CN111763211A - Raatinib hydrochloride, preparation method and application - Google Patents
Raatinib hydrochloride, preparation method and application Download PDFInfo
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- CN111763211A CN111763211A CN202010778538.0A CN202010778538A CN111763211A CN 111763211 A CN111763211 A CN 111763211A CN 202010778538 A CN202010778538 A CN 202010778538A CN 111763211 A CN111763211 A CN 111763211A
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a larotinib hydrochloride, which relates to the technical field of pharmaceutical chemistry, and has the following structural formula:
the invention also discloses a preparation method of the erlotinib hydrochloride, which comprises the following steps: reacting (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl]Pyrazolo [1,5-A]Pyrimidin-3-yl]Dissolving the-3-hydroxy-1-pyrrolidine formamide in an alcohol solvent, adding hydrochloric acid, cooling, stirring to separate out a solid, and filtering to obtain the erlotinib hydrochloride. The invention has the beneficial effects that: the preparation method is simple, the erlotinib hydrochloride is prepared on the basis of the existing erlotinib, the stability is good, and the preparation method is suitable for being used for the research of preparations in the form of bulk drugsAnd (4) hair and production.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a crystal form of erlotinib hydrochloride, a crystal form of erlotinib hydrochloride and a preparation method of the crystal form.
Background
(3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-a ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide, the english name larotrytinib, the chinese name larotinib, is a marketed anti-cancer drug approved by the FDA in 2018 at 11 months, and is a potent, oral, selective Tropomyosin Receptor Kinase (TRKs) inhibitor, effective against up to 17 cancers. Can be used for treating adult and children locally advanced or metastatic solid tumor patients carrying NTRK gene fusion, does not need to consider the occurrence area of cancer, and can be treated by using Larotrectinib as long as the NTRK gene fusion exists.
The drug was developed and marketed by Loxo Oncology and Bayer, Germany, in the United states. The structural formula of the medicine is disclosed in patents WO2010048314A1 and WO2013088256, and the subsequent patent WO2016077841A1 discloses Larotrectinib sulfate and a crystal form thereof, and the Larotrectinib sulfate is shown as follows:
The free base of erlotinib is an amorphous solid and does not form a good solid powder crystalline form in conventional solvents, and thus is not suitable for use as a bulk drug substance in the manufacture of formulations.
Disclosure of Invention
The technical problem to be solved by the invention is that in the prior art, the free base of the larotinib cannot form a better solid powder crystal form in a conventional solvent, and the larotinib hydrochloride is provided.
The invention solves the technical problems through the following technical means:
a Larotenib hydrochloride having the following structural formula:
has the advantages that: the solid form of the erlotinib hydrochloride has good stability, is suitable for being used as a raw material medicine form for research and development and production of preparations, and has practical commercial value and medicinal application.
Preferably, the preparation method of the erlotinib hydrochloride comprises the following steps: dissolving (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidine formamide in an alcohol solvent, adding hydrochloric acid, cooling, stirring to separate out a solid, and filtering to obtain the Larotenib hydrochloride.
Preferably, the alcoholic solvent is ethanol or isopropanol.
Preferably, the ratio of the mass of the (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide to the volume of ethanol is 1g (4ml-6 ml).
Preferably, the mass fraction of the concentrated hydrochloric acid is 36%.
Preferably, the volume ratio of the ethanol to the concentrated hydrochloric acid is (20-30): (1.2-2).
Preferably, the temperature is reduced to-5-10 ℃.
Preferably, the crystalline form of erlotinib hydrochloride comprises a powder X-ray diffraction pattern of two or more peaks at 2 Θ values selected from: 9.42 °, 12.06 °, 13.68 °, 15.06 °, 17.82 °, 18.98 °, 22.04 °, 22.72 °, 25.54 ° and 26.92 ° 2 θ ± 0.2 ° 2 θ.
Preferably, the crystalline form of erlotinib hydrochloride comprises an X-ray diffraction pattern of peaks at the following 2 Θ values: 9.42 °, 15.06 °, 17.82 °, 18.98 °, 22.04 °, 25.54 ° and 26.92 ° 2 θ ± 0.2 ° 2 θ.
Preferably, the crystalline form of erlotinib hydrochloride comprises an X-ray diffraction pattern of peaks at the following 2 Θ values: 9.42 °, 22.04 °, and 26.92 ° 2 θ ± 0.2 ° 2 θ.
Preferably, the crystalline form of erlotinib hydrochloride comprises an X-ray diffraction pattern of peaks at the following 2 Θ values: 9.42 ° 2 θ ± 0.2 ° 2 θ.
Preferably, the crystalline form of erlotinib hydrochloride comprises an X-ray diffraction pattern of peaks at the following 2 Θ values: 22.04 ° 2 θ ± 0.2 ° 2 θ.
