CN104744443A - Novel crystal of pyrimidinedione compound hydrochloride and preparation method thereof - Google Patents
Novel crystal of pyrimidinedione compound hydrochloride and preparation method thereof Download PDFInfo
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- CN104744443A CN104744443A CN201310731554.4A CN201310731554A CN104744443A CN 104744443 A CN104744443 A CN 104744443A CN 201310731554 A CN201310731554 A CN 201310731554A CN 104744443 A CN104744443 A CN 104744443A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention relates to a novel crystal of pyrimidinedione compound hydrochloride and a preparation method thereof. The invention discloses the novel crystal of 5-chloro-6-[(2-imino-1-pyrrolidyl)methyl]-2,4(1H, 3H)-pyrimidinedione hydrochloride shown in the formula I and the preparation method thereof. The novel crystal can produce X-ray diffraction peaks at diffraction angles 2 theta of 11.73 degrees, 13.03 degrees, 17.33 degrees, 17.97 degrees, 23.45 degrees, 27.23 degrees, 29.40 degrees and 32.85 degrees, has good stability and reappearance and is suitable for medicine development and application.
Description
Technical field
The present invention relates to pyrimidine dione compounds hydrochloride, especially the crystal formation and preparation method thereof of the chloro-6-of Tipiracil hydrochloride 5-[(2-imino--1-tetramethyleneimine) methyl]-2,4 (1H, 3H)-pyrimidine dione hydrochloride.
Background technology
TAS-102, by the Subsidiary Company of the large tomb pharmacy of Taiho(Japan) develop, be the compound of nucleoside analog trifluridine and thymidine phosphorylase inhibitor (TIP) Tipracil hydrochloride (MUP-98156), be used for the treatment of the cancer comprising colorectal cancer.In February, 2013, Taiho submits to TAS-102 to be used for the treatment of the application of unresectable late recurrent colorectal cancer in Japan.Aspect, market, current this product is not yet gone on the market.
According to American Cancer Society's statistics, 2005-2009, the sickness rate of U.S.'s colorectal cancer is annual 46.3/10 ten thousand, wherein Asian group's sickness rate about 40/,100,000.According to ministry of Health of China statistics, 2004-2005, the mortality ratio of China's colorectal cancer occupies the 4th of mortality of malignant tumors, up to 7.25/10 ten thousand.
Tipiracil hydrochloride has multiple crystal formation.At present temporarily without the report of crystal formation aspect.
Summary of the invention
The object of the invention is to the problem solving prior art, provide structure such as formula the new crystal of the Tipiracil hydrochloride shown in I.
Wherein, formula I is crystal formation I:
It is (a) 11.73 °, (b) 13.03 °, (c) 17.33 °, (d) 17.97 °, (e) 23.45 °, (f) 27.23 °, display X-ray diffraction peak, (g) 29.40 °, (h) 32.85 ° place at diffraction angle 2 θ;
It is display X-ray diffraction peak, (a) 11.73 ° place at diffraction angle 2 θ, and the relative line intensity that described peak has is 73; Diffraction angle 2 θ be (c) 17.33 ° place display X-ray diffraction peak, the relative line intensity that described peak has is 63; Diffraction angle 2 θ be (d) 17.97 ° place display X-ray diffraction peak, the relative line intensity that described peak has is 86; Diffraction angle 2 θ be (e) 23.45 ° place display X-ray diffraction peak, the relative line intensity that described peak has is 64; Diffraction angle 2 θ be (g) 29.40 ° place display X-ray diffraction peak, the relative line intensity that described peak has is 100;
It has in the display of diffraction angle 2 θ place the X-ray diffraction spectral line (spectral line intensity provides in bracket) that relative line intensity is 20 or more: 11.73 ° (73), 13.03 ° (48), 17.33 ° (63), 17.97 ° (86), 19.04 ° (25), 23.45 ° (65), 27.23 ° (50), 29.40 ° (100), 32.85 ° (30);
It has in the display of diffraction angle 2 θ place the X-ray diffraction spectral line (spectral line intensity provides in bracket) that relative line intensity is 10 or more: 11.73 ° (73), 13.03 ° (48), 17.33 ° (63), 17.97 ° (86), 19.04 ° (25), 21.45 ° (14), 21.6 ° (16), 23.45 ° (65), 23.88 ° (11), 24.83 ° (13), 25.20 ° (18), 27.23 ° (50), 28.14 ° (12), 29.40 ° (100), 30.64 ° (13), 31.87 ° (14), 32.85 ° (30), 35.82 ° (10),
Preferably, in the x-ray diffraction pattern of crystal formation I, the relative peak intensities at each peak does not depart from more than 20% of above-mentioned corresponding peak relative peak intensities.
