CN109867674A - A kind of new salt of substituted heterocycle fused gamma-carbolines and preparation method thereof and crystal form - Google Patents
A kind of new salt of substituted heterocycle fused gamma-carbolines and preparation method thereof and crystal form Download PDFInfo
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Abstract
4- ((6bR provided by the invention, 10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydro -1H- pyridos [3 ', 4 ': 4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl)-two tosilate of -1- (4- fluorophenyl) -1- butanone, with crystallinity height, the complete advantage of crystal form, product purity reach 99% or more, and thermal cracking temperature is higher than the thermal cracking temperature of reported crystal form, the thermal stability of product is more preferable, has better application prospect.
Description
Technical field
The present invention relates to the crystal form of a kind of salt of substituted heterocycle fused gamma-carbolines and salt characterization and preparation methods.
Background technique
ITI-007 (lumateperone), chemical name 4- ((6bR, 10aS) -3- methyl -2,3,6b, 9,10,10a- six
Hydrogen -1H- pyrido [3 ', 4 ': 4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorophenyl) -1- butanone -
Tosilate, structural formula are a novel anti-of drugmaker, U.S. Intra-Cellular research and development as shown in following formula II
Chlorpromazine is currently in three phase clinical stages.Its mechanism of action is novel, be 5-HT2A receptor antagonist (Ki=0.54nM),
Presynaptic D2 acceptor portion agonist and postsynaptic D2 receptor antagonist can also block 5-HT transporter (SERT).In addition, ITI-
007 reaches 60 times of D2 receptor affinity with the affinity of 5-HT2A receptor, this number is significantly larger than at present on the market almost
All atypical antipsychotic agents have good market prospects.
United States Patent (USP) US2011112105A1 disclose ITI-007 i.e. 4- ((6bR, 10aS) -3- methyl -2,3,6b, 9,
10,10a- hexahydro -1H- pyrido [3 ', 4 ': 4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorobenzene
Base) free alkali of -1- butanone and its preparation method of tosilate (Formula II)；And the tosilate (Formula II)
Two kinds of crystal forms (crystal form A and crystal form B), are respectively provided with different fusing points, DSC and XRPD diffraction data.
Different salt, crystal form, solvate, hydrate and it is unformed be API form of ownership, can have difference
Biochemistry and biological property, exploration and discovery to the various physical forms of API can provide improve drug performance characteristic
Chance therefore obtain the crystal form of extensive optional salt and these and other known salts and effectively stablize and pacify to help to prepare
Full drug, it will be very favorable.
Summary of the invention
The object of the present invention is to provide a kind of new 4- ((6bR, 10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydros -
1H- pyrido [3 ', 4 ': 4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorophenyl) -1- butanone is to first
Benzene sulfonate, and preparation method thereof and crystal form.
The technical solution adopted by the present invention is as follows:
The salt as shown in following formula I:
The preparation method of Formulas I, comprising the following steps:
(1) by 4- ((6bR, 10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydro -1H- pyrido [3 ', 4 ': 4,5] pyrrole
Cough up simultaneously [1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorophenyl) -1- butanone free alkali and p-methyl benzenesulfonic acid be added to alcohol
With the in the mixed solvent of water；
(2) heating is so that cooling after system clarification be precipitated target product formula I.
Preferably, in the step (1), 4- ((6bR, 10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydro -1H-
Pyrido [3 ', 4 ': 4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorophenyl) -1- butanone free alkali with
The molar ratio of p-methyl benzenesulfonic acid is 1:1.5-3, further preferably 1:1.8-2.2, most preferably 1:2.
In the step (1), alcohol used includes methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol and isobutanol, excellent
Select methanol, ethyl alcohol and isopropanol.
Preferably, in the step (1), the volume ratio of alcohol used and water is 10:1-3:1.
Preferably, in the step (2), heating temperature is at 50 DEG C -75 DEG C.
Preferably, it in the step (2), cools to suitable temperature to -25 DEG C -0 DEG C.Further, filtering is precipitated
Solid, drying, obtain salt described in high-purity formula I.
