CN101948436B - Method for preparing high-purity bendamustine hydrochloride - Google Patents
Method for preparing high-purity bendamustine hydrochloride Download PDFInfo
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- CN101948436B CN101948436B CN 201010212009 CN201010212009A CN101948436B CN 101948436 B CN101948436 B CN 101948436B CN 201010212009 CN201010212009 CN 201010212009 CN 201010212009 A CN201010212009 A CN 201010212009A CN 101948436 B CN101948436 B CN 101948436B
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- methyl
- amino
- benzoglyoxaline
- butyrate
- ethyl
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- ZHSKUOZOLHMKEA-UHFFFAOYSA-N 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid;hydron;chloride Chemical compound Cl.ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 ZHSKUOZOLHMKEA-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 229960001215 bendamustine hydrochloride Drugs 0.000 title claims abstract description 75
- 238000000034 method Methods 0.000 title abstract description 18
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims abstract description 193
- 239000007787 solid Substances 0.000 claims abstract description 148
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 91
- 238000003756 stirring Methods 0.000 claims abstract description 91
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 70
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000002425 crystallisation Methods 0.000 claims abstract description 23
- 230000008025 crystallization Effects 0.000 claims abstract description 23
- 238000001914 filtration Methods 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 134
- 238000002360 preparation method Methods 0.000 claims description 62
- 239000008213 purified water Substances 0.000 claims description 50
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- 229960002707 bendamustine Drugs 0.000 claims description 31
- 238000009413 insulation Methods 0.000 claims description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 27
- 238000007605 air drying Methods 0.000 claims description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 23
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 claims description 22
- 238000010992 reflux Methods 0.000 claims description 21
- 238000001816 cooling Methods 0.000 claims description 20
- 239000012530 fluid Substances 0.000 claims description 19
- 238000010438 heat treatment Methods 0.000 claims description 19
- 238000010907 mechanical stirring Methods 0.000 claims description 19
- 238000001291 vacuum drying Methods 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 11
- 239000012044 organic layer Substances 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 6
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 6
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 5
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 5
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 5
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 3
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 239000008247 solid mixture Substances 0.000 claims 1
- 239000000243 solution Substances 0.000 abstract description 36
- 239000000047 product Substances 0.000 abstract description 19
- -1 alkyl acetate Chemical compound 0.000 abstract description 12
- 239000012535 impurity Substances 0.000 abstract description 10
- 230000008901 benefit Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 238000007670 refining Methods 0.000 abstract description 3
- 238000005660 chlorination reaction Methods 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 abstract 2
- 239000011259 mixed solution Substances 0.000 abstract 2
- 150000003839 salts Chemical class 0.000 abstract 2
- 238000004090 dissolution Methods 0.000 abstract 1
- 229930195733 hydrocarbon Natural products 0.000 abstract 1
- 150000002430 hydrocarbons Chemical class 0.000 abstract 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 19
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 239000000543 intermediate Substances 0.000 description 12
- 239000002994 raw material Substances 0.000 description 9
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 229960005243 carmustine Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000002932 luster Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 229960001924 melphalan Drugs 0.000 description 4
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 3
- 229960004618 prednisone Drugs 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000000824 cytostatic agent Substances 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 2
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 0 C*(C(*)=*c1c2)c1ccc2N Chemical compound C*(C(*)=*c1c2)c1ccc2N 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010025327 Lymphopenia Diseases 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
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- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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- 230000001085 cytostatic effect Effects 0.000 description 1
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- 235000019441 ethanol Nutrition 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
- 231100001023 lymphopenia Toxicity 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 238000012009 microbiological test Methods 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for preparing high-purity bendamustine hydrochloride. The method comprises the following steps of: (1) completely dissolving oily or colloidal 4-{5-[bis-(2-ethoxyl)amino]-1-methyl-2 benzimidazole}ethyl butyrate in 0.1 to 0.5g/ml solution of C1 to C4 alkyl acetate, wherein the dissolution temperature is 0 to 40 DEG C; (2) adding C5 to C8 hydrocarbons into the solution obtained in the step (1) dropwise, stirring the mixed solution at the temperature of between 10 DEG C below zero and 40 DEG C for crystallization, filtering the mixed solution to obtain solids of 4-{5-[bis-(2-ethoxyl)amino]-1-methyl-2 benzimidazole}ethyl butyrate; (3) performing chlorination on the solids of 4-{5-[bis-(2-ethoxyl)amino]-1-methyl-2 benzimidazole}ethyl butyrate obtained in the step 2 and thionyl chloride, performing hydrolysis by using concentrated hydrochloric acid to obtain salts, and purifying the salts to obtain the crude products of bendamustine hydrochloride; and (4) refining the crude products of bendamustine hydrochloride obtained in the step 3 by using water to obtain the finished products of bendamustine hydrochloride. The purity of the products prepared by the method of the invention is over 99.5 percent, and the content of single impurity is below 0.1 percent; and the method has the advantages of high yield, high product stability and suitability for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of high-purity hydrochloric acid bendamustine, belong to medical production technical field.
Background technology
Bendamustine hydrochloride, chemical being called [1-methyl-2-(4 '-the butyric acid base)-5-N, N '-two-(2 '-chloroethyl)]-1H-benzoglyoxaline hydrochloride, structural formula is:
Bendamustine hydrochloride early than the initial stage sixties 19th century by Ozegowski and the microbiological test association development of its colleague at Jena, Germany.The synthetic purpose is to make a kind of alkylation mustargen (a kind of NOT-function alkylating agent) connect a purine and amino acid.New synthetic compound is compared main advantage with TV be the water-soluble of it.Anger et al. discloses the initial clinical effectiveness of bendamustine to plasmoma patient successful Application.Bendamustine is produced by Jenapharm GmbH & Co. KG with the trade(brand)name of Cytostasan from 1971 by 1992.After 1993, this cytostatic agent is by the trade(brand)name list marketing of ribosepharm GmbH company with Ribomustine.
These article are used for Hodgkin, non Hodgkin lymphoma, multiple myeloma, CLL and mammary cancer.Its dosage leukemia is 50～60mg/m2/d, and 3～5 days or per 3～4 weeks are 100～120mg/m2; Per 4 weeks of solid tumor are 120～150mg/m2, every day 1 time, 30～60min intravenous drip.Bendamustine hydrochloride as single with or combined chemotherapy, the therapeutic response rate of Hodgkin and non Hodgkin lymphoma is respectively 61%～97% and 41%～48%.To the myelomatosis multiplex people, the complete reaction rate higher (32%) of bendamustine/prednisone treatment, melphalan/prednisone therapy reaction is more lasting.In endoxan, vincristine(VCR), prednisone regimen, bendamustine replaces endoxan, and low toxicity non Hodgkin lymphoma in the development is had similar reactivity.In endoxan, methotrexate, fluorouracil in treatment scheme, bendamustine replaces endoxan, makes metastatic breast cancer patient's catabasis extend to 15.2 months from 6.2 months.
