CN109180643A - Phthalazines ketone compound crystal form A and preparation method thereof - Google Patents
Phthalazines ketone compound crystal form A and preparation method thereof Download PDFInfo
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- CN109180643A CN109180643A CN201811164088.5A CN201811164088A CN109180643A CN 109180643 A CN109180643 A CN 109180643A CN 201811164088 A CN201811164088 A CN 201811164088A CN 109180643 A CN109180643 A CN 109180643A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/00—Antineoplastic agents
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- 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
Abstract
The invention belongs to medicinal chemistry arts; more particularly to compound [2 (1H)-but-2-ene acyl groups -3 with function of tumor; 4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] a kind of novel crystal forms of benzyl ester mesylate, preparation method, the composition comprising the crystal form; and the purposes of the crystal form or the composition comprising the crystal form in medicine preparation; the A crystal form has good physical and chemical stability, solubility and bioavilability, is suitble to formulation development.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to compound [2 (1H)-but-2-ene acyls with function of tumor
Base -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate one kind is newly
Crystal form, preparation method, the composition comprising the crystal form and the crystal form or the composition comprising the crystal form are in drug
Purposes in preparation.
Background technique
Bu Ludun histidine kinase (Bruton's tyrosine kinase, BTK) belongs to the member of Tec family.It is by only
N- terminal domains, that is, PH (pleckstrin homology) structural domain, TH (Tec homology) homologous region, SH3 (Src of spy
Homology3) structural domain, SH2 (Src homology2) structural domain and catalyst structure domain, also referred to as SH1/TK
(Srchomologyl/Tyrosine kinase) structural domain or kinase domain composition (Akinleye et al:
Ibrutinib and novel BTK inhibitors in clinical development.Journal of
Hematology&Oncology2013,6:59).In bone-marrow-derived lymphocyte development process, BTK gene difference protein domain
Correct expression has key effect in the function of B cell and a variety of transduction pathway.
It is B cell class tumour such as leukaemia, hair property myeloma based on BTK signal transduction pathway exploitation small molecule targeted drug
And the treatment of B cell para-immunity disease provides a completely new approach.The evidence of effect of the BTK in autoimmune disease is
(Kil LP, et al:Bruton's tyrosine is provided by BTK- deletion form mouse and BTK- abundance type mouse model experiment
kinase mediated signaling enhances leukemogenesis in a mouse model for
Chronic lymphocytic leukemia.Am J Blood Res2013,3 (1): 71-83.).It is white in chronic lymphocytic
In blood disease (CLL) mouse model, BTK- deletion form mouse abrogates chronic lymphocytic leukemia completely, and BTK overexpression can add
Fast leukaemia morbidity, increases the death rate.
Have several BTK inhibitor at present to be developed, compound [2 (1H)-but-2-ene acyl group -3,4- dihydro isoquinolines
Quinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate, there is formula:
The compound has good inhibiting effect, IC to kinase b TK50Up to 1nM rank, external Romas cell activity
Evaluation also shows that good inhibitory activity, can be used for treatment and/or pre- preventing tumor.
This field knows that the difference of drug crystal forms will cause the difference of various physicochemical properties, as solubility, dissolution rate,
Fusing point, density, hardness, optical and electrical properties, steam pressure etc..These differences can be reflected in thermodynamic stability, as stable type,
Metastable type and instability mode；It can also be reflected on physical and chemical stability, such as hygroscopicity, crystal transfer, sample degradation.This
A little differences directly affect prescription preparation process, storage method, internal medicine the generation dynamic performance of drug, and then influence the safety of drug
Property and validity.
Therefore, [8- is fluoro- by carbamic acid -4- for research [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -
(2H)-phthalazines -1- ketone group] benzyl ester mesylate polymorphism and select significant and stably and controllable on clinical treatment
Crystal form tool be of great significance to.
Summary of the invention
To [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (the 2H)-phthalein of 8-
Piperazine -1- ketone group] benzyl ester mesylate crystal form research in, the present inventor has found tens kinds of crystal forms altogether, and experiment shows
In obtained numerous crystal forms, wherein A crystal form has good physical and chemical stability, solubility and bioavilability, is suitble to
Formulation development.