It exists with the form of related substance more than 99.5%.
Preferably, its crystal form X RD spectrogram as shown in Figure 1.
Another object of the present invention is also to provide a kind of method preparing described crystal formation I, comprises and joins in purified water by Compound I, after heating for dissolving, drips concentrated acid, insulated and stirred crystallization; Optional, also comprise and add the step of the further Temperature fall of alcohol reagent to room temperature crystallization.Described alcohol reagent particular methanol, ethanol, propyl alcohol or Virahol, more preferably ethanol.
Described concentrated acid is concentrated hydrochloric acid or hydrogen chloride gas, preferred concentrated hydrochloric acid.
This crystal formation is a kind of new crystal, and its stability and circulation ratio are very good, is applicable to pharmaceutical developments application.
Accompanying drawing explanation
Fig. 1 is the x-ray diffraction pattern of the crystal formation I of formula I Tipiracil hydrochloride obtained in embodiment 1.
Embodiment
To specifically set forth content of the present invention by drawings and Examples below, but and not mean that the present invention only comprises following content.
Embodiment 1: use dilute hydrochloric acid to prepare the crystal formation I of Tipiracil hydrochloride
By compound 1(50g, 0.18mol) join in purified water (250L), be heated to 70 DEG C make dissolving after, drip 25mL concentrated hydrochloric acid, after insulated and stirred crystallization 2h, Temperature fall is to room temperature crystallization 2h.Filter, the 40 DEG C of forced air dryings of gained solid are to constant weight.Obtain target product (42.3g, white solid), productive rate 84.6%.
Embodiment 2: use acidic alcohol to prepare the crystal formation I of Tipiracil hydrochloride
By compound 1(50g, 0.18mol) add in purified water (250L), be heated to 70 DEG C make dissolving after, drip 25mL concentrated hydrochloric acid, after insulated and stirred crystallization 2h, add 1000mL ethanol, Temperature fall is to room temperature crystallization 2h.Filter, the 40 DEG C of forced air dryings of gained solid are to constant weight.Obtain target product (46.5g, white solid), productive rate 93.0%.
Experimental example 1: influence factor is tested
INSTRUMENT MODEL: D8Advance Germany Bruker X-ray powder diffractometer;
Ray: monochromatic Cu-K alpha-ray
Scan mode: θ/2 θ;
Sweep limit: 2-40 °;
Electric current: 40mA;
Voltage: 40kV.
X-ray diffraction Data Comparison is in table 1.
The data statistics of table 1 crystal formation I of the present invention influence factor
As can be seen from above-mentioned experiment, it is very good that crystalline form of the present invention all shows at various influence factor condition stability inferior, illustrates that this crystal formation is applicable to new drug development application.
Claims (10)
1. the crystal formation I of formula I,
2. the characteristic peak of as claimed in claim 1 crystal formation I, the X-ray powder diffraction figure of wherein said crystal formation I represents with 2 θ (± 0.2 ° of 2 θ) and is positioned at (a) 11.73 °, (b) 13.03 °, (c) 17.33 °, (d) 17.97 °, (e) 23.45 °, (f) 27.23 °, (g) 29.40 °, (h) 32.85 ° place.