Bendamustine hydrochloride is the dual-functional group alkylating agent, and external have cytotoxicity to HOC and mammary cancer, and external have the part cross tolerance with endoxan, melphalan (melphalan), carmustine (carmustine) and cis-platinum.To the cytostatic IC50 of breast cancer cell line MCF7 is 138 μ mol/L, is 157 μ mol/L to the IC50 of cis-platinum resistance ovarian cancer cell line A27802CP2, is 187 μ mol/L to the IC50 of Dx resistance breast cancer cell line MCF7AD.Waiting under the toxic concentration (IC50s), bendamustine causes more dna double spiral fracture than melphalan, endoxan or carmustine, and is more lasting than carmustine or endoxan effect.External B2 chronic lymphocytic leukemia (B2CLL) apoptosis that causes concentration dependent, (fludarabine) share with fludarabine, and apoptosis rate is high 1.4 times in 48h.In the I clinical trial phase, bendamustine 60～8,0mg,/m2 1 time weekly to 8 weeks, causes persistent full lymphopenia to the refractory solid tumors patient, is mainly the B cytotoxicity.After 4 weeks, peripheral blood B cell, nk cell and T cell descend respectively more than 90%, 70% and 60%.
Report that the earliest bendamustine hydrochloride synthetic document is Journal fur praktische Chemie.4.Reihe.Band 20,166-177 (1963) and Journal fur praktische Chemie.4.Reihe.Band 20,178-186 (1963).The synthetic of relevant bendamustine hydrochloride also can be with reference to German patent DE 159877 (1983).
German patent DE 34727 discloses a kind of preparation method of bendamustine verivate, and different with the bendamustine structure is the substituting group on 1.
The synthetic route basically identical of the disclosed bendamustine hydrochloride of existing literature; All with 2, the 4-DNCB is that starting raw material obtains the title product bendamustine hydrochloride through replacement, reduction, acidylate, cyclization, nitroreduction, replacement, chloro, hydrolysis, salt-forming reaction.Synthetic route is following:
Above-mentioned reaction process midbody 7 chemistry are by name: 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } ethyl n-butyrate; The midbody 7 of bibliographical information all exists with oily matter or gluey form, and not only purity is low, poor stability; Can not satisfy necessary storage stability; In the preservation process, cause purity to descend inevitably, similar substance content increases, color burn etc.; Midbody 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline by oily matter or gluey form } ethyl n-butyrate is extremely low through the bendamustine hydrochloride yield that chloro, hydrolysis salify make; And can make the purity of finished product reach 99% reluctantly through recrystallization method repeatedly; But to continue to improve very difficulty of its purity on this basis; Especially needing single Control of Impurities is being to be beyond one's reach below 0.1%; Be difficult to satisfy the specification of quality of injection raw material; Do not reach the correlation technique requirement of the quality approach technical director of European Union principle ICH equally, make the research and development stagnation of bendamustine hydrochloride injection, make the bendamustine hydrochloride bulk drug can not be exported to American-European countries.
Summary of the invention
The objective of the invention is to overcome the weak point that exists in the prior art, a kind of preparation method of high-purity hydrochloric acid bendamustine is provided.
The preparation method of highly purified bendamustine hydrochloride of the present invention may further comprise the steps:
(1) with oily or gelationus 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } ethyl n-butyrate is dissolved in the C that concentration is 0.1g/ml～0.5g/ml fully
1-4Acetate alkyl ester solution, solvent temperature are 0～40 ℃;
(2) in the solution in (1) step, drip C
5-8Hydrocarbon-10～40 ℃ of following stirring and crystallizing, is crossed and is filtered 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } the ethyl n-butyrate solid;
(3) with 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline in (2) step } ethyl n-butyrate solid and sulfur oxychloride carry out chlorination, and pass through concentrated hydrochloric acid hydrolysis salify and purification again and make the bendamustine hydrochloride bullion;
(4) with (3) step in the bendamustine hydrochloride bullion through purification the bendamustine hydrochloride finished product.
Preferably, said C
1-4Alkyl acetates is selected from one or more in methyl acetate, ETHYLE ACETATE, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, the tert.-butyl acetate;
Said C
5-8Hydrocarbon is selected from one or more in Skellysolve A, normal hexane, normal heptane, octane, 2-methylpentane, benzene, toluene, the m-xylene;
C
5-8Hydrocarbon and C
1-4The volume ratio of alkyl acetates is (1～10): 1.
Wherein said C
5-8Hydrocarbon is a latent solvent, all belongs to non-polar solvent, adds C
1-4The product crystallization is come out, and impurity is stayed in the solvent, has reached the effect of purify intermediates.
The present invention is through a large amount of experimental studies; Study the relation of each midbody and finished product purity and yield one by one, confirm that finally the purity of bendamustine hydrochloride synthetic intermediate 7 (chemistry is by name: 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } ethyl n-butyrate) will directly influence the purity and the yield of finished product; Midbody 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } control of purity of ethyl n-butyrate seems particularly crucial, if it is very low to control the bad synthesis yield that will cause, and influence end product quality also can't purifying.Former technology is improved; To improve its synthesis yield; Avoid product to need purified troublesome operation repeatedly, and make through refining bendamustine hydrochloride finished product purity once and reach more than 99%, single Control of Impurities seems particularly important the production technology 0.1% below exploitation.
Oily or gelationus 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } ethyl n-butyrate detects purity through HPLC and has only about 78%; Color is dark red brown, and in the room temperature put procedure, color and luster adds the plutonic aterrimus gradually; Purity drop has only about 50%; Detect to calculate find 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline through LC-MS } ethyl n-butyrate take place degraded destroy become 4-{5-[(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline ethyl n-butyrate or 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate (midbody 6).
Degradation impurity 4-{5-[(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } the ethyl n-butyrate chemical structural formula is:
Degradation impurity 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate (midbody 6 raw materials) chemical structural formula is:
Adopting oily or gelationus 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } ethyl n-butyrate (HPLC purity about 78%) carries out the bendamustine hydrochloride that chloro, concentrated hydrochloric acid hydrolysis salify, water once make through sulfur oxychloride; Product purity has only 96%; Maximum single assorted is 2.5%, yield about 15% (in 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } ethyl n-butyrate); Product is made with extra care for twice through water again, and it is 99% that product purity can reach, and maximum single assorted 0.6%.Because bendamustine hydrochloride produces destruction in water, twice yield of re-refining also has only about 50%, and the entire reaction yield is extremely low, is difficult to clinical enough samples and the up-to-standard sample of providing, and technology also is difficult to amplify industrialization.
The present invention is through to oily or gelationus midbody 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } ethyl n-butyrate makes with extra care; Improve its purity; Carry out chloro, concentrated hydrochloric acid hydrolysis salify, water through sulfur oxychloride again and once make the bendamustine hydrochloride finished product; The invention solves oily or gluey midbody 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } ethyl n-butyrate purity is low, shelf-stability is poor, the high problem of prepared bendamustine hydrochloride related substance, has following technique effect:
1) bendamustine hydrochloride finished product purity can reach more than 99.5%, maximum single assorted caning be controlled in below 0.1%, yield about 68% (in 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } ethyl n-butyrate).Improve product purity, simplified operation, made product purity can satisfy the specification of quality of injection raw material, reached the correlation technique requirement of the quality approach technical director of European Union principle ICH equally, satisfied the technical requirements of bendamustine hydrochloride bulk drug outlet; For the research of hydrochloride for injection bendamustine up-to-standard starting material are provided simultaneously.
2) in addition; Midbody 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline of handling through the present invention } the ethyl n-butyrate proterties is faint yellow to white solid; Its purity is not less than 98%; In room temperature shelf-stability investigation process, considerable change does not all take place in its proterties, purity etc., effectively raises the stability of this midbody.This provides very big benefit to scheduling of production, need not step reaction down immediately after this intermediate preparation finishes, and brings very big benefit simultaneously for next step accurately feeds intake, quantitative mol ratio feeds intake etc.
3) the pharmaceutical prepn impurity that adopts method of the present invention to process is few, good effect, and untoward reaction is low, for tumour patient brings maximum benefit.
