CN109678766A - A kind of synthetic method of pmethylsulfonyl phenyleneserine copper - Google Patents
A kind of synthetic method of pmethylsulfonyl phenyleneserine copper Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
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Abstract
A kind of synthetic method of DL- pmethylsulfonyl phenyleneserine copper.It can be shortened the reaction time as copper reagent, Lai Hecheng DL- pmethylsulfonyl phenyleneserine copper is contained using one or more of Kocide SD, basic copper carbonate, copper oxide and realize that mother liquor is repeatedly applied, reduce the yield of copper-containing wastewater.The following steps are included: being added in reaction flask containing copper reagent, glycine is added, to aldehyde and deionized water or upper batch of mother liquor, about 20h is reacted at 40-55 DEG C, cools down after reaction, be filtered, washed, being drying to obtain product, and yield is 90% or more and satisfactory quality.This method shortens the reaction time and realizes repeatedly applying for cupric mother liquor.
Description
Technical field
The present invention relates to medicine intermediate fields, and in particular to a kind of synthetic method of pmethylsulfonyl phenyleneserine copper.
Background technique
The chloro- N- of the Florfenicol entitled 2,2- bis- of chemistry [(1S, 2R) -1- methyl fluoride -2- hydroxyl -2- [4- (mesyl)
Benzene] ethyl] acetamide is the antimicrobial for animals of Schering-Plough Animal Health company, U.S. research and development, nineteen ninety
It is listed for the first time in Japan, because its extraordinary therapeutic effect is widely used quickly after listing, the sales volume from the current whole nation
From the point of view of be always maintained at increase trend.Wherein, D- D-4-methylsulfonylphserine serine ethyl ester (abbreviation D- ethyl ester) is synthesis fluorobenzene Buddhist nun
Examine most important bulk pharmaceutical chemicals.
The technique that the country generallys use at present is with DL-p-methylsulfonylpserine serine ethyl ester mixture (abbreviation DL- ethyl ester)
Optically pure D- ethyl ester is obtained to split, and DL- ethyl ester is usually with to methyl sulfone benzaldehyde, glycine and copper sulphate, in alkali
Property under the conditions of condensation generate DL- pmethylsulfonyl phenyleneserine copper, then with the concentrated sulfuric acid ethyl alcohol esterification acquisition (Han Yuying etc., chemical work
Industry and engineering, 2011,28 (2), 28~34), reaction equation is as follows:
The most key step of the technique is that the first step generates DL- pmethylsulfonyl phenyleneserine copper, is referred to as condensed mantoquita, should
The mechanism of reaction are as follows: first complexing generates cupric glycinate under alkaline condition for glycine and copper sulphate, the α-H acid of glycine after complexing
Property enhancing, be easy to leave away, form carbanion in the presence of alkali, attack is to the carbonyl of methyl sulfone benzaldehyde, to generate pair
Methylsulfonyl benzene serine copper precipitating, used here as copper there are also another effect, originally coming here there are two carbon is chiral carbon, theoretically
Four pmethylsulfonyl phenyleneserine copper are generated, using the complexing of copper, have simply generated two isomers, one is us
The D type said, one is L-type, if not with copper, and with other, it is assumed that four isomers have, that yield highest 25%, and
And extremely difficult separation can generate 4 kinds of isomers, for example Co, Ni, copper use if not having to copper, can only generate D and L-type.Cause
Necessarily leading to sulfuric acid while forming cupric glycinate complex compound for copper sulphate and glycine reactant, glycine acidity is weak compared with sulfuric acid,
The alkali regulation system pH value for making reaction carry out thoroughly needing to be added equivalent or more is strong basicity, and the sulfuric acid of generation is disappeared
It consumes, makes reaction balance positive mobile, until the reaction is complete.Such that being generated in system largely based on sodium sulphate
Inorganic salts, and the inorganic salts in system directly affect the generation of pmethylsulfonyl phenyleneserine copper, so mother in the prior art
Liquid is usually that cannot apply.
