CN107141232A - A kind of preparation method of ubenimex - Google Patents
A kind of preparation method of ubenimex Download PDFInfo
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- CN107141232A CN107141232A CN201710552900.0A CN201710552900A CN107141232A CN 107141232 A CN107141232 A CN 107141232A CN 201710552900 A CN201710552900 A CN 201710552900A CN 107141232 A CN107141232 A CN 107141232A
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- ubenimex
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- ethyl acetate
- carbobenzoxy
- amido
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
Abstract
The invention provides a kind of preparation method of ubenimex, comprise the following steps：L leucine benzyl esters tosilate, HOBt are condensed to yield activated ester solution；By (2S, 3R) phenylbutyric acid of 3 carbobenzoxy amido, 2 hydroxyl 4, the mixing of weak acid highly basic inorganic salts, activated ester solution reaction is added dropwise and obtains N [the phenyl butyryl of 2 hydroxyl of (2S, 3R) 3 carbobenzoxy amido 4] L leucines；N [the phenyl butyryl of 2 hydroxyl of (2S, 3R) 3 carbobenzoxy amido 4] L leucines obtain ubenimex in hydrogen reducing.In the preparation method of the ubenimex of the present invention, organic solvent is only with ethyl acetate, cost has been saved while avoiding the potential safety hazard brought using tetrahydrofuran, base catalyst is used as using weak acid highly basic inorganic salts, while cost-effective, avoid using organic solvent during whole preparation method, operating process is easy.
Description
Technical field
The present invention relates to pharmaceutical field, in particular to a kind of preparation method of ubenimex.
Background technology
Ubenimex (I Ubenimex；NN), also referred to as bestatin, chemical formula is N- [(2S, 3R) -3- amino -2-
Hydroxy-4-phenyl bytyry]-L-Leu is a kind of emulative, reversible protease inhibitors.It is to arginyl amino
Peptase (aminopeptidase B), the leukotriene A 4 hydrolase (zinc metalloprotein of display epoxide hydrolase and aminopeptidase activities
Enzyme), alanylamino peptase (Aminopeptidase M/N), leucyl/cystyl aminopeptidase (oxytocins/vasopressing enzyme) is (white
Triolefin D4 hydrolases) there is inhibitory action.Study for treating acute myelogenous leukemia.It is derived from olive streptomycete
(Streptomyces olivoreticuli).It has been found that Ubenimex suppresses oxytocins, pitressin, enkephalins and various other
The enzymatic degradation of peptide and compound.
Ubenimex improving immunocompetence, for anticancer chemotherapy, the auxiliary treatment of radiotherapy, senile immunodeficiency
Deng.Chemotherapy, radiotherapy can be coordinated and leukaemia, Huppert's disease, RAEB and Hematopoietic Stem is united and applied in
After cell transplantation, and other patients with solid tumor.
In the prior art, ubenimex uses tetrahydrofuran mostly in building-up process, triethylamine is as solvent or urges
Agent etc., these reagents in itself not environmentally, bear than larger, can produce substantial amounts of waste water and gas, and triethylamine by subsequent treatment
This organic base is easily remained in the product, the problem of causing organic solvent residual.
In view of this, it is special to propose the present invention.
The content of the invention
The first object of the present invention is to provide have been abandoned in the past in a kind of preparation method of ubenimex, the preparation method
The organic solvents such as organic base, tetrahydrofuran, dichloromethane, N, the N-dimethylformamide of use are used as reaction dissolvent, ethyl acetate
It is used as extractant.Directly cost has been saved while avoiding and has used tetrahydrochysene as reaction and extractant using ethyl acetate
The safety and environmental protection hidden danger that furans, dichloromethane, N, N-dimethylformamide are brought, is urged using weak acid highly basic inorganic salts as alkali
Agent, reduces cost, while during avoiding influence of the triethylamine residual solvent to final product quality, whole preparation method fully
Accomplish to avoid using organic solvent, easy to operate, environmental protection, while ubenimex product quality is improved, yield
It is high.
