CN103896850B - A kind of preparation method of bendamustine hydrochloride dimerization impurity - Google Patents
A kind of preparation method of bendamustine hydrochloride dimerization impurity Download PDFInfo
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- CN103896850B CN103896850B CN201410110769.9A CN201410110769A CN103896850B CN 103896850 B CN103896850 B CN 103896850B CN 201410110769 A CN201410110769 A CN 201410110769A CN 103896850 B CN103896850 B CN 103896850B
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Abstract
The preparation method of a kind of bendamustine hydrochloride dimerization impurity provided by the invention.This preparation method's technique is simple, purity is high, can provide qualified reference substance for the quality control of bendamustine hydrochloride.
Description
Technical field
The invention belongs to the field of chemical synthesis, particularly a kind of preparation method of bendamustine hydrochloride dimerization impurity.
Background technology
Bendamustine hydrochloride (bendamustine hydrochloride) is the alkanisation antitumor drug developed by Merckle company, and go on the market in October, 2003 in Germany, commodity are called Ribomustin.Salmedix company is authorized in America & Canada exploitation, and commodity are called Treanda (SDX2105), are in for III phase at present clinical.
Dimerization impurity, shown in I, is one of impurity common in bendamustine hydrochloride.Mass analysis is carried out to bendamustine hydrochloride and must have qualified formula I product in contrast.But, have not yet to see the preparation method that open source information reported dimerization impurity.
Summary of the invention
Goal of the invention: in order to overcome above-mentioned the deficiencies in the prior art, the object of the present invention is to provide a kind of preparation method of bendamustine hydrochloride dimer impurity, is that starting raw material prepares bendamustine hydrochloride dimer impurity with [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline.
Technical scheme: the preparation method of a kind of bendamustine hydrochloride dimerization impurity provided by the invention, comprise the following steps: (1) with [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline for starting raw material, catalytic hydrogenation under Pd/C exists, obtains [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline:
Reaction formula is as follows:
(2) in the presence of a reducing agent, [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and phenyl aldehyde reaction, obtain [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline;
Reaction formula is as follows:
(3) [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline and reacting ethylene oxide, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
Reaction formula is as follows:
(4) in the basic conditions, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)] saponification of-1H-benzoglyoxaline, [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
Reaction formula is as follows:
(5) in acid condition, [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and benzylalcohol reaction, [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
Reaction formula is as follows:
(6) in the presence of an organic base, [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and Bian bromine reaction, obtain [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline;
Reaction formula is as follows:
(7) in the basic conditions, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline saponification reaction, obtains [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline;
Reaction formula is as follows:
(8) under condensation reagent exists, [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and the reaction of [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline, obtain 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-base]-amino }-ethyl ester;
Reaction formula is as follows:
(9) 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-base]-amino }-ethyl ester, catalytic hydrogenation under Pd/C exists, obtains 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid;
Reaction formula is as follows:
(10) in acid condition, and 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji) reaction of-butyric acid, to obtain final product;
Reaction formula is as follows:
In step (1), the mol ratio of [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline and Pd/C is 100:(5 ~ 20); Temperature of reaction is 5 DEG C-40 DEG C, and the reaction times is 10h-30h; Reaction solvent is the organic solvent of 1-10 carbon atom, the organic solvent of a preferred 1-4 carbon atom, more preferably methylene dichloride, trichloromethane, methyl alcohol, ethanol, acetone, ethyl acetate, acetonitrile, acetic acid, tetracol phenixin or tetrahydrofuran (THF).
In step (2), the mol ratio of [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and phenyl aldehyde is 1:(1 ~ 5); Temperature of reaction is 5 DEG C-50 DEG C, and the reaction times is 1h-10h; Described reductive agent is sodium borohydride, and the amount ratio of reductive agent and reaction substrate [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline is (1 ~ 5): 1; Reaction solvent is the organic solvent of 1-10 carbon atom, the organic solvent of a preferred 1-4 carbon atom, more preferably methylene dichloride, trichloromethane, methyl alcohol, ethanol, acetone, ethyl acetate, acetonitrile, acetic acid, tetracol phenixin or tetrahydrofuran (THF).
