CN109705003A - A kind of racemization method of L- D-4-methylsulfonylphserine serine ethyl ester - Google Patents
A kind of racemization method of L- D-4-methylsulfonylphserine serine ethyl ester Download PDFInfo
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Abstract
A kind of racemization method of L- D-4-methylsulfonylphserine serine ethyl ester, from the left-handed body of light of L- D-4-methylsulfonylphserine serine ethyl ester, racemization prepares DL-p-methylsulfonylpserine serine ethyl ester.Using one or more of purchase or homemade Kocide SD, basic copper carbonate, copper oxide as containing copper reagent, cupric glycinate is generated in the solution, under the conditions of low alkalinity, pass through hydroformylation with L- ethyl ester, pass through the equilibrium system of reversible reaction, it is practical to generate racemization effect, most of generation DL- pmethylsulfonyl phenyleneserine copper.The racemization mantoquita of generation can be generated DL-p-methylsulfonylpserine serine ethyl ester, i.e. DL- ethyl ester through esterification again.Yield is in 60%--80%.
Description
Technical field
The present invention relates to medicine intermediate fields, and in particular to a kind of L- D-4-methylsulfonylphserine serine ethyl ester racemization preparation
The method of DL-p-methylsulfonylpserine serine ethyl ester.
Background technique
Florfenicol is chloromycetin broad-spectrum antibiotic of new generation, in clinical treatment and agriculturally there is extensive purposes.
D- D-4-methylsulfonylphserine serine ethyl ester (abbreviation D- ethyl ester) is the synthesis most important bulk pharmaceutical chemicals of Florfenicol.
The technique that the country generallys use at present is to mix ester with DL- pmethylsulfonyl phenyleneserine second, and abbreviation DL- ethyl ester is split
Optically pure D- ethyl ester is obtained, and another structure L- D-4-methylsulfonylphserine serine ethyl ester (abbreviation L- ethyl ester) is invalid product, such as
Fruit can not recycle and reuse, then can greatly improve the cost of product, while as waste, it is very difficult to it handles,
Substantially increase the pollution of danger wastes.Traditional Yan Guohe, Hu Zhongkan are by right to the processing method of L- ethyl ester
It carries out racemization, process by complicated multistep are as follows: strong basicity will be first tuned into L- ethyl ester aqueous solution, complete hydrolysis is L- to first
Then sulfuryl benzene serine salt is being tuned into highly acid completely, L- pmethylsulfonyl phenyleneserine to be fully converted to, then by solution body
System is adjusted to alkalinity and copper sulphate, glycine, and racemization generates DL- pmethylsulfonyl phenyleneserine mantoquita under alkaline condition, referred to as
Racemization mantoquita (referring to: L- (-)-Su Shi-in Thiamphenicol synthesis studies methylsulfonyl Phenserine ethyl ester Racemic of N
[J], Chinese Journal of Pharmaceuticals, 1992,23 (10): 433-436 pages).Racemization mantoquita esterification can be prepared DL- ethyl ester,
The last prepared DL- ethyl ester yield highest of the technical process also only has 40% or so, and working hour is long, at high cost, waste water is more and useless
Difficult substance is more in water, subsequent processing be practically impossible to complete task, and from its used a large amount of NaOH and
CuSO4 finds out, will be with the presence of a large amount of Na2SO4 and CuSO4, it is known that such waste water is difficult to handle, through excessive in waste water
Secondary recrystallization inorganic salts are all indivisible.How preferably to utilize the L- ethyl ester, how by it in high conversion and low
It is translated into optically inactive substance in the case where output waste water, is used as raw material application again, is that the prior art does not solve problem.
