CN109369619A - Phthalazines ketone compound crystal form B and preparation method thereof - Google Patents

Phthalazines ketone compound crystal form B and preparation method thereof Download PDF

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CN109369619A
CN109369619A CN201811164081.3A CN201811164081A CN109369619A CN 109369619 A CN109369619 A CN 109369619A CN 201811164081 A CN201811164081 A CN 201811164081A CN 109369619 A CN109369619 A CN 109369619A
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water
compound
crystal form
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phthalazines
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郭程杰
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Nanjing Advanced Biomaterials And Process Equipment Research Institute Co Ltd
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Nanjing Advanced Biomaterials And Process Equipment Research Institute Co Ltd
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

A kind of phthalazines ketone compound crystal form B and preparation method thereof.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 B crystal form is with good stability, it is extremely low draw it is moist, suitable for pharmaceutical preparation is made.

Description

Phthalazines ketone compound crystal form B and preparation method thereof
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 B crystal form high income, and have good physical and chemical stability, hygroscopicity low, convenient for storage It deposits, can preferably be used as medical effective component.
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 B crystal form, institute Crystal form high income is stated, and has good physical and chemical stability, hygroscopicity low, convenient for storage.
It is a further object to provide the preparation methods of the B 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 B crystal form and at least one pharmaceutically acceptable carrier Use composition.
Fourth object of the present invention is to provide a kind of B 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 B crystal form, radiated using Cu-Ka, Its X-ray powder diffraction is to show at 6.7 ± 0.2 °, 17.8 ± 0.2 °, 20.8 ± 0.2 °, 29.7 ± 0.2 ° in 2 θ of the angle of diffraction Characteristic peak.
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 B 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 B crystal form, is radiated, X-ray powder diffraction is being spread out using Cu-Ka 2 θ of firing angle be 4.9 ± 0.2 °, 6.7 ± 0.2 °, 9.7 ± 0.2 °, 12.6 ± 0.2 °, 12.9 ± 0.2 °, 16.9 ± 0.2 °, 17.8 ± 0.2°、18.3±0.2°、19.9±0.2°、20.26±0.2°、20.8±0.2°、25.1±0.2°、27.7±0.2°、29.7 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 B crystal form, is radiated, X-ray powder diffraction using Cu-Ka It is 4.0 ± 0.2 °, 4.3 ± 0.2 °, 4.9 ± 0.2 °, 5.5 ± 0.2 °, 6.7 ± 0.2 °, 9.7 ± 0.2 °, 12.6 in 2 θ of the angle of diffraction ±0.2°、12.9±0.2°、13.7±0.2°、15.6±0.2°、16.4±0.2°、16.9±0.2°、17.8±0.2°、19.0 ±0.2°、19.9±0.2°、20.2±0.2°、20.8±0.2°、21.3±0.2°、22.4±0.2°、23.0±0.2°、24.2 ±0.2°、24.6±0.2°、25.1±0.2°、25.8±0.2°、26.6±0.2°、27.7±0.2°、29.0±0.2°、29.7 Characteristic peak is shown at ± 0.2 °, 30.3 ± 0.2 °, 37.3 ± 0.2 °, 40.8 ± 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 B 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 B 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: tetrahydrofuran-water or acetonitrile-water mixed solvent is added in formula (I) compound methanesulfonic acid salt obtained by step E In, 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 B crystal form.
According to the preparation method, tetrahydrofuran-water described in step F or acetonitrile-water in the mixed solvent tetrahydrofuran It is 1~2:1 with the volume ratio of water or acetonitrile and water；Preferably, tetrahydrofuran-water described in step F or acetonitrile-water mixing are molten The volume ratio of tetrahydrofuran and water or acetonitrile and water is 1.5:1 in agent.
According to the preparation method, the usage amount of tetrahydrofuran-water or acetonitrile-water mixed solvent described in step F is Every gram of [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 use tetrahydrofuran-water or acetonitrile-water mixed solvent 5-15mL；Preferably, four described in step F The usage amount of hydrogen furans-water or acetonitrile-water mixed solvent is every gram of [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 is mixed using tetrahydrofuran-water or acetonitrile-water Bonding 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 B 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 B 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 B 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 B 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 B 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 B 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 B crystal form is with good stability, it is extremely low draw it is moist, suitable for being made Pharmaceutical preparation.
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 B 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/z 165。
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 B crystal form preparation
Weighing 5.0g [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] in reaction flask, tetrahydrofuran-water that addition 25mL volume ratio is 1:1 mixes benzyl ester mesylate Solution, flow back 15min, cooled to room temperature, and 0-5 DEG C of crystallization 12h obtains that [2 (1H)-but-2-ene acyl group -3,4- dihydros are different Quinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate B crystal form, yield 90.6%.
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 B crystal form preparation
Weighing 10.0g [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, tetrahydrofuran-water that addition 100mL volume ratio is 1.5:1 is mixed Solution is closed, flow back 15min, 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 B crystal form, yield 93.9%.
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 B 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] benzyl ester mesylate is in reaction flask, the acetonitrile-water mixed solution that addition 15mL volume ratio is 2:1, Flow back 15min, cooled to room temperature, and 0-5 DEG C of crystallization 12h obtains [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinolines - 5- yl]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate B crystal form, yield 85.3%.
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 B crystal form preparation
Weighing 3.0g [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] in reaction flask, tetrahydrofuran-water that addition 45mL volume ratio is 1:1 mixes benzyl ester mesylate Solution, flow back 15min, cooled to room temperature, and 0-5 DEG C of crystallization 12h obtains that [2 (1H)-but-2-ene acyl group -3,4- dihydros are different Quinoline -5- base]-carbamic acid -4- [fluoro- (2H)-phthalazines -1- ketone group of 8-] benzyl ester mesylate B crystal form, yield 89.7%.
[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 B 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 B 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 B 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 60 days, 1 part of opening is placed 60 days, 1 part under the conditions of being placed in 75% relative humidity of room temperature (RH) Opening is placed 60 days under the conditions of being placed in 92.5% relative humidity of room temperature (RH), is sampled in the 0th, 5,10,30,60 day, and examination is maximum Single miscellaneous, total impurities, crystal form and appearance variations, 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 B crystal form has good chemical stability and physics steady It is qualitative, and low in hygroscopicity.

