CN105503852B - Thiazole carboxamides nitrogen oxides - Google Patents
Thiazole carboxamides nitrogen oxides Download PDFInfo
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- CN105503852B CN105503852B CN201410504689.1A CN201410504689A CN105503852B CN 105503852 B CN105503852 B CN 105503852B CN 201410504689 A CN201410504689 A CN 201410504689A CN 105503852 B CN105503852 B CN 105503852B
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- hydrochloric acid
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- acetonitrile
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Abstract
The invention discloses a kind of thiazole carboxamides nitrogen oxides, also disclose the preparation method of the compound and its purposes as reference substance.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, more particularly to a kind of thiazole carboxamides nitrogen oxides：That is N- (the chloro- 6- first of 2-
Base phenyl) -2- [[6- [4- (2- ethoxys)-piperazinyl -1] -2- methyl-5-chloros-pyrimidine radicals -4] amino] -5- thiazole carboxamides
Nitrogen-oxide and preparation method thereof.
Background field
Dasatinib (formula 2) is researched and developed by Bristol-Myers Squibb companies of the U.S., and monohydrate lists for 2006
Sale is the oral multiple tyrosine kinase inhibitor of first approval listing, is clinically used for the past treatment failure or does not tolerate
It is grown up each stage chronic myeloid leukemia, it can also be used to treat to other therapies drug resistance or the Philadelphia chromosome not tolerated sun
Property acute lymphatic leukemia adult patients.
The most common adverse reaction of its preparation include fluid retention (pleural effusion), gastrointestinal reaction (including diarrhea, nausea,
Abdominal pain and vomiting) and bleeding episode.Most common serious adverse reaction includes fever (9%), pleural effusion (6%), pneumonia
(6%), thrombopenia (5%), febrile neutropenic (7%), hemorrhage of gastrointestinal tract (6%), blood platelet subtract
Few disease (5%), expiratory dyspnea (4%), anaemia (3%) and diarrhea (2%).It can also result in serious thrombopenia, neutrality
Granulocyte reduces and anaemia.Bone marrow suppression late in CML or PH+ALL patients incidence compared with chronic phase CML patient height.In addition,
It can also result in that platelet function is bad in vitro, there are about 1% in the patient for receiving its treatment to occur severe central nervous system
Bleeding or even death.
A series of above-mentioned adverse reactions, however not excluded that be caused by the impurity generated in its building-up process or degradation.Through medicine
It manages toxicological study to find, a variety of impurity of the drug have stronger hepatotoxicity, neurotoxicity and genotoxicity, easily cause to include liver function
Can extremely, bone marrow suppression, the adverse reaction including a variety of side reactions such as bleeding.To ensure the safety of drug, reduce bad anti-
It should occur, must keep under strict control every impurity in standard；It is urgent problem to specify each impurity item.
Invention content：
For the demand of the prior art, the present invention provides 1 compound represented of formula, structural formula is as follows：
Molecular formula is C22H25Cl2N7O3S is named as N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [[6- [4- (2- ethoxys)-piperazines
Piperazine base -1] -2- methyl-5-chloros-pyrimidine radicals -4] amino] -5- thiazole carboxamides nitrogen-oxide is a kind of thiazole carboxamides nitrogen oxygen
Compound.
The present invention also provides the preparation methods of above-mentioned 1 compound of formula, it includes following operating procedure：
(1) formula (2) is dissolved in the mixed liquor of hydrochloric acid-acetonitrile, hydrogen peroxide is added in, reaction solution is obtained by the reaction.
(2) reaction solution obtained by step (1), it is purified after to get 1 compound of formula.
Wherein, the mixed liquor of the hydrochloric acid-acetonitrile preferably its volume ratio is 1:(0.2-3)；It is preferred that hydrochloric acid is a concentration of
0.1-1mol/L；It is preferred that the mass fraction of hydrogen peroxide is 1%~10%；Formula (2) and hydrochloric acid, hydrogen peroxide substance amount it
Than being 1：(1-50)：(1-10)；Preferably, the reaction temperature in step (1) is 70~100 DEG C；Reaction time in step (1)
For 8~20h.