The step is using water as solvent, and the dosage of water is very big in reaction process, for 10~20 to methyl sulfone benzaldehyde
Times, a small amount of product, copper ion, excessive glycine, the sulfuric acid of the alkali production of addition are contained in the waste water filtered out after reaction
Salt etc., complicated component, salt content are high, and copper ion is difficult to remove by coprecipitation mode, since the bactericidal effect of copper can not yet
It is handled by biochemical mode, is the most intractable sewage of factory, it is existing especially in the case where current environmental requirement is increasingly stringent
There is the above-mentioned short slab of technology obvious, production cost is high.
In the prior art, due to, as raw material, being constantly adjusted to alkalinity during the reaction again, then instead using copper sulphate
Containing the largely inorganic salts based on sodium sulphate in mother liquor after answering, one, such mother liquor is impossible to repeat to apply, non-
It often wastes water, second is the inorganic salts based on a large amount of sulfur acid sodium and the navy blue high-COD waste water containing excessive cupric glycinate
The extremely difficult processing of waste water, the bactericidal effect of the inorganic salts and copper that contain all make the waste water can not biochemical treatment, in addition to distillation do not have
Good method, and thermal energy is wasted, it is a kind of very uneconomic behavior that treatment effect is again bad.Mother liquor can not be applied and be wasted water,
Waste water is difficult to handle, this is the big drawback of the prior art apparent two.
Summary of the invention
It is an object of the invention to overcome deficiency in the prior art, using purchase or homemade Kocide SD, alkali formula carbon
The copper reagent of one or more of sour copper or copper oxide carries out the side of synthesis DL- pmethylsulfonyl phenyleneserine copper as raw material
Method.This method generates DL- pmethylsulfonyl phenyleneserine copper, and resulting mother liquor is of high quality, and can apply repeatedly without processing
At least 4-6 times, and be also not much even if 4-6 times used, in waste water the inorganic salts based on sodium sulphate, subsequent processing at
This is low, and processing is convenient.Waste water compared to the prior art can only utilize one time, due to wherein a large amount of inorganic salts, and can not
It is used further to production serine copper, wherein having a large amount of sodium sulphate and copper sulphate, wastewater treatment bears very different.
Above-mentioned technical problem of the invention is mainly to be addressed by following technical proposals: a kind of pair of methylsulfonyl benzene silk
The synthetic method of propylhomoserin copper, it is characterized in that being synthesized by following step.
1) preliminary step: the mother liquor for removing ionized water or last consignment of reaction is put into large container as reaction dissolvent
In stirred with the speed of 30-70r/min, glycine is added, stirs 10-20min.
2) copper reagent step is added: after stirring, being added at one time copper reagent, heating systems are stirred to react 20- to 40 DEG C
40min, until system is in uniform navy blue milkiness shape.
3) synthesis step: being added in system to methyl sulfone benzaldehyde, while adjusting pH with lye is 8-10, at 40-80 DEG C
Lower reaction 10-30h, every 15-30min detection pH value is primary, adds a small amount of lye to improve pH every time when pH is reached or fallen below 8
Value, with thin-layer chromatography monitoring to methyl sulfone benzaldehyde, tracking reaction measures to thin layer and does not exist substantially to methyl sulfone benzaldehyde
Afterwards, it is believed that reaction terminates, and system mixture is filtered.
4) purification step: the resulting mixture of step (3) being filtered, much filtrate is washed 1-3 times with appropriate amount of deionized water,
Room temperature low speed air blast is dried to get DL- pmethylsulfonyl phenyleneserine copper；Filtrate and cleaning solution are mixed into the mother of last consignment of reaction
Liquid can be covered and be reacted for next group, and the mother liquor of the batch reaction since deionized water at least can be by above-mentioned steps (1)-(4)
It applies 4-6 times.
Used copper reagent is one of purchase or homemade Kocide SD, basic copper carbonate or copper oxide or several
Kind.
The amount of the substance of copper in copper reagent: to methyl sulfone benzaldehyde: glycine molar ratio=5-8:8-12:10-20, step
(1) the quality quality of reaction dissolvent is 10~20 times to methyl sulfone benzaldehyde quality in.
