CN108570064A - A kind of purification process of bortezomib - Google Patents
A kind of purification process of bortezomib Download PDFInfo
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- CN108570064A CN108570064A CN201810857550.3A CN201810857550A CN108570064A CN 108570064 A CN108570064 A CN 108570064A CN 201810857550 A CN201810857550 A CN 201810857550A CN 108570064 A CN108570064 A CN 108570064A
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- Prior art keywords
- bortezomib
- crude product
- ethyl acetate
- acetate solution
- crystallization
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- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 title claims abstract description 50
- 229960001467 bortezomib Drugs 0.000 title claims abstract description 49
- 238000000746 purification Methods 0.000 title claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000000034 method Methods 0.000 claims abstract 8
- 239000012043 crude product Substances 0.000 claims description 22
- 238000002425 crystallisation Methods 0.000 claims description 14
- 230000008025 crystallization Effects 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract 2
- 239000000047 product Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 0 C*[C@@](C[C@]1C(C)(C)[C@@]2CC1)[C@]2(**[C@](*C(C)IC)**(C)C)C=C Chemical compound C*[C@@](C[C@]1C(C)(C)[C@@]2CC1)[C@]2(**[C@](*C(C)IC)**(C)C)C=C 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000004007 reversed phase HPLC Methods 0.000 description 3
- MOILFCKRQFQVFS-VUMZSGCYSA-N (3r,4s)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol Chemical compound C1C2C(C)(C)C1C[C@@H](O)[C@]2(O)C MOILFCKRQFQVFS-VUMZSGCYSA-N 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 239000011549 crystallization solution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical class C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000019838 Blood disease Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- HFOKLWWMOJMTDR-UHFFFAOYSA-N CC(C)(C)[ClH]C(C)=C Chemical compound CC(C)(C)[ClH]C(C)=C HFOKLWWMOJMTDR-UHFFFAOYSA-N 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 125000002435 L-phenylalanyl group Chemical class O=C([*])[C@](N([H])[H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
- 208000021937 marginal zone lymphoma Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The present invention relates to a kind of purification process of bortezomib, and bortezomib is recrystallized in ethyl acetate, and energy high-purity prepares bortezomib.The method increase bortezomib production efficiencys, reduce production cost, are suitable for mass producing.
Description
Technical field
The present invention relates to medicinal chemistry arts, and in particular to the crystallization purification process of bortezomib.
Background technology
Bortezomib (Bortezomib), trade name Bortezomib (Velcade) are ground by Millennium drugmakers of the U.S.
The new type antineoplastic medicine of hair.The medicine is 26S proteasome inhibitors, by blocking intracellular a variety of regulating cell apoptosis and letter
Number conduction protein degradation, lead to death of neoplastic cells.Numerous studies find that bortezomib is to kinds of tumors, especially
Huppert's disease, jacket cell type lymthoma and other B cell type lymthomas in neoplastic hematologic disorder (diffuse large B cell type, filter
Cystencyte type, small lymphocyte type/chronic lymphocytic leukemia, marginal zone lymphoma), Hodgkin lymphoma have it is stronger anti-
Tumor promotion.
CN1960996A discloses N- (2- pyrazinecarbonyls)-L-phenylalanines and (1S, 2S, 3R, 5S)-pinane diol 1- tri-
Fluorine ammonium acetate -3- methybutane -1- borate condensations prepare bortezomib precursor, later by deprotection, refined and etc.
To bortezomib, synthetic route is as follows:
CN1168633A is disclosed with N- tertbutyloxycarbonyls-L-phenylalanine, pyrazine -2- formic acid and (1S, 2S, 3R, 5S) -
Pinane diol 1- trifluoracetic acid ammonium -3- methybutane -1- borates be starting material, successively by condensation, deprotection, condensation,
Deprotection and refined five steps obtain bortezomib, and synthetic route is as follows:
CN101812026A is disclosed using 3- methylbutyraldehyds and R- (+) -1- phenyl ethylamines as starting material, by being condensed, selecting
The addition of selecting property borate, hydrogenation deprotection and the condensation of L-phenylalanine derivative, deprotection etc. obtain bortezomib, synthesize road
Line is as follows:
Bortezomib lmpurities made from the above synthetic route are more, need to develop it is a kind of can reduce bortezomib at
Impurity and the purification process of product quality is improved in product.