1 compound of gained formula is by a series of characterizations, such as elemental analysis, ultra-violet absorption spectrum (UV), infrared absorption spectrum
(IR), nuclear magnetic resonance (NMR), mass spectrum (MS) carry out structural identification, as a result as follows：
Elemental analysis
Molecular formula can be released to be respectively less than for sample C, H, N, S, Cl content actual measurement average value and calculated value error
0.3%, calculate that the content of O is 0.0916 according to the measurement result of C, H, N, S, Cl, it is basically identical with theoretical value.
Ultra-violet absorption spectrum (UV)
UV collection of illustrative plates point of the compound in water, 0.1mol/L hydrochloric acid solutions, 0.1mol/L sodium hydroxide solutions and methanol
Attached drawing 1- attached drawings 4 are not seen, and absorption maximum is respectively for 324nm, 328nm, 374nm, 322nm.
Infrared absorption spectrum (IR, KBr tabletting)
The IR spectrograms of the compound are shown in attached drawing 5.Partial data is as follows：(1)3400cm-1It is inhaled for O-H stretching vibrations in hydroxyl
It receives.
(2)3265cm-1It is absorbed for N-H stretching vibrations in amido, 1643cm-1C=O stretching vibrations for amidocarbonylation are inhaled
It receives,.
(3)2926cm-1、2821cm-1C-H stretching vibrations for methylene absorb.
(4)1592cm-1、1499cm-1Stretching vibration absworption peak for C=C in phenyl ring；770cm-1Face for phenyl ring proton
Outside sweep absorption of vibrations.
1H H NMR spectroscopies
The hydrogen spectrogram of the compound is shown in attached drawing 6-9, and data are as follows：1H-NMR(DMSO-d6)δ：9.96 (s, 1H), δ：8.30
(s, 1H), δ：(7.41-7.26 d, 1H), δ：7.30 (d, 1H), δ：7.26 (t, 1H), δ：4.45 (brs, 1H), δ：3.54 (m,
6H), δ：2.55 (m, 4H), δ：2.47 (s, 3H), δ：2.45 (t, 2H), δ：2.25 (s, 3H).
13C H NMR spectroscopies
The carbon spectrogram of the compound is shown in attached drawing 10-13, and data are as follows：13C NMR(DMSO-d6)δ：162.71 162.34,
161.25,160.17,154.50,139.75,139.22,133.81,132.82,129.49,128.68,127.47,126.43,
97.50,60.62,58.84,53.44,47.92,25.24,18.74.
MS-ESI mass spectrums
The MS-ESI mass spectrograms of the compound are shown in attached drawing 14.MS(ESI)m/z：522.1[M-O]+, m/z：1067.2[2(M-
O)+Na]+。
HPLC is detected：
By attached drawing 15 as it can be seen that the purity of the compound (30.8min) can make up to more than 99.5% as reference substance
With.
Since above compound is the slowly degradation generation in drug storage and transport process, bulk pharmaceutical chemicals and preparation initial stage its
Content is relatively small, and the impurity is caused to be not easy to be found in conventional bulk pharmaceutical chemicals and preparation, but the generation of the compound can pole
The big adverse reaction rate for increasing patient after medication.Inventor has found unintentionally the substance, concentrates on studies, and synthesizes and detaches
Go out the substance and identify the structure of the substance.
Simultaneously as the compound and the structure of Dasatinib and other impurity are relatively similar, the reservation line on chromatogram
To be close, thus it is accurate qualitative and quantitative there is an urgent need for reference substance to it, and do not have the above-mentioned record up to compound in the prior art.Needle
To this problem, the present invention provides above compounds.
The present invention also provides above compound in Dasatinib raw material and preparation Related substances separation as impurity pair
According to the purposes of product.In the purposes, 1 compound of formula that the present invention is illustrated is not limited to institute's public affairs of the invention as the use of reference substance
The chromatographic condition opened, i.e., when 1 compound of formula as reference substance in use, can use chromatographic condition provided by the present invention,
Other any feasible testing conditions can also be used.
The beneficial effects of the present invention are：
(1) the present invention provides 1 compound of formula, purity can be used as working reference substance, use up to more than 99.5% after purification
The content of this kind of impurity in detection Dasatinib raw material and preparation, the quality control for drug contribute.
