CN107778295A - Mai Rui replaces Buddhist nun's compound - Google Patents
Mai Rui replaces Buddhist nun's compound Download PDFInfo
- Publication number
- CN107778295A CN107778295A CN201610708704.3A CN201610708704A CN107778295A CN 107778295 A CN107778295 A CN 107778295A CN 201610708704 A CN201610708704 A CN 201610708704A CN 107778295 A CN107778295 A CN 107778295A
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- China
- Prior art keywords
- buddhist nun
- hydrate
- auspicious
- mai rui
- years
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, and in particular to step it is auspicious for Buddhist nun's hydrate and preparation method thereof, the present invention obtain it is advanced in years it is auspicious replace Buddhist nun's hydrate, containing a hypocrystalline water, have the advantage that：Purity is high, and stability is good, and the invention further relates to use the application stepped in the auspicious manufacture treatment non-small cell lung cancer drug for Buddhist nun's hydrate.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to and it is advanced in years auspicious for Buddhist nun's hydrate and preparation method thereof, it is of the invention also to relate to
And the composition using this hydrate, and the application in non-small cell lung cancer drug is treated in manufacture.
Background technology
Mai Rui replaces Buddhist nun（Mereletinib）It is a kind of oral irreversible, selective mutant EGFR inhibitor, it is chemical
Entitled N- [2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl groups -5- [[4- (1- Methyl-1H-indole -3- bases) -
2- pyrimidine radicals] amino] phenyl] -2- acrylamides.
Molecular formula：C28H33N7O2
Molecular weight：499.61
Its structural formula is：
Mai Rui is on the books in WO2013014448A1 for the preparation method of Buddhist nun.
In research process, the method for repeating document, what is obtained is advanced in years auspicious more for Buddhist nun's impurity number, and total impurities are higher.
The present invention obtain it is advanced in years it is auspicious replace Buddhist nun, containing a hypocrystalline water, have the advantage that：Purity is high, and maximum contaminant is less than 0.5 ‰；Surely
It is qualitative good.
The content of the invention
One object of the present invention, disclose a kind of step and auspicious replace Buddhist nun's hydrate.
Another object of the present invention, disclose the auspicious preparation method for Buddhist nun's hydrate advanced in years.
A further object of the present invention, disclose comprising the auspicious pharmaceutical composition for Buddhist nun's hydrate advanced in years.
The invention also discloses step the auspicious application for Buddhist nun's hydrate in non-small cell lung cancer drug is treated in manufacture.
Present invention is specifically described in conjunction with the purpose of the present invention.
Stepped the invention provides one kind and auspicious replace Buddhist nun's hydrate（Shown in formula I）,
（Ⅰ）
Karl_Fischer method（Karl Fischer methods）Be it is a kind of determine material in moisture all kinds of chemical methodes in, it is the most special to water
First, method the most accurate, has been listed in the standard method of determination of moisture in many materials, especially organic compound, as a result
Reliably.
After sample constant weight, determined through continuous 4 batches, the moisture that described invention compound contains is 5.04% -5.25%
Between (percentage by weight).Mai Rui is 5.13% for the theoretical content of Buddhist nun times semihydrate reclaimed water, it can be assumed that invention compound contains
There is a hypocrystalline water.
| Batch | Moisture（%） | Batch | Moisture（%） |
| 1 | 5.04 | 2 | 5.14 |
| 3 | 5.25 | 4 | 5.20 |
Mai Rui replaces Buddhist nun times hemi-hydrate crystalline, is determined using D/Max-2500.9161 types x-ray diffractometer, determines bar
Part：Cu Ka targets, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak（2θ）, d values and relative intensity are such as
Under.
| Spectral line number | 2θ（Degree） | Interplanar distance（d） | I/I0 |
| 1 | 14.420 | 6.1374 | 100 |
| 2 | 19.640 | 4.5164 | 8 |
| 3 | 26.060 | 3.4165 | 2 |
| 4 | 27.240 | 3.2711 | 4 |
| 5 | 27.960 | 3.1885 | 2 |
| 6 | 28.300 | 3.1509 | 1 |
| 7 | 29.240 | 3.0517 | 2 |
| 8 | 30.860 | 2.8915 | 2 |
| 9 | 32.360 | 2.7643 | 1 |
| 10 | 35.120 | 2.5531 | 1 |
| 11 | 37.020 | 2.4263 | 19 |
| 12 | 40.020 | 2.2511 | 1 |
| 13 | 40.580 | 2.2213 | 2 |
| 14 | 42.180 | 2.1407 | 1 |
| 15 | 43.320 | 2.0869 | 1 |
| 16 | 44.860 | 2.0188 | 6 |
The measure of 2 θ values uses light source in the present invention, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allow have one
Fixed rational error range, its error range are ± 0.2 °.