Invention content
The present invention provides a kind of purification process of bortezomib, include the following steps:
A, bortezomib crude product is dissolved by heating and bortezomib crude product ethyl acetate solution is made in ethyl acetate;
B, bortezomib crude product ethyl acetate solution cooling crystallization, filtering, dry bortezomib;
In a kind of preferred scheme, a concentration of 20~300mg/mL of bortezomib crude product ethyl acetate solution.
In a kind of preferred scheme, a concentration of 30~90mg/mL of bortezomib crude product ethyl acetate solution can also be
30mg/mL or 60mg/mL.
In a kind of preferred scheme, the heating for dissolving temperature of bortezomib crude product is selected from 60~65 DEG C.
In a kind of preferred scheme, bortezomib crude product ethyl acetate solution stands crystallization, crystallization time at 20~30 DEG C
It is 20~24 hours.
In a kind of preferred scheme, drying temperature is selected from 30~40 DEG C, and drying time is selected from 18~20 hours.
Bortezomib prepared by purification process of the present invention has good granularity normal distribution and crystal grain is smaller molten
Speed is solved, X-ray powder diffraction collection is as shown in Figure 3.
The purification process of the present invention, purification effect is good easy to operate, saves a large amount of manpower and materials, reduces and be produced into
This, is suitable for mass producing.
Description of the drawings
Fig. 1 is the RP-HPLC collection of illustrative plates of bortezomib crude product;
Fig. 2 is the RP-HPLC collection of illustrative plates of 4 gained bortezomib of embodiment;
Fig. 3 is the X-ray powder diffraction collection of 4 gained bortezomib of embodiment.
Specific embodiment
Below in conjunction with specific embodiment, embodiment of the present invention is described in detail.Following example is only used for
Illustrate the present invention, and should not be taken as limiting the scope of the invention.
Following embodiment use bortezomib crude product RP-HPLC collection of illustrative plates as shown in Figure 1, bortezomib crude product purity
It is 97.70%, the impurity content that wherein relative retention time RRT is 1.50 is 0.95%.
Embodiment 1
A certain amount of bortezomib crude product is added in appropriate ethyl acetate and is heated to 60~65 DEG C of dissolvings, is prepared into respectively
To tetra- kinds of solution of a concentration of 300mg/mL, 90mg/mL, 60mg/mL and 30mg/mL, it is cooled to 25 DEG C and stands crystallization 22 hours, mistake
Bortezomib finished product is filtered to obtain, takes and detects purity for liquid phase on a small quantity, calculating of weighing after 30~40 DEG C of vacuum drying of remaining sample is received
Rate.
Serial number | Crystallization concentration | Finished product purity | RRT=1.50 impurity | Product yield |
1 | 300mg/mL | 97.92% | 0.91% | 88.2% |
2 | 90mg/mL | 98.95% | 0.59% | 75.3% |
3 | 60mg/mL | 99.68% | 0.02% | 74.5% |
4 | 30mg/mL | 99.62% | 0.03% | 53.2% |
Embodiment 2
A certain amount of bortezomib crude product is added in appropriate ethyl acetate and is heated to 60~65 DEG C of dissolvings, is prepared dense
Degree is the crystallization solution of 60mg/mL, selects 40 DEG C, 30 DEG C, 20 DEG C, 10 DEG C and 0 DEG C four kinds of different recrystallization temperatures respectively, is stood
Crystallization 22 hours filters to obtain bortezomib finished product, takes and detects purity, 30~40 DEG C of vacuum drying of remaining sample for liquid phase on a small quantity
After weigh calculated yield.