Summary of the invention
It is an object of the invention to overcome deficiency in the prior art, using Kocide SD, basic copper carbonate or copper oxide
One or more of copper reagent as medium, obtain a kind of synthetic method of efficient catalytic L- ethyl ester racemization.This method
It is not necessary that L- ethyl ester is hydrolyzed to L- pmethylsulfonyl phenyleneserine, reduce reaction step, while substantially reducing the reaction time.It receives
Rate problem is also critically important, and synthetic route is also without practical significance, the final practical receipts of the route of the application if yield is too low
Rate is at least more than 60%, and actually within the acceptable range, yield can be more than 80% to yield under accurate operation, has very
Good economy；Matter of time is also puzzlement point, and the route that the application is taken does not need the too many reaction time, operates as early as possible
It then can totally be completed within 12h or even shorter, it is very friendly for production requirement；The favorable repeatability of reaction, the application
Preparation route experienced hundred times or more the repetitions that more people carry out jointly, all maintain set yield, can in this way very
Practical, application feature is stablized.Outstanding advantages of the invention are there are also being exactly that waste water is few, almost without surplus if copper addition is just right
Remaining, waste water is only no the lye of inorganic salts, had in waste water compared to the prior art a large amount of sodium sulphate with
Copper sulphate, wastewater treatment bear big difference.
Above-mentioned technical problem of the invention is mainly to be addressed by following technical proposals: a kind of L- is to methylsulfonyl benzene
The racemization method of serine ethyl ester, the racemization method are that L- D-4-methylsulfonylphserine serine ethyl ester racemization is instigated to be prepared DL- pairs
The method that methylsulfonyl benzene serine second mixes ester, it is characterized in that being made of following step:.
1) preparation process: taking a four-hole bottle A, be put into the deionized water of 6-12 times of glycine weight, glycine is first added,
Copper reagent is slowly added gradually among four-hole bottle B, and stirred with the speed of 2-10r/s by stirring up to being completely dissolved at 40 DEG C
It mixes, until whole copper reagent dissolutions, keep stirring at least 20-40min at 40 DEG C；The copper reagent is Kocide SD, alkali formula carbon
One or more of sour copper or copper oxide；And the amount of the substance of copper reagent be added is at least so that glycine is completely converted into
1.2-1.5 times or more of the amount of cupric glycinate.
2) pH value regulating step: keeping four-hole bottle A at 40 DEG C, stirs 20-40min with the speed of 2-10r/s, is added
L- ethyl ester, with pH meter real-time detection system pH, with lye regulation system pH value between 8-10；Stir 20-40min.
3) continuous racemization step: being heated to certain steady temperature between 50-80 DEG C for mixture in four-hole bottle A and keep,
Keep the speed stirring of 2-10r/s.And it is primary every 10min observation, when pH value is down to 8.5 or less, several drop lye are added dropwise
Until the pH value of real-time monitoring returns to 8.5 or more；React 4-10h, mixture is filtered, then with 100ml deionized water with
100ml ethyl alcohol washs repeatedly repeatedly, and decompression drying obtains DL- pmethylsulfonyl phenyleneserine copper.
The lye is selected from sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate
Solution, potassium bicarbonate solution perhaps one of ammonium hydroxide or it is several mixed according to arbitrary proportion, lye is dissolved in deionized water
In, the hydroxyl total concentration of alkaloid substance is between 0.1-0.01mol/L；The amount of the substance of the equivalent copper of copper reagent: L- ethyl ester: sweet
Propylhomoserin molar ratio=4-10:8-12:1-6.
4) DL- ester preparation step: by the resulting DL- pmethylsulfonyl phenyleneserine copper of step (3) in excessive ethanol sulfuric acid
It is reacted in solution, decolourizes through over-churning, recycling copper sulphate, crystallization, copper removal, obtain optically inactive DL- to methylsulfonyl benzene silk ammonia
Sour second mixes ester.
The racemization method of a kind of L- D-4-methylsulfonylphserine serine ethyl ester above-mentioned, which is characterized in that method specifically: 1) quasi-
Standby step: taking a four-hole bottle A, be put into 8 times of glycine weight of deionized water, glycine is first added, the stirring at 40 DEG C until
It is completely dissolved, copper reagent is slowly added gradually among four-hole bottle B, and with the stirring of the speed of 5r/s, until whole copper reagent
Dissolution keeps stirring at least 25min at 40 DEG C；The copper reagent is one of Kocide SD, basic copper carbonate or copper oxide
Or it is several；And the amount of the substance of copper reagent be added is at least so that glycine is completely converted into 1.3 times of the amount of cupric glycinate
More than.