Lye is sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution, carbon
One of potassium hydrogen phthalate solution or ammonium hydroxide are several, and total hydroxyl particle concentration is between 2-0.2mol/L.
Further, each plus a small amount of lye in step (3), is actually added into volume so that pH value is increased to 8 or 8 or more
The amount of being actually added into subject to.It can be dropped between over one hundred ml several.
A kind of application of medicine intermediate is used the preparation-obtained pmethylsulfonyl phenyleneserine copper of preceding method, is used as
Medicine intermediate is 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 16-20 hours can be completed
Journey, the prior art are analyzed according to the document, at least need 30-48h or so, and used time difference is obvious；2) it can generate in the prior art very
More waste 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 proper operating
In the case of some lye are contained only in waste water, it is extremely low to react inorganic salt content in post mother liquor, handle it is very simple, it is at low cost
It is honest and clean；(3) mother liquor can be covered repeatedly for the same reaction process, can at least apply 4 times or so, this inherently water resource
It greatly saves.4) core of the invention inventive concept is original creation, and principle is to be based on, and the preparation of the cupric glycinate of the application does not have
Have and introduces a large amount of inorganic ion, especially sulfate radical, one or more of Kocide SD, basic copper carbonate or copper oxide
Sulfate radical will not be all introduced, avoids the difficult situation that largely sulfate can not be handled after reaction, the present invention embodies extremely strong
Inventive concept and creativeness, achieve good preparation effect, having no more similar public information in the prior art can
For using for reference, the present invention program has originality.5) it applies six times, using waste water of processing, the copper content of the inside is also few, can
With single treatment, processing load mitigates significantly.This method has step clear, and waste is few, and yield is higher, and the time is short, saves former
Material and easily operated advantage.Copper sulphate is substituted for application Kocide SD, basic copper carbonate or copper oxide, the prior art has no
Enlightenment, the waste water that the present invention generates is easily processed, and can apply the innovation of water-saving repeatedly, and the prior art is also without open
Or provide enlightenment.
Detailed description of the invention
Fig. 1 is the synthesis process schematic diagram that final product is prepared in the present invention.
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 is, in the case that cupric glycinate there are, Kocide SD, basic copper carbonate or copper oxide is added,
While generating cupric glycinate, a large amount of inorganic salts are not introduced, and cupric glycinate can continue instead with to methyl sulfone benzaldehyde
DL- pmethylsulfonyl phenyleneserine copper should be generated, keeping system by the adjustment of lye is alkalescent, so that aldehyde is completely converted into
DL- pmethylsulfonyl phenyleneserine copper.
Embodiment 1
A kind of synthetic method of pmethylsulfonyl phenyleneserine copper, it is characterised in that: 1) preliminary step: removing ionized water, or
The mother liquor of person's last consignment of reaction is put into large container and is stirred with the speed of 40r/min as reaction dissolvent, and glycine is added,
Stir 12min；2) copper reagent step is added: after stirring, being added at one time copper reagent, heating systems are stirred to react to 40 DEG C
25min, until system is in uniform navy blue milkiness shape；3) it synthesis step: is added in system to methyl sulfone benzaldehyde, while using alkali
It is 8-9 that liquid, which adjusts pH, and 18h is reacted at 40-60 DEG C, and every 1h detection pH value is primary, adds every time when pH is reached or fallen below 8 few
Lye is measured to improve pH value, with thin-layer chromatography monitoring to methyl sulfone benzaldehyde, tracking reaction measures basic not to first to thin layer
After sulfuryl benzaldehyde exists, it is believed that reaction terminates, and system mixture is filtered；4) purification step: step (3) is resulting
Mixture filters, and much filtrate is washed 1 time with appropriate amount of deionized water, and room temperature low speed air blast drying is to get DL- to methylsulfonyl benzene silk
Propylhomoserin copper；Filtrate and cleaning solution are mixed into the mother liquor of last consignment of reaction, can cover and be reacted for next group, since deionized water
The mother liquor of a batch reaction can at least be applied 4 times by above-mentioned steps (1)-(4)；Used copper reagent is homemade hydroxide
Copper；The amount of the substance of copper in copper reagent: to methyl sulfone benzaldehyde: glycine molar ratio=5:9:11, reaction dissolvent in step (1)
Quality quality be to 16 times of methyl sulfone benzaldehyde quality；Lye is that sodium hydroxide solution, potassium hydroxide solution, sodium carbonate are molten
One of liquid, solution of potassium carbonate, sodium bicarbonate solution, potassium bicarbonate solution or ammonium hydroxide are several, total hydroxyl particle
Concentration is between 2-1mol/L.