In step (3), the mol ratio of [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline and oxyethane is 1:(10 ~ 50) ,-10 DEG C ~-5 DEG C reaction 2h-4h or normal-temperature reaction 10h-20h; The aqueous solutions of organic acids of reaction solvent to be massfraction be 1-6 the carbon atom of 10% ~ 80%, the aqueous solutions of organic acids of a preferred 1-4 carbon atom, described organic acid is formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid or butanic acid.
In step (4), temperature of reaction is 80 DEG C-120 DEG C, and the reaction times is 1h-10h, reaction system pH is 8-14.
In step (5), temperature of reaction is 80 DEG C-120 DEG C, and the reaction times is 1h-10h, reaction system pH is 1-6; The mol ratio of [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and benzylalcohol is 1:(10 ~ 50).
In step (6), the mol ratio of [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and Bian bromine is 1:(1 ~ 20), temperature of reaction is 5 DEG C ~ 45 DEG C, and the reaction times is 20h ~ 30h; Described organic bases is salt of wormwood, sodium carbonate, sodium hydroxide, triethylamine, DIPEA or pyridine, and the consumption of organic bases is 1 ~ 10 times of substrate; Reaction solvent is the organic solvent of 1-10 carbon atom, the organic solvent of a preferred 1-4 carbon atom, more preferably methylene dichloride, trichloromethane, methyl alcohol, ethanol, acetone, ethyl acetate, acetonitrile, acetic acid, tetracol phenixin or tetrahydrofuran (THF).
In step (7), temperature of reaction is 80 DEG C-120 DEG C, and the reaction times is 1h-10h, reaction system pH is 8-14.
In step (8), temperature of reaction is 5 DEG C-50 DEG C, reaction times is 10h-30h, and the mol ratio of [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline is (0.5-5): 1; Reaction solvent is the organic solvent of 1-10 carbon atom, the organic solvent of a preferred 1-4 carbon atom, more preferably methylene dichloride, trichloromethane, methyl alcohol, ethanol, acetone, ethyl acetate, acetonitrile, acetic acid, tetracol phenixin or tetrahydrofuran (THF); Wherein, condensation reagent is carbonyl dimidazoles (CDI), dicyclohexylcarbodiimide (DCC), DIC (DIC) and 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI), O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU), phenylbenzene chlorine phosphine oxide (DPP-Cl) or N-bromo-succinimide (NBS).
In step (9), 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-base]-amino } mol ratio of-ethyl ester and Pd/C is 100:(5 ~ 30), temperature of reaction is 10 DEG C-35 DEG C, and the reaction times is 72h-120h; The aqueous solutions of organic acids of reaction solvent to be massfraction be 1-6 the carbon atom of 10% ~ 80%, the aqueous solutions of organic acids of a preferred 1-4 carbon atom, described organic acid is formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid or butanic acid.
In step (10), the mol ratio of 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid and oxyethane is 1:(10 ~ 200), react at-10 DEG C ~-5 DEG C reaction 2h-4h, or react 72h-120h at normal temperatures; The aqueous solutions of organic acids of reaction solvent to be massfraction be 1-6 the carbon atom of 10% ~ 80%, the aqueous solutions of organic acids of a preferred 1-4 carbon atom, described organic acid is formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid or butanic acid.
Beneficial effect: preparation method's technique of bendamustine hydrochloride dimer impurity provided by the invention is simple, purity is high, can provide qualified reference substance for the quality control of bendamustine hydrochloride.
Accompanying drawing explanation
Fig. 1 is the mass spectrum of [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline.
Fig. 2 is the mass spectrum of [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline.
Fig. 3 is the mass spectrum of [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline.
Fig. 4 is the mass spectrum of [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline.
Fig. 5 is 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-base]-amino } mass spectrum of-ethyl ester.
Fig. 6 is the mass spectrum of 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid.
Fig. 7 is 4-{6-[[2-(4-{6-[two-(2-hydroxy-ethyl)-amino]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji }-butyryl acyloxy)-ethyl]-(2-hydroxy-ethyl)-amino]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji } mass spectrum of-butyric acid.