Embodiment
Come the present invention is done further detailed description below in conjunction with embodiment.
Among the embodiment, oily or gelationus 4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline } but 2007 the 16th volume the 23rd phases (1960-1961) of ethyl n-butyrate reference " Chinese Journal of New Drugs " or Journal fur praktische Chemie.4.Reihe.Band 20.1963 (178-186) make;
4-{5-[two-(2-hydroxyethyl) amino]-1-methyl-2 benzoglyoxaline by solid-state form } but ethyl n-butyrate and sulfur oxychloride carry out chloro, concentrated hydrochloric acid hydrolysis salify, crystal's system also reference " Chinese Journal of New Drugs " 2007 the 16th volume the 23rd phase (1960-1961) or Journal furpraktische Chemie.4.Reihe.Band 20.1963 (178-186) and prepare highly purified bendamustine hydrochloride.
The preparation of embodiment 1 oily or gelationus 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (midbody)
Oily or gelationus 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (midbody) but reference literature Journal fur praktische Chemie.4.Reihe.Band20.1963 (178-186) make, also can be with reference to the preparation of following method:
(1) preparation of N-methyl-(2, the 4-dinitrobenzene) aniline (midbody 1)
With 2,4-DNCB 438g, methylamine hydrochloride 141g, sodium acetate trihydrate 573g and N, dinethylformamide 1050ml join in the 3L there-necked flask, reflux, stirring reaction 3h, stopped reaction behind the no raw material of TLC detection.Pour into fast in the 3000ml frozen water after reaction solution is cold slightly, leave standstill crystallization.Filter, filter cake removes DMF with the suitable quantity of water eccysis, and filter cake is in 80 ℃ of forced air dryings.Obtain yellow solid 397.3g (midbody 1), yield: 93.3%, mp:178.6～179 ℃.
(2) preparation of 2-methylamino--4-N-methyl-p-nitroaniline (midbody 2)
200g midbody 1 and 3680ml methyl alcohol are joined in the 5L there-necked flask; Stir adding 650g nine hydrated sodium sulfides down, be warming up to 50 ℃, add the solution that 227.2g sodium hydrogencarbonate and 1000ml purified water prepare; Be warming up to backflow 4h, stopped reaction behind the no raw material of TLC detection.Residue is poured in the 2000ml frozen water, and crystallization filters, washing, and the solid that obtains obtains red-purple solid 125g (midbody 2), yield in 80 ℃ of forced air dryings: 73.5%, mp:176～178 ℃.
(3) preparation of [(2-methylamino--5 nitro) phenyl] monoamide butyric acid (midbody 3)
With 120g midbody 2,81g Pyroglutaric acid and 840ml toluene join in the 2L there-necked flask, are warming up to backflow, and reaction 40min is after TLC detection raw material reaction is complete.Be cooled to room temperature, filter, filter cake washs with an amount of ETHYLE ACETATE, gets filter cake and obtains yellow powder shape solid 148.3g (midbody 3), yield: 73.5% in 80 ℃ of forced air dryings
(4) preparation of 5-nitro-1-methyl-2-benzoglyoxaline butyric acid (midbody 4)
The 3NHCl solution of 140g midbody 3 and 2200ml is joined in the 3L there-necked flask, be warming up to backflow, reaction 4h is after raw material reaction is complete; Add gac 14g, stir 15min, filtered while hot; After the filtrating cooling, regulate pH to 4～5, separate out pale brown look solid with strong aqua; Filter, filter cake is with an amount of washing, and the solid that obtains is in 80 ℃ of forced air dryings.Obtain pale brown look solid 116g (midbody 4), yield: 88.5%, mp:209～210 ℃
Ultimate analysis (C
12H
13N
3O
4(263.3)) theory: C 54.74; H 4.97; N 15.96;
Actual measurement: C 54.71; H 4.91; N 15.89;
(5) preparation of 5-nitro-1-methyl-2-benzoglyoxaline ethyl n-butyrate (midbody 5)
With 70g midbody 4, the 360ml absolute ethyl alcohol joins in the 1L there-necked flask, stirs slowly to be added dropwise to the 26ml vitriol oil down; Drip and finish back adding 64.8g anhydrous magnesium sulfate, reflux 3～4 hours after reacting completely, is poured in the water while hot; Solid is dissolved entirely, transfer pH to neutral with saturated sodium bicarbonate solution, add ethyl acetate extraction, ethyl acetate layer is used anhydrous magnesium sulfate drying; Filter, filtrating concentrating obtains solid, and solid is in 50 ℃ of forced air dryings.Obtain pale solid 70.5g (midbody 5), yield: 91%, mp:108～109.4 ℃
Ultimate analysis (C
14H
17N
3O
4(291.3)) theory: C 57.72; H 5.88; N 14.43;
Actual measurement: C 54.65; H 5.86; N 14.49;
(6) preparation of 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate (midbody 6)
With 35g midbody 5, the mixed solvent of 280ml ETHYLE ACETATE/280ml methyl alcohol, the Raney's nickel catalyst of bright system joins in the reaction flask; Stir, slowly drip 85% Hydrazine Hydrate 80 38.5ml under the room temperature, drip off back room temperature reaction 3h; The complete after-filtration of raw material reaction, filtrating is concentrated into dried to the greatest extent, filters; Filter cake is used a little washing with alcohol, in 50 ℃ of forced air dryings.Get faint yellow solid 26.2g (midbody 6), yield: 83%; Mp:131～132 ℃
Ultimate analysis (C
14H
19N
3O
4, 261.3) and theory: C 64.35; H 7.33; N 16.08;
Actual measurement: C 64.27; H 7.28; N 16.12;
(7) preparation of oily or gelationus 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (midbody)
With purified water 97ml, (26.1g 0.1mol) adds in the reaction flask, stirs, and is cooled to 0～5 ℃, is added dropwise to oxyethane 25ml, dropwises 0～5 ℃ of insulation reaction 1h in back, and room temperature reaction spends the night for acetate 97ml and midbody 6.After reacting completely reaction solution is evaporated to no overhead product; Add purified water 100ml, regulate pH to 6～7,55 with sodium hydrogencarbonate and ℃ be evaporated to dried reddish-brown oily matter; Oily matter is with ETHYLE ACETATE/purified water dissolving; Isolate water, the organic layer that obtains is evaporated to dried, gets reddish-brown oily matter 24.2g;
This oily matter midbody forms gelationus 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate gradually after room temperature is placed 2 hours.
HPLC detects purity: 78.32%.
The HPLC detection method: get the about 25mg of these article, the accurate title, decide, and puts in the 25ml volumetric flask, adds a small amount of moving phase jolting earlier and make dissolving, adds mixed solvent again and be diluted to scale, shakes up, as need testing solution; Precision is measured this solution 1ml and is put in the 100ml volumetric flask, adds mixed solvent and is diluted to scale, shakes up, as contrast solution.(use octadecylsilane chemically bonded silica to be weighting agent according to chromatographic condition under the assay item; 0.05% lauryl sodium sulfate aqueous solution (with 10% phosphoric acid adjust pH to 4.0)-acetonitrile (55: 45) is a moving phase; The detection wavelength is 233nm).Get contrast solution 20 μ l and inject liquid chromatograph, regulate detection sensitivity, the peak height that makes the principal constituent chromatographic peak is 10%～25% of a full range.Precision is measured each 20 μ l of need testing solution and contrast solution again, injects liquid chromatograph respectively, 4 times of record color atlas to principal constituent peak RT.In the need testing solution color atlas if any impurity peaks, each impurity peak area with must not be greater than contrast solution main peak area, maximum single impurity must not be greater than contrast solution main peak area 1/2.