The invention aims to solve the technical problem that in the prior art, the free base of the erlotinib cannot form a better solid powder crystal form in a conventional solvent, and provides a preparation method of the erlotinib hydrochloride.
The invention solves the technical problems through the following technical means:
the preparation method of the erlotinib hydrochloride comprises the following steps: dissolving (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidine formamide in an alcohol solvent, adding hydrochloric acid, cooling, stirring to separate out a solid, and filtering to obtain the Larotenib hydrochloride.
Has the advantages that: the preparation method is simple, the erlotinib hydrochloride is prepared on the basis of the existing erlotinib, the stability is good, and the preparation method is suitable for being used as a raw material medicine form for research, development and production of preparations.
Preferably, the alcoholic solvent is ethanol or isopropanol.
Preferably, the ratio of the mass of the (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide to the volume of ethanol is 1g (4ml-6 ml).
Preferably, the mass fraction of the concentrated hydrochloric acid is 36%.
Preferably, the volume ratio of the ethanol to the concentrated hydrochloric acid is (20-30): (1.2-2).
Preferably, the temperature is reduced to-5-10 ℃.
The technical problem to be solved by the invention is that in the prior art, neither the free base of the erlotinib can form a better solid powder crystal form in a conventional solvent, and a pharmaceutical composition containing the erlotinib hydrochloride is provided.
The invention solves the technical problems through the following technical means:
a pharmaceutical composition comprising erlotinib hydrochloride and a pharmaceutically acceptable carrier or excipient.
Has the advantages that: the solid form of the erlotinib hydrochloride has good stability, is suitable for being used as a raw material medicine form for research and development and production of preparations, and can be used for treating mammal cancers.
Preferably, the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulation, solution or suspension.
The invention has the advantages that: the preparation method is simple, the solid form of the erlotinib hydrochloride has good stability, is suitable for being used as a raw material medicine form for research and development and production of preparations, and has practical commercial value and medicinal application.
Drawings
FIG. 1 is an XRPD pattern of the I-HS crystal form of Larotrectinib sulfate in the invention;
FIG. 2 is an XRPD pattern for Laritinib hydrochloride of example 3 of the present invention;
FIG. 3 is an HPLC chromatogram of Racaninib hydrochloride in example 3 of this invention;
FIG. 4 is a HNMR map of Ralitinib hydrochloride in example 3 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Test materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The specific techniques or conditions not specified in the examples can be performed according to the techniques or conditions described in the literature in the field or according to the product specification.
Example 1
500g of (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide are dissolved in 3000ml of ethanol, and (2) cooling to 5 ℃ under stirring, dropwise adding 120ml of concentrated hydrochloric acid (the mass fraction is 36%), keeping the temperature at 15 ℃ after dropwise adding, stirring, separating out a solid, stirring for 5h, and performing suction filtration to obtain 520g of I-HC crystal form yellow solid powder of (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide hydrochloride.
Example 2
5g of (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide are dissolved in 20ml of ethanol and cooled to-5 ℃ with stirring, 1.5ml of concentrated hydrochloric acid is added, stirring was carried out at 20 ℃ for 4 hours with heat preservation, and filtration was carried out to obtain 5.1g of a yellow solid powder as crystal form I-HC of (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide hydrochloride.
Example 3
50g of (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide are dissolved in 250ml of isopropanol, the temperature is reduced to 0 ℃ with stirring, 20ml of concentrated hydrochloric acid is added, stirring is carried out at 18 ℃ for 2h under the condition of heat preservation, and filtration is carried out to obtain 45g of I-HC crystal form yellow solid powder of (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidine formamide hydrochloride.
The characterization comprises the following steps:
figure 2 is an XRPD pattern (form I-HC) of (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-a ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide hydrochloride (larotinib hydrochloride). PeakSearch Report (37Peaks, Max P/N ═ 16.4) [ H371.raw ] a PEAK 19-pts/Parabolic Filter, Threshold ═ 9.0, Cutoff ═ 2.0%, BG ═ 7/1.0, Peak-Top ═ Summit.
Table 1 is a lapatinib hydrochloride crystalline form X-ray diffraction diagram. FIG. 3 is an HPLC chromatogram of (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide hydrochloride (Laretinib hydrochloride), and FIG. 4 is an HNMR chromatogram of (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidinecarboxamide hydrochloride (Laretinib hydrochloride).
Table 1 shows a crystal form X-ray diffraction chart of erlotinib hydrochloride
(II) performance measurement:
(1) the stability of crystalline form I-HC of ralotinib hydrochloride was determined: the temperature was 45. + -. 2 ℃ and the relative humidity was 60%. + -. 5% RH.
NMT represents the single unknown impurity limit of the starting material.
