CN107098935B - A kind of method of cooling-dissolved coupling crystal refining fosfomycin phenylethylamine calt - Google Patents

A kind of method of cooling-dissolved coupling crystal refining fosfomycin phenylethylamine calt Download PDF

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Publication number
CN107098935B
CN107098935B CN201710262109.6A CN201710262109A CN107098935B CN 107098935 B CN107098935 B CN 107098935B CN 201710262109 A CN201710262109 A CN 201710262109A CN 107098935 B CN107098935 B CN 107098935B
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fosfomycin phenylethylamine
phenylethylamine calt
cooling
fosfomycin
filtrate
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CN107098935A (en
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龙秉文
谢竞祺
王子乐
丁一刚
查树义
杜治平
刘生鹏
邓伏礼
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HUBEI XUNDA PHARMACEUTICAL CO Ltd
Wuhan Institute of Technology
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HUBEI XUNDA PHARMACEUTICAL CO Ltd
Wuhan Institute of Technology
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65502Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a three-membered ring
    • C07F9/65505Phosphonic acids containing oxirane groups; esters thereof

Abstract

The present invention relates to compound purification technique fields, more particularly to a kind of cooling-dissolved coupling crystal refining fosfomycin phenylethylamine calt method, this method dissolves crude salt using deionized water as solvent, it adds ethylene glycol and solution is warming up to 40~45 DEG C, then it is aoxidized with hydrogen peroxide, active carbon decolourizes, then mixed solution stirring is warming up to 70-75 DEG C, filtrate is cooled to 20-30 DEG C of crystallization after filtering while hot, acetone is added after filtering into filtrate and carries out dilution crystallization, it filters again, filtrate isolates acetone after distilling and water is recycled, the left salt yield of the fine work crystallized twice is up to 80% or more.The method of the present invention simple process can carry out at normal temperature, not need cryogenic crystallization, and low energy consumption, and solvent acetone and water base instinct are recycled and recycled completely, and blowdown is few.