The preparation of the 4-of embodiment 2 solid forms [5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (midbody)
In oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate 23g that embodiment 1 prepares, add ETHYLE ACETATE 100ml; Room temperature (24 ℃) stirring and dissolving gets settled solution; In solution, drip normal heptane 1000ml and separate out solid, mixture continued stirring and crystallizing about 30 minutes down in room temperature 7 (24 ℃), filtered to isolate solid; 40 ℃ of forced air dryings get off-white color solid: 14.7g, yield: 64.1%;
Mp:105～106.5 ℃, HPLC purity 98.8%.
Ultimate analysis (C
18H
27N
3O
4): theory: C 61.87%; H 7.79%; N 12.02%;
Actual measurement: C 61.82%; H 7.82%; N 12.01%;
1H-NMR(CD
3OD)：
δ6.59，7.03，7.54(m，Ar-H)，δ4.12(m，2H)，δ3.76(m，2H)，δ3.62(s，3H)，δ3.54(m，2H)，δ2.55(m，2H)，δ2.25(m，2H)，δ2.03(m，2H)，2.0(s，1H)，δ1.32(s，1H)；
Stability test
4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate sample of embodiment 1 oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate and embodiment 2 solid forms was placed 3 months in room temperature, with the relatively variation of indexs such as appearance luster, related substance before the placement; Experimental result is seen table 1:
The table 1 midbody analytical results that keeps sample
The result shows: the oily 4-of embodiment 1 [5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate midbody is in the room temperature put procedure; Color and luster is deepened gradually; Purity drop, and the 4-of the solid form of embodiment 2 [5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate sample in put procedure index such as appearance luster, purity with place before do not see considerable change.
The preparation of embodiment 3 bendamustine hydrochlorides
Will be by solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (17.5g of embodiment 2 preparations; 0.05mol), methylene dichloride 350ml, add in the 1L reaction flask mechanical stirring; Be cooled to 0～5 ℃; Dripping thionyl chloride 30ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again.Be evaporated to driedly, in this viscous fluid, add concentrated hydrochloric acid 350ml, heating reflux reaction 3h adds gac 3g, stirs 10min, filtered while hot, and filtrating is concentrated into dried, and resistates is added among the purified water 50ml, stirs and separates out solid.Filter, solid obtains 15.9g bendamustine hydrochloride bullion, yield in 50 ℃ of vacuum-drying 5h: 80.6%, and purity 98.3%, maximum single assorted 0.55%.
Above-mentioned bendamustine hydrochloride bullion 15.9g is placed reaction flask, add entry 70ml, be heated to 70～80 ℃, the dissolving back adds gac 0.5g, filters cooling crystallization.Filter, the dry white solid 13.5g that gets, yield 84.9%, purity 99.68%, maximum list mixes 0.06%, total recovery: 68% (calculating with 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate).
The preparation of embodiment 4 bendamustine hydrochlorides
Add methyl acetate 30ml among gluey 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate 15g that obtains by embodiment 1 preparation method; Stirring and dissolving gets settled solution under 40 ℃ of temperature; In solution, drip normal hexane 30ml and separate out solid, mixture continued stirring and crystallizing about 30 minutes down at-10 ℃, filtered to isolate solid; 40 ℃ of forced air dryings get off-white color solid: 9.1g, yield: 60.7%; Mp:104.5～106.5 ℃, HPLC purity 98.1%.
Solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (9g with above-mentioned preparation; 0.026mol), methylene dichloride 180ml, add in the 500ml reaction flask mechanical stirring; Be cooled to 0～5 ℃; Dripping thionyl chloride 15ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again.Be evaporated to driedly, in this viscous fluid, add concentrated hydrochloric acid 180ml, heating reflux reaction 3h adds gac 3g, stirs 10min, filtered while hot, and filtrating is concentrated into dried, and resistates is added among the purified water 26ml, stirs and separates out solid.Filter, solid obtains 8.4g bendamustine hydrochloride bullion, yield in 50 ℃ of vacuum-drying 5h: 81.9%, and purity 98.5%, maximum single assorted 0.49%.
Above-mentioned bendamustine hydrochloride bullion 8.4g is placed reaction flask, add entry 40ml, be heated to 70～80 ℃, the dissolving back adds gac 0.3g, filters cooling crystallization.Filter the dry white solid 6.8g that gets, yield 81.0%, purity 99.75%, maximum single assorted 0.08%.
The preparation of embodiment 5 bendamustine hydrochlorides
Add tert.-butyl acetate 50ml among oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate 5g that obtains by embodiment 1 preparation method; Stirring and dissolving gets settled solution under 0 ℃ of temperature; In solution, drip Skellysolve A 250ml and separate out solid, mixture continued stirring and crystallizing about 30 minutes down at 9 ℃, filtered to isolate solid; 40 ℃ of forced air dryings get off-white color solid 3.4g, yield: 68%; Mp:105.2～107.1 ℃, HPLC purity 98.7%.
Solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (3.4g with above-mentioned preparation; 0.01mol), methylene dichloride 68ml, add in the 250ml reaction flask mechanical stirring; Be cooled to 0～5 ℃; Dripping thionyl chloride 5.9ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again.Be evaporated to driedly, in this viscous fluid, add concentrated hydrochloric acid 68ml, heating reflux reaction 3h adds gac 1g, stirs 10min, filtered while hot, and filtrating is concentrated into dried, and resistates is added among the purified water 10ml, stirs and separates out solid.Filter, solid obtains 3.1g bendamustine hydrochloride bullion, yield in 50 ℃ of vacuum-drying 5h: 78.5%, and purity 97.4%, maximum single assorted 0.73%.
Above-mentioned bendamustine hydrochloride bullion 3.1g is placed reaction flask, add entry 15ml, be heated to 70～80 ℃, the dissolving back adds gac 0.2g, filters cooling crystallization.Filter the dry white solid 2.5g that gets, yield 80.6%, purity 99.59%, maximum single assorted 0.09%.
The preparation of embodiment 6 bendamustine hydrochlorides
Add isopropyl acetate 25ml among oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate 5g that obtains by embodiment 1 preparation method; Stirring and dissolving gets settled solution under 10 ℃ of temperature; In solution, drip octane 200ml and separate out solid, mixture continued stirring and crystallizing about 30 minutes down at 40 ℃, filtered to isolate solid; 40 ℃ of forced air dryings get off-white color solid 2.8g, yield: 56%; Mp:105.5～107.5 ℃, HPLC purity 98.2%.
Solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (2.8g with above-mentioned preparation; 0.008mol), methylene dichloride 60ml, add in the 250ml reaction flask mechanical stirring; Be cooled to 0～5 ℃; Dripping thionyl chloride 4.8ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again.Be evaporated to driedly, in this viscous fluid, add concentrated hydrochloric acid 60ml, heating reflux reaction 3h adds gac 1g, stirs 10min, filtered while hot, and filtrating is concentrated into dried, and resistates is added among the purified water 8ml, stirs and separates out solid.Filter, solid obtains 2.6g bendamustine hydrochloride bullion, yield in 50 ℃ of vacuum-drying 5h: 82.3%, and purity 97.5%, maximum single assorted 0.72%.
Above-mentioned bendamustine hydrochloride bullion 2.6g is placed reaction flask, add entry 12ml, be heated to 70～80 ℃, the dissolving back adds gac 0.2g, filters cooling crystallization.Filter the dry white solid 2.2g that gets, yield 84.6%, purity 99.79%, maximum single assorted 0.04%.
