CN108530425A - A kind of Ni Lapani tosilate hydrate crystal forms and preparation method thereof - Google Patents
A kind of Ni Lapani tosilate hydrate crystal forms and preparation method thereof Download PDFInfo
- Publication number
- CN108530425A CN108530425A CN201810402877.1A CN201810402877A CN108530425A CN 108530425 A CN108530425 A CN 108530425A CN 201810402877 A CN201810402877 A CN 201810402877A CN 108530425 A CN108530425 A CN 108530425A
- Authority
- CN
- China
- Prior art keywords
- solvent
- piperidyls
- protonic solvent
- phenyl
- reaction dissolvent
- Prior art date
- 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.)
- Withdrawn
Links
- 0 C=C1C(C(N)=O)=CC=CC1=C*CN Chemical compound C=C1C(C(N)=O)=CC=CC1=C*CN 0.000 description 1
- ZZAJVZCDEKJIEC-UHFFFAOYSA-N Cc1ccc(C2CNCCC2)cc1 Chemical compound Cc1ccc(C2CNCCC2)cc1 ZZAJVZCDEKJIEC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D401/10—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 carbon chain containing aromatic rings
-
- 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
The invention belongs to chemical medicines, more particularly to the crystal form A and preparation method thereof of Ni Lapani (2 [4 ((3S) 3 piperidyl) phenyl] 2H indazoles, 7 formamide) tosilate, crystal form A, X ray powder diffraction pattern in the present invention has characteristic peak at 2theta values is 9.5 ± 0.2 °, 13.2 ± 0.2 °, 15.1 ± 0.2 °, 18.4 ± 0.2 °, 19.4 ± 0.2 °, 21.0 ± 0.2 °, 24.6 ± 0.2 ° and 30.0 ± 0.2 °.There is the crystal form A of the Ni Lapani tosilate of the present invention high stability, nothing or moist almost without drawing, property to stablize, be unlikely to deteriorate, and be conducive to maintain drug effect.
Description
Technical field
The invention belongs to chemical medicines, are related to 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamides
(Ni Lapani) tosilate hydrate crystal forms A and preparation method thereof.
Background technology
The DNA damage moment, external cause included ionising radiation, chemical toxicant along with mammalian cell, and internal cause includes cell
The stimulation of own metabolism product, DNA itself chemical bond ruptures etc., the damage number that average each cell occurs daily is up to number with ten thousand
Meter.Such as cannot in time, accurately DNA plerosis damage can lead to genomic instability, and genome it is indefinite be canceration important spy
Sign.DNA damage repair mechanism is for maintaining the stability of genome to have a very important role.Radiotherapy and many antineoplastics
Object is all to achieve the purpose that kill tumour cell by damage dna, but tumour cell can activate the injury repair of itself DNA
Mechanism is repaired, and is generated resistance to drug and radiotherapy so as to cause it, is also detected that DNA repair enzymes really in tumour cell
Overexpression.Therefore blocking dna repair pathways are an important channels of oncotherapy.
PARP and BRCA is intracellular two kinds important DNA repair mechanisms, the former main single-stranded damage of DNA plerosis, the latter
Main DNA plerosis double-strand damage, it is dual to guard cell health, ensure that intracellular DNA damage is repaired and avoids canceration in time.
Any repair mechanism failures of PARP and BRCA, damage dna can be accumulated in the cell leads to canceration, and it is thin that accumulation excessively also results in cancer
Born of the same parents are dead.Due to the congenital or day after tomorrow, BRCA genes mutate and lose activity some people, into the cell can be because of damage
DNA accumulations cause risk of cancer to increase, especially breast cancer and ovarian cancer risk.And BRCA saltant types cancer cell is lost due to BRCA
Living, DNA damage reparation becomes very dependent on PARP, if PARP activity is further suppressed, when these cell divisions just
A large amount of DNA damages are will produce, cancer cell death is caused.
Entitled 2- [4- ((3S) -3- piperidyls) the phenyl] -2H- indazole -7- formyls of Ni Lapani chemistry are by Tesaro public affairs
A kind of oral Poly ADP-ribose polymerase (PARP) inhibitor for taking charge of research and development, can inhibit reparation of the cell to DNA damage, main needle
To the cancer for thering is BRCA to be mutated, such as oophoroma and breast cancer.3 clinical trial phases in 2016 the result shows that, for platinum medicine
The patient alleviated completely or partially is obtained through platiniferous chemotherapy again after chemosensitivity recurrence, is compared using Ni Lapani maintaining treatments
It is treated in placebo, 2 times is almost turned over the effect of delaying in terms of progression of disease, promoted and arrive nearly 4 times.