The amount of substance about copper: to methyl sulfone benzaldehyde: glycine molar ratio, here in order to guarantee the application into
Row, also wanting a key point is exactly the setting of the mass ratio of the material example, here the amount of the substance of copper: the reaction to methyl sulfone benzaldehyde
Proportion is 1:2, actually needs copper slightly excessive, such as 5:9, the amount of the substance of copper: glycine reactant ratio should be 1:2,
Here in order to guarantee the fully reacting as far as possible of copper, glycine is slightly excessive, such as 5:11.Other slight excess of setting proportions
All be the application the considerations of within the scope of.
Embodiment 2
A kind of synthetic method of pmethylsulfonyl phenyleneserine copper, it is characterised in that: 1) preliminary step: removing ionized water, or
The mother liquor of person's last consignment of reaction is put into large container and is stirred with the speed of 50r/min as reaction dissolvent, and glycine is added,
Stir 16min；2) copper reagent step is added: after stirring, being added at one time copper reagent, heating systems are stirred to react to 40 DEG C
30min, until system is in uniform navy blue milkiness shape；3) it synthesis step: is added in system to methyl sulfone benzaldehyde, while using alkali
It is 8-9.5 that liquid, which adjusts pH, is reacted at 45-65 DEG C for 24 hours, and every 1.2h detection pH value is primary, each when pH is reached or fallen below 8
Add a small amount of lye to improve pH value, with thin-layer chromatography monitoring to methyl sulfone benzaldehyde, tracking reaction, measure to thin layer does not have substantially
After existing to methyl sulfone benzaldehyde, it is believed that reaction terminates, and system mixture is filtered；4) purification step: by step (3) institute
The mixture obtained filters, and much filtrate is washed 2 times with appropriate amount of deionized water, and room temperature low speed air blast drying is to get DL- to methylsulfonyl
Benzene serine copper；Filtrate and cleaning solution are mixed into the mother liquor of last consignment of reaction, can cover and be reacted for next group, from deionized water
The mother liquor of the batch reaction started can at least be applied 5 times by above-mentioned steps (1)-(4)；Used copper reagent is homemade alkali
Formula copper carbonate；The amount of the substance of copper in copper reagent: to methyl sulfone benzaldehyde: glycine molar ratio=11:20:23, in step (1)
The quality quality of reaction dissolvent is 18 times to methyl sulfone benzaldehyde quality；Lye be sodium hydroxide solution, potassium hydroxide solution,
One of sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution, potassium bicarbonate solution or ammonium hydroxide are several, total hydrogen
Oxygen root particle concentration is between 1.5-0.5mol/L.