It is an object of the present invention to provide compound [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5-
Base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate a kind of crystal form for being named as A crystal form, institute
Crystal form is stated with good physical and chemical stability, solubility and bioavilability.
It is a further object to provide the preparation methods of the A crystal form, and this method is easy to operate, convenient for industrialization
Mass production.
It is also another object of the present invention to provide the medicines for containing the A crystal form and at least one pharmaceutically acceptable carrier
Use composition.
Fourth object of the present invention is to provide a kind of A crystal form in preparation prevention and/or the drug for the treatment of tumour
In application.
For foregoing invention purpose, in a first aspect, the present invention provides [2 (1H)-but-2-ene acyl group -3,4- dihydro isoquinolines
Quinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form, radiated using Cu-Ka,
Its X-ray powder diffraction 2 θ of the angle of diffraction be 4.3 ± 0.2 °, 19.0 ± 0.2 °, 19.3 ± 0.2 °, 20.3 ± 0.2 °, 20.6 ±
Characteristic peak is shown at 0.2 °, 24.6 ± 0.2 ° and 24.9 ± 0.2 °.
This field knows, when with the crystallization of X-ray diffraction measure compound, due to the instrument of measurement or condition of measurement etc.
Influence, for measured summit, there are the relative intensities of certain measurement error, especially x-ray diffraction pattern with test
The variation of condition and change.For example, the evaluated error of 2 θ values can be about ± 0.2 °, the evaluated error of relative intensity can for ±
20%.Therefore, when determining every kind of crystalline texture, it should take into account this error.It can be understood as any and the application A
There is crystal form the crystal form of essentially identical or similar x-ray diffraction pattern to belong within scope of the present application.
Specifically, [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid-provided by the invention
4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form, is radiated, X-ray powder diffraction is being spread out using Cu-Ka
2 θ of firing angle be 4.3 ± 0.2 °, 8.8 ± 0.2 °, 9.4 ± 0.2 °, 14.5 ± 0.2 °, 15.1 ± 0.2 °, 15.6 ± 0.2 °, 19.0 ±
0.2°、19.3±0.2°、20.3±0.2°、20.6±0.2°、23.1±0.2°、24.1±0.2°、24.6±0.2°、24.9±
Characteristic peak is shown at 0.2 °.
More specifically, [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-amino first provided by the invention
Acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form, is radiated, X-ray powder diffraction using Cu-Ka
2 θ of the angle of diffraction be 4.3 ± 0.2 °, 8.8 ± 0.2 °, 9.4 ± 0.2 °, 14.5 ± 0.2 °, 15.1 ± 0.2 °, 15.6 ± 0.2 °,
19.0±0.2°、19.3±0.2°、20.3±0.2°、20.6±0.2°、23.1±0.2°、24.1±0.2°、24.6±0.2°、
Characteristic peak is shown at 24.9 ± 0.2 °, 30.1 ± 0.2 ° and 30.9 ± 0.2 °.
[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-provided by the invention [8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate A crystal form have X- diffraction pattern as described in Figure 1.
Second aspect, the present invention provide [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-ammonia of the invention
The preparation method of base formic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form, the method include such as
Lower step:
Step A: the compound of formula (1) and the compound condensation of formula (2) obtain the compound of formula (3)；
Step B: the compound of formula (3) reacts to obtain the compound of formula (5) with the compound of formula (4)；
Step C: the compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；
Step D: the compound of formula (6) reacts to obtain compound of formula I with acryloyl chloride；
Step E: formula (I) compound is reacted with methanesulfonic acid is made formula (I) compound methanesulfonic acid salt, and reaction route is as follows:
Step F: formula (I) compound methanesulfonic acid salt obtained by step E is added in methanol-acetone-water mixed solvent, reflux,
0-5 DEG C of crystallization is to get [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- fluoro- (2H) -
Phthalazines -1- ketone group] benzyl ester mesylate A crystal form.
According to the preparation method, the body of methanol, acetone and water in methanol-acetone-water mixed solvent described in step F
Product is than being (10~15): 2:2；Preferably, methanol in methanol-acetone-water mixed solvent described in step F, acetone and water
Volume ratio is 6:1:1.