In order to realize the above-mentioned purpose of the present invention, spy uses following technical scheme：
The invention provides a kind of preparation method of ubenimex, comprise the following steps：
(A) under DCC (dicyclohexylcarbodiimide) catalytic condition, solvent is ethyl acetate, by L-Leu benzyl ester to first
Benzene sulfonate, HOBt (1- hydroxy benzo triazoles) are condensed to yield activated ester solution；
(B) (2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyric acid, weak acid highly basic inorganic salts are mixed
During, the activated ester solution is added dropwise and react obtaining N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls
Butyryl]-L-Leu；
(C) N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl]-L-Leus are catalyzed in Pd/C
Under, hydrogen reducing obtains ubenimex.
In the prior art, due to ubenimex improving immunocompetence, for anticancer chemotherapy, the auxiliary treatment of radiotherapy, always
Year property immunodeficiency etc..Chemotherapy, radiotherapy can be coordinated and to be united and applied in leukaemia, Huppert's disease, myelosis different
After normal syndrome and HSCT, and other patients with solid tumor, therefore in view of it is widely applied, to its specific system
The research of standby technique seems there is very much practical significance.
But, traditional ubenimex uses tetrahydrofuran, dichloromethane, N, N dimethyl first mostly in building-up process
Acid amides, triethylamine are as solvent or catalyst etc., and these reagents in itself not environmentally, bear than larger, can produce by subsequent treatment
Substantial amounts of waste water and gas, and the easy residual of this organic base of triethylamine is in the product, the problem of producing organic solvent residual.
In order to solve the above technical problems, The present invention provides a kind of preparation method of ubenimex, in the preparation method,
Traditional this organic base of triethylamine is replaced using inorganic weak acid strong alkali salt, inorganic salts are preferably selected sodium acid carbonate or bicarbonate
Potassium, is more preferably selected as sodium acid carbonate, alkalescent is presented so as to promote being smoothed out for reaction due to being dissolved in during water, but need note
Meaning, the salt that should not necessarily select alkalescence too strong here, because if alkaline too strong, L-Leu benzyl ester tosilate
Benzyl ester can come off, so as to have influence on being smoothed out for reaction, therefore alkalescence is selected than convenient salt when being selected.
In addition, the present invention selected in solvent selection for ethyl acetate, improving tradition needs while using tetrahydrochysene furan
Mutter, one kind is that reaction dissolvent, ethyl acetate are extractant in dichloromethane, N, N-dimethylformamide.Avoid two kinds of solvents same
When use.Avoid what is brought using tetrahydrofuran, dichloromethane, N, N-dimethylformamide etc. while having saved cost
Potential safety hazard.Why traditional handicraft needs to use tetrahydrofuran, dichloromethane, N, N-dimethylformamide, is because tetrahydrochysene furan
Mutter, itself dissolubility of dichloromethane, N, N-dimethylformamide it is good, raw material (2S, 3R) -3- carbobenzoxy amido -2- hydroxyls -4-
Phenylbutyric acid, also HOBt (1- hydroxy benzo triazoles) can react it is critical that it has good solubility
It is fully dispersed to promote being normally carried out for reaction in medium, but present invention utilizes DCC catalysis to be initially formed activated ester solution,
Make and use ethyl acetate for solvent after Acibenzolar, its dissolubility can meet technological requirement, it is not necessary to use tetrahydrochysene furan
Mutter, dichloromethane, N, N-dimethylformamide ensure being smoothed out for reaction, and by using weak acid highly basic inorganic salts
A part solves deliquescent problem, improves dissolubility, it is seen that the weak acid highly basic inorganic salts that the present invention is used are not only acted as
Catalytic action, also serves the effect as dissolving medium indirectly.
The overall reaction equation of the preparation technology of ubenimex of the present invention is：
In step (A), it is preferable that first add L-Leu benzyl ester tosilate, HOBt, ethyl acetate, and by temperature
Then degree control add the ethyl acetate solution containing DCC, temperature be increased between 15-20 DEG C between 0-5 DEG C, reacts
4-5h, raises temperature to ensure being normally carried out for reaction typically when subsequently really reacting, early stage temperature is in 0-5
It is to prevent the generation of the too high side reaction of temperature between DEG C.