Embodiment
Below in conjunction with accompanying drawing the present invention made and further illustrating.
Embodiment 1
The preparation method of bendamustine hydrochloride dimerization impurity, comprises the following steps:
(1) take methylene dichloride as solvent, mol ratio is [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline and Pd/C catalytic hydrogenation 20h at 10 DEG C of 100:5, and reaction terminates filtering separation, revolves and steam [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline;
(2) take methylene dichloride as solvent, mol ratio is the sodium borohydride of 3:1:2, [1-methyl-2-(4 '-ethyl butyrate base)-5-amino]-1H-benzoglyoxaline and phenyl aldehyde 10 DEG C reaction 5h, and reaction end adds water, organic extractant phase, washing, drying, be spin-dried for [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(3) take massfraction as the formic acid of 40% be solvent, mol ratio be [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline of 1:10 and oxyethane in enclosed system-10 DEG C react 4h, reaction terminates extraction into ethyl acetate, washing, drying, is spin-dried for, column chromatography for separation obtains [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(4) pH to 8 is adjusted, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline 80 DEG C carries out soap solution reaction 5h, reaction terminates rear concentrated, separate out product, [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(5) pH to 1 is adjusted, mol ratio is [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and the benzylalcohol 80 DEG C reaction 5h of 1:10, reaction terminates extraction into ethyl acetate, washing, drying, concentrated, column chromatography, [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(6) take methylene dichloride as solvent, under salt of wormwood exists, mol ratio is [1-methyl-2-(4 '-ethyl butyrate base)-5-amino]-1H-benzoglyoxaline and the Bian bromine 10 DEG C reaction 30h of 1:2, and reaction terminates rear concentrated, column chromatography and obtains [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline; The consumption of salt of wormwood is 1 times of [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and Bian bromine mole number;
(7) pH to 8 is adjusted, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline 80 DEG C of soap solution reaction 5h, reaction terminates rear concentrated, precipitation product, obtains [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline;
(8) take methylene dichloride as solvent, under carbonyl dimidazoles exists, mol ratio is [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline 5 DEG C reaction 30h of 0.5:1, reaction terminates rear refrigeration and filters, concentrated, column chromatography obtains 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-base]-amino }-ethyl ester,
(9) with massfraction be 40% formic acid for solvent, mol ratio is 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-the base]-amino of 100:10 }-ethyl ester and Pd/C catalytic hydrogenation 120h at 10 DEG C, reaction terminates filtering separation and obtains 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji) the thick product of-butyric acid;
(10) take massfraction as the formic acid of 40% be solvent, mol ratio be 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-the Ji)-butyric acid of 1:10 and oxyethane in enclosed system-10 DEG C react 4h, reaction terminates column chromatography for separation, be separated to obtain white solid, be 4-{6-[[2-(4-{6-[two-(2-hydroxy-ethyl)-amino]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji }-butyryl acyloxy)-ethyl]-(2-hydroxy-ethyl)-amino]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji }-butyric acid, HPLC detects purity 96.0%.