2) pH value regulating step: keeping four-hole bottle A at 40 DEG C, stirs 25min with the speed of 5r/s, L- second is added
Ester, with pH meter real-time detection system pH, with lye regulation system pH value between 8-9；Stir 25min.
3) continuous racemization step: being heated to certain steady temperature between 50-65 DEG C for mixture in four-hole bottle A and keep,
Keep the speed stirring of 5r/s.
And it is primary every 10min observation, when pH value is down to 8.5 or less, several drop lye are added dropwise up to real-time monitoring
PH value returns to 8.5 or more；4-7h is reacted, mixture is filtered, then is washed repeatedly with 100ml deionized water and 100ml ethyl alcohol
Repeatedly, decompression drying obtains DL- pmethylsulfonyl phenyleneserine copper.
The lye is selected from sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate
Solution, potassium bicarbonate solution perhaps one of ammonium hydroxide or it is several mixed according to arbitrary proportion, lye is dissolved in deionized water
In, the hydroxyl total concentration of alkaloid substance is between 0.1-0.04mol/L；The amount of the substance of the equivalent copper of copper reagent: L- ethyl ester: sweet
Propylhomoserin molar ratio=6:9:3.
4) DL- ester preparation step: by the resulting DL- pmethylsulfonyl phenyleneserine copper of step (3) in excessive ethanol sulfuric acid
It is reacted in solution, decolourizes through over-churning, recycling copper sulphate, crystallization, copper removal, obtain optically inactive DL- to methylsulfonyl benzene silk ammonia
Sour second mixes ester.
Also, a kind of application of medicine intermediate, with the aforementioned preparation-obtained DL- of any one method to methyl sulfone
Base benzene serine second mixes the D- D-4-methylsulfonylphserine serine ethyl ester that ester splits out, as medicine intermediate to prepare drug.
Compared with the prior art, the advantages of the present invention are as follows: 1) reaction used time short, and most short 4-10 hours can be completed
Journey, the prior art are analyzed according to the document, at least need 48h or so, and used time difference is obvious；2) it can generate in the prior art many useless
Water, and contain a large amount of sulfate, it is extremely difficult to it handles, one step of the present processes show that wastewater flow rate is few, and is operating proper situation
Some lye and a small amount of copper are contained only in lower waste water, processing is very simple, low in cost；(3) method of the invention turns
Rate is very high, at least 60% or more, and can achieve 80% by cautiously operating highest.4) core of the invention invention structure
Think of is original creation, and principle is to be based on, and applicant analyzes the discovery of L- second ester hydrolysis, big in the presence of such as NaOH under strong basicity
Amount direct hydrolysis is L- acid sodium, but in weakly alkaline environment, in the case where there is double condition existing for excessive free copper, L- ethyl ester
It can be hydrolyzed to L acid copper, and L- acid copper is unstable, generation can be decomposed to this achiral intermediate material of methyl sulfone benzaldehyde, with
And cupric glycinate, this reaction is reversible reaction, and it is more interesting be a bit, since this aldehyde is achiral, then reversible
When being reversed, L- acid copper can have not only been generated, but also D- acid copper can have been generated, namely produce racemization effect, cupric glycinate is in body
It is in system existing for complexing, and since System Design copper is excessive, then the amount of cupric glycinate is more sufficient, so that whole machine balancing is towards L-
The direction of sour copper and D- acid copper is mobile, and since solubility is low in water for L- acid copper and D- acid copper, under our condition design,
Aldehyde is not much in end reaction system, is all changed for DL- acid copper substantially, the main points of this reaction are that weakly alkaline environment
Holding, just can guarantee that the carry out directionality of reaction, the present invention embody extremely strong inventive concept and creativeness, achieve good
Preparation effect, have no in the prior art more similar public information for use for reference, the present invention program have originality.It should
Method has step clear, and waste is few, and yield is higher, and the time is short, saves raw material and easily operated advantage.In contrast, existing
There is the method in technology simple and crude, step is too many, and contains a large amount of CuSO4 in waste water, is difficult to handle.