(2) the present invention provides a kind of simple and convenient process for preparing of 1 compound of formula：Using acetonitrile, hydrochloric acid, hydrogen peroxide as molten
Agent and reaction dissolvent are solved, does not introduce new impurity, is detached convenient for subsequent purification, dissolvent residual easily removes.
(3) 1 compounds process for production thereof step of formula provided by the invention is few, high income, easily prepares, at low cost.
Description of the drawings：
Fig. 1 is the UV spectrograms of 1 compound of formula in water
Fig. 2 is UV spectrogram of 1 compound of formula in 0.1mol/L hydrochloric acid solutions
Fig. 3 is UV spectrogram of 1 compound of formula in 0.1mol/L sodium hydroxide solutions
Fig. 4 is the UV spectrograms of 1 compound of formula in methyl alcohol
Fig. 5 is the IR spectrograms of 1 compound of formula
Fig. 6 is the nuclear magnetic resonance of 1 compound of formula1H-NMR spectrum
Fig. 7 is the hydrogen nuclear magnetic resonance spectrogram (partial enlargement) of 1 compound of formula
Fig. 8 is related (gCOSY) spectrogram of hydrogen nuclear magnetic resonance-hydrogen of 1 compound of formula
Fig. 9 is that the nuclear magnetic resonance heavy water of 1 compound of formula exchanges hydrogen spectrogram
Figure 10 is the nuclear magnetic resonance of 1 compound of formula13C-NMR spectrograms
Figure 11 is the nuclear magnetic resonance DEPT spectrograms of 1 compound of formula
Figure 12 is related (gHMQC) spectrogram of nuclear magnetic resonance carbon-hydrogen of 1 compound of formula
Figure 13 is related (gHMBC) spectrogram of nuclear magnetic resonance remote carbon-hydrogen of 1 compound of formula
Figure 14 is the MS spectrograms of 1 compound of formula
Figure 15, the 16 HPLC spectrograms for 1 compound of formula
Specific embodiment：
The present invention is described further, but the present invention is not intended to be limited thereto with reference to specific embodiment.
Embodiment 1：
Dasatinib 0.1g is taken, is put in the three-necked flask with reflux condensate device, with 0.5mol/L hydrochloric acid solutions-acetonitrile
(the volume ratio 1 of hydrochloric acid solution-acetonitrile:1) after 40ml dissolvings, the hydrogen peroxide of 0.48g 5% is added in, with balloon sealed condensating
Pipe.Magnetic agitation is opened, temperature is set as 90 DEG C.7h is reacted, stops heating, is down to room temperature.Bottle in liquid through preparing chromatogram purification,
And it is lyophilized with freeze dryer.Obtain off-white powder 0.080g, yield 80%, purity 99.6%.
Embodiment 2：
Dasatinib 0.1g is taken, is put in the three-necked flask with reflux condensate device, with 0.1mol/L hydrochloric acid solutions-acetonitrile
(the volume ratio 1 of hydrochloric acid solution-acetonitrile:2) after 30ml dissolvings, the hydrogen peroxide of 0.68g 1% is added in, with balloon sealed condensating
Pipe.Magnetic agitation is opened, temperature is set as 80 DEG C.11h is reacted, stops heating, is down to room temperature.Liquid is through preparing chromatographically pure in bottle
Change, and be lyophilized with freeze dryer.Obtain off-white powder 0.072g, yield 72%, purity 99.3%.
Embodiment 3：
Dasatinib 0.1g is taken, is put in the three-necked flask with reflux condensate device, with 0.2mol/L hydrochloric acid solutions-acetonitrile
(the volume ratio 1 of hydrochloric acid solution-acetonitrile:3) after 8ml dissolvings, the hydrogen peroxide of 0.102g 10% is added in, with balloon sealed condensating
Pipe.Magnetic agitation is opened, temperature is set as 70 DEG C.12h is reacted, stops heating, is down to room temperature.Liquid is through preparing chromatographically pure in bottle
Change, and be lyophilized with freeze dryer.Obtain off-white powder 0.069g, yield 69%, purity 98.9%.