Embodiment 2
The preparation method of bendamustine hydrochloride dimerization impurity, comprises the following steps:
(1) take methyl alcohol as solvent, mol ratio is [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline and Pd/C catalytic hydrogenation 10h at 35 DEG C of 100:15, and reaction terminates filtering separation, revolves and steam [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline;
(2) take methyl alcohol as solvent, mol ratio is the sodium borohydride of 1:1:1, [1-methyl-2-(4 '-ethyl butyrate base)-5-amino]-1H-benzoglyoxaline and phenyl aldehyde 35 DEG C reaction 2h, and reaction end adds water, organic extractant phase, washing, drying, be spin-dried for [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(3) take massfraction as the acetic acid of 80% be solvent, mol ratio be [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline of 1:50 and oxyethane in enclosed system-5 DEG C react 2h, reaction terminates extraction into ethyl acetate, washing, drying, is spin-dried for, column chromatography for separation obtains [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(4) pH to 14 is adjusted, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline 100 DEG C carries out soap solution reaction 2h, reaction terminates rear concentrated, separate out product, [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(5) pH to 6 is adjusted, mol ratio is [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and the benzylalcohol 100 DEG C reaction 10h of 1:50, reaction terminates extraction into ethyl acetate, washing, drying, concentrated, column chromatography, [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(6) take methyl alcohol as solvent, under sodium hydroxide exists, mol ratio is [1-methyl-2-(4 '-ethyl butyrate base)-5-amino]-1H-benzoglyoxaline and the Bian bromine 45 DEG C reaction 20h of 1:5, and reaction terminates rear concentrated, column chromatography and obtains [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline; The consumption of sodium hydroxide is 10 times of [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and Bian bromine mole number;
(7) pH to 14 is adjusted, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline 90 DEG C of soap solution reaction 10h, reaction terminates rear concentrated, precipitation product, obtains [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline;
(8) take methyl alcohol as solvent, under dicyclohexylcarbodiimide exists, mol ratio is [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline 50 DEG C reaction 10h of 2:1, reaction terminates rear refrigeration and filters, concentrated, column chromatography obtains 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-base]-amino }-ethyl ester,
(9) take massfraction as the acetic acid aqueous solution of 80% be solvent, mol ratio is 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-the base]-amino of 100:10 }-ethyl ester and Pd/C catalytic hydrogenation 72h at 35 DEG C, reaction terminates filtering separation and obtains 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji) the thick product of-butyric acid;
(10) take massfraction as the acetic acid aqueous solution of 80% be solvent, mol ratio be 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-the Ji)-butyric acid of 1:200 and oxyethane in enclosed system-5 DEG C react 2h, be separated to obtain white solid, be 4-{6-[[2-(4-{6-[two-(2-hydroxy-ethyl)-amino]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji }-butyryl acyloxy)-ethyl]-(2-hydroxy-ethyl)-amino]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji }-butyric acid, HPLC detects purity 95.7%.
Embodiment 3
The preparation method of bendamustine hydrochloride dimerization impurity, comprises the following steps:
(1) take acetone as solvent, mol ratio is [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline and Pd/C catalytic hydrogenation 15h at 20 DEG C of 100:10, and reaction terminates filtering separation, revolves and steam [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline;
(2) take acetone as solvent, mol ratio is the sodium borohydride of 5:1:1.2, [1-methyl-2-(4 '-ethyl butyrate base)-5-amino]-1H-benzoglyoxaline and phenyl aldehyde 5 DEG C reaction 10h, and reaction end adds water, organic extractant phase, washing, drying, be spin-dried for [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(3) be that the propionic acid aqueous solution of 10% is for solvent with massfraction, mol ratio is [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline and oxyethane normal-temperature reaction 20h in enclosed system of 1:30, and reaction terminates extraction into ethyl acetate, washing, drying, is spin-dried for, column chromatography for separation obtains [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(4) pH to 10 is adjusted, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline 90 DEG C carries out soap solution reaction 10h, reaction terminates rear concentrated, separate out product, [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(5) pH to 3 is adjusted, mol ratio is [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and the benzylalcohol 120 DEG C reaction 1h of 1:20, reaction terminates extraction into ethyl acetate, washing, drying, concentrated, column chromatography, [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(6) take acetone as solvent, under triethylamine exists, mol ratio is [1-methyl-2-(4 '-ethyl butyrate base)-5-amino]-1H-benzoglyoxaline and the Bian bromine 5 DEG C reaction 30h of 1:1, and reaction terminates rear concentrated, column chromatography and obtains [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline; The consumption of triethylamine is 5 times of [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and Bian bromine mole number;
(7) pH to 10 is adjusted, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline 85 DEG C of soap solution reaction 3h, reaction terminates rear concentrated, precipitation product, obtains [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline;
(8) take acetone as solvent, under DIC exists, mol ratio is [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline 20 DEG C reaction 25h of 1:1, reaction terminates rear refrigeration and filters, concentrated, column chromatography obtains 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-base]-amino }-ethyl ester,
(9) be that the propionic acid aqueous solution of 10% is for solvent with massfraction, mol ratio is 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-the base]-amino of 100:30 }-ethyl ester and Pd/C catalytic hydrogenation 90h at 20 DEG C, reaction terminates filtering separation and obtains 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji) the thick product of-butyric acid;
(10) be that the propionic acid aqueous solution of 10% is for solvent with massfraction, mol ratio is 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid and oxyethane normal-temperature reaction 120h in enclosed system of 1:100, be separated to obtain white solid, be 4-{6-[[2-(4-{6-[two-(2-hydroxy-ethyl)-amino]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji }-butyryl acyloxy)-ethyl]-(2-hydroxy-ethyl)-amino]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji }-butyric acid, HPLC detects purity 96.8%.