3. crystal formation I as claimed in claim 2, is characterized in that, described crystal formation I is display X-ray diffraction peak, (a) 11.73 ° place at diffraction angle 2 θ, and the relative line intensity that described peak has is 73; Diffraction angle 2 θ be (c) 17.33 ° place display X-ray diffraction peak, the relative line intensity that described peak has is 63; Diffraction angle 2 θ be (d) 17.97 ° place display X-ray diffraction peak, the relative line intensity that described peak has is 86; Diffraction angle 2 θ be (e) 23.45 ° place display X-ray diffraction peak, the relative line intensity that described peak has is 64; Diffraction angle 2 θ be (g) 29.40 ° place display X-ray diffraction peak, the relative line intensity that described peak has is 100.
4. crystal formation I as claimed in claim 2, is characterized in that, described crystal formation I shows at diffraction angle 2 θ place and has the X-ray diffraction spectral line that relative line intensity is 20 or more, is wherein positioned at 11.73 °, 13.03 °, 17.33 °, 17.97 °, 19.04 °, 23.45 °, 27.23 °, 29.40 °, locating relative peak intensities corresponding respectively for 32.85 ° is: 73,48,63,86,25,65,50,100,30.
5. crystal formation I as claimed in claim 2, it is characterized in that, described crystal formation I has in the display of diffraction angle 2 θ place the X-ray diffraction spectral line that relative line intensity is 10 or more, wherein be positioned at 11.73 °, 13.03 °, 17.33 °, 17.97 °, 19.04 °, 21.45 °, 21.6 °, 23.45 °, 23.88 °, 24.83 °, 25.20 °, 27.23 °, 28.14 °, 29.40 °, 30.64 °, 31.87 °, 32.85 °, locating relative peak intensities corresponding respectively for 35.82 ° is: 73, 48, 63, 86, 25, 14, 16, 65, 11, 13, 18, 50, 12, 100, 13, 14, 30, 10.
6. as the crystal formation I in claim 1-5 as described in any one, it is characterized in that, it exists with the form of related substance more than 99.5%.
7. as the crystal formation I in claim 1-5 as described in any one, it is characterized in that, in its x-ray diffraction pattern, the relative peak intensities of each respective peaks does not depart from more than 20% of relative peak intensities as claimed in claim 5.
8. crystal formation I as claimed in claim 1, it is characterized in that, its crystal form X RD spectrogram as shown in Figure 1.
9. prepare the method as the crystal formation I in claim 1-8 as described in any one, it is characterized in that, Compound I is joined in purified water, after heating for dissolving, drip concentrated acid, insulated and stirred crystallization; Optional, also comprise and add the step of the further Temperature fall of alcohol reagent to room temperature crystallization.
10. method as claimed in claim 9, it is characterized in that, described concentrated acid is concentrated hydrochloric acid or hydrogen chloride gas, preferred concentrated hydrochloric acid.