According to the preparation method, methanol-acetone-water mixed solvent usage amount described in step F is every gram [2
(1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester
Mesylate uses methanol-acetone-water mixed solvent 5-15mL；Preferably, methanol-acetone described in step F-water mixing is molten
The usage amount of agent be every gram [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-[8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate use methanol-acetone-water mixed solvent 5-10mL.
The third aspect, the present invention provide pharmaceutical composition, and it includes [2 (1H)-but-2-ene acyl groups -3,4- bis- of the invention
Hydrogen isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form and pharmaceutically may be used
The carrier of receiving.By [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalein of 8-
Piperazine -1- ketone group] benzyl ester mesylate A crystal form and pharmaceutically acceptable carrier be prepared by mixing into pharmaceutical preparation, be suitable for through
Mouth or parenteral.Medication includes, but are not limited to that intradermal, intramuscular, peritonaeum is interior, intravenous, subcutaneous, intranasal and oral way
Diameter.The preparation can be applied by any approach, such as by being transfused or injecting, by transepithelial or it is mucocutaneous (such as
Oral mucosa or rectum etc.) absorb approach application.Administration can be whole body or local.The example packet of oral administration preparation
Solid or liquid dosage form are included, specifically, including tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspension etc..
The preparation can be prepared by methods known in the art, and include the conventional use of carrier of field of pharmaceutical preparations.
Fourth aspect, the present invention provide [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -
4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form or [2 (1H)-but-2-ene acyl group -3,4- dihydro isoquinolines
Quinoline -5- base] pharmaceutical composition of-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form making
Application in the standby drug for preventing and/or treating tumour, including crowd or tumor patient application therapeutically effective amount are easily sent out to tumour
[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines-of 8- of the invention
1- ketone group] benzyl ester mesylate A crystal form or [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4-
The pharmaceutical composition of [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form, Tumor incidence is effectively reduced, prolongs
Bearing tumor patient vitals.
[8- is fluoro- by carbamic acid -4- for [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-of the invention
(2H)-phthalazines -1- ketone group] benzyl ester mesylate A crystal form is with good stability, solubility and bioavilability, it is suitble to use
In pharmaceutical preparation is made.
Detailed description of the invention
Fig. 1 is [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalein of 8-
Piperazine -1- ketone group] benzyl ester mesylate A crystal form x-ray diffraction pattern.
Specific embodiment
The present invention is explained in more detail with reference to embodiments, the embodiment of the present invention is merely to illustrate technology of the invention
Scheme not limits the scope of the invention.
Embodiment 1 [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- fluoro- (2H) -
Phthalazines -1- ketone group] benzyl ester preparation
Step 1: weighing -2 (1H)-t-butyl formate (50mmol) of 5- amino -3,4- dihydro-isoquinoline and DIPEA
(100mmol) is added methylene chloride 300ml, is stirred at room temperature down and chloro-carbonic acid is slowly added dropwise to benzyl chloride ester in reaction flask
(51mmol), drop finish, and continue to stir 1h at room temperature, stop reaction, and ethyl acetate 70ml, dilute salt is added in concentrated reaction mixture
Aqueous acid (0.2-0.3N) and saturated common salt water washing, anhydrous sodium sulfate dry, filter, and are concentrated to give (3,4- dihydro-isoquinolines-
