CN108892625A - A kind of preparation method of ubenimex γ crystal form - Google Patents
A kind of preparation method of ubenimex γ crystal form Download PDFInfo
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
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- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
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- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- 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
Abstract
The present invention relates to a kind of preparations of ubenimex γ crystal form, it is controlled by each key parameter during the preparation method, the application preparation method can significantly improve the yield of γ crystal form, and obtain single crystal form, technique favorable reproducibility, so that realizing that commercial production conditions are controllable, be conducive to extensive industrialization.
Description
Technical field
This application involves drug crystal forms fields, and in particular to a kind of ubenimex γ crystal form and preparation method thereof.
Background technique
Ubenimex (Ubenimex), its chemical name is：N- [(2S, 3R) -3- amino -2- hydroxy-4-phenyl butyryl] -
L-Leu；Molecular formula：C16H24N2O4；Molecular weight：308.37；Its structural formula is as follows：
Ubenimex is to be isolated from the culture solution of the netted streptomycete of olive by Japanese scholars Mei Ze shore husband for 1976
Dipeptide compound, the inhibition aminopeptidase B and leucine peptase and caspase etc. of contestable, inducing apoptosis of tumour cell
With promotion host immune function.Chemotherapy, radiotherapy can be cooperated and to be united and applied in leukaemia, Huppert's disease, myelosis different
After normal syndrome and hematopoietic stem cell transplantation and other patients with solid tumor.
A kind of method of the preparation for ubenimex that United States Patent (USP) US4281180 is provided：Ubenimex 1N dissolving with hydrochloric acid,
After adding active carbon decoloring, insoluble matter is separated, isolate weak aqua ammonia tune PH to 5-6 collects the solid of precipitating after filtering,
With acetone washing, vacuum drying obtains ubenimex beta crystal.
United States Patent (USP) US4786754 discloses two kinds of methods for preparing ubenimex γ crystal form, and points out that beta crystal is placed on
It will become the alpha-crystal form of dihydrate by absorbing moisture in air.Turn crystalline substance first is that α, beta crystal are heated at 148~200 DEG C and be
γ crystal form, but this method turns brilliant temperature height, and the related substance of product is caused to increase；Second is that dispersing acetone, methyl second for α, beta crystal
Base ketone, metacetone, tetrahydrofuran, dioxane, isopropanol, stir to get γ crystal form in methanol aqueous solution at ethyl acetate, this
A little solvent toxicities are big, and environmental pollution is serious.
Chinese patent CN101891647A is disclosed using glacial acetic acid as solvent, and compound (12) is obtained crow with palladium hydrogenated carbon
Crude product, is then dissolved in hydrochloric acid by benzene U.S. department crude product, is adjusted to pH=5-6 with ammonium hydroxide, and filtering, wet product is impregnated in acetone, then
Filtering, vacuum drying obtain the process of ubenimex finished product, and the process is actually consistent with technique disclosed in US4786754,
It is impregnated in organic solvent-acetone and obtains ubenimex γ crystal form.
Chinese patent CN103910648A provides a kind of preparation method of hydrochloric acid ubenimex crystal-form compound：By hydrochloric acid
Ubenimex is added to isopropyl acetate and the in the mixed solvent low-grade fever of dimethylformamide dissolves, and stirs 1-5h, stands volatilization
Dry solvent.This method volatilization time is long, is suitable only for low dose of crystal form preparation, is unable to satisfy the preparation of high-volume crystal form and requires.
Therefore, it is simple to still need to provide a kind of preparation process for this field, product quality more preferably γ crystal, and of the invention
Meet such demand.
Summary of the invention
The application is groped in constantly research process by test, and the new ubenimex of one kind is unexpectedly obtained
The preparation method of γ crystal form.
This application discloses a kind of preparation methods of ubenimex γ crystal form, specifically comprise the steps of：
(1) by ubenimex in purified water stirring to pulp, wherein the usage ratio of ubenimex and purified water be 1g：
(5ml~30ml), stirring to pulp temperature are 40~70 DEG C, stirring to pulp time 2h~16h, stirring rate 200r/min~
500r/min；
(2) reaction solution obtained by step (1) is cooled to 0~20 DEG C of stirring and crystallizing, crystallization time 0.5h~3h；
(3) step (2) acquired solution is filtered；
(4) filter cake obtained by step (3) is placed in dry 4h in 50~80 DEG C of vacuum drying ovens~for 24 hours.