The preparation of embodiment 7 bendamustine hydrochlorides
Add n-butyl acetate 30ml among gluey 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate 10g that obtains by embodiment 1 preparation method; Stirring and dissolving gets settled solution under 30 ℃ of temperature; In solution, drip benzene 120ml and separate out solid, mixture continued stirring and crystallizing about 30 minutes down at 30 ℃, filtered to isolate solid; 40 ℃ of forced air dryings get off-white color solid 7.4g, yield: 74%; Mp:105.5～107 ℃, HPLC purity 98.4%.
Solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (7.4g with above-mentioned preparation; 0.021mol), methylene dichloride 150ml, add in the 500ml reaction flask mechanical stirring; Be cooled to 0～5 ℃; Dripping thionyl chloride 12.6ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again.Be evaporated to driedly, in this viscous fluid, add concentrated hydrochloric acid 150ml, heating reflux reaction 3h adds gac 2g, stirs 10min, filtered while hot, and filtrating is concentrated into dried, and resistates is added among the purified water 20ml, stirs and separates out solid.Filter, solid obtains 7.1g bendamustine hydrochloride bullion, yield in 50 ℃ of vacuum-drying 5h: 85.7%, and purity 98.9%, maximum single assorted 0.38%.
Above-mentioned bendamustine hydrochloride bullion 7.1g is placed reaction flask, add entry 30ml, be heated to 70～80 ℃, the dissolving back adds gac 0.3g, filters cooling crystallization.Filter the dry white solid 5.8g that gets, yield 81.7%, purity 99.81%, maximum single assorted 0.05%.
The preparation of embodiment 8 bendamustine hydrochlorides
Add n-propyl acetate 25ml among oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate 10g that obtains by embodiment 1 preparation method; Stirring and dissolving gets settled solution under 25 ℃ of temperature; In solution, drip toluene 50ml and separate out solid, mixture continued stirring and crystallizing about 30 minutes down at 10 ℃, filtered to isolate solid; 40 ℃ of forced air dryings get off-white color solid 6.7g, yield: 67%; Mp:106～107.5 ℃, HPLC purity 98.7%.
Solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (6.7g with above-mentioned preparation; 0.019mol), methylene dichloride 130ml, add in the 500ml reaction flask mechanical stirring; Be cooled to 0～5 ℃; Dripping thionyl chloride 11ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again.Be evaporated to driedly, in this viscous fluid, add concentrated hydrochloric acid 130ml, heating reflux reaction 3h adds gac 2g, stirs 10min, filtered while hot, and filtrating is concentrated into dried, and resistates is added among the purified water 20ml, stirs and separates out solid.Filter, solid obtains 6.2g bendamustine hydrochloride bullion, yield in 50 ℃ of vacuum-drying 5h: 82.8%, and purity 98.1%, maximum single assorted 0.38%.
Above-mentioned bendamustine hydrochloride bullion 6.2g is placed reaction flask, add entry 30ml, be heated to 70～80 ℃, the dissolving back adds gac 0.3g, filters cooling crystallization.Filter the dry white solid 5.2g that gets, yield 83.9%, purity 99.53%, maximum single assorted 0.08%.
The preparation of embodiment 9 bendamustine hydrochlorides
Add isobutyl acetate 25ml among gluey 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate 10g that obtains by embodiment 1 preparation method; Stirring and dissolving gets settled solution under 20 ℃ of temperature; In solution, drip 2-methylpentane 150ml and separate out solid, mixture continued stirring and crystallizing about 30 minutes down at 20 ℃, filtered to isolate solid; 40 ℃ of forced air dryings get off-white color solid 6.5g, yield: 65%; Mp:105.5～107.5 ℃, HPLC purity 98.5%.
Solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (6.5g with above-mentioned preparation; 0.019mol), methylene dichloride 130ml, add in the 500ml reaction flask mechanical stirring; Be cooled to 0～5 ℃; Dripping thionyl chloride 11ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again.Be evaporated to driedly, in this viscous fluid, add concentrated hydrochloric acid 130ml, heating reflux reaction 3h adds gac 3g, stirs 10min, filtered while hot, and filtrating is concentrated into dried, and resistates is added among the purified water 19ml, stirs and separates out solid.Filter, solid obtains 6.7g bendamustine hydrochloride bullion, yield in 50 ℃ of vacuum-drying 5h: 89.3%, and purity 98.1%, maximum single assorted 0.69%.
Above-mentioned bendamustine hydrochloride bullion 6.7g is placed reaction flask, add entry 28ml, be heated to 70～80 ℃, the dissolving back adds gac 0.2g, filters cooling crystallization.Filter the dry white solid 5.8g that gets, yield 86.6%, purity 99.72%, maximum single assorted 0.09%.
The preparation of embodiment 10 bendamustine hydrochlorides
Add ETHYLE ACETATE 500ml and methyl acetate 200ml among oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate 175.6g that obtains by embodiment 1 preparation method; Stirring and dissolving gets settled solution under 26 ℃ of temperature; Dropping normal heptane 2500ml and Skellysolve A 1000ml separate out solid in solution, and mixture continued stirring and crystallizing about 30 minutes down at 30 ℃, filtered to isolate solid; 40 ℃ of forced air dryings get off-white color solid 115.3g, yield: 65.7%; Mp:105～107 ℃, HPLC purity 98.1%.
Solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (115g with above-mentioned preparation; 0.329mol), methylene dichloride 2300ml, add in the 5L reaction flask mechanical stirring; Be cooled to 0～5 ℃; Dripping thionyl chloride 197ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again.Be evaporated to driedly, in this viscous fluid, add concentrated hydrochloric acid 2300ml, heating reflux reaction 3h adds gac 20g, stirs 10min, filtered while hot, and filtrating is concentrated into dried, and resistates is added among the purified water 250ml, stirs and separates out solid.Filter, solid obtains 113.7g bendamustine hydrochloride bullion, yield in 50 ℃ of vacuum-drying 5h: 87.6%, and purity 98.2%, maximum single assorted 0.82%.
Above-mentioned bendamustine hydrochloride bullion 113.7g is placed reaction flask, add entry 450ml, be heated to 70～80 ℃, the dissolving back adds gac 10g, filters cooling crystallization.Filter the dry white solid 94.5g that gets, yield 83.1%, purity 99.75%, maximum single assorted 0.04%.
The preparation of embodiment 11 bendamustine hydrochlorides
Add tert.-butyl acetate 25ml among oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate 10g that obtains by embodiment 1 preparation method; Stirring and dissolving gets settled solution under 20 ℃ of temperature; In solution, drip m-xylene 150ml and separate out solid, mixture continued stirring and crystallizing about 30 minutes down at 20 ℃, filtered to isolate solid; 40 ℃ of forced air dryings get off-white color solid 5.4g, yield: 54%; Mp:105.5～107.5 ℃, HPLC purity 98.3%.
Solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (2.9g with above-mentioned preparation; 0.009mol), methylene dichloride 60ml, add in the 250ml reaction flask mechanical stirring; Be cooled to 0～5 ℃; Dripping thionyl chloride 4.8ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again.Be evaporated to driedly, in this viscous fluid, add concentrated hydrochloric acid 60ml, heating reflux reaction 3h adds gac 1g, stirs 10min, filtered while hot, and filtrating is concentrated into dried, and resistates is added among the purified water 8ml, stirs and separates out solid.Filter, solid obtains 2.6g bendamustine hydrochloride bullion, yield in 50 ℃ of vacuum-drying 5h: 81.5%, and purity 97.2%, maximum single assorted 0.88%.