2 (1H)-t-butyl formate -5- bases)-carbamic acid to benzyl chloride ester, is directly used in next step, ESI-MS:[M+H]+m/z 417。
Step 2: weighing the fluoro- 1- dimethoxy-methyl benzene (500mmol) of 3- in reaction flask, tetrahydrofuran is added
(800ml) dissolution, 60 DEG C, under nitrogen protection, be added s-BuLi (565mmol), reaction solution is stirred into 1h at -60 DEG C；It weighs
Dry ice (50mmol) is added tetrahydrofuran (200ml) in another reaction flask, is added n-BuLi (5ml), stirred under nitrogen atmosphere
After 2h, said mixture is added, continues to stir 30min, stops reaction, water 1000ml is added, adjusts pH to 2 with concentrated hydrochloric acid, point
From organic phase, water phase is extracted with ethyl acetate, and merges organic phase, and saturated common salt water washing, anhydrous sodium sulfate is dry, recrystallizes
To the fluoro- 2- dimethoxy-methyl benzoic acid of 6-；Weigh the fluoro- 2- dimethoxy-methyl benzoic acid (400mmol) of 6-, acetic acid
(93mmol), hydrazine (600mmol) are in reaction flask, addition isopropanol 300ml, and under nitrogen protection, 100 DEG C of back flow reaction 2h stop
It only reacts, ethyl acetate 300ml, water 500ml is added, extraction merges organic phase, and anhydrous sodium sulfate is dry, and outstanding dry, column chromatography is pure
Change to obtain the fluoro- 2H- phthalazines -1- ketone of 8-, ESI-MS:[M+H]+m/z165。
Step 3: weighing the fluoro- 2H- phthalazines -1- ketone (150mmol) of 8-, (3,4- dihydro-isoquinoline -2 (the 1H)-tertiary fourth of formic acid
Ester -5- base) in reaction flask, DMF100ml is added to benzyl chloride ester (195mmol) in-carbamic acid, and it reacts at 55 DEG C overnight, stops
Water 100ml, methylene chloride 200ml is added in reaction, and extraction separates organic phase, and water phase continues that (3* is extracted with dichloromethane
50ml), merge organic phase, anhydrous sodium sulfate is dry, and column chromatographic purifying obtains (- 2 (1H)-t-butyl formate-of 3,4- dihydro-isoquinoline
5- yl)-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester.
Step 4: weighing (3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate -5- base) -, [8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] in reaction flask, addition trifluoroacetic acid 20ml stirs 1h at room temperature, depressurizes dense benzyl ester (50mmol)
It is reduced to dry, addition ethyl acetate 80ml, successively with 1.5M disodium hydrogen phosphate aqueous solution and saturated common salt water washing, anhydrous sodium sulfate
It dries, filters, intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) fluoro- 2- of carbamic acid -8- (2H)-phthalazines-is concentrated under reduced pressure to obtain
1- ketone group benzyl ester；Weigh gained intermediate (1,2,3,4- tetrahydroisoquinoline -5- base) fluoro- 2- of carbamic acid -8- (2H)-phthalazines -
1- ketone group benzyl ester (20mmol) is added methylene chloride 100ml dissolution, DIEA (40mmol) is added at 0 DEG C, stirring in reaction flask
After 30min, continuing that acryloyl chloride (20mmol) is added dropwise at 0 DEG C, drop finishes, and is stirred at room temperature 3h, stops reaction, add water 100ml, two
Chloromethanes extracts (3*50ml), merges organic phase, and anhydrous sodium sulfate is dry, and column chromatographic purifying obtains [2 (1H)-but-2-ene acyl groups-
3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H), 8.10 (s, 1H), 7.88~7.85 (m, 1H),
7.77~7.75 (m, 1H), 7.54~7.52 (m, 3H), 7.34~7.32 (m, 2H), 7.21~7.18 (m, 3H), 6.57~
6.55 (m, 1H), 6.41~6.39 (m, 1H), 4.65 (s, 2H), 4.22 (s, 2H), 3.61~3.59 (m, 2H), 3.13~3.11
(m, 2H), 2.05~2.03 (m, 3H)
ESI–MS:[M+H]+m/z 513。
Embodiment 2:[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-[8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate preparation
1 compound of embodiment (0.5mmol) is weighed in reaction flask, acetone 5mL is added to stir 0.5h at room temperature, methylsulphur is added dropwise
Sour acetone soln (containing methanesulfonic acid 0.55mmol) 1mL, drop finish, continue to stir 1h at room temperature, solvent is evaporated off in pressurization, at room temperature vacuum
It is dry to obtain title compound.
