CN109721505A - A kind of impurity and preparation method thereof in ubenimex synthesis - Google Patents
A kind of impurity and preparation method thereof in ubenimex synthesis Download PDFInfo
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Abstract
The present invention provides the impurity in a kind of ubenimex bulk pharmaceutical chemicals, the structure of the impurity is confirmed, is conducive to the quality control of ubenimex to obtain the ubenimex bulk pharmaceutical chemicals of high quality.The present invention also provides the preparation method of the impurity, the product purity that this method is prepared is high, can use as the impurity reference substance of ubenimex bulk pharmaceutical chemicals quality research process.
Description
Technical field
The present invention relates to pharmaceutical synthesis method fields, and in particular to the one kind generated in a kind of synthesis of ubenimex bulk pharmaceutical chemicals
Impurity N- [(2S, 3R) -3- amino -2- hydroxy-4-phenyl butyryl]-l-Isoleucine and preparation method thereof.
Background technique
Ubenimex (Ubenimex；It Bestatin) is the one kind being isolated from the culture solution of the netted streptomycete of olive
Low molecule dipeptide compound, it, which has, inhibits tumor cell surface aminopeptidase B, N and leucine aminopeptidase effect, and induction is swollen
Apoptosis of tumor and promotion host cell immune function, enhance the dual function of antitumaous effect, list in 1987 in Japan.Crow
Clinically normal and other chemotherapy drugs in combination are applied to acute myelogenous leukaemia, the leukaemia of chronic Myelogenous, lung for benzene U.S. department
The treatment of squamous carcinoma, malignant mela noma, stomach tumor etc.；And chemotherapy combined radiotherapy is also used to each for the treatment of the tumor diseases such as nasopharyngeal carcinoma
Immunologic hypofunction person caused by kind of factor tries out controlling in Myelodysplastic syndromes and simple red blood cell regeneration disease
It treats.Various clinical effectiveness feed back the drug has significant curative effect in terms of enhancing human immunological competence, and ubenimex can be mentioned significantly
The survival rate of high cancer patient improves its quality of life.Entitled N- [(2S, the 3R) -4- phenyl -3- amino -2- of ubenimex chemistry
Maloyl group]-L-Leu, structural formula is as shown in formula I:
The method of synthesis ubenimex is biochemical bacterial fermentation processes earliest, is disclosed in by Umezawa H etc.
J.Antibiot.1976,29,97.As the whole world is continuously increased ubenimex demand, only by fermenting and producing ubenimex
It is not able to satisfy the demand of drug market, and is more advantageous to industrialized production, more and moreization using chemically synthesized method
Synthetic method is learned to be reported.But since structure is complicated for ubenimex, the peptide bond in structure is sensitive to soda acid, and unstable under high temperature
Fixed, reported some synthetic routes need to use expensive practical and hazardous chemical or product purity too low, therefore can apply
There was only one at present in the route of industrialized production, by antibiotic magazine (Journal of Antibiotics, 1983,36
(6): 695-699 it) delivers, reaction route are as follows:
Ubenimex contains there are three chiral centre, therefore may have 7 in the obtained ubenimex bulk pharmaceutical chemicals of synthesis
Furthermore optical isomer impurity can also generate a series of derivative impurity such as formula VI, VII compound in synthesis process.
Issuable so many optical isomer and derivative impurity, lead to ubenimex bulk pharmaceutical chemicals in synthesis process
Quality control there are difficulty, it is difficult to produce the ubenimex raw material of high quality.Moreover, inventor is preparing ubenimex original
Expect to find during medicine, in obtained product other than published impurity, there is also amounts seldom but to bulk pharmaceutical chemicals product quality
Influential impurity.It seldom is difficult to collect carry out structural identification due to measuring, be brought for the quality control of ubenimex bulk pharmaceutical chemicals
It is difficult.But in order to obtain the ubenimex bulk pharmaceutical chemicals of high quality and further prepare safely and effectively ubenimex preparation, having must
Structural identification is carried out to the impurity and synthesize quality of the higher impurity compound of purity for ubenimex bulk pharmaceutical chemicals
Control process.
Summary of the invention
The present invention provides the impurity in a kind of ubenimex bulk pharmaceutical chemicals, and the structure of the impurity is confirmed, are conducive to crow
The quality of benzene U.S. department is controlled to obtain the ubenimex bulk pharmaceutical chemicals of high quality.The present invention also provides the preparation method of the impurity,
The product purity that this method is prepared is high, can make as the impurity reference substance of ubenimex bulk pharmaceutical chemicals quality research process
With.
