CN108484704A - A kind of preparation method of gemcitabine hydrochloride oxidation impurities - Google Patents
A kind of preparation method of gemcitabine hydrochloride oxidation impurities Download PDFInfo
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- CN108484704A CN108484704A CN201810184380.7A CN201810184380A CN108484704A CN 108484704 A CN108484704 A CN 108484704A CN 201810184380 A CN201810184380 A CN 201810184380A CN 108484704 A CN108484704 A CN 108484704A
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- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
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- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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Abstract
The present invention provides a kind of preparation methods of gemcitabine hydrochloride oxidation impurities, include the following steps：Using gemcitabine hydrochloride as starting material, passes through bromo-reaction and hydrolysis successively, obtain oxidation impurities (1).The advantage of the invention is that：Agents useful for same is simple and easy to get, and synthetic route is brief, easy to operate, and yield is higher, and the purity of gained impurity product is higher (99% or more HPLC purity), can be applied to research of the chemical standard product.
Description
Technical field
The invention belongs to medicinal chemistry arts, in particular to a kind of preparation side of gemcitabine hydrochloride oxidation impurities
Method.
Background technology
Gemcitabine hydrochloride (Gemcitabine hydrochloride), chemical name：2- deoxidation -2,2- hydrochloric acid difluoros are de-
Oxygen cytidine (β-isomers) is that one kind that Lilly Co., Eli. (Eli Lilly and Company) develops in nineteen eighty-three is novel
Difluoronucleosides series antineoplastic medicament, the medicine are approved to list in nineteen ninety-five in countries such as South Africa, Sweden, Holland, Australia, and 1996
Year is granted in U.S. FDA, and trade name gemzar (Gemzar) is clinically used for non-small cell lung cancer and the first-line treatment of cancer of pancreas,
It is the goldstandard of current treatment advanced pancreatic cancer.The end of the year 2000 were approved for treatment carcinoma of urinary bladder.Gemcitabine hydrochloride is at present
Through obtaining extensive clinical application in more than 100 a countries.In American-European and Asia, it is approved for the one of metastatic breast cancer
The treatment of the oophoroma recurred after line treatment, platinum class treatment.
The oxidation impurities of drug are to influence one of the principal element of drug quality, to the preparations of bulk pharmaceutical chemicals and pharmaceutical preparation,
Stability and bioavilability etc. have very important influence.Gemcitabine hydrochloride is as a kind of novel Difluoronucleosides class
Antitumor drug all there is apparent advantage therefore to be aoxidized to it in treatment advanced pancreatic cancer and in terms of reducing adverse reaction
Miscellaneous Quality Research is of great significance.By the research to gemcitabine hydrochloride oxidation impurities, analysis medicine that can be qualitative, quantitative
The level of impurity in product provides guarantee so as to improve the quality standard of gemcitabine hydrochloride for the safe medication of patient.
Keep sample to test through forced degradation experiment, influence factor experiment and stability and confirm, gemcitabine hydrochloride is in oxidation and storage for a long time
Storage may generate following oxidation impurities during setting：
Invention content
In order to improve the quality of gemcitabine hydrochloride, the risk of clinical application is reduced, the present invention provides a kind of new systems
For the chemical method of gemcitabine hydrochloride oxidation impurities, chemical reagent is simple and easy to get used in this method, easy to operate, high income,
Impurity product obtained can product as a contrast, the purity for controlling, detecting gemcitabine hydrochloride.
The object of the present invention is to provide a kind of preparation methods of new gemcitabine hydrochloride oxidation impurities.
In embodiments of the invention, the present invention provides a kind of preparation sides of gemcitabine hydrochloride oxidation impurities (1)
Method includes the following steps：
Using gemcitabine hydrochloride as starting material, successively through bromo-reaction and hydrolysis, to obtain 4- amino -1-
(bis- fluoro- 4- hydroxyls -5- hydroxymethyl tetrahydrofuran -2- bases of (2R, 4R, 5R) -3,3-) -5- hydroxy pyrimidines -2 (1H) -one, that is, aoxidize
Impurity (1), specific reaction equation are as follows:
In embodiments of the invention, the preparation side of a kind of gemcitabine hydrochloride oxidation impurities (1) provided by the invention
Method, wherein brominated reagent is used in the bromo-reaction, the brominated reagent is bromine.