Embodiment 4
The preparation method of bendamustine hydrochloride dimerization impurity, comprises the following steps:
(1) take ethyl acetate as solvent, mol ratio is [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline and Pd/C catalytic hydrogenation 13h at 40 DEG C of 100:12, and reaction terminates filtering separation, revolves and steam [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline;
(2) take ethyl acetate as solvent, mol ratio is the sodium borohydride of 2:1:5, [1-methyl-2-(4 '-ethyl butyrate base)-5-amino]-1H-benzoglyoxaline and phenyl aldehyde 50 DEG C reaction 1h, and reaction end adds water, organic extractant phase, washing, drying, be spin-dried for [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(3) take massfraction as the oxalic acid aqueous solution of 20% be solvent, mol ratio is [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline and oxyethane normal-temperature reaction 10h in enclosed system of 1:40, and reaction terminates extraction into ethyl acetate, washing, drying, is spin-dried for, column chromatography for separation obtains [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(4) pH to 14 is adjusted, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline 120 DEG C carries out soap solution reaction 1h, reaction terminates rear concentrated, separate out product, [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(5) pH to 2 is adjusted, mol ratio is [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and the benzylalcohol 85 DEG C reaction 4h of 1:30, reaction terminates rear extraction into ethyl acetate, washing, drying, concentrated, column chromatography, [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(6) take ethyl acetate as solvent, at N, under N-diisopropylethylamine exists, mol ratio is [1-methyl-2-(4 '-ethyl butyrate base)-5-amino]-1H-benzoglyoxaline and the Bian bromine 20 DEG C reaction 28h of 1:20, and reaction terminates rear concentrated, column chromatography and obtains [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline; The consumption of DIPEA is 5 times of [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and Bian bromine mole number;
(7) pH to 14 is adjusted, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline 120 DEG C of soap solution reaction 1h, reaction terminates rear concentrated, precipitation product, obtains [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline;
(8) take ethyl acetate as solvent, under 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide exists, mol ratio is [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline 30 DEG C reaction 25h of 5:1, reaction terminates rear refrigeration and filters, concentrated, column chromatography obtains 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-base]-amino }-ethyl ester,
(9) take massfraction as the oxalic acid aqueous solution of 20% be solvent, mol ratio is 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-the base]-amino of 100:5 }-ethyl ester and Pd/C catalytic hydrogenation 80h at 30 DEG C, reaction terminates filtering separation and obtains 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji) the thick product of-butyric acid;
(10) take massfraction as the oxalic acid aqueous solution of 20% be solvent, mol ratio is 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid and oxyethane normal-temperature reaction 72h in enclosed system of 1:150, be separated to obtain white solid, be 4-{6-[[2-(4-{6-[two-(2-hydroxy-ethyl)-amino]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji }-butyryl acyloxy)-ethyl]-(2-hydroxy-ethyl)-amino]-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji }-butyric acid, HPLC detects purity 96.4%.
Embodiment 5
Substantially the same manner as Example 3, difference is only: adopt acetonitrile to replace methylene dichloride in step (1), (2), (6), (8), trifluoroacetic acid is adopted to replace formic acid in step (3), (9), (10), O-(7-nitrogen benzotriazole)-N is adopted in step (3), N, N', N'-tetramethyl-urea phosphofluoric acid ester replaces DIC.