Embodiment 3
A kind of synthetic method of pmethylsulfonyl phenyleneserine copper, it is characterised in that: 1) preliminary step: removing ionized water, or
The mother liquor of person's last consignment of reaction is put into large container and is stirred with the speed of 60r/min as reaction dissolvent, and glycine is added,
Stir 20min；2) copper reagent step is added: after stirring, being added at one time copper reagent, heating systems are stirred to react to 40 DEG C
35min, until system is in uniform navy blue milkiness shape；3) it synthesis step: is added in system to methyl sulfone benzaldehyde, while using alkali
It is 8.5-10 that liquid, which adjusts pH, 25h is reacted at 50-70 DEG C, every 1.5h detection pH value is primary, when pH is reached or fallen below 8.5
Every time plus a small amount of lye is to improve pH value, and with thin-layer chromatography monitoring to methyl sulfone benzaldehyde, tracking reaction measures substantially to thin layer
After not existing to methyl sulfone benzaldehyde, it is believed that reaction terminates, and system mixture is filtered；4) purification step: by step
(3) resulting mixture filters, and much filtrate is washed 2 times with appropriate amount of deionized water, and room temperature low speed air blast is dried to get DL- pairs
Methylsulfonyl benzene serine copper；Filtrate and cleaning solution are mixed into the mother liquor of last consignment of reaction, can cover and be reacted for next group, from going
The mother liquor for the batch reaction that ionized water starts can at least be applied 6 times by above-mentioned steps (1)-(4)；Used copper reagent is purchase
That buys is ground into the copper oxide of fine powder in advance；The amount of the substance of copper in copper reagent: to methyl sulfone benzaldehyde: glycine molar ratio=6:
11:13, the quality quality of reaction dissolvent is 20 times to methyl sulfone benzaldehyde quality in step (1)；Lye is that sodium hydroxide is molten
One in liquid, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution, potassium bicarbonate solution or ammonium hydroxide
Kind is several, and total hydroxyl particle concentration is between 1-0.2mol/L.
Embodiment 4
A kind of application of medicine intermediate is used the preparation-obtained pmethylsulfonyl phenyleneserine copper of preceding method, is used as
Medicine intermediate is to prepare drug.
Embodiment 5
A kind of synthetic method of pmethylsulfonyl phenyleneserine copper, it is characterised in that: 1) preliminary step: anti-in 5L reaction flask
It answers, the mother liquor for removing ionized water or last consignment of reaction is put into the speed in large container with 1.5r/s as reaction dissolvent
Glycine is added in stirring, stirs 20min.
2) copper reagent step is added: after stirring, being slowly added to copper reagent, heating systems are stirred to react 35min to 40 DEG C,
Reaction to system all generates navy blue cupric glycinate.
3) synthesis step: being added into system to methyl sulfone benzaldehyde, while adjusting pH with lye is 9 or so ± 0.2,
28h is reacted at 50 DEG C, every 1-2h detection pH value is primary, adds a small amount of lye to improve pH value when pH is reached or fallen below 9.With thin
Layer chromatography monitoring filters methyl sulfone benzaldehyde, tracking reaction after being reacted completely methyl sulfone benzaldehyde.
4) purification step: the resulting mixture of step (3) is filtered, much filtrate is washed 3 with appropriate amount of deionized water repeatedly
Secondary, decompression drying is to get DL- pmethylsulfonyl phenyleneserine copper；Filtrate and cleaning solution are mixed into the mother liquor of last consignment of reaction, it can
Set is reacted for next group, and the mother liquor of the batch reaction since deionized water at least can apply 6 by above-mentioned steps (1)-(4)
It is secondary.
Used copper reagent is the copper oxide for being ground into fine powder in advance of purchase；The amount of the substance of copper in copper reagent: to first
Sulfuryl benzaldehyde: glycine molar ratio=6:11:13, the quality quality of reaction dissolvent is to methyl sulfone benzaldehyde in step (1)
20 times of quality；Lye is that sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate are molten
One of liquid, potassium bicarbonate solution or ammonium hydroxide are several, and total hydroxyl particle concentration is between 4-0.4mol/L.
Embodiment 6
It is tested by 100 times or more, the molar yield of reaction is generally between 90-97%, measured value such as 91.3,
96.4,94.5 etc., mother liquor, which at least can permit, to be applied 4 times, and optimistic situation can apply 6-7 times, be saved greatly water resource.
The end mark of reaction can be with TLC reaction confirmation to methyl sulfone benzaldehyde fully reacting.