XRPD, HNMR, DSC, TGA, IR analysis are carried out to target product formula I to confirm the crystal form and structure of product, discovery
The crystal form of the salt and previously reported difference, confirm as new crystal form.The crystal form has crystallinity high, and crystal form is completely excellent
Point, product purity reach 99% or more, and the thermal cracking temperature of thermal cracking temperature crystal form more reported than patent is higher, product
Thermal stability is more preferable.
A kind of crystal form of salt shown in Formulas I includes feature diffraction shown in the angle following 2 θ in X-ray powder diffraction collection
Peak: 4.10 ± 0.2 °, 6.09 ± 0.2 °, 8.21 ± 0.2 °, 10.34 ± 0.2 °, 14.13 ± 0.2 °, 14.48 ± 0.2 °, 14.84
±0.2°、15.31±0.2°、15.86±0.2°、16.40±0.2°、17.05±0.2°、17.88±0.2°、18.65±
0.2°、20.36±0.2°、20.72±0.2°、21.58±0.2°、22.42±0.2°、22.87±0.2°、23.90±0.2°、
25.10±0.2°、27.27±0.2°、27.61±0.2°。
A kind of crystal form of salt shown in Formulas I, X-ray powder diffraction collection data are as shown in the table:
A kind of crystal form of salt shown in Formulas I, XRPD diffraction data are as shown in the table:
A kind of crystal form of salt shown in Formulas I has XRPD powder diffractogram as shown in Figure 1.
A kind of crystal form of salt shown in Formulas I, DSC spectrogram include that peak temperature is 186.7 DEG C -191.5 DEG C (such as 190.5 DEG C)
Single endothermic peak.Its DSC spectrogram is as shown in Figure 2.
A kind of crystal form of salt shown in Formulas I, TGA spectrogram are as shown in Figure 3.
A kind of crystal form of salt shown in Formulas I, IR spectrogram are as shown in Figure 5.
It is a kind of for treating the drug of schizophrenia and its related disease, include salt shown in Formulas I or its unique crystal form
Salt.
Beneficial effects of the present invention:
4- provided by the invention ((6bR, 10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydro -1H- pyrido [3 ',
4 ': 4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorophenyl) -1- butanone-two tosilate tool
There is crystallinity high, the complete advantage of crystal form, product purity reaches 99% or more, heat of the thermal cracking temperature than reported crystal form
Cracking temperature is higher, and the thermal stability of product is more preferable, has better application prospect.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction figure of the salt (Formulas I) in the present invention.
Fig. 2 is the DSC spectrogram of the salt (Formulas I) in the present invention.
Fig. 3 is the TGA spectrogram of the salt (Formulas I) in the present invention.
Fig. 4 is the HNMR spectrogram of the salt (Formulas I) in the present invention.
Fig. 5 is the IR spectrogram of the salt (Formulas I) in the present invention.
Fig. 6 is the LCMS spectrogram of the salt (Formulas I) in the present invention.
Fig. 7 is ITI-007 tosilate crystal form A disclosed in CN200980108387.X (US2011112105A1)
X-ray powder diffraction spectrogram.
Fig. 8 is ITI-007 tosilate crystal form A disclosed in CN200980108387.X (US2011112105A1)
DSC-TGA spectrogram.
Fig. 9 is ITI-007 tosilate crystal form B disclosed in CN200980108387.X (US2011112105A1)
X-ray powder diffraction spectrogram.
Specific embodiment
The present invention is specifically described below by embodiment, it is necessary to which indicated herein is that following embodiment is only used
In invention is further explained, it should not be understood as limiting the scope of the invention, person skilled in art can
To make some nonessential modifications and adaptations to the present invention according to aforementioned present invention content.
Below with specific embodiment to further illustrate the technical scheme of the present invention, but protection scope of the present invention is not limited to
This.
