tens of kg.
Summary of the invention
It is in the experimentation of synthetic method of optimization or improving countermeasure 1 in target, it has now surprisingly been found that permissible
High yield separates the pemetrexed diethylester 2 with highly purified crystal form.This experimental result is entirely unexpectedly, because
Relate to analyzing preparation from the only example reporting the document that pemetrexed diethylester 2 separates as solid, be wherein roughened
Compound by chromatogram purification, is collected in the solution, then by evaporation solvent separate (E.C.Taylor and B.Liu,
J.Org.Chem.2003, page 68,9938-9947,9945, synthesis of compound25a(compound25aConjunction
Become), m.p.84-86 DEG C, there is IR and characterize；C.J.Barnett, T.W.Wilson and M.E.Kobierski,
Org.Proc.Res.&Develop., page 1999,3,184-188,188, synthesis of compound13(compound13Synthesis), m.p.169-171).
Therefore, the present invention relates to prepare the new method of pemetrexed diethylester 2
Described method includes being purified by aprotic organic solvent, can promote depositing of chemical agent that peptide bond is formed
Under, the step of the mixture that compound 1 and 1a reaction obtains,
It is characterized in that, this mixture stands following steps:
A) wash with alkaline aqueous solution, and subsequently the aqueous phase so obtained is separated with organic facies；
B) organic facies is concentrated；
C) polar organic solvent and/or the mixture of polar organic solvent are added；
D) precipitation pemetrexed diethylester 2.
In accordance with the invention it is possible to promote peptide bond formed chemical agent be preferably selected from CDMT (2-chloro-4,6-dimethoxy-1,
3,5-triazine), DCC (N, N '-dicyclohexylcarbodiimide), HOBT (hydroxybenzotriazole), EDC (1-ethyl-3-(3-diformazan
Base aminopropyl) carbodiimide), more preferably CDMT (2-chlorine-4,6-dimethoxy-1,3,5-triazine).
According to the present invention, aprotic organic solvent be preferably selected from dimethylformamide, dimethyl acetylamide, dichloromethane,
Chloroform, ethyl acetate and/or its mixture, and more preferably dimethylformamide and the mixture of dichloromethane.
According to the present invention, alkaline aqueous solution be preferably alkali metal or the hydroxide of alkaline-earth metal, phosphate, carbonate or
The solution of the solution of bicarbonate, more preferably sodium bicarbonate.
Alkaline aqueous solution has preferably 7 to 10, more preferably greater than 7 and is less than or equal to the pH of 8.
According to the present invention, polar organic solvent is preferably C1-C4Alcohol, aliphatic ketone or aromatic ketone, dimethyl sulfoxide or its mixing
Thing, more preferably ethanol.
Preferably, 5 to 15 volumes, the polar organic solvent (ml) of more preferably 8 to 12 volumes is used for concentrating organic facies
Pemetrexed ester 2 (g) of 1 part by weight of titration in the residue of rear acquisition.
According to the present invention, precipitation is preferably by the mixture obtained in step c) is heated to 50 DEG C to 80 DEG C, more
The temperature of preferably 60 DEG C to 65 DEG C, is then cooled to the temperature of preferably 0 DEG C to 10 DEG C, is more preferably cooled to about 5 DEG C and comes real
Existing；This temperature preferably maintains the time of 1 to 10 hour, preferably 4 hours.
In a preferred embodiment of the present invention, it is deposited in 30 DEG C to 60 DEG C, sends out at a temperature of preferably from about 45 DEG C
Raw.
The further subject matter of the present invention is by said method obtainable pemetrexed diethylester 2.
The further subject matter of the present invention is the pemetrexed diethylester 2 of crystal form.
The pemetrexed diethylester 2 of crystal form is preferably characterized in that the purity being more than 99.0% by weight.
The purity of pemetrexed diethylester 2 can be evaluated by methods known in the art.Such as, the following provide in basis
The HPLC method used between the development period of the method for the present invention.
Operating condition
Gradient program:
Accompanying drawing explanation
Fig. 1 shows by analysis method described above, by analyzing the pemetrexed that the method according to the invention obtains
The HPLC purity curve that diethylester 2 obtains.
Fig. 2 shows the PXRD diffraction pattern of the pemetrexed diethylester 2 of crystal form.
Fig. 3 shows the FT-IR curve of the pemetrexed diethylester 2 of crystal form.
Fig. 4 shows the DSC curve of the pemetrexed diethylester 2 of crystal form.
Fig. 5 shows the TGA curve of the pemetrexed diethylester 2 of crystal form.