In embodiments of the invention, the preparation side of a kind of gemcitabine hydrochloride oxidation impurities (1) provided by the invention
Method, wherein the hydrolysis uses hydrolysing agent, and the hydrolysing agent can be selected from n,N-diisopropylethylamine
(DIPEA), trimethylpyridine or sodium hydroxide, preferably DIPEA.
In embodiments of the invention, the preparation side of a kind of gemcitabine hydrochloride oxidation impurities (1) provided by the invention
Method, wherein the molar ratio of starting material and brominated reagent is 1 in the bromo-reaction:0.1~10.
In embodiments of the invention, the preparation side of a kind of gemcitabine hydrochloride oxidation impurities (1) provided by the invention
Method, wherein the molar ratio of starting material (i.e. gemcitabine hydrochloride) and the hydrolysing agent in the hydrolysis is 1:0.1~
20。
In embodiments of the invention, the preparation side of a kind of gemcitabine hydrochloride oxidation impurities (1) provided by the invention
Method, wherein the reaction temperature of the bromo-reaction is 0~20 DEG C, and the reaction time is 0.5~3h.
In embodiments of the invention, the preparation side of a kind of gemcitabine hydrochloride oxidation impurities (1) provided by the invention
Method, wherein the reaction temperature of the hydrolysis is 20~90 DEG C, and the reaction time is 0.5~50h.
Compared with prior art, the preparation method of gemcitabine hydrochloride oxidation impurities (1) provided by the invention has used
Reagent is simple and easy to get, and synthetic route is brief, easy to operate, and yield is higher, higher (the HPLC purity 99% of gained impurity product purity
More than), the features such as can be applied to research of the chemical standard product.
Specific implementation mode
It will be helpful to understand the present invention by following embodiments, but do not limit present disclosure.
Embodiment 1
Gemcitabine hydrochloride (10g, 0.033mol) is taken, 280ml water stirring and dissolvings are added, is cooled to 0~5 DEG C, liquid feeding bromine
(9ml, 0.176mol), the system color of waiting for no longer disappears, insulated and stirred 1h, and the washing of 120ml n-hexanes is added into system and removes
Excessive bromine collects water phase.DIPEA (100ml, 0.574mol) is added into water phase, 1.6g tetra-n-butyl ammonium bromides are added,
It is warming up to 55~60 DEG C and is stirred to react 1h, HPLC monitors reaction process, and room temperature is down to after the completion of reaction, and liquid separation retains water phase, water
It is mutually washed with 100ml dichloromethane, water phase is concentrated to dryness, 70ml toluene band water is used in combination, rufous is obtained after concentration
Grease filters after being repeatedly beaten with water, and filter cake is dissolved with methanol, and filtering is spin-dried for obtaining dark gray solid (6.58g, 70.8%),
As gemcitabine hydrochloride oxidation impurities (1).Characterization of The Products data are shown in embodiment 5.
Embodiment 2
Gemcitabine hydrochloride (10g, 0.033mol) is taken, adds 280ml purified water stirring and dissolvings, is cooled to 0~5 DEG C, liquid feeding
Bromine (9ml, 0.176mol), the system color of waiting for no longer disappears, insulated and stirred 1h, and the washing of 120ml n-hexanes is added into system and removes
Excessive bromine is gone, water phase is collected.Trimethylpyridine (45ml, 0.34mol) is added into water phase, 1.6g tetra-n-butyl bromines are added
Change ammonium, be stirred to react 48h at room temperature, HPLC monitors reaction process, and room temperature is down to after the completion of reaction, and liquid separation retains water phase, water phase
It is washed with 100ml dichloromethane, water phase is concentrated to dryness, 70ml toluene band water is used in combination, rufous oil is obtained after concentration
Shape object filters after being repeatedly beaten with water, and filter cake is dissolved with methanol, and filtering is spin-dried for obtaining dark gray solid (2.01g, 21.6%), i.e.,
For gemcitabine hydrochloride oxidation impurities (1).Characterization of The Products data are shown in embodiment 5.