Detailed description of the invention
Fig. 1 is the synthesis process the schematic diagram how present invention obtains aldehyde from L- ethyl ester.
Fig. 2 is that the present invention obtains the schematic diagram how aldehyde realizes racemization later.
Specific embodiment
The preferred embodiment of the present invention is described in detail with reference to the accompanying drawing, so that advantages and features of the invention energy
It is easier to be readily appreciated by one skilled in the art, so as to make a clearer definition of the protection scope of the present invention.This hair
It is bright to be embodied in many different forms, and should not be construed as limited to embodiment set forth herein.On the contrary, providing these
Design of the invention so that open will be thorough and complete, and will be fully conveyed to those skilled in the art by embodiment
Member, the present invention will only be defined by the appended claims.
The principle of the present invention as shown in Figure 1, L- ethyl ester in weak acid environment, can decompose generation to methyl sulfone benzaldehyde,
And in the case that cupric glycinate there are, cupric glycinate can with to methyl sulfone benzaldehyde the reaction was continued generate DL- to methylsulfonyl benzene silk
Propylhomoserin copper, such reaction drive L- ethyl ester but also carrying out to the hydrolysis to methyl sulfone benzaldehyde is constantly positive for L- ethyl ester
Forward reaction, by being excessively completely converted into DL- pmethylsulfonyl phenyleneserine copper to methyl sulfone benzaldehyde.
Embodiment 1
1) preparation process: taking a four-hole bottle A, is put into 8 times of glycine weight of deionized water, glycine is first added, 40
Copper reagent is slowly added gradually among four-hole bottle B, and with the stirring of the speed of 5r/s, directly by stirring up to being completely dissolved at DEG C
It is dissolved to whole copper reagent, keeps stirring at least 25min at 40 DEG C；The copper reagent is Kocide SD, basic copper carbonate or oxygen
Change one or more of copper；And the amount of the substance of copper reagent be added is at least so that glycine is completely converted into cupric glycinate
1.3 times of amount.
2) pH value regulating step: keeping four-hole bottle A at 40 DEG C, stirs 25min with the speed of 5r/s, L- second is added
Ester, with pH meter real-time detection system pH, with lye regulation system pH value between 8-9；Stir 25min.
3) continuous racemization step: being heated to certain steady temperature between 50-65 DEG C for mixture in four-hole bottle A and keep,
Keep the speed stirring of 5r/s；And it is primary every 10min observation, when pH value is down to 8.5 or less, be added dropwise several drop lye up to
The pH value of real-time monitoring returns to 8.5 or more；4-7h is reacted, mixture is filtered, then with 100ml deionized water and 100ml second
Alcohol washs repeatedly repeatedly, and decompression drying obtains DL- pmethylsulfonyl phenyleneserine copper；The lye is selected from sodium hydroxide solution, hydrogen
One of potassium oxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution, potassium bicarbonate solution or ammonium hydroxide, or
Person is several to be mixed according to arbitrary proportion, and lye is dissolved in deionized water, and the hydroxyl total concentration of alkaloid substance is in 0.1-0.04mol/L
Between；The amount of the substance of the equivalent copper of copper reagent: L- ethyl ester: glycine molar ratio=6:9:3.
4) DL- ester preparation step: by the resulting DL- pmethylsulfonyl phenyleneserine copper of step (3) in excessive ethanol sulfuric acid
It is reacted in solution, decolourizes through over-churning, recycling copper sulphate, crystallization, copper removal, obtain optically inactive DL- to methylsulfonyl benzene silk ammonia
Sour second mixes ester.