Preferably, the ethyl acetate solution containing DCC is carried out in the way of dropwise addition, can be with by way of being gradually added dropwise
Ensure the progress of reacting balance, to control extent of reaction, it is to avoid vigorous reaction.
In step (B), sodium acid carbonate is best formulated as to 10-20wt% sodium bicarbonate solution, because sodium acid carbonate is logical
Cross and be configured to solution, the dispersiveness of reaction raw materials can be improved, improve the catalytic performance of reaction.
In addition, after addition sodium bicarbonate solution, temperature general control is between 10-15 DEG C, and the side by quickly stirring
Formula is to accelerate dissolving each other between each raw material.
Preferably, it is added dropwise after activated ester solution, 4-5h is reacted between 15-20 DEG C, purpose product is obtained, but need for
The step of later separation, to purify purpose product, typically tracks reaction end (ethyl acetate using TLC：Petroleum ether=2:1、
Ultraviolet 254nm).
Preferably, it is after reaction that product N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl]-L- is bright
The a series of separating step of propylhomoserin progress obtains product after purification, and specific steps are preferably carried out according to following operation：Filtering point
After organic phase, washing, dry and concentration operation obtain concentrate after drying, petroleum ether and stirring 2- are added into concentrate
3h, filtering is dried to concentrate, and purpose product also for being preferably dispersed in inside organic phase by the addition of petroleum ether.
Preferably, petroleum ether and stirring 2-3h is added into concentrate, after filtering, is dried under conditions of 40-45 DEG C, through overdrying
Product after being isolated and purified after dry, more than 94% can be reached by the yield for determining the step.
In step (C), solvent use for glacial acetic acid, reaction pressure control between 1.5-2MPa, reaction temperature control
Between 20-30 DEG C.The step passes through N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl]-L- is bright
CBZ protection group is taken off under conditions of propylhomoserin catalysis reduction, Pd/C, hydrogen, final purpose product ubenimex is obtained, still
The ubenimex now obtained is crude product, and the method sunk subsequently through sour molten alkali crystallizes to obtain finished product.Therefore preferably will reaction
Obtained ubenimex crude product is filtered, separates to be further purified.
Finally, follow-up post-processing step is preferably carried out in accordance with the following steps：By ubenimex crude product in 70-80 DEG C, pressure
After being concentrated between power -0.05~-0.1MPa, after addition acetone stirring, filtering is added after ammoniacal liquor crystallization, filtering.
Preferably, after addition ammoniacal liquor, the pH value of solution is adjusted between 5-6,0-5 DEG C of crystallization 4-5h.
Also preferably, filtering adds acetone stirring 2-3h after crystallization, be dried to obtain between 40-50 DEG C ubenimex into
Product.
The one kettle way of prior art is in synthesis N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl]-L-
Ethyl acetate conduct is used only in the two kinds of solvents of tetrahydrofuran, ethyl acetate used during leucine, technique of the invention
Solvent, avoids the potential safety hazard brought using tetrahydrofuran while having saved cost.Further, one kettle way is in synthesis N-
It is alkali that triethylamine is used during [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl]-L-Leu
Catalyst, the present invention uses sodium acid carbonate for base catalyst, while cost-effective, it is to avoid triethylamine residual solvent is into quality
The influence of amount.In addition, one kettle way is in synthesis N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl] bright ammonia of-L-
Need to carry out concentration tetrahydrofuran in the process of acid, and the technological reaction of the present invention terminates direct extraction processing, it is more easy to operate, and
Tetrahydrofuran need not individually be handled, it is time saving and energy saving, it is also more environmentally friendly.Finally, one pot process N- [(2S, 3R)-
3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl] the technique height of-L- leucines yield without the present invention.