Document report Ni Lapani is to mesylate (Org.Process Res.Dev.2014,18,215-227) at present
Synthetic route is as follows：
Compound 3 and tert-butylamine obtain amide intermediate 4 by condensation reaction, then the idol for passing through copper catalysis with compound 2
Intermediate 5 is obtained by the reaction in connection, through deprotection, forms tosilate crude product.
Invention content
Present invention aims at a kind of 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamides of offer to first
Benzene sulfonate hydrate crystal forms and its method and preparation method.
On the one hand, 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamides provided by the invention are to toluene sulphur
Hydrochloride hydrates crystal form, we are named as crystal form A, and structural formula is shown in formula I：
The characteristic peak measured comprising the following angles 2theta in its X-ray powder diffraction collection：13.2±0.2°、15.1±
0.2 °, 21.0 ± 0.2 ° and 30.0 ± 0.2 °.
More specifically, the characteristic peak measured comprising the following angles 2theta in its X-ray powder diffraction collection：9.5±
0.2 °, 13.2 ± 0.2 °, 15.1 ± 0.2 °, 18.4 ± 0.2 °, 19.4 ± 0.2 °, 21.0 ± 0.2 °, 24.6 ± 0.2 ° and 30.0
±0.2°。
More specifically, it is with X-ray powder diffraction collection shown in Figure of description 1.
Further, 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide p-methyl benzenesulfonic acid salt hydrates
Crystal form A, differential scanning calorimetry (DSC) analysis are being heated to 107.41 DEG C of initial temperature, first endothermic peak of appearance nearby,
Nearby there is second endothermic peak for 162.3 DEG C in peak temperature, nearby third endothermic peak occur for 231.3 DEG C in peak temperature,
It is specific as shown in Figure 2.
On the other hand, the present invention also provides 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamides to first
Benzene sulfonate hydrate crystal forms A is being used to prepare treatment epithelial ovarian, carcinoma of fallopian tube, lung cancer, breast cancer, prostate cancer or original
Purposes in the drugs of diseases such as hair property peritoneal cancer.
On the other hand, the present invention also provides a kind of pharmaceutical compositions, contain 2- [4- ((3S) -3- piperidyls) benzene
Base] -2H- indazoles -7- formamides tosilate hydrate crystal forms A and its pharmaceutically acceptable carrier.
On the other hand, the present invention also provides 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamides to first
The preparation method of benzene sulfonate hydrate crystal forms A.
This method can be method 1：By to 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyls (Ni La
Pa Ni) obtained after tosilate hydrate crystallization.
Specifically, it comprises the steps of：
S1. the crude product of Ni Lapani tosilate monohydrates is added in reaction dissolvent；
S2. it is heated to 50 to 100 DEG C under nitrogen protection；It is preferably heated to 75 DEG C~85 DEG C；
S3. it is slowly stirred and is cooled to -10 to 30 DEG C；And temperature control stirring crystallization two hours or more；Preferably, temperature control is 20
DEG C, temperature control stirring crystallization is 2 to 4 hours；
S4. product is obtained by filtering or centrifuging；
S5. it is dried in vacuo at 20 DEG C~60 DEG C, preferably 35 DEG C~45 DEG C vacuum drying.
Alternatively, method 2：By 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyls, 2- [4- ((3S) -3- piperazines
Piperidinyl) phenyl] -2H- indazoles -7- formyls mesylate or 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyl salt
Hydrochlorate with p-methyl benzenesulfonic acid monohydrate by salt-forming reaction by being prepared.
Specifically, it comprises the steps of：
1) by 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyls, 2- [4- ((3S) -3- piperidyls) benzene
Base] -2H- indazoles -7- formyls mesylate or 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazoles -7- formyls hydrochlorides with
Reaction dissolvent mixes, and temperature control is at 10 DEG C -100 DEG C；It is preferred that temperature control is at 20 DEG C~40 DEG C；
2) toluenesulfonic acid monohydrate is added under nitrogen protection；
3) temperature control is in -10 to 30 DEG C of stirring and crystallizings two hours or more；Preferably, temperature control was in 20 DEG C of stirring and crystallizings 2-4 hours；
4) product through washing by obtaining again after filtering or centrifugation；
5) it is dried in vacuo at 20 DEG C~60 DEG C, preferably 35 DEG C~45 DEG C vacuum drying.