Embodiment 6
Substantially the same manner as Example 3, difference is only: adopt tetrahydrofuran (THF) to replace methylene dichloride in step (1), (2), (6), (8), adopt hexanodioic acid to replace formic acid in step (3), (9), (10), in step (3), adopt phenylbenzene chlorine phosphine oxide or N-bromo-succinimide to replace DIC.
Embodiment 7
Substantially the same manner as Example 3, difference is only: adopt tetracol phenixin to replace methylene dichloride in step (1), (2), (6), (8).
Embodiment 8
Substantially the same manner as Example 3, difference is only: adopt trichloromethane to replace methylene dichloride in step (1), (2), (6), (8).
Embodiment 9
Substantially the same manner as Example 3, difference is only: adopt ethanol to replace methylene dichloride in step (1), (2), (6), (8).
Embodiment 10
Substantially the same manner as Example 3, difference is only: adopt oil of apple to replace methylene dichloride in step (1), (2), (6), (8).
Claims (10)
1. a preparation method for bendamustine hydrochloride dimerization impurity, is characterized in that: comprise the following steps:
(1) with [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline for starting raw material, catalytic hydrogenation under Pd/C exists, obtains [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline;
(2) in the presence of a reducing agent, [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and phenyl aldehyde reaction, obtain [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(3) [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline and reacting ethylene oxide, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(4) in the basic conditions, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)] saponification of-1H-benzoglyoxaline, [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(5) in acid condition, [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and benzylalcohol reaction, [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline;
(6) in the presence of an organic base, [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and Bian bromine reaction, obtain [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline;
(7) in the basic conditions, [1-methyl-2-(4 '-ethyl butyrate base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline saponification reaction, obtains [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline;
(8) under condensation reagent exists, [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and the reaction of [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline, obtain 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-base]-amino }-ethyl ester;
(9) 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-base]-amino }-ethyl ester, catalytic hydrogenation under Pd/C exists, obtains 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid;
(10) in acid condition, and 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji) reaction of-butyric acid, obtain target product.
2. the preparation method of a kind of bendamustine hydrochloride dimerization impurity according to claim 1, it is characterized in that: in step (1), the mol ratio of [1-methyl-2-(4 '-ethyl butyrate base)-5-nitro]-1H-benzoglyoxaline and Pd/C is 100:(5 ~ 20); Temperature of reaction is 5 DEG C-40 DEG C, and the reaction times is 10h-30h; Reaction solvent is the organic solvent of 1-10 carbon atom.
3. the preparation method of a kind of bendamustine hydrochloride dimerization impurity according to claim 1, it is characterized in that: in step (2), the mol ratio of [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and phenyl aldehyde is 1:(1 ~ 5); Temperature of reaction is 5 DEG C-50 DEG C, and the reaction times is 1h-10h; Described reductive agent is sodium borohydride, and the amount ratio of reductive agent and reaction substrate [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline is (1 ~ 5): 1; Reaction solvent is the organic solvent of 1-10 carbon atom.
4. the preparation method of a kind of bendamustine hydrochloride dimerization impurity according to claim 1, it is characterized in that: in step (3), the mol ratio of [1-methyl-2-(4 '-ethyl butyrate base)-5-N-(2 '-phenylethyl)]-1H-benzoglyoxaline and oxyethane is 1:(10 ~ 50) ,-10 DEG C ~-5 DEG C reaction 2h-4h or normal-temperature reaction 10h-20h; The aqueous solutions of organic acids of reaction solvent to be massfraction be 1-6 the carbon atom of 10% ~ 80%, described organic acid is formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid or butanic acid.
5. the preparation method of a kind of bendamustine hydrochloride dimerization impurity according to claim 1, it is characterized in that: in step (4), temperature of reaction is 80 DEG C-120 DEG C, and the reaction times is 1h-10h, reaction system pH is 8-14.
6. the preparation method of a kind of bendamustine hydrochloride dimerization impurity according to claim 1, it is characterized in that: in step (5), temperature of reaction is 80 DEG C-120 DEG C, and the reaction times is 1h-10h, reaction system pH is 1-6; The mol ratio of [1-methyl-2-(4 '-butyric acid base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and benzylalcohol is 1:(10 ~ 50).
