CN104402738A - Selective reduction method for nitro - Google Patents
Selective reduction method for nitro Download PDFInfo
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- CN104402738A CN104402738A CN201410606755.6A CN201410606755A CN104402738A CN 104402738 A CN104402738 A CN 104402738A CN 201410606755 A CN201410606755 A CN 201410606755A CN 104402738 A CN104402738 A CN 104402738A
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- methyl
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- ethyl butyrate
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- 238000000034 method Methods 0.000 title claims abstract description 22
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 15
- 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 claims abstract description 10
- 229960001215 bendamustine hydrochloride Drugs 0.000 claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- 230000002829 reductive effect Effects 0.000 claims abstract description 8
- 239000000852 hydrogen donor Substances 0.000 claims abstract 4
- 238000006555 catalytic reaction Methods 0.000 claims abstract 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 54
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 239000000706 filtrate Substances 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 23
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 21
- 235000019253 formic acid Nutrition 0.000 claims description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- 239000002244 precipitate Substances 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- XIFJZJPMHNUGRA-UHFFFAOYSA-N n-methyl-4-nitroaniline Chemical compound CNC1=CC=C([N+]([O-])=O)C=C1 XIFJZJPMHNUGRA-UHFFFAOYSA-N 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000008346 aqueous phase Substances 0.000 claims description 8
- KABXUUFDPUOJMW-UHFFFAOYSA-N 2-azaniumyl-5-oxopentanoate Chemical compound OC(=O)C(N)CCC=O KABXUUFDPUOJMW-UHFFFAOYSA-N 0.000 claims description 7
- PQGDJRZMFGTARR-UHFFFAOYSA-N 5-amino-1-methylcyclohexa-3,5-diene-1,3-dicarboxylic acid Chemical compound CC1(CC(C(=O)O)=CC(=C1)N)C(=O)O PQGDJRZMFGTARR-UHFFFAOYSA-N 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- -1 2,4-dinitrobenzene-methylphenylamine Chemical compound 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims description 3
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 239000012047 saturated solution Substances 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims 11
- 238000011944 chemoselective reduction Methods 0.000 claims 2
- 239000003880 polar aprotic solvent Substances 0.000 claims 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 229940126214 compound 3 Drugs 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 5
- 238000010992 reflux Methods 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- XKJMBINCVNINCA-UHFFFAOYSA-N Alfalone Chemical compound CON(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XKJMBINCVNINCA-UHFFFAOYSA-N 0.000 description 2
- ZPHQBFRCXUIIAZ-UHFFFAOYSA-N benzene;hydrochloride Chemical compound Cl.C1=CC=CC=C1 ZPHQBFRCXUIIAZ-UHFFFAOYSA-N 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- VYZAHLCBVHPDDF-UHFFFAOYSA-N Dinitrochlorobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 VYZAHLCBVHPDDF-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 238000009156 water cure Methods 0.000 description 1
Abstract
The invention relates to an intermediate compound of bendamustine hydrochloride obtained by selective reduction of polynitro compound. The method uses an active hydrogen donor under palladium-carbon catalysis, then the active hydrogen donor is gradually added in reduced amino ortho nitro to obtain the corresponding compound. The compound can conveniently synthesize bendamustine hydrochloride through the method in the invention.
Description
Technical field
The present invention relates to and describing a kind of selective reduction nitro is amino method, uses different reductive agents to reduce to the multiple nitros in reactant.
Background technology
Hydrochloric acid benzene Da Mositing (Bendamustine Hydrochloride, compound 1) be by Cephalon company of the U.S. research and develop be used for the treatment of lymphocytic leukemia medicine, can be used for (the Wang Xiaokun such as treatment mammary cancer, multiple myeloma, inertia B cell non-Hodgkin lymphoma, Shandong medicine thing, 2009,28 (9), 573-574; Chen Dong, Chinese pharmaceutical chemistry magazine 2009,19 (2) 159-160).
Its chemosynthesis is mainly with 2,4-dinitrochlorobenzene (compound 2) starts, hydrochloric acid benzene Da Mositing (Koryo plum, Wang Yanxiang, Song Danqing is obtained by carrying out different modifications to the selective reduction of the nitro of two wherein, Chinese Journal of New Drugs, 2007,16 (23) 1960-1961; Ren Jian, Chinese pharmaceutical chemistry magazine, 2008,18 (5) 399).As figure mono-:
Wherein, the nitroreduction of compound 2, mainly adopts nine water cure sodium to carry out, and its taste is large, reinforced slow, has the danger of punching material.And the nitroreduction of compound 6 adopts tin protochloride, the too many and easy emulsification of solution of reaction spent acid, is difficultly separated.