Embodiment 4
Dasatinib 0.1g is taken, is put in the three-necked flask with reflux condensate device, with 1mol/L hydrochloric acid solutions-acetonitrile (salt
The volume ratio 5 of acid solution-acetonitrile:1) after 12ml dissolvings, the hydrogen peroxide of 0.17g 10% is added in, with balloon sealed condensating pipe.
Magnetic agitation is opened, temperature is set as 100 DEG C.7h is reacted, stops heating, is down to room temperature.Bottle in liquid through preparing chromatogram purification, and
It is lyophilized with freeze dryer.Obtain off-white powder 0.079g, yield 79%, purity 99.6%.
Embodiment 5：
Dasatinib 0.1g is taken, is put in the three-necked flask with reflux condensate device, with 0.2mol/L hydrochloric acid solutions-acetonitrile
(the volume ratio 1 of hydrochloric acid solution-acetonitrile:3) after 40ml dissolvings, the hydrogen peroxide of 0.68g 2% is added in, with balloon sealed condensating
Pipe.Magnetic agitation is opened, temperature is set as 90 DEG C.9h is reacted, stops heating, is down to room temperature.Bottle in liquid through preparing chromatogram purification,
And it is lyophilized with freeze dryer.Obtain off-white powder 0.073g, yield 73%, purity 99.2%.
Embodiment 6：
Dasatinib 0.1g is taken, is put in the three-necked flask with reflux condensate device, with 0.2mol/L hydrochloric acid solutions-acetonitrile
(the volume ratio 1 of hydrochloric acid solution-acetonitrile:3) after 8ml dissolvings, the hydrogen peroxide of 0.102g 10% is added in, with balloon sealed condensating
Pipe.Magnetic agitation is opened, temperature is set as 80 DEG C.10h is reacted, stops heating, is down to room temperature.Liquid is through preparing chromatographically pure in bottle
Change, and be lyophilized with freeze dryer.Obtain off-white powder 0.069g, yield 69%, purity 99.0%.
Embodiment 7：
Dasatinib 0.1g is taken, is put in the three-necked flask with reflux condensate device, with 0.2mol/L hydrochloric acid solutions-acetonitrile
(the volume ratio 1 of hydrochloric acid solution-acetonitrile:4) after 8ml dissolvings, the hydrogen peroxide of 0.102g 10% is added in, with balloon sealed condensating
Pipe.Magnetic agitation is opened, temperature is set as 90 DEG C.10h is reacted, stops heating, is down to room temperature.Liquid is through preparing chromatographically pure in bottle
Change, and be lyophilized with freeze dryer.Obtain off-white powder 0.058g, yield 68%, purity 98.8%.
Embodiment 8
Take Dasatinib 0.1g, in the three-necked flask for putting the 200ml with reflux condensate device, with 2mol/L hydrochloric acid solutions-
Acetonitrile (the volume ratio 1 of hydrochloric acid solution-acetonitrile:1) after 20ml dissolvings, 1% hydrogen peroxide 3ml is added in, with balloon sealed condensating
Pipe.Magnetic agitation is opened, temperature is set as 90 DEG C.10h is reacted, stops heating, is down to room temperature.Liquid is through preparing chromatographically pure in bottle
Change, and be lyophilized with freeze dryer.Obtain off-white powder 0.056g, yield 56%, purity 98.6%.
Embodiment 9
It is filler with octadecylsilane chemically bonded silica；With 0.05mol/L ammonium acetate solutions (pH5.25)-acetonitrile (90:
10) it is mobile phase A, 0.05mol/L ammonium acetate solutions (pH5.25)-acetonitrile-methanol (10: 90) is Mobile phase B, is carried out according to following table
Gradient elution；Flow velocity is 1.2ml/min, and Detection wavelength 320nm, column temperature is 35 DEG C.
