CN108570064A - A kind of purification process of bortezomib - Google Patents
A kind of purification process of bortezomib Download PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- bortezomib
- crude product
- ethyl acetate
- acetate solution
- crystallization
- 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.)
- Pending
Links
- 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
- 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
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 System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810857550.3A CN108570064A (en) | 2018-08-21 | 2018-08-21 | A kind of purification process of bortezomib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810857550.3A CN108570064A (en) | 2018-08-21 | 2018-08-21 | A kind of purification process of bortezomib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108570064A true CN108570064A (en) | 2018-09-25 |
Family
ID=63571863
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810857550.3A Pending CN108570064A (en) | 2018-08-21 | 2018-08-21 | A kind of purification process of bortezomib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108570064A (en) |
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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2015374763B2 (en) | Method for preparing Sofosbuvir crystal form-6 | |
| WO2017050171A1 (en) | Crystal form of pyrroloquinoline quinone sodium salt and preparation method and use thereof | |
| CN108570064A (en) | A kind of purification process of bortezomib | |
| CN106795159B (en) | A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor | |
| CN103167872B (en) | For the production of the method for VBT tartrate | |
| CN112469698B (en) | Preparation method of indocyanine green triethylamine salt | |
| US10196360B2 (en) | Crystal forms of bedaquiline fumarate and preparation methods therefor | |
| CN101768105A (en) | Crystal form of butyric acid clevidipine | |
| CN107722005B (en) | A kind of refining methd of pa Berkeley | |
| CN102532226B (en) | Ribavirin crystal form and preparation method thereof | |
| CN103319473A (en) | Two crystal forms of azilsartan and preparation method thereof | |
| US6346603B1 (en) | Crystal of depsipeptide derivative and process for producing the same | |
| CN103833741A (en) | Emtricitabine salicylate and preparation method and application thereof | |
| CN104093731A (en) | Anhydrous polymorphs of [(2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)]methyl nitrate and processes of preparation thereof | |
| CN103664771B (en) | Crystal form A of Xarelto and preparation method thereof | |
| CN105992769A (en) | L-proline compound of sodium-glucose cotransporter 2 inhibitor, and monohydrate and crystal of l-proline compound | |
| CN109963855A (en) | A kind of crystal form and preparation method of BTK kinase inhibitor | |
| CN106065016B (en) | A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor | |
| CN107141328A (en) | A kind of Vidarabine Monophosphate novel crystal forms and preparation method thereof | |
| CN112028838B (en) | Preparation method of 2-ethoxy-5-fluorouracil impurity | |
| CN111087380B (en) | Preparation method of ticagrelor intermediate | |
| CN108373473B (en) | Oxidized indole spiro tetrahydrofuran fluoride and crystal thereof, and preparation method and application thereof | |
| CN106431943B (en) | Preparation method of bupropion hydrochloride crystal | |
| CN106279355A (en) | The preparation technology of bortezomib | |
| CN113512079A (en) | Preparation method of beta-nicotinamide mononucleotide |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180925 |