Embodiment 3
Gemcitabine hydrochloride (10g, 0.033mol) is taken, adds 280ml purified water stirring and dissolvings, is cooled to 0~5 DEG C, liquid feeding
Bromine (9ml, 0.176mol), the system color of waiting for no longer disappears, insulated and stirred 1h, and the washing of 120ml n-hexanes is added into system and removes
Excessive bromine is gone, water phase is collected.Sodium hydroxide (3.96g, 0.099mol) is added into water phase, 1.6g tetra-n-butyl bromines are added
Change ammonium, is warming up to 85~90 DEG C and is stirred to react 18h, HPLC monitors reaction process, and room temperature is down to after the completion of reaction, and liquid separation retains
Water phase, water phase are washed with 100ml dichloromethane, water phase are concentrated to dryness, and 70ml toluene band water is used in combination, after concentration
Rufous grease filters after being repeatedly beaten with water, and filter cake is dissolved with methanol, filtering, be spin-dried for dark gray solid (1.31g,
14.1%), as gemcitabine hydrochloride oxidation impurities (1).Characterization of The Products data are shown in embodiment 5.
HPLC method for detecting purity of the embodiment 4 in relation to gemcitabine hydrochloride oxidation impurities (1)：
Example 1 prepare gemcitabine hydrochloride oxidation impurities (1), be dissolved in water and dilute be made in every 1ml containing about
The solution of gemcitabine hydrochloride oxidation impurities (1) 2mg, shakes up, as test solution.Use octyl silane group silica gel for
Filler (is taken sodium dihydrogen phosphate 13.8g and phosphoric acid 2.5ml, is dissolved in water and is diluted to 0.14mol/L phosphate buffers
1000ml, pH value should be 2.5 ± 0.1) (volume ratio of 0.14mol/L phosphate buffers and methanol is 97 to-methanol：3) it is stream
Dynamic phase A, with 0.14mol/L phosphate buffer salts-methanol, (volume ratio of 0.14mol/L phosphate buffers and methanol is 50:
50) it is Mobile phase B, according to the form below progress gradient elution, coutroi velocity 1.0ml/min, Detection wavelength 275nm, column temperature 25
DEG C, precision measures 20 μ l test solutions injection liquid chromatograph (1260 high performance liquid chromatographs of Agilent), records chromatography
Figure and result.
Gradient elution table
The result of the chromatogram is as follows：
| It numbers at peak | Retention time | Type | Peak width (min) | Peak area mAus | Peak height (mAu) | Peak area % |
| 1 | 10.613 | BB | 0.2281 | 1918.05322 | 129.53123 | 100.0000 |
| It amounts to | 1918.05322 | 129.53123 |
Embodiment 5 gemcitabine hydrochloride oxidation impurities (1) structural identification data
Ultra-violet absorption spectrum, infrared absorption spectrum, mass spectrum and the nuclear magnetic resonance of product prepared by embodiment 1 are measured respectively
Spectrum, another embodiment 2 and 3 structural identification data of embodiment are the same as embodiment 1.
Ultra-violet absorption spectrum (UV)：Shimadzu UV-2500PC ultraviolet spectrometers, solvent are methanol, wavelength is 200~
500nm。
Ultra-violet absorption spectrum (UV) data
| Solvent | λmax(nm) | ε | λmax(nm) | ε |
| Methanol | 294.5 | 6675 | 220.0 | 1.23*104 |
In methanol solution, λ max 294.5nm, 220.0nm are -2 (1H) -one segment of 4- amino -5- hydroxyls
π → π * transition characteristics of conjugated system absorb.