(2) The stability of crystalline form I-HC of ralotinib hydrochloride was determined: the temperature is 5 + -1 deg.C and the relative humidity is 60% + -5% RH.
As can be seen from tables 1 and 2, the solid form of the erlotinib hydrochloride in the invention has good stability and is suitable for being used as a raw material form for research and development and production of preparations.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. A Raatinib hydrochloride, which is characterized in that: the structural formula is as follows:
2. the erlotinib hydrochloride according to claim 1, wherein: the crystalline form of erlotinib hydrochloride comprises a powder X-ray diffraction pattern of two or more peaks at 2 Θ values selected from: 9.42 °, 12.06 °, 13.68 °, 15.06 °, 17.82 °, 18.98 °, 22.04 °, 22.72 °, 25.54 ° and 26.92 ° 2 θ ± 0.2 ° 2 θ.
3. The erlotinib hydrochloride according to claim 1, wherein: the crystalline form of erlotinib hydrochloride comprises an X-ray diffraction pattern of peaks at the following 2 Θ values: 9.42 °, 15.06 °, 17.82 °, 18.98 °, 22.04 °, 25.54 ° and 26.92 ° 2 θ ± 0.2 ° 2 θ.
4. The erlotinib hydrochloride according to claim 1, wherein: the preparation method of the erlotinib hydrochloride comprises the following steps: dissolving (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidine formamide in an alcohol solvent, adding hydrochloric acid, cooling, stirring to separate out a solid, and filtering to obtain the Larotenib hydrochloride.
5. The erlotinib hydrochloride according to claim 4, wherein: the alcohol solvent is ethanol or isopropanol.
6. The erlotinib hydrochloride according to claim 4, wherein: the ratio of the mass of the (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidine formamide to the volume of ethanol is 1g (4ml-6 ml).
7. The erlotinib hydrochloride according to claim 4, wherein: the mass fraction of the concentrated hydrochloric acid is 36%.
8. A process for the preparation of the lapatinib hydrochloride of any of claims 1-3, characterized in that: the method comprises the following steps: dissolving (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidine formamide in an alcohol solvent, adding hydrochloric acid, cooling, stirring to separate out a solid, and filtering to obtain the Larotenib hydrochloride.
9. The process for preparing erlotinib hydrochloride according to claim 8, wherein: the alcohol solvent is ethanol or isopropanol.
10. The process for preparing erlotinib hydrochloride according to claim 8, wherein: the ratio of the mass of the (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidinyl ] pyrazolo [1,5-A ] pyrimidin-3-yl ] -3-hydroxy-1-pyrrolidine formamide to the volume of ethanol is 1g (4ml-6 ml).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111620881A (en) * | 2020-07-08 | 2020-09-04 | 浙江合聚生物医药有限公司 | Raatinib derivative and preparation method and application thereof |
| CN114163445A (en) * | 2021-12-06 | 2022-03-11 | 重庆医科大学 | Raatinib intermediate and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107428760A (en) * | 2014-11-16 | 2017-12-01 | 阵列生物制药公司 | (S) crystal formation of the formamide disulfate of N (base of 5 (base of (R) 2 (2,5 difluorophenyl) pyrrolidines 1) pyrazolo [1,5 A] pyrimidine 3) 3 hydroxyl pyrrolidine 1 |
| CN109310694A (en) * | 2016-04-04 | 2019-02-05 | 洛克索肿瘤学股份有限公司 | Methods of treating pediatric cancers |
| WO2019089668A1 (en) * | 2017-10-31 | 2019-05-09 | Teva Pharmaceuticals Usa, Inc. | Salts and solid state forms of larotrectinib |
-
2020
- 2020-08-05 CN CN202010778538.0A patent/CN111763211A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107428760A (en) * | 2014-11-16 | 2017-12-01 | 阵列生物制药公司 | (S) crystal formation of the formamide disulfate of N (base of 5 (base of (R) 2 (2,5 difluorophenyl) pyrrolidines 1) pyrazolo [1,5 A] pyrimidine 3) 3 hydroxyl pyrrolidine 1 |
| CN109310694A (en) * | 2016-04-04 | 2019-02-05 | 洛克索肿瘤学股份有限公司 | Methods of treating pediatric cancers |
| WO2019089668A1 (en) * | 2017-10-31 | 2019-05-09 | Teva Pharmaceuticals Usa, Inc. | Salts and solid state forms of larotrectinib |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111620881A (en) * | 2020-07-08 | 2020-09-04 | 浙江合聚生物医药有限公司 | Raatinib derivative and preparation method and application thereof |
| CN114163445A (en) * | 2021-12-06 | 2022-03-11 | 重庆医科大学 | Raatinib intermediate and preparation method thereof |
| CN114163445B (en) * | 2021-12-06 | 2023-06-20 | 重庆医科大学 | Larotinib intermediate and preparation method thereof |
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