CN105085405A - Preparation method and application of 4-[1-methyl-5-(2-chloroethyl-2-ethoxyl)amino-2-benzimidazolyl]butyric acid hydrochloride - Google Patents
Preparation method and application of 4-[1-methyl-5-(2-chloroethyl-2-ethoxyl)amino-2-benzimidazolyl]butyric acid hydrochloride Download PDFInfo
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- CN105085405A CN105085405A CN201410188102.0A CN201410188102A CN105085405A CN 105085405 A CN105085405 A CN 105085405A CN 201410188102 A CN201410188102 A CN 201410188102A CN 105085405 A CN105085405 A CN 105085405A
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Abstract
The invention relates to a preparation method and application of 4-[1-methyl-5-(2-chloroethyl-2-ethoxyl)amino-2-benzimidazolyl]butyric acid hydrochloride as shown in a formula II. The preparation method comprises the steps of hydrolyzing bendamustine hydrochloride and performing column chromatography separation. The compound in the formula II can be used as a reference substance for detecting bendamustine hydrochloride related substances, and is used for controlling purity of raw materials or preparations of the bendamustine hydrochloride.
Description
Technical field
The present invention relates to preparation method and the application of 4-[1-methyl-5-(2-chloroethyl-2-hydroxyethyl) amido-2-benzimidazolyl-] butyrates hydrochlorate (i.e. monohydroxy bendamustine hydrochloride), monohydroxy bendamustine hydrochloride is the important impurity in bendamustine hydrochloride raw material or preparation process.
Background technology
Bendamustine hydrochloride obtains early than the development of the microbiological test association at Jena, Germany in 1963, is a kind of dual-functional group alkylating agent.After 1993, RibosepharmGmbH company completes the larger scale clinical proof test of bendamustine hydrochloride first, is gone on the market by German official approval after reunification, trade(brand)name
be mainly used in the treatment of Hodgkin's disease, non-Hodgkin lymphoma, plasmoma (multiple myeloma), chronic lymphocytic leukemia (CLL) and mammary cancer.On March 20th, 2008, the hydrochloride for injection bendamustine that FDA ratifies the exploitation of Cephalon company goes on the market in the U.S., for the treatment of " chronic lymphocytic leukemia (CLL) ", and trade(brand)name
on October 31 the same year, FDA ratifies again the treatment of this medicine for " accepting Mabthera or the inertia B cell non-Hodgkin lymphoma (NHL) containing progress in Mabthera scheme 6 months ".In July, 2010, Mundipharma company is with trade(brand)name
in Europe, listing is used for the treatment of NHL, CLL and multiple myeloma (MM), and in December, 2010, Eisai company of Japan was with trade(brand)name
listing is used for the treatment of NHL and lymphoma mantle cell (MCL).The chemical structural formula of bendamustine hydrochloride is such as formula shown in I:
About monohydroxy bendamustine hydrochloride (HP1, shown in formula II compound), document " InvestigationsontheStabilityofBendamustin, aCytostaticAgentoftheNitrogenMustardType, I.Synthesis, Isolation, andCharacterizationofReferenceSubstances " (Monatsheftefurchemie.128, 1997, 291-299), " degraded product in bendamustine hydrochloride clinical administration process and structural identification thereof " (Chinese Journal of New Drugs and Clinical Remedies 2013, 32 (3), 211-216) only its determination and analysis method is reported with patent documentation CN102375033A, do not relate to the concrete preparation of this compound.The synthetic method of CN103351346A to this compound is reported, in this patent documentation, with [1-methyl-2-(4 '-ethyl butyrate base)-5-is amino]-1H-benzoglyoxaline (shown in formula IV) for raw material, monohydroxy bendamustine hydrochloride is prepared again through four-step reaction, wherein all there is the complex operations such as column chromatography purification in first three step, make whole technological process longer, complicated operation, yield is lower; Simultaneously, chlorine atom in bendamustine and analogue structure thereof belongs to easy leavings group, complicated operation and the long chloroethyl that easily makes of preparation cycle is degraded into hydroxyethyl, generates two hydroxy bendamustine hydrochloride (shown in formula III), makes end product quality be difficult to ensure.
Therefore be necessary that a kind of more stable, more convenient, that quality is higher method of exploitation prepares monohydroxy bendamustine hydrochloride.
To the quality control of bendamustine hydrochloride raw material and preparation, up-to-standard impurity reference substance must be had.4-of the present invention [1-methyl-5-(2-chloroethyl-2-hydroxyethyl) amido-2-benzimidazolyl-] butyrates hydrochlorate is bendamustine hydrochloride impurity, can control the purity of bendamustine hydrochloride raw material or preparation as impurity reference substance.