1H NMR(600MHz,CDCl3) (δ, ppm): 9.50 (s, 1H disappear after heavy water exchange), 8.10 (s, 1H), 7.88
~7.85 (m, 1H), 7.77~7.75 (m, 1H), 7.54~7.52 (m, 3H), 7.34~7.32 (m, 2H), 7.21~7.18 (m,
3H), 6.57~6.55 (m, 1H), 6.41~6.39 (m, 1H), 5.17 (s, 2H), 4.22 (s, 2H), 3.61~3.59 (m, 2H),
3.13~3.11 (m, 2H), 2.84~2.81 (s, 3H), 2.05~2.03 (m, 3H)
Embodiment 3:[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-[8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate A crystal form preparation
Weighing 1.0g [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -, [8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] for benzyl ester mesylate in reaction flask, methanol-acetone-water that addition 12mL volume ratio is 5:1:1 is mixed
Solution is closed, flow back 10min, cooled to room temperature, and 0-5 DEG C of crystallization 12h obtains [2 (1H)-but-2-ene acyl group -3,4- dihydros
Isoquinolin -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form.
Embodiment 4:[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-[8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate A crystal form preparation
Weighing 1.0g [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -, [8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] for benzyl ester mesylate in reaction flask, methanol-acetone-water that addition 10mL volume ratio is 6:1:1 is mixed
Solution is closed, flow back 10min, cooled to room temperature, and 0-5 DEG C of crystallization 12h obtains [2 (1H)-but-2-ene acyl group -3,4- dihydros
Isoquinolin -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form.
Embodiment 5:[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-[8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate A crystal form preparation
Weighing 1.0g [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -, [8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] for benzyl ester mesylate in reaction flask, methanol-acetone-water that addition 7mL volume ratio is 6:1:1 is mixed
Solution is closed, flow back 10min, cooled to room temperature, and 0-5 DEG C of crystallization 12h obtains [2 (1H)-but-2-ene acyl group -3,4- dihydros
Isoquinolin -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form.
Embodiment 6:[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-[8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] benzyl ester mesylate A crystal form preparation
Weighing 1.0g [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base] -, [8- is fluoro- by carbamic acid -4-
(2H)-phthalazines -1- ketone group] for benzyl ester mesylate in reaction flask, methanol-acetone-water that addition 5mL volume ratio is 15:2:2 is mixed
Solution is closed, flow back 10min, cooled to room temperature, and 0-5 DEG C of crystallization 12h obtains [2 (1H)-but-2-ene acyl group -3,4- dihydros
Isoquinolin -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form.
[2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid-of above embodiments 3-6 preparation
4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form has essentially identical X ray diffracting spectrum through measurement,
See Fig. 1.
Embodiment 7 [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- fluoro- (2H) -
Phthalazines -1- ketone group] benzyl ester mesylate A crystal form stability test
Weigh 3 parts of [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- fluoro- (2H) -
Phthalazines -1- ketone group] benzyl ester mesylate A crystal form 1.0g, it is laid in culture dish respectively, 1 part of opening is placed in illumination illumination and is
It is placed under the conditions of 4500Lx ± 500Lx 10 days, 1 part of opening is placed 10 days, 1 part under the conditions of being placed in 75% relative humidity of room temperature (RH)
Opening is placed under the conditions of 92.5% relative humidity of room temperature (RH) and places 10 days, samples in the 0th, 5,10 day, examination largest single impurity, always
The variation of impurity, crystal form and appearance, experimental result are shown in Table 1.
Table 1
Above-mentioned experimental result shows [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-ammonia of the invention
Base formic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form has good chemical stability and physics steady
It is qualitative.
Claims (10)
- [1. 2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone of 8- Base] benzyl ester mesylate A crystal form, radiated using Cu-Ka, X-ray powder diffraction 2 θ of the angle of diffraction be 4.3 ± 0.2 °, Feature is shown at 19.0 ± 0.2 °, 19.3 ± 0.2 °, 20.3 ± 0.2 °, 20.6 ± 0.2 °, 24.6 ± 0.2 ° and 24.9 ± 0.2 ° Peak.
- 2. A crystal form as described in claim 1, it is characterised in that: radiated using Cu-Ka, X-ray powder diffraction is in diffraction 2 θ of angle be 4.3 ± 0.2 °, 8.8 ± 0.2 °, 9.4 ± 0.2 °, 14.5 ± 0.2 °, 15.1 ± 0.2 °, 15.6 ± 0.2 °, 19.0 ± 0.2°、19.3±0.2°、20.3±0.2°、20.6±0.2°、23.1±0.2°、24.1±0.2°、24.6±0.2°、24.9± Characteristic peak is shown at 0.2 °.