Summary of the invention
The present invention seeks to for above-mentioned weak point, provide a kind of method of selective reduction nitro: under the effect of palladium-carbon catalyst, use the nitro at the donor reduction phenyl ring 1 bit amino ortho position of active hydrogen.
Present invention also offers and utilize the method for selective reduction nitro of the present invention by 2,4-dinitrobenzene-methylphenylamine (compound 3) prepares the method for bendamustine hydrochloride (compound 1), specifically 2,4-dinitrobenzene-methylphenylamine (compound 3) selective reduction ortho position nitro under the effect of palladium-carbon catalyst is that amino obtains 2-methylamino-5-N-methyl-p-nitroaniline (compound 4), then prepares bendamustine hydrochloride (compound 1) by 2-methylamino-5-N-methyl-p-nitroaniline (compound 4) by 5 step popular responses.
Embodiment
Below by embodiment, technical scheme of the present invention is described in further detail.
The synthesis of embodiment 1:2-methylamino-5-N-methyl-p-nitroaniline (compound 4)
2 of 5.0g, 4-dinitrobenzene-methylphenylamine (compound 3) is dissolved in 30mL acetonitrile, add 0.5g palladium carbon (water content 48%), then cool to-10 DEG C, drip the acetonitrile solution (5mL formic acid joins configuration in the acetonitrile of 10mL and forms) of formic acid.After dropwising, temperature rising reflux reaction 3hr, collecting by filtration filtrate.Filtrate is poured in the pure water of 50mL ice, stirs, treat that material separates out to filter completely afterwards and obtain precipitate 2.9g (compound 4), yield 68.4%.
The synthesis of embodiment 2:2-methylamino-5-N-methyl-p-nitroaniline (compound 4)
2 of 5.0g, 4-dinitrobenzene-methylphenylamine (compound 3) is dissolved in 30mL acetonitrile, add 0.5g palladium carbon (water content 48%), then cool to-20 DEG C, drip the acetonitrile solution (5mL formic acid joins configuration in the acetonitrile of 5mL and forms) of formic acid.After dropwising, temperature rising reflux reaction 3hr, collecting by filtration filtrate.Filtrate is poured in the pure water of 50mL ice, stirs, and treats that material separates out to filter completely afterwards and obtains precipitate 30.5g (compound 4), yield 71.9%.
The synthesis of embodiment 3:2-methylamino-5-N-methyl-p-nitroaniline (compound 4)
2 of 5.0g, 4-dinitrobenzene-methylphenylamine (compound 3) is dissolved in 25mL acetonitrile, add 0.375g palladium carbon (water content 48%), then cool to-30 DEG C, drip the acetonitrile solution (5mL formic acid joins configuration in the acetonitrile of 5mL and forms) of formic acid.After dropwising, temperature rising reflux reaction 3hr, collecting by filtration filtrate.Filtrate is poured in the pure water of 62.5mL ice, stirs, and treats that material separates out to filter completely afterwards and obtains precipitate 123.2g (compound 4), yield 72.6%.
The synthesis of embodiment 4:2-methylamino-5-N-methyl-p-nitroaniline (compound 4)
2 of 5.0g, 4-dinitrobenzene-methylphenylamine (compound 3) is dissolved in the N of 30mL, in dinethylformamide, add 0.5g palladium carbon (water content 48%), then-10 DEG C are cooled to, drip the acetonitrile solution (5mL formic acid joins configuration in the DMF of 10mL and forms) of formic acid.After dropwising, be warmed up to 80 DEG C of reaction 3hr, collecting by filtration filtrate.Filtrate is poured in the pure water of 50mL ice, stirs, treat that material separates out to filter completely afterwards and obtain precipitate 2.6g (compound 4), yield 61.3%.