Infrared absorption spectrum (IR)：27 type infrared spectrometers of Bruker TENSOR are measured using KBr pressed disc methods.
Infrared absorption spectrum (IR) data
3347cm-1:O-H stretching vibrations；1405cm-1:O-H bending vibrations；1203、1130、1071、837cm-1：C-O stretches
Contracting vibration.Prove that there are primary alconol, secondary alcohol and phenol (Ar-OH) structures in this product structure；3347cm-1:N-H stretching vibrations；1590cm-1：N-H bending vibrations；1359cm-1:C-N stretching vibrations.Prove that there are primary amine (Ar-NH2) structures in this product structure；2935cm-1:- C-H stretching vibrations.Prove the C-H structures containing saturation in this product structure；1359、1146、779cm-1:C-F stretching vibrations.It proves
The group containing-CHF2 in this product structure；1672、1590、1509、1405cm-1:C=O, C=C, C=N stretching vibration.Prove this product
Ring structure containing substituted pyrimidines in structure；1291、1071、875cm-1:C-O-C stretching vibrations.Prove in this product structure containing cyclic ethers and
Dioxane ether (ROR ') structure.By infrared spectrum it is found that have in this product structure primary alconol, secondary alcohol, phenol (Ar-OH), primary amine (Ar-NH2),
Cyclic ethers, dioxane ether (ROR '), substituted pyrimidines ring, saturation C-H and-CHF2 groups etc..Above-mentioned ir data and gemcitabine hydrochloride
He is consistent at shore oxidation impurities (1) structure.
Mass spectrum (Waters Q-TOF micro：Mass spectrograph, solvent methanol, ESI (+), 20V；ESI (-), 20V).
It follows that [M+H] of gemcitabine hydrochloride oxidation impurities+[M-H]-The mass-to-charge ratio at peak is respectively 280 and 278,
The molecular weight of this product is 279, is consistent with the molecular weight of gemcitabine hydrochloride oxidation impurities；The molecular weight of this product is odd number, molecule
In should contain odd number N atoms, this is consistent with this product containing 3 N atoms.
Nuclear magnetic resoance spectrum：(NMR) BRUKER AV-500 types Nuclear Magnetic Resonance, solvent DMSO-d6, internal standard TMS, temperature are
303K。
Nucleus magnetic hydrogen spectrum (1H-NMR) data
| Chemical shift (ppm) | Proton number | Peak shape | Ownership | Remarks |
| 10~3 | nH | br | Multiple Labile protons | |
| 7.13 | 1H | s | H6 | |
| 6.15 | 1H | t | H7 | J=8.4Hz |
| 4.13 | 1H | m | H9, H10, H11 | |
| 3.78 | 2H | m | ||
| 3.62 | 1H | dd | H11 | J=3.6,12.5Hz |
Outside 5 Labile protons for removing δ 10~3,1H-NMR provides 5 groups of peaks, and integral is 1: 1 than (by low field to High-Field)
: 1: 2: 1, totally 6 protons.From chemical displacement value and peak shape：δ 7.13 (1H, s) is olefinic proton H6；δ6.15(1H,t)、
4.13 (1H, m), 3.78 (2H, m) and 3.62 (1H, dd) are 5 on 3,3-, bis- fluoro- 4- hydroxyls -5- hydroxymethyl tetrahydrofurans
Non-interactive proton, by its chemical displacement value it is found that δ 6.15 (1H, t) is H7；δ 3.62 (1H, dd) is wherein 1 H11；δ4.13
(1H, m) and 3.78 (2H, m) are then H9, H10 and another H11.
Nuclear-magnetism carbon spectrum (13C-NMR) data
By carbon spectrum it is found that there are 14 peaks in carbon spectrum in addition to solvent peak, contain 9 C in this product molecule, this is by two fluorine atoms
Caused by being split point to the coupling of C.From peak shape, peak intensity and chemical displacement value：δ 121.2,127.2,153.7 and 161.4：4
A unsaturation C, in conjunction with gemcitabine chemical displacement value it is found that they are respectively C5, C6, C2 and C4；δ69.1(t)、83.6
(t) and 123.2 (t)：3 saturation C split point by 2 fluorine atoms, by its coupling constant and chemical displacement value it is found that they distinguish
For C9, C7 and C8；δ 59.0 and 80.3：2 saturation C not split point by fluorine atom, by its chemical displacement value it is found that they distinguish
For C10 and C11.