Summary of the invention
One aspect of the present invention provides the preparation method of monohydroxy bendamustine hydrochloride, and its chemical structural formula is such as formula shown in II, and chemistry is called 4-[1-methyl-5-(2-chloroethyl-2-hydroxyethyl) amido-2-benzimidazolyl-] butyrates hydrochlorate.
Document " study on the synthesis of bendamustine hydrochloride " (Strait Pharmaceutical Journal; 2011; 23 (11); 227-229) report the synthesis of bendamustine hydrochloride; be starting raw material with DNFB, be substituted, reduce, acidylate, cyclization and reduction; obtain [1-methyl-2-(4 '-ethyl butyrate base)-5-amino]-1H-benzoglyoxaline (shown in formula IV), then be substituted, chloro and hydrolysis obtain bendamustine hydrochloride.Whole technological operation is simple and efficient, does not have column chromatography purification step, is applicable to suitability for industrialized production.
The present invention is preparing on the basis of bendamustine hydrochloride with reference to above-mentioned document " study on the synthesis of bendamustine hydrochloride ", the bendamustine hydrochloride impurity developed---the new synthetic method of-monohydroxy bendamustine hydrochloride.Compare with CN103351346A, patent of the present invention adopts the method for stable process conditions, obtains monohydroxy bendamustine hydrochloride by an one-step hydrolysis and purifying, solves convenience and the stability of the acquisition of this impurity; The particularly important is, the present invention studies in detail monohydroxy bendamustine hydrochloride purification process, filter out more stable column chromatography for separation condition, purity is higher, make two hydroxy bendamustine hydrochloride content drop to 0.2% (HPLC method) below, monohydroxy bendamustine hydrochloride HPLC purity can reach more than 99%.Preparation condition gentleness of the present invention is controlled, can prepare highly purified monohydroxy bendamustine hydrochloride efficiently and easily.
The preparation process of monohydroxy bendamustine hydrochloride: the bendamustine hydrochloride of formula I is hydrolyzed reaction by (1) in reaction soln; (2) after hydrolysis reaction, then obtain monohydroxy bendamustine hydrochloride by column chromatography method separation, concentrated, lyophilize obtains monohydroxy bendamustine hydrochloride.
Further, the reaction soln described in step (1) is water or basic solution.
Further, described basic solution is selected from the aqueous solution of one or more of salt of wormwood, sodium carbonate, cesium carbonate, saleratus, sodium bicarbonate, potassium hydroxide or sodium hydroxide, and basic solution concentration expressed in percentage by weight is not more than 5%.
Further, when described reaction soln is basic solution, is also included in step (1) and regulates the pH value of reaction soln to 1 ~ 5 after hydrolysis reaction.
Further, described in step (1), hydrolysising reacting temperature is 25 ~ 70 DEG C, and the reaction times is 1 ~ 3h.
Further, column chromatography method described in step (2) uses octadecylsilane chemically bonded silica (ODS-C
18) be separated, moving phase is selected from the mixed solution of acetonitrile and dilute hydrochloric acid, methyl alcohol and dilute hydrochloric acid.
Further, the pH of dilute hydrochloric acid is 1 ~ 5.
Further, the pH of dilute hydrochloric acid is 2 ~ 3.
On the other hand, the invention provides the purposes of compound 4-[1-methyl-5-(2-chloroethyl-2-hydroxyethyl) amido-2-benzimidazolyl-] the butyrates hydrochlorate of preparation, it can be used as the related substance detection reference substance of bendamustine hydrochloride, for the quality control of bendamustine hydrochloride and related preparations thereof.
The hydrochloride aqueous solution of dilute hydrochloric acid described in the present invention for obtaining after concentrated hydrochloric acid and water mixing, concentrated hydrochloric acid volumetric molar concentration is not more than 12mol/L, and described dilute hydrochloric acid concentration controls 10
-1~ 10
-5between mol/L, its pH value is 1 ~ 5.
The beneficial effect of the technical solution used in the present invention is simple operation, and reaction conditions gentleness is controlled, greatly improves the stability of reaction, and reaction product purity is high.
