CN108727318A - The crystal form object of Mycophenolic Acid - Google Patents
The crystal form object of Mycophenolic Acid Download PDFInfo
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- CN108727318A CN108727318A CN201710273540.0A CN201710273540A CN108727318A CN 108727318 A CN108727318 A CN 108727318A CN 201710273540 A CN201710273540 A CN 201710273540A CN 108727318 A CN108727318 A CN 108727318A
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- mycophenolic acid
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- 0 CC(CCC(O)=O)=CCc1c(*)c(C(OC2)=O)c2c(C)c1* Chemical compound CC(CCC(O)=O)=CCc1c(*)c(C(OC2)=O)c2c(C)c1* 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention mainly relates to crystal form object of Mycophenolic Acid and preparation method thereof, its X-ray powder diffraction figure of the crystal form has in 2 θ=7.75,10.56,10.82,15.58,26.60,29.45 characteristic absorption peak, is specifically shown in Fig. 1, and fusing point is 140.8~141.5 DEG C.The crystal form purity high stability is good, and preparation method is simple, easily operated, is suitble to industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to the crystal form of Mycophenolic Acid.
Background technology
Mycophenolic Acid (Mycophenolic acid) also known as mycophenolic acid, chemical name are：E-4- methyl -6- (1,3- dihydros
- 7- methyl -4- hydroxyl -6- methoxyl group -3- oxo -5- isobenzofuran-bases) -4- hexenoic acids, molecular formula C17H20O6, molecular weight
320.34, CAS 24280-93-1, shown in structure such as formula (I).Mycophenolic Acid generates Mycophenolate Mofetil after esterification,
It is a kind of neotype immunosuppressant；Shown in its structure such as formula (II).Mycophenolate Mofetil is approved for kidney transplant, 1998
It is approved for heart transplant again.
Polymorphism --- presence of different crystal forms --- is the property of some molecules and molecular complex.Unimolecule or
Molecular complex can generate different crystal structure and physical property, such as fusing point, thermal behavior (pass through thermogravimetry-
" TGA " or differential scanning calorimetry-" DSC " measure).Powder x-ray diffraction (PXRD), infrared absorption fingerprint (IR) and solid-state
H NMR spectroscopy, one or more of technologies can be used to identify the different polymorphs of compound.
WO2004/020426 is disclosed by by Mycophenolic Acid or its ammonium salt or dibenzyl-amine salt and C2-C10 carboxylic acid sodiums
Reactant salt, the method to prepare Mycophenolate Sodium.It converts Mycophenolic Acid to ammonium salt by being reacted with ammonia.By the compound and second
The sodium salt of Mycophenolic Acid is obtained by the reaction in sour sodium.
WO2004/064806 discloses the other polymorphic of Mycophenolate Sodium and Mycophenolic Acid.
WO2006/012385 disclose be named as M1, M3, M4, M5, M6, M7, M8, M9, M10, M11, M15, M16,
The one sodium crystal form of Mycophenolic Acid of M17, M18, M19, M20, M21, M22, M26, M27 and M28 crystal form, amorphous Mycophenolic Acid
One sodium M12, crystallization Mycophenolic Acid two sodium crystal D1 and D2 and preparation method thereof.
At present both at home and abroad to the more of the crystal form object and preparation method of Mycophenolate Sodium report, to the crystal form object of Mycophenolic Acid
And preparation method rarely has disclosure.
Invention content
In view of the deficiencies in the prior art, the present invention provides a kind of crystal form of Mycophenolic Acid and preparation method thereof.
First aspect present invention provides a kind of crystal form of Mycophenolic Acid, hereinafter referred to as crystal form B, X-ray powder diffraction figure
With in 2 θ=7.75,10.56,10.82,15.58,26.60,29.45 characteristic absorption peak is specifically shown in Fig. 1.Its fusing point is
140.8~141.5 DEG C.
Preferably, crystal form B of the present invention, X-ray powder diffraction figure have in 2 θ=7.75, and 10.56,10.82,
13.49,14.39,15.58,16.21,22.34,24.02,26.05,26.60,29.45 characteristic diffraction peak.
It is further preferred that crystal form B of the present invention, X-ray powder diffraction figure has in 2 θ=7.75,10.56,
10.82,13.49,14.07,14.39,14.21,15.58,16.21,20.40,22.34,24.02,24.20,26.05,
26.20,26.60,29.45,31.91,32.81,38.60 characteristic diffraction peak.