Fig. 6 shows the chromatogram curve by being obtained, described training by described HPLC methods analyst pemetrexed disodium 5
U.S. bent plug disodium salt 5 is obtained by the method according to the invention.
Detailed description of the invention
Fig. 1 shows by analysis method described above, by analyzing the pemetrexed that the method according to the invention obtains
The HPLC purity curve that diethylester 2 obtains.
The pemetrexed diethylester 2 of crystal form is preferably characterized with PXRD diffraction pattern, provides its feature in table 1
Peak.
Table 1
Particularly, the pemetrexed diethylester 2 of crystal form is characterized with the PXRD diffraction pattern including following main peaks:
3.48；4.32；6.32；6.88；7.83；8.51；9.25；10.36；11.55；13.86；14.89；16.64；17.50；18.55；
19.76；21.30；21.75；29.58 ± 0.1 2 θ, preferably as shown in Figure 2 PXRD diffraction pattern.
The pemetrexed diethylester 2 of crystal form is also to include that the FT-IR curve of following main peaks is characterized: 3456；
3440；3321；3193；2981；2931；2910；2875；2807；2763；1731；1673；1634；1609；1582；1530；
1505；1480；1445；1374；1355；1318；1202；1187；1167；1158；1104；1023；833.6；783.4；
762.2；725.5；679.2±2cm-1, FT-IR curve preferably as shown in Figure 3.
The pemetrexed diethylester 2 of crystal form is also characterized with DSC curve, and this DSC curve shows the heat release of 143.2 DEG C
Peak, 135.7 DEG C of beginnings；The endothermic peak of 151.7 DEG C, 148.4 DEG C of beginnings；The exothermic peak of 174.0 DEG C, 170.7 DEG C of beginnings,
DSC curve preferably as shown in Figure 4, and/or be characterized with TGA curve, TGA curve preferably as shown in Figure 5.
Then, it has therefore been surprisingly found that prepared by the method for the present invention and there is the purity being more than 99.0% by weight
The pemetrexed diethylester 2 of crystal form it can be made to use same as before, to prepare pemetrexed disodium 5；That is, need not
Must be purified by such as preparing derivant or the salt of salt such as p-methyl benzenesulfonic acid as known in the art.
Then it was unexpectedly observed that the availability with the pemetrexed diethylester 2 of highly purified crystal form makes training U.S. bent
Plug disodium salt 5 can be obtained by single synthesis step, and quality meets the demand required by active component.
In the method described in the literature, by the pemetrexed diethylester 3 of p-methyl benzenesulfonic acid salt form, first will training
Beautiful Qu Sai separates with acid form 4, is then peeled off pemetrexed disodium 5, as shown in scheme 1.
According in the method preparing pemetrexed disodium 5 of the present invention, the fact that do not use p-methyl benzenesulfonic acid it is super
Cross the advantage of prior art, because it is it can be avoided that p-toluenesulfonic esters is formed as possible by-product.It is true that aryl sulphur
Acid esters and alkyl sulfonic ester, the clearest and the most definite p-toluenesulfonic esters, it is categorized into genotoxic alkylating agent material, it is by each
Acid formed by reacting with alcohol.In active constituents of medicine, their content (sees in being reduced to low-down limit
Genotoxic and carcinogenic impurities in drug substances:recommended
Approaches (in medicine genetoxic and the impurity of carcinogenecity: the method for recommendation) FDA 2008).
Therefore, the further subject matter of the present invention is the method preparing disodium salt 5
It includes the above-mentioned method preparing pemetrexed diethylester 2.
In a preferred embodiment in accordance with this invention, the method preparing disodium salt 5 comprises the following steps:
E) pemetrexed diethylester 2 is dissolved in the mixing of protic polar organic solvents and/or protic polar organic solvents
In thing, and
F) hydrolyze subsequently.
According to the present invention, protic polar organic solvents is preferably C1-C4Alcohol, more preferably ethanol.
According to the present invention, hydrolysis preferably basic hydrolysis, more preferably with the aqueous solution of basic sodium salt, even more preferably from sodium hydroxide
The basic hydrolysis that carries out of aqueous solution.
Aqueous solution has preferably 10 to 13, the pH of more preferably 12 to 13.
The further subject matter of the present invention is by the obtainable pemetrexed disodium of said method 5.
The further subject matter of the present invention is the pemetrexed disodium 5 of the purity with preferably greater than 99.7%.
The purity of pemetrexed disodium 5 can be evaluated by methods known in the art.For example, it may be possible, using with carry above
Confession for analyzing the HPLC method that the method for pemetrexed diethylester 2 is identical.