Embodiment 1
By starting material 4- ((6bR, 10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydro -1H- pyrido [3 ', 4 ':
4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorophenyl) -1- butanone free alkali (10.0g, 1.0eq) is molten
Solution stirs half an hour after active carbon (500mg) is added at room temperature in methanol (50ml) and water (10ml), filters, and filter cake is with less
Measure methanol washing.P-methyl benzenesulfonic acid monohydrate (7.24g, 1.5eq) is added into combined filtrate, is heated to 50 DEG C, dissolution
After clarification, it is cooled to the brown white solid slurry of -25 DEG C of precipitations, is stirred 2.5 hours.Filtering is washed, just with a small amount of cold methanol
Heptane wash is primary, collect solid, 35 DEG C are dried under vacuum to constant weight, obtain two tosilate (15.5g, yield 82.7%,
HPLC purity 99.0%, LCMS:M+=394.3)
Embodiment 2
By starting material 4- ((6bR, 10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydro -1H- pyrido [3 ', 4 ':
4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorophenyl) -1- butanone free alkali (10.0g, 1.0eq) is molten
Solution stirs half an hour after active carbon (500mg) is added at room temperature in isopropanol (100ml) and water (10ml), filters, and filter cake is used
A small amount of isopropanol washing.P-methyl benzenesulfonic acid monohydrate (14.5g, 3.0eq) is added into combined filtrate, is heated to 75 DEG C,
After dissolution clarification, it is cooled to the brown white solid slurry of 0 DEG C of precipitation, is stirred 2 hours.Filtering is washed with a small amount of cold isopropanol,
Normal heptane washed once, collect solid, 35 DEG C are dried under vacuum to constant weight, obtain two tosilate (15.0g, yield 80%,
HPLC purity 98.5%, LCMS:M+=394.3).
Embodiment 3
By starting material 4- ((6bR, 10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydro -1H- pyrido [3 ', 4 ':
4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorophenyl) -1- butanone free alkali (10.0g, 1.0eq) is molten
Solution stirs half an hour after active carbon (500mg) is added at room temperature in ethyl alcohol (60ml) and water (10ml), filters, and filter cake is with less
Measure ethanol washing.P-methyl benzenesulfonic acid monohydrate (10.6g, 2.2eq) is added into combined filtrate, is heated to 65 DEG C, dissolution
After clarification, it is cooled to the brown white solid slurry of -10 DEG C of precipitations, is stirred 3.5 hours.Filtering, with a small amount of cold ethanol washing, just
Heptane wash is primary, collect solid, 35 DEG C are dried under vacuum to constant weight, obtain two tosilate (17g, yield 90.7%,
HPLC purity 98.7%, LCMS:M+=394.3).
Embodiment 4
By starting material 4- ((6bR, 10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydro -1H- pyrido [3 ', 4 ':
4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorophenyl) -1- butanone free alkali (10.0g, 1.0eq) is molten
Solution stirs half an hour after active carbon (500mg) is added at room temperature in methanol (30ml) and water (10ml), filters, and filter cake is with less
Measure methanol washing.P-methyl benzenesulfonic acid monohydrate (9.67g, 2.0eq) is added into combined filtrate, is heated to 55 DEG C, dissolution
After clarification, it is cooled to the brown white solid slurry of -15 DEG C of precipitations, is stirred 3.5 hours.Filtering, with a small amount of cold ethanol washing, just
Heptane wash is primary, collect solid, 35 DEG C are dried under vacuum to constant weight, obtain two tosilate (17.3g, yield 92.3%,
HPLC purity 99.1%, 187 DEG C~188 DEG C of fusing point, LCMS:M+=394.3, nuclear-magnetism parsing is as follows, and correlation analysis spectrogram is shown in attached
Fig. 1-6).
HNMR(CDCl3, 400MHZ), δ=9.25 (br, s, 2H), 8.04 (dd, J=12Hz, 2H), 7.49 (d, J=
8Hz, 4H), 7.38 (t, J=20Hz, 2H), 7.12 (d, J=8Hz, 4H), 6.61 (t, J=8Hz, 1H), 6.55 (d, J=4Hz,
1H), 6.46 (d, J=8Hz, 1H), 3.58 (dd, J=8Hz, 1H), 3.51-3.41 (m, 3H), 3.37-3.30 (m, 2H), 3.24
(br, 1H), 3.19-3.04 (m, 5H), 2.83 (s, 3H), 2.75 (m, 1H), 2.58 (q, J=11HZ, 1H), 2.50 (DMSO-
), d6 2.29 (s, 6H), 2.25 (s, 1H), 2.11 (m, 1H), 2.05 (m, J=16Hz, 2H).
Pharmaceutical composition comprising compound of formula I can the technology known to conventional thinner or excipient and the field
It prepares, can be a variety of different dosage forms, such as tablet, capsule etc..