Fusing point test：According to Pharmacopoeia of People's Republic of China（2010 editions, two）The first methods of C of annex VI measure, which steps, auspicious replaces Buddhist nun
The fusing point of times hemi-hydrate crystalline, the fusing point measured are 193.3 DEG C -194.1 DEG C.
Another object of the present invention, step the auspicious preparation method for Buddhist nun times hemi-hydrate crystalline.
The present inventor is by largely testing, and exploring refining solvent includes water, acetonitrile, benzene, toluene, chlorobenzene, ethyl acetate,
The one kind such as dimethylformamide, acetone, tetrahydrofuran, methanol, ethanol, isopropanol, isopropyl ether, methyl tertiary butyl ether(MTBE), two kinds or
Three kinds of mixed liquor and different process conditions and the obtained auspicious relation for Buddhist nun's crystal advanced in years, especially wherein the number of impurity with
The amount of each impurity.Eventually through will step it is auspicious dissolved by heating for Buddhist nun in distilled water-isopropanol-tetrahydrofuran solution, Ran Houfen
Stage cools, and obtains the present invention and step auspicious to replace Buddhist nun's hydrate crystal.
Specifically include the following steps：Mai Rui adds 5-6 times for Buddhist nun（Weight or measurement (WM) ratio）Water-isopropanol-tetrahydrofuran=9：
0.5-1：In 0.5-1 mixed liquor, 78 DEG C -83 DEG C are heated to, is filtered while hot, be cooled to 50 DEG C, 47 DEG C -50 DEG C, insulated and stirred
4-5 hours；Then, be cooled to 25 DEG C, 23 DEG C -25 DEG C, be incubated 5-6 hours, separate out crystallization, filtering, through room temperature in vacuo dry to
Constant weight, obtain above-mentioned step of high-purity and auspicious replace Buddhist nun's hydrate crystal.
This method is reproducible, is amplified to pilot-scale, and purity and crystal formation can reappear very well.
Mai Rui used can easily be prepared for Buddhist nun according to document, such as WO2013014448A1, can also pass through commercial sources
It is commercially available.
A further object of the present invention, there is provided auspicious can pharmaceutically be connect with one or more for Buddhist nun's hydrate crystal comprising stepping
The auspicious composition for Buddhist nun's hydrate advanced in years for the carrier composition received.
The pharmaceutical composition of the present invention prepares as follows：Using standard and conventional technique, make the compounds of this invention and preparation
Acceptable solid or liquid-carrier combine on, and be allowed to arbitrarily with acceptable adjuvant and excipient on galenic pharmacy
With reference to being prepared into particulate or microballoon.Said composition is used to prepare oral formulations.
The active ingredient contained in pharmaceutical composition and unit dosage form（The compounds of this invention）Amount can be according to patient
The state of an illness, the situation of diagnosis be specifically applied, the amount or concentration of compound used are in a wider scope
Regulation, the amount scope of reactive compound are the 0.5%~20% of composition（Weight）.
Present invention also offers step the auspicious application for Buddhist nun's hydrate in non-small cell lung cancer drug is treated in manufacture.
Stability test
Inventor is studied the auspicious chemical stability for Buddhist nun's hydrate advanced in years of the present invention, and investigation condition is high temperature（60℃
±2℃）, strong illumination（4500Lx±500lx）, high humidity（92.5%,RH）Inspection target is outward appearance, content and relevant material.
As a result：From 0-10 days under strong light, high temperature, super-humid conditions, outward appearance, relevant material, content do not change, explanation
Chemical stability is good, is adapted to the manufacture of pharmaceutical preparation and long-term storage.
At 40 DEG C, different relative humidity（RH）Condition（75%, 92.5%）Under, the survey of moisture in hydrate crystal of the present invention
It is fixed：
As a result：At 40 DEG C, different relative humidity（RH）Condition（75%, 92.5%）Under, water tariff collection is constant, illustrates that stability is good
It is good, it is adapted to the manufacture of pharmaceutical preparation and long-term storage.
Embodiment：
With reference to embodiment, the present invention is described further, professional and technical personnel in the field is better understood from this hair
It is bright.Embodiment is only explanatory, is in no way intended to the scope that it limit the invention in any way.
Mai Rui used can easily be prepared for Buddhist nun according to document in the present invention, such as WO2013014448A1, optical purity
97.7% (HPLC normalization methods), its chemical constitution are confirmed through proton nmr spectra, elementary analysis, high resolution mass spectrometry, it was demonstrated that are changed
It is correct to learn structure.