Wherein, in method 1 and method 2, the reaction dissolvent appointing in protonic solvent and non-protonic solvent
Meaning one or more combination；
Wherein, the protonic solvent is selected from least one of alcohol, acid and the water of C1-C4；It is highly preferred that described
Protonic solvent is selected from least one of ethyl alcohol, methanol and isopropanol；
Wherein, the non-protonic solvent is selected from alkane, esters, DMF, DMSO, DMAc, THF, the dioxy six of C1-C12
Ring, the ketone of C1-C4, NMP, at least one of ethers and benzene class；It is highly preferred that the non-protonic solvent is selected from acetic acid second
At least one of ester, n-hexane, normal heptane, dichloromethane, toluene, acetone, butanone, methyl tertiary butyl ether(MTBE) and THF；
As an alternative embodiment, the reaction dissolvent in method 1 and method 2 be selected from protonic solvent and
The combination of non-protonic solvent, further, the volume ratio of protonic solvent and non-protonic solvent is 1:99 to 99:1；It is preferred that
The volume ratio of ground, the protonic solvent and non-protonic solvent is 1:10 to 10:1.
As a preferred embodiment, the reaction dissolvent in method 1 and method 2 be selected from lower alcohol/ketone and
The mixture of water, the lower alcohol/ketone are one or more in methanol, ethyl alcohol and acetone；It is highly preferred that described is low
The volume ratio of grade alcohol/ketone and water is 1:5 to 5:1.
As a preferred embodiment, the reaction dissolvent in method 2 can also be independently chosen from water.
Wherein, in method 1 and method 2, the ratio of the volume of reaction dissolvent and the quality that feeds intake is 3mL/g~100mL/g；It is more excellent
The ratio of selection of land, the volume of reaction dissolvent and the quality that feeds intake is 5mL/g~20mL/g.
In method 2, the range of the mass fraction of the toluenesulfonic acid monohydrate solution that step 2 is added 5%~60%
It is interior；It is preferred that the mass fraction for the toluenesulfonic acid monohydrate solution being preferably added to is in the range of 40%~55%.Wherein, should
The solvent of toluenesulfonic acid monohydrate solution is preferably water, and the dosage of the solution is preferably controlled in the toluenesulfonic acid made in step 2)
Monohydrate and feeding intake in S1 (institute is to the solid chemical compound raw material that is mixed with solvent i.e. in step 1)) the two mass ratio is
60~80:100；It is preferred that 70~75:100.
What is used in the methods of the invention stirs the requirement on not particularly severe rotating speed.Inventor has found, is controlling
On the basis of other good above-mentioned conditions, in the case where very significantly mixing speed changes, the crystal form that will not be obtained to the present invention produces
It is raw to influence.For example, under the range of speeds of 50~1000rmp.
Beneficial effects of the present invention：
(1) present invention is prepared for 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamides to toluene sulphur for the first time
Hydrochloride hydrates crystal form A, the crystal form is with good stability, and after stability experiment 90 days, crystal form is unchanged.
(2) 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate prepared by the present invention
Its low in hygroscopicity of hydrate crystal forms A, only 0.1%, for ensureing that it is highly beneficial that drug effect has the effect of.
Description of the drawings
Fig. 1 is 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate hydrate crystal forms
X-ray powder diffraction (XRD) collection of illustrative plates of A.
Fig. 2 is 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate hydrate crystal forms
Differential scanning calorimetric analysis (DSC) collection of illustrative plates of A.
Fig. 3 is 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate in embodiment 8
TGA collection of illustrative plates of the hydrate crystal forms A stability tests after one month.
Specific implementation mode
Below by way of the technical solution that specific embodiment further illustrates the present invention, specific embodiment does not represent to this hair
The limitation of bright protection domain.Other people still fall within this hair according to some nonessential modifications and adjustment that theory of the present invention is made
Bright protection domain.
As used herein, term " containing " or " comprising " include "comprising", " substantially by ... constitute " and
" by ... constitute ".Term " effective quantity " refers to that function or active and can be by people and/or animal can be generated to people and/or animal
The amount received.
Term " pharmaceutically acceptable " refers to suitable for people and/or animal and without excessively bad side reaction (such as toxicity, thorn
Swash and allergy), that is, have rational benefit/risk than substance.
Term " pharmaceutically acceptable carrier " refers to the carrier for Therapeutic Administration, including various fillers, disintegrant,
Lubricant, glidant, effervescent agent, corrigent, covering material, excipient or slow/controlled releasing agent etc..In the pharmaceutical composition of the present invention
In object, pharmaceutically acceptable carrier can contain liquid, such as water, brine, glycerine and ethyl alcohol.The term refers to some such medicaments and carries
Body：It themselves is not necessary active constituent, and does not have excessive toxicity after applying.Suitable carrier is that this field is common
Known to technical staff.