A kind of ubenimex impurity compound provided by the invention is it is characterized in that, have structural formula shown in formula II:
II compound of formula during preparing ubenimex bulk pharmaceutical chemicals yield it is few, inventor is by synthesizing
To ubenimex crude product recrystallizing and refining filtering obtain dirt solution be collected, the molecular weight that LC-MS is tested
Identical as ubenimex is 308.Convert after the test of multiple chromatographic conditions that the substance exists as the result is shown, and retention time is equal
It is different from ubenimex, it is confirmed as impurity.In order to carry out structural identification to the impurity compound, inventor carries out reaction process
Carried out multiple prediction after analysis, and synthesize prior art has disclosed all optical isomers as reference substance, by efficient
The analysis of liquid phase liquid phase test comparison, but prove that the compound is not the optical isomer of ubenimex.Due to ubenimex
Starting material is qualified through detection purity, without obvious impurity, so the structural confirmation of the impurity in sintetics encounters difficulty.
Inventor synthesizes the isomer of ubenimex, and use by speculating all possible isomer
Liquid chromatogram test is simultaneously compared with ubenimex bulk pharmaceutical chemicals chromatograms, finds that the impurity compound is closed by ubenimex finally
At the impurity l-Isoleucine benzyl ester tosilate contained in one of starting material L-Leu benzyl ester tosilate
(formula IV) and (2S, 3R) -4- phenyl -3- carbobenzoxy base -2- hydroxybutyric acid (Z-AHPA, III compound of formula) are condensed, further
Such as II compound represented of formula caused by hydrogenated reduction, and the compound is never by any document report mistake.Prepare the change
The reaction equation for closing object is as follows:
Comprising the following steps:
Step 1): (2S, 3R) -4- phenyl -3- carbobenzoxy base -2- hydroxybutyric acid and l-Isoleucine benzyl ester are to toluene sulphur
Hydrochlorate reaction under condensing agent effect obtains condensation product；
Step 2): gained condensation product is reacted through palladium charcoal catalytic hydrogen reduction at room temperature, obtains II crude compound of formula；
Step 3): being dissolved in hydrochloric acid solution for crude product, is 4-6, crystallization, filtration drying with adjusting PH with base value.
Wherein, the step 1) condensing agent is that (N, N-- diisopropyl carbon two is sub- by HOBt (I-hydroxybenzotriazole)/DIC
Amine), HOBt/DCC (1,3- dicyclohexylcarbodiimide)/triethylamine, PyBOP (Phosphonium hexafluorophosphate)/HOBt/DIPEA (N,
N- diisopropylethylamine), TBTU (O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester)/HOBt/DIPEA,
HBTU (2- (1H- benzotriazole)-N, N, N ', N '-tetramethylurea hexafluorophosphate)/HOBt/DIPEA, preferably HOBt/DIC.Contracting
Close preferably 10~15 DEG C of reaction temperature.
Step 2) the hydrogen reducing reaction pressure is 0.8-1.2MPa.
Crude product is dissolved in hydrochloric acid solution by step 3), may be selected to increase active carbon decolorization process according to the color of solution；Use alkali
If ammonium hydroxide tune pH value is 5-5.5, using the crystallization mode of 0-5 DEG C of stirring and crystallizing, filtration drying after filter cake water and acetone washing.
II compound of formula provided by the invention, by finding in ubenimex bulk pharmaceutical chemicals synthesis process, being speculated and synthesized can
The substance of energy, and compareed by liquid phase and Mass Spectrometer Method with ubenimex bulk pharmaceutical chemicals, it is determined that the compound is by synthesizing black benzene
Impurity l-Isoleucine benzyl ester in one of the starting material of U.S. department L-Leu benzyl ester tosilate is raw in ubenimex
Generation is further reacted during producing, those skilled in the art can be by controlling impurity l-Isoleucine benzyl in the starting material
The content of ester tosilate controls the quality of ubenimex bulk pharmaceutical chemicals.The present invention prepares purity by three steps
95% or more II compound of formula can be used as defects inspecting and content control of the reference substance applied to ubenimex bulk pharmaceutical chemicals.
The present invention will be further described for embodiment With reference to embodiment and Figure of description.