Embodiment 5
In special embodiment, compound of formula I can be prepared in capsule as follows:
Preparation method is as follows: by compound of formula I and mannitol (100SD NF), cross-linked carboxymethyl fiber
Plain sodium, Imperial Talc 500 mix, pelletized with dry granulating machine, then by pelleting mixed with glycerin monostearate
Uniformly, it is filled into capsule.
Stability test
4- ((6bR, 10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydro -1H- that embodiment 4 is prepared in we
Pyrido [3 ', 4 ': 4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorophenyl)-two pairs of first of -1- butanone
Benzene sulfonate and according to patent document CN200980108387.X (US2011112105A1) the crystal form A being prepared respectively and crystalline substance
Type B has carried out relevant stability study.
1. high-temperature closed is tested
Two tosilate produced by the present invention and the salt (crystal form A and crystal form B) in patent document are respectively placed in
It in the vial of closed cleaning, is placed in 60 DEG C of testing chamber for medicine stabilities, after 1 month, 2 months, 3 months, 6 months
Sample detection, and compareed in 0 day result, it as a result see the table below 3:
Table 3
2. high temperature and humidity opening is tested
Salt (crystal form A and crystal form B) in two tosilate produced by the present invention and patent document is uniformly divided respectively
Booth is into open culture dish, and thickness≤5mm is placed in 60 DEG C, in the testing chamber for medicine stability that relative humidity is 75 ± 5%, point
The sample detection not after 1 month, 2 months, 3 months, 6 months, and compareed in 0 day result, it as a result see the table below 4:
Table 4
Stability test the result shows that, the salt of Formulas I of the invention, under hot and humid environment, crystal form does not change, purity
All preferable with stable content, single miscellaneous smaller, related substance does not have significant change, is compared to (the crystal form A of salt in patent document
With crystal form B), there is some superiority in stability, stored for a long time convenient for its preparation.
Testing conditions:
Pillar: Waters symmetry Shield RP18 (5 μm of 4.6*150mm)
Mobile phase: mobile phase A: the water containing 0.1%TFA
Mobile phase B: the acetonitrile containing 0.1%TFA
Flow velocity: 1.0ml/min
Volume injected: 10ul
Detection: DAD@250nm
Runing time: 50 minutes
Column temperature: 30 DEG C
Gradient program:
| Time (min) | % mobile phase A | % Mobile phase B |
| 0 | 95 | 5 |
| 25 | 50 | 50 |
| 40 | 10 | 90 |
| 42 | 95 | 5 |
| 50 | 95 | 5 |
Diluents: acetonitrile: water=60:40.
Claims (15)
1. the salt as shown in following formula I:
It include the angle following 2 θ in X-ray powder diffraction collection 2. a kind of crystal form of salt shown in Formulas I as described in claim 1
Shown in characteristic diffraction peak: 4.10 ± 0.2 °, 6.09 ± 0.2 °, 8.21 ± 0.2 °, 10.34 ± 0.2 °, 14.13 ± 0.2 °,
14.48±0.2°、14.84±0.2°、15.31±0.2°、15.86±0.2°、16.40±0.2°、17.05±0.2°、17.88
±0.2°、18.65±0.2°、20.36±0.2°、20.72±0.2°、21.58±0.2°、22.42±0.2°、22.87±
0.2°、23.90±0.2°、25.10±0.2°、27.27±0.2°、27.61±0.2°。
3. a kind of crystal form of salt shown in Formulas I as claimed in claim 2, it is characterised in that: X-ray powder diffraction collection data
It is as shown in the table:
4. a kind of crystal form of salt shown in Formulas I as claimed in claim 2, it is characterised in that: XRPD diffraction data is as shown in the table:
5. a kind of crystal form of salt shown in Formulas I as claimed in claim 2, it is characterised in that: have XRPD powder as shown in Figure 1
Diffraction spectrogram.
6. it is a kind of for treating the drug of schizophrenia and its related disease, include salt shown in Formulas I described in claim 1
Or a kind of crystal form of any salt of claim 2-5.