- 3. A crystal form as described in claim 1, it is characterised in that: radiated using Cu-Ka, X-ray powder diffraction is in diffraction 2 θ of angle be 4.3 ± 0.2 °, 8.8 ± 0.2 °, 9.4 ± 0.2 °, 14.5 ± 0.2 °, 15.1 ± 0.2 °, 15.6 ± 0.2 °, 19.0 ± 0.2°、19.3±0.2°、20.3±0.2°、20.6±0.2°、23.1±0.2°、24.1±0.2°、24.6±0.2°、24.9± Characteristic peak is shown at 0.2 °, 30.1 ± 0.2 ° and 30.9 ± 0.2 °.
- 4. the preparation method of A crystal form described in claim 1, includes the following steps:Step A: the compound of formula (1) and the compound condensation of formula (2) obtain the compound of formula (3)；Step B: the compound of formula (3) reacts to obtain the compound of formula (5) with the compound of formula (4)；Step C: the compound of formula (5) sloughs protecting group and obtains the compound of formula (6)；Step D: the compound of formula (6) reacts to obtain compound of formula I with acryloyl chloride；Step E: formula (I) compound is reacted with methanesulfonic acid is made formula (I) compound methanesulfonic acid salt, and reaction route is as follows:Step F: formula (I) compound methanesulfonic acid salt obtained by step E is added in methanol-acetone-water mixed solvent, reflux, and 0-5 DEG C Crystallization is to get [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [fluoro- (the 2H)-phthalazines-of 8- 1- ketone group] benzyl ester mesylate A crystal form.
- 5. preparation method as claimed in claim 4, it is characterised in that: methanol-acetone-water mixed solvent described in step F The volume ratio of middle methanol, acetone and water is (10~15): 2:2.
- 6. preparation method as claimed in claim 4, it is characterised in that: methanol-acetone-water mixed solvent described in step F The volume ratio of middle methanol, acetone and water is 6:1:1.
- 7. preparation method as claimed in claim 4, it is characterised in that: methanol-acetone-water mixed solvent described in step F Usage amount be every gram of [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- fluoro- (2H) - Phthalazines -1- ketone group] benzyl ester mesylate use methanol-acetone-water mixed solvent 5-15mL.
- 8. preparation method as claimed in claim 4, it is characterised in that: methanol-acetone-water mixed solvent described in step F Usage amount be every gram of [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-carbamic acid -4- [8- fluoro- (2H) - Phthalazines -1- ketone group] benzyl ester mesylate use methanol-acetone-water mixed solvent 5-10mL.
- 9. a kind of pharmaceutical composition includes described in any item [2 (1H)-but-2-ene acyl group -3, the 4- dihydros of claim 1-3 Isoquinolin -5- base] it-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form and can pharmaceutically connect The carrier received.
- 10. claim 1-3 described in any item [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-amino Formic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate A crystal form or pharmaceutical composition as claimed in claim 9 exist Application in the drug of preparation prevention and/or treatment tumour.
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| US20140107151A1 (en) * | 2011-05-17 | 2014-04-17 | Principia Biophama Inc. | Tyrosine kinase inhibitors |
| US20150064196A1 (en) * | 2012-04-20 | 2015-03-05 | Advinus Therapeutics Limited | Substituted Hetero-Bicyclic Compounds, Compositions and Medicinal Applications Thereof |
| CN104812746A (en) * | 2012-11-16 | 2015-07-29 | 弗·哈夫曼-拉罗切有限公司 | Inhibitors of bruton's tyrosine kinase |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140107151A1 (en) * | 2011-05-17 | 2014-04-17 | Principia Biophama Inc. | Tyrosine kinase inhibitors |
| US20150064196A1 (en) * | 2012-04-20 | 2015-03-05 | Advinus Therapeutics Limited | Substituted Hetero-Bicyclic Compounds, Compositions and Medicinal Applications Thereof |
| CN104812746A (en) * | 2012-11-16 | 2015-07-29 | 弗·哈夫曼-拉罗切有限公司 | Inhibitors of bruton's tyrosine kinase |
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