It is highly preferred that crystal form B of the present invention, X-ray powder diffraction figure has in 2 θ=7.36,7.75,9.47,
10.56,10.82,13.49,14.07,14.39,14.21,15.58,16.21,19.95,20.40,21.79,22.34,
22.51,23.22,24.02,24.20,26.05,26.20,26.60,29.45,31.04,31.91,32.81,38.60 spy
Levy diffraction maximum.
In a preferred embodiment of the invention, the Mycophenolic Acid crystal form B has X-ray powder as shown in Figure 1
Last diffracting spectrum.
It is a further object of the present invention to provide the preparation methods of Mycophenolic Acid crystal form object.
The preparation method of Mycophenolic Acid crystal form B of the present invention is：Mycophenolic Acid is heated, stirring and dissolving is taken out in chloroform
Filter, cooling, stirring and crystallizing filter, and wash, dry, obtain white powder Mycophenolic Acid crystal form B solids.
This method specifically includes following steps：Mycophenolic Acid is added in chloroform, stirring is warming up to 40~60 DEG C of dissolvings,
Insoluble impurity is filtered, filtrate cools to 0 DEG C, and stirring and crystallizing 3~4 hours filters, with appropriate chloroform filter cake, 40 DEG C of dryings 6
~8h obtains white powder Mycophenolic Acid crystal form B solids.
The mass volume ratio of the Mycophenolic Acid and chloroform is 1：7~1：11, unit K g/L.
It is further preferred that described method includes following steps：It is 1 that Mycophenolic Acid, which is added to mass volume ratio,：7~1：
In the chloroform of 11 (unit K g/L), stirring is warming up to 40~60 DEG C of dissolvings, filters insoluble impurity, and filtrate cools to 0 DEG C, stirring analysis
3~4 hours brilliant, filtering, with appropriate chloroform filter cake, it is solid to obtain white powder Mycophenolic Acid crystal form B by 40 DEG C of dry 6~8h
Body.
A kind of Mycophenolic Acid crystal form B provided by the invention has good chemical stability and crystal form purity, is easy to scale
Change and prepare, be conducive to transport and preserve, helps to improve the purity of the Mycophenolate Mofetil prepared in next step；There is provided a kind of prepare simultaneously
The method of Mycophenolic Acid crystal form B, it is easy to operate, it preferably can be suitable for preparing pharmaceutical preparation and large-scale production, have wide
Wealthy application prospect.
Description of the drawings
Fig. 1:The X-ray powder diffraction figure of Mycophenolic Acid crystal form B.
Fig. 2:The X-ray powder diffraction figure integrogram of Mycophenolic Acid crystal form B
Fig. 3:The X-ray powder diffraction figure integrogram of Mycophenolic Acid crystal form B
Specific implementation mode：
Below by way of specific embodiment, the above of the present invention is described in further detail, but should not be incited somebody to action
This is interpreted as any restrictions to subject matter of the present invention.All technical solutions realized based on the above of the present invention are belonged to
The scope of the present invention.
Embodiment 1：The preparation of Mycophenolic Acid crystal form B
320g mycophenolic acids and 2240ml chloroforms are added into 3L there-necked flasks, is warming up to 50~60 DEG C, stirs dissolved clarification,
10min is stirred after dissolved clarification, filters insoluble impurity, and filtrate stirring is cooled to 0 DEG C, 3~4h of stirring and crystallizing, filters, and appropriate chloroform is washed
Filter cake to be washed, is drained, 40 DEG C of 6~8h of vacuum drying, obtain white powdery solids in vacuum drying chamber, yield 86.6%, purity
99.96%.After measured, X-RPD collection of illustrative plates and Fig. 1 are almost the same.
Embodiment 2：The preparation of Mycophenolic Acid crystal form B
320g mycophenolic acids and 3520ml chloroforms are added into 5L there-necked flasks, is warming up to 40~50 DEG C, stirs dissolved clarification,
10min is stirred after dissolved clarification, filters insoluble impurity, and filtrate stirring is cooled to 0 DEG C, 3~4h of stirring and crystallizing, filters, and appropriate chloroform is washed
Filter cake is washed, is drained, 40 DEG C of 6~8h of vacuum drying, obtain white powdery solids, yield 83.9%, purity in vacuum drying chamber
99.98%.After measured, X-RPD collection of illustrative plates and Fig. 1 are almost the same.