Wherein, in step (1), the usage ratio of the ubenimex and purified water is preferably 1g：(10ml~15ml), is stirred
Mixing mashing temperature is preferably 50~60 DEG C, and the stirring to pulp time is preferably 2h~4h, and speed of agitator is 300r/min~400r/
min。
Wherein, in step (2), preferably 0~10 DEG C of the stirring and crystallizing temperature, the crystallization time is preferably 1~2h.
Wherein in step (4), the drying time is 8h~16h, and the temperature condition is 70~80 DEG C.
It is had the following advantages that using ubenimex γ crystal form prepared by the application：
1, the preparation of γ crystal form in the prior art, one is α, beta crystals that use first prepares ubenimex, then in 148-
200 DEG C of dryings carry out turning crystalline substance, and temperature is higher to cause related substance to obviously increase (largest single impurity before turning brilliant：0.06%, it is total miscellaneous：
0.19%, largest single impurity after turning brilliant：1.13%, it is total miscellaneous：2.04%), hence it is evident that be higher than in national drug registration process for raw material
Single miscellaneous and total miscellaneous limit, does not meet product quality requirement in medicine.Another preparation method is by α, beta crystal in organic solvent
Middle stirring is converted to obtain, and solvent for use includes butanone, metacetone, ethyl acetate, dioxane, tetrahydrofuran
Deng the big (1g of these solvent usages：10ml), manufacturing cost is high, and toxicity is big, and environmental pollution is serious.And the application crystal form system
Reaction condition is mild, easy to operate in standby technique, and solvent for use is only purified water, is conducive to environmental protection, reduces reagent cost and energy
It consumes and has certain refining effect to product.Products obtained therefrom quality purity is high, and related substance is low, is significantly better than that the prior art, and
Meet related raw material drug registration requirement.
2, it is controlled by each key parameter in the application γ crystal form preparation process, the application preparation method can be mentioned significantly
The yield of high γ crystal form, and single crystal form is obtained, technique favorable reproducibility is conducive to so that realizing that commercial production conditions are controllable
Extensive industrialization.
Detailed description of the invention
The HPLC map of 1 ubenimex γ crystal form of Fig. 1 embodiment
The XRPD map of 1 ubenimex γ crystal form of Fig. 2 embodiment
The infared spectrum of 1 ubenimex γ crystal form of Fig. 3 embodiment
The XRPD map of Fig. 4 comparative example ubenimex beta crystal
Specific embodiment
The application is described in further detail below with reference to embodiment, embodiments herein is merely to illustrate this
The technical solution of application not limits the spirit and scope of the application.
The structure of compound be by nuclear magnetic resonance (1HNMR it) measures.Nuclear magnetic resonance (1H NMR) (δ) is displaced with hundred
A ten thousandth (ppm) provides for unit.Instrument：Bruker AVII-600MHz nuclear magnetic resonance chemical analyser；Detect foundation：Middle Chinese
People republic pharmacopeia four 0441 nuclear magnetic resonance spectroscopies of general rule of version in 2015；Solvent：DMSO is inside designated as TMS.
The measurement of X-ray powder diffraction (XRPD) described herein is spread out using the great member DX-2700X powder in Dandong
It penetrates instrument to be acquired, design parameter such as following table：
The measurement of HPLC spectrogram is carried out using Agilent Agilent1260DAD type liquid chromatograph.
The instrument model of infrared analysis：Fourier transformation infrared spectrometer Spectrum Two
In the application, ubenimex HPLC purity carries out using the following method：
(1) using octadecylsilane chemically bonded silica as the chromatographic column (5 μm of partial sizes, 25 DEG C of column temperature) of filler；
(2) mobile phase A：Diluted 0.1mol/L potassium dihydrogen phosphate (13 → 20) and acetonitrile mixture (V/V=17/
3)；
Mobile phase B：Potassium dihydrogen phosphate (13 → 20) mixture (V/V=2/1) of acetonitrile and diluted 0.1mol/L；
Mobile phase A and the gradient of B see the table below：
| Time (min) | Mobile phase A (%, V/V) | Mobile phase B (%, V/V) |
| 0-20 | 100 | 0 |
| 20-60 | 100→0 | 0→100 |
| 60-70 | 0 | 100 |
| 70-71 | 0→100 | 100→0 |
| 71-80 | 100 | 0 |
(3) detector：UV absorption photometer (wavelength：220nm)；
(4) flow velocity：Flow velocity is adjusted, so that the retention time of ubenimex is about 14 minutes；
(5) runing time：The timing since solvent peak, about the 5 of ubenimex retention time times；
(6) test solution：This product 30mg is taken, it is accurately weighed, add dilution dissolved dilution to be made in every 1ml containing about 3mg
Solution, as test solution；
(7) sample volume：20 μ l measure sample solution by ubenimex in calculated by peak area sample by automatic integration
Purity.