" pharmaceutical composition " can be in the form of Injectable solution, drops or potus (juices) as liquid in the present invention
Pharmaceutical preparation, as semisolid pharmaceutical formulation in the form of granule, tablet, pill, patch, capsule, paste or aerosol
It is administered.Administering mode can be oral medication, buccal administration (per orally), parenteral administration, intravenous administration,
Intraperitoneal medication, intradermal administration, intramuscular administration, intranasal administration, oral administration (buccally), rectally or local administration
Such as to skin, mucous membrane or ophthalmic administration.The appropriate dosage form being administered orally is tablet, dragee, capsule, granule, liquid
Drops, potus and syrup, and the appropriate form of parenteral administration, local administration and inhalation is solution, suspension, is easy to
Reconstitutable dry preparation and spray.With storage form, dissolved form or ointment, it is optionally added into promotion Cutaneous permeation
Reagent, be the preparation of suitable percutaneous dosing.In principle, it is possible to be incorporated as art technology into drug according to the present invention
Further active component known to personnel.
Term " treatment " refers to any treatment of the disease or illness in the individual to such as mammal comprising：In advance
Prevent or prevent disease or illness, that is, clinical symptoms is caused not develop；Inhibit disease or illness, that is, prevents or inhibit to face
The development of bed symptom；And/or alleviate disease or illness, that is, clinical symptoms is caused to subside.
Term " feed intake quality "：It feeds intake and refers to and the quality for the solid chemical compound that will be mixed with solvent.For example, in method 1
In, the step S1 quality that feeds intake refers to 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyls (Ni Lapani) to toluene
The quality of sulfonate monohydrate；In method 2, the quality that feeds intake of step S1 refers to 2- [4- ((3S) -3- piperidyls) phenyl] -
2H- indazole -7- formyls, 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazoles -7- formyls mesylates or 2- [4- ((3S) -
3- piperidyls) phenyl] -2H- indazole -7- formyl hydrochlorides quality.
Term " protonic solvent " can provide proton and mutually associate or formed the one of coordination cation with hydrogen bond with solute molecule
Class solvent, the generally compound containing hydroxyl or amino, such as：Water, ethyl alcohol, formic acid, acetic acid etc..They tend to keep polarity molten
Matter molecule forms unstable reactive intermediate, has catalytic action, can promote the formation of ion, be conducive to monomolecular reaction.
It is almost no acidic compared with water without proton in term " non-protonic solvent " molecule, also without ambisexuality, but have compared with
It is weak that receive proton tendency different with degree at bonding ability, such as amides, ketone, nitrile, dimethyl sulfoxide, pyridine.
Embodiment 1
The conjunction of 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate hydrate crystal forms A
At method
120g 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyl tosilate is added in reaction bulb
Monohydrate, ethyl alcohol 980mL, water 250mL, stirred under nitrogen atmosphere are heated to 80 DEG C, and solid dissolving stirs lower slow cooling extremely
20 DEG C and temperature control stirring 2 hours, filtering, 40 DEG C are dried in vacuo to obtain crystal form A 105g.
Embodiment 2
The conjunction of 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate hydrate crystal forms A
At method
100g2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyl mesylates, water are added in reaction bulb
1000mL, temperature control slowly add the p-methyl benzenesulfonic acid (70g) one of 50% (mass fraction) to be hydrated to 20 DEG C -30 DEG C under nitrogen protection
Object solution finishes 20 DEG C of rear temperature control and stirs 4 hours, and filtering washing, 40 DEG C are dried in vacuo to obtain crystal form A 100g.
Embodiment 3
The conjunction of 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate hydrate crystal forms A
At method
Addition 100g 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyls in reaction bulb, ethyl alcohol 750mL,
Water 250mL temperature controls slowly add the p-methyl benzenesulfonic acid (75g) one of 50% (mass fraction) to be hydrated to 20 DEG C -30 DEG C under nitrogen protection
Object solution finishes 20 DEG C of rear temperature control and stirs 4 hours, and filtering washing, 40 DEG C are dried in vacuo to obtain crystal form A 110g.