7. the preparation method of salt shown in any formula I of claim 1-5, comprising the following steps:
(1) by 4- ((6bR, 10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydro -1H- pyrido [3 ', 4 ': 4,5] pyrrolo-
[1,2,3-de] quinoxaline -8 (7H)-yl) -1- (4- fluorophenyl) -1- butanone free alkali and p-methyl benzenesulfonic acid be added to alcohol and water
In the mixed solvent；
(2) heating is so that cooling after system clarification be precipitated target product formula I.
8. the preparation method of salt shown in formula I as claimed in claim 7, it is characterised in that: in step (1), 4- ((6bR,
10aS) -3- methyl -2,3,6b, 9,10,10a- hexahydro -1H- pyrido [3 ', 4 ': 4,5] pyrrolo- [1,2,3-de] quinoxaline -
8 (7H)-yls) molar ratio of -1- (4- fluorophenyl) -1- butanone free alkali and p-methyl benzenesulfonic acid is 1:1.5-3.
9. the preparation method of salt shown in formula I as claimed in claim 8, it is characterised in that: 4- ((6bR, 10aS) -3- methyl -
2,3,6b, 9,10,10a- hexahydro -1H- pyrido [3 ', 4 ': 4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -1-
The molar ratio of (4- fluorophenyl) -1- butanone free alkali and p-methyl benzenesulfonic acid is 1:1.8-2.2.
10. the preparation method of salt shown in formula I as claimed in claim 9, it is characterised in that: 4- ((6bR, 10aS) -3- first
Base -2,3,6b, 9,10,10a- hexahydro -1H- pyrido [3 ', 4 ': 4,5] pyrrolo- [1,2,3-de] quinoxaline -8 (7H)-yl) -
The molar ratio of 1- (4- fluorophenyl) -1- butanone free alkali and p-methyl benzenesulfonic acid is 1:2.
11. the preparation method of salt shown in formula I as claimed in claim 7, it is characterised in that: alcohol used in step (1) includes
Methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol and isobutanol.
12. the preparation method of salt shown in formula I as claimed in claim 11, it is characterised in that: alcohol used in step (1) is first
Alcohol, ethyl alcohol or isopropanol.
13. the preparation method of salt shown in formula I as claimed in claim 7, it is characterised in that: in step (1), alcohol used with
The volume ratio of water is between 10:1-3:1.
14. the preparation method of salt shown in formula I as claimed in claim 7, it is characterised in that: in step (2), heating temperature exists
Between 50 DEG C -75 DEG C.
15. the preparation method of salt shown in formula I as claimed in claim 7, it is characterised in that: in step (2), cool to
Suitable temperature is to -25 DEG C -0 DEG C.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040022178A1 (en) * | 2002-08-05 | 2004-02-05 | Samsung Electronics Co., Ltd. | Radio equipment for compensating transmission signals |
| US20070066677A1 (en) * | 2003-07-21 | 2007-03-22 | Igo David H | (2S,4s)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-I-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt and anhydrous crystalline forms thereof |
| CN102046175A (en) * | 2008-03-12 | 2011-05-04 | 细胞内治疗公司 | Substituted heterocycle fused gamma-carbolines solid |
-
2017
- 2017-12-05 CN CN201711265914.0A patent/CN109867674A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040022178A1 (en) * | 2002-08-05 | 2004-02-05 | Samsung Electronics Co., Ltd. | Radio equipment for compensating transmission signals |
| US20070066677A1 (en) * | 2003-07-21 | 2007-03-22 | Igo David H | (2S,4s)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-I-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt and anhydrous crystalline forms thereof |
| CN102046175A (en) * | 2008-03-12 | 2011-05-04 | 细胞内治疗公司 | Substituted heterocycle fused gamma-carbolines solid |
| CN105237536A (en) * | 2008-03-12 | 2016-01-13 | 细胞内治疗公司 | Substituted heterocycle fused gamma-carbolines solid |
Non-Patent Citations (2)
| Title |
|---|
| LI, P.A: "Discovery of a Tetracyclic Quinoxaline Derivative as a Potent and Orally Active Multifunctional Drug Candidate for the Treatment of Neuropsychiatric and Neurological Disorders", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 张海枝等: "新型多靶点5-羟色胺受体抑制剂ITI-007 ", 《现代药物与临床》 * |
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