Specific embodiment：
Embodiment 1：The preparation of ubenimex γ crystal form
It disperses 19.40g ubenimex in 195ml purified water, in 45 DEG C of stirring to pulp 3h, stirring rate 360r/
Min, ice bath are cooled to 5 DEG C, stirring and crystallizing 1h；Negative pressure leaching, filter cake are placed in dry 8h in 70 DEG C of vacuum drying ovens, obtain white solid
Powder 17.90g, yield 92.3%.HPLC purity is 99.96%, largest single impurity 0.02%.X-ray is carried out using Cu-ka ray
Powder measurement, map have the angle of diffraction and interplanar distance shown in following table：
Nuclear-magnetism result is as follows：
1H NMR (600MHz, DMSO)：δ 8.08 (d, 1H, J=7.8Hz), 7.32 (m, 5H), 3.96 (q, 1H, J=
7.2Hz), 3.87 (d, 1H, J=3.0Hz), 3.54 (m, 1H), 2.96 (m, 2H), 1.61 (d, 2H, J=4.2Hz), 0.86 (m,
6H)
13C NMR(600MHz,DMSO)：δ175.52(s,1C),172.09(s,1C),137.91(s,1C),129.92(s,
2C),128.84(s,2C),126.94(s,1C),69.20(s,1C),55.76(s,1C),53.41(s,1C),40.70(s,
1C), 36.12 (s, 1C), 25.18 (s, 1C), 23.72 (s, 1C), 21.84 (s, 1C)
Infared spectrum is as shown in Fig. 3.
Embodiment 2：The preparation of ubenimex γ crystal form
It disperses 10.0g ubenimex in 150ml purified water, in 40 DEG C of stirring to pulp 16h, stirring rate 500r/
Min, ice bath are cooled to 10 DEG C, stirring and crystallizing 1h；Negative pressure leaching, filter cake are placed in dry 16h in 50 DEG C of vacuum drying ovens, obtain white solid
Body powder 9.07g, yield 90.07%.HPLC purity is 99.94%, largest single impurity 0.03%, total miscellaneous 0.06%.
Its nuclear magnetic data, powder diffraction data and 1 data of embodiment keep almost the same.
Embodiment 3：The preparation of ubenimex γ crystal form
It disperses 10.0g ubenimex in 50ml purified water, in 70 DEG C of stirring to pulp 2h, stirring rate 200r/min,
Ice bath is cooled to 10 DEG C, stirring and crystallizing 0.5h；Negative pressure leaching, filter cake are placed in drying in 60 DEG C of vacuum drying ovens and for 24 hours, obtain white solid
Powder 9.07g, yield 90.07%.HPLC purity is 99.94%, largest single impurity 0.03%, total miscellaneous 0.06%.
Its nuclear magnetic data, powder diffraction data and 1 data of embodiment keep almost the same.
Embodiment 4：The preparation of ubenimex γ crystal form
It disperses 10.0g ubenimex in 300ml purified water, in 60 DEG C of stirring to pulp 2h, stirring rate 350r/min,
Ice bath is cooled to 5 DEG C, stirring and crystallizing 1.0h；Negative pressure leaching, filter cake are placed in dry 8h in 70 DEG C of vacuum drying ovens, obtain white solid powder
Last 8.79g, yield 87.9%.HPLC purity is 99.96%, largest single impurity 0.02%, total miscellaneous 0.04%.
Its nuclear magnetic data, powder diffraction data and 1 data of embodiment keep almost the same.
Embodiment 5：The preparation of ubenimex γ crystal form
It disperses 10.0g ubenimex in 200ml purified water, in 50 DEG C of stirring to pulp 4h, stirring rate 300r/min,
Ice bath is cooled to 20 DEG C, stirring and crystallizing 2h；Negative pressure leaching, filter cake are placed in dry 4h in 80 DEG C of vacuum drying ovens, obtain white solid powder
Last 8.97g, yield 89.70%.HPLC purity is 99.95%, largest single impurity 0.02%, total miscellaneous 0.05%.
Its nuclear magnetic data, powder diffraction data and 1 data of embodiment keep almost the same.
Embodiment 6：The preparation of ubenimex γ crystal form
It disperses 4.60kg ubenimex in 46.0kg purified water, in 50 DEG C of stirring to pulp 4h, stirring rate 350r/
Min is cooled to 0 DEG C, stirring and crystallizing 3h；Negative pressure leaching, filter cake are placed in dry 8h in 70 DEG C of vacuum drying ovens, obtain white solid powder
4.38kg, yield 95.22%.HPLC purity is 99.92%, largest single impurity 0.04%, total miscellaneous 0.08%.