Formula II compound structure is through nuclear magnetic resonance spectrum and mass spectrum confirmation, and concrete data are: mass spectrum (MS): m/z=340 [M+H]
+, m/z=338 [M-H]
+; High resolution mass spectrum (HRMS): m/z=340.1431 [M+H]
+, m/z=338.1274 [M-H]
+;
1hNMR (DMSO-d
6) δ 15.04 (br, 1H), 7.70 (d, 1H), 7.10 (dd, 1H), 6.90 (d, 1H), 3.91 (s, 3H), 3.78 (s, 4H), 3.59 (t, 2H), 3.55 (t, 2H), 3.18 (t, 2H), 2.42 (t, 2H), 2.42 (m, 2H);
13c-NMR (DMSO-d
6) δ 173.5,151.3,146.3,131.5,124.2,113.2,112.2,94.1,57.9,53.4,52.8,40.8,32.6,30.9,23.9,21.6.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of monohydroxy bendamustine hydrochloride.
Embodiment
The present invention will in hereafter by the more detailed description of embodiment, and these embodiments exemplarily for further illustrating, and should not be considered as limitation of the present invention.
Embodiment compounds of formula I (bendamustine hydrochloride) is according to document " study on the synthesis of bendamustine hydrochloride " (Strait Pharmaceutical Journal; 2011; 23 (11); the synthetic method of bendamustine hydrochloride 227-229) reported; with 2; 4-dinitrochlorobenzene is starting raw material, is substituted, reduces, acidylate, cyclization, reduction, replacement, chloro and hydrolysis prepare bendamustine hydrochloride.Other materials and reagent are commercially.
The preparation of monohydroxy bendamustine hydrochloride
Embodiment 1:
Formula I (1g) and 5%K
2cO
35ml mix and blend, is heated to 25 DEG C, reacts 1 hour, and regulate pH to 5 with the hydrochloric acid soln of 3mol/L, add acetonitrile, filter, mother liquor adopts column chromatography method purifying.Concrete column chromatography condition: silica gel is octadecylsilane chemically bonded silica (ODS-C
18), moving phase is dilute hydrochloric acid (pH is 5): acetonitrile=3:1 (volume ratio), and flow velocity is 2ml/ minute, collects corresponding component, and concentrating under reduced pressure postlyophilization below 10 DEG C, obtains 0.35g Compound II per, HPLC purity 99.5%.
Embodiment 2:
Formula I (3g) and 5%NaHCO
325ml mix and blend, is heated to 35 DEG C, reacts 2 hours, and regulate pH to 2 with the hydrochloric acid soln of 3mol/L, add acetonitrile, filter, mother liquor adopts column chromatography method purifying.Concrete column chromatography condition: silica gel is octadecylsilane chemically bonded silica (ODS-C
18), moving phase is dilute hydrochloric acid (pH is 2): acetonitrile=3:1 (volume ratio), and flow velocity is 5ml/ minute, collects corresponding component, and concentrating under reduced pressure postlyophilization below 10 DEG C, obtains 0.72g Compound II per, HPLC purity 99.1%.
Embodiment 3:
Formula I (0.5g) and 0.5%NaOH5ml mix and blend, be heated to 25 DEG C, reacts 1 hour, and regulate pH to 1 with the hydrochloric acid soln of 3mol/L, add methyl alcohol, filter, mother liquor adopts column chromatography method purifying.Concrete column chromatography condition: silica gel is octadecylsilane chemically bonded silica (ODS-C
18), moving phase is dilute hydrochloric acid (pH is 3): acetonitrile=3:1 (volume ratio), and flow velocity is 1ml/ minute, collects corresponding component, and concentrating under reduced pressure postlyophilization below 10 DEG C, obtains 0.13g Compound II per, HPLC purity 99.2%.
Embodiment 4:
Formula I (10g) and water 50ml mix and blend, be heated to 70 DEG C, reacts 3 hours, and cooling, adds after methyl alcohol makes dissolution of solid and adopt column chromatography method purifying.Concrete column chromatography condition: silica gel is octadecylsilane chemically bonded silica (ODS-C
18), moving phase is dilute hydrochloric acid (pH is 2.8): methyl alcohol=3:1 (volume ratio), and flow velocity is 6ml/ minute, collects corresponding component, and concentrating under reduced pressure postlyophilization below 10 DEG C, obtains 3.42g Compound II per, HPLC purity 99.3%.
Claims (10)
1. a preparation method for the monohydroxy bendamustine hydrochloride of formula II, is characterized in that comprising the steps:
(1) be hydrolyzed the bendamustine hydrochloride of formula I in reaction soln reaction;
(2) after hydrolysis reaction, then be separated by column chromatography method, concentrated, lyophilize obtains monohydroxy bendamustine hydrochloride;
2. preparation method according to claim 1, is characterized in that: the reaction soln described in step (1) is basic solution or water.