Figure of description
1 ubenimex liquid chromatogram of attached drawing (impurity peaks and ubenimex peak partial enlarged view)
The mass spectrogram that the LC-MS of the isolated target impurity of attached drawing 2 is tested
3 formula of attached drawing, II compound liquid chromatogram
Specific embodiment
The synthesis of 1 ubenimex of embodiment, the collection of II compound of formula
The preparation of i ubenimex crude product
Tetrahydrofuran 1000mL is added in three-necked flask, opens stirring, sequentially adds Z-AHPA 100g, L-Leu
Benzyl ester tosilate 131.5g and I-hydroxybenzotriazole (HOBt) 48.5g, is then cooled to 0 ± 2 DEG C.Three second are added
Amine 33.6g and dicyclohexylcarbodiimide (DCC) 74.5g, adds 12 ± 2 DEG C of rear temperature control, is stirred to react 20~24 hours, reaction
Reaction solution is filtered after completely.It concentrates filtrate to no fraction to steam, obtains grease, add ethyl acetate and stir to oil
Shape object is completely dissolved.Respectively with 0.5mol/L hydrochloric acid 650mL, purified water 650mL, saturated sodium bicarbonate solution 650mL, saturation chlorine
Change sodium solution 650mL and washs above-mentioned ethyl acetate solution.Organic layer is added anhydrous magnesium sulfate and dries, filters, 50 DEG C of filtrate decompressions
No fraction is concentrated into steam；Ethyl acetate 270mL is added, is heated to 70 ± 2 DEG C, stirring after being cooled to 5 ± 2 DEG C, is stirred to dissolving
Mix 2 hours crystallizations.Filtering, filter cake are washed 2 times with ethyl acetate/petroleum ether (1:2), each 100mL.Filtering finishes, and takes out filter
Cake, it is dry, obtain condensation product product 140g.
Glacial acetic acid 130mL is added in 2000mL hydrogenation reaction cauldron, ubenimex condensation product 140g and 10% palladium charcoal is added
Air 3 times in 16g nitrogen displacement kettle, then with hydrogen replace 3 times.Logical hydrogen is opened stirring, is mended to reacting kettle inner pressure 1MPa
Hydrogen to almost no longer inhale hydrogen (pressure is unchanged in half an hour in kettle).Reaction solution is released in emptying；Reaction kettle glacial acetic acid 100mL
It washed once, reaction solution is filtered, filter cake is washed with acetic acid, 60 DEG C of filtrate reduced pressures；When no fraction steams, acetone is added
530mL is stirred 2~3 hours at room temperature.Filtering, filter cake acetone washing is dry, obtains ubenimex crude product 85g, yield
60.7%.
The purification of ii ubenimex
900mL1mol/L hydrochloric acid solution is added to the container, is heated to 55 DEG C, the total 85g of ubenimex crude product, stirring is added
To dissolution.Active carbon 3.35g, stirring decoloration 15 minutes, filtering is added.Filtrate ammonium hydroxide tune pH value of solution=5.5, are cooled to 0-5
DEG C, stirring and crystallizing 2 hours, filtering, filter cake 250mL purified water washing three times, filter cake is transferred in three-necked flask, was added third
Ketone 900mL is stirred 4 hours at room temperature.Filtering, filter cake are dried to obtain ubenimex with acetone washing 2 times, each 80mL
72.2g.The liquid chromatogram of ubenimex is shown in attached drawing 1.
The collection of II compound of iii formula
The mother liquor filtered three times after crystallization is collected, is concentrated to dryness 200 milliliters or so, pH value of solution=5.5 is adjusted, there is crystalline substance
Body is precipitated.It is cooled to 0-5 DEG C, is continued stirring and crystallizing 2 hours, filtering, filter cake purifying water washing depressurizes the mother liquor after merging
60 milliliters or so are concentrated into, pH value of solution=5.5, stirring and crystallizing are adjusted.It is cooled to 0-5 DEG C, is continued stirring and crystallizing 2 hours, filtering is female
Liquid is concentrated to dryness, washing, is dried to obtain 3 grams of solid, target impurity compound purity 35%, preparation chromatographic isolation obtains mesh
0.05 gram of impurity product of mark, LC-MS chromatography measure product purity 98.2%, and mass spectrum ESI (+) is 309.14 (M+1).Liquid matter
The mass spectrogram of combination test is shown in attached drawing 2.