Weigh 1 compound of formula, N- removes ethoxy Dasatinib, Dasatinib reference substance, N- (the chloro- 6- aminomethyl phenyls of 2-)-
2- [[6- [4- (2- ethoxys) -1- piperazinyls] -2- methyl -4- pyrimidine radicals] amino] -5- thiazole carboxamides nitrogen-oxide is each suitable
Amount, it is respectively the molten of 0.28 μ g/ml to be dissolved with mixed solvent [0.1mol/L hydrochloric acid solutions: acetonitrile (50: 50)] and be diluted to concentration
Liquid, mixing, as system suitability solution.In chromatogram obtained by system suitability, the reservation at Dasatinib peak
Time should be in the range of 26~31min, and the tailing factor at Dasatinib peak should be in the range of 0.8~1.5；N- (the chloro- 6- of 2-
Aminomethyl phenyl) -2- [[6- [4- (2- ethoxys) -1- piperazinyls] -2- methyl -4- pyrimidine radicals] amino] -5- thiazole carboxamides nitrogen -
The separating degree that oxide and N- are gone between ethoxy Dasatinib should be not less than 1.2；The separating degree of 1 compound of formula and Dasatinib
It should be greater than 1.5；The separating degree of other chromatographic peaks should meet regulation.HPLC spectrograms are shown in attached drawing 16.
Claims (9)
1. a kind of compound, it is characterized in that structural formula is as follows：
2. compound as described in claim 1 is in Dasatinib raw material and preparation Related substances separation as impurity reference substance
Purposes.
3. the preparation method of compound as described in claim 1, comprises the steps of：
(1) starting materials of formulae (2) is dissolved in hydrochloric acid solution-acetonitrile in the mixed solvent, adds in hydrogen peroxide, insulation reaction；
(2) reaction solution obtained by step (1), it is purified after to get formula (1) compound.
4. the preparation method of compound as described in claim 1, it is characterised in that：Hydrochloric acid solution-acetonitrile described in step (1)
Volume ratio be 1:(0.2-3).
5. the preparation method of compound as described in claim 1, it is characterised in that：A concentration of 0.1- of hydrochloric acid in step (1)
1mol/L。
6. the preparation method of compound as described in claim 1, it is characterised in that：The mass fraction of hydrogen peroxide in step (1)
It is 1%~10%.
7. the preparation method of compound as described in claim 1, it is characterised in that：Step (1) Chinese style (2) and hydrochloric acid, peroxidating
The ratio between amount of substance of hydrogen is 1：(1-50)：(1-10).
8. the preparation method of compound as described in claim 1, it is characterised in that：Reaction temperature in step (1) is 70~100
℃。
9. the preparation method of compound as described in claim 1, it is characterised in that：Reaction time in step (1) is 8~20h.
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| CN106632279A (en) * | 2016-12-01 | 2017-05-10 | 北京万全德众医药生物技术有限公司 | Preparation method for vilazodone monoxide |
| CN113493413B (en) * | 2020-03-19 | 2024-03-26 | 苏中药业集团股份有限公司 | Substituted butenamide-N-oxide and preparation method and application thereof |
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| PE20061394A1 (en) * | 2005-03-15 | 2006-12-15 | Bristol Myers Squibb Co | METABOLITES OF N- (2-CHLORO-6-METHYLPHENYL) -2 - [[6- [4- (2-HYDROXYETHYL) -1-PIPERAZINYL] -2-METHYL-4-PYRIMIDINYL] AMINO] -5-THIAZOLCARBOXAMIDES |
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2014
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Non-Patent Citations (5)
| Title |
|---|
| "A validated LC–MS/MS assay for the simultaneous determination of the anti-leukemic agent dasatinib and two pharmacologically active metabolites in human plasma: Application to a clinical pharmacokinetic study";Michael T. Furlong，et al.;《Journal of Pharmaceutical and Biomedical Analysis》;20110916;第58卷;130–135 * |
| "Lacteal Secretion, Fetal and Maternal Tissue Distribution of Dasatinib in Rats";Kan He，et al.;《DRUG METABOLISM AND DISPOSITION》;20081231;第36卷(第12期);2564–2570 * |
| "达沙替尼原料中的杂质研究";梁晓东，等;《中国新药杂志》;20130930;第22卷(第18期);2210-2214 * |
| Lisa J. Christopher，et al.."Metabolism and Disposition of Dasatinib after Oral Administration to Humans".《DRUG METABOLISM AND DISPOSITION》.2008,第36卷(第7期),1357–1364. * |
| Zhongzhou Shen，et al.."Metabolite profiling of dasatinib dosed to Wistar Han rats using automated dried blood spot collection".《Journal of Pharmaceutical and Biomedical Analysis》.2012,第67-68卷92–97. * |
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