Fig. 6 shows the chromatogram curve by being obtained by described HPLC methods analyst pemetrexed disodium 5, described
Pemetrexed disodium 5 is obtained by the method according to the invention.
According to a preferred aspect of the present invention, by the protic polar organic solvents (ml) of 5 to 8 volumes, preferably 6 to 7 bodies
Long-pending, for pemetrexed diethylester 2 (g) of 1 part by weight.
A further preferred aspect according to the present invention, every volume polar organic solvent (ml) uses 0.5 to 2 volume
Alkaline aqueous solution (ml), preferably 0.7 to 1.3 volume.
By pemetrexed diethylester 2, obtain the pemetrexed two of the quality being applicable to active component with one step
The ability of sodium salt 5 can produce shorter range sequence, and produces the less operation relating to processing cytotoxic compound, and suddenly
The probability of the reduction of product (it is sensitive to air) signs of degradation occurs, and its quality may be had by product degradation phenomenon
Adverse effect.
Following example provide the detailed description of the method that the present invention relates to, and constitute the limit to it never in any form
System.
Embodiment
Embodiment 1
Pemetrexed diethylester 2 (N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-
5-yl) ethyl] benzoyl] diethylester of-Pidolidone) preparation
By 200ml dimethylformamide, the N-methylmorpholine being followed by 200ml dichloromethane and 18.5g joins loading
Maintain 50g 4-in 2000ml flask in a nitrogen atmosphere [2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,
3-d] pyrimidine-5-base) ethyl] benzoic acid.The temperature making the mixture of acquisition reaches 5 ± 2 DEG C, and the time of about 1 hour
In, include 31.7g 2-chlorine-4,6-dimethoxy-1,3,5-triazine, 100ml dimethylformamide to what its addition was additionally prepared
With the solution of 200ml dichloromethane, temperature is maintained 5 ± 2 DEG C simultaneously.Then, temperature is maintained 5 ± 2 DEG C and continues another
Hour, and while being still maintained at 5 ± 2 DEG C, within the time of about 40 minutes, add and be included in 100ml dimethyl methyl
The solution of the 43.5g Pidolidone diethylester hydrochlorate in amide.After this adds, immediately by 18.5g N-methyl
Quinoline is poured in reactant mixture.Make temperature rise to 20 ± 2 DEG C within the time of about 30 minutes, maintain these conditions three hours.So
After, 500ml dichloromethane is joined in reactant mixture, and within the time of about 15 minutes, the mixture of acquisition is poured into
In solution including 500ml deionized water and 500ml 10% sodium bicarbonate solution.Overall stirring 10 minutes at 20 ± 2 DEG C,
Then stand each phase to separate.Suitable with 500ml deionized water, 500ml 10% sodium bicarbonate aqueous solution and 1000ml deionized water
Secondary washing lower floor organic facies.The organic facies that evaporation obtains, the grease easily stirred (residue weight 390g).Will
1000ml dehydrated alcohol adds residue, and solvent distillation, with the grease (residue weight 185g) easily stirred.Will
640ml dehydrated alcohol is poured on this residue, and heats the mixture to 60-65 DEG C, to obtain settled solution.About 2
Hour time in, solution is cooled to 5 DEG C from 60-65 DEG C, maintains stirring at such a temperature, continue 4 hours.At about 45 DEG C
Under, white solid starts precipitation.When at the end of the maintenance of 5 DEG C, leach gained solid through Gooch filter, and with two parts of 50ml without
Water-ethanol is 5 DEG C of washings.After (1mbar) is dried 16 hours at 60 DEG C under vacuo, it is thus achieved that 48.3g desired product (yield
63%).
Analyze products therefrom by PXRD, DSC, TGA and IR, and the data obtained can be with the N-[4-about crystal form
[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base) ethyl] benzoyl]-Pidolidone
The data overlap of Fig. 1 of diethylester, 2,3 and 4.The HPLC purity of the product obtained is more than 99.0%.
Embodiment 2
Pemetrexed disodium 5 (N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-
5-yl) ethyl] benzoyl]-Pidolidone disodium salt) preparation
By 56g N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base) ethyl]
Benzoyl]-Pidolidone diethylester and 360ml degassed absolute ethanol introduce in 2000ml flask.
Mixture is placed in 20 ± 2 DEG C, stirring under, and within the time of about 10 minutes to its add 360ml 1M hydrogen-oxygen
Change sodium water solution (being prepared by deionised degassed water and sodium hydroxide pearl).