Above-mentioned bendamustine hydrochloride bullion 2.6g is placed reaction flask, add entry 12ml, be heated to 70～80 ℃, the dissolving back adds gac 0.2g, filters cooling crystallization.Filter the dry white solid 2.1g that gets, yield 80.8%, purity 99.77%, maximum single assorted 0.09%.
Reference examples is directly with oily midbody 7 preparation bendamustine hydrochlorides
Buttery midbody 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate (13g with embodiment 1 preparation; 0.037mol), methylene dichloride 260ml, add in the 1L reaction flask mechanical stirring; Be cooled to 0～5 ℃; Dripping thionyl chloride 22ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again.Be evaporated to driedly, in this viscous fluid, add concentrated hydrochloric acid 260ml, heating reflux reaction 3h adds gac 3g, stirs 10min, filtered while hot, and filtrating is concentrated into dried, and resistates is added among the purified water 37ml, stirs and separates out solid.Filter, solid obtains 3.6g bendamustine hydrochloride bullion, yield in 50 ℃ of vacuum-drying 5h: 24.7%, and purity 92.1%, maximum single assorted 3.61%.
Above-mentioned bendamustine hydrochloride bullion 3.6g is placed reaction flask, add entry 15ml, be heated to 70～80 ℃, the dissolving back adds gac 0.1g, filters cooling crystallization.Filter dry white solid 2.1g, the yield 58.3% of getting.Purity 96.41%, maximum list mixes 2.5%, total recovery: 14.4% (calculating with 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate).The 2.1g bullion is re-refined twice according to last method water, get 1.1g, yield: 52.4%, purity: 99.04%, maximum single assorted: 0.60%.
Claims (9)
1. the preparation method of a high-purity hydrochloric acid bendamustine is characterized in that, comprises following steps:
With purified water 97ml, acetate 97ml and 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate 26.1g, 0.1mol add in the reaction flask, stir; Be cooled to 0～5 ℃, be added dropwise to oxyethane 25ml, dropwise 0～5 ℃ of insulation reaction 1h in back; Room temperature reaction spends the night, and after reacting completely reaction solution is evaporated to no overhead product, adds purified water 100ml; Regulate pH to 6～7,55 with sodium hydrogencarbonate and ℃ be evaporated to dried reddish-brown oily matter, oily matter dissolves with ETHYLE ACETATE/purified water; Isolate water, the organic layer that obtains is evaporated to dried, gets reddish-brown oily matter 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 24.2g;
In oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 23g, add ETHYLE ACETATE 100ml; 24 ℃ of stirring and dissolving get settled solution; In solution, drip normal heptane 1000ml and separate out solid; Mixture continued stirring and crystallizing about 30 minutes down at 24 ℃, filtered to isolate solid, and 40 ℃ of forced air dryings get off-white color solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 14.7g;
With solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 17.5g, the methylene dichloride 350ml of preparation, add in the 1L reaction flask, mechanical stirring is cooled to 0～5 ℃; Dripping thionyl chloride 30ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again, is evaporated to dried; In this viscous fluid, add concentrated hydrochloric acid 350ml, heating reflux reaction 3h adds gac 3g, stirs 10min; Filtered while hot, filtrating is concentrated into dried, and resistates is added among the purified water 50ml, stirs and separates out solid; Filter, solid obtains 15.9g bendamustine hydrochloride bullion in 50 ℃ of vacuum-drying 5h;
Above-mentioned bendamustine hydrochloride bullion 15.9g is placed reaction flask, add entry 70ml, be heated to 70～80 ℃, dissolve the back and add gac 0.5g, filter, cooling crystallization filters, the dry bendamustine hydrochloride white solid finished product 13.5g that gets.
2. the preparation method of a high-purity hydrochloric acid bendamustine is characterized in that, comprises following steps:
With purified water 97ml, acetate 97ml and 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate 26.1g, 0.1mol add in the reaction flask, stir; Be cooled to 0～5 ℃, be added dropwise to oxyethane 25ml, dropwise 0～5 ℃ of insulation reaction 1h in back; Room temperature reaction spends the night, and after reacting completely reaction solution is evaporated to no overhead product, adds purified water 100ml; Regulate pH to 6～7 with sodium hydrogencarbonate; 55 ℃ are evaporated to dried reddish-brown oily matter, and oily matter is isolated water with ETHYLE ACETATE/purified water dissolving; The organic layer that obtains is evaporated to dried, gets reddish-brown oily matter 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 24.2g; This oily matter midbody forms gelationus 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate gradually after room temperature is placed 2 hours;
In gluey 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 15g, add methyl acetate 30ml; Stirring and dissolving gets settled solution under 40 ℃ of temperature; In solution, drip normal hexane 30ml and separate out solid; Mixture continued stirring and crystallizing about 30 minutes down at-10 ℃, filtered to isolate solid, and 40 ℃ of forced air dryings get off-white color solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 9.1g;
With solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 9g, the methylene dichloride 180ml of preparation, add in the 500ml reaction flask, mechanical stirring is cooled to 0～5 ℃; Dripping thionyl chloride 15ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again, is evaporated to dried; In this viscous fluid, add concentrated hydrochloric acid 180ml, heating reflux reaction 3h adds gac 3g, stirs 10min; Filtered while hot, filtrating is concentrated into dried, and resistates is added among the purified water 26ml, stirs and separates out solid; Filter, solid obtains 8.4g bendamustine hydrochloride bullion in 50 ℃ of vacuum-drying 5h;
Above-mentioned bendamustine hydrochloride bullion 8.4g is placed reaction flask, add entry 40ml, be heated to 70～80 ℃, the dissolving back adds gac 0.3g, filters, and cooling crystallization filters dry bendamustine hydrochloride white solid finished product 6.8g.
3. the preparation method of a high-purity hydrochloric acid bendamustine is characterized in that, comprises following steps:
With purified water 97ml, acetate 97ml and 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate 26.1g, 0.1mol add in the reaction flask, stir; Be cooled to 0～5 ℃, be added dropwise to oxyethane 25ml, dropwise 0～5 ℃ of insulation reaction 1h in back; Room temperature reaction spends the night, and after reacting completely reaction solution is evaporated to no overhead product, adds purified water 100ml; Regulate pH to 6～7,55 with sodium hydrogencarbonate and ℃ be evaporated to dried reddish-brown oily matter, oily matter dissolves with ETHYLE ACETATE/purified water; Isolate water, the organic layer that obtains is evaporated to dried, gets reddish-brown oily matter 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 24.2g;
In oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 5g, add tert.-butyl acetate 50ml; Stirring and dissolving gets settled solution under 0 ℃ of temperature; In solution, drip Skellysolve A 250ml and separate out solid; Mixture continued stirring and crystallizing about 30 minutes down at 9 ℃, filtered to isolate solid, and 40 ℃ of forced air dryings get off-white color solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 3.4g;
With solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate 3.4g of preparation, 0.01mol, methylene dichloride 68ml add in the 250ml reaction flask mechanical stirring; Be cooled to 0～5 ℃, dripping thionyl chloride 5.9ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again; Be evaporated to driedly, in this viscous fluid, add concentrated hydrochloric acid 68ml, heating reflux reaction 3h adds gac 1g; Stir 10min, filtered while hot, filtrating is concentrated into dried, and resistates is added among the purified water 10ml; Solid is separated out in stirring, filters, and solid obtains 3.1g bendamustine hydrochloride bullion in 50 ℃ of vacuum-drying 5h;
Above-mentioned bendamustine hydrochloride bullion 3.1g is placed reaction flask, add entry 15ml, be heated to 70～80 ℃, dissolve the back and add gac 0.2g, filter, cooling crystallization filters, the dry bendamustine hydrochloride white solid finished product 2.5g that gets.