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 (6)
1. a kind of synthetic method of pmethylsulfonyl phenyleneserine copper, it is characterized in that being synthesized by following step:
1) preliminary step: remove ionized water or last consignment of reaction mother liquor, as reaction dissolvent, be put into large container with
The speed of 30-70r/min stirs, and glycine is added, and stirs 10-20min；
2) copper reagent step is added: after stirring, being added at one time copper reagent, heating systems are stirred to react 20-40min to 40 DEG C,
It is in uniform navy blue milkiness shape to system；
3) synthesis step: being added in system to methyl sulfone benzaldehyde, while adjusting pH with lye is 8-10, anti-at 40-80 DEG C
10-30h is answered, every 15-30min detection pH value is primary, and add a small amount of lye to improve pH value every time when pH is reached or fallen below 8,
With thin-layer chromatography monitoring to methyl sulfone benzaldehyde, tracking is reacted, after thin layer measures and does not exist substantially to methyl sulfone benzaldehyde,
Think that reaction terminates, system mixture is filtered；
4) purification step: the resulting mixture of step (3) is filtered, much filtrate is washed 1-3 times with appropriate amount of deionized water, room temperature
Low speed air blast is dried to get DL- pmethylsulfonyl phenyleneserine copper；Filtrate and cleaning solution are mixed into the mother liquor of last consignment of reaction,
It can cover and be reacted for next group, the mother liquor of the batch reaction since deionized water can at least be covered by above-mentioned steps (1)-(4)
With 4-6 times；
Used copper reagent is one or more of purchase or homemade Kocide SD, basic copper carbonate or copper oxide；
The amount of the substance of copper in copper reagent: to methyl sulfone benzaldehyde: glycine molar ratio=5-8:8-12:10-20, step (1)
The quality quality of middle reaction dissolvent is 10~20 times to methyl sulfone benzaldehyde quality；
Lye is sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution, bicarbonate
One of potassium solution or ammonium hydroxide are several, and total hydroxyl particle concentration is between 2-0.2mol/L.
2. a kind of synthetic method of pmethylsulfonyl phenyleneserine copper according to claim 1, it is characterised in that:
Each plus a small amount of lye in the step (3), is actually added into volume so that the reality that pH value is increased to 8 or 8 or more adds
Enter subject to amount.
3. a kind of synthetic method of pmethylsulfonyl phenyleneserine copper according to claim 2, it is characterised in that:
1) preliminary step: remove ionized water or last consignment of reaction mother liquor, as reaction dissolvent, be put into large container with
The speed of 40r/min stirs, and glycine is added, and stirs 12min；
2) copper reagent step is added: after stirring, being added at one time copper reagent, heating systems are stirred to react 25min to 40 DEG C, until
System is in uniform navy blue milkiness shape；
3) synthesis step: being added in system to methyl sulfone benzaldehyde, while adjusting pH with lye is 8-9, is reacted at 40-60 DEG C
18h, every 1h detection pH value is primary, adds a small amount of lye to improve pH value every time when pH is reached or fallen below 8, is supervised with thin-layer chromatography
It surveys to methyl sulfone benzaldehyde, tracking reaction, after thin layer measures and do not exist substantially to methyl sulfone benzaldehyde, it is believed that reaction knot
Beam filters system mixture；
4) purification step: the resulting mixture of step (3) is filtered, much filtrate is washed 1 time with appropriate amount of deionized water, room temperature is low
Fast air blast drying is to get DL- pmethylsulfonyl phenyleneserine copper；Filtrate and cleaning solution are mixed into the mother liquor of last consignment of reaction, it can
Set is reacted for next group, and the mother liquor of the batch reaction since deionized water at least can apply 4 by above-mentioned steps (1)-(4)
It is secondary；
Used copper reagent is homemade Kocide SD；
The amount of the substance of copper in copper reagent: to methyl sulfone benzaldehyde: glycine molar ratio=5:9:11, the middle reaction of step (1) are molten
The quality quality of agent is 16 times to methyl sulfone benzaldehyde quality；
Lye is sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution, bicarbonate
One of potassium solution or ammonium hydroxide are several, and total hydroxyl particle concentration is between 2-1mol/L.