3. preparation method according to claim 2, is characterized in that: described basic solution is selected from the aqueous solution of one or more of salt of wormwood, sodium carbonate, cesium carbonate, saleratus, sodium bicarbonate, potassium hydroxide or sodium hydroxide.
4. preparation method according to claim 2, is characterized in that: described basic solution concentration expressed in percentage by weight is not more than 5%.
5. the preparation method according to claim 3 or 4, is also included in step (1) and regulates the pH value of reaction soln to 1 ~ 5 after hydrolysis reaction.
6. the preparation method according to any one of claim 1-4, is characterized in that: in step (1), the temperature of hydrolysis reaction is 25 ~ 70 DEG C, and the reaction times is 1 ~ 3h.
7. preparation method according to claim 1, is characterized in that: column chromatography method described in step (2) uses octadecylsilane chemically bonded silica to be separated, and moving phase is selected from the mixed solution of acetonitrile and dilute hydrochloric acid, methyl alcohol and dilute hydrochloric acid.
8. preparation method according to claim 7, is characterized in that: the pH value of described dilute hydrochloric acid is 1 ~ 5.
9. preparation method according to claim 7, is characterized in that: the pH value of described dilute hydrochloric acid is 2 ~ 3.
10. the application of monohydroxy bendamustine hydrochloride according to claim 1 in the impurity reference substance preparing bendamustine hydrochloride raw material or preparation.
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| CN201410188102.0A CN105085405A (en) | 2014-05-06 | 2014-05-06 | Preparation method and application of 4-[1-methyl-5-(2-chloroethyl-2-ethoxyl)amino-2-benzimidazolyl]butyric acid hydrochloride |
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| CN201410188102.0A CN105085405A (en) | 2014-05-06 | 2014-05-06 | Preparation method and application of 4-[1-methyl-5-(2-chloroethyl-2-ethoxyl)amino-2-benzimidazolyl]butyric acid hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107129437A (en) * | 2016-02-29 | 2017-09-05 | 江苏先声药业有限公司 | The preparation method of 4- [(2- chloroethyl -2- ethoxys) amino -]-L-phenylalanine hydrochloride and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102375033A (en) * | 2010-08-18 | 2012-03-14 | 重庆华邦胜凯制药有限公司 | High performance liquid chromatographic analysis method of bendamustine hydrochloride and its related substances |
| CN103351346A (en) * | 2013-07-29 | 2013-10-16 | 东南大学 | Preparation method of impurity HP1 in bendamustine hydrochloride |
-
2014
- 2014-05-06 CN CN201410188102.0A patent/CN105085405A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102375033A (en) * | 2010-08-18 | 2012-03-14 | 重庆华邦胜凯制药有限公司 | High performance liquid chromatographic analysis method of bendamustine hydrochloride and its related substances |
| CN103351346A (en) * | 2013-07-29 | 2013-10-16 | 东南大学 | Preparation method of impurity HP1 in bendamustine hydrochloride |
Non-Patent Citations (6)
| Title |
|---|
| H.WEBER,等: "Pharmacokinetics of bendamustin (Cytostasan) in B6D2F1-mice", 《PHARMAZIE》 * |
| R. GUST,等: "Investigations on the Stability of Bendamustin,a Cytostatic Agent of the Nitrogen Mustard Type, I. Synthesis, Isolation, and Characterization of Reference Substances", 《MONATSHEFTE FUER CHEMIE》 * |
| W.WERNER,等: "Hydrolysis products of the antitumor drug Cytostasan(bendamustin)", 《PHARMAZIE》 * |
| 刘珍仁,等: "盐酸苯达莫司汀临床给药过程中的降解产物及其结构确证", 《中国新药与临床杂志》 * |
| 宗在伟,等: "盐酸苯达莫司汀的合成研究", 《海峡药学》 * |
| 彭安顺,等: "《有机化学》", 30 September 2012 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107129437A (en) * | 2016-02-29 | 2017-09-05 | 江苏先声药业有限公司 | The preparation method of 4- [(2- chloroethyl -2- ethoxys) amino -]-L-phenylalanine hydrochloride and application |
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Inventor after: Zhang Liandi Inventor after: Liao Mingyi Inventor after: Yang Shaoning Inventor after: Ren Jinsheng Inventor after: Ding Lei Inventor before: Zhang Liandi Inventor before: Liao Mingyi Inventor before: Yang Shaoning Inventor before: Ding Lei |
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Application publication date: 20151125 |