Claims (10)

  1. [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 B crystal form, radiated using Cu-Ka, X-ray powder diffraction 2 θ of the angle of diffraction be 6.7 ± 0.2 °, Characteristic peak is shown at 17.8 ± 0.2 °, 20.8 ± 0.2 °, 29.7 ± 0.2 °.
  2. 2. B 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 4.9 ± 0.2 °, 6.7 ± 0.2 °, 9.7 ± 0.2 °, 12.6 ± 0.2 °, 12.9 ± 0.2 °, 16.9 ± 0.2 °, 17.8 ± 0.2°、18.3±0.2°、19.9±0.2°、20.26±0.2°、20.8±0.2°、25.1±0.2°、27.7±0.2°、29.7 Characteristic peak is shown at ± 0.2 °.
  3. 3. B 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 4.0 ± 0.2 °, 4.3 ± 0.2 °, 4.9 ± 0.2 °, 5.5 ± 0.2 °, 6.7 ± 0.2 °, 9.7 ± 0.2 °, 12.6 ± 0.2 °, 12.9±0.2°、13.7±0.2°、15.6±0.2°、16.4±0.2°、16.9±0.2°、17.8±0.2°、19.0±0.2°、 19.9±0.2°、20.2±0.2°、20.8±0.2°、21.3±0.2°、22.4±0.2°、23.0±0.2°、24.2±0.2°、 24.6±0.2°、25.1±0.2°、25.8±0.2°、26.6±0.2°、27.7±0.2°、29.0±0.2°、29.7±0.2°、 Characteristic peak is shown at 30.3 ± 0.2 °, 37.3 ± 0.2 °, 40.8 ± 0.2 °.
  4. 4. the preparation method of B 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: tetrahydrofuran-water or acetonitrile-water in the mixed solvent is added in formula (I) compound methanesulfonic acid salt obtained by step E, is returned Stream, [8- is fluoro- by carbamic acid -4- to get [2 (1H)-but-2-ene acyl group -3,4- dihydro-isoquinoline -5- base]-for 0-5 DEG C of crystallization (2H)-phthalazines -1- ketone group] benzyl ester mesylate B crystal form.
  5. 5. preparation method as claimed in claim 4, it is characterised in that: tetrahydrofuran-water or acetonitrile-water described in step F The volume ratio of in the mixed solvent tetrahydrofuran and water or acetonitrile and water is 1~2:1.
  6. 6. preparation method as claimed in claim 4, it is characterised in that: tetrahydrofuran-water or acetonitrile-water described in step F The volume ratio of in the mixed solvent tetrahydrofuran and water or acetonitrile and water is 1.5:1.
  7. 7. preparation method as claimed in claim 4, it is characterised in that: tetrahydrofuran-water or acetonitrile-water described in step F The usage amount of mixed solvent is 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 tetrahydrofuran-water or acetonitrile-water mixed solvent 5-15mL.
  8. 8. preparation method as claimed in claim 4, it is characterised in that: tetrahydrofuran-water or acetonitrile-water described in step F The usage amount of mixed solvent is 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 tetrahydrofuran-water or acetonitrile-water mixed solvent 5-10mL.
  9. 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 B crystal form and can pharmaceutically connect The carrier received.
  10. 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 B crystal form or pharmaceutical composition as claimed in claim 9 exist Application in the drug of preparation prevention and/or treatment tumour.
CN201811164081.3A 2018-10-04 2018-10-04 Phthalazines ketone compound crystal form B and preparation method thereof Withdrawn CN109369619A (en)

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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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Application publication date: 20190222