4. a kind of synthetic method of pmethylsulfonyl phenyleneserine copper according to claim 2, it is characterised in that:
1) preliminary step: remove ionized water or last consignment of reaction mother liquor, as reaction dissolvent, be put into large container with
The speed of 50r/min stirs, and glycine is added, and stirs 16min；
2) copper reagent step is added: after stirring, being added at one time copper reagent, heating systems are stirred to react 30min to 40 DEG C, until
System is in uniform navy blue milkiness shape；
3) synthesis step: being added in system to methyl sulfone benzaldehyde, while adjusting pH with lye is 8-9.5, anti-at 45-65 DEG C
Should for 24 hours, every 1.2h detection pH value is primary, adds a small amount of lye to improve pH value every time when pH is reached or fallen below 8, with thin layer color
Spectrum monitoring is to methyl sulfone benzaldehyde, tracking reaction, after thin layer measures and do not exist substantially to methyl sulfone benzaldehyde, it is believed that reaction
Terminate, system mixture is filtered；
4) purification step: the resulting mixture of step (3) is filtered, much filtrate is washed 2 times with appropriate amount of deionized water, room temperature is low
Fast air blast drying is to get DL- pmethylsulfonyl phenyleneserine copper；Filtrate and cleaning solution are mixed into the mother liquor of last consignment of reaction, it can
Set is reacted for next group, and the mother liquor of the batch reaction since deionized water at least can apply 5 by above-mentioned steps (1)-(4)
It is secondary；
Used copper reagent is homemade basic copper carbonate；
The amount of the substance of copper in copper reagent: to methyl sulfone benzaldehyde: glycine molar ratio=11:20:23, the middle reaction of step (1)
The quality quality of solvent is 18 times to methyl sulfone benzaldehyde quality；
Lye is sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution, bicarbonate
One of potassium solution or ammonium hydroxide are several, and total hydroxyl particle concentration is between 1.5-0.5mol/L.
5. a kind of synthetic method of pmethylsulfonyl phenyleneserine copper according to claim 2, it is characterised in that:
1) preliminary step: remove ionized water or last consignment of reaction mother liquor, as reaction dissolvent, be put into large container with
The speed of 60r/min stirs, and glycine is added, and stirs 20min；
2) copper reagent step is added: after stirring, being added at one time copper reagent, heating systems are stirred to react 35min to 40 DEG C, until
System is in uniform navy blue milkiness shape；
3) synthesis step: being added in system to methyl sulfone benzaldehyde, while adjusting pH with lye is 8.5-10, at 50-70 DEG C
25h is reacted, every 1.5h detection pH value is primary, adds a small amount of lye to improve pH value every time when pH is reached or fallen below 8.5, use is thin
Layer chromatography monitoring is to methyl sulfone benzaldehyde, tracking reaction, after thin layer measures and do not exist substantially to methyl sulfone benzaldehyde, it is believed that
Reaction terminates, and system mixture is filtered；
4) purification step: the resulting mixture of step (3) is filtered, much filtrate is washed 2 times with appropriate amount of deionized water, room temperature is low
Fast air blast drying is to get DL- pmethylsulfonyl phenyleneserine copper；Filtrate and cleaning solution are mixed into the mother liquor of last consignment of reaction, it can
Set is reacted for next group, and the mother liquor of the batch reaction since deionized water at least can apply 6 by above-mentioned steps (1)-(4)
It is secondary；
Used copper reagent is the copper oxide for being ground into fine powder in advance of purchase；
The amount of the substance of copper in copper reagent: to methyl sulfone benzaldehyde: glycine molar ratio=6:11:13, the middle reaction of step (1) are molten
The quality quality of agent is 20 times to methyl sulfone benzaldehyde quality；
Lye is sodium hydroxide solution, potassium hydroxide solution, sodium carbonate liquor, solution of potassium carbonate, sodium bicarbonate solution, bicarbonate
One of potassium solution or ammonium hydroxide are several, and total hydroxyl particle concentration is between 1-0.2mol/L.
6. a kind of application of medicine intermediate, preparation-obtained to methylsulfonyl benzene with any one method of claim 1-5
Serine copper, as medicine intermediate to prepare drug.
Priority Applications (1)
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