Embodiment 2
The racemization method is to instigate L- D-4-methylsulfonylphserine serine ethyl ester racemization that DL- pmethylsulfonyl phenyleneserine is prepared
The method that second mixes ester, it is characterized in that being made of following step: 1) preparation process: taking a four-hole bottle A, is put into 10 times of glycine weight
Deionized water, glycine is first added, copper reagent is slowly added gradually to four-hole bottle until be completely dissolved by stirring at 40 DEG C
Among B, and with the stirring of the speed of 7r/s, until whole copper reagent dissolutions, keep stirring at least 30min at 40 DEG C；The copper examination
Agent is one or more of Kocide SD, basic copper carbonate or copper oxide；And the amount of the substance of copper reagent be added is at least
So that glycine is completely converted into 1.4 times of the amount of cupric glycinate.
2) pH value regulating step: keeping four-hole bottle A at 40 DEG C, stirs 30min with the speed of 7r/s, L- second is added
Ester, with pH meter real-time detection system pH, with lye regulation system pH value between 8.5-9.5；Stir 30min.
3) continuous racemization step: being heated to certain steady temperature between 55-70 DEG C for mixture in four-hole bottle A and keep,
Keep the speed stirring of 5r/s；And it is primary every 10min observation, when pH value is down to 8.5 or less, be added dropwise several drop lye up to
The pH value of real-time monitoring returns to 8.5 or more；4-10h is reacted, mixture is filtered, then with 100ml deionized water and 100ml second
Alcohol washs repeatedly repeatedly, and decompression drying obtains DL- pmethylsulfonyl phenyleneserine copper；The lye is selected from sodium hydroxide solution, hydrogen
One of potassium oxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution, potassium bicarbonate solution or ammonium hydroxide, or
Person is several to be mixed according to arbitrary proportion, and lye is dissolved in deionized water, and the hydroxyl total concentration of alkaloid substance is in 0.1-0.01mol/L
Between；The amount of the substance of the equivalent copper of copper reagent: L- ethyl ester: glycine molar ratio=4-10:8-12:1-6.
4) DL- ester preparation step: by the resulting DL- pmethylsulfonyl phenyleneserine copper of step (3) in excessive ethanol sulfuric acid
It is reacted in solution, decolourizes through over-churning, recycling copper sulphate, crystallization, copper removal, obtain optically inactive DL- to methylsulfonyl benzene silk ammonia
Sour second mixes ester.
Embodiment 3
A kind of racemization method of L- D-4-methylsulfonylphserine serine ethyl ester, which is characterized in that method specifically: 1) prepare step
It is rapid: to take a four-hole bottle A, be put into 12 times of glycine weight of deionized water, glycine is first added, the stirring at 40 DEG C is until completely
Dissolution, copper reagent is slowly added gradually among four-hole bottle B, and with the stirring of the speed of 9r/s, until whole copper reagent dissolve,
It keeps stirring at least 35min at 40 DEG C；The copper reagent is one of Kocide SD, basic copper carbonate or copper oxide or several
Kind；And the amount of the substance of copper reagent be added is at least so that glycine is completely converted into 1.5 times of the amount of cupric glycinate.
2) pH value regulating step: keeping four-hole bottle A at 40 DEG C, stirs 35min with the speed of 9r/s, L- second is added
Ester, with pH meter real-time detection system pH, with lye regulation system pH value between 8.5-10；Stir 35min.
3) continuous racemization step: being heated to certain steady temperature between 60-80 DEG C for mixture in four-hole bottle A and keep,
Keep the speed stirring of 9r/s；And it is primary every 10min observation, when pH value is down to 8.5 or less, be added dropwise several drop lye up to
The pH value of real-time monitoring returns to 8.5 or more；7-10h is reacted, mixture is filtered, then with 100ml deionized water and 100ml second
Alcohol washs repeatedly repeatedly, and decompression drying obtains DL- pmethylsulfonyl phenyleneserine copper；The lye is selected from sodium hydroxide solution, hydrogen
One of potassium oxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution, potassium bicarbonate solution or ammonium hydroxide, or
Person is several to be mixed according to arbitrary proportion, and lye is dissolved in deionized water, and the hydroxyl total concentration of alkaloid substance is in 0.07-0.01mol/
Between L；The amount of the substance of the equivalent copper of copper reagent: L- ethyl ester: glycine molar ratio=9:12:6.