Mixture is under agitation maintained 20 ± 2 DEG C, continues 3 hours, it was observed that solid is completely dissolved, and the most still exists
20 ± 2 DEG C, add 1M HCl/water solution, until the pH value of mixture reaches 8.1 ± 0.1 (about 100ml).Mixture is micro-through 0.45
Filter filters, and 900ml degassed absolute ethanol and 125ml deionised degassed water are added filtrate.Filtrate is heated to 55 DEG C, and
Maintain under those circumstances, continue 10 minutes.Then, within the time of about 1 hour, solution is cooled to 20 ± 2 DEG C, and by institute
Obtain suspension and under agitation maintain other 16 hours.Then leach gained precipitation, and wash by 2 parts of 200ml degassed absolute ethanol.
Discharge solid, and be dried 3 hours at 60 DEG C under vacuum (1mbar).It is derived from 54g pemetrexed disodium 5 (yield
90%).
The product purity evaluated by HPLC is more than 99.7%.
Embodiment 3
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d]-pyrimidine-5-base) ethyl] benzene first
Acyl group] preparation of-Pidolidone diethylester
To load maintain 3000ml reactor under nitrogen atmosphere 60g 4-[2-(2-amino-4,7-dihydro-4-oxo-
1H-pyrrolo-[2,3-d]-pyrimidine-5-base) ethyl] benzoic acid adds 240ml dimethylformamide, it is subsequently added 240ml bis-
Chloromethanes and 22.3g N-Methyl-morpholine.The temperature making mixture reaches 5 ± 2 DEG C, and will be by 38.7g 2-chloro-4,6-diformazan
Oxy-1, the solution that 3,5-triazine, 120ml dimethylformamide and 240ml dichloromethane are additionally prepared added in about 30 minutes
Enter in this mixture, keep the internal temperature of 5 ± 2 DEG C simultaneously.Hold the mixture in 5 ± 2 DEG C and continue other 1 hour, and
At that same temperature in about 10 minutes, add the 120ml dimethylformamide of 52.8g Pidolidone diethylester hydrochlorate
Solution.After this adds, at once 22.3g N-Methyl-morpholine is joined in reactant mixture.Then by temperature about
It is increased to 20 ± 2 DEG C in 30 minutes, keeps these conditions 3 hours.Then, add 600ml dichloromethane to reactant mixture, and
In about 15 minutes, this mixture is poured into 1200ml 5% sodium bicarbonate solution.Mixture is stirred 10 minutes at 20 ± 2 DEG C,
Then each being separated is made.Lower floor's organic facies 600ml deionized water wash 2 times.Thus obtained organic facies (obtains 40 DEG C of distillations
Obtain about 700ml distillate), stay can well-stirred residue, to its add 1800ml dehydrated alcohol.Mixture is at T=78
DEG C distillation (reclaiming about 900ml solvent).Then, add other 900ml dehydrated alcohol, and distill out about 900ml at T=78 DEG C
Solvent.Gained solution is cooled to 5 DEG C, maintains 4 hours at this temperature.At about 45 DEG C, white solid starts precipitation.Obtain
Solid above filters at Gooch filter (gooch), and with two parts of 60ml dehydrated alcohol 5 DEG C of washings.At 60 DEG C at vacuum (1mbar)
Under be dried 16 hours after, it is thus achieved that the desired product of 74g (yield 80%).
Products therefrom is analyzed by PXRD, DSC, TGA and IR.The data obtained and the N-[4-[2-about crystal form A
(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d] pyrimidine-5-base) ethyl] benzoyl]-Pidolidone diethyl
The data of Fig. 1 of ester, 2,3 and 4 are suitable.The HPLC purity of products therefrom is > 99.5%.
Embodiment 4
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-d]-pyrimidine-5-base) ethyl] benzene first
Acyl group] preparation of-Pidolidone disodium salt (pemetrexed disodium)
70g N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo-[2,3-is loaded in 2000ml flask
D]-pyrimidine-5-base) ethyl] benzoyl]-Pidolidone diethylester and 460ml degassed absolute ethanol.
Make the temperature that mixture reaches 10 ± 2 DEG C under an inert atmosphere, then add 760ml0.6M sodium hydroxide water to it
Solution (is prepared by deionised degassed water and sodium hydroxide pearl).
The temperature of mixture was risen to 20 DEG C in about 30 minutes, then maintains 1 hour.Then 1M HCl/water solution is added
Enter mixture, until the pH of mixture reaches the value (about 100ml) of 7.9 ± 0.1.Heat the mixture to 55 ± 2 DEG C, then lead to
Cross 0.45 microstrainer to filter, at T=55 DEG C, to filtrate addition 1130ml degassed absolute ethanol, and by mixture with this understanding
Maintain 10 minutes.In about 1 hour, solution is cooled to 20 ± 2 DEG C, and gained suspension is kept stirring for other 4 hour.