Embodiment 3：The preparation of Mycophenolic Acid crystal form B
320g mycophenolic acids and 2560ml chloroforms are added into 3L there-necked flasks, is warming up to 40~50 DEG C, stirs dissolved clarification,
10min is stirred after dissolved clarification, filters insoluble impurity, and filtrate stirring is cooled to 0 DEG C, 3~4h of stirring and crystallizing, filters, and appropriate chloroform is washed
Filter cake is washed, is drained, 40 DEG C of 6~8h of vacuum drying, obtain white powdery solids, yield 84.7%, purity in vacuum drying chamber
99.97%.After measured, X-RPD collection of illustrative plates and Fig. 1 are almost the same.
Embodiment 4：The preparation of Mycophenolic Acid crystal form B
320g mycophenolic acids and 1920ml chloroforms are added into 3L there-necked flasks, is warming up to 40~50 DEG C, stirs dissolved clarification,
10min is stirred after dissolved clarification, filters insoluble impurity, and filtrate stirring is cooled to 0 DEG C, 3~4h of stirring and crystallizing, filters, and appropriate chloroform is washed
Filter cake is washed, is drained, 40 DEG C of 6~8h of vacuum drying, obtain white powdery solids, yield 84.5%, purity in vacuum drying chamber
99.90%.After measured, X-RPD collection of illustrative plates and Fig. 1 are almost the same.
Embodiment 5：The preparation of Mycophenolic Acid crystal form B
320g mycophenolic acids and 3840ml chloroforms are added into 5L there-necked flasks, is warming up to 40~50 DEG C, stirs dissolved clarification,
10min is stirred after dissolved clarification, filters insoluble impurity, and filtrate stirring is cooled to 0 DEG C, 3~4h of stirring and crystallizing, filters, and appropriate chloroform is washed
Filter cake is washed, is drained, 40 DEG C of 6~8h of vacuum drying, obtain white powdery solids, yield 79.0%, purity in vacuum drying chamber
99.93%.After measured, X-RPD collection of illustrative plates and Fig. 1 are almost the same.
Stability test
It takes Mycophenolic Acid crystal form samples to be placed under conditions of 35 DEG C, investigates and placing 1 month, 2 months, 3 months, 6
The stability of the moon, test result are shown in Table 1.
The method that the method for specific study on the stability is referred to 2010 editions second annex XIX C of Chinese Pharmacopoeia；It is pure
Degree detection HPLC methods, the method for being referred to 2010 editions second annex V D of Chinese Pharmacopoeia.
The stability test result of Mycophenolic Acid crystal form：The Mycophenolic Acid crystal form B that Examples 1 to 5 is prepared passes through 6
Moon stability test, the purity of sample, crystal form do not change, for embodiment 3, place 0 month purity 99.97%, place 6
A month purity 99.97%；Illustrate that Mycophenolic Acid novel crystal forms provided by the invention are stablized, and there is good chemical stability.The back of the body
Then stability is substantially less than the application crystal form B to crystal form listed by scape technology, and purity decreased significantly when placing 3 months.
Claims (9)
1. a kind of Mycophenolic Acid crystal form B, X-ray powder diffraction figure has in 2 θ=7.75,10.56,10.82,15.58,
26.60,29.45 characteristic absorption peak.
2. Mycophenolic Acid crystal form B according to claim 1, which is characterized in that its X-ray powder diffraction figure have 2 θ=
7.75,10.56,10.82,13.49,14.39,15.58,16.21,22.34,24.02,26.05,26.60,29.45 feature
Diffraction maximum.
3. Mycophenolic Acid crystal form B according to claim 1, which is characterized in that its X-ray powder diffraction figure have 2 θ=
7.75,10.56,10.82,13.49,14.07,14.39,14.21,15.58,16.21,20.40,22.34,24.02,24.20,
26.05,26.20,26.60,29.45,31.91,32.81,38.60 characteristic diffraction peak.
4. Mycophenolic Acid crystal form B according to claim 1, which is characterized in that its X-ray powder diffraction figure have 2 θ=
7.36,7.75,9.47,10.56,10.82,13.49,14.07,14.39,14.21,15.58,16.21,19.95,20.40,
21.79,22.34,22.51,23.22,24.02,24.20,26.05,26.20,26.60,29.45,31.04,31.91,
32.81,38.60 characteristic diffraction peak.
5. Mycophenolic Acid crystal form B according to claim 1, which is characterized in that its fusing point is 140.8~141.5 DEG C.