The synthesis of 2 formula of embodiment, II compound
The preparation of V compound of i intermediate formula
Tetrahydrofuran 226mL is added in three-necked flask, sequentially adds Z-AHPA20g, l-Isoleucine benzyl ester in stirring
Then tosilate 26.3g and I-hydroxybenzotriazole (HOBt) 9.7g is cooled to 0 ± 2 DEG C, triethylamine 6.72g is added
With dicyclohexylcarbodiimide (DCC) 14.9g, add 12 ± 2 DEG C of rear temperature control, be stirred to react 20~24 hours, HPLC monitor to
Reaction solution is filtered in fully reacting, and filter cake is washed with tetrahydrofuran 25mL.Nothing is concentrated under reduced pressure into after filtrate, washing lotion are merged to evaporate
Divide and steam, obtain grease, ethyl acetate 260mL is added and dissolves grease, successively uses 0.5mol/L hydrochloric acid 133.3mL, purified water
133.3mL, saturated sodium bicarbonate solution 133.3mL, saturated sodium chloride solution 133.3mL wash above-mentioned ethyl acetate solution.Have
Machine layer is added after anhydrous magnesium sulfate dries, filters and is concentrated under reduced pressure into no fraction and steams for 50 DEG C.Ethyl acetate 54mL is added in concentrate,
70 ± 2 DEG C are heated to, stirring is cooled to 5 ± 2 DEG C, stirring and crystallizing 1~2 hour to dissolving.Filtering, filter cake ethyl acetate/stone
Oily ether (1/2) washing, is filtered, dry, obtains V compound 26g of formula.
The preparation of II crude compound of ii formula
Glacial acetic acid 250mL is added in 500mL hydrogenation reaction cauldron, condensation product (formula V) 26g and 10% palladium charcoal 5.3g is added
It is replaced 3 times with air 3 times in nitrogen displacement kettle, then with hydrogen.Logical hydrogen opens stirring, mends hydrogen to reacting kettle inner pressure 1MPa
To almost no longer suction hydrogen (pressure is unchanged in half an hour in kettle).Reaction solution is released, reaction solution is filtered, filter cake is washed with acetic acid
It washs, 60 DEG C of filtrate reduced pressures；When no fraction steams, acetone 107mL is added and stirs 2~3 hours crystallizations at room temperature.Filtering,
Filter cake acetone washing, it is dry, obtain II crude compound 13g of formula, yield 50%.
Iii purification
180mL1mol/L hydrochloric acid solution is added in three-necked flask, is heated to 55 DEG C；Add II crude compound of formula
13g maintains the temperature at 55 DEG C, is completely dissolved product.Active carbon 666.7g is added, stirring decoloration 15 minutes at 55 DEG C.It crosses
Filter, filter cake is washed with 1mol/L hydrochloric acid solution, with ammonium hydroxide tune pH value of solution=5.5, stirring and crystallizing.Feed liquid is cooled to 3 ± 2 DEG C,
Continue stirring 2 hours or more, filtering, filter cake 50mL purifies water washing three times, filter cake is transferred in three-necked flask, is added third
Ketone 150mL is stirred 4 hours at room temperature.Filtering, filter cake acetone washing are dried to obtain product 11g, yield 84.6%, purity
99.0%.
The synthesis of 3 formula of embodiment, II compound
The preparation of V compound of i intermediate formula
Tetrahydrofuran 226mL is added in three-necked flask, sequentially adds Z-AHPA20g, l-Isoleucine benzyl ester in stirring
Then tosilate 26.3g and I-hydroxybenzotriazole (HOBt) 9.7g, PyBOP37.3g is cooled to 0 ± 2 DEG C, be added
DIPEA8.58g adds 12 ± 2 DEG C of rear temperature control, is stirred to react 20~24 hours, and HPLC is monitored to fully reacting, by reaction solution mistake
Filter, filter cake are washed with tetrahydrofuran 25mL.No fraction is concentrated under reduced pressure into after filtrate, washing lotion are merged to steam, obtains grease, is added
Ethyl acetate 260mL dissolves grease, successively uses 0.5mol/L hydrochloric acid 133.3mL, purified water 133.3mL, saturated sodium bicarbonate
Solution 133.3mL, saturated sodium chloride solution 133.3mL wash above-mentioned ethyl acetate solution.It is dry that anhydrous magnesium sulfate is added in organic layer
It is dry, it is concentrated under reduced pressure into no fraction after filtering and steams for 50 DEG C.Ethyl acetate 54mL is added in concentrate, is heated to 70 ± 2 DEG C, stirring is extremely
Dissolution, is cooled to 5 ± 2 DEG C, stirring and crystallizing 1~2 hour.Filtering, filter cake are washed with ethyl acetate/petroleum ether (1/2), are filtered,
It is dry, obtain V compound 28g of formula.