The synthesis of embodiment 5:2-methylamino-5-N-methyl-p-nitroaniline (compound 4)
The g2 of 5.0,4-dinitrobenzene-methylphenylamine (compound 3) is dissolved in the N of 30mL, in dinethylformamide, add 0.5g palladium carbon (water content 48%), then-20 DEG C are cooled to, drip the acetonitrile solution (5mL formic acid joins configuration in the DMF of 5mL and forms) of formic acid.After dropwising, be warmed up to 120 DEG C of reaction 3hr, collecting by filtration filtrate.Filtrate is poured in the pure water of 50mL ice, stirs, and treats that material separates out to filter completely afterwards and obtains precipitate 26.6g (compound 4), yield 62.8%.
The synthesis of embodiment 6:2-methylamino-5-N-methyl-p-nitroaniline (compound 4)
2 of 5.0g, 4-dinitrobenzene-methylphenylamine (compound 3) is dissolved in the N of 25mL, in dinethylformamide, add 0.375g palladium carbon (water content 48%), cool to-25 DEG C, drip the acetonitrile solution (5mL formic acid joins configuration in the DMF of 5mL and forms) of formic acid.After dropwising, be warmed up to 100 DEG C of reaction 3hr, collecting by filtration filtrate.Filtrate is poured in the pure water of 62.5mL ice, stirs, and treats that material separates out to filter completely afterwards and obtains precipitate 106.2g (compound 4), yield 62.6%.
The synthesis of embodiment 7:5-(2-methylamino--5-nitro) amino-5-oxo valeric acid (compound 5)
2-methylamino-5-the N-methyl-p-nitroaniline (compound 4) of 10g joins in 60mL toluene, adds 10g Pyroglutaric acid and is heated with stirring to backflow, reaction 3hr.Be cooled to room temperature, the KHCO3 saturated solution extraction adding 50mL obtains aqueous phase.Aqueous phase, with after 50mL toluene wash, has precipitate with after the pH to 3-4 of 3mol/L HCl solution water transfer phase.Filter after waiting to separate out completely, collect precipitate dry, obtain 15g product (compound 5), yield 89.1%.
Embodiment 8:[1-methyl-2-(4 '-ethyl butyrate base)-5-nitro] synthesis of-1H-benzoglyoxaline (compound 6)
5-(2-methylamino--5-nitro) the amino-5-oxo valeric acid (compound 5) of 15g is dispersed in 90mL dehydrated alcohol, be heated to backflow, drip the ethanolic soln (the 4mL vitriol oil joins configuration in the dehydrated alcohol of 10mL and forms) of sulfuric acid.Dropwise, back flow reaction 3hr.After being cooled to room temperature, ice-water bath cooling is spent the night.Next day collecting by filtration precipitate, drying obtains 13.1g product (compound 6).Yield 94.6%.
The synthesis of embodiment 9:5-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ethyl butyrate (compound 7)
[1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline (compound 6) of 10.0g is dissolved in 80ml methyl alcohol, add 1.0g palladium carbon (water content 48%), catalytic hydrogenation 3hr under room temperature 0.5MPa, collecting by filtration filtrate, filtrate evaporate to dryness obtains 6.1g compound 7.Yield 90.9%.
The synthesis of embodiment 10:5-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ethyl butyrate (compound 7)
[1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline (compound 6) of 10.0g is dissolved in 80ml methyl alcohol, add the Raney Ni of 1.2g, catalytic hydrogenation 3hr under room temperature 0.5MPa, collecting by filtration filtrate, filtrate evaporate to dryness obtains 5.9g compound 7.Yield 87.9%.
Embodiment 11:6-[1-methyl-2-(4 '-ethyl butyrate base)-5-N, N-bis-(2 '-hydroxyethyl)]-1H-benzoglyoxaline (compound 8)
Under room temperature, 5-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ethyl butyrate (compound 7) of 6g is dissolved in the mixed solution of 15mL Glacial acetic acid and 20mL pure water, drips the 10mL oxyethane of precooling.Dropwise rear room temperature reaction to spend the night.Next day, reaction soln neutralizes through saturated KHCO3 solution and adjusts pH to 8-9.The chloroform extraction of the reaction solution 50mL after adjust ph collects aqueous phase 2 times afterwards.Aqueous phase is after anhydrous sodium sulfate drying, and filter, concentrating under reduced pressure, obtains 7g product (compound 8).Yield 87.2%.