Embodiment 4
The conjunction of 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate hydrate crystal forms A
At method
100g 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyl hydrochlorides, methanol are added in reaction bulb
800mL, water 200mL temperature controls slowly add the p-methyl benzenesulfonic acid (75g) of 50% (mass fraction) to 20 DEG C -30 DEG C under nitrogen protection
Monohydrate solution finishes 20 DEG C of rear temperature control and stirs 4 hours, and filtering washing, 40 DEG C are dried in vacuo to obtain crystal form A 100g.
Embodiment 5
The conjunction of 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate hydrate crystal forms A
At method
120g 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyl tosilate is added in reaction bulb
Monohydrate, acetone 900mL, water 300mL, stirred under nitrogen atmosphere are heated to 70 DEG C, and solid dissolving stirs lower slow cooling extremely
20 DEG C and temperature control stirring 2 hours, filtering, 40 DEG C are dried in vacuo to obtain crystal form A 100g.
Embodiment 6
The X- of 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate hydrate crystal forms A
Diffraction analysis
Detect object：The crystal form A that embodiment 1,2,4 is obtained；
Detecting instrument：Sharp shadow X-ray diffractometer；
Testing conditions：Cu target K а rays, voltage 40Kv, electric current 40mA, 2 θ ranges：3 ° -60 °, 0.02 ° of step-length often walks and stops
Stay time 40S；
Detect foundation：Pharmacopoeia of People's Republic of China four 0451X ray diffraction methods of version in 2015；
Testing result：As shown in Figure 1 and shown in the following table 1.
Table 1
Peak List：(Bookmark 3)
Continued 1
Embodiment 7
The difference of 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate hydrate crystal forms A
Show scanning thermometric analysis
Detect object：The crystal form A that embodiment 1,2,4 is obtained；
Detecting instrument：German NETZSCH companies DSC204F1 differential scanning calorimeters；
Testing conditions：Atmosphere：Nitrogen, 20mL/min；
Detect foundation：JY/T 014-1996 heat analysis method general rules；
Testing result：As shown in Fig. 2, the crystal form is at 107.41 ± 5 DEG C, 162.3 ± 5 DEG C, 231.3 ± 5 DEG C have endothermic peak.
8 stability of crystal form of embodiment is tested
2- [4- ((3S) -3- piperidyls) the phenyl] -2H- indazole -7- first arbitrarily prepared using the above embodiment of the present invention
Amide tosilate hydrate crystal forms A carries out stability of crystal form experiment.Experimental procedure：According to Chinese Pharmacopoeia version in 2015
Bulk pharmaceutical chemicals and pharmaceutical preparation stability test guideline carry out Acceleration study after being packed using double-deck PE bags sealing to crystal form,
Placement condition：40 DEG C ± 2 DEG C, relative humidity：75% ± 5% climatic chamber；25 DEG C ± 2 DEG C, relative humidity：60% ± 5%
Climatic chamber；Standing time：1 month；DSC and XRD ray powder diffractions were detected respectively at the 30th, 60,90 day.
Testing result：Extract after sample prepared by multiple batches tested, multiple batches in section of different testing times
DSC with XRD powder diffractions testing result it is identical with Fig. 2 with Fig. 1 respectively, after placing 1 month, the crystal form of sample without
Variation, stable crystal form.
After placing one 1,2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide p-methyl benzenesulfonic acid brine
Close TGA collection of illustrative plates such as Fig. 3 of object crystal form A.
9 hygroscopicity test of embodiment
2- [4- ((3S) -3- piperidyls) the phenyl] -2H- indazole -7- first arbitrarily prepared using the above embodiment of the present invention
Amide tosilate hydrate crystal forms A carries out hygroscopicity test.Specific experiment step is：2 sample bottles are taken to weigh respectively
Afterwards, it weighs after same batch sample is added；After being placed 24 hours under the conditions of relative humidity be 85% temperature is 25 degree, claim again
Weight, next calculating are drawn moist.More detailed experimental procedure refers to States Pharmacopoeia specifications.
It is that one of batch draws moist measurement data below, is computed that draw moist be 0.1%, remaining batch is drawn moist
It is identical.
Table 2
Experimental result：Under conditions of high humidity, it is 0.1% that crystal form of the invention, which draws moist, and nothing or moist almost without drawing is not easy
It is mouldy, rotten, do not interfere with drug effect.
Claims (12)
1. a kind of 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formamide tosilate hydrate crystal forms A,
It is characterized in that, the characteristic peak measured comprising the following angles 2theta in its X-ray powder diffraction collection：13.2±0.2°、15.1
± 0.2 °, 21.0 ± 0.2 ° and 30.0 ± 0.2 °.