Description

A kind of method of cooling-dissolved coupling crystal refining fosfomycin phenylethylamine calt
Technical field
The present invention relates to the separating and purifying technology fields of fine chemicals, and in particular to one kind is coupled by cooling-dissolved The method of crystal refining fosfomycin phenylethylamine calt.
Background technique
Fosfomycin phenylethylamine calt is also referred to as the left-handed dextrorotation phenyl ethylamine salt of phosphonomycin, the left-handed cis- Phosphonomycin-D- of scientific name α-phenylethylamine salt is that Glamkowski method prepares the new chromatographics degerming medicine such as fosfomycin sodium, fosfomycin calcium, fosfomycin trometamol Intermediate.The purification of industrial fosfomycin phenylethylamine calt is being realized by way of the crystallisation by cooling of solvent using ethyl alcohol.Due to a left side The solubility of the right amine salt of phosphorus in ethanol is smaller, and whole system is easy solidification completely when low temperature, therefore the practical left phosphorus of dissolution is right Ethanol consumption is larger when amine salt, usually in 1:8 or so.In addition, the solution temperature of fosfomycin phenylethylamine calt is at 70-75 DEG C, close to ethyl alcohol Boiling point, therefore the volatilization phenomenon of ethyl alcohol in actual operation is extremely serious, causes a large amount of solvent losses, increases and be produced into This.A large amount of volatilizations of ethyl alcohol can also be such that operating environment deteriorates simultaneously, influence the health of operator and bring the peace of fire and explosion Full hidden danger.
Existing patent, which is disclosed using water, replaces ethyl alcohol as solvent, refines fosfomycin phenylethylamine calt by crystallisation by cooling.Due to The solubility of fosfomycin phenylethylamine calt in water is smaller than much bigger and water volatility in ethanol, therefore this method can greatly improve Single batch processing ability and solvent loss is small.But the solubility of fosfomycin phenylethylamine calt in water is still bigger than in ethanol under low temperature Very much, which results in for recycling fosfomycin phenylethylamine calt as much as possible, it is necessary to solution is cooled to lower temperature, and the ratio of water Heat is three times of ethyl alcohol specific heat, therefore this just needs to increase larger energy consumption, corresponding fosfomycin phenylethylamine calt aqueous solution heat temperature raising mistake The energy consumption of journey consumption is also higher.
Summary of the invention
It is an object of the invention to solve the prior art purification fosfomycin phenylethylamine calt during above shortcomings, propose A method of crystal refining fosfomycin phenylethylamine calt is coupled by cooling-dissolved, and optimal technological parameter, including crude product has been determined The type and dosage of fosfomycin phenylethylamine calt and the ratio of water mixing, the best final temperature of crystallisation by cooling, solvent.The method overcome The disadvantages of generally existing utilization rate of equipment and installations is low in the prior art, solvent loss is big, operating environment is poor and energy consumption is high, for industry The industrialization of upper fosfomycin phenylethylamine calt crystal refining technique provides foundation.To achieve the above object, the technology used in the present invention Scheme is as follows:
A kind of cooling-dissolved coupling crystal refining fosfomycin phenylethylamine calt method, comprising the following steps: (a) is by the left phosphorus of crude product Right amine salt is mixed with deionized water, adds ethylene glycol and heat temperature raising, is eventually adding hydrogen peroxide and is carried out oxidation reaction;(b) anti- Active carbon is added after should completing into mixed solution to decolourize, is filtered, is washed with deionized after continuing heating, merged Cleaning solution and filtrate;(c) the mixed filtrate crystallisation by cooling for obtaining step (b), after suction filtration fine work fosfomycin phenylethylamine calt;(d) to Acetone is added in filtrate obtained by step (c), filters obtain fine work fosfomycin phenylethylamine calt after mixing evenly;(e) it is right to merge the left phosphorus of fine work Filtrate obtained by step (d) is distilled in amine salt and drying, recycles acetone and water is recycled.
According to above scheme, mass ratio when crude product fosfomycin phenylethylamine calt is mixed with deionized water is 1:1.5-3.5.
Preferably, mass ratio when crude product fosfomycin phenylethylamine calt is mixed with deionized water is 1:2.5-3.
According to above scheme, the mass ratio of crude product fosfomycin phenylethylamine calt and ethylene glycol, hydrogen peroxide is 1:0.1-0.25:0.1- 0.2。
It is added according to above scheme, in step (a) after ethylene glycol and solution is heated to 40-45 DEG C, oxidation time is 30min。
According to above scheme, active carbon is added into solution at 50 DEG C in step (b) and decolourizes, it will be molten after the completion of decoloration Liquid is warming up to 70-75 DEG C and is filtered, and the additional amount of active carbon is the 1-2% of crude product fosfomycin phenylethylamine calt quality.
According to above scheme, mixed filtrate is cooled to 20-30 DEG C and is crystallized in step (c).
According to above scheme, the mass ratio of deionized water is 7-10 in the additional amount and step (a) of acetone in step (d): 1。
Preferably, the mass ratio of deionized water is 9:1 in the additional amount Yu step (a) of acetone in step (d).Acetone adds The yield for entering the more fosfomycin phenylethylamine calts of amount is higher, but considers economic factor, this ratio not only can guarantee refining effect but also can take into account The economy of entire technique.
The present invention is using deionized water as solvent, through impurity removal process such as hydrogen peroxide oxidation, activated carbon adsorption decolorations, using cooling Fine work fosfomycin phenylethylamine calt has been made in crystallization and the new process high yield that is coupled of dilution crystallization, and by dilution crystallization when is added Acetone solvent and the water recycling that is added of when dissolution.Compared with prior art, the invention has the following advantages:
(1) making full use of fosfomycin phenylethylamine calt, solubility is big in water, varies with temperature also big characteristic, is molten with suitable quantity of water Agent is prepared fine work fosfomycin phenylethylamine calt at 75 DEG C near room temperature by the way of crystallisation by cooling, improves single batch equipment utilization Rate;Simultaneously because the volatility of water is small, solvent loss is small, and manual operation environment substantially improves.
(2) using the fosfomycin phenylethylamine calt extremely low characteristic of solubility in acetone, using acetone as dissolved solvent, at normal temperature into Row dilution crystallization avoids the need for the operation of the further crystallisation by cooling recycling fosfomycin phenylethylamine calt of low temperature (- 8 DEG C -2 DEG C), saves significantly Energy consumption is saved;In addition, the maximization economic recovery of fosfomycin phenylethylamine calt may be implemented by the additional amount for optimizing acetone.