Compared with prior art, beneficial effects of the present invention are：
(1) preparation method of ubenimex of the invention, has abandoned organic base, the tetrahydrofuran of conventional use etc. organic molten
The addition of agent, organic solvent has saved cost while avoiding the peace brought using tetrahydrofuran only with ethyl acetate
Full hidden danger, using weak acid highly basic inorganic salts as base catalyst, while cost-effective, it is to avoid triethylamine residual solvent is to finished product
Avoid using organic solvent during the influence of quality, whole preparation method, operating process is easy, and easily operation, is being improved
While ubenimex product, high income；
(2) it is of the invention to make use of DCC to be initially formed activated ester solution after being catalyzed, make and ethyl acetate is utilized after Acibenzolar
For solvent, dissolubility can meet technological requirement, it is not necessary to can meet dissolubility using tetrahydrofuran, and by adopting
Deliquescent problem is solved with a weak acid highly basic inorganic salts also part, dissolubility is improved, it is seen that the weak acid that the present invention is used
Highly basic inorganic salts have not only acted as catalytic action, the effect of dissolving are also served indirectly, it is seen that also have from technical flow design
There is certain novelty, be initially formed the dissolubility requirement that Acibenzolar reduces reaction system.
Brief description of the drawings
, below will be right in order to illustrate more clearly of invention embodiment of the present invention or technical scheme of the prior art
The accompanying drawing used required in embodiment or description of the prior art is briefly described, it should be apparent that, describe below
In accompanying drawing be some embodiments for inventing of the present invention, for those of ordinary skill in the art, do not paying creativeness
On the premise of work, other accompanying drawings can also be obtained according to these accompanying drawings.
Fig. 1-2 be the embodiment of the present invention 1 in ubenimex product confirmation collection of illustrative plates.
Embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the present invention.It is unreceipted specific in embodiment
Condition person, the condition advised according to normal condition or manufacturer is carried out.Agents useful for same or the unreceipted production firm person of instrument, be
The conventional products that can be obtained by commercially available purchase.
Embodiment 1
The preparation method of ubenimex is as follows：
1) L-Leu benzyl ester tosilate, HOBt, 10 times of (V/m) ethyl acetate are added sequentially to reactor
In, the completion that feeds intake is stirred continuously cooling, is slowly added between DCC ethyl acetate solution, 0-5 DEG C of adition process system temperature.
System reacts 4h, TLC tracking reaction end (ethyl acetate between 15-20 DEG C after the completion of feeding intake：Petroleum ether=2:1st, it is ultraviolet
254nm), the activated ester solution of L-Leu benzyl ester tosilate is obtained；
2) by (2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyric acid, 10 times of (V/m) 10% sodium acid carbonate
Solution is added sequentially in reactor, is stirred to being completely dissolved, is cooled to 10-15 DEG C, and quick stirring is lower to be added dropwise L-Leu benzyl
The activated ester solution of ester tosilate, reacts 4h or so, TLC tracking reaction ends between 15-20 DEG C after being added dropwise to complete
(ethyl acetate：Petroleum ether=2:1st, ultraviolet 254nm)；
3) filtering point liquid, aqueous phase is extracted with 7 times, 2 times of (V/m) ethyl acetate successively, combined ethyl acetate phase, ethyl acetate
Mutually it washed once successively with 6 times of 0.5wt% hydrochloric acid, 6 times of 5wt% saturated sodium bicarbonate washed once, 6 times of purifying water washings
Once；Ethyl acetate solution is filtered, is concentrated to dryness through anhydrous sodium sulfate drying 2h, and 5 times of (V/m) oil are added into concentrate
Ether, stirring 2h disperses, filtering, dry N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyl fourths at 40-45 DEG C
Acyl]-L-Leu, yield 94-98%；
4) at room temperature by N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl]-L-Leu, Pd/
C (30%) is dissolved in the glacial acetic acid of 15 times (v/m), is added to after being uniformly mixed in reactor, and nitrogen hydrogen is put successively
Change three times, stirring reaction is extremely to hydrogen is not inhaled under 1.5-2MPa；
5) filtrate after filtering is concentrated to dryness under 80 DEG C, -0.1MPa, and 10 times of (v/m) acetone are added in concentrate, are stirred
Mix scattered 4h, filtering, at 40-45 DEG C forced air drying obtain ubenimex acetate；
6) ubenimex acetate is dissolved in hydrochloric acid solution, solution is cooled between 0-5 DEG C, with 15wt% ammonia
Water adjusts solution ph to 5-6.Crystallization 5h at 0-5 DEG C, filtering, solid is beaten 3h with acetone, filters, and crow is dried to obtain at 40 DEG C
Department of benzene U.S. finished product, yield is 90.5%, specific to confirm that collection of illustrative plates is shown in accompanying drawing 1-2.