2. crystal form A according to claim 2, which is characterized in that comprising following in its X-ray powder diffraction collection
The characteristic peak that the angles 2theta measure：9.5±0.2°、13.2±0.2°、15.1±0.2°、18.4±0.2°、19.4±0.2°、
21.0 ± 0.2 °, 24.6 ± 0.2 ° and 30.0 ± 0.2 °.
3. crystal form A according to claim 1, which is characterized in that have as follows it is characterized in that, it shows
The collection of illustrative plates of the X-ray powder diffraction for the characteristic peak that 2theta values indicate.
4. crystal form A according to claim 1, which is characterized in that its X-ray powder diffraction collection is as shown in Figure 1.
5. crystal form A according to claim 1, which is characterized in that the analysis collection of illustrative plates of its differential scanning calorimetry is 107.41
± 5 DEG C, 162.3 ± 5 DEG C, 231.3 ± 5 DEG C have endothermic peak.
6. any crystal form A of claim 1-5 are being used to prepare treatment epithelial ovarian, carcinoma of fallopian tube, lung cancer, mammary gland
Purposes in the drug of cancer, prostate cancer or Primary peritoneal carcinoma disease.
7. a kind of drug, which is characterized in that it contains crystal form A according to any one of claims 1 to 5；
Preferably, the drug can also contain pharmaceutically acceptable carrier.
8. a kind of method preparing crystal form A according to any one of claims 1 to 5, it is characterised in that selected from following methods 1 and side
Any one of method 2：
Method 1 is：2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyls are recrystallized in reaction dissolvent to toluene
It is obtained after sulfonate monohydrate；
Method 2 is：By 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyls, 2- [4- ((3S) -3- piperidyls) benzene
Base] -2H- indazoles -7- formyls mesylate or 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyl hydrochlorides be logical
It crosses and p-methyl benzenesulfonic acid monohydrate is obtained by salt-forming reaction.
9. according to the method described in claim 8, it is characterized in that, method 1 specifically comprises the steps of：
S1. the crude product of 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyl tosilate monohydrates is added
Enter into reaction dissolvent；
S2. it is heated to 50 to 100 DEG C under nitrogen protection；It is preferably heated to 75 DEG C~85 DEG C；
S3. it is slowly stirred and is cooled to -10 to 30 DEG C；And temperature control stirring crystallization two hours or more；Preferably, temperature control is at 20 DEG C, control
Warm stirring and crystallizing 2 to 4 hours；
S4. product is obtained by filtering or centrifuging；
S5. temperature control is dried in vacuo at 20 DEG C~60 DEG C, preferably 35 DEG C~45 DEG C vacuum drying.
10. according to the method described in claim 9, it is characterized in that,
In step S1, any one or several group of the reaction dissolvent in protonic solvent and non-protonic solvent
It closes；
Preferably, the protonic solvent is selected from least one of alcohol, acid and the water of C1-C4；It is highly preferred that the matter
Sub- property solvent is selected from least one of ethyl alcohol, methanol and isopropanol；
Preferably, the non-protonic solvent is selected from alkane, esters, DMF, DMSO, DMAc, THF, the dioxy six of C1-C12
Ring, the ketone of C1-C4, NMP, at least one of ethers and benzene class；It is highly preferred that the non-protonic solvent is selected from acetic acid second
At least one of ester, n-hexane, normal heptane, dichloromethane, toluene, acetone, butanone, methyl tertiary butyl ether(MTBE) and THF；
Preferably, in step S1, the reaction dissolvent is selected from the combination of protonic solvent and non-protonic solvent；Matter therein
The volume ratio of sub- property solvent and non-protonic solvent is 1:99 to 99:1；It is highly preferred that the protonic solvent and non-proton
Property solvent volume ratio be 1:10 to 10:1；
Or preferably, in step S1, the reaction dissolvent is the mixture of lower alcohol/ketone and water, the lower alcohol/ketone
It is one or more in methanol, ethyl alcohol and acetone；It is highly preferred that the volume ratio of the lower alcohol/ketone and water is 1:5 to
5:1；
Preferably, the ratio of the volume of reaction dissolvent and the quality that feeds intake is 3mL/g~100mL/g；It is highly preferred that the body of reaction dissolvent
The ratio of product and the quality that feeds intake is 5mL/g~20mL/g.