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| CN201310731554.4A CN104744443A (en) | 2013-12-26 | 2013-12-26 | Novel crystal of pyrimidinedione compound hydrochloride and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945385A (en) * | 2014-03-31 | 2015-09-30 | 江苏豪森药业股份有限公司 | Novel crystal form of Tipracil hydrochloride and preparation method thereof |
| CN105859691A (en) * | 2016-04-07 | 2016-08-17 | 扬子江药业集团南京海陵药业有限公司 | Novel crystal form of thymidine phosphorylase inhibitor and preparation method thereof |
| WO2019002407A1 (en) | 2017-06-28 | 2019-01-03 | Amneal Pharmaceuticals Company Gmbh | Process for the preparation of tipiracil hydrochloride |
| US10457666B2 (en) | 2013-06-17 | 2019-10-29 | Taiho Pharmaceutical Co., Ltd. | Stable crystal form of tipiracil hydrochloride and crystallization method for the same |
| JP2021501772A (en) * | 2017-11-02 | 2021-01-21 | プロコス ソシエタ ペル アチオニＰｒｏｃｏｓ Ｓ．Ｐ．Ａ． | Method for Producing Tipiracil Hydrochloride Crystal Type III |
Citations (3)
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|---|---|---|---|---|
| WO1996030346A1 (en) * | 1995-03-29 | 1996-10-03 | Taiho Pharmaceutical Co., Ltd. | Uracil derivatives, and antitumor effect potentiator and antitumor agent containing the same |
| CN1297350A (en) * | 1999-03-23 | 2001-05-30 | 大鹏药品工业株式会社 | Agents for relieving side effects |
| CN104395307A (en) * | 2013-06-17 | 2015-03-04 | 大鹏药品工业株式会社 | Stabilized crystal of tipiracil hydrochloride, and crystallization method for same |
-
2013
- 2013-12-26 CN CN201310731554.4A patent/CN104744443A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996030346A1 (en) * | 1995-03-29 | 1996-10-03 | Taiho Pharmaceutical Co., Ltd. | Uracil derivatives, and antitumor effect potentiator and antitumor agent containing the same |
| CN1297350A (en) * | 1999-03-23 | 2001-05-30 | 大鹏药品工业株式会社 | Agents for relieving side effects |
| CN104395307A (en) * | 2013-06-17 | 2015-03-04 | 大鹏药品工业株式会社 | Stabilized crystal of tipiracil hydrochloride, and crystallization method for same |
Non-Patent Citations (3)
| Title |
|---|
| SHINGO YANO ET AL.: "Synthesis and evaluation of 6-methylene-bridged uracil derivatives. Part 2: Optimization of inhibitors of human thymidine phosphorylase and their selectivity with uridine phosphorylase", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 吕扬 等: "《晶型药物（第1版）》", 31 October 2009, 人民卫生出版社 * |
| 裴光文 等: "《单晶、多晶和非晶物质的X射线衍射》", 30 June 1989, 山东大学出版社 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10457666B2 (en) | 2013-06-17 | 2019-10-29 | Taiho Pharmaceutical Co., Ltd. | Stable crystal form of tipiracil hydrochloride and crystallization method for the same |
| CN104945385A (en) * | 2014-03-31 | 2015-09-30 | 江苏豪森药业股份有限公司 | Novel crystal form of Tipracil hydrochloride and preparation method thereof |
| CN105859691A (en) * | 2016-04-07 | 2016-08-17 | 扬子江药业集团南京海陵药业有限公司 | Novel crystal form of thymidine phosphorylase inhibitor and preparation method thereof |
| WO2019002407A1 (en) | 2017-06-28 | 2019-01-03 | Amneal Pharmaceuticals Company Gmbh | Process for the preparation of tipiracil hydrochloride |
| JP2021501772A (en) * | 2017-11-02 | 2021-01-21 | プロコス ソシエタ ペル アチオニＰｒｏｃｏｓ Ｓ．Ｐ．Ａ． | Method for Producing Tipiracil Hydrochloride Crystal Type III |
| JP7330180B2 (en) | 2017-11-02 | 2023-08-21 | プロコス ソシエタ ペル アチオニ | Method for producing tipiracil hydrochloride crystal form III |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP LIANYUNGANG HONGCHUANG PHARMACEUTICAL Co.,Ltd. |
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Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: Jiangsu best Pharmaceutical Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address after: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant after: Jiangsu best Pharmaceutical Co.,Ltd. Applicant after: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
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Effective date of registration: 20160324 Address after: 222047 Lianyungang economic and Technological Development Zone, Jiangsu Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: Tenth Industrial Zone, Lianyungang, Jiangsu, China, 222047 Applicant before: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: Lianyungang Hongchuang Pharmaceutical Co.,Ltd. |
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