CN105272920B - Bendamustine hydrochloride mannitol ester and preparation method and application thereof - Google Patents
Bendamustine hydrochloride mannitol ester and preparation method and application thereof Download PDFInfo
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- CN105272920B CN105272920B CN201410341785.9A CN201410341785A CN105272920B CN 105272920 B CN105272920 B CN 105272920B CN 201410341785 A CN201410341785 A CN 201410341785A CN 105272920 B CN105272920 B CN 105272920B
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- 229960001215 bendamustine hydrochloride Drugs 0.000 title claims abstract description 47
- 229930195725 Mannitol Natural products 0.000 title claims abstract description 23
- 239000000594 mannitol Substances 0.000 title claims abstract description 23
- 235000010355 mannitol Nutrition 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- -1 Bendamustine hydrochloride mannitol ester Chemical class 0.000 title abstract description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 44
- 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 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims abstract description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 13
- 238000004440 column chromatography Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 8
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 5
- 239000000377 silicon dioxide Substances 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 9
- 238000002347 injection Methods 0.000 abstract description 8
- 239000007924 injection Substances 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 5
- 239000013558 reference substance Substances 0.000 abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 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
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229960004641 rituximab Drugs 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 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
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 208000011821 Indolent B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 241000764238 Isis Species 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to bendamustine hydrochloride impurities shown as a formula IV and a preparation method thereof. The preparation method comprises reacting bendamustine hydrochloride with mannitol in hydrochloric acid solution to obtain bendamustine hydrochloride mannitol ester (shown in formula IV). The compound shown in the formula IV can be used as a reference substance for detecting related substances of bendamustine hydrochloride for injection and is used for controlling the purity of bendamustine hydrochloride preparations.
Description
Technical Field
The invention relates to (2R,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl 4- [ 1-methyl-5-bis (2-chloroethyl) amino-2-benzimidazolyl ] butyrate hydrochloride (bendamustine hydrochloride mannitol ester) and a preparation method and application thereof, wherein the bendamustine hydrochloride mannitol ester is an important impurity in a bendamustine hydrochloride preparation process.
Background
Bendamustine hydrochloride was first developed in 1963 by the microbiological testing institute in jena, germany and was a bifunctional alkylating agent. After 1993, the company Riboserem GmbH first completed a large-scale clinical verification test of bendamustine hydrochloride, which was approved to be on the market by German after unification, and the trade name of the bendamustine hydrochloride is
Is mainly used for treating Hodgkin's disease, non-Hodgkin's lymphoma, plasmacytoma (multiple myeloma), Chronic Lymphocytic Leukemia (CLL) and breast cancer. Bendamustine hydrochloride for injection developed by FDA-approved Cephalon corporation, marketed in the united states for the treatment of "Chronic Lymphocytic Leukemia (CLL)" on 20/3/2008, under the trade name
On 31 days 10 months in the same year, FDA further approved the drug for use in "indolent B cell non-Hodgkin's lymphoma (NHL) that received rituximab or progressed within 6 months of the rituximab-containing regimen) "treatment of the disease. 7.2010, Mundiphiharma under the trade name
Marketed in Europe for the treatment of NHL, CLL and Multiple Myeloma (MM) under the trade name Eisai, 12 months and a year 2010Marketed for the treatment of NHL and Mantle Cell Lymphoma (MCL). The chemical structural formula of bendamustine hydrochloride is shown as formula I:
in the production of bendamustine hydrochloride preparations, mannitol (shown in formula V) is selected as an excipient, and finally a clinical product, namely bendamustine hydrochloride for injection, is obtained. The inventor of the application finds that bendamustine hydrochloride and mannitol which is an excipient of the bendamustine hydrochloride can react to generate bendamustine hydrochloride mannitol ester (BM1 mannitol ester), namely the compound shown in the formula IV in the process of quality research of the bendamustine hydrochloride for injection. The level of this impurity increases as the length of time that bendamustine hydrochloride is allowed to remain for injection increases.
Because the bendamustine hydrochloride preparation is a freeze-dried powder injection and directly enters a human body in an injection mode, the impurities are very necessary to be deeply researched, the quality control of the product is enhanced, and the quality of the medicine and the life safety of a patient using the medicine are ensured.
For quality control of bendamustine hydrochloride preparations, quality-qualified impurity controls are required. The (2R,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl 4- [ 1-methyl-5-bis (2-chloroethyl) amino-2-benzimidazolyl ] butyrate hydrochloride is bendamustine hydrochloride impurity, and can be used as an impurity reference substance to control the quality of a bendamustine hydrochloride preparation.
The structural formula and the preparation method of the bendamustine hydrochloride impurity, namely bendamustine hydrochloride mannitol ester, are not reported at home and abroad.