By H NMR spectroscopy it is found that the NMR data of this product is consistent with gemcitabine hydrochloride oxidation impurities (1) structure, i.e., this product is salt
Sour gemcitabine oxidation impurities (1).
In conclusion this product is 4- amino -1- (bis- fluoro- 4- hydroxyls -5- hydroxymethyl tetrahydrofurans-of (2R, 4R, 5R) -3,3-
2- yls) -5- hydroxy pyrimidines -2 (1H) -one, as gemcitabine hydrochloride oxidation impurities (1), structural formula is as follows, and structural identification is related
Collection of illustrative plates (mass spectrum, infrared, ultraviolet, nuclear-magnetism).
Although above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, some modification, equivalent replacement and improvement etc. can be made to it, this is aobvious to those skilled in the art
And it is clear to.Therefore, these modification, equivalent replacement and improvement for being made without departing from theon the basis of the spirit of the present invention etc.,
Belong to the scope of protection of present invention.
Claims (9)
1. a kind of preparation method of gemcitabine hydrochloride oxidation impurities (1), includes the following steps：
Using gemcitabine hydrochloride as starting material, successively through bromo-reaction and hydrolysis, to obtain oxidation impurities (1), tool
Vivo reaction type is as follows:
2. preparation method according to claim 1, wherein use brominated reagent, the bromo in the bromo-reaction
Reagent is bromine.
3. preparation method according to claim 1, wherein the hydrolysis uses hydrolysing agent, the hydrolysis examination
Agent is selected from n,N-diisopropylethylamine, trimethylpyridine or sodium hydroxide, preferably n,N-diisopropylethylamine.
4. preparation method according to claim 2, wherein the starting material of the bromo-reaction and mole of brominated reagent
Than being 1:0.1~10.
5. preparation method according to claim 3, wherein the molar ratio of the starting material and hydrolysing agent is 1:0.1
~20.
6. preparation method according to any one of claim 1 to 5, wherein the reaction temperature of the bromo-reaction be 0~
20℃。
7. preparation method according to any one of claim 1 to 5, wherein the reaction time of the bromo-reaction is 0.5
~3h.
8. preparation method according to any one of claim 1 to 5, wherein the reaction temperature of the hydrolysis is 20
~90 DEG C.
9. preparation method according to any one of claim 1 to 5, wherein the reaction time of the hydrolysis is 0.5
~50h.
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| CN201810184380.7A CN108484704A (en) | 2018-03-06 | 2018-03-06 | A kind of preparation method of gemcitabine hydrochloride oxidation impurities |
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| CN201810184380.7A CN108484704A (en) | 2018-03-06 | 2018-03-06 | A kind of preparation method of gemcitabine hydrochloride oxidation impurities |
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| CN201810184380.7A Pending CN108484704A (en) | 2018-03-06 | 2018-03-06 | A kind of preparation method of gemcitabine hydrochloride oxidation impurities |
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2018
- 2018-03-06 CN CN201810184380.7A patent/CN108484704A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| FRANCOIS SAMSON-THIBAULT，等: ""Profiling Cytosine Oxidation in DNA by LC-MS/MS"", 《CHEM. RES. TOXICOL.》 * |
| PASCAL A. KUPFER，等: "Synthesis, base pairing properties and trans-lesion synthesis by reverse transcriptases of oligoribonucleotides containing the oxidatively damaged base 5-hydroxycytidine", 《 NUCLEIC ACIDS RESEARCH》 * |
| 甄汉深，等: "《药物分析学》", 31 August 2017, 中国中医药出版社 * |
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Application publication date: 20180904 |