The preparation of II crude compound of ii formula
Glacial acetic acid 250mL is added in 500mL hydrogenation reaction cauldron, condensation product (V compound of formula) 28g and 10% palladium is added
Air 3 times in charcoal 5.3g nitrogen displacement kettle, then with hydrogen replace 3 times.For logical hydrogen to reacting kettle inner pressure 1MPa, stirring is anti-
It answers, mends hydrogen to almost no longer suction hydrogen (pressure is unchanged in half an hour in kettle).Reaction solution is released, reaction solution is filtered, filter cake is used
Acetic acid washing, 60 DEG C of filtrate reduced pressures；When no fraction steams, acetone 107mL is added and stirs 2~3 hours crystallizations at room temperature.
Filtering, filter cake acetone washing is dry, obtains II crude compound 14g of formula, yield 50%.
Iii purification
180mL1mol/L hydrochloric acid solution is added in three-necked flask, is heated to 55 DEG C, II crude compound 14g of formula is added,
55 DEG C are maintained the temperature at, product is completely dissolved.Active carbon 0.67g is added, stirring decoloration 15 minutes at 55 DEG C.Filtering, filter
Cake is washed with 1mol/L hydrochloric acid solution, with ammonium hydroxide tune pH value of solution=5.5, stirring and crystallizing.Feed liquid is cooled to 3 ± 2 DEG C, continues to stir
It mixes 2 hours or more, filters, filter cake 50mL purifies water washing three times, filter cake is transferred in three-necked flask, and acetone is added
150mL is stirred 4 hours at room temperature.Filtering, filter cake acetone washing are dried to obtain product 12.1g, yield 86.4%, purity
96.8%.
The synthesis of 4 formula of embodiment, II compound
The preparation of V compound of i intermediate formula
Tetrahydrofuran 226mL is added in three-necked flask, sequentially adds Z-AHPA20g, l-Isoleucine benzyl ester in stirring
Then tosilate 26.3g and I-hydroxybenzotriazole (HOBt) 9.7g is cooled to 0 ± 2 DEG C, diisopropyl carbon is added
Diimine (DIC) 9.1g adds 12 ± 2 DEG C of rear temperature control and is stirred to react 20~24 hours, and HPLC is monitored to fully reacting, will be reacted
Liquid filtering, filter cake are washed with tetrahydrofuran 25mL.No fraction is concentrated under reduced pressure into after filtrate, washing lotion are merged to steam, and obtains grease,
Ethyl acetate 260mL is added and dissolves grease, successively uses 0.5mol/L hydrochloric acid 133.3mL, purified water 133.3mL, unsaturated carbonate
Hydrogen sodium solution 133.3mL, saturated sodium chloride solution 133.3mL wash above-mentioned ethyl acetate solution.Anhydrous slufuric acid is added in organic layer
It is concentrated under reduced pressure into no fraction after magnesium dries, filters and steams for 50 DEG C.Ethyl acetate 54mL is added in concentrate, is heated to 70 ± 2 DEG C, stirs
It mixes to dissolution, is cooled to 5 ± 2 DEG C, stirring and crystallizing 1~2 hour.Filtering, filter cake are washed with ethyl acetate/petroleum ether (1/2),
Filtering, filtration cakes torrefaction obtain V compound 31.5g of formula.
The preparation of II crude compound of ii formula
Glacial acetic acid 300mL is added in 500mL hydrogenation reaction cauldron, condensation product (V compound of formula) 31.5g and 10% is added
Palladium charcoal 6.3g is replaced 3 times with air 3 times in nitrogen displacement kettle, then with hydrogen.Logical hydrogen is opened to reacting kettle inner pressure 1MPa
Stirring mends hydrogen to almost no longer suction hydrogen (pressure is unchanged in half an hour in kettle).Reaction solution is released, reaction solution is filtered, filter cake
It is washed with acetic acid, 60 DEG C of filtrate reduced pressures；When no fraction steams, acetone 126mL is added and stirs analysis in 2~3 hours at room temperature
It is brilliant.Filtering, filter cake acetone washing is dry, obtains II crude compound 16.7g of formula, yield 53%.