Embodiment 12: the synthesis of bendamustine hydrochloride (compound 1)
By the 7g product (compound 8) in embodiment 11, be dissolved in 60mL chloroform, after ice-water bath cooling, drip the chloroformic solution (15mL sulfur oxychloride joins configuration in the chloroform of 20mL and forms) of sulfur oxychloride, after dropwising, continue reaction 2hr.After decompression steams chloroform, add 50mL concentrated hydrochloric acid, be heated to 100 DEG C, reaction 4hr.Be cooled to 60 DEG C, add 0.5g gac, decoloring reaction 0.5hr, filter.Filtrate reduced in volume, steams most of hydrogen chloride gas, obtains 5g product (compound 1) with 15mL purified water recrystallization.Yield 63.2%.
Claims (9)
1. a method for selective reduction phenyl ring amino ortho position nitro, reduction reaction is carried out in polar aprotic solvent, it is characterized by: add palladium-carbon catalyst and active hydrogen donor.
2. the method for the amino ortho position of a kind of selective reduction phenyl ring according to claim 1 nitro, is characterized by: described active hydrogen donor is formic acid.
3. the method for the amino ortho position of a kind of selective reduction phenyl ring according to claim 2 nitro, is characterized by: described polar aprotic solvent is acetonitrile or DMF.
4. the method for the amino ortho position of a kind of selective reduction phenyl ring according to claim 3 nitro, is characterized by: the temperature of reduction reaction is 80 DEG C to 120 DEG C.
5. the method for the amino ortho position of a kind of selective reduction phenyl ring according to claim 4 nitro, it is characterized by: after reduction reaction, the filtrate of reaction solution pours in pure water the product of separating out reduction reaction into.
6. the method for the amino ortho position of a kind of selective reduction phenyl ring according to claim 5 nitro, it is characterized by: the initial compounds of Chemoselective reduction is 2,4-dinitrobenzene-methylphenylamine, get 2 of 5.0g, 4-dinitrobenzene-methylphenylamine is dissolved in 25-30mL acetonitrile, adds the palladium carbon that 0.375-0.5g water content is 48%, then cools to-30 ~-10 DEG C, drip the acetonitrile solution of formic acid again, the acetonitrile solution compound method of formic acid is that 5mL formic acid joins in the acetonitrile of 5 ~ 10mL; After the acetonitrile solution dropwise of formic acid, be warmed up to 80 ~ 120 DEG C of back flow reaction 3hr, collecting by filtration filtrate; Filtrate be poured in the pure water of 50 ~ 62.5mL ice, stir, treat that material separates out to filter completely afterwards and obtain precipitate, this precipitate is reduzate 2-methylamino-5-N-methyl-p-nitroaniline.
7. the method for the amino ortho position of a kind of selective reduction phenyl ring according to claim 5 nitro, it is characterized by: the initial compounds of Chemoselective reduction is 2, 4-dinitrobenzene-methylphenylamine, get 2 of 5.0g, 4-dinitrobenzene-methylphenylamine is dissolved in the N of 25-30mL, in dinethylformamide, add the palladium carbon that 0.375-0.5g water content is 48%, then-25 ~-10 DEG C are cooled to, drip the N of formic acid again, dinethylformamide solution, the N of formic acid, dinethylformamide solution preparation method is the N that 5mL formic acid joins 5 ~ 10mL, in dinethylformamide, after the DMF solution of formic acid dropwises, be warmed up to 80 ~ 120 DEG C of back flow reaction 3hr, collecting by filtration filtrate, filtrate be poured in the pure water of 50 ~ 62.5mL ice, stir, treat that material separates out to filter completely afterwards and obtain precipitate, this precipitate is reduzate 2-methylamino-5-N-methyl-p-nitroaniline.
8. prepare the method for bendamustine hydrochloride for one kind, it is characterized by: utilize method described in claim 1-7 any one claim by 2,4-dinitrobenzene-methylphenylamine is reduced to 2-methylamino-5-N-methyl-p-nitroaniline, reacted by 2-methylamino-5-N-methyl-p-nitroaniline and Pyroglutaric acid again and generate 5-(2-methylamino--5-nitro) amino-5-oxo valeric acid, 5-(2-methylamino--5-nitro) amino-5-oxo valeric acid generates [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline under the effect of sulfuric acid, [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline generates 5-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ethyl butyrate under the catalysis of palladium carbon or Raney Ni, 5-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ethyl butyrate and reacting ethylene oxide generate 6-[1-methyl-2-(4 '-ethyl butyrate base)-5-N, N-bis-(2 '-hydroxyethyl)]-1H-benzoglyoxaline, 6-[1-methyl-2-(4 '-ethyl butyrate base)-5-N, N-bis-(2 '-hydroxyethyl)]-1H-benzoglyoxaline and sulfur oxychloride obtain bendamustine hydrochloride with HCl treatment after reacting.