(3) when dilution crystallization further recycles fosfomycin phenylethylamine calt, make full use of water differed with acetone boiling point larger (36 DEG C), Extremely segregative characteristic can be realized the complete recycling of high-purity acetone and water using common atmospheric distillation, be recycled, molten Agent loss is extremely low.
(4) total recovery of the method for the present invention is controlled in 80% (butt), 3-5% higher than existing simple cooling and crystallizing process.
Specific embodiment
To make those of ordinary skill in the art fully understand technical solution of the present invention and beneficial effect, below in conjunction with specific Embodiment is further described.Following embodiment is only better embodiment of the invention, not to technical side of the invention Case, which is constituted, to be limited.
A kind of method of cooling-dissolved coupling crystal refining fosfomycin phenylethylamine calt, comprising the following steps: (a) is according to 1:1.5- The mass ratio of (3.5:0.1-0.25:0.1-0.2 the ratio of crude salt and water is preferably 1:2.5-3) by crude product fosfomycin phenylethylamine calt with go Ionized water mixing, adds ethylene glycol and is heated to 40-45 DEG C, is eventually adding hydrogen peroxide oxidation reaction 30min;(b) anti- 1-2% should be added into mixed solution (using crude product fosfomycin phenylethylamine calt quality as ginseng after the completion when solution temperature is 50 DEG C According to) active carbon decolourize, be continuously heating to 70-75 DEG C after having decolourized and filtered, active carbon is washed with deionized, close And cleaning solution and filtrate;(c) mixed filtrate for obtaining step (b) is cooled to 20-30 DEG C and crystallizes, and it is left that fine work is obtained after suction filtration The right amine salt of phosphorus;(d) according to the mass ratio 1:7-10 of deionized water and acetone used in dissolution crude product fosfomycin phenylethylamine calt (preferably 1: 9) acetone is added into the filtrate that step (c) obtains in ratio, obtains fine work fosfomycin phenylethylamine calt through filtering after stirring evenly;(e) Merge fine work fosfomycin phenylethylamine calt and drying made from two step crystallisation by cooling of front and dilution crystallization, by filtrate obtained by step (d) into Row distillation, obtained acetone recycle are back to dilution crystallization, and obtained water is recycled to be used in the dissolution of crude product fosfomycin phenylethylamine calt.
Embodiment 1
To verify the feasibility of new process of the present invention and higher yield can be reached, in the premise for saving removal step It is lower to have been carried out cooling down-dissolved coupling crystallization experiment with fosfomycin phenylethylamine calt refined salt.It is first that 40.22 grams of fosfomycin phenylethylamine calt refined salt are (dry Base) it is mixed with 121.2 grams of deionized waters, mixed solution is heated with stirring to 75 DEG C and is completely dissolved, then naturally cools to it Room temperature, it is dry after filtering to obtain 26.7 grams of fine work fosfomycin phenylethylamine calts.850g acetone, stirring 30 are added into filtrate obtained by back It is filtered after minute, 5.44 grams of fine work fosfomycin phenylethylamine calts will be obtained after filtration cakes torrefaction, add up to and obtain 32.14 grams of right amine of the left phosphorus of fine work Salt, total recovery 79.9% (butt).Confirmatory experiment shows that the method for the present invention is truly feasible and can obtain higher yield.
Embodiment 2
40.22 grams of fosfomycin phenylethylamine calt crude salts (wet basis) are mixed with 120.63 grams of deionized waters, add 8.11 grams of second two Mixed solution is heated to 40~45 DEG C by alcohol, is subsequently added into the hydrogen peroxide that 5.05 gram mass scores are 50%, oxidation reaction 30min.Mixed solution temperature is risen to 50 DEG C after the completion of oxidation reaction, 0.6 gram of active carbon is added and decolourizes, continue to heat So that mixed solution is warming up to 70 DEG C, filters out active carbon after material is entirely molten.With appropriate amount of deionized water detergent active charcoal, merging is washed Wash water and filtrate.Mixed filtrate is naturally cooled to 25-26 DEG C, it is dry after filtering, obtain 22.92 grams of fine work fosfomycin phenylethylamine calts. 1000 grams of acetone are added into back filtrate, stirring is filtered after 30 minutes, and 8.69 grams of left phosphorus of fine work will be obtained after filtration cakes torrefaction Right amine salt adds up to and obtains 31.61 grams of fine work fosfomycin phenylethylamine calts, total recovery 83.4% (butt).After final step acetone dissolved Resulting filtrate rotary distillation, recycles acetone and water is recycled.
Embodiment 3
5.00 grams of fosfomycin phenylethylamine calt crude salts (wet basis) are mixed with 15.26 grams of deionized waters, add 1.04 grams of ethylene glycol, Mixed solution is heated to 40~45 DEG C, is subsequently added into 0.69 gram of hydrogen peroxide (50%), aoxidizes 30min.After the completion of oxidation reaction Mixed solution temperature is risen to 50 DEG C, adds 0.07 gram of active carbon decoloring, continuing heating makes mixed solution be warming up to 70 DEG C, to Material it is complete it is molten after filter out active carbon.With appropriate amount of deionized water detergent active charcoal, merge washing water and filtrate, mixed filtrate is cold But dry after filtering to 25-26 DEG C, obtain 2.55 grams of fine work fosfomycin phenylethylamine calts.137 grams of acetone are added into back filtrate, Stirring is filtered after 30 minutes, 0.98 gram of fine work fosfomycin phenylethylamine calt will be obtained after filtration cakes torrefaction, is added up to and obtain 3.53 grams of left phosphorus of fine work Right amine salt, total recovery 78.4% (butt).Filtrate is distilled with Rotary Evaporators, recycles 121.4 grams of acetone, recycle-water 10.9 Gram, it remains to be recycled.
Embodiment 4
It is (wet with fosfomycin phenylethylamine calt crude salt after 5.7 grams of fresh deionized waters of supplement in 10.9 grams of water that embodiment 3 is recycled Base) 5.00 grams of mixing, 1.1 grams of ethylene glycol are added, mixed solution is heated to 40~45 DEG C, are subsequently added into 0.85 gram of hydrogen peroxide (50%), 30min is aoxidized.Mixed solution temperature is risen to 50 DEG C after the completion of oxidation reaction, it is de- to add 0.075 gram of active carbon Color, continuing heating makes mixed solution be warming up to 70 DEG C, filters out active carbon after material is entirely molten.Work is washed with appropriate amount of deionized water Property charcoal, merge washing water and filtrate, mixed filtrate be cooled to dry after 25-26 DEG C of filtering, it is right to obtain the left phosphorus of 2.35 grams of fine work Amine salt.The filtrate that back obtains is added after 45 grams of fresh acetones are added in the 121.4 grams of acetone recycled to embodiment 3, stirring It is filtered after 30 minutes, 1.12 grams of fine work fosfomycin phenylethylamine calts will be obtained after filtration cakes torrefaction, add up to and obtain 3.47 grams of right amine of the left phosphorus of fine work Salt, total recovery 77.1% (butt).By resulting filtrate rotary distillation after final step acetone dissolved, recycles acetone and water continues It is recycled.