11. method according to claim 8, which is characterized in that method 2 specifically comprises the steps of：
1) by 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazole -7- formyls, 2- [4- ((3S) -3- piperidyls) phenyl] -
2H- indazoles -7- formyls mesylate or 2- [4- ((3S) -3- piperidyls) phenyl] -2H- indazoles -7- formyls hydrochlorides with react
Solvent mixes, and temperature control is at 10 DEG C -100 DEG C；It is preferred that temperature control is at 20 DEG C~40 DEG C；
2) toluenesulfonic acid monohydrate solution is added under nitrogen protection；
3) temperature control is in -10 to 30 DEG C of stirring and crystallizings two hours or more；Preferably, temperature control was in 20 DEG C of stirring and crystallizings 2-4 hours；
4) product through washing by obtaining again after filtering or centrifugation；
5) in 20 DEG C~60 DEG C vacuum drying of temperature control, preferably 35 DEG C~45 DEG C vacuum drying.
12. according to the method for claim 11, which is characterized in that in step 1), the reaction dissolvent is selected from protic
Any one in solvent and non-protonic solvent or several combinations；
Preferably, the protonic solvent is selected from least one of alcohol, acid and the water of C1-C4；It is highly preferred that the matter
Sub- property solvent is selected from least one of ethyl alcohol, methanol and isopropanol；
Preferably, the non-protonic solvent is selected from alkane, esters, the ethers of C1-C12, the ketone of NMP, C1-C4, DMF,
At least one of DMSO, DMAc, THF, dioxane, benzene class；It is highly preferred that the non-protonic solvent is selected from acetic acid second
At least one of ester, n-hexane, normal heptane, dichloromethane, toluene, acetone, butanone, methyl tertiary butyl ether(MTBE) and THF；
Preferably, in step 1), the reaction dissolvent is selected from the combination of protonic solvent and non-protonic solvent；Matter therein
The volume ratio of sub- property solvent and non-protonic solvent is 1:99 to 99:1；It is highly preferred that the protonic solvent and non-proton
Property solvent volume ratio be 1:10 to 10:1；
Or preferably, in step 1), mixture of the reaction dissolvent selected from lower alcohol/ketone and water, the lower alcohol/
Ketone is one or more in methanol, ethyl alcohol and acetone；It is highly preferred that the volume ratio of the lower alcohol/ketone and water is 1:5
To 5:1；
Or preferably, in step 1), the reaction dissolvent is selected from water；
Preferably, the ratio of the volume of reaction dissolvent and the quality that feeds intake is 3mL/g~100mL/g；It is highly preferred that the body of reaction dissolvent
The ratio of product and the quality that feeds intake is 5mL/g~20mL/g；
Preferably, in step 2), the mass fraction of toluenesulfonic acid monohydrate solution is in the range of 5%~60%；More preferably
In 40%~55% range；
Preferably, the solvent of toluenesulfonic acid monohydrate solution is water；
Preferably, toluenesulfonic acid monohydrate and the two mass ratio that feeds intake are 60~80:100；More preferable 70~75:100.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710389837 | 2017-05-27 | ||
| CN2017103898373 | 2017-05-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108530425A true CN108530425A (en) | 2018-09-14 |
Family
ID=63475981
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810402877.1A Withdrawn CN108530425A (en) | 2017-05-27 | 2018-04-28 | A kind of Ni Lapani tosilate hydrate crystal forms and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108530425A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20200017462A1 (en) | 2017-03-27 | 2020-01-16 | Tesaro, Inc. | Niraparib compositions |
| JP2022504228A (en) * | 2018-10-03 | 2022-01-13 | テサロ， インコーポレイテッド | Crystal form of niraparib free base |
| US11236066B2 (en) | 2019-07-16 | 2022-02-01 | Apotex Inc. | Crystalline forms of niraparib tosylate |
| US11730725B2 (en) | 2017-09-26 | 2023-08-22 | Tesaro, Inc. | Niraparib formulations |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014088983A1 (en) * | 2012-12-07 | 2014-06-12 | Merck Sharp & Dohme Corp. | Regioselective n-2 arylation of indazoles |
| CN106008460A (en) * | 2008-01-08 | 2016-10-12 | 默沙东有限公司 | Pharmaceutically acceptable salts of 2-{4-[(3S)-piperidin-3- yl]phenyl} -2H-indazole-7-carboxamide |