9. a kind of method preparing bendamustine hydrochloride according to claim 8, is characterized by step as follows:
(1) utilize the method described in claim 1-7 any one claim that 2,4-dinitrobenzene-methylphenylamine is reduced to 2-methylamino-5-N-methyl-p-nitroaniline;
(2) 5-(2-methylamino--5-nitro) amino-5-oxo valeric acid is prepared by 2-methylamino-5-N-methyl-p-nitroaniline:
2-methylamino-5-the N-methyl-p-nitroaniline of 10g joins in 60mL toluene, adds 10g Pyroglutaric acid and is heated with stirring to backflow, reaction 3hr; Be cooled to room temperature, the KHCO3 saturated solution extraction adding 50mL obtains aqueous phase; Aqueous phase, with after 50mL toluene wash, has precipitate with after the pH to 3-4 of 3mol/L HCl solution water transfer phase; Filter after waiting to separate out completely, collect precipitate dry, obtain 15g product (compound 5), yield 89.1%;
(3) [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline is prepared by 5-(2-methylamino--5-nitro) amino-5-oxo valeric acid:
5-(2-methylamino--5-nitro) the amino-5-oxo valeric acid of 15g is dispersed in 90mL dehydrated alcohol, be heated to backflow, drip the ethanolic soln of sulfuric acid, the ethanolic soln compound method of sulfuric acid is that the 4mL vitriol oil joins configuration in the dehydrated alcohol of 10mL and forms; Dropwise, back flow reaction 3hr; After being cooled to room temperature, ice-water bath cooling is spent the night; Next day collecting by filtration precipitate, drying obtains 13.1g product; Yield 94.6%;
(4) 5-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ethyl butyrate is prepared by [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline:
[1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline of 10.0g is dissolved in 80ml methyl alcohol, add the 1.0g palladium carbon of water content 48%, catalytic hydrogenation 3hr under room temperature 0.5MPa, collecting by filtration filtrate, filtrate evaporate to dryness obtains the 5-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ethyl butyrate of 6.1g; Yield 90.9%;
Or [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline of 10.0g is dissolved in 80ml methyl alcohol, add the Raney Ni of 1.2g, catalytic hydrogenation 3hr under room temperature 0.5MPa, collecting by filtration filtrate, filtrate evaporate to dryness obtains 5.9g5-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ethyl butyrate; Yield 87.9%;
(5) 6-[1-methyl-2-(4 '-ethyl butyrate base)-5-N, N-bis-(2 '-hydroxyethyl)]-1H-benzoglyoxaline is prepared by 5-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ethyl butyrate:
Under room temperature, the 5-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-ethyl butyrate of 6g is dissolved in the mixed solution of 15mL Glacial acetic acid and 20mL pure water, drips the 10mL oxyethane of precooling; Dropwise rear room temperature reaction to spend the night; Next day, reaction soln neutralizes through saturated KHCO3 solution and adjusts pH to 8-9; The chloroform extraction of the reaction solution 50mL after adjust ph collects aqueous phase 2 times afterwards; Aqueous phase is after anhydrous sodium sulfate drying, and filter, concentrating under reduced pressure, obtains 7g6-[1-methyl-2-(4 '-ethyl butyrate base)-5-N, N-bis-(2 '-hydroxyethyl)]-1H-benzoglyoxaline; Yield 87.2%;
(6) bendamustine hydrochloride is prepared by 6-[1-methyl-2-(4 '-ethyl butyrate base)-5-N, N-bis-(2 '-hydroxyethyl)]-1H-benzoglyoxaline:
By 6-[1-methyl-2-(4 '-ethyl butyrate base)-5-N of 7g, N-bis-(2 '-hydroxyethyl)]-1H-benzoglyoxaline, be dissolved in 60mL chloroform, after ice-water bath cooling, drip the chloroformic solution of sulfur oxychloride, the compound method of the chloroformic solution of sulfur oxychloride is that 15mL sulfur oxychloride joins in the chloroform of 20mL; After dropwising, continue reaction 2hr; After decompression steams chloroform, add 50mL concentrated hydrochloric acid, be heated to 100 DEG C, reaction 4hr; Be cooled to 60 DEG C, add 0.5g gac, decoloring reaction 0.5hr, filter; Filtrate reduced in volume, steams most of hydrogen chloride gas, obtains 5g product with 15mL purified water recrystallization.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106018054A (en) * | 2016-05-18 | 2016-10-12 | 山东省食品药品检验研究院 | Pretreatment method for testing residual palladium in bendamustine hydrochloride sample with graphite furnace atomic absorption spectrophotometry |
| CN107325003A (en) * | 2017-08-01 | 2017-11-07 | 安徽东至广信农化有限公司 | A kind of method that Liquid-phase Hydrogenation Process synthesizes o-chloraniline |
| CN112812018A (en) * | 2021-01-11 | 2021-05-18 | 浙江工业大学上虞研究院有限公司 | Catalytic hydrogenation method for preparing nitroaniline from dinitrobenzene |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD34727A1 (en) * | 1963-12-21 | 1964-12-28 | Dietrich Krebs | A process for the preparation of 1-position substituted [5-bis (chloroethyl) amino-benzimidazolyl (2)] - alkanecarboxylic acids |
| CN101948436A (en) * | 2010-06-28 | 2011-01-19 | 江苏奥赛康药业有限公司 | Method for preparing high-purity bendamustine hydrochloride |
| WO2012007966A2 (en) * | 2010-07-15 | 2012-01-19 | Biophore India Pharmaceuticals Pvt. Ltd. | Process for preparation of intermediates of bendamustine |
| WO2013150020A1 (en) * | 2012-04-03 | 2013-10-10 | Synthon Bv | Process for making bendamustine |
-
2014
- 2014-10-31 CN CN201410606755.6A patent/CN104402738A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD34727A1 (en) * | 1963-12-21 | 1964-12-28 | Dietrich Krebs | A process for the preparation of 1-position substituted [5-bis (chloroethyl) amino-benzimidazolyl (2)] - alkanecarboxylic acids |
| CN101948436A (en) * | 2010-06-28 | 2011-01-19 | 江苏奥赛康药业有限公司 | Method for preparing high-purity bendamustine hydrochloride |
| WO2012007966A2 (en) * | 2010-07-15 | 2012-01-19 | Biophore India Pharmaceuticals Pvt. Ltd. | Process for preparation of intermediates of bendamustine |
| WO2013150020A1 (en) * | 2012-04-03 | 2013-10-10 | Synthon Bv | Process for making bendamustine |
Non-Patent Citations (7)
| Title |
|---|
| GIOVANNI PIERSANTI,ET AL.: "Synthesis of benzo[1,2-d;3,4-d"]diimidazole and 1H-pyrazolo[4,3-b]pyridine as putative A2A receptor antagonists", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
| GIOVANNI PIERSANTI,ET AL.: "Synthesis of benzo[1,2-d;3,4-d"]diimidazole and 1H-pyrazolo[4,3-b]pyridine as putative A2A receptor antagonists", 《ORGANIC & BIOMOLECULAR CHEMISTRY》, vol. 5, no. 16, 13 July 2007 (2007-07-13), pages 2567 - 2571 * |
| 任健，等: "盐酸苯达莫司汀（bendamustine hydrochloride）", 《中国药物化学杂志》 * |
| 何新华，等: "新型CD4抑制剂J2的合成及其活性评价", 《中国药物化学杂志》 * |
| 何新华，等: "新型CD4抑制剂J2的合成及其活性评价", 《中国药物化学杂志》, vol. 19, no. 4, 31 August 2009 (2009-08-31) * |
| 陈磊，等: "盐酸苯达莫司汀的合成工艺改进", 《中国药师》 * |
| 高丽梅，等: "盐酸苯达莫司汀的合成", 《中国新药杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106018054A (en) * | 2016-05-18 | 2016-10-12 | 山东省食品药品检验研究院 | Pretreatment method for testing residual palladium in bendamustine hydrochloride sample with graphite furnace atomic absorption spectrophotometry |
| CN107325003A (en) * | 2017-08-01 | 2017-11-07 | 安徽东至广信农化有限公司 | A kind of method that Liquid-phase Hydrogenation Process synthesizes o-chloraniline |
| CN112812018A (en) * | 2021-01-11 | 2021-05-18 | 浙江工业大学上虞研究院有限公司 | Catalytic hydrogenation method for preparing nitroaniline from dinitrobenzene |
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