Iii purification
200mL1mol/L hydrochloric acid solution is added in three-necked flask, is heated to 55 DEG C；It is total to add II crude compound of formula
16.7g maintains the temperature at 55 DEG C, is completely dissolved product.Active carbon 0.67g is added, stirring decoloration 15 minutes at 55 DEG C.It crosses
Filter, filter cake is washed with 1mol/L hydrochloric acid solution, with ammonium hydroxide tune pH value of solution=5.5, stirring and crystallizing.Feed liquid is cooled to 3 ± 2 DEG C,
Continue stirring 2 hours or more, filtering, filter cake 50mL purifies water washing three times, filter cake is transferred in three-necked flask, is added third
Ketone 180mL is stirred 4 hours at room temperature.Filtering, filter cake acetone washing are dried to obtain product 14.8g, yield 88.6%, purity
99.63%.Liquid chromatogram is shown in attached drawing 3.
Hydrogen nuclear magnetic resonance modal data (CDCl3) and ownership:
| Chemical shift | Peak type | Proton number | H ownership |
| 0.820~0.840 | s | 3 | H-15 or H-16 |
| 0.840~0.853 | s | 3 | H-15 or H-16 |
| 1.152~1.208 | m | 1 | 1/2H-14 |
| 1.443~1.466 | m | 1 | 1/2H-14 |
| 1.842 | brs | 1 | H-13 |
| 2.708~2.748 | dd | 1 | 1/2H-7 |
| 2.906~2.946 | dd | 1 | 1/2H-7 |
| 3.402 | br | 1 | H-8 |
| 3.955 | brs | 1 | H-9 |
| 4.055 | br | 1 | H-12 |
| 7.201~7.313 | m | 5 | H-2、H-3、H-4、H-5、H-6 |
| 7.853 | br | 1 | H-11 |
Claims (8)
1. a kind of ubenimex bulk pharmaceutical chemicals impurity compound, it is characterised in that have following structure formula:
2. the preparation method of compound described in claim 1, which is characterized in that reaction equation are as follows:
Comprising the following steps:
Step 1): (2S, 3R) -4- phenyl -3- carbobenzoxy base -2- hydroxybutyric acid and l-Isoleucine benzyl ester tosilate
Reaction obtains condensation product under condensing agent effect；
Step 2): gained condensation product is reacted through palladium charcoal catalytic hydrogen reduction at room temperature, obtains II crude compound of formula；
Step 3): being dissolved in hydrochloric acid solution for crude product, is 4-6, crystallization, filtration drying with adjusting PH with base value.
3. preparation method according to claim 2, which is characterized in that the step 1) condensing agent be selected from HOBt/DIC,
HOBt/DCC/ triethylamine, PyBOP/HOBt/DIPEA, TBTU/HOBt/DIPEA, HBTU/HOBt/DIPEA.
4. preparation method according to claim 2, which is characterized in that the step 1) condensing agent is HOBt/DIC.
5. preparation method according to claim 2, which is characterized in that reaction temperature is 10~15 DEG C when step 1) is condensed.
6. preparation method according to claim 2, which is characterized in that Hydrogen Vapor Pressure when step 2) hydro-reduction is
0.8-1.2MPa。
7. preparation method according to claim 2, which is characterized in that the step 3) alkali is ammonium hydroxide.
8. preparation method according to claim 2, which is characterized in that step 3) the tune pH is 5-5.5.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112125951A (en) * | 2020-10-22 | 2020-12-25 | 深圳万乐药业有限公司 | Impurities in ubenimex bulk drug and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4189604A (en) * | 1975-07-22 | 1980-02-19 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Bestatin |
| CN101891647A (en) * | 2010-03-15 | 2010-11-24 | 浙江普洛康裕制药有限公司 | Preparation method for ubenimex |
| CN107141232A (en) * | 2017-07-07 | 2017-09-08 | 国药集团川抗制药有限公司 | A kind of preparation method of ubenimex |
-
2018
- 2018-12-26 CN CN201811598546.6A patent/CN109721505A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4189604A (en) * | 1975-07-22 | 1980-02-19 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Bestatin |
| CN101891647A (en) * | 2010-03-15 | 2010-11-24 | 浙江普洛康裕制药有限公司 | Preparation method for ubenimex |
| CN107141232A (en) * | 2017-07-07 | 2017-09-08 | 国药集团川抗制药有限公司 | A kind of preparation method of ubenimex |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112125951A (en) * | 2020-10-22 | 2020-12-25 | 深圳万乐药业有限公司 | Impurities in ubenimex bulk drug and preparation method thereof |
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