7. the preparation method of a kind of bendamustine hydrochloride dimerization impurity according to claim 1, it is characterized in that: in step (6), the mol ratio of [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline and Bian bromine is 1:(1 ~ 20), temperature of reaction is 5 DEG C ~ 45 DEG C, and the reaction times is 20h ~ 30h; Described organic bases is salt of wormwood, sodium carbonate, sodium hydroxide, triethylamine, DIPEA or pyridine, and the consumption of organic bases is 1 ~ 10 times of substrate; Reaction solvent is the organic solvent of 1-10 carbon atom.
8. the preparation method of a kind of bendamustine hydrochloride dimerization impurity according to claim 1, it is characterized in that: in step (7), temperature of reaction is 80 DEG C-120 DEG C, and the reaction times is 1h-10h, reaction system pH is 8-14.
9. the preparation method of a kind of bendamustine hydrochloride dimerization impurity according to claim 1, it is characterized in that: in step (8), temperature of reaction is 5 DEG C-50 DEG C, reaction times is 10h-30h, and the mol ratio of [1-methyl-2-(4 '-butyric acid benzene methyl base)-5-N-(2 '-hydroxyethyl) – N '-(2 '-phenylethyl)]-1H-benzoglyoxaline and [1-methyl-2-(4 '-butyric acid base)-5-N-N-two (2 '-phenylethyl)]-1H-benzoglyoxaline is (0.5-5): 1; Reaction solvent is the organic solvent of 1-10 carbon atom; Wherein, condensation reagent is carbonyl dimidazoles, dicyclohexylcarbodiimide, DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, phenylbenzene chlorine phosphine oxide or N-bromo-succinimide.
10. the preparation method of a kind of bendamustine hydrochloride dimerization impurity according to claim 1, it is characterized in that: in step (9), 4-(6-dibenzylamine-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid 2-{ benzyl-[2-(3-Benzyloxycarbonyl-propyl)-3-methyl-3H-benzoglyoxaline-5-base]-amino } mol ratio of-ethyl ester and Pd/C is 100:(5 ~ 30), temperature of reaction is 10 DEG C-35 DEG C, and the reaction times is 72h-120h; The aqueous solutions of organic acids of reaction solvent to be massfraction be 1-6 the carbon atom of 10% ~ 80%, described organic acid is formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid or butanic acid; In step (10), the mol ratio of 4-(6-{2-[4-(6-amino-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyryl acyloxy]-ethylamino-}-1-methyl isophthalic acid H-benzimidazolyl-2 radicals-Ji)-butyric acid and oxyethane is 1:(10 ~ 200), react at-10 DEG C ~-5 DEG C reaction 2h-4h, or react 72h-120h at normal temperatures; The aqueous solutions of organic acids of reaction solvent to be massfraction be 1-6 the carbon atom of 10% ~ 80%, described organic acid is formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid or butanic acid.
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| CN102558069A (en) * | 2011-12-14 | 2012-07-11 | 武汉长联来福制药股份有限公司 | Method for preparing intermediate in process of preparing bendamustine hydrochloride |
| WO2012103226A2 (en) * | 2011-01-25 | 2012-08-02 | Dr. Reddy's Laboratories Ltd. | Bendamustine formulations |
| CN103443084A (en) * | 2011-01-31 | 2013-12-11 | 赛福伦公司 | Methods for preparing bendamustine |
| US20140080880A1 (en) * | 2012-09-18 | 2014-03-20 | Innopharma, Inc. | Bendamustine Formulations |
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| WO2012103226A2 (en) * | 2011-01-25 | 2012-08-02 | Dr. Reddy's Laboratories Ltd. | Bendamustine formulations |
| CN103443084A (en) * | 2011-01-31 | 2013-12-11 | 赛福伦公司 | Methods for preparing bendamustine |
| CN102558069A (en) * | 2011-12-14 | 2012-07-11 | 武汉长联来福制药股份有限公司 | Method for preparing intermediate in process of preparing bendamustine hydrochloride |
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