4) DL- ester preparation step: by the resulting DL- pmethylsulfonyl phenyleneserine copper of step (3) in excessive ethanol sulfuric acid
It is reacted in solution, decolourizes through over-churning, recycling copper sulphate, crystallization, copper removal, obtain optically inactive DL- to methylsulfonyl benzene silk ammonia
Sour second mixes ester.
Embodiment 4
A kind of application of medicine intermediate specifically mixes ester with DL- second prepared by one of aforementioned any embodiment and is used as doctor
Preparation of the medicine intermediate to prepare drug, for other drugs.
Embodiment 5
By 100 times or more synthesising racemations, general evaluation system data are shown, from L- ethyl ester to DL- ester yield in 60%--
Between 80%, individual times can be more than 80%, generally more than 60%, through liquid phase detection purity in 98% or more, D- ester, L- ethyl ester
Ratio respectively accounts for 50% or so, and racemization is very complete, and product is substantially without optical activity.
The above description is merely a specific embodiment, but scope of protection of the present invention is not limited thereto, any
The change or replacement expected without creative work, should be covered by the protection scope of the present invention.Therefore, of the invention
Protection scope should be determined by the scope of protection defined in the claims.
Claims (5)
1. a kind of racemization method of L- D-4-methylsulfonylphserine serine ethyl ester, the racemization method are to instigate L- pmethylsulfonyl phenyleneserine
The method that DL- pmethylsulfonyl phenyleneserine second mixes ester is prepared in ethyl ester racemization, it is characterized in that being made of following step:
1) preparation process: a four-hole bottle A is taken, the deionized water of 6-12 times of glycine weight is put into, glycine is first added, at 40 DEG C
Copper reagent is slowly added gradually among four-hole bottle B, and with the stirring of the speed of 2-10r/s, directly by lower stirring up to being completely dissolved
It is dissolved to whole copper reagent, keeps stirring at least 20-40min at 40 DEG C；The copper reagent be Kocide SD, basic copper carbonate or
One or more of copper oxide；And the amount of the substance of copper reagent be added is at least so that glycine is completely converted into glycine
1.2-1.5 times or more of the amount of copper；
2) pH value regulating step: keeping four-hole bottle A at 40 DEG C, stirs 20-40min with the speed of 2-10r/s, L- second is added
Ester, with pH meter real-time detection system pH, with lye regulation system pH value between 8-10；Stir 20-40min；
3) continuous racemization step: mixture in four-hole bottle A is heated to certain steady temperature between 50-80 DEG C and is kept, is kept
The speed of 2-10r/s stirs；
And it is primary every 10min observation, when pH value is down to 8.5 or less, several drop lye are added dropwise up to the pH value of real-time monitoring
Return to 8.5 or more；4-10h is reacted, mixture is filtered, then is washed repeatedly with 100ml deionized water and 100ml ethyl alcohol more
Secondary, decompression drying obtains DL- pmethylsulfonyl phenyleneserine copper；
The lye be selected from sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution,
Potassium bicarbonate solution perhaps one of ammonium hydroxide or it is several mixed according to arbitrary proportion, lye is dissolved in deionized water, alkali object
The hydroxyl total concentration of matter is between 0.1-0.01mol/L；The amount of the substance of the equivalent copper of copper reagent: L- ethyl ester: glycine rubs
You are ratio=4-10:8-12:1-6；
4) DL- ester preparation step: by the resulting DL- pmethylsulfonyl phenyleneserine copper of step (3) in excessive ethanol sulfuric acid solution
Middle reaction decolourizes through over-churning, recycling copper sulphate, crystallization, copper removal, obtains optically inactive DL- pmethylsulfonyl phenyleneserine second
Mixed ester.