4. the preparation method of a high-purity hydrochloric acid bendamustine is characterized in that, comprises following steps:
With purified water 97ml, acetate 97ml and 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate 26.1g, 0.1mol add in the reaction flask, stir; Be cooled to 0～5 ℃, be added dropwise to oxyethane 25ml, dropwise 0～5 ℃ of insulation reaction 1h in back; Room temperature reaction spends the night, and after reacting completely reaction solution is evaporated to no overhead product, adds purified water 100ml; Regulate pH to 6～7,55 with sodium hydrogencarbonate and ℃ be evaporated to dried reddish-brown oily matter, oily matter dissolves with ETHYLE ACETATE/purified water; Isolate water, the organic layer that obtains is evaporated to dried, gets reddish-brown oily matter 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 24.2g;
In oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 5g, add isopropyl acetate 25ml; Stirring and dissolving gets settled solution under 10 ℃ of temperature; In solution, drip octane 200ml and separate out solid; Mixture continued stirring and crystallizing about 30 minutes down at 40 ℃, filtered to isolate solid, and 40 ℃ of forced air dryings get off-white color solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 2.8g;
With solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 2.8g, the methylene dichloride 60ml of above-mentioned preparation, add in the 250ml reaction flask, mechanical stirring is cooled to 0～5 ℃; Dripping thionyl chloride 4.8ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again, is evaporated to dried; In this viscous fluid, add concentrated hydrochloric acid 60ml, heating reflux reaction 3h adds gac 1g, stirs 10min; Filtered while hot, filtrating is concentrated into dried, and resistates is added among the purified water 8ml, stirs and separates out solid; Filter, solid obtains 2.6g bendamustine hydrochloride bullion in 50 ℃ of vacuum-drying 5h;
Above-mentioned bendamustine hydrochloride bullion 2.6g is placed reaction flask, add entry 12ml, be heated to 70～80 ℃, dissolve the back and add gac 0.2g, filter, cooling crystallization filters, the dry bendamustine hydrochloride white solid finished product 2.2g that gets.
5. the preparation method of a high-purity hydrochloric acid bendamustine is characterized in that, comprises following steps:
With purified water 97ml, acetate 97ml and 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate 26.1g, 0.1mol add in the reaction flask, stir; Be cooled to 0～5 ℃, be added dropwise to oxyethane 25ml, dropwise 0～5 ℃ of insulation reaction 1h in back; Room temperature reaction spends the night, and after reacting completely reaction solution is evaporated to no overhead product, adds purified water 100ml; Regulate pH to 6～7,55 with sodium hydrogencarbonate and ℃ be evaporated to dried reddish-brown oily matter, oily matter dissolves with ETHYLE ACETATE/purified water; Isolate water, the organic layer that obtains is evaporated to dried, gets reddish-brown oily matter 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 24.2g; This oily matter midbody forms gelationus 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate gradually after room temperature is placed 2 hours;
In gluey 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 10g, add n-butyl acetate 30ml; Stirring and dissolving gets settled solution under 30 ℃ of temperature; In solution, drip benzene 120ml and separate out solid; Mixture continued stirring and crystallizing about 30 minutes down at 30 ℃, filtered to isolate solid, and 40 ℃ of forced air dryings get off-white color solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 7.4g;
With solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 7.4g, the methylene dichloride 150ml of above-mentioned preparation, add in the 500ml reaction flask, mechanical stirring is cooled to 0～5 ℃; Dripping thionyl chloride 12.6ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again, is evaporated to dried; In this viscous fluid, add concentrated hydrochloric acid 150ml, heating reflux reaction 3h adds gac 2g, stirs 10min; Filtered while hot, filtrating is concentrated into dried, and resistates is added among the purified water 20ml, stirs and separates out solid; Filter, solid obtains 7.1g bendamustine hydrochloride bullion in 50 ℃ of vacuum-drying 5h;
Above-mentioned bendamustine hydrochloride bullion 7.1g is placed reaction flask, add entry 30ml, be heated to 70～80 ℃, dissolve the back and add gac 0.3g, filter, cooling crystallization filters, the dry bendamustine hydrochloride white solid finished product 5.8g that gets.
6. the preparation method of a high-purity hydrochloric acid bendamustine is characterized in that, comprises following steps:
With purified water 97ml, acetate 97ml and 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate 26.1g, 0.1mol add in the reaction flask, stir; Be cooled to 0～5 ℃, be added dropwise to oxyethane 25ml, dropwise 0～5 ℃ of insulation reaction 1h in back; Room temperature reaction spends the night, and after reacting completely reaction solution is evaporated to no overhead product, adds purified water 100ml; Regulate pH to 6～7 with sodium hydrogencarbonate; 55 ℃ are evaporated to dried reddish-brown oily matter, and oily matter is isolated water with ETHYLE ACETATE/purified water dissolving; The organic layer that obtains is evaporated to dried, gets reddish-brown oily matter 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 24.2g;
In oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 10g, add n-propyl acetate 25ml; Stirring and dissolving gets settled solution under 25 ℃ of temperature; In solution, drip toluene 50ml and separate out solid; Mixture continued stirring and crystallizing about 30 minutes down at 10 ℃, filtered to isolate solid, and 40 ℃ of forced air dryings get off-white color solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 6.7g;
With solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 6.7g, the methylene dichloride 130ml of above-mentioned preparation, add in the 500ml reaction flask, mechanical stirring is cooled to 0～5 ℃; Dripping thionyl chloride 11ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again, is evaporated to dried; In this viscous fluid, add concentrated hydrochloric acid 130ml, heating reflux reaction 3h adds gac 2g, stirs 10min; Filtered while hot, filtrating is concentrated into dried, and resistates is added among the purified water 20ml, stirs and separates out solid; Filter, solid obtains 6.2g bendamustine hydrochloride bullion in 50 ℃ of vacuum-drying 5h;
Above-mentioned bendamustine hydrochloride bullion 6.2g is placed reaction flask, add entry 30ml, be heated to 70～80 ℃, dissolve the back and add gac 0.3g, filter, cooling crystallization filters, the dry bendamustine hydrochloride white solid finished product 5.2g that gets.