Claims (6)

1. a kind of cooling-dissolved coupling crystal refining fosfomycin phenylethylamine calt method, which comprises the following steps:
(a) crude product fosfomycin phenylethylamine calt is mixed with deionized water, adds ethylene glycol and heat temperature raising, be eventually adding hydrogen peroxide into Row oxidation reaction;
(b) active carbon is added into mixed solution after the reaction was completed to decolourize, is filtered after continuing heating, uses deionized water Washing merges cleaning solution and filtrate;
(c) the mixed filtrate crystallisation by cooling for obtaining step (b), after suction filtration fine work fosfomycin phenylethylamine calt;
(d) acetone is added into filtrate obtained by step (c), filters obtain fine work fosfomycin phenylethylamine calt after mixing evenly;
(e) merge fine work fosfomycin phenylethylamine calt and drying, filtrate obtained by step (d) is distilled, recycling acetone and water circulation makes With;
It is added in step (a) after ethylene glycol and solution is heated to 40-45 DEG C, oxidation time 30min;In step (b) 50 DEG C are added active carbon into solution and decolourize, and solution is warming up to 70-75 DEG C after the completion of decoloration and is filtered, active carbon Additional amount is the 1%-2% of crude product fosfomycin phenylethylamine calt quality;Mixed filtrate is cooled to 20-30 DEG C and is crystallized in step (c).
2. a kind of cooling as described in claim 1-dissolved coupling crystal refining fosfomycin phenylethylamine calt method, it is characterised in that: Mass ratio when crude product fosfomycin phenylethylamine calt is mixed with deionized water is 1:1.5-3.5.
3. a kind of cooling as claimed in claim 2-dissolved coupling crystal refining fosfomycin phenylethylamine calt method, it is characterised in that: Mass ratio when crude product fosfomycin phenylethylamine calt is mixed with deionized water is 1:2.5-3.
4. a kind of cooling as described in claim 1-dissolved coupling crystal refining fosfomycin phenylethylamine calt method, it is characterised in that: The mass ratio of crude product fosfomycin phenylethylamine calt and ethylene glycol, hydrogen peroxide is 1:0.1-0.25:0.1-0.2.
5. a kind of cooling as described in claim 1-dissolved coupling crystal refining fosfomycin phenylethylamine calt method, it is characterised in that: The mass ratio of deionized water is 7-10:1 in the additional amount Yu step (a) of acetone in step (d).
6. a kind of cooling as claimed in claim 5-dissolved coupling crystal refining fosfomycin phenylethylamine calt method, it is characterised in that: The mass ratio of deionized water is 9:1 in the additional amount Yu step (a) of acetone in step (d).
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4222970A (en) * 1976-08-04 1980-09-16 Roberto Montanari Process for producing phosphonomycin
CN1385435A (en) * 2002-06-07 2002-12-18 清华大学 Process for synthesizing fosfomycin using cis-propenyl phosphonic acid as raw material

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4222970A (en) * 1976-08-04 1980-09-16 Roberto Montanari Process for producing phosphonomycin
CN1385435A (en) * 2002-06-07 2002-12-18 清华大学 Process for synthesizing fosfomycin using cis-propenyl phosphonic acid as raw material

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A New Synthesis of the Antibiotic Phosphonomycin;EDWARD J.GLAMKOW et al;《J.Org.Chem.》;19701231;第35卷;第3510-3512页
左磷右胺盐精制工艺的改进研究及应用;张庆武等;《当代化工》;20061231;第35卷;第307-308页,第365页

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