Disclosure of Invention
The first object of the present invention is to provide a novel compound, bendamustine hydrochloride mannitol ester, having the chemical name: (2R,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl 4- [ 1-methyl-5-bis (2-chloroethyl) amino-2-benzimidazolyl ] butyrate hydrochloride, and the chemical structural formula is shown in a formula IV:
a second object of the present invention is to provide a process for the preparation of the compound of formula IV. The invention relates to a synthesis method of bendamustine hydrochloride mannitol ester (shown in formula IV) which is developed by preparing bendamustine hydrochloride through a strait pharmaceutical preparation 2011, 23(11), 227-. The specific synthetic route is as follows:
the preparation steps of the compound shown in the formula IV are as follows: the bendamustine hydrochloride is used as a starting material and is obtained by reacting with mannitol in a hydrochloric acid solution.
Further, the preparation steps include: step (1): bendamustine hydrochloride (shown in formula I) is used as a starting material and reacts with mannitol in hydrochloric acid; step (2): and (3) purifying the reaction liquid obtained in the step (1) by adopting column chromatography to obtain bendamustine hydrochloride mannitol ester.
Further, as a reaction solvent, the hydrochloric acid solution is selected from hydrochloric acid having a concentration of not less than 6 mol/L.
Still further, the hydrochloric acid solution is preferably concentrated hydrochloric acid.
Further, the column chromatography was carried out using octadecylsilane chemically bonded silica (ODS-C)18) Separating to obtain mobile phase of mixed solution of acetonitrile and dilute hydrochloric acid.
Further, the pH of the dilute hydrochloric acid is between 1 and 3.
The dilute hydrochloric acid in the column chromatography purification step is a hydrogen chloride water solution obtained by mixing concentrated hydrochloric acid and water, and the molar concentration of the hydrogen chloride water solution is not more than 12 mol/L. In the invention, the concentration of the dilute hydrochloric acid is controlled to be 10-1～10-3The pH value is 1-3 between mol/L. The concentration of the concentrated hydrochloric acid is 12 mol/L.
The third object of the invention is to provide the use of the hydrochloride of the compound (2R,3R,4R,5R) -2,3,4,5, 6-pentahydroxyhexyl 4- [ 1-methyl-5-bis (2-chloroethyl) amino-2-benzimidazolyl ] butyrate of the formula IV as a reference substance for detecting the bendamustine hydrochloride related substances for injection, and the hydrochloride is used for the quality control of bendamustine hydrochloride preparations.
The technical scheme adopted by the invention has the advantages that: firstly, a novel compound is provided, and the quality of the preparation is better controlled by using the novel compound as a reference substance of bendamustine hydrochloride impurities; secondly, the preparation method of the bendamustine hydrochloride mannitol ester is provided, the method is convenient to operate, the reaction conditions are mild and controllable, the reaction process and the post-treatment purification process keep an acidic environment, the degradation of the prepared bendamustine hydrochloride mannitol ester in the purification process can be effectively avoided, and the purity of the obtained reaction product is high.
The structure of the compound shown in formula IV in example 1 is confirmed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the specific data are as follows: mass Spectrum (MS): 522[ M + H ] M/z]+，m/z＝520[M-H]+(ii) a High Resolution Mass Spectrometry (HRMS): 522.1777[ M + H ] M/z]+，m/z＝520.1620[M-H]+；1H NMR(DMSO-d6)δ14.81(br,1H),7.73(d,1H),7.13(dd,1H),6.93(d,1H),5.27(br,5H),4.28(dd,1H),4.00(dd,1H),3.91(s,3H),3.83(t,4H),3.78(t,4H),3.71(ddd,1H),3.62(dd,1H),3.57(t,2H),3.48(ddd,1H),3.40(dd,1H),3.20(t,2H),2.51(t,2H),2.08(m,2H)；13C-NMR(DMSO-d6)δ172.2,151.6,145.7,131.5,124.7,113.4,112.4,94.7,71.1,69.5,69.3,68.1,67.1,63.8,52.4,41.0,32.5,31.0,23.8,21.6。
Detailed Description
The invention will be described in more detail hereinafter by means of examples, which are intended to be illustrative further and should not be construed as limiting the invention.
In the examples, the compound of formula I (bendamustine hydrochloride) is prepared by using 2, 4-dinitrochlorobenzene as a starting material and performing substitution, reduction, acylation, cyclization, reduction, substitution, chlorination and hydrolysis according to the synthesis method of bendamustine hydrochloride reported in the literature "research on the synthesis of bendamustine hydrochloride" (strait pharmaceutical, 2011, 23(11), 227-. Other materials and reagents are commercially available.