Embodiment 2
The preparation method of ubenimex is as follows：
1) L-Leu benzyl ester tosilate, HOBt, 10 times of (V/m) ethyl acetate are added sequentially to reactor
In, the completion that feeds intake is stirred continuously cooling, is slowly added between DCC ethyl acetate solution, 0-5 DEG C of adition process system temperature.
System reacts 5h, TLC tracking reaction end (ethyl acetate between 15-20 DEG C after the completion of feeding intake：Petroleum ether=2:1st, it is ultraviolet
254nm), the activated ester solution of L-Leu benzyl ester tosilate is obtained；
2) by (2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyric acid, 10 times of (V/m) 20% sodium acid carbonate
Solution is added sequentially in reactor, is stirred to being completely dissolved, is cooled to 10-15 DEG C, and quick stirring is lower to be added dropwise L-Leu benzyl
The activated ester solution of ester tosilate, reacts 5h or so, TLC tracking reaction ends between 15-20 DEG C after being added dropwise to complete
(ethyl acetate：Petroleum ether=2:1st, ultraviolet 254nm)；
3) filtering point liquid, aqueous phase is extracted with 7 times, 2 times of (V/m) ethyl acetate successively, combined ethyl acetate phase, ethyl acetate
Mutually it washed once successively with 6 times of 0.5wt% hydrochloric acid, 6 times of 5wt% saturated sodium bicarbonate washed once, 6 times of purifying water washings
Once；Ethyl acetate solution is filtered, is concentrated to dryness through anhydrous sodium sulfate drying 2h, and 5 times of (V/m) oil are added into concentrate
Ether, stirring 3h disperses, filtering, dry N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyl fourths at 40-45 DEG C
Acyl]-L-Leu, yield 94-98%；
4) it is under the conditions of 20-30 DEG C that N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl]-L- is bright
Propylhomoserin, Pd/C (30%) are dissolved in the glacial acetic acid of 15 times (v/m), are added to after being uniformly mixed in reactor, nitrogen hydrogen
Gas is replaced three times successively, and stirring reaction is extremely to hydrogen is not inhaled under 1.5-2MPa；
5) filtrate after filtering is concentrated to dryness under 70 DEG C, -0.05MPa, and 10 times of (v/m) acetone are added in concentrate, are stirred
Mix scattered 5h, filtering, at 40-45 DEG C forced air drying obtain ubenimex acetate；
6) ubenimex acetate is dissolved in hydrochloric acid solution, solution is cooled between 0-5 DEG C, with 15wt% ammonia
Water adjusts solution ph to 5-6.Crystallization 4h at 0-5 DEG C, filtering, solid is beaten 3h with acetone, filters, and crow is dried to obtain at 50 DEG C
Department of benzene U.S. finished product, yield is 92.3%.
Embodiment 3
The preparation method of ubenimex is as follows：
1) L-Leu benzyl ester tosilate, HOBt, 10 times of (V/m) ethyl acetate are added sequentially to reactor
In, the completion that feeds intake is stirred continuously cooling, is slowly added between DCC ethyl acetate solution, 0-5 DEG C of adition process system temperature.