Embodiment 1
Equipped with stirring, thermometer, condenser 5L reaction bulbs in, add water-isopropyls of 350 Ke Mairui for Buddhist nun and 1750ml
Alcohol-tetrahydrofuran（9：0.5：0.5）Mixed liquor, 78 DEG C -83 DEG C are heated to, is filtered while hot, be cooled to 50 DEG C, 47 DEG C -50 DEG C, protect
Temperature stirring 4 hours；Then, 25 DEG C are cooled to, 23 DEG C -25 DEG C, is incubated 5 hours, crystallization is separated out, filtering, is dried through room temperature in vacuo
To constant weight, obtain high-purity it is above-mentioned step it is auspicious replace 322.3 grams of Buddhist nun's hydrate crystal, fusing point is 153.3 DEG C -154.1 DEG C.Optical voidness
Degree 99.97%.Dissolvent residual detection meets the requirements.
Determined through Karl_Fischer method, the moisture containing 5.15% (percentage by weight).
The crystallization instrument model and condition determination：The type diffractometers of Rigaku D/max 2500； CuKa 40Kv
100mA;2 θ scanning ranges：0-50°。
Embodiment 2
Equipped with stirring, thermometer, condenser 5L reaction bulbs in, add water-isopropyls of 320 Ke Mairui for Buddhist nun and 2100ml
Alcohol-tetrahydrofuran（9：0.8：0.7）Mixed liquor, 78 DEG C -83 DEG C are heated to, is filtered while hot, be cooled to 50 DEG C, 47 DEG C -50 DEG C, protect
Temperature stirring 5 hours；Then, 25 DEG C are cooled to, 23 DEG C -25 DEG C, is incubated 6 hours, crystallization is separated out, filtering, is dried through room temperature in vacuo
To constant weight, obtain above-mentioned step of high-purity and auspicious replace 288.9 grams of Buddhist nun's hydrate crystal, optical purity 99.95%.Dissolvent residual detection symbol
Close and require.
Determined through Karl_Fischer method, the moisture containing 5.21% (percentage by weight).
Embodiment 3
Equipped with stirring, thermometer, condenser 5L reaction bulbs in, add water-isopropyls of 320 Ke Mairui for Buddhist nun and 1920ml
Alcohol-tetrahydrofuran（9：1：1）Mixed liquor, 78 DEG C -83 DEG C are heated to, is filtered while hot, be cooled to 50 DEG C, 47 DEG C -50 DEG C, insulation is stirred
Mix 4.5 hours；Then, 25 DEG C are cooled to, 23 DEG C -25 DEG C, is incubated 5.5 hours, crystallization is separated out, filtering, is dried through room temperature in vacuo
To constant weight, obtain above-mentioned step of high-purity and auspicious replace 300.8 grams of Buddhist nun's hydrate crystal, optical purity 99.96%.Dissolvent residual detection symbol
Close and require.
Determined through Karl_Fischer method, the moisture containing 5.10% (percentage by weight).
Embodiment 4
Equipped with stirring, thermometer, condenser 5L reaction bulbs in, add water-isopropyls of 300 Ke Mairui for Buddhist nun and 1500ml
Alcohol-tetrahydrofuran（9：0.9：0.6）Mixed liquor, 78 DEG C -83 DEG C are heated to, is filtered while hot, be cooled to 50 DEG C, 47 DEG C -50 DEG C, protect
Temperature stirring 5 hours；Then, 25 DEG C are cooled to, 23 DEG C -25 DEG C, is incubated 5 hours, crystallization is separated out, filtering, is dried through room temperature in vacuo
To constant weight, obtain above-mentioned step of high-purity and auspicious replace 277.3 grams of Buddhist nun's hydrate crystal, optical purity 99.97%.Dissolvent residual detection symbol
Close and require.
Determined through Karl_Fischer method, the moisture containing 5.11% (percentage by weight).
Using standard and conventional technique, make the compounds of this invention and acceptable solid or liquid-carrier knot on galenic pharmacy
Close, and be allowed to arbitrarily be combined with acceptable adjuvant and excipient on galenic pharmacy and be prepared into particulate or microballoon.The combination
Thing is used to prepare oral formulations.Only citing is illustrated, and is in no way intended to the scope that it limit the invention in any way.
Embodiment 5
Contain the auspicious tablet for Buddhist nun's hydrate advanced in years
Prescription：Mai Rui replaces 51.4 grams of Buddhist nun times semihydrate, 4 grams of N-METHYL-ALPHA-L-GLUCOSAMINE, 16 grams of polyvinylpyrrolidone, microcrystalline cellulose
250 grams of element, 20 grams of taurine, 185 grams of sodium carboxymethyl starch, 10 grams of magnesium stearate, appropriate amount of water is distilled, is made 10000.