2. a kind of racemization method of L- D-4-methylsulfonylphserine serine ethyl ester as claimed in claim, which is characterized in that method tool
Body are as follows:
1) preparation process: taking a four-hole bottle A, is put into 8 times of glycine weight of deionized water, glycine is first added, at 40 DEG C
Copper reagent is slowly added gradually among four-hole bottle B, and with the stirring of the speed of 5r/s, up to being completely dissolved until complete by stirring
Copper reagent dissolution in portion's keeps stirring at least 25min at 40 DEG C；The copper reagent is Kocide SD, basic copper carbonate or copper oxide
One or more of；And the amount of the substance of copper reagent be added is at least so that glycine is completely converted into the amount of cupric glycinate
1.3 times；
2) pH value regulating step: keeping four-hole bottle A at 40 DEG C, stirs 25min with the speed of 5r/s, L- ethyl ester is added, use
PH meter real-time detection system pH, with lye regulation system pH value between 8-9；Stir 25min；
3) continuous racemization step: mixture in four-hole bottle A is heated to certain steady temperature between 50-65 DEG C and is kept, is kept
The speed of 5r/s stirs；
And it is primary every 10min observation, when pH value is down to 8.5 or less, several drop lye are added dropwise up to the pH value of real-time monitoring
Return to 8.5 or more；4-7h is reacted, mixture is filtered, then is washed repeatedly repeatedly with 100ml deionized water and 100ml ethyl alcohol,
Decompression drying obtains DL- pmethylsulfonyl phenyleneserine copper；
The lye be selected from sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution,
Potassium bicarbonate solution perhaps one of ammonium hydroxide or it is several mixed according to arbitrary proportion, lye is dissolved in deionized water, alkali object
The hydroxyl total concentration of matter is between 0.1-0.04mol/L；The amount of the substance of the equivalent copper of copper reagent: L- ethyl ester: glycine rubs
You are ratio=6:9:3；
4) DL- ester preparation step: by the resulting DL- pmethylsulfonyl phenyleneserine copper of step (3) in excessive ethanol sulfuric acid solution
Middle reaction decolourizes through over-churning, recycling copper sulphate, crystallization, copper removal, obtains optically inactive DL- pmethylsulfonyl phenyleneserine second
Mixed ester.
3. a kind of racemization method of L- D-4-methylsulfonylphserine serine ethyl ester, the racemization method are to instigate L- pmethylsulfonyl phenyleneserine
The method that DL- pmethylsulfonyl phenyleneserine second mixes ester is prepared in ethyl ester racemization, it is characterized in that being made of following step:
1) preparation process: taking a four-hole bottle A, is put into 10 times of glycine weight of deionized water, glycine is first added, at 40 DEG C
Copper reagent is slowly added gradually among four-hole bottle B, and with the stirring of the speed of 7r/s, up to being completely dissolved until complete by stirring
Copper reagent dissolution in portion's keeps stirring at least 30min at 40 DEG C；The copper reagent is Kocide SD, basic copper carbonate or copper oxide
One or more of；And the amount of the substance of copper reagent be added is at least so that glycine is completely converted into the amount of cupric glycinate
1.4 times；
2) pH value regulating step: keeping four-hole bottle A at 40 DEG C, stirs 30min with the speed of 7r/s, L- ethyl ester is added, use
PH meter real-time detection system pH, with lye regulation system pH value between 8.5-9.5；Stir 30min；
3) continuous racemization step: mixture in four-hole bottle A is heated to certain steady temperature between 55-70 DEG C and is kept, is kept
The speed of 5r/s stirs；
And it is primary every 10min observation, when pH value is down to 8.5 or less, several drop lye are added dropwise up to the pH value of real-time monitoring
Return to 8.5 or more；4-10h is reacted, mixture is filtered, then is washed repeatedly with 100ml deionized water and 100ml ethyl alcohol more
Secondary, decompression drying obtains DL- pmethylsulfonyl phenyleneserine copper；
The lye be selected from sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution,
Potassium bicarbonate solution perhaps one of ammonium hydroxide or it is several mixed according to arbitrary proportion, lye is dissolved in deionized water, alkali object
The hydroxyl total concentration of matter is between 0.1-0.01mol/L；The amount of the substance of the equivalent copper of copper reagent: L- ethyl ester: glycine rubs
You are ratio=4-10:8-12:1-6；
4) DL- ester preparation step: by the resulting DL- pmethylsulfonyl phenyleneserine copper of step (3) in excessive ethanol sulfuric acid solution
Middle reaction decolourizes through over-churning, recycling copper sulphate, crystallization, copper removal, obtains optically inactive DL- pmethylsulfonyl phenyleneserine second
Mixed ester.