| CN106854176A (en) * | 2016-12-21 | 2017-06-16 | 南京艾德凯腾生物医药有限责任公司 | A kind of method for preparing Ni Lapani tosilate monohydrates |
-
2018
- 2018-04-28 CN CN201810402877.1A patent/CN108530425A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106008460A (en) * | 2008-01-08 | 2016-10-12 | 默沙东有限公司 | Pharmaceutically acceptable salts of 2-{4-[(3S)-piperidin-3- yl]phenyl} -2H-indazole-7-carboxamide |
| WO2014088983A1 (en) * | 2012-12-07 | 2014-06-12 | Merck Sharp & Dohme Corp. | Regioselective n-2 arylation of indazoles |
| CN106854176A (en) * | 2016-12-21 | 2017-06-16 | 南京艾德凯腾生物医药有限责任公司 | A kind of method for preparing Ni Lapani tosilate monohydrates |
Non-Patent Citations (2)
| Title |
|---|
| CHEOL K. CHUNG, ET AL.: "Process Development of C-N Cross-Coupling and Enantioselective Biocatalytic Reactions for the Asymmetric Synthesis of Niraparib", 《ORG. PROCESS RES. DEV.》 * |
| DEBRA J. WALLACE, ET AL.: "Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor", 《ORG. PROCESS RES. DEV.》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20200017462A1 (en) | 2017-03-27 | 2020-01-16 | Tesaro, Inc. | Niraparib compositions |
| US11091459B2 (en) | 2017-03-27 | 2021-08-17 | Tesaro, Inc. | Niraparib compositions |
| US11673877B2 (en) | 2017-03-27 | 2023-06-13 | Tesaro, Inc. | Niraparib compositions |
| US11730725B2 (en) | 2017-09-26 | 2023-08-22 | Tesaro, Inc. | Niraparib formulations |
| JP2022504228A (en) * | 2018-10-03 | 2022-01-13 | テサロ， インコーポレイテッド | Crystal form of niraparib free base |
| US11236066B2 (en) | 2019-07-16 | 2022-02-01 | Apotex Inc. | Crystalline forms of niraparib tosylate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108530425A (en) | A kind of Ni Lapani tosilate hydrate crystal forms and preparation method thereof | |
| CN101255119B (en) | Novel tetrahydro curcumin derivatives and salt | |
| US10377757B2 (en) | Crystal form of JAK inhibitor and preparation method thereof | |
| CN109988164B (en) | Eutectic crystal of berberine hydrochloride and malic acid, preparation method, composition and application thereof | |
| CN109384799B (en) | Crystal form A of multi-target kinase inhibitor compound, preparation method and pharmaceutical composition containing crystal form A | |
| CN110483486A (en) | A kind of western Tenylidone of Austria coughs up hydrochlorate crystal form and preparation method thereof | |
| CN101691372B (en) | Aildenafil citrate crystal form C and preparation method and application thereof | |
| US9663439B2 (en) | Aildenafil citrate crystal form O, preparation method and use thereof | |
| CN102740842A (en) | Formulations, salts and polymorphs of transnorsertraline and uses thereof | |
| CN109843868A (en) | The active inhibition of OLIG2 | |
| WO2016101867A1 (en) | Α-crystal form of naproxen imatinib p-toluene sulfonate, preparation method thereof, and pharmaceutical composition containing same | |
| CN104230912B (en) | Quinoline, Its Preparation Method And Use | |
| WO2023193563A1 (en) | Crystal form a of thienopyridine compound, and preparation method therefor and pharmaceutical composition thereof | |
| US20210094961A1 (en) | Form of ponatinib | |
| CN104276960B (en) | Tapentadol hydrochloride and celecoxib eutectic and combinations thereof thing and preparation method | |
| US20230002343A1 (en) | Left-handed bicyclic morpholine and salt thereof, preparation method therefor, pharmaceutical composition, and use | |
| WO2016101868A1 (en) | Β-crystalline form of naputinib tosylate, preparation method therefor and pharmaceutical composition containing same | |
| CN105732642B (en) | A kind of eutectic and preparation method thereof of CDK inhibitor and mek inhibitor | |
| WO2018099451A1 (en) | Crystal form of compound | |
| Jia et al. | The bioavailability enhancement and insight into the action mechanism of poorly soluble natural compounds from co-crystals preparation: Oridonin as an example | |
| CN115317485B (en) | Application of isoliensinine and neferine in preparation of anti-hepatic fibrosis drugs | |
| CN105801647B (en) | Mecobalamin compound and contain its preparation and preparation method | |
| WO2023006057A1 (en) | Crystal of amino pyrazolopyrimidine compound | |
| WO2023011512A1 (en) | Crystal forms of kuding saponin a compound, pharmaceutical composition and use thereof | |
| CN108658945A (en) | A kind of Antitubulin（VDA-1）A crystal forms |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20180914 |