Its nuclear magnetic data, powder diffraction data and 1 data of embodiment keep almost the same.
Embodiment 7：The preparation of ubenimex γ crystal form
It disperses 4.30kg ubenimex in 60.0kg purified water, in 45 DEG C of stirring to pulp 4h, stirring rate 400r/
Min cools to 5 DEG C, stirring and crystallizing 1.5h；Negative pressure leaching, filter cake are placed in dry 16h in 70 DEG C of vacuum drying ovens, obtain white
Solid powder 4.05kg, yield 94.19%.HPLC purity is 99.95%, largest single impurity 0.03%, total miscellaneous 0.05%.
Its nuclear magnetic data, powder diffraction data and 1 data of embodiment keep almost the same.
Embodiment 8：The preparation of ubenimex γ crystal form
It disperses 6.30kg ubenimex in 95.0kg purified water, in 60 DEG C of stirring to pulp 3h, stirring rate 300r/
Min is cooled to 10 DEG C, stirring and crystallizing 2h；Negative pressure leaching, filter cake are placed in dry 12h in 80 DEG C of vacuum drying ovens, obtain white solid powder
Last 5.98kg, yield 94.92%.HPLC purity is 99.93%, largest single impurity 0.04%, total miscellaneous 0.07%.
Its nuclear magnetic data, powder diffraction data and 1 data of embodiment keep almost the same.
Comparative example:
The preparation of γ crystal form is the α for first preparing ubenimex, beta crystal in US4786754, then 148-200 DEG C it is dry into
Row turns brilliant and obtains γ crystal, and temperature is higher to cause related substance to obviously increase and (specifically see the table below), or is having by α, beta crystal
Stirring is converted to obtain in solvent, and solvent for use includes butanone, metacetone, ethyl acetate, dioxane, tetrahydro
Furans etc., the big (1g of these solvent usages：10ml), manufacturing cost is high, and toxicity is big, and environmental pollution is serious.
| Sample ID | Crystal form | Related substance |
| Before turning brilliant | Beta crystal | Largest single impurity：0.06%, it is total miscellaneous：0.19%, chromatographic purity：99.81% |
| 150 DEG C of dry 3h | γ crystal form | Largest single impurity：1.04%, it is total miscellaneous：1.87%, chromatographic purity：98.13% |
| 150 DEG C of dry 8h | γ crystal form | Largest single impurity：1.13%, it is total miscellaneous：2.04%, chromatographic purity：97.96% |
| 150 DEG C of dry 10h | γ crystal form | Largest single impurity：1.14%, it is total miscellaneous：2.03%, chromatographic purity：97.97% |
| Embodiment 1 | γ crystal form | Largest single impurity：0.02%, it is total miscellaneous：0.04%, chromatographic purity：99.96% |
| Embodiment 2 | γ crystal form | Largest single impurity：0.03%, it is total miscellaneous：0.06%, chromatographic purity：99.94% |
| Embodiment 3 | γ crystal form | Largest single impurity：0.03%, it is total miscellaneous：0.05%, chromatographic purity：99.95% |
Therefore, compared with the prior art for the preparation method of γ crystal form, the application's prepares that reaction condition is mild, operation
Simply, technique favorable reproducibility, environmentally friendly, products obtained therefrom purity is high, solvent for use is only water, is conducive to environmental protection, is recycled
It is convenient, reagent cost and energy consumption are reduced, toxicity need to be used big with existing preparation process or have the organic solvent phase of environmental pollution
Than more environmentally friendly.
For the ordinary skill in the art it is evident that without departing from the application spirit or scope the case where
Under, can to the application compound, composition with and preparation method thereof carry out a variety of modification and transformations, therefore, the guarantor of the application
Shield range cover to the application carry out various modification and transformations, as long as it is described modification or variation in claim and its etc.
In the range of covering with embodiment.