Then, filter gained precipitation, and wash by two parts of 200ml degassed absolute ethanol.Take off solid, and under vacuum (1mbar)
35 DEG C are dried 3 hours, are then dried 3 hours at 50 DEG C.In this way, it is thus achieved that 64g pemetrexed disodium (yield 86%).
The product purity evaluated by HPLC > 99.8%.
PXRD (powder X-ray diffraction)
Experiment condition
FTIR(ATR)
Experiment condition
DSC/TGA
Experiment condition
Claims (12)
1. the method preparing pemetrexed diethylester 2
Described method includes being purified by aprotic organic solvent, can promote the existence of chemical agent that peptide bond is formed
Under, the step of the mixture that compound 1 and 1a reaction obtains,
It is characterized in that, described mixture stands following steps:
A) washing with alkaline aqueous solution, described alkaline aqueous solution has the pH of 7 to 10；
B) organic facies is concentrated；
C) adding polar organic solvent, described polar organic solvent is ethanol；
D) precipitation pemetrexed diethylester 2, described precipitation is by the mixture obtained in step c) is heated to 50 DEG C extremely
The temperature of 80 DEG C, the temperature being then cooled to 0 DEG C to 10 DEG C realizes.
Method the most according to claim 1, it is characterised in that described alkaline aqueous solution has more than 7 and less than or equal to 8
PH.
Method the most according to claim 1, it is characterised in that described heating is heated to the temperature of 60 DEG C to 65 DEG C.
Method the most according to claim 1, it is characterised in that described cooling is to be cooled to 5 DEG C.
Method the most according to claim 1, it is characterised in that described in be deposited at a temperature of 30 DEG C to 60 DEG C occur.
Method the most according to claim 5, it is characterised in that described in be deposited at a temperature of 45 DEG C occur.
7. the method preparing disodium salt 5
Including the method preparing pemetrexed diethylester 2 according to any one of claim 1 to 6, wherein prepare disodium
The described method of salt 5 is further comprising the steps of:
E) described pemetrexed diethylester 2 is dissolved in the mixing of protic polar organic solvents and/or protic polar organic solvents
In thing, and
F) hydrolyze subsequently.
Method the most according to claim 7, it is characterised in that described protic polar organic solvents is C1-C4Alcohol.
Method the most according to claim 8, it is characterised in that described protic polar organic solvents is ethanol.
Method the most according to claim 7, it is characterised in that described hydrolysis is basic hydrolysis.
11. methods according to claim 10, it is characterised in that described hydrolysis is the aqueous solution with the pH with 10 to 13
Obtain.
12. methods according to claim 10, it is characterised in that described hydrolysis is the aqueous solution with the pH with 12 to 13
Obtain.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2010A001351A IT1401677B1 (en) | 2010-07-22 | 2010-07-22 | NEW PROCESS FOR THE SYNTHESIS OF PEMETREXED DISODIUM SALT |
| ITMI2010A001351 | 2010-07-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102344452A CN102344452A (en) | 2012-02-08 |
| CN102344452B true CN102344452B (en) | 2016-12-14 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000011004A1 (en) * | 1998-08-21 | 2000-03-02 | The Trustees Of Princeton University | Process for the preparation of pyrrolo[2,3-d]pyrimidines |
| CN1821219A (en) * | 2006-03-29 | 2006-08-23 | 浙江工业大学 | Diethyl 4(4-oxobutyl) benzoyl-L-glutamate and its preparation and use |
| CN1840530A (en) * | 2005-03-28 | 2006-10-04 | 齐鲁制药有限公司 | Process for preparing pemetrexed |
| CN101560206A (en) * | 2009-05-21 | 2009-10-21 | 苏州立新制药有限公司 | Intermediate of pemetrexed disodium, preparation method thereof and method for preparing pemetrexed disodium thereby |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000011004A1 (en) * | 1998-08-21 | 2000-03-02 | The Trustees Of Princeton University | Process for the preparation of pyrrolo[2,3-d]pyrimidines |
| CN1840530A (en) * | 2005-03-28 | 2006-10-04 | 齐鲁制药有限公司 | Process for preparing pemetrexed |
| CN1821219A (en) * | 2006-03-29 | 2006-08-23 | 浙江工业大学 | Diethyl 4(4-oxobutyl) benzoyl-L-glutamate and its preparation and use |
| CN101560206A (en) * | 2009-05-21 | 2009-10-21 | 苏州立新制药有限公司 | Intermediate of pemetrexed disodium, preparation method thereof and method for preparing pemetrexed disodium thereby |
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