Technique：To step it is auspicious be dissolved in for Buddhist nun times semihydrate and excipient in 80 DEG C of distilled water containing taurine, add micro-
1 percent amounts of crystalline cellulose, are dried in vacuo after mixing, crush, and cross 100 mesh sieves, tabletting after being mixed with other materials.
Embodiment 6
Contain the auspicious capsule for Buddhist nun's hydrate advanced in years
Prescription：Mai Rui replaces 102.8 grams of Buddhist nun times semihydrate, 300 grams of Celluloasun Microcrystallisatum, 250 grams of pregelatinized starch, polyvinyl pyrrole
35 grams of alkanone, 22 grams of magnesium stearate, is made 10000.
Technique：Will be advanced in years auspicious for Buddhist nun times semihydrate, Celluloasun Microcrystallisatum sieving, it is sufficiently mixed, adds polyvinylpyrrolidone
Solution, it is sufficiently mixed, softwood processed, sieves, granulation, 55 DEG C of -60 DEG C of dryings, magnesium stearate and talcum powder is sieved, are added to
State in particle, it is encapsulated to produce.
Claims (6)
1. Mai Rui shown in formula I replaces the hydrate of Buddhist nun,
（Ⅰ）
Determined with Karl_Fischer method, the hydrate contains 5.04% -5.25% moisture；
The Mai Rui replaces Buddhist nun's hydrate, in being determined by the use of CuKa rays as characteristic X-ray powder, relative intensity I/I in its collection of illustrative plates0
Peak more than 6, there is the following 2 θ angles of diffraction, interplanar distance：
The Mai Rui replaces Buddhist nun's hydrate, and fusing point is 193.3 DEG C -194.1 DEG C.
2. Mai Rui described in claim 1 replace Buddhist nun's hydrate preparation method, by will step it is auspicious for Buddhist nun in distilled water-isopropanol-four
Dissolve by heating in hydrogen tetrahydrofuran solution, then cool stage by stage, obtain the present invention and step auspicious to replace Buddhist nun's hydrate.
3. the method for claim 2, it is characterised in that comprise the following steps：Mai Rui adds 5-6 times for Buddhist nun（Weight or measurement (WM) ratio）
Water-isopropanol-tetrahydrofuran=9：0.5-1：In 0.5-1 mixed liquor, 78 DEG C -83 DEG C are heated to, is filtered while hot, is cooled to 50
DEG C, 47 DEG C -50 DEG C, insulated and stirred 4-5 hours；Then, 25 DEG C are cooled to, 23 DEG C -25 DEG C, 5-6 hours is incubated, separates out crystallization,
Filtering, is dried through room temperature in vacuo, is obtained above-mentioned step of high-purity and auspicious is replaced Buddhist nun's hydrate.
It is 4. a kind of containing advanced in years auspicious for Buddhist nun's hydrate and one or more pharmaceutically acceptable carriers composition described in claim 1
The auspicious composition for Buddhist nun's hydrate advanced in years.
5. the auspicious composition for Buddhist nun's hydrate advanced in years described in claim 4, it is characterised in that said composition is used to prepare oral system
Agent.
6. applications of the Mai Rui described in claim 1 for Buddhist nun's hydrate in non-small cell lung cancer drug is treated in manufacture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610708704.3A CN107778295A (en) | 2016-08-24 | 2016-08-24 | Mai Rui replaces Buddhist nun's compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610708704.3A CN107778295A (en) | 2016-08-24 | 2016-08-24 | Mai Rui replaces Buddhist nun's compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107778295A true CN107778295A (en) | 2018-03-09 |
Family
ID=61387899
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610708704.3A Pending CN107778295A (en) | 2016-08-24 | 2016-08-24 | Mai Rui replaces Buddhist nun's compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107778295A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113372331A (en) * | 2020-03-10 | 2021-09-10 | 鲁南制药集团股份有限公司 | Novel crystal form of oxitinib monohydrate |
| CN113372332A (en) * | 2020-03-10 | 2021-09-10 | 鲁南制药集团股份有限公司 | Novel crystal form of oxitinib |
-
2016
- 2016-08-24 CN CN201610708704.3A patent/CN107778295A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113372331A (en) * | 2020-03-10 | 2021-09-10 | 鲁南制药集团股份有限公司 | Novel crystal form of oxitinib monohydrate |
| CN113372332A (en) * | 2020-03-10 | 2021-09-10 | 鲁南制药集团股份有限公司 | Novel crystal form of oxitinib |
| CN113372331B (en) * | 2020-03-10 | 2023-09-12 | 鲁南制药集团股份有限公司 | Novel crystal form of Orientinib monohydrate |
| CN113372332B (en) * | 2020-03-10 | 2023-09-12 | 鲁南制药集团股份有限公司 | Novel crystal form of octreotide |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20180309 |
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| WD01 | Invention patent application deemed withdrawn after publication |