Serial number | Recrystallization temperature | Finished product purity | RRT=1.50 impurity | Product yield |
1 | 0℃ | 99.51% | 0.04% | 72.7% |
2 | 10℃ | 99.48% | 0.05% | 70.3% |
3 | 20℃ | 99.70% | 0.02% | 70.6% |
4 | 30℃ | 99.70% | 0.02% | 68.2% |
5 | 40℃ | 99.51% | 0.04% | 65.7% |
Embodiment 3
A certain amount of bortezomib crude product is added in appropriate ethyl acetate and is heated to 60~65 DEG C of dissolvings, is prepared dense
Degree is the crystallization solution of 60mg/mL, is cooled to 20~30 DEG C of standing crystallizations, investigates different crystallization time teams bortezomib yield
It influences.
Serial number | Recrystallization temperature | The crystallization time | Product yield |
1 | 20~30 DEG C | 10 hours | 56.4% |
2 | 20~30 DEG C | 20 hours | 77.3% |
3 | 20~30 DEG C | 24 hours | 76.5% |
Embodiment 4
Bortezomib crude product 600g is taken, is added in ethyl acetate 10L and is heated to 60~65 DEG C of dissolvings, be prepared a concentration of
The solution of 60mg/mL is cooled to 25 DEG C and stands crystallization 22 hours, and filtering, 30~40 DEG C are dried in vacuo 20 hours, obtain bortezomib
Finished product 468g, yield 78%, purity 99.72%, RRT=1.50 impurity 0.02%.
Claims (8)
1. a kind of purification process of bortezomib, includes the following steps,
A, bortezomib crude product is dissolved by heating in ethyl acetate, bortezomib crude product ethyl acetate solution is made;
B, bortezomib crude product ethyl acetate solution cooling crystallization, filtering, dry bortezomib;
Wherein, a concentration of 20~300mg/mL of bortezomib crude product ethyl acetate solution.
2. method according to claim 1, which is characterized in that a concentration of the 30 of bortezomib crude product ethyl acetate solution~
90mg/mL。
3. method according to claim 1, which is characterized in that a concentration of 30mg/ of bortezomib crude product ethyl acetate solution
ML or 60mg/mL.
4. method according to claim 1, which is characterized in that the heating for dissolving temperature of bortezomib crude product is selected from 60~65
℃。
5. method according to claim 1, which is characterized in that bortezomib crude product ethyl acetate solution is stood at 20~30 DEG C
Crystallization.
6. method according to claim 1, which is characterized in that the crystallization time is 20~24 hours.
7. method according to claim 1, which is characterized in that drying temperature is selected from 30~40 DEG C.
8. method according to claim 1, which is characterized in that drying time is selected from 18~20 hours.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111187336A (en) * | 2018-11-14 | 2020-05-22 | 正大天晴药业集团股份有限公司 | Refining method of bortezomib |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103012551A (en) * | 2012-12-14 | 2013-04-03 | 江苏奥赛康药业股份有限公司 | Synthetic method of high-purity bortezomib and intermediate thereof |
CN103044468A (en) * | 2012-11-28 | 2013-04-17 | 深圳万乐药业有限公司 | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid |
CN103450331A (en) * | 2012-06-05 | 2013-12-18 | 山东新时代药业有限公司 | Method for refining bortezomib |
CN103497233A (en) * | 2013-09-30 | 2014-01-08 | 哈药集团技术中心 | Preparation method for bortezomib |
-
2018
- 2018-08-21 CN CN201810857550.3A patent/CN108570064A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103450331A (en) * | 2012-06-05 | 2013-12-18 | 山东新时代药业有限公司 | Method for refining bortezomib |
CN103044468A (en) * | 2012-11-28 | 2013-04-17 | 深圳万乐药业有限公司 | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid |
CN103012551A (en) * | 2012-12-14 | 2013-04-03 | 江苏奥赛康药业股份有限公司 | Synthetic method of high-purity bortezomib and intermediate thereof |
CN103497233A (en) * | 2013-09-30 | 2014-01-08 | 哈药集团技术中心 | Preparation method for bortezomib |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111187336A (en) * | 2018-11-14 | 2020-05-22 | 正大天晴药业集团股份有限公司 | Refining method of bortezomib |
CN111187336B (en) * | 2018-11-14 | 2022-05-20 | 正大天晴药业集团股份有限公司 | Refining method of bortezomib |
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Application publication date: 20180925 |