Claims (7)
1. a kind of preparation method of ubenimex γ crystal form, which is characterized in that include the following steps：
(1) by ubenimex in purified water stirring to pulp, wherein the usage ratio of ubenimex and purified water be 1g：(5ml~
30ml), stirring to pulp temperature is 40~70 DEG C, stirring to pulp time 2h~16h, stirring rate 200r/min~500r/min；
(2) reaction solution obtained by step (1) is cooled to 0~20 DEG C of stirring and crystallizing, crystallization time 0.5h~3h；
(3) step (2) acquired solution is filtered；
(4) filter cake obtained by step (3) is placed in dry 4h in 50~80 DEG C of vacuum drying ovens~for 24 hours；
Wherein, γ crystal has the angle of diffraction as described below：3.238±0.2,6.479±0.2,12.999±0.2,15.960
±0.2、17.441±0.2、18.560±0.2、19.560±0.2、20.181±0.2、23.602±0.2、26.122±
0.2。
2. preparation method according to claim 1, which is characterized in that the dosage of ubenimex and purified water in step (1)
Ratio is 1g：(10ml~15ml), stirring to pulp temperature are 50~60 DEG C, and the stirring to pulp time is preferably 2h~4h, and stirring turns
Speed is 300r/min~400r/min.
3. preparation method according to claim 1, which is characterized in that stirring and crystallizing temperature is 0~10 DEG C in step (2),
The crystallization time is 1~2h.
4. preparation method according to claim 1, which is characterized in that drying time is 8h~16h in step (4), described
Temperature condition is 70~80 DEG C.
5. preparation method according to claim 1, which is characterized in that include the following steps：
(1) it dispersing 19.40g ubenimex in 194ml purified water, stirring to pulp temperature is 45 DEG C, stirring to pulp time 3h,
Stirring rate 360r/min；
(2) reaction solution obtained by step (1) is cooled to 5 DEG C, stirring and crystallizing 1h；
(3) by reaction solution negative pressure leaching obtained by step (2)；
(4) filter cake obtained by step (3) is placed in dry 8h in 70 DEG C of vacuum drying ovens, obtains white solid powder 17.90g, yield
92.3%.
6. preparation method according to claim 1, which is characterized in that include the following steps：
It disperses 10.0g ubenimex in 150ml purified water, in 40 DEG C of stirring to pulp 16h, stirring rate 500r/min, ice
Bath is cooled to 10 DEG C, stirring and crystallizing 1h；Negative pressure leaching, filter cake are placed in dry 16h in 50 DEG C of vacuum drying ovens, obtain white solid powder
9.07g, yield 90.07%.HPLC purity is 99.94%, largest single impurity 0.03%, total miscellaneous 0.06%.
7. preparation method according to claim 1, which is characterized in that include the following steps：
It disperses 10.0g ubenimex in 50ml purified water, in 70 DEG C of stirring to pulp 2h, stirring rate 200r/min, ice bath
10 DEG C are cooled to, stirring and crystallizing 0.5h；Negative pressure leaching, filter cake are placed in drying in 60 DEG C of vacuum drying ovens and for 24 hours, obtain white solid powder
9.07g, yield 90.07%.HPLC purity is 99.94%, largest single impurity 0.03%, total miscellaneous 0.06%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4786754A (en) * | 1981-12-24 | 1988-11-22 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Hai | Crystalline upsilon-form bestatin and processes for its preparation |
| CN104447394A (en) * | 2014-12-17 | 2015-03-25 | 成都傲飞生物化学品有限责任公司 | Novel synthesis process of ubenimex |
| CN105968026A (en) * | 2016-08-01 | 2016-09-28 | 四川青木制药有限公司 | Preparation method of high-purity Ubenimex |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1280550C (en) * | 1981-12-24 | 1991-02-19 | Masaaki Ishizuka | Crystalline y-form bestatin and processes for its preparation |
| CN101891647B (en) * | 2010-03-15 | 2012-12-19 | 浙江普洛康裕制药有限公司 | Preparation method for ubenimex |
| CN103360277A (en) * | 2013-04-01 | 2013-10-23 | 上海信谊万象药业股份有限公司 | Method for recrystallizing ubenimex |
| CN103333089A (en) * | 2013-06-20 | 2013-10-02 | 深圳万乐药业有限公司 | Crystal form of N-[(2S, 3R)-4-phenyl-3-benzyl-3-formylaminobenzoxy-2-hydroxybutyryl]-L-benzyl leucine and preparation method thereof |
| CN106117075B (en) * | 2016-01-14 | 2020-06-12 | 上海信谊万象药业股份有限公司 | Novel ubenimex recrystallization method |
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2018
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- 2018-07-09 CN CN202110958700.1A patent/CN113563221A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4786754A (en) * | 1981-12-24 | 1988-11-22 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Hai | Crystalline upsilon-form bestatin and processes for its preparation |
| CN104447394A (en) * | 2014-12-17 | 2015-03-25 | 成都傲飞生物化学品有限责任公司 | Novel synthesis process of ubenimex |
| CN105968026A (en) * | 2016-08-01 | 2016-09-28 | 四川青木制药有限公司 | Preparation method of high-purity Ubenimex |
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