System reacts 4h, TLC tracking reaction end (ethyl acetate between 15-20 DEG C after the completion of feeding intake：Petroleum ether=2:1st, it is ultraviolet
254nm), the activated ester solution of L-Leu benzyl ester tosilate is obtained；
2) by (2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyric acid, 10 times of (V/m) 20% sodium acid carbonate
Solution is added sequentially in reactor, is stirred to being completely dissolved, is cooled to 10-15 DEG C, and quick stirring is lower to be added dropwise L-Leu benzyl
The activated ester solution of ester tosilate, reacts 4h or so, TLC tracking reaction ends between 15-20 DEG C after being added dropwise to complete
(ethyl acetate：Petroleum ether=2:1st, ultraviolet 254nm)；
3) filtering point liquid, aqueous phase is extracted with 7 times, 2 times of (V/m) ethyl acetate successively, combined ethyl acetate phase, ethyl acetate
Mutually it washed once successively with 6 times of 0.5wt% hydrochloric acid, 6 times of 5wt% saturated sodium bicarbonate washed once, 6 times of purifying water washings
Once；Ethyl acetate solution is filtered, is concentrated to dryness through anhydrous sodium sulfate drying 2h, and 5 times of (V/m) oil are added into concentrate
Ether, stirring 2h disperses, filtering, dry N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyl fourths at 40-45 DEG C
Acyl]-L-Leu, yield 94-98%；
4) it is under the conditions of 20-30 DEG C that N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl]-L- is bright
Propylhomoserin, Pd/C (30%) are dissolved in the glacial acetic acid of 15 times (v/m), are added to after being uniformly mixed in reactor, nitrogen hydrogen
Gas is replaced three times successively, and stirring reaction is extremely to hydrogen is not inhaled under 1.5-2MPa；
5) filtrate after filtering is concentrated to dryness under 75 DEG C, -0.085MPa, and 10 times of (v/m) acetone are added in concentrate,
Dispersed with stirring 4h, filtering, at 40-45 DEG C forced air drying obtain ubenimex acetate；
6) ubenimex acetate is dissolved in hydrochloric acid solution, solution is cooled between 0-5 DEG C, with 20wt% ammonia
Water adjusts solution ph to 5-6.Crystallization 5h at 0-5 DEG C, filtering, solid is beaten 2h with acetone, filters, and crow is dried to obtain at 45 DEG C
Department of benzene U.S. finished product, yield is 91.4%.
Comparative example 1
By (2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyric acid, L-Leu benzyl ester tosilate,
HOBt, tetrahydrofuran are molten to be added sequentially in reactor, and 0 DEG C or so is cooled under the completion system that feeds intake stirring, slow successively to add
Enter triethylamine and DCC, adition process system temperature is no more than 10 DEG C.System is reacted between 15 DEG C~20 DEG C after the completion of feeding intake, and is stirred
Mix reaction to stay overnight, TLC tracking reaction end (ethyl acetate：Petroleum ether=2:1st, ultraviolet 254nm).
Filtering, filtrate is concentrated under reduced pressure into dry under 45 DEG C, -0.085Mpa, obtains yellow oil concentrate, adds 15 times
(V/m) ethyl acetate dissolves, and solution washed once with 4 times of 0.5N hydrochloric acid successively, 4 times of 0.5N saturated sodium bicarbonate washs one
Secondary, 4 times of purified waters washed once, and ethyl acetate solution was through anhydrous sodium sulfate drying 2 hours.
Filter, be concentrated to dryness, into concentrate add 10 times of (V/m) petroleum ethers, stir 2 hours disperse, filtering, 40 DEG C~
Dry N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl]-L-Leu, yield 80%- at 45 DEG C
82%.
Although illustrate and describing the present invention with specific embodiment, but it will be appreciated that without departing substantially from the present invention's
Many other changes and modification can be made in the case of spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of preparation method of ubenimex, it is characterised in that mainly comprise the following steps：
(A) under DCC catalytic conditions, solvent is ethyl acetate, and L-Leu benzyl ester tosilate, HOBt are condensed to yield into work
Change ester solution；
(B) by (2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyric acid, weak acid highly basic inorganic salts mixing process
In, the activated ester solution is added dropwise and react obtaining N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyl fourths
Acyl]-L-Leu；
(C) N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl]-L-Leus are under Pd/C catalysis, hydrogen
Reduction obtains ubenimex；
Preferably, the weak acid highly basic inorganic salts include the one of which in sodium acid carbonate, saleratus, and more excellent is bicarbonate
Sodium.
2. the preparation method of ubenimex according to claim 1, it is characterised in that in the step (A), first add L-
Leucine benzyl ester tosilate, HOBt, ethyl acetate, and by temperature control between 0-5 DEG C, then addition contains DCC
Ethyl acetate solution, temperature is increased between 15-20 DEG C, react 4-5h.
3. the preparation method of ubenimex according to claim 2, it is characterised in that the ethyl acetate solution containing DCC
Carried out in the way of dropwise addition.