6. the preparation method of Mycophenolic Acid crystal form B described in a kind of claim 1, which is characterized in that include the following steps：Wheat is examined
Phenolic acid heats, and stirring and dissolving filters in chloroform, cooling, and stirring and crystallizing filters, and washing is drying to obtain.
7. preparation method according to claim 6, which is characterized in that this method specifically includes following steps：By Mycophenolic Acid
It is added in chloroform, stirring is warming up to 40~60 DEG C of dissolvings, filters insoluble impurity, filtrate cools to 0 DEG C, and stirring and crystallizing 3~4 is small
When, filtering, with appropriate chloroform filter cake, 40 DEG C of dry 6~8h to obtain the final product.
8. preparation method according to claim 6, which is characterized in that the mass volume ratio of the Mycophenolic Acid and chloroform is 1：
7~1：11, unit K g/L.
9. preparation method according to claim 6, which is characterized in that described method includes following steps：By Mycophenolic Acid plus
It is 1 to enter to quality volume Kg/L ratios：7~1：In 11 chloroform, stirring is warming up to 40~60 DEG C of dissolvings, filters insoluble impurity, filters
Liquid cools to 0 DEG C, and stirring and crystallizing 3~4 hours, filtering, with appropriate chloroform filter cake, 40 DEG C of dry 6~8h to obtain the final product.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001064931A1 (en) * | 2000-02-29 | 2001-09-07 | Biocon India Limited | Manufacture and purification of mycophenolic acid |
| CN1738605A (en) * | 2003-01-20 | 2006-02-22 | 诺瓦提斯公司 | Process for modifying drug crystal formation |
| WO2006031665A1 (en) * | 2004-09-10 | 2006-03-23 | Ivax Pharmaceuticals S.R.O. | Process for isolation of mycophenolic acid |
| CN1906186A (en) * | 2004-04-26 | 2007-01-31 | 特瓦药厂私人有限公司 | Process for preparation of mycophenolic acid and ester derivatives thereof |
| TW201103897A (en) * | 2009-07-21 | 2011-02-01 | Chunghwa Chemical Synthesis & Biotech Co Ltd | Purification method of mycophenolic acid and method for preparing high purity sodium mycophenolate using the same |
| CN103570655A (en) * | 2012-07-31 | 2014-02-12 | 北大方正集团有限公司 | Method for extracting mycophenolic acid |
| CN103880798A (en) * | 2012-12-19 | 2014-06-25 | 北大方正集团有限公司 | Mycophenolic acid purification method |
-
2017
- 2017-04-25 CN CN201710273540.0A patent/CN108727318A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001064931A1 (en) * | 2000-02-29 | 2001-09-07 | Biocon India Limited | Manufacture and purification of mycophenolic acid |
| CN1738605A (en) * | 2003-01-20 | 2006-02-22 | 诺瓦提斯公司 | Process for modifying drug crystal formation |
| CN1906186A (en) * | 2004-04-26 | 2007-01-31 | 特瓦药厂私人有限公司 | Process for preparation of mycophenolic acid and ester derivatives thereof |
| WO2006031665A1 (en) * | 2004-09-10 | 2006-03-23 | Ivax Pharmaceuticals S.R.O. | Process for isolation of mycophenolic acid |
| TW201103897A (en) * | 2009-07-21 | 2011-02-01 | Chunghwa Chemical Synthesis & Biotech Co Ltd | Purification method of mycophenolic acid and method for preparing high purity sodium mycophenolate using the same |
| CN103570655A (en) * | 2012-07-31 | 2014-02-12 | 北大方正集团有限公司 | Method for extracting mycophenolic acid |
| CN103880798A (en) * | 2012-12-19 | 2014-06-25 | 北大方正集团有限公司 | Mycophenolic acid purification method |
Non-Patent Citations (6)
| Title |
|---|
| COVARRUBIAS-ZUNIGA 等: "Crystal structure of mycophenolic acid: 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methyl-hex-4-enoic acid", 《ANALYTICAL SCIENCES》 * |
| PAUL A. BROOKES 等: "Total Synthesis of Mycophenolic Acid by a Palladium-Catalyzed Decarboxylative Allylation and Biomimetic Aromatization Sequence", 《EUR. J. ORG. CHEM.》 * |
| W. HARRISON 等: "Crystal Structure of Mycophenolic Acid", 《J.C.S. PERKIN I1》 * |
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| 高兴蓉: "新型免疫抑制剂霉酚酸及霉酚酸酯的研制", 《中国学位论文全文数据库》 * |
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