4. a kind of racemization method of L- D-4-methylsulfonylphserine serine ethyl ester as claimed in claim, which is characterized in that method tool
Body are as follows:
1) preparation process: taking a four-hole bottle A, is put into 12 times of glycine weight of deionized water, glycine is first added, at 40 DEG C
Copper reagent is slowly added gradually among four-hole bottle B, and with the stirring of the speed of 9r/s, up to being completely dissolved until complete by stirring
Copper reagent dissolution in portion's keeps stirring at least 35min at 40 DEG C；The copper reagent is Kocide SD, basic copper carbonate or copper oxide
One or more of；And the amount of the substance of copper reagent be added is at least so that glycine is completely converted into the amount of cupric glycinate
1.5 times；
2) pH value regulating step: keeping four-hole bottle A at 40 DEG C, stirs 35min with the speed of 9r/s, L- ethyl ester is added, use
PH meter real-time detection system pH, with lye regulation system pH value between 8.5-10；Stir 35min；
3) continuous racemization step: mixture in four-hole bottle A is heated to certain steady temperature between 60-80 DEG C and is kept, is kept
The speed of 9r/s stirs；
And it is primary every 10min observation, when pH value is down to 8.5 or less, several drop lye are added dropwise up to the pH value of real-time monitoring
Return to 8.5 or more；7-10h is reacted, mixture is filtered, then is washed repeatedly with 100ml deionized water and 100ml ethyl alcohol more
Secondary, decompression drying obtains DL- pmethylsulfonyl phenyleneserine copper；
The lye be selected from sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution,
Potassium bicarbonate solution perhaps one of ammonium hydroxide or it is several mixed according to arbitrary proportion, lye is dissolved in deionized water, alkali object
The hydroxyl total concentration of matter is between 0.07-0.01mol/L；The amount of the substance of the equivalent copper of copper reagent: L- ethyl ester: glycine rubs
You are ratio=9:12:6；
4) DL- ester preparation step: by the resulting DL- pmethylsulfonyl phenyleneserine copper of step (3) in excessive ethanol sulfuric acid solution
Middle reaction decolourizes through over-churning, recycling copper sulphate, crystallization, copper removal, obtains optically inactive DL- pmethylsulfonyl phenyleneserine second
Mixed ester.
5. a kind of application of medicine intermediate, with the preparation-obtained DL- of any one method of claim 1-4 to methylsulfonyl
Benzene serine second mixes the D- D-4-methylsulfonylphserine serine ethyl ester that ester splits out, as medicine intermediate to prepare drug.
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| CN115073333A (en) * | 2022-07-20 | 2022-09-20 | 江苏八巨药业有限公司 | Racemization method based on active copper molecular sieve |
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| CN107417585A (en) * | 2017-06-22 | 2017-12-01 | 浙江海翔川南药业有限公司 | A kind of synthetic method of pharmaceutical intermediate |
| CN108912019A (en) * | 2018-08-03 | 2018-11-30 | 江苏八巨药业有限公司 | The method that one kind recycling mantoquita and ethyl alcohol from D, L- Su Shi-D-4-methylsulfonylphserine serine ethyl ester mother liquor |
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| CN115073333B (en) * | 2022-07-20 | 2024-01-19 | 江苏八巨药业有限公司 | Racemization method based on active copper molecular sieve |
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