7. the preparation method of a high-purity hydrochloric acid bendamustine is characterized in that, comprises following steps:
With purified water 97ml, acetate 97ml and 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate 26.1g, 0.1mol add in the reaction flask, stir; Be cooled to 0～5 ℃, be added dropwise to oxyethane 25ml, dropwise 0～5 ℃ of insulation reaction 1h in back; Room temperature reaction spends the night, and after reacting completely reaction solution is evaporated to no overhead product, adds purified water 100ml; Regulate pH to 6～7,55 with sodium hydrogencarbonate and ℃ be evaporated to dried reddish-brown oily matter, oily matter dissolves with ETHYLE ACETATE/purified water; Isolate water, the organic layer that obtains is evaporated to dried, gets reddish-brown oily matter 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 24.2g; This oily matter midbody forms gelationus 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate gradually after room temperature is placed 2 hours;
In gluey 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 10g, add isobutyl acetate 25ml; Stirring and dissolving gets settled solution under 20 ℃ of temperature; In solution, drip 2-methylpentane 150ml and separate out solid; Mixture continued stirring and crystallizing about 30 minutes down at 20 ℃, filtered to isolate solid, and 40 ℃ of forced air dryings get off-white color solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 6.5g;
With solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 6.5g, the methylene dichloride 130ml of above-mentioned preparation, add in the 500ml reaction flask, mechanical stirring is cooled to 0～5 ℃; Dripping thionyl chloride 11ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again, is evaporated to dried; In this viscous fluid, add concentrated hydrochloric acid 130ml, heating reflux reaction 3h adds gac 3g, stirs 10min; Filtered while hot, filtrating is concentrated into dried, and resistates is added among the purified water 19ml, stirs and separates out solid; Filter, solid obtains 6.7g bendamustine hydrochloride bullion in 50 ℃ of vacuum-drying 5h;
Above-mentioned bendamustine hydrochloride bullion 6.7g is placed reaction flask, add entry 28ml, be heated to 70～80 ℃, dissolve the back and add gac 0.2g, filter, cooling crystallization filters, the dry bendamustine hydrochloride white solid finished product 5.8g that gets.
8. the preparation method of a high-purity hydrochloric acid bendamustine is characterized in that, comprises following steps:
With purified water 97ml, acetate 97ml and 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate 26.1g, 0.1mol add in the reaction flask, stir; Be cooled to 0～5 ℃, be added dropwise to oxyethane 25ml, dropwise 0～5 ℃ of insulation reaction 1h in back; Room temperature reaction spends the night, and after reacting completely reaction solution is evaporated to no overhead product, adds purified water 100ml; Regulate pH to 6～7,55 with sodium hydrogencarbonate and ℃ be evaporated to dried reddish-brown oily matter, oily matter dissolves with ETHYLE ACETATE/purified water; Isolate water, the organic layer that obtains is evaporated to dried, gets reddish-brown oily matter 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 24.2g;
In oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 175.6g, add ETHYLE ACETATE 500ml and methyl acetate 200ml; Stirring and dissolving gets settled solution under 26 ℃ of temperature; Dropping normal heptane 2500ml and Skellysolve A 1000ml separate out solid in solution; Mixture continued stirring and crystallizing about 30 minutes down at 30 ℃; Filter to isolate solid, 40 ℃ of forced air dryings get off-white color solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 115.3g;
With solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 115g, the methylene dichloride 2300ml of above-mentioned preparation, add in the 5L reaction flask, mechanical stirring is cooled to 0～5 ℃; Dripping thionyl chloride 197ml drips off 0～5 ℃ of insulation reaction 1h in back, under room temperature, reacts 3h again, is evaporated to dried; In this viscous fluid, add concentrated hydrochloric acid 2300ml, heating reflux reaction 3h adds gac 20g, stirs 10min; Filtered while hot, filtrating is concentrated into dried, and resistates is added among the purified water 250ml, stirs and separates out solid; Filter, solid obtains 113.7g bendamustine hydrochloride bullion in 50 ℃ of vacuum-drying 5h;
Above-mentioned bendamustine hydrochloride bullion 113.7g is placed reaction flask, add entry 450ml, be heated to 70～80 ℃, dissolve the back and add gac 10g, filter, cooling crystallization filters, the dry bendamustine hydrochloride finished product white solid finished product 94.5g that gets.
9. the preparation method of a high-purity hydrochloric acid bendamustine is characterized in that, comprises following steps:
With purified water 97ml, acetate 97ml and 5-amino-1-methyl-2-benzoglyoxaline ethyl n-butyrate 26.1g, 0.1mol add in the reaction flask, stir; Be cooled to 0～5 ℃, be added dropwise to oxyethane 25ml, dropwise 0～5 ℃ of insulation reaction 1h in back; Room temperature reaction spends the night, and after reacting completely reaction solution is evaporated to no overhead product, adds purified water 100ml; Regulate pH to 6～7,55 ℃ concentrating under reduced pressure as for getting reddish-brown oily matter with sodium hydrogencarbonate, oily matter is with ETHYLE ACETATE/purified water dissolving; Isolate water, the organic layer that obtains is evaporated to dried, gets reddish-brown oily matter 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 24.2g;
In oily 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 10g, add tert.-butyl acetate 25ml stirring and dissolving under 20 ℃ of temperature get settled solution in solution, drips m-xylene 150ml separate out solid mixture 20 ℃ down the continuation stirring and crystallizing filtered to isolate 40 ℃ of forced air dryings of solid in about 30 minutes and get off-white color solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] ethyl n-butyrate 5.4g;
Solid intermediate 4-[5-[two-(2-hydroxyethyl) amino]-1-methyl-2-benzoglyoxaline] the ethyl n-butyrate 2.9g of above-mentioned preparation, methylene dichloride 60ml are added in the 250ml reaction flask mechanical stirring to be cooled to 0～5 ℃ of dripping thionyl chloride 4.8ml and to drip off 0～5 ℃ of insulation reaction 1h in back and under room temperature, react 3h again; Be evaporated to do and in this viscous fluid, add concentrated hydrochloric acid 60ml heating reflux reaction 3h; Adding gac 1g stirring 10min filtered while hot filtrating is concentrated into to stir among capable person's resistates adding purified water 8ml separates out solid, and solids filtered obtains 2.6g bendamustine hydrochloride bullion in 50 ℃ of vacuum-drying 5h;
Place reaction flask to add above-mentioned bendamustine hydrochloride bullion 2.6g and add gac 0.2g filtration cooling crystallization after entry 12ml is heated to 70～80 ℃ of dissolvings, filtration drying gets bendamustine hydrochloride finished product white solid finished product 2.1g.
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| CA2819017A1 (en) * | 2011-01-31 | 2012-08-09 | Cephalon, Inc. | Methods for the preparation of bendamustine |
| ES2613838T3 (en) * | 2011-09-26 | 2017-05-26 | Fresenius Kabi Oncology Ltd | An improved procedure for the preparation of bendamustine hydrochloride |
| US8987469B2 (en) | 2012-07-24 | 2015-03-24 | Heyl Chemisch-Pharmazeutische Fabrik Gmbh & Co. Kg | Process for the preparation of bendamustine |
| CN103351347A (en) * | 2013-07-29 | 2013-10-16 | 东南大学 | Preparation method of impurity DCE in bendamustine hydrochloride |
| CN103896850B (en) * | 2014-03-24 | 2015-10-07 | 东南大学 | A kind of preparation method of bendamustine hydrochloride dimerization impurity |
| CN104402738A (en) * | 2014-10-31 | 2015-03-11 | 南京大学 | Selective reduction method for nitro |
| CN109422695B (en) * | 2017-08-28 | 2022-03-18 | 扬子江药业集团有限公司 | Preparation method of bendamustine hydrochloride crude product |
| CN108358848A (en) * | 2018-01-16 | 2018-08-03 | 吴江信凯医药科技有限公司 | A kind of synthetic method of bendamustine hydrochloride intermediate |
| CN110759867B (en) * | 2018-07-27 | 2022-08-23 | 连云港润众制药有限公司 | Preparation method of bendamustine hydrochloride |
| CN112624980B (en) * | 2020-12-30 | 2022-10-04 | 深圳万乐药业有限公司 | Preparation method of bendamustine hydrochloride suitable for industrial production |
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| Title |
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| 高丽梅等.盐酸苯达莫司汀的合成.《中国新药杂志》.2007,第16卷(第23期),1960-1961,1970. * |
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