Example 1: preparation of Compounds of formula IV
Mixing 0.35g of bendamustine hydrochloride, 0.33g of mannitol and 10mL of concentrated hydrochloric acid, stirring, reacting at room temperature for 3 days, adding 30mL of purified water for dilution, and purifying by column chromatography. The specific column chromatography conditions are as follows: the silica gel is octadecylsilane chemically bonded silica (ODS-C)18) The mobile phase is diluted hydrochloric acid (pH 3): acetonitrile 5: 1 (volume ratio), flow rate 1 ml/min, determination of the different fractions by Mass Spectrometry (MS), collection of M/z 522[ M + H ]]+ fraction, concentrated at below 5 ℃ to remove acetonitrile, and freeze-dried to yield 0.19g of Compound IV. The molar yield was 38.34%, with an HPLC purity of 96.9%.
Example 2: preparation of Compounds of formula IV
0.21g of bendamustine hydrochloride, 0.58g of mannitol and 10mL of 6mol/L diluted hydrochloric acid are mixed and stirred, reacted for 5 days at room temperature, added with 30mL of purified water for dilution, and purified by adopting a column chromatography method. The specific column chromatography conditions are as follows: the silica gel is octadecylsilane chemically bonded silica (ODS-C)18) The mobile phase is diluted hydrochloric acid (pH 3): acetonitrile 5: 1 (volume ratio), flow rate 1 ml/min, determination of the different fractions by Mass Spectrometry (MS), collection of M/z 522[ M + H ]]+ fraction, concentrated at below 10 ℃ to remove acetonitrile, and freeze-dried to yield 0.13g of Compound IV. The molar yield was 43.7% and the HPLC purity 97.6%.
Example 3: preparation of Compounds of formula IV
2g of bendamustine hydrochloride, 3.69g of mannitol and 15ml of concentrated hydrochloric acid are mixed and stirred, reacted for 3 days at room temperature, diluted by 55ml of purified water and purified by a column chromatography method. The specific column chromatography conditions are as follows: the silica gel is octadecylsilane chemically bonded silica (ODS-C)18) The mobile phase is diluted hydrochloric acid (pH 1): acetonitrile 3:1 (volume ratio) at a flow rate of 3 ml/min, the different fractions were determined by Mass Spectrometry (MS), and M/z 522[ M + H ] was collected]+ fraction, concentrated at below 5 ℃ to remove acetonitrile, and freeze-dried to yield 0.96g of Compound IV. The molar yield was 33.9% and the HPLC purity 98.2%.
Claims (2)
1. A process for the preparation of a compound of formula IV, characterized in that: the method comprises the following steps:
step (1): bendamustine hydrochloride of the formula I is used as a starting material and reacts with mannitol in a hydrochloric acid solution;
step (2): purifying the reaction liquid obtained in the step 1 by adopting column chromatography to obtain a compound shown in a formula IV;
the concentration of the hydrochloric acid solution is not lower than 6mol/L, and the molar ratio of the mannitol to the bendamustine hydrochloride is 4: 1-6: the column chromatography uses octadecylsilane chemically bonded silica for separation, the mobile phase is a mixed solution of acetonitrile and dilute hydrochloric acid, and the pH value of the dilute hydrochloric acid is 1-3.
2. A process for the preparation of a compound of formula IV according to claim 1, characterized in that: the hydrochloric acid solution is concentrated hydrochloric acid.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410341785.9A CN105272920B (en) | 2014-07-17 | 2014-07-17 | Bendamustine hydrochloride mannitol ester and preparation method and application thereof |
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| CN201410341785.9A CN105272920B (en) | 2014-07-17 | 2014-07-17 | Bendamustine hydrochloride mannitol ester and preparation method and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101119708A (en) * | 2005-01-14 | 2008-02-06 | 赛福伦公司 | Bendamustine pharmaceutical compositions |
| CN103351347A (en) * | 2013-07-29 | 2013-10-16 | 东南大学 | Preparation method of impurity DCE in bendamustine hydrochloride |
-
2014
- 2014-07-17 CN CN201410341785.9A patent/CN105272920B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101119708A (en) * | 2005-01-14 | 2008-02-06 | 赛福伦公司 | Bendamustine pharmaceutical compositions |
| CN103351347A (en) * | 2013-07-29 | 2013-10-16 | 东南大学 | Preparation method of impurity DCE in bendamustine hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| Development and validation of RP-HPLC method for determination of related substances of bendamustine hydrochloride in bulk drug;E. Sasi Kiran Goud，等;《Der Pharmacia Sinica》;20131231;第4卷(第1期);29-36 * |
| Stability-Indicating LC Method for the Estimation of Bendamustine Hydrochloride and its Related Impurities;Srinivasulu Kasa，等;《Journal of Chromatographic Science》;20141231;第52卷;573-583 * |
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