4. the preparation method of ubenimex according to claim 1, it is characterised in that in the step (B), by bicarbonate
Sodium is configured to 10-20wt% sodium bicarbonate solution；
Preferably, after addition sodium bicarbonate solution, temperature control is between 10-15 DEG C.
5. the preparation method of ubenimex according to claim 1, it is characterised in that in the step (B), is added dropwise described
After activated ester solution, 4-5h is reacted between 15-20 DEG C.
6. the preparation method of ubenimex according to claim 1, it is characterised in that in the step (B), will after reaction
Product N- [(2S, 3R) -3- carbobenzoxy amido -2- hydroxy-4-phenyls butyryl]-L-Leu carries out being separated by filtration organic phase
Afterwards, wash, dry and concentration operation；
Preferably, concentrate is obtained after drying, petroleum ether and stirring 2-3h is added into concentrate, filtering is dried described to carry out
Concentration；
Preferably, petroleum ether and stirring 2-3h is added into concentrate, after filtering, is dried under conditions of 40-45 DEG C.
7. the preparation method of ubenimex according to claim 1, it is characterised in that in the step (C), solvent is used
For glacial acetic acid, reaction pressure is controlled between 1.5-2MPa, and reaction temperature is controlled between 20-30 DEG C.
8. the preparation method of ubenimex according to claim 1, it is characterised in that in the step (C), reaction is obtained
Ubenimex crude product filtered, separate with purify.
9. the preparation method of ubenimex according to claim 8, it is characterised in that by ubenimex crude product in 70-80
DEG C, concentrated between pressure -0.05~-0.1MPa after, after addition acetone stirring, filtering, after addition ammoniacal liquor crystallization, filtering is
Can.
10. the preparation method of ubenimex according to claim 9, it is characterised in that after addition ammoniacal liquor, regulation solution
PH value is between 5-6,0-5 DEG C of crystallization 4-5h；
Preferably, filtering addition acetone stirs and is dried to obtain ubenimex finished product between 2-3h, 40-50 DEG C after crystallization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710552900.0A CN107141232A (en) | 2017-07-07 | 2017-07-07 | A kind of preparation method of ubenimex |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109721505A (en) * | 2018-12-26 | 2019-05-07 | 深圳万乐药业有限公司 | A kind of impurity and preparation method thereof in ubenimex synthesis |
| CN111574396A (en) * | 2020-06-03 | 2020-08-25 | 深圳万乐药业有限公司 | Ubenimex acetate monocrystal and preparation method and application thereof |
| CN112341356A (en) * | 2019-08-09 | 2021-02-09 | 成都苑东生物制药股份有限公司 | (2S,3R) -3-amino-2-hydroxy-4-phenylbutylamide derivative, and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0156279A2 (en) * | 1984-03-26 | 1985-10-02 | Microbial Chemistry Research Foundation | A novel process for the preparation of bestatin derivatives and intermediates thereof |
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2017
- 2017-07-07 CN CN201710552900.0A patent/CN107141232A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0156279A2 (en) * | 1984-03-26 | 1985-10-02 | Microbial Chemistry Research Foundation | A novel process for the preparation of bestatin derivatives and intermediates thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109721505A (en) * | 2018-12-26 | 2019-05-07 | 深圳万乐药业有限公司 | A kind of impurity and preparation method thereof in ubenimex synthesis |
| CN112341356A (en) * | 2019-08-09 | 2021-02-09 | 成都苑东生物制药股份有限公司 | (2S,3R) -3-amino-2-hydroxy-4-phenylbutylamide derivative, and preparation method and application thereof |
| CN112341356B (en) * | 2019-08-09 | 2023-04-28 | 成都苑东生物制药股份有限公司 | (2S, 3R) -3-amino-2-hydroxy-4-phenylbutyramide derivative, preparation method and application thereof |
| CN111574396A (en) * | 2020-06-03 | 2020-08-25 | 深圳万乐药业有限公司 | Ubenimex acetate monocrystal and preparation method and application thereof |
| CN111574396B (en) * | 2020-06-03 | 2023-02-10 | 深圳万乐药业有限公司 | Ubenimex